id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
25dde6de0e0d2d20620a47f496cf75399483768f
|
nice
|
High-intensity focused ultrasound for symptomatic benign thyroid nodules
|
High-intensity focused ultrasound for symptomatic benign thyroid nodules
Evidence-based recommendations on high-intensity focused ultrasound for symptomatic benign thyroid nodules in adults. This involves using heat made by high-frequency sound waves to destroy the nodule. The aim is to make the nodule smaller to relieve pressure symptoms and improve appearance.
# Recommendations
The evidence on the safety of high-intensity focused ultrasound for symptomatic benign thyroid nodules raises no major safety concerns, however the current evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do high-intensity focused ultrasound for symptomatic benign thyroid nodules should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on high-intensity focused ultrasound for symptomatic benign thyroid nodules is recommended.
Audit and review clinical outcomes of all patients having high-intensity focused ultrasound for symptomatic benign thyroid nodules. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Further research should report details of patient selection, nodule size and position, and whether the nodule is cystic.# The condition, current treatments and procedure
# The condition
Thyroid nodules may be cystic, colloid, hyperplastic, adenomatous or cancerous. Most thyroid nodules are benign and are usually asymptomatic. There may be a single thyroid nodule (solitary nodule) or multiple thyroid nodules (multinodular goitre). Some thyroid nodules produce thyroxine or triiodothyronine and cause thyrotoxicosis. These are called hyperfunctioning or toxic thyroid nodules.
# Current treatments
Treatment of benign thyroid nodules may be needed if they cause symptoms or cosmetic problems. Conventional treatment includes surgery. Other less invasive approaches than surgery include ethanol ablation, percutaneous laser ablation, radiofrequency ablation and microwave ablation.
# The procedure
High-intensity focused ultrasound is a minimally invasive technique that aims to reduce symptoms and improve cosmetic appearance, while preserving thyroid function, and with fewer complications than surgery.
High-intensity focused ultrasound for symptomatic benign thyroid nodules is usually done using sedation and systemic analgesia, in an outpatient setting. The patient is placed in the supine position with moderate neck extension. The focused ultrasound device is positioned on the patient's neck to deliver the treatment and allow for simultaneous imaging of the treatment area. The technology uses high-energy sound waves that pass through the tissues, generating local heat and inducing coagulative necrosis, protein denaturation and cellular destruction. A strong acute inflammatory response follows. The treatment duration depends on the nodule size.
|
{'Recommendations': "The evidence on the safety of high-intensity focused ultrasound for symptomatic benign thyroid nodules raises no major safety concerns, however the current evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do high-intensity focused ultrasound for symptomatic benign thyroid nodules should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on high-intensity focused ultrasound for symptomatic benign thyroid nodules is recommended.\n\nAudit and review clinical outcomes of all patients having high-intensity focused ultrasound for symptomatic benign thyroid nodules. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFurther research should report details of patient selection, nodule size and position, and whether the nodule is cystic.", 'The condition, current treatments and procedure': "# The condition\n\nThyroid nodules may be cystic, colloid, hyperplastic, adenomatous or cancerous. Most thyroid nodules are benign and are usually asymptomatic. There may be a single thyroid nodule (solitary nodule) or multiple thyroid nodules (multinodular goitre). Some thyroid nodules produce thyroxine or triiodothyronine and cause thyrotoxicosis. These are called hyperfunctioning or toxic thyroid nodules.\n\n# Current treatments\n\nTreatment of benign thyroid nodules may be needed if they cause symptoms or cosmetic problems. Conventional treatment includes surgery. Other less invasive approaches than surgery include ethanol ablation, percutaneous laser ablation, radiofrequency ablation and microwave ablation.\n\n# The procedure\n\nHigh-intensity focused ultrasound is a minimally invasive technique that aims to reduce symptoms and improve cosmetic appearance, while preserving thyroid function, and with fewer complications than surgery.\n\nHigh-intensity focused ultrasound for symptomatic benign thyroid nodules is usually done using sedation and systemic analgesia, in an outpatient setting. The patient is placed in the supine position with moderate neck extension. The focused ultrasound device is positioned on the patient's neck to deliver the treatment and allow for simultaneous imaging of the treatment area. The technology uses high-energy sound waves that pass through the tissues, generating local heat and inducing coagulative necrosis, protein denaturation and cellular destruction. A strong acute inflammatory response follows. The treatment duration depends on the nodule size."}
|
https://www.nice.org.uk/guidance/ipg643
|
Evidence-based recommendations on high-intensity focused ultrasound for symptomatic benign thyroid nodules in adults. This involves using heat made by high-frequency sound waves to destroy the nodule. The aim is to make the nodule smaller to relieve pressure symptoms and improve appearance.
|
521ab6c067badb4d43cf50e0f03b8f12345a3159
|
nice
|
Venetoclax with rituximab for previously treated chronic lymphocytic leukaemia
|
Venetoclax with rituximab for previously treated chronic lymphocytic leukaemia
Evidence-based recommendations on venetoclax (Venclyxto) with rituximab for previously treated chronic lymphocytic leukaemia in adults.
# Recommendations
Venetoclax with rituximab is recommended, within its marketing authorisation, as an option for treating chronic lymphocytic leukaemia in adults who have had at least 1 previous therapy. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
People with previously treated chronic lymphocytic leukaemia usually have ibrutinib. Clinical trial evidence shows that venetoclax plus rituximab increases how long people live for before their disease gets worse compared with bendamustine plus rituximab (a combination that is not frequently used). There is no trial directly comparing venetoclax plus rituximab with ibrutinib. Indirect comparisons of venetoclax plus rituximab with ibrutinib have limitations, but can be used for decision making because there is no other evidence.
Estimates from the cost-effectiveness analyses range from venetoclax plus rituximab being less costly and more effective to it being less costly and less effective, when compared with ibrutinib. Although it is uncertain how effective venetoclax is compared with ibrutinib, a cost-comparison analysis shows that venetoclax plus rituximab is considered to be a cost-effective use of NHS resources and it is recommended for routine use in the NHS.# Information about venetoclax with rituximab
# Marketing authorisation indication
Venetoclax (Venclyxto, AbbVie) plus rituximab is indicated 'for the treatment of adult patients with chronic lymphocytic leukaemia who have received at least 1 prior therapy.'
# Dosage in the marketing authorisation
Venetoclax should be administered:
in the titration phase, 20 mg orally once daily for 7 days, increasing by gradual weekly increments over 5 weeks to 400 mg once daily
in the post-titration phase, 400 mg orally once daily.Rituximab should be administered after the patient has completed the dose‑titration schedule and has had the recommended daily dose of 400 mg venetoclax for 7 days. Rituximab 375 mg/m2 is given intravenously on day 1 of cycle 1 (a cycle is 28 days), followed by 500 mg/m2 on day 1 of cycles 2 to 6. Rituximab is stopped after cycle 6.Venetoclax can be taken for a maximum of 2 years from day 1 of cycle 1 of rituximab, or until disease progression or unacceptable toxicity (see the summary of product characteristics).
# Price
A 112-pack of 100-mg tablets costs £4,789.47 (excluding VAT; British national formulary online, accessed September 2018). The company has a commercial arrangement. This makes venetoclax with rituximab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with chronic lymphocytic leukaemia would welcome a new treatment option
The clinical and patient experts noted that people with previously treated chronic lymphocytic leukaemia (relapsed or refractory chronic lymphocytic leukaemia) have limited treatment options. They explained that some people spend a long time in the 'watch and wait' stage of the treatment pathway, which can have a psychological effect on them because of worry about relapse. The patient experts highlighted that some people have cardiovascular comorbidities, which limits their treatment options, so they would welcome a range of treatments. The committee understood that although venetoclax plus rituximab can cause serious side effects (tumour lysis syndrome) it is generally well tolerated. It concluded that venetoclax plus rituximab would be welcomed as a new treatment option for people with relapsed or refractory chronic lymphocytic leukaemia.
# Clinical management
## Current treatment for chronic lymphocytic leukaemia is ibrutinib and this is the most appropriate comparator
The committee understood that venetoclax plus rituximab would be used to treat relapsed or refractory chronic lymphocytic leukaemia in people who have had at least 1 previous therapy. The clinical experts stated that people with chronic lymphocytic leukaemia whose disease has relapsed after 1 previous chemo-immunotherapy would be eligible for a B‑cell receptor pathway inhibitor, such as ibrutinib or idelalisib. They confirmed that most people have ibrutinib rather than idelalisib plus rituximab, because idelalisib plus rituximab has an intensive dosing regimen and is associated with increased risk of infection. The clinical experts confirmed that, within the clinical pathway, both ibrutinib and venetoclax plus rituximab can be used for chronic lymphocytic leukaemia. The committee concluded that established clinical management is ibrutinib, making it a relevant comparator for this appraisal.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS clinical practice in England
The main clinical evidence came from MURANO (n=389), a phase III, multicentre, open-label, parallel-arm randomised controlled trial. It included patients aged 18 years or over with relapsed or refractory chronic lymphocytic leukaemia, and compared venetoclax plus rituximab (n=194) with bendamustine plus rituximab (n=195). In the company's original submission, the data came from a May 2017 data cut with a median follow-up of 23.8 months from starting treatment. In response to consultation the company presented data from a May 2018 data cut, with a median follow-up of 36 months from starting treatment. Venetoclax plus rituximab was given for at most 2 years in MURANO, or until disease progression or unacceptable toxic effects, whichever occurred sooner (specified in the summary of product characteristics). The clinical experts explained that this was a reasonable approach because in this time about 60% of patients in the trial had undetectable minimal residual disease, which is a strong predictor of lasting remission in patients with chronic lymphocytic leukaemia. The patient experts stated that people would welcome a fixed treatment duration, especially if this was explained to them when treatment was started. The committee concluded that the clinical-effectiveness evidence is relevant to NHS clinical practice in England.
# Clinical effectiveness
## Venetoclax plus rituximab is clinically effective compared with bendamustine plus rituximab
The primary outcome measure in MURANO was investigator-assessed median progression-free survival. The May 2018 data cut showed that progression-free survival was statistically significantly longer with venetoclax plus rituximab than with bendamustine plus rituximab (median not reached, compared with 16 months respectively; hazard ratio 0.16, 95% confidence interval 0.12 to 0.23; p<0.0001). Overall survival was longer with venetoclax plus rituximab than with bendamustine plus rituximab (median not reached in either group; hazard ratio 0.50, 95% CI 0.30 to 0.85; p=0.0093). The committee considered how many patients did not have undetectable minimal residual disease because they might need additional treatment after 2 years of therapy with venetoclax plus rituximab. The latest data cut from MURANO confirmed that at 24 months 48% of people had undetectable minimal residual disease and after an additional 9.9 months of follow-up most patients still had undetectable minimal residual disease. In the bendamustine plus rituximab arm only 2% of patients had undetectable minimal residual disease at 24 months. The committee concluded that venetoclax plus rituximab was clinically effective compared with bendamustine plus rituximab.
## The company's unanchored matched-adjusted indirect comparison analysis has limitations
Because the comparator in MURANO was bendamustine plus rituximab, a combination that is no longer standard care (see section 3.2), the company did a matched-adjusted indirect comparison (MAIC) to indirectly compare progression-free survival and overall survival for venetoclax plus rituximab with ibrutinib or idelalisib plus rituximab. The committee had previously agreed that idelalisib plus rituximab was not a relevant comparator so only considered the comparison with ibrutinib. The committee discussed the appropriateness of this approach. At the first committee meeting, it noted the ERG's concerns that the results from the unanchored analysis for venetoclax plus rituximab compared with ibrutinib were clinically implausible. This was because the estimated hazard ratio for progression-free survival (hazard ratio 0.696, 95% CI 0.412 to 1.178) was much higher than the estimate for overall survival (hazard ratio 0.297, 95% CI 0.129 to 0.684), which was not the case in the comparator trials. The clinical experts stated that the overall survival hazard-ratio estimate was not plausible whereas the progression-free survival estimate was. They explained that they believed venetoclax plus rituximab to have similar, or better, efficacy to ibrutinib and that it was unlikely to be inferior to ibrutinib. In response to consultation, the company presented a new MAIC based on the May 2018 data cut from MURANO. The ERG noted that the results of the analysis were still clinically implausible, and the hazard-ratio estimate for progression-free survival (hazard ratio 0.797, 95% CI 0.505 to 1.258) was higher than the estimate for overall survival (hazard ratio 0.445, 95% CI 0.218 to 0.909). The ERG also highlighted that the effectiveness of ibrutinib was still underestimated in the analysis. The committee concluded that the company's updated MAIC had some limitations, but because there was no other evidence it was acceptable for decision making.
## The ERG's network meta-analysis also has limitations
The ERG did an alternative indirect comparison using a fixed-effect network meta-analysis to estimate the relative benefits of venetoclax plus rituximab compared with ibrutinib. The network meta-analysis showed that progression-free survival and overall survival were shorter with venetoclax plus rituximab than with ibrutinib (progression-free survival hazard ratio 1.43, 95% CI 0.78 to 2.61; overall survival hazard ratio 1.08, 95% CI 0.42 to 2.73). The ERG also highlighted that the network meta-analysis was based on Hillmen et al. (2015), which relies on a simple adjustment that may have biased the results. In response to consultation and the company's new evidence the ERG produced a new network meta-analysis based on the May 2018 data cut from MURANO. The revised analysis still showed that progression-free survival and overall survival were shorter with venetoclax plus rituximab than with ibrutinib (progression-free survival hazard ratio 1.20, 95% CI 0.68 to 2.12; overall survival hazard ratio 1.12, 95% CI 0.48 to 2.63). The committee noted that the new network meta-analysis was also based on the uncertain data from Hillmen et al. (2015) and therefore the limitations still applied. The committee concluded that neither the company's MAIC nor the ERG's network meta-analysis were ideal but, because there were no other analyses, it agreed that they can be used for decision making (see section 3.13).
# Adverse effects
## Venetoclax plus rituximab is generally well tolerated
The clinical experts explained that venetoclax is occasionally associated with tumour lysis syndrome. This is caused by a rapid breakdown of cancer cells, and can lead to complications such as kidney failure. The clinical experts explained that the 5‑week dose escalation schedule helps to prevent tumour lysis syndrome. They noted that there have been few cases of tumour lysis syndrome since this dosing schedule was implemented in clinical practice for venetoclax monotherapy. The committee noted the risks associated with venetoclax plus rituximab, but concluded that it is generally well tolerated.
# The company's economic model
## The model structure is appropriate for decision making
The company's model was a de novo partitioned survival model with 3 states (progression-free, progressed disease and death). Data from MURANO was used to estimate progression-free and overall survival using parametric curves fitted to Kaplan−Meier data. In the model, venetoclax plus rituximab was taken for at most 2 years or until disease progression or unacceptable toxic effects, whichever occurred sooner. This was similar to how it was used in MURANO (see section 3.3). The committee concluded that the model structure was appropriate for decision making.
## The extrapolation of survival data is reasonable
The company explored various approaches for extrapolating survival data. It chose a Weibull distribution as the preferred parametric model for both overall and progression-free survival. The committee noted that the extrapolation did not represent the correct population because it was based on the original trial population instead of the matched population. The committee also noted that the matching had not been done correctly. In response to consultation, the company presented a scenario in which the extrapolation was based on the matched population rather than on the original population from MURANO. The committee concluded that the company's new approach for extrapolating survival data was reasonable and noted that it had little effect on the incremental cost-effectiveness ratio (ICER).
## Potential loss of treatment effect after 2 years with venetoclax plus rituximab is reflected in the company's revised analyses
The committee recalled that a 2‑year stopping rule was incorporated into MURANO and is also specified in the summary of product characteristics. In its original submission, the company assumed in its base case that venetoclax plus rituximab remained effective throughout the model's time horizon of 30 years, irrespective of time off treatment or whether treatment was stopped at 2 years. The company also provided scenarios assuming diminishing of treatment effect after 2 years. In response to consultation the company presented further scenario analyses with a diminishing treatment effect from 2 years, with annual increases in hazard ratios of 5%, 10%, 20%, 30% and 40%. The ERG repeated these analyses and agreed that the diminishing treatment effect was correctly incorporated into the company's base-case analysis. The committee noted that there were limited data from MURANO on the effect of stopping treatment at 2 years because the latest data cut only has a median follow-up of 36 months. The committee concluded that given the lack of evidence it was not possible to know how much venetoclax plus rituximab's treatment effect continues over time after treatment has stopped. But because there were no other data it agreed that the range of estimates could be used for decision making.
# Utility values in the model
## The utility values in the company's economic model are reasonable
The company stated that the utility values from MURANO were too high and implausible to use in the economic model. It used utility values from previous NICE technology appraisal guidance for chronic lymphocytic leukaemia, including venetoclax monotherapy and idelalisib with rituximab. In response to consultation, the company presented scenarios using utility values from MURANO for the pre-progression state. It explored a range of potential values for the post-progression state because these could be not obtained from the trial because of lack of available data. The committee concluded that the difference between the utility values for pre- and post-progression-free survival from MURANO was uncertain and noted that it had little effect on the ICER.
# Costs and resource use in the economic model
## The costs of treatment and the treatment-effect duration with venetoclax plus rituximab are captured in the company's revised analyses
The company limited the cost of venetoclax treatment to 2 years, similar to the treatment duration of venetoclax in MURANO. The committee recalled that the company provided a range of analyses to account for the diminishing treatment effect of venetoclax with rituximab (see section 3.10). The committee agreed that the scenario analyses captured the loss of treatment effect of venetoclax plus rituximab well. It concluded that there was no direct evidence to define the most appropriate continued treatment effect for venetoclax plus rituximab, and therefore it would consider the range of estimates presented.
# Cost-effectiveness results
## The company's and the ERG's ICERs differ greatly but are within the range considered a cost-effective use of NHS resources
The company's revised analyses submitted in response to consultation used results from the new MAIC analysis (see section 3.5) and the discounted price for venetoclax. The ERG's revised base-case analysis used results from the new network meta-analysis (see section 3.6) and the discounted prices for both venetoclax and ibrutinib. The committee noted that the company's cost-effectiveness estimates showed that venetoclax plus rituximab was cheaper and more effective than ibrutinib, but the ERG's base-case analysis showed venetoclax to be cheaper but less effective (the ICERs incorporated confidential discounts so cannot be reported here). The committee agreed that because of the lack of trial data directly comparing venetoclax plus rituximab with ibrutinib, and limitations in the MAIC and the network meta-analysis, it could not decide which analysis was more appropriate for decision making. It was therefore not able to determine the most plausible ICER. The committee concluded that even though the relative treatment effect of venetoclax plus rituximab compared with ibrutinib was uncertain, both sets of analyses produced ICERs within the range considered to be an acceptable use of NHS resources based on the cost per quality-adjusted life year (QALY) lost or gained.
## The cost-comparison analysis provides supporting evidence that venetoclax plus rituximab is a cost-effective use of NHS resources
In response to consultation, the company presented a cost comparison for venetoclax plus rituximab with ibrutinib to address uncertainties in the modelling expressed by the committee during the first committee meeting (see section 3.5 and section 3.6, and sections 3.9 to 3.12). The company based the cost-comparison analysis on the assumption of equal efficacy between venetoclax plus rituximab and ibrutinib. The committee concluded that this was appropriate based on the clinical experts' opinion and because there was no evidence of a difference in treatment effect. The company's cost-comparison analysis provided scenarios for 30%, 50% and 100% of people having subsequent ibrutinib treatment after 2 years of treatment with venetoclax plus rituximab (see section 3.4). The ERG repeated these scenario analyses but they used a generalised gamma curve for the extrapolation of treatment effect instead of Weibull curve for the extrapolation, which was the company's preferred approach. The committee considered that based on the May 2018 data cut from MURANO the scenarios for 30% to 50% of people having ibrutinib were the most clinically plausible, and the 100% scenario was too pessimistic and not supported by the evidence. It concluded that both the company's and the ERG's analyses supported the estimates from the cost-effectiveness analyses (the analyses include confidential discounts so exact values cannot be reported here).
# Innovation
## There are no additional benefits that are not captured in the cost-effectiveness analysis
The company considered venetoclax plus rituximab to be an innovative treatment. This was because it increases the chance of enduring remission and having undetectable minimal residual disease, without the associated risks of repeated lines of chemotherapy or other agents that offer little chance of having undetectable minimal residual disease. It also offers another very good treatment option to people with relapsed or refractory chronic lymphocytic leukaemia, so should be available as a choice of therapy for this group. The committee concluded that venetoclax plus rituximab would be beneficial. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# End of life
## Venetoclax plus rituximab does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a life-extending treatment at the end of life if it is indicated for patients with a short life expectancy (normally less than 24 months) and it offers an extension to life, normally a mean value of at least an additional 3 months compared with current NHS treatment. The committee noted that the results of MURANO suggest that venetoclax plus rituximab could increase life expectancy by more than 3 months compared with bendamustine plus rituximab, although this is not the appropriate comparator. The short life-expectancy criterion of less than 24 months was not met because people with chronic lymphocytic leukaemia have a life expectancy of more than 2 years. Overall, the committee concluded that venetoclax does not meet the criteria to be considered a life-extending treatment at the end of life.
# Conclusion
## Venetoclax plus rituximab is a cost-effective use of NHS resources and is recommended
In response to consultation the company presented additional data from MURANO showing that venetoclax plus rituximab increases progression-free survival compared with bendamustine plus rituximab, and that most patients had undetectable minimal residual disease after 2 years of treatment. Therefore the committee concluded that venetoclax plus rituximab is a clinically effective treatment compared with bendamustine plus rituximab (see section 3.4). It considered the new MAIC and network meta-analysis comparing venetoclax plus rituximab with ibrutinib (the appropriate comparator), but it could not decide which was more appropriate because of their limitations. However, because there were no other analyses it agreed to take them into account during decision making. It noted that the ICERs ranged from venetoclax plus rituximab being less costly and more effective than ibrutinib (company estimates) to venetoclax plus rituximab being less costly and less effective than ibrutinib (ERG estimates). However, both analyses produced ICERs showing that venetoclax was a cost-effective treatment (see section 3.13). The committee noted that the cost-comparison analysis supported the conclusions from the cost-effectiveness analysis. The committee concluded that venetoclax with rituximab was a cost-effective use of NHS resources and could be recommended as an option for treating chronic lymphocytic leukaemia in adults after at least 1 previous treatment.
|
{'Recommendations': 'Venetoclax with rituximab is recommended, within its marketing authorisation, as an option for treating chronic lymphocytic leukaemia in adults who have had at least 1\xa0previous therapy. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople with previously treated chronic lymphocytic leukaemia usually have ibrutinib. Clinical trial evidence shows that venetoclax plus rituximab increases how long people live for before their disease gets worse compared with bendamustine plus rituximab (a combination that is not frequently used). There is no trial directly comparing venetoclax plus rituximab with ibrutinib. Indirect comparisons of venetoclax plus rituximab with ibrutinib have limitations, but can be used for decision making because there is no other evidence.\n\nEstimates from the cost-effectiveness analyses range from venetoclax plus rituximab being less costly and more effective to it being less costly and less effective, when compared with ibrutinib. Although it is uncertain how effective venetoclax is compared with ibrutinib, a cost-comparison analysis shows that venetoclax plus rituximab is considered to be a cost-effective use of NHS resources and it is recommended for routine use in the NHS.', 'Information about venetoclax with rituximab': "# Marketing authorisation indication\n\nVenetoclax (Venclyxto, AbbVie) plus rituximab is indicated 'for the treatment of adult patients with chronic lymphocytic leukaemia who have received at least 1 prior therapy.'\n\n# Dosage in the marketing authorisation\n\nVenetoclax should be administered:\n\nin the titration phase, 20\xa0mg orally once daily for 7\xa0days, increasing by gradual weekly increments over 5\xa0weeks to 400\xa0mg once daily\n\nin the post-titration phase, 400\xa0mg orally once daily.Rituximab should be administered after the patient has completed the dose‑titration schedule and has had the recommended daily dose of 400\xa0mg venetoclax for 7\xa0days. Rituximab 375\xa0mg/m2 is given intravenously on day\xa01 of cycle\xa01 (a cycle is 28\xa0days), followed by 500\xa0mg/m2 on day\xa01 of cycles\xa02\xa0to\xa06. Rituximab is stopped after cycle\xa06.Venetoclax can be taken for a maximum of 2\xa0years from day\xa01 of cycle\xa01 of rituximab, or until disease progression or unacceptable toxicity (see the summary of product characteristics).\n\n# Price\n\nA 112-pack of 100-mg tablets costs £4,789.47 (excluding VAT; British national formulary online, accessed September 2018). The company has a commercial arrangement. This makes venetoclax with rituximab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with chronic lymphocytic leukaemia would welcome a new treatment option\n\nThe clinical and patient experts noted that people with previously treated chronic lymphocytic leukaemia (relapsed or refractory chronic lymphocytic leukaemia) have limited treatment options. They explained that some people spend a long time in the 'watch and wait' stage of the treatment pathway, which can have a psychological effect on them because of worry about relapse. The patient experts highlighted that some people have cardiovascular comorbidities, which limits their treatment options, so they would welcome a range of treatments. The committee understood that although venetoclax plus rituximab can cause serious side effects (tumour lysis syndrome) it is generally well tolerated. It concluded that venetoclax plus rituximab would be welcomed as a new treatment option for people with relapsed or refractory chronic lymphocytic leukaemia.\n\n# Clinical management\n\n## Current treatment for chronic lymphocytic leukaemia is ibrutinib and this is the most appropriate comparator\n\nThe committee understood that venetoclax plus rituximab would be used to treat relapsed or refractory chronic lymphocytic leukaemia in people who have had at least 1\xa0previous therapy. The clinical experts stated that people with chronic lymphocytic leukaemia whose disease has relapsed after 1\xa0previous chemo-immunotherapy would be eligible for a B‑cell receptor pathway inhibitor, such as ibrutinib or idelalisib. They confirmed that most people have ibrutinib rather than idelalisib plus rituximab, because idelalisib plus rituximab has an intensive dosing regimen and is associated with increased risk of infection. The clinical experts confirmed that, within the clinical pathway, both ibrutinib and venetoclax plus rituximab can be used for chronic lymphocytic leukaemia. The committee concluded that established clinical management is ibrutinib, making it a relevant comparator for this appraisal.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS clinical practice in England\n\nThe main clinical evidence came from MURANO (n=389), a phase\xa0III, multicentre, open-label, parallel-arm randomised controlled trial. It included patients aged 18\xa0years or over with relapsed or refractory chronic lymphocytic leukaemia, and compared venetoclax plus rituximab (n=194) with bendamustine plus rituximab (n=195). In the company's original submission, the data came from a May 2017 data cut with a median follow-up of 23.8\xa0months from starting treatment. In response to consultation the company presented data from a May 2018 data cut, with a median follow-up of 36\xa0months from starting treatment. Venetoclax plus rituximab was given for at most 2\xa0years in MURANO, or until disease progression or unacceptable toxic effects, whichever occurred sooner (specified in the summary of product characteristics). The clinical experts explained that this was a reasonable approach because in this time about 60% of patients in the trial had undetectable minimal residual disease, which is a strong predictor of lasting remission in patients with chronic lymphocytic leukaemia. The patient experts stated that people would welcome a fixed treatment duration, especially if this was explained to them when treatment was started. The committee concluded that the clinical-effectiveness evidence is relevant to NHS clinical practice in England.\n\n# Clinical effectiveness\n\n## Venetoclax plus rituximab is clinically effective compared with bendamustine plus rituximab\n\nThe primary outcome measure in MURANO was investigator-assessed median progression-free survival. The May 2018 data cut showed that progression-free survival was statistically significantly longer with venetoclax plus rituximab than with bendamustine plus rituximab (median not reached, compared with 16\xa0months respectively; hazard ratio 0.16, 95% confidence interval [CI] 0.12\xa0to\xa00.23; p<0.0001). Overall survival was longer with venetoclax plus rituximab than with bendamustine plus rituximab (median not reached in either group; hazard ratio 0.50, 95% CI 0.30 to 0.85; p=0.0093). The committee considered how many patients did not have undetectable minimal residual disease because they might need additional treatment after 2\xa0years of therapy with venetoclax plus rituximab. The latest data cut from MURANO confirmed that at 24\xa0months 48% of people had undetectable minimal residual disease and after an additional 9.9\xa0months of follow-up most patients still had undetectable minimal residual disease. In the bendamustine plus rituximab arm only 2% of patients had undetectable minimal residual disease at 24\xa0months. The committee concluded that venetoclax plus rituximab was clinically effective compared with bendamustine plus rituximab.\n\n## The company's unanchored matched-adjusted indirect comparison analysis has limitations\n\nBecause the comparator in MURANO was bendamustine plus rituximab, a combination that is no longer standard care (see section\xa03.2), the company did a matched-adjusted indirect comparison (MAIC) to indirectly compare progression-free survival and overall survival for venetoclax plus rituximab with ibrutinib or idelalisib plus rituximab. The committee had previously agreed that idelalisib plus rituximab was not a relevant comparator so only considered the comparison with ibrutinib. The committee discussed the appropriateness of this approach. At the first committee meeting, it noted the ERG's concerns that the results from the unanchored analysis for venetoclax plus rituximab compared with ibrutinib were clinically implausible. This was because the estimated hazard ratio for progression-free survival (hazard ratio 0.696, 95% CI 0.412 to 1.178) was much higher than the estimate for overall survival (hazard ratio 0.297, 95% CI 0.129 to 0.684), which was not the case in the comparator trials. The clinical experts stated that the overall survival hazard-ratio estimate was not plausible whereas the progression-free survival estimate was. They explained that they believed venetoclax plus rituximab to have similar, or better, efficacy to ibrutinib and that it was unlikely to be inferior to ibrutinib. In response to consultation, the company presented a new MAIC based on the May 2018 data cut from MURANO. The ERG noted that the results of the analysis were still clinically implausible, and the hazard-ratio estimate for progression-free survival (hazard ratio 0.797, 95% CI 0.505 to 1.258) was higher than the estimate for overall survival (hazard ratio 0.445, 95% CI 0.218 to 0.909). The ERG also highlighted that the effectiveness of ibrutinib was still underestimated in the analysis. The committee concluded that the company's updated MAIC had some limitations, but because there was no other evidence it was acceptable for decision making.\n\n## The ERG's network meta-analysis also has limitations\n\nThe ERG did an alternative indirect comparison using a fixed-effect network meta-analysis to estimate the relative benefits of venetoclax plus rituximab compared with ibrutinib. The network meta-analysis showed that progression-free survival and overall survival were shorter with venetoclax plus rituximab than with ibrutinib (progression-free survival hazard ratio 1.43, 95% CI 0.78 to 2.61; overall survival hazard ratio 1.08, 95% CI 0.42 to 2.73). The ERG also highlighted that the network meta-analysis was based on Hillmen et al. (2015), which relies on a simple adjustment that may have biased the results. In response to consultation and the company's new evidence the ERG produced a new network meta-analysis based on the May 2018 data cut from MURANO. The revised analysis still showed that progression-free survival and overall survival were shorter with venetoclax plus rituximab than with ibrutinib (progression-free survival hazard ratio 1.20, 95% CI 0.68 to 2.12; overall survival hazard ratio 1.12, 95% CI 0.48 to 2.63). The committee noted that the new network meta-analysis was also based on the uncertain data from Hillmen et al. (2015) and therefore the limitations still applied. The committee concluded that neither the company's MAIC nor the ERG's network meta-analysis were ideal but, because there were no other analyses, it agreed that they can be used for decision making (see section\xa03.13).\n\n# Adverse effects\n\n## Venetoclax plus rituximab is generally well tolerated\n\nThe clinical experts explained that venetoclax is occasionally associated with tumour lysis syndrome. This is caused by a rapid breakdown of cancer cells, and can lead to complications such as kidney failure. The clinical experts explained that the 5‑week dose escalation schedule helps to prevent tumour lysis syndrome. They noted that there have been few cases of tumour lysis syndrome since this dosing schedule was implemented in clinical practice for venetoclax monotherapy. The committee noted the risks associated with venetoclax plus rituximab, but concluded that it is generally well tolerated.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company's model was a de novo partitioned survival model with 3\xa0states (progression-free, progressed disease and death). Data from MURANO was used to estimate progression-free and overall survival using parametric curves fitted to Kaplan−Meier data. In the model, venetoclax plus rituximab was taken for at most 2\xa0years or until disease progression or unacceptable toxic effects, whichever occurred sooner. This was similar to how it was used in MURANO (see section\xa03.3). The committee concluded that the model structure was appropriate for decision making.\n\n## The extrapolation of survival data is reasonable\n\nThe company explored various approaches for extrapolating survival data. It chose a Weibull distribution as the preferred parametric model for both overall and progression-free survival. The committee noted that the extrapolation did not represent the correct population because it was based on the original trial population instead of the matched population. The committee also noted that the matching had not been done correctly. In response to consultation, the company presented a scenario in which the extrapolation was based on the matched population rather than on the original population from MURANO. The committee concluded that the company's new approach for extrapolating survival data was reasonable and noted that it had little effect on the incremental cost-effectiveness ratio (ICER).\n\n## Potential loss of treatment effect after 2\xa0years with venetoclax plus rituximab is reflected in the company's revised analyses\n\nThe committee recalled that a 2‑year stopping rule was incorporated into MURANO and is also specified in the summary of product characteristics. In its original submission, the company assumed in its base case that venetoclax plus rituximab remained effective throughout the model's time horizon of 30\xa0years, irrespective of time off treatment or whether treatment was stopped at 2\xa0years. The company also provided scenarios assuming diminishing of treatment effect after 2\xa0years. In response to consultation the company presented further scenario analyses with a diminishing treatment effect from 2\xa0years, with annual increases in hazard ratios of 5%, 10%, 20%, 30% and 40%. The ERG repeated these analyses and agreed that the diminishing treatment effect was correctly incorporated into the company's base-case analysis. The committee noted that there were limited data from MURANO on the effect of stopping treatment at 2\xa0years because the latest data cut only has a median follow-up of 36\xa0months. The committee concluded that given the lack of evidence it was not possible to know how much venetoclax plus rituximab's treatment effect continues over time after treatment has stopped. But because there were no other data it agreed that the range of estimates could be used for decision making.\n\n# Utility values in the model\n\n## The utility values in the company's economic model are reasonable\n\nThe company stated that the utility values from MURANO were too high and implausible to use in the economic model. It used utility values from previous NICE technology appraisal guidance for chronic lymphocytic leukaemia, including venetoclax monotherapy and idelalisib with rituximab. In response to consultation, the company presented scenarios using utility values from MURANO for the pre-progression state. It explored a range of potential values for the post-progression state because these could be not obtained from the trial because of lack of available data. The committee concluded that the difference between the utility values for pre- and post-progression-free survival from MURANO was uncertain and noted that it had little effect on the ICER.\n\n# Costs and resource use in the economic model\n\n## The costs of treatment and the treatment-effect duration with venetoclax plus rituximab are captured in the company's revised analyses\n\nThe company limited the cost of venetoclax treatment to 2\xa0years, similar to the treatment duration of venetoclax in MURANO. The committee recalled that the company provided a range of analyses to account for the diminishing treatment effect of venetoclax with rituximab (see section\xa03.10). The committee agreed that the scenario analyses captured the loss of treatment effect of venetoclax plus rituximab well. It concluded that there was no direct evidence to define the most appropriate continued treatment effect for venetoclax plus rituximab, and therefore it would consider the range of estimates presented.\n\n# Cost-effectiveness results\n\n## The company's and the ERG's ICERs differ greatly but are within the range considered a cost-effective use of NHS resources\n\nThe company's revised analyses submitted in response to consultation used results from the new MAIC analysis (see section\xa03.5) and the discounted price for venetoclax. The ERG's revised base-case analysis used results from the new network meta-analysis (see section\xa03.6) and the discounted prices for both venetoclax and ibrutinib. The committee noted that the company's cost-effectiveness estimates showed that venetoclax plus rituximab was cheaper and more effective than ibrutinib, but the ERG's base-case analysis showed venetoclax to be cheaper but less effective (the ICERs incorporated confidential discounts so cannot be reported here). The committee agreed that because of the lack of trial data directly comparing venetoclax plus rituximab with ibrutinib, and limitations in the MAIC and the network meta-analysis, it could not decide which analysis was more appropriate for decision making. It was therefore not able to determine the most plausible ICER. The committee concluded that even though the relative treatment effect of venetoclax plus rituximab compared with ibrutinib was uncertain, both sets of analyses produced ICERs within the range considered to be an acceptable use of NHS resources based on the cost per quality-adjusted life year (QALY) lost or gained.\n\n## The cost-comparison analysis provides supporting evidence that venetoclax plus rituximab is a cost-effective use of NHS resources\n\nIn response to consultation, the company presented a cost comparison for venetoclax plus rituximab with ibrutinib to address uncertainties in the modelling expressed by the committee during the first committee meeting (see section 3.5 and section 3.6, and sections 3.9 to 3.12). The company based the cost-comparison analysis on the assumption of equal efficacy between venetoclax plus rituximab and ibrutinib. The committee concluded that this was appropriate based on the clinical experts' opinion and because there was no evidence of a difference in treatment effect. The company's cost-comparison analysis provided scenarios for 30%, 50% and 100% of people having subsequent ibrutinib treatment after 2\xa0years of treatment with venetoclax plus rituximab (see section\xa03.4). The ERG repeated these scenario analyses but they used a generalised gamma curve for the extrapolation of treatment effect instead of Weibull curve for the extrapolation, which was the company's preferred approach. The committee considered that based on the May\xa02018 data cut from MURANO the scenarios for 30% to 50% of people having ibrutinib were the most clinically plausible, and the 100% scenario was too pessimistic and not supported by the evidence. It concluded that both the company's and the ERG's analyses supported the estimates from the cost-effectiveness analyses (the analyses include confidential discounts so exact values cannot be reported here).\n\n# Innovation\n\n## There are no additional benefits that are not captured in the cost-effectiveness analysis\n\nThe company considered venetoclax plus rituximab to be an innovative treatment. This was because it increases the chance of enduring remission and having undetectable minimal residual disease, without the associated risks of repeated lines of chemotherapy or other agents that offer little chance of having undetectable minimal residual disease. It also offers another very good treatment option to people with relapsed or refractory chronic lymphocytic leukaemia, so should be available as a choice of therapy for this group. The committee concluded that venetoclax plus rituximab would be beneficial. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# End of life\n\n## Venetoclax plus rituximab does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a life-extending treatment at the end of life if it is indicated for patients with a short life expectancy (normally less than 24\xa0months) and it offers an extension to life, normally a mean value of at least an additional 3\xa0months compared with current NHS treatment. The committee noted that the results of MURANO suggest that venetoclax plus rituximab could increase life expectancy by more than 3\xa0months compared with bendamustine plus rituximab, although this is not the appropriate comparator. The short life-expectancy criterion of less than 24\xa0months was not met because people with chronic lymphocytic leukaemia have a life expectancy of more than 2\xa0years. Overall, the committee concluded that venetoclax does not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Conclusion\n\n## Venetoclax plus rituximab is a cost-effective use of NHS resources and is recommended\n\nIn response to consultation the company presented additional data from MURANO showing that venetoclax plus rituximab increases progression-free survival compared with bendamustine plus rituximab, and that most patients had undetectable minimal residual disease after 2\xa0years of treatment. Therefore the committee concluded that venetoclax plus rituximab is a clinically effective treatment compared with bendamustine plus rituximab (see section\xa03.4). It considered the new MAIC and network meta-analysis comparing venetoclax plus rituximab with ibrutinib (the appropriate comparator), but it could not decide which was more appropriate because of their limitations. However, because there were no other analyses it agreed to take them into account during decision making. It noted that the ICERs ranged from venetoclax plus rituximab being less costly and more effective than ibrutinib (company estimates) to venetoclax plus rituximab being less costly and less effective than ibrutinib (ERG estimates). However, both analyses produced ICERs showing that venetoclax was a cost-effective treatment (see section\xa03.13). The committee noted that the cost-comparison analysis supported the conclusions from the cost-effectiveness analysis. The committee concluded that venetoclax with rituximab was a cost-effective use of NHS resources and could be recommended as an option for treating chronic lymphocytic leukaemia in adults after at least 1\xa0previous treatment."}
|
https://www.nice.org.uk/guidance/ta561
|
Evidence-based recommendations on venetoclax (Venclyxto) with rituximab for previously treated chronic lymphocytic leukaemia in adults.
|
15c0b9ce61b5a5ec3c0d4992284d286e94a33535
|
nice
|
Encorafenib with binimetinib for unresectable or metastatic BRAF V600 mutation-positive melanoma
|
Encorafenib with binimetinib for unresectable or metastatic BRAF V600 mutation-positive melanoma
Evidence-based recommendations on encorafenib (Braftovi) with binimetinib (Mektovi) for treating unresectable or metastatic BRAF V600 mutation-positive melanoma in adults.
# Recommendations
Encorafenib with binimetinib is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma in adults. It is recommended only if the company provides encorafenib and binimetinib according to the commercial arrangements.
Why the committee made these recommendations
Current treatments for unresectable or metastatic BRAF V600 mutation-positive melanoma include targeted therapy, usually using a combination of a BRAF and MEK inhibitor (dabrafenib with trametinib) or sometimes monotherapy with a BRAF inhibitor (vemurafenib or dabrafenib).
Clinical trial evidence shows that, compared with vemurafenib, encorafenib with binimetinib extends the time until melanoma progresses and also how long people live. There are no trials directly comparing it against dabrafenib with trametinib. But compared indirectly, encorafenib with binimetinib appears to be as effective as dabrafenib with trametinib.
When the commercial arrangements for encorafenib, binimetinib, dabrafenib and trametinib are taken into account, encorafenib with binimetinib is considered to be a cost-effective use of NHS resources. It is therefore recommended.# Information about encorafenib with binimetinib
# Marketing authorisation
Encorafenib (Braftovi, Pierre Fabre) in combination with binimetinib (Mektovi, Pierre Fabre) is indicated for 'the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation'.
# Dosage in the marketing authorisation
For encorafenib, the recommended dose is 450 mg (6×75‑mg capsules) taken orally, once daily. For binimetinib, the recommended dose is 45 mg (3×15‑mg tablets) taken orally, twice daily, 12 hours apart.
# Price
The list price for 42 capsules of encorafenib 75 mg is £1,400 and for 84 tablets of binimetinib 15 mg is £2,240 (company submission). The company has a commercial arrangement for each drug. This makes encorafenib with binimetinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pierre Fabre and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need and current management
## People with unresectable or metastatic BRAF V600 mutation-positive melanoma would welcome an additional treatment option
Melanoma often affects people at a younger age than some other cancers. It has a substantial effect on patients, their carers and wider society. Advanced (unresectable or metastatic) melanoma can cause severe and debilitating symptoms and is life threatening. The clinical and patient experts stated that they would welcome the availability of another targeted combination treatment for BRAF V600 mutation-positive melanoma, in addition to the currently available combination of dabrafenib with trametinib. Encorafenib with binimetinib has a different toxicity profile. The patient expert emphasised the value of having a choice of treatments available and that a favourable safety profile would improve the quality of life of patients. The committee concluded that people with unresectable or metastatic BRAF V600 mutation-positive melanoma would welcome an additional treatment option.
## The position in the care pathway is uncertain for targeted therapies of BRAF V600 mutation-positive melanoma
The committee acknowledged that the management of unresectable or metastatic BRAF V600 mutation-positive melanoma is changing rapidly with the availability of new immunotherapy and other treatments. The clinical experts explained that standard treatment is either immunotherapies such as nivolumab, ipilimumab or pembrolizumab (alone or in combination) or targeted therapy. Targeted therapy is usually dabrafenib in combination with trametinib but sometimes dabrafenib, trametinib or vemurafenib are taken alone. The clinical experts explained that there is no consensus on whether first-line treatment should be targeted therapies or immunotherapies. They noted that there may be a preference to use immunotherapies first-line for people who have a good performance status, however this is not standard practice across the NHS. Most patients with BRAF V600 mutation-positive melanoma are likely be offered a targeted therapy at some point in the treatment pathway. The committee concluded that the management of advanced melanoma is evolving, making it difficult to determine the position of targeted therapies in the care pathway for mutation-positive melanoma.
# Clinical evidence
## The clinical evidence is relevant to clinical practice in England but does not provide a direct comparison with the comparator specified in the scope
The clinical evidence comes from COLUMBUS. This is an open-label, randomised trial of encorafenib plus binimetinib compared with vemurafenib in people with unresectable or metastatic BRAF V600 mutation-positive melanoma. It included people who had not had treatment for advanced disease, and people with disease that had progressed on or after first-line immunotherapy. The ERG explained that very few people in COLUMBUS had brain metastases, and that people with a poor performance status (2 or above) were excluded from the trial. However, the clinical experts noted that people with unresectable or metastatic BRAF V600 mutation-positive melanoma generally have good performance status even with high-volume disease. The ERG highlighted that only 6% of people in the trial had had treatment with immunotherapy for metastatic disease, which may not reflect the population in the NHS who would have encorafenib and binimetinib. The committee recalled that there is no consensus on whether immunotherapies or targeted therapy should be used first in advanced mutation-positive melanoma (see section 3.2). It noted that the clinical experts do not consider that immunotherapy will affect the response to subsequent targeted therapies, because of their different mechanism of action. The ERG noted that although COLUMBUS has some limitations, overall it was well conducted and generally representative of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma who would be treated in the NHS. The committee concluded that COLUMBUS was well conducted and representative of clinical practice in England but noted that it does not directly compare encorafenib with binimetinib against dabrafenib with trametinib, which is the comparator specified in the NICE scope.
## Encorafenib with binimetinib is more clinically effective than vemurafenib in the clinical trial population
Progression-free survival, assessed by blinded independent review, is the primary endpoint in COLUMBUS. At a median follow up of 11.8 months, median progression-free survival for encorafenib with binimetinib is 14.9 months (95% confidence interval 11.0 to 18.5) compared with 7.3 months (95% CI 5.6 to 8.2) for vemurafenib. The committee noted that the hazard ratio (HR) for progression-free survival for encorafenib with binimetinib compared with vemurafenib is 0.54 (95% CI 0.41 to 0.71), representing an estimated 46% reduction in the risk of disease progression. It also noted that investigator-assessed progression-free survival is very similar to the results from blinded independent review. In addition, median overall survival is longer for encorafenib with binimetinib (33.6 months; 95% CI 24.4 to 39.2) compared with vemurafenib (16.9 months; 95% CI 14.0 to 24.5), representing a 39% reduction in the risk of death (HR 0.61, 95% CI 0.47 to 0.79; p<0.0001). The committee concluded that encorafenib with binimetinib is more clinically effective than vemurafenib in the clinical trial population.
## The clinical effectiveness of encorafenib with binimetinib is likely to be similar to dabrafenib with trametinib, but this is associated with uncertainty
The committee noted that in the absence of trial evidence directly comparing encorafenib with binimetinib against dabrafenib with trametinib, the company did network meta-analyses (NMAs) to indirectly estimate progression-free survival, overall survival, health-related quality of life and incidence of grade 3 or 4 adverse events. The NMAs included 7 randomised controlled trials of BRAF-inhibitor therapies, all reporting clinical efficacy and safety data, of which 5 reported health-related quality of life data. The committee noted that the company's NMAs show no statistically significant difference between the treatment combinations for investigator-assessed progression-free survival, overall survival, adverse events or health-related quality of life, and that the credible intervals are wide for all base-case and sensitivity analyses. It noted that these results should be viewed with caution because of methodological limitations highlighted by both the company and the ERG. However it acknowledged clinical expert opinion suggesting that the clinical effectiveness of encorafenib with binimetinib is likely to be similar to dabrafenib with trametinib. The committee concluded that the clinical effectiveness of encorafenib and binimetinib is likely to be similar to dabrafenib with trametinib, but this is associated with uncertainty.
## Encorafenib with binimetinib may have a favourable safety profile compared with current treatments
The committee noted that the frequency of adverse events in COLUMBUS is similar for encorafenib with binimetinib, compared with vemurafenib. The trial does not include the relevant comparator (dabrafenib with trametinib), however the committee noted that adverse events for encorafenib with binimetinib were infrequent and serious adverse events were low. The clinical experts stated that encorafenib with binimetinib may offer a more favourable side-effect profile than dabrafenib with trametinib. They explained that some people taking dabrafenib with trametinib develop pyrexia during the first month of treatment, which may lead to hospitalisations and dose interruptions. This did not seem to happen as frequently for encorafenib with binimetinib in COLUMBUS. The committee concluded that encorafenib with binimetinib may have a more favourable adverse-effects profile than dabrafenib with trametinib.
# The company's economic model
## The company's model is appropriate for decision making
The company presented a 3 state transition model comparing encorafenib with binimetinib against dabrafenib with trametinib. The progression-free and post-progression states included tunnel states to account for people being 'on' or 'off' primary treatment, reflecting clinical practice. Extrapolation of outcomes beyond the trial period was done using parametric curves that were selected based on best fit to the trial data and visual inspection. The committee concluded that the model structure is appropriate for decision making.
## Clinical inputs, utility values and adverse events included in the model are appropriate
The committee noted that the efficacy and clinical parameters in the model were derived from COLUMBUS data, the company's NMA results and cancer registry data. The committee noted that the clinical effectiveness of encorafenib with binimetinib was based on an indirect comparison against dabrafenib with trametinib, not direct trial evidence (see section 3.5). It acknowledged comments from the ERG that it would be inappropriate to model any difference in efficacy or utility because the company's NMAs show no statistically significant differences between encorafenib with binimetinib and dabrafenib with trametinib for investigator-assessed progression-free survival, overall survival, adverse events and health-related quality of life. The ERG suggested a cost-minimisation approach as their preferred method of analysis, based on an assumption of clinical equivalence. The clinical experts stated that it is biologically plausible that encorafenib with binimetinib and dabrafenib with trametinib are similar in efficacy, in the absence of robust evidence suggesting any differences. However, the committee noted that equivalent efficacy has not been proven. It concluded that the differences in efficacy between treatments using the company's approach are small, and the assumptions in the company's model can be used for decision making alongside the ERG's cost-minimisation approach.
## The ERG's correction for relative dose intensity in the company's base case is appropriate
In the company model, treatment-related costs are calculated from time on treatment, administration costs, relative dose-intensity multipliers and drug costs. The company assumed that the relative dose-intensity multiplier for encorafenib and binimetinib is lower than for dabrafenib with trametinib. The committee noted that the ERG does not consider this analysis to be robust. The ERG stated that both treatment combinations should have the same multipliers, time on treatment and administration costs (given that they have the same mode of delivery). The ERG therefore corrected the company's base case for relative dose intensity. The committee concluded that this approach is appropriate.
# Cost-effectiveness estimates
## Taking into account all the commercial arrangements, encorafenib with binimetinib is a cost-effective use of NHS resources
The committee saw in confidence the company's corrected base case and the ERG's preferred base case using the confidential patient access schemes for encorafenib and binimetinib and for dabrafenib with trametinib. It concluded that encorafenib with binimetinib is a cost-effective use of NHS resources and can be recommended for routine commissioning for treating unresectable or metastatic BRAF V600 mutation-positive melanoma.
|
{'Recommendations': 'Encorafenib with binimetinib is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma in adults. It is recommended only if the company provides encorafenib and binimetinib according to the commercial arrangements.\n\nWhy the committee made these recommendations\n\nCurrent treatments for unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma include targeted therapy, usually using a combination of a BRAF and MEK inhibitor (dabrafenib with trametinib) or sometimes monotherapy with a BRAF inhibitor (vemurafenib or dabrafenib).\n\nClinical trial evidence shows that, compared with vemurafenib, encorafenib with binimetinib extends the time until melanoma progresses and also how long people live. There are no trials directly comparing it against dabrafenib with trametinib. But compared indirectly, encorafenib with binimetinib appears to be as effective as dabrafenib with trametinib.\n\nWhen the commercial arrangements for encorafenib, binimetinib, dabrafenib and trametinib are taken into account, encorafenib with binimetinib is considered to be a cost-effective use of NHS resources. It is therefore recommended.', 'Information about encorafenib with binimetinib': "# Marketing authorisation\n\nEncorafenib (Braftovi, Pierre Fabre) in combination with binimetinib (Mektovi, Pierre Fabre) is indicated for 'the treatment of adult patients with unresectable or metastatic melanoma with a BRAF\xa0V600 mutation'.\n\n# Dosage in the marketing authorisation\n\nFor encorafenib, the recommended dose is 450\xa0mg (6×75‑mg capsules) taken orally, once daily. For binimetinib, the recommended dose is 45\xa0mg (3×15‑mg tablets) taken orally, twice daily, 12\xa0hours apart.\n\n# Price\n\nThe list price for 42\xa0capsules of encorafenib 75\xa0mg is £1,400 and for 84\xa0tablets of binimetinib 15\xa0mg is £2,240 (company submission). The company has a commercial arrangement for each drug. This makes encorafenib with binimetinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Pierre Fabre and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need and current management\n\n## People with unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma would welcome an additional treatment option\n\nMelanoma often affects people at a younger age than some other cancers. It has a substantial effect on patients, their carers and wider society. Advanced (unresectable or metastatic) melanoma can cause severe and debilitating symptoms and is life threatening. The clinical and patient experts stated that they would welcome the availability of another targeted combination treatment for BRAF\xa0V600 mutation-positive melanoma, in addition to the currently available combination of dabrafenib with trametinib. Encorafenib with binimetinib has a different toxicity profile. The patient expert emphasised the value of having a choice of treatments available and that a favourable safety profile would improve the quality of life of patients. The committee concluded that people with unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma would welcome an additional treatment option.\n\n## The position in the care pathway is uncertain for targeted therapies of BRAF\xa0V600 mutation-positive melanoma\n\nThe committee acknowledged that the management of unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma is changing rapidly with the availability of new immunotherapy and other treatments. The clinical experts explained that standard treatment is either immunotherapies such as nivolumab, ipilimumab or pembrolizumab (alone or in combination) or targeted therapy. Targeted therapy is usually dabrafenib in combination with trametinib but sometimes dabrafenib, trametinib or vemurafenib are taken alone. The clinical experts explained that there is no consensus on whether first-line treatment should be targeted therapies or immunotherapies. They noted that there may be a preference to use immunotherapies first-line for people who have a good performance status, however this is not standard practice across the NHS. Most patients with BRAF\xa0V600 mutation-positive melanoma are likely be offered a targeted therapy at some point in the treatment pathway. The committee concluded that the management of advanced melanoma is evolving, making it difficult to determine the position of targeted therapies in the care pathway for mutation-positive melanoma.\n\n# Clinical evidence\n\n## The clinical evidence is relevant to clinical practice in England but does not provide a direct comparison with the comparator specified in the scope\n\nThe clinical evidence comes from COLUMBUS. This is an open-label, randomised trial of encorafenib plus binimetinib compared with vemurafenib in people with unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma. It included people who had not had treatment for advanced disease, and people with disease that had progressed on or after first-line immunotherapy. The ERG explained that very few people in COLUMBUS had brain metastases, and that people with a poor performance status (2\xa0or above) were excluded from the trial. However, the clinical experts noted that people with unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma generally have good performance status even with high-volume disease. The ERG highlighted that only 6% of people in the trial had had treatment with immunotherapy for metastatic disease, which may not reflect the population in the NHS who would have encorafenib and binimetinib. The committee recalled that there is no consensus on whether immunotherapies or targeted therapy should be used first in advanced mutation-positive melanoma (see\xa0section 3.2). It noted that the clinical experts do not consider that immunotherapy will affect the response to subsequent targeted therapies, because of their different mechanism of action. The ERG noted that although COLUMBUS has some limitations, overall it was well conducted and generally representative of patients with unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma who would be treated in the NHS. The committee concluded that COLUMBUS was well conducted and representative of clinical practice in England but noted that it does not directly compare encorafenib with binimetinib against dabrafenib with trametinib, which is the comparator specified in the NICE scope.\n\n## Encorafenib with binimetinib is more clinically effective than vemurafenib in the clinical trial population\n\nProgression-free survival, assessed by blinded independent review, is the primary endpoint in COLUMBUS. At a median follow up of 11.8\xa0months, median progression-free survival for encorafenib with binimetinib is 14.9\xa0months (95% confidence interval [CI] 11.0 to 18.5) compared with 7.3\xa0months (95% CI 5.6 to 8.2) for vemurafenib. The committee noted that the hazard ratio (HR) for progression-free survival for encorafenib with binimetinib compared with vemurafenib is 0.54 (95% CI 0.41 to 0.71), representing an estimated 46% reduction in the risk of disease progression. It also noted that investigator-assessed progression-free survival is very similar to the results from blinded independent review. In addition, median overall survival is longer for encorafenib with binimetinib (33.6\xa0months; 95% CI 24.4 to 39.2) compared with vemurafenib (16.9\xa0months; 95% CI 14.0 to 24.5), representing a 39% reduction in the risk of death (HR 0.61, 95% CI 0.47 to 0.79; p<0.0001). The committee concluded that encorafenib with binimetinib is more clinically effective than vemurafenib in the clinical trial population.\n\n## The clinical effectiveness of encorafenib with binimetinib is likely to be similar to dabrafenib with trametinib, but this is associated with uncertainty\n\nThe committee noted that in the absence of trial evidence directly comparing encorafenib with binimetinib against dabrafenib with trametinib, the company did network meta-analyses (NMAs) to indirectly estimate progression-free survival, overall survival, health-related quality of life and incidence of grade\xa03 or\xa04 adverse events. The NMAs included 7\xa0randomised controlled trials of BRAF-inhibitor therapies, all reporting clinical efficacy and safety data, of which 5\xa0reported health-related quality of life data. The committee noted that the company's NMAs show no statistically significant difference between the treatment combinations for investigator-assessed progression-free survival, overall survival, adverse events or health-related quality of life, and that the credible intervals are wide for all base-case and sensitivity analyses. It noted that these results should be viewed with caution because of methodological limitations highlighted by both the company and the ERG. However it acknowledged clinical expert opinion suggesting that the clinical effectiveness of encorafenib with binimetinib is likely to be similar to dabrafenib with trametinib. The committee concluded that the clinical effectiveness of encorafenib and binimetinib is likely to be similar to dabrafenib with trametinib, but this is associated with uncertainty.\n\n## Encorafenib with binimetinib may have a favourable safety profile compared with current treatments\n\nThe committee noted that the frequency of adverse events in COLUMBUS is similar for encorafenib with binimetinib, compared with vemurafenib. The trial does not include the relevant comparator (dabrafenib with trametinib), however the committee noted that adverse events for encorafenib with binimetinib were infrequent and serious adverse events were low. The clinical experts stated that encorafenib with binimetinib may offer a more favourable side-effect profile than dabrafenib with trametinib. They explained that some people taking dabrafenib with trametinib develop pyrexia during the first month of treatment, which may lead to hospitalisations and dose interruptions. This did not seem to happen as frequently for encorafenib with binimetinib in COLUMBUS. The committee concluded that encorafenib with binimetinib may have a more favourable adverse-effects profile than dabrafenib with trametinib.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company presented a 3\xa0state transition model comparing encorafenib with binimetinib against dabrafenib with trametinib. The progression-free and post-progression states included tunnel states to account for people being 'on' or 'off' primary treatment, reflecting clinical practice. Extrapolation of outcomes beyond the trial period was done using parametric curves that were selected based on best fit to the trial data and visual inspection. The committee concluded that the model structure is appropriate for decision making.\n\n## Clinical inputs, utility values and adverse events included in the model are appropriate\n\nThe committee noted that the efficacy and clinical parameters in the model were derived from COLUMBUS data, the company's NMA results and cancer registry data. The committee noted that the clinical effectiveness of encorafenib with binimetinib was based on an indirect comparison against dabrafenib with trametinib, not direct trial evidence (see\xa0section 3.5). It acknowledged comments from the ERG that it would be inappropriate to model any difference in efficacy or utility because the company's NMAs show no statistically significant differences between encorafenib with binimetinib and dabrafenib with trametinib for investigator-assessed progression-free survival, overall survival, adverse events and health-related quality of life. The ERG suggested a cost-minimisation approach as their preferred method of analysis, based on an assumption of clinical equivalence. The clinical experts stated that it is biologically plausible that encorafenib with binimetinib and dabrafenib with trametinib are similar in efficacy, in the absence of robust evidence suggesting any differences. However, the committee noted that equivalent efficacy has not been proven. It concluded that the differences in efficacy between treatments using the company's approach are small, and the assumptions in the company's model can be used for decision making alongside the ERG's cost-minimisation approach.\n\n## The ERG's correction for relative dose intensity in the company's base case is appropriate\n\nIn the company model, treatment-related costs are calculated from time on treatment, administration costs, relative dose-intensity multipliers and drug costs. The company assumed that the relative dose-intensity multiplier for encorafenib and binimetinib is lower than for dabrafenib with trametinib. The committee noted that the ERG does not consider this analysis to be robust. The ERG stated that both treatment combinations should have the same multipliers, time on treatment and administration costs (given that they have the same mode of delivery). The ERG therefore corrected the company's base case for relative dose intensity. The committee concluded that this approach is appropriate.\n\n# Cost-effectiveness estimates\n\n## Taking into account all the commercial arrangements, encorafenib with binimetinib is a cost-effective use of NHS resources\n\nThe committee saw in confidence the company's corrected base case and the ERG's preferred base case using the confidential patient access schemes for encorafenib and binimetinib and for dabrafenib with trametinib. It concluded that encorafenib with binimetinib is a cost-effective use of NHS resources and can be recommended for routine commissioning for treating unresectable or metastatic BRAF\xa0V600 mutation-positive melanoma."}
|
https://www.nice.org.uk/guidance/ta562
|
Evidence-based recommendations on encorafenib (Braftovi) with binimetinib (Mektovi) for treating unresectable or metastatic BRAF V600 mutation-positive melanoma in adults.
|
d0f27b9b6e56406b9d2a72e2234ac42c1da65844
|
nice
|
Abemaciclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
|
Abemaciclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
Evidence-based recommendations on abemaciclib (Verzenios) for treating locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults who have not had endocrine-based therapy before.
# Recommendations
Abemaciclib with an aromatase inhibitor is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer as first endocrine-based therapy in adults. Abemaciclib is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Palbociclib or ribociclib, taken with an aromatase inhibitor, are usually the first treatments for locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer. They are cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, as is abemaciclib.
Clinical trial evidence shows that abemaciclib with an aromatase inhibitor increases how long people live without their disease getting worse, compared with an aromatase inhibitor alone. It is not known whether abemaciclib increases the length of time people live, because the final trial results are not available yet. Abemaciclib, palbociclib and ribociclib have different side effects, but they all appear to work as well as each other.
Taking into account the commercial arrangements for all the CDK 4/6 inhibitors, abemaciclib is a cost-effective use of NHS resources and it can be recommended.# Information about abemaciclib
# Marketing authorisation
Abemaciclib (Verzenios, Eli Lilly) is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer in combination with an aromatase inhibitor, as initial endocrine-based therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
# Dosage in the marketing authorisation
The recommended dose is 150 mg taken orally, twice daily, alongside treatment with an aromatase inhibitor. Treatment should be continued as long as the patient is having clinical benefit or until unacceptable toxicity occurs. Some adverse reactions may need to be managed by temporary dose reductions, dose interruptions, or permanently stopping the treatment.
# Price
£2,950 for 56×150 mg tablets (excluding VAT; MIMS online, accessed December 2018). The company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Current management
## Palbociclib and ribociclib, with an aromatase inhibitor, are the appropriate comparators
The committee was aware that metastatic breast cancer is an incurable condition. First-line treatment for locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor (HER2)-negative breast cancer is usually a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, currently palbociclib or ribociclib (see NICE's technology appraisal guidance on palbociclib and ribociclib), with an aromatase inhibitor (letrozole or anastrozole). The committee noted that since the CDK 4/6 inhibitors have been recommended, not many patients have an aromatase inhibitor alone. If symptoms are severe or the disease is rapidly progressive, then chemotherapy may be needed in the first instance, and tamoxifen can also be offered to some people in line with NICE's guideline on advanced breast cancer. The committee concluded that the company has placed abemaciclib, which is a new CDK 4/6 inhibitor, appropriately in the treatment pathway. Palbociclib and ribociclib, with an aromatase inhibitor, are the appropriate comparators for this appraisal.
## Abemaciclib is a further treatment option that may be preferred by some people
The patient expert stated that staying progression-free for as long as possible is very highly valued by patients and their families. Abemaciclib shows improved progression-free survival when used with an aromatase inhibitor, compared with an aromatase inhibitor alone (see section 3.4). The committee was aware from past appraisals for advanced breast cancer that patients value improvements in progression-free survival, and this was considered important in the palbociclib and ribociclib appraisals. The clinical experts explained that the dosing regimens and adverse-effect profiles of the 3 CDK 4/6 inhibitors differ. Abemaciclib is taken continuously, twice daily. Palbociclib and ribociclib are taken once daily for 21 days, followed by 7 days off-treatment before restarting a new 28‑day cycle. Palbociclib is associated with an increased incidence of neutropenia and needs full blood counts during treatment. Ribociclib is also associated with an increased incidence of neutropenia and needs regular electrocardiogram assessments and liver function tests during treatment. Abemaciclib is associated with an increased incidence of diarrhoea. The patient expert highlighted the importance of patients being involved in choosing the most appropriate treatment option, and that people have different attitudes to risks. The committee acknowledged that abemaciclib provides a further treatment option that may be preferred by some people.
# Clinical evidence
## MONARCH 3 is relevant to NHS practice, but there is no evidence directly comparing abemaciclib with palbociclib and ribociclib
MONARCH 3 is a double blind, placebo-controlled, randomised trial comparing abemaciclib with placebo (both taken with letrozole or anastrozole). It included 493 postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer who had not had any treatment for advanced disease. The committee noted that the percentage of patients in the trial presenting at the start with advanced or metastatic disease was larger than would be expected in the NHS. The clinical expert stated that this is not a concern because the treatment benefit was large and was seen in all groups of patients included in the trial. The ERG stated that MONARCH 3 is a well conducted trial but a high frequency of diarrhoea with abemaciclib could have led to unblinding. It also noted that, despite some limitations, the population is representative of women with hormone receptor-positive, HER2-negative breast cancer who have not had treatment for advanced disease. There are no trials directly comparing abemaciclib with palbociclib and ribociclib. The committee concluded that the MONARCH 3 population is generalisable to NHS clinical practice, but noted that the trial evidence does not provide a comparison of abemaciclib with palbociclib and ribociclib.
## Abemaciclib improves progression-free survival compared with letrozole or anastrozole alone
Progression-free survival in MONARCH 3 was assessed by the investigators and by independent review. In the final investigator-assessed progression-free survival analysis, median progression-free survival was 28.18 months for abemaciclib and 14.76 months for placebo (hazard ratio 0.540, 95% confidence interval 0.418 to 0.698). In the final independent review, median progression-free survival was not reached for abemaciclib and was 19.36 months for placebo (HR 0.465, 95% CI 0.339 to 0.636). The ERG raised concerns that the investigator review may not be the most objective outcome measure because of the high incidence of diarrhoea and potential unblinding for abemaciclib. However, it noted that independent-review results are usually more conservative than investigator assessment, which was not the case in MONARCH 3. The committee concluded that abemaciclib with an aromatase inhibitor improves progression-free survival compared with letrozole or anastrozole alone.
## It is not known whether abemaciclib improves overall survival
The overall-survival data from MONARCH 3 are immature. At the final progression-free survival analysis (93 deaths were observed across the 2 groups), overall survival was similar between the treatment groups (HR 1.057, 95% CI 0.683 to 1.633). A final overall-survival analysis will be done after 315 events. The committee concluded that there are not enough data to decide whether abemaciclib with an aromatase inhibitor improves overall survival, compared with an aromatase inhibitor alone.
# Indirect evidence: network meta-analyses
## The results suggest similar efficacy for abemaciclib, palbociclib and ribociclib
The company did network meta-analyses including 18 studies to compare abemaciclib with palbociclib and ribociclib (each with an aromatase inhibitor). Analyses included progression-free survival (8 studies), overall survival (15 studies) and a number of response-rates analyses (10 to 17 studies), but networks were not possible for adverse events, treatment duration and quality of life. The results are confidential but similar treatment effects were shown for all 3 CDK 4/6 inhibitors. The company noted a level of heterogeneity among 4 trials of CDK 4/6 inhibitors with an aromatase inhibitor, compared with an aromatase inhibitor alone (MONARCH 3, MONALEESA 2, PALOMA 1 and PALOMA 2) because of differences in the site of disease and the degree of visceral involvement. It also noted that the overall-survival data are immature in 3 out of the 4 trials (final overall-survival data are available in PALOMA 1 only). The ERG agreed with the company and added that because of reporting limitations a full assessment of clinical heterogeneity is not possible. Therefore the effect of clinical heterogeneity on the results is unknown. It also noted that the proportional-hazards assumption does not hold for all analyses, and that the results need to be interpreted with caution. Despite the limitations and uncertainties of the analyses, the clinical experts considered the results to be plausible. The committee agreed that there are no large differences between the 3 CDK 4/6 inhibitors, although it noted some uncertainty in the treatment-effect estimates. It concluded that no real difference in efficacy has been shown between abemaciclib, palbociclib and ribociclib.
# Abemaciclib and other CDK 4/6 inhibitors
## It is appropriate to consider that abemaciclib, palbociclib and ribociclib have a class effect
The clinical experts explained that abemaciclib, palbociclib and ribociclib have similar clinical effectiveness. They consider that the 3 CDK 4/6 inhibitors have a class effect, even though they are not identical. They highlighted that although their clinical effectiveness is similar, the safety profiles differ for the 3 treatments (see section 3.2). However they each have an acceptable safety profile. The company suggested that some of the differences in the safety profiles (for example, bone marrow suppression rather than gastrointestinal problems) can be explained by differences in the proportions of CDK 4 and CDK 6 inhibitors in the 3 drugs. The committee noted that there is an absence of evidence of a difference in clinical efficacy between the 3 treatments (see section 3.6). It agreed with the clinical experts that based on the evidence available, the 3 treatments are clinically similar. The committee therefore concluded that it is appropriate to consider that the CDK 4/6 inhibitors have a class effect.
# The company's economic model
## The model is different to those seen in the 2 previous CDK 4/6 inhibitor appraisals
The company submitted a state-transition model with 2 health states (progression-free survival and post-progression survival on first-line treatment) and death, with a 'fixed pay-off' submodel. The submodel is a separate partitioned survival model with 2 health states (progression-free survival and post-progression survival) and death, representing health outcomes and costs incurred on second-line and subsequent treatments applied post progression. Calibration is used to adjust the time spent in the submodel to reflect the assumed relationship between progression-free survival and overall survival. The ERG noted that this is a new approach that explicitly models second-line treatments to reduce uncertainty around overall survival. This approach has similarities, but is not identical, to that used in NICE's technology appraisal guidance on ribociclib. The committee acknowledged that this model differs to those used in the 2 previous CDK 4/6 inhibitor appraisals for the same disease area.
# Key issues with assumptions and inputs in the economic model
## The ERG's approach to progression-free survival on first-line treatment, pre-progression death, second-line utility, and overall survival on second-line treatment is preferred
The company estimated progression-free survival on first-line treatment and pre-progression death using the MONARCH 3 data for abemaciclib (with an aromatase inhibitor) and an aromatase inhibitor alone. It used the hazard ratios for palbociclib and ribociclib from the network meta-analyses relative to the aromatase inhibitor data from MONARCH 3. The ERG noted inconsistency in the company's approach and explained that hazard ratios from the network meta-analyses should be used for all 3 treatments (abemaciclib, palbociclib and ribociclib). The committee agreed with the ERG's approach. It also noted that the company's second-line utility value is higher than the first-line value, and it agreed that the ERG's suggested value of 0.69 (as used in NICE's technology appraisal guidance on ribociclib) for progression-free survival on second-line treatment is more plausible. The ERG also critiqued the company's extrapolation of overall survival on second-line treatment using trial data from both MONARCH 2 (exponential distribution) and CONFIRM (Weibull distribution). It presented another scenario extrapolating overall survival on second-line treatment using MONARCH 2 data only (Gompertz distribution). The committee concluded that it preferred the ERG's approach to modelling progression-free survival on first-line treatment, pre-progression death, second-line utility value, and overall survival on second-line treatment.
## Model inputs for time on treatment lack plausibility
Networks for treatment duration were not available, so MONARCH 3 data were used for abemaciclib (with an aromatase inhibitor) and an aromatase inhibitor alone. Data from the summary of product characteristics were used for palbociclib and ribociclib. The ERG questioned the large difference in the time on treatment for the 3 CDK 4/6 inhibitors (the results are confidential). The clinical experts agreed with the ERG and noted that progression-free survival and treatment duration should be similar. The company was not able to explain the difference in treatment duration. The committee acknowledged that the difference in the modelled time on treatment is unexplained and highly uncertain. It noted that it would be difficult to explain how abemaciclib could produce a similar clinical effect with a shorter time on treatment than palbociclib and ribociclib. The committee concluded that there is no reason to expect a difference in treatment duration between the 3 CDK 4/6 inhibitors.
# Cost-effectiveness results
## A cost-comparison approach is preferred
The company presented results using list prices for abemaciclib, palbociclib and ribociclib. The company's deterministic results show that abemaciclib is the cheapest treatment with the highest quality-adjusted life years (QALYs) gained (abemaciclib dominating ribociclib and palbociclib; that is, costs less and works better). The ERG's preferred base case also uses the list prices for all the CDK 4/6 inhibitors but with different assumptions (see section 3.9), and it too shows abemaciclib dominating ribociclib and palbociclib. The results using patient access schemes for all 3 CDK 4/6 inhibitors are confidential. The committee noted that the differences in QALYs between the CDK 4/6 inhibitors are very small, and that the QALY-based ranking of the treatments changes across the company's and ERG's scenario analyses. The committee also recalled that the models use different treatment durations for the 3 CDK 4/6 inhibitors, which it does not consider plausible (see section 3.10). The committee noted that there is no evidence of a difference between the 3 treatments (see section 3.6) and that it is appropriate to consider a class effect for the CDK 4/6 inhibitors (see section 3.7). It concluded that, assuming the clinical effectiveness of abemaciclib, palbociclib and ribociclib is comparable, a cost-comparison approach is preferred.
## Abemaciclib with an aromatase inhibitor is a cost-effective use of NHS resources and is recommended for locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer
In response to consultation, consultees and commentators agreed that it is appropriate to consider the 3 CDK 4/6 inhibitors as a class, and therefore the costs associated with the treatments can be compared directly. In response to the consultation document, the company increased the discount in their patient access scheme. Using the company's model and the committees preferred assumptions (see section 3.9), and assuming the same treatment duration for all 3 CDK 4/6 inhibitors (see section 3.10), the ERG calculated the total cost of treatment with abemaciclib, ribociclib and palbociclib using the confidential patient access schemes for all 3 CDK 4/6 inhibitors. The committee concluded that abemaciclib with an aromatase inhibitor is a cost-effective use of NHS resources and it can be recommended as an option for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer.
|
{'Recommendations': 'Abemaciclib with an aromatase inhibitor is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer as first endocrine-based therapy in adults. Abemaciclib is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPalbociclib or ribociclib, taken with an aromatase inhibitor, are usually the first treatments for locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer. They are cyclin-dependent kinase\xa04 and\xa06 (CDK\xa04/6) inhibitors, as is abemaciclib.\n\nClinical trial evidence shows that abemaciclib with an aromatase inhibitor increases how long people live without their disease getting worse, compared with an aromatase inhibitor alone. It is not known whether abemaciclib increases the length of time people live, because the final trial results are not available yet. Abemaciclib, palbociclib and ribociclib have different side effects, but they all appear to work as well as each other.\n\nTaking into account the commercial arrangements for all the CDK\xa04/6 inhibitors, abemaciclib is a cost-effective use of NHS resources and it can be recommended.', 'Information about abemaciclib': "# Marketing authorisation\n\nAbemaciclib (Verzenios, Eli Lilly) is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer in combination with an aromatase inhibitor, as initial endocrine-based therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.\n\n# Dosage in the marketing authorisation\n\nThe recommended dose is 150\xa0mg taken orally, twice daily, alongside treatment with an aromatase inhibitor. Treatment should be continued as long as the patient is having clinical benefit or until unacceptable toxicity occurs. Some adverse reactions may need to be managed by temporary dose reductions, dose interruptions, or permanently stopping the treatment.\n\n# Price\n\n£2,950 for 56×150\xa0mg tablets (excluding VAT; MIMS online, accessed December 2018). The company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Current management\n\n## Palbociclib and ribociclib, with an aromatase inhibitor, are the appropriate comparators\n\nThe committee was aware that metastatic breast cancer is an incurable condition. First-line treatment for locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor (HER2)-negative breast cancer is usually a cyclin-dependent kinase\xa04 and\xa06 (CDK\xa04/6) inhibitor, currently palbociclib or ribociclib (see NICE's technology appraisal guidance on palbociclib and ribociclib), with an aromatase inhibitor (letrozole or anastrozole). The committee noted that since the CDK\xa04/6 inhibitors have been recommended, not many patients have an aromatase inhibitor alone. If symptoms are severe or the disease is rapidly progressive, then chemotherapy may be needed in the first instance, and tamoxifen can also be offered to some people in line with NICE's guideline on advanced breast cancer. The committee concluded that the company has placed abemaciclib, which is a new CDK\xa04/6 inhibitor, appropriately in the treatment pathway. Palbociclib and ribociclib, with an aromatase inhibitor, are the appropriate comparators for this appraisal.\n\n## Abemaciclib is a further treatment option that may be preferred by some people\n\nThe patient expert stated that staying progression-free for as long as possible is very highly valued by patients and their families. Abemaciclib shows improved progression-free survival when used with an aromatase inhibitor, compared with an aromatase inhibitor alone (see\xa0section 3.4). The committee was aware from past appraisals for advanced breast cancer that patients value improvements in progression-free survival, and this was considered important in the palbociclib and ribociclib appraisals. The clinical experts explained that the dosing regimens and adverse-effect profiles of the 3\xa0CDK\xa04/6 inhibitors differ. Abemaciclib is taken continuously, twice daily. Palbociclib and ribociclib are taken once daily for 21\xa0days, followed by 7\xa0days off-treatment before restarting a new 28‑day cycle. Palbociclib is associated with an increased incidence of neutropenia and needs full blood counts during treatment. Ribociclib is also associated with an increased incidence of neutropenia and needs regular electrocardiogram assessments and liver function tests during treatment. Abemaciclib is associated with an increased incidence of diarrhoea. The patient expert highlighted the importance of patients being involved in choosing the most appropriate treatment option, and that people have different attitudes to risks. The committee acknowledged that abemaciclib provides a further treatment option that may be preferred by some people.\n\n# Clinical evidence\n\n## MONARCH\xa03 is relevant to NHS practice, but there is no evidence directly comparing abemaciclib with palbociclib and ribociclib\n\nMONARCH\xa03 is a double blind, placebo-controlled, randomised trial comparing abemaciclib with placebo (both taken with letrozole or anastrozole). It included 493\xa0postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer who had not had any treatment for advanced disease. The committee noted that the percentage of patients in the trial presenting at the start with advanced or metastatic disease was larger than would be expected in the NHS. The clinical expert stated that this is not a concern because the treatment benefit was large and was seen in all groups of patients included in the trial. The ERG stated that MONARCH\xa03 is a well conducted trial but a high frequency of diarrhoea with abemaciclib could have led to unblinding. It also noted that, despite some limitations, the population is representative of women with hormone receptor-positive, HER2-negative breast cancer who have not had treatment for advanced disease. There are no trials directly comparing abemaciclib with palbociclib and ribociclib. The committee concluded that the MONARCH\xa03 population is generalisable to NHS clinical practice, but noted that the trial evidence does not provide a comparison of abemaciclib with palbociclib and ribociclib.\n\n## Abemaciclib improves progression-free survival compared with letrozole or anastrozole alone\n\nProgression-free survival in MONARCH\xa03 was assessed by the investigators and by independent review. In the final investigator-assessed progression-free survival analysis, median progression-free survival was 28.18\xa0months for abemaciclib and 14.76\xa0months for placebo (hazard ratio [HR] 0.540, 95% confidence interval [CI] 0.418 to 0.698). In the final independent review, median progression-free survival was not reached for abemaciclib and was 19.36\xa0months for placebo (HR 0.465, 95% CI 0.339 to 0.636). The ERG raised concerns that the investigator review may not be the most objective outcome measure because of the high incidence of diarrhoea and potential unblinding for abemaciclib. However, it noted that independent-review results are usually more conservative than investigator assessment, which was not the case in MONARCH\xa03. The committee concluded that abemaciclib with an aromatase inhibitor improves progression-free survival compared with letrozole or anastrozole alone.\n\n## It is not known whether abemaciclib improves overall survival\n\nThe overall-survival data from MONARCH\xa03 are immature. At the final progression-free survival analysis (93\xa0deaths were observed across the 2\xa0groups), overall survival was similar between the treatment groups (HR 1.057, 95% CI 0.683 to 1.633). A final overall-survival analysis will be done after 315\xa0events. The committee concluded that there are not enough data to decide whether abemaciclib with an aromatase inhibitor improves overall survival, compared with an aromatase inhibitor alone.\n\n# Indirect evidence: network meta-analyses\n\n## The results suggest similar efficacy for abemaciclib, palbociclib and ribociclib\n\nThe company did network meta-analyses including 18\xa0studies to compare abemaciclib with palbociclib and ribociclib (each with an aromatase inhibitor). Analyses included progression-free survival (8\xa0studies), overall survival (15\xa0studies) and a number of response-rates analyses (10\xa0to 17\xa0studies), but networks were not possible for adverse events, treatment duration and quality of life. The results are confidential but similar treatment effects were shown for all 3\xa0CDK\xa04/6 inhibitors. The company noted a level of heterogeneity among 4\xa0trials of CDK\xa04/6 inhibitors with an aromatase inhibitor, compared with an aromatase inhibitor alone (MONARCH\xa03, MONALEESA\xa02, PALOMA\xa01 and PALOMA\xa02) because of differences in the site of disease and the degree of visceral involvement. It also noted that the overall-survival data are immature in 3 out of the 4\xa0trials (final overall-survival data are available in PALOMA\xa01 only). The ERG agreed with the company and added that because of reporting limitations a full assessment of clinical heterogeneity is not possible. Therefore the effect of clinical heterogeneity on the results is unknown. It also noted that the proportional-hazards assumption does not hold for all analyses, and that the results need to be interpreted with caution. Despite the limitations and uncertainties of the analyses, the clinical experts considered the results to be plausible. The committee agreed that there are no large differences between the 3\xa0CDK\xa04/6 inhibitors, although it noted some uncertainty in the treatment-effect estimates. It concluded that no real difference in efficacy has been shown between abemaciclib, palbociclib and ribociclib.\n\n# Abemaciclib and other CDK\xa04/6 inhibitors\n\n## It is appropriate to consider that abemaciclib, palbociclib and ribociclib have a class effect\n\nThe clinical experts explained that abemaciclib, palbociclib and ribociclib have similar clinical effectiveness. They consider that the 3\xa0CDK\xa04/6 inhibitors have a class effect, even though they are not identical. They highlighted that although their clinical effectiveness is similar, the safety profiles differ for the 3\xa0treatments (see\xa0section 3.2). However they each have an acceptable safety profile. The company suggested that some of the differences in the safety profiles (for example, bone marrow suppression rather than gastrointestinal problems) can be explained by differences in the proportions of CDK\xa04 and CDK\xa06 inhibitors in the 3\xa0drugs. The committee noted that there is an absence of evidence of a difference in clinical efficacy between the 3\xa0treatments (see\xa0section 3.6). It agreed with the clinical experts that based on the evidence available, the 3\xa0treatments are clinically similar. The committee therefore concluded that it is appropriate to consider that the CDK\xa04/6 inhibitors have a class effect.\n\n# The company's economic model\n\n## The model is different to those seen in the 2 previous CDK\xa04/6 inhibitor appraisals\n\nThe company submitted a state-transition model with 2\xa0health states (progression-free survival and post-progression survival on first-line treatment) and death, with a 'fixed pay-off' submodel. The submodel is a separate partitioned survival model with 2\xa0health states (progression-free survival and post-progression survival) and death, representing health outcomes and costs incurred on second-line and subsequent treatments applied post progression. Calibration is used to adjust the time spent in the submodel to reflect the assumed relationship between progression-free survival and overall survival. The ERG noted that this is a new approach that explicitly models second-line treatments to reduce uncertainty around overall survival. This approach has similarities, but is not identical, to that used in NICE's technology appraisal guidance on ribociclib. The committee acknowledged that this model differs to those used in the 2 previous CDK\xa04/6 inhibitor appraisals for the same disease area.\n\n# Key issues with assumptions and inputs in the economic model\n\n## The ERG's approach to progression-free survival on first-line treatment, pre-progression death, second-line utility, and overall survival on second-line treatment is preferred\n\nThe company estimated progression-free survival on first-line treatment and pre-progression death using the MONARCH\xa03 data for abemaciclib (with an aromatase inhibitor) and an aromatase inhibitor alone. It used the hazard ratios for palbociclib and ribociclib from the network meta-analyses relative to the aromatase inhibitor data from MONARCH\xa03. The ERG noted inconsistency in the company's approach and explained that hazard ratios from the network meta-analyses should be used for all 3\xa0treatments (abemaciclib, palbociclib and ribociclib). The committee agreed with the ERG's approach. It also noted that the company's second-line utility value is higher than the first-line value, and it agreed that the ERG's suggested value of 0.69 (as used in NICE's technology appraisal guidance on ribociclib) for progression-free survival on second-line treatment is more plausible. The ERG also critiqued the company's extrapolation of overall survival on second-line treatment using trial data from both MONARCH\xa02 (exponential distribution) and CONFIRM (Weibull distribution). It presented another scenario extrapolating overall survival on second-line treatment using MONARCH\xa02 data only (Gompertz distribution). The committee concluded that it preferred the ERG's approach to modelling progression-free survival on first-line treatment, pre-progression death, second-line utility value, and overall survival on second-line treatment.\n\n## Model inputs for time on treatment lack plausibility\n\nNetworks for treatment duration were not available, so MONARCH\xa03 data were used for abemaciclib (with an aromatase inhibitor) and an aromatase inhibitor alone. Data from the summary of product characteristics were used for palbociclib and ribociclib. The ERG questioned the large difference in the time on treatment for the 3\xa0CDK\xa04/6 inhibitors (the results are confidential). The clinical experts agreed with the ERG and noted that progression-free survival and treatment duration should be similar. The company was not able to explain the difference in treatment duration. The committee acknowledged that the difference in the modelled time on treatment is unexplained and highly uncertain. It noted that it would be difficult to explain how abemaciclib could produce a similar clinical effect with a shorter time on treatment than palbociclib and ribociclib. The committee concluded that there is no reason to expect a difference in treatment duration between the 3\xa0CDK\xa04/6 inhibitors.\n\n# Cost-effectiveness results\n\n## A cost-comparison approach is preferred\n\nThe company presented results using list prices for abemaciclib, palbociclib and ribociclib. The company's deterministic results show that abemaciclib is the cheapest treatment with the highest quality-adjusted life years (QALYs) gained (abemaciclib dominating ribociclib and palbociclib; that is, costs less and works better). The ERG's preferred base case also uses the list prices for all the CDK\xa04/6 inhibitors but with different assumptions (see\xa0section 3.9), and it too shows abemaciclib dominating ribociclib and palbociclib. The results using patient access schemes for all 3\xa0CDK\xa04/6 inhibitors are confidential. The committee noted that the differences in QALYs between the CDK\xa04/6 inhibitors are very small, and that the QALY-based ranking of the treatments changes across the company's and ERG's scenario analyses. The committee also recalled that the models use different treatment durations for the 3\xa0CDK\xa04/6 inhibitors, which it does not consider plausible (see\xa0section 3.10). The committee noted that there is no evidence of a difference between the 3\xa0treatments (see\xa0section 3.6) and that it is appropriate to consider a class effect for the CDK\xa04/6 inhibitors (see\xa0section 3.7). It concluded that, assuming the clinical effectiveness of abemaciclib, palbociclib and ribociclib is comparable, a cost-comparison approach is preferred.\n\n## Abemaciclib with an aromatase inhibitor is a cost-effective use of NHS resources and is recommended for locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer\n\nIn response to consultation, consultees and commentators agreed that it is appropriate to consider the 3\xa0CDK\xa04/6 inhibitors as a class, and therefore the costs associated with the treatments can be compared directly. In response to the consultation document, the company increased the discount in their patient access scheme. Using the company's model and the committees preferred assumptions (see\xa0section 3.9), and assuming the same treatment duration for all 3\xa0CDK\xa04/6 inhibitors (see\xa0section 3.10), the ERG calculated the total cost of treatment with abemaciclib, ribociclib and palbociclib using the confidential patient access schemes for all 3\xa0CDK\xa04/6 inhibitors. The committee concluded that abemaciclib with an aromatase inhibitor is a cost-effective use of NHS resources and it can be recommended as an option for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer."}
|
https://www.nice.org.uk/guidance/ta563
|
Evidence-based recommendations on abemaciclib (Verzenios) for treating locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults who have not had endocrine-based therapy before.
|
f7f71b32e15af0915250e221638b4d663ad56ca4
|
nice
|
Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal
|
Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal
Evidence-based recommendations on Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal in adults. This involves using the ileum to create a pouch on the inside of the abdominal wall to collect waste.
# Recommendations
The evidence on the safety of Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal shows that there are serious but well-recognised safety concerns. Current evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
Clinicians wishing to do Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. They should provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Audit, review and publish clinical outcomes of all patients having Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal. This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
The procedure should only be done by experienced colorectal surgeons with training and mentoring in the specific technique.
Further research should include details of patient selection, durability and the incidence of complications. Outcomes should be published.# The condition, current treatments and procedure
# The condition
Various groups of patients may need surgery to remove the colon and sometimes the rectum. They include patients with: ulcerative colitis that is unresponsive to medical treatment or who cannot tolerate the treatment; familial adenomatous polyposis; Crohn's disease; or cancer-related problems. An ileostomy is then needed to allow intestinal contents to exit the body through a stoma on the abdominal wall.
# Current treatments
There are different surgical techniques for creating an ileostomy, including: a Brooke ileostomy (this involves creating a standard stoma that empties intestinal contents continuously into an external ileostomy bag); or a Kock continent ileostomy (this involves creating an internal ileal reservoir connected through the abdominal wall, which is drained intermittently by the patient). In patients with good anal sphincter control, a long-term ileostomy may be avoided by creating an ileal pouch reservoir connected directly to the anus (ileal pouch-anal anastomosis).
The Barnett Continent Intestinal Reservoir is a type of continent ileostomy and may be considered as an option for some patients.
# The procedure
The Barnett Continent Intestinal Reservoir procedure is done under general anaesthesia, usually through a midline incision. It may be done as a primary procedure, when the colon and rectum are removed, or to modify a pre-existing ileostomy. A pouch incorporating a collar and an isoperistaltic valve is created using the last 60 cm of the ileum. The valve is made by intussuscepting a segment of small bowel and fixing it to the pouch wall with staples. This valve functions in the opposite direction to that in a Kock pouch, ensuring the bowel's normal peristaltic action keeps intestinal contents in the pouch rather than expelling them. The collar is formed by wrapping a segment of small bowel around the top of the pouch and valve. It holds the valve in place and provides further continence when the pouch is full and under high pressure. The flat stoma opening is located just above the pubic area and covered with a small adhesive dressing.
When there is a sensation of fullness, the patient drains the pouch by inserting a catheter through the stoma and valve into the pouch. This is typically done 2 or 3 times a day, but the patient determines the exact frequency.
|
{'Recommendations': "The evidence on the safety of Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal shows that there are serious but well-recognised safety concerns. Current evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to do Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. They should provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nAudit, review and publish clinical outcomes of all patients having Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal. This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nThe procedure should only be done by experienced colorectal surgeons with training and mentoring in the specific technique.\n\nFurther research should include details of patient selection, durability and the incidence of complications. Outcomes should be published.", 'The condition, current treatments and procedure': "# The condition\n\nVarious groups of patients may need surgery to remove the colon and sometimes the rectum. They include patients with: ulcerative colitis that is unresponsive to medical treatment or who cannot tolerate the treatment; familial adenomatous polyposis; Crohn's disease; or cancer-related problems. An ileostomy is then needed to allow intestinal contents to exit the body through a stoma on the abdominal wall.\n\n# Current treatments\n\nThere are different surgical techniques for creating an ileostomy, including: a Brooke ileostomy (this involves creating a standard stoma that empties intestinal contents continuously into an external ileostomy bag); or a Kock continent ileostomy (this involves creating an internal ileal reservoir connected through the abdominal wall, which is drained intermittently by the patient). In patients with good anal sphincter control, a long-term ileostomy may be avoided by creating an ileal pouch reservoir connected directly to the anus (ileal pouch-anal anastomosis).\n\nThe Barnett Continent Intestinal Reservoir is a type of continent ileostomy and may be considered as an option for some patients.\n\n# The procedure\n\nThe Barnett Continent Intestinal Reservoir procedure is done under general anaesthesia, usually through a midline incision. It may be done as a primary procedure, when the colon and rectum are removed, or to modify a pre-existing ileostomy. A pouch incorporating a collar and an isoperistaltic valve is created using the last 60\xa0cm of the ileum. The valve is made by intussuscepting a segment of small bowel and fixing it to the pouch wall with staples. This valve functions in the opposite direction to that in a Kock pouch, ensuring the bowel's normal peristaltic action keeps intestinal contents in the pouch rather than expelling them. The collar is formed by wrapping a segment of small bowel around the top of the pouch and valve. It holds the valve in place and provides further continence when the pouch is full and under high pressure. The flat stoma opening is located just above the pubic area and covered with a small adhesive dressing.\n\nWhen there is a sensation of fullness, the patient drains the pouch by inserting a catheter through the stoma and valve into the pouch. This is typically done 2\xa0or\xa03 times a day, but the patient determines the exact frequency."}
|
https://www.nice.org.uk/guidance/ipg642
|
Evidence-based recommendations on Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal in adults. This involves using the ileum to create a pouch on the inside of the abdominal wall to collect waste.
|
6263feb3a42a9546ab5285f434471c76b00daba9
|
nice
|
Cough (acute): antimicrobial prescribing
|
Cough (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute cough associated with an upper respiratory tract infection or acute bronchitis in adults, young people and children. It aims to limit antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing acute cough
For guidance on managing acute cough in people with suspected or confirmed COVID-19, follow our rapid guideline on managing COVID-19.
Be aware that an acute cough:
is usually self-limiting and gets better within 3 to 4 weeks without antibiotics
is most commonly caused by a viral upper respiratory tract infection, such as a cold or flu
can also be caused by acute bronchitis, a lower respiratory tract infection, which is usually a viral infection but can be bacterial
can also have other infective or non-infective causes.
For children under 5 with an acute cough and fever, follow the NICE guideline on fever in under 5s: assessment and initial management.
For adults, children and young people with an acute cough and suspected pneumonia, follow:
-ur COVID-19 rapid guideline on managing COVID-19 for guidance on pneumonia secondary to COVID-19
the NICE guidelines on pneumonia (community-acquired): antimicrobial prescribing and pneumonia (hospital-acquired): antimicrobial prescribing for guidance on pneumonia not secondary to COVID-19.
## Referral and seeking specialist advice
Refer people with an acute cough to hospital, or seek specialist advice on further investigation and management, if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis, a pulmonary embolism or lung cancer).
## Treatment
Give general advice to people about:
the usual course of acute cough (lasts up to 3 or 4 weeks)
how to manage their symptoms with self-care (see the recommendations on self-care)
when to seek medical help, for example if symptoms worsen rapidly or significantly, do not improve after 3 to 4 weeks, or the person becomes systemically very unwell.
Do not offer the following treatments to people for an acute cough associated with an upper respiratory tract infection or acute bronchitis unless the person has an underlying airways disease, such as asthma:
an oral or inhaled bronchodilator (for example, salbutamol) or
an oral or inhaled corticosteroid.
Do not offer a mucolytic (for example acetylcysteine or carbocisteine) to treat an acute cough associated with an upper respiratory tract infection or acute bronchitis.
Do not offer an antibiotic to treat an acute cough associated with an upper respiratory tract infection in people who are not systemically very unwell or at higher risk of complications (see recommendation 1.1.15). Give advice about why an antibiotic is not needed.
Do not routinely offer an antibiotic to treat an acute cough associated with acute bronchitis in people who are not systemically very unwell or at higher risk of complications (see recommendation 1.1.15).
Be aware that:
antibiotics do not improve the overall clinical condition of people with acute bronchitis
antibiotics make little difference to how long symptoms of acute bronchitis last (on average they shorten cough duration by about half a day)
antibiotics have possible adverse effects, particularly diarrhoea and nausea.
This recommendation has been removed.
When no antibiotic prescription is given, give advice about why an antibiotic is not needed.
If an antibiotic prescription is given, give advice about possible adverse effects of the antibiotic, particularly diarrhoea and nausea.
For people with an acute cough who are identified as systemically very unwell (ideally at a face‑to‑face clinical examination), offer an immediate antibiotic prescription (for choice of antibiotic, see recommendation 1.3.1).
Be aware that people with an acute cough may be at higher risk of complications if they:
have a pre-existing comorbidity, such as significant heart, lung, renal, liver or neuromuscular disease, immunosuppression or cystic fibrosis
are young children who were born prematurely
are older than 65 years with 2 or more of the following criteria, or older than 80 years with 1 or more of the following criteria:
hospitalisation in previous year
type 1 or type 2 diabetes
history of congestive heart failure
current use of oral corticosteroids.
For people with an acute cough who are identified as at higher risk of complications (ideally at a face‑to‑face clinical examination), consider:
an immediate antibiotic prescription (for choice of antibiotic, see recommendation 1.3.1) or
a back-up antibiotic prescription.
When an immediate antibiotic prescription is given, give advice about possible adverse effects of the antibiotic, particularly diarrhoea and nausea.
When a back-up antibiotic prescription is given, give advice about:
an antibiotic not being needed immediately
using the back-up prescription if symptoms worsen rapidly or significantly at any time.
## Reassessment
Reassess people with an acute cough if their symptoms worsen rapidly or significantly, taking account of:
alternative diagnoses, such as pneumonia
any symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis
previous antibiotic use, which may have led to resistant bacteria.
See the evidence and committee discussion on bronchodilators, corticosteroids, mucolytics, no antibiotic, back-up antibiotics and choice of antibiotic.
# Self-care
Be aware that some people may wish to try the following self-care treatments, which have limited evidence of some benefit for the relief of cough symptoms:
honey (in people aged over 1 year)
pelargonium (a herbal medicine; in people aged 12 and over)
-ver-the-counter cough medicines containing the expectorant guaifenesin (in people aged 12 and over)
-ver-the-counter cough medicines containing cough suppressants, except codeine, (in people aged 12 and over who do not have a persistent cough, such as in asthma, or excessive secretions).
Be aware that limited evidence suggests that antihistamines, decongestants and codeine-containing cough medicines do not help cough symptoms.
See the evidence and committee discussion on self-care.
# Choice of antibiotic
When prescribing antibiotics for an acute cough follow:
table 1 for adults aged 18 years and over
table 2 for children and young people under 18 years.
Treatment
Antibiotic, dosage and course length
First choice
Doxycycline:
mg on first day, then 100 mg once a day for 4 days (5‑day course in total)
Alternative first choices
Amoxicillin:
mg three times a day for 5 days
Clarithromycin:
mg to 500 mg twice a day for 5 days
Erythromycin:
mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breast-feeding.
The possibility of pregnancy should be considered in women of childbearing age. Doxycycline should not be used in pregnancy. Amoxicillin is the preferred antibiotic in pregnancy. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
Treatment
Antibiotic, dosage and course length
First choice
Amoxicillin:
month to 11 months, 125 mg three times a day for 5 days
year to 4 years, 250 mg three times a day for 5 days
years to 17 years, 500 mg three times a day for 5 days
Alternative first choices
Clarithromycin:
month to 11 years:
Under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years, 250 mg to 500 mg twice a day for 5 days
Erythromycin:
month to 1 year, 125 mg four times a day or 250 mg twice a day for 5 days
years to 7 years, 250 mg four times a day or 500 mg twice a day for 5 days
years to 17 years, 250 mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
Doxycycline:
years to 17 years, 200 mg on first day, then 100 mg once a day for 4 days (5‑day course in total)
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.
The possibility of pregnancy should be considered in women of childbearing age. Doxycycline should not be used in pregnancy. Amoxicillin is the preferred antibiotic in pregnancy. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
See the committee discussion on choice of antibiotic and antibiotic course length.# Terms used in the guideline
# Acute cough
Acute cough is commonly defined as a cough that lasts less than 21 days (3 weeks). The average duration is 18 days, although it can sometimes last for up to 29 days (over 4 weeks). It is most commonly caused by an upper respiratory tract infection, such as a cold or flu, which are viral infections. It can also be caused by acute bronchitis, a lower respiratory tract infection, which is usually a viral infection but can be bacterial.
Other infective causes of cough include COVID-19, pneumonia, acute exacerbations of asthma, chronic obstructive pulmonary disease or bronchiectasis (which may also be non-infective exacerbations), and viral-induced wheeze, bronchiolitis, croup or whooping cough. Non-infective causes may include lung cancer, a foreign body, interstitial lung disease, pneumothorax, pulmonary embolism, heart failure, use of certain medicines (for example, an angiotensin-converting enzyme inhibitor), upper airway cough syndrome (post-nasal drip), or gastro-oesophageal reflux disease. (NICE clinical knowledge summaries on cough, chest infections – adult, cough – acute with chest signs in children and Ebell et al. 2013).
# Acute bronchitis
Acute bronchitis is a lower respiratory tract infection with temporary inflammation of the airways (the trachea and major bronchi) that causes cough and mucus production lasting for up to 3 weeks. It is usually caused by a viral infection, but may be caused by a bacterial infection. (NICE clinical knowledge summary on chest infections – adult).
# Self-care treatments
Self-care treatments available for acute cough include honey, herbal medicines and over-the-counter cough medicines (for example, expectorants and cough suppressants ).# Summary of the evidence
# Self-care
## Honey
Honey significantly reduced the frequency and severity of cough at 1 day follow-up compared with placebo, no treatment or an antihistamine (diphenhydramine) by about 0.5 to 2 points on a carer‑reported 7-point Likert scale in children and young people with an acute cough caused by an upper respiratory tract infection (low to moderate quality evidence). Carer responses about cough symptoms ranged from 'extremely' (6 points) to 'not at all' (0 points), but it was not clear how these responses were defined.
However, honey did not reduce the frequency and severity of cough at 1 day follow-up compared with an antitussive (dextromethorphan; very low quality evidence).
Honey significantly reduced bothersome cough by about 2 points on a 7‑point Likert scale compared with placebo (moderate quality evidence), but not compared with no treatment or dextromethorphan (low quality evidence).
Honey had no significant effect on children's or parents' sleep quality compared with placebo or dextromethorphan, but was significantly better compared with no treatment or diphenhydramine (by about 0.5 to 1 point on a 7-point Likert scale; low to moderate quality evidence).
There was no data on the effect of honey on cough duration because follow-up was for 1 day only.
There was no significant difference in gastrointestinal side effects with honey compared with placebo or dextromethorphan (very low to low quality evidence). There were also no significant differences in mild adverse effects (for example, nervousness, insomnia, hyperactivity and drowsiness) compared with dextromethorphan (very low quality evidence). No significant difference in sleepiness was found when honey was compared with diphenhydramine (very low quality evidence).
Based on Oduwole et al. (2014), a systematic review and meta-analysis including 3 randomised controlled trials (RCTs) in 568 children and young people (aged 1 to 17 years) with acute cough caused by an upper respiratory tract infection.
Honey should not be given to children until they are aged over 1 year because of concerns about infant botulism. It is also a sugar, and there are concerns about tooth decay. (NHS – foods to avoid giving babies and young children)
## Herbal medicines
A. paniculata (as liquid or tablets) significantly reduced the frequency and severity of cough compared with placebo in people with acute cough as a symptom of upper respiratory tract infection or common cold (frequency: standardised mean difference −1.00, 95% confidence interval −1.85 to −0.15; very low quality evidence; severity: SMD −0.57, 95% CI −1.01 to −0.14; very low quality evidence).
No safety data for A. paniculata were reported.
Based on Wagner et al. (2015), a systematic review and meta-analysis of 6 RCTs with dosages of 31.5 mg to 200 mg for 3 to 10 days.
Ivy, primrose or thyme as various combined or single preparations (as liquid or tablets) significantly reduced 'cough' (not defined and follow-up time was not reported) compared with placebo in people with an acute cough as a symptom of upper respiratory tract infection or common cold (77.4% versus 54.9%; very low quality evidence).
No safety data for ivy, primrose or thyme were reported.
Based on Wagner et al. (2015), a systematic review and meta-analysis of 4 RCTs.
Echinacea significantly improved 'cough' (not defined) compared with placebo in people with an acute cough as a symptom of an upper respiratory tract infection or common cold (SMD −0.68, 95% CI −1.32 to −0.04; low quality evidence).
However, this was a meta-analysis of just 2 studies, and the authors reported that most studies in the systematic review did not report any significant reduction in patients' cough symptoms. It is not clear if this was due to the absence of data for this outcome, or the lack of effectiveness for echinacea.
No safety data for echinacea were reported.
Based on Wagner et al. (2015), a systematic review and meta-analysis including 8 RCTs with dosages of 0.3 g to 6 g daily for 1 to 12 weeks.
Pelargonium sidoides (P. sidoides, as a liquid) significantly reduced 'failure to resolve all symptoms' by day 7 (61.0% versus 95.3%; very low quality evidence), 'failure to resolve cough' by day 7 (very low quality evidence) and 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in adults with acute bronchitis.
P. sidoides tablets (any dosage) significantly reduced 'failure to resolve all symptoms' by day 7 (92.7% versus 99.0%; low quality evidence) and 'failure to resolve cough' by day 7 (low quality evidence) compared with placebo in adults with acute bronchitis, although, individually, only the 30‑mg dose achieved a significant reduction for 'failure to resolve cough' (low quality evidence).
P. sidoides (as a liquid) significantly reduced 'failure to resolve all symptoms' by day 7 (79.9% versus 97.1%; low quality evidence), 'failure to resolve cough' by day 7 (low quality evidence) and 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in children or young people with acute bronchitis.
P. sidoides tablets (any dosage) did not significantly reduce 'failure to resolve all symptoms' by day 7 (low quality evidence) or 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in children or young people with acute bronchitis. Only P. sidoides tablets of 20 mg significantly reduced 'failure to resolve cough symptoms' by day 7 (low quality evidence) compared with placebo.
P. sidoides (as a liquid or tablet) significantly increased the number of people (adults, young people and children) with adverse events (19.5% versus 15.1%; very low quality evidence) compared with placebo, which were mainly gastrointestinal. However, there was no significant difference in the number of people with adverse events which led to withdrawal (0.5% versus 1.0%; very low quality evidence).
Based on 2 systematic reviews and meta-analyses, Wagner et al. (2015) and Timmer et al. (2013), in adults, young people or children with an acute cough or acute bronchitis.
NSAIDs (naproxen or ibuprofen) were not significantly different to placebo for a cumulative cough score at follow-up in adults with a common cold (very low quality evidence). NSAIDs significantly reduced associated individual symptoms scores for headache (very low quality evidence), joint and muscle pain (low quality evidence), earache (very low quality evidence) and sneezing (low quality evidence).
NSAIDs were not significantly different to placebo for overall symptom score, severity of illness, duration of illness, throat irritation or hoarseness, malaise or fatigue, chilliness, nasal irritation, pain on swallowing, eye itching, rhinorrhoea, nasal obstruction or dryness, number of nose blows, total weight of mucous, tissue count, sense of smell or adverse effects in adults with a common cold (very low to low quality evidence).
Based on Kim et al. (2015), a systematic review and meta-analysis of 9 RCTs of NSAIDs in adults with a common cold.
NSAIDs are associated with cardiovascular and gastrointestinal risks (Drug Safety Update, October 2012 and Drug Safety Update, December 2007).
## Over-the-counter expectorants
Guaifenesin significantly reduced patient reported cough frequency and intensity compared with placebo in 1 RCT in adults and young people over 12 years with an acute cough or upper respiratory tract infection (75% said guaifenesin was helpful compared with 31% in the placebo group, p<0.01; low quality evidence). There was no significant difference in cough frequency or severity in another RCT, but guaifenesin significantly reduced sputum thickness compared with placebo (p=0.001; low quality evidence). Extended-release guaifenesin reduced symptom severity scores at 4 days (p=0.04) but not at 7 days compared with placebo in 1 RCT (low quality evidence).
In 2 RCTs reporting adverse events, there was no difference between guaifenesin and placebo (no p values reported; very low quality evidence).
Based on Smith et al. (2014), a systematic review including 3 RCTs of adults and young people over 12 years with an acute cough or upper respiratory tract infection.
Over-the-counter cough medicines containing the expectorant guaifenesin are subject to MHRA advice on how to use cough and cold medicines safely for children under 12 years (Drug Safety Update, April 2009).
## Over-the-counter cough suppressants (antitussives)
Codeine was no more effective than placebo, either as a single dose of 30 mg or in a total daily dose of 120 mg (30 mg four times a day), in reducing cough symptoms in adults with acute cough (low quality evidence). A single dose of codeine (50 mg) was no more effective than placebo in reducing cough symptoms at 90 minutes in adults with acute cough (low quality evidence).
Codeine as a single dose at bedtime (10 mg in 5 ml plus guaifenesin) for 3 nights was no more effective than placebo in reducing cough score on day 3 in children with acute cough (p=0.70, low quality evidence).
No safety data for codeine were reported for adults. In children, adverse effects (mainly drowsiness, diarrhoea and hyperactivity) were not significantly different between codeine and placebo (very low quality evidence).
Dextromethorphan (as a single 30‑mg dose) was no more effective than placebo for reduction in cough frequency or reduction in cough severity in 1 RCT of adults with acute cough (very low quality evidence). However, in another RCT, a single 30‑mg dose of dextromethorphan significantly reduced cough counts (not further defined) in adults (mean changes of cough counts between dextromethorphan and placebo varied from 19% to 36%, p<0.05; very low quality evidence). A third RCT found that a single 30‑mg dose of dextromethorphan significantly reduced cough bouts (average treatment difference 12% to 17%, p=0.004), cough components (p=0.003), cough effort (p=0.001) and cough latency (p=0.002) compared with placebo in adults with acute cough (very low quality evidence).
Oral dextromethorphan with salbutamol was no more effective than placebo or dextromethorphan alone in reducing cough frequency (very low quality evidence) or daytime cough severity (low quality evidence) in 1 RCT of adults with acute cough. Dextromethorphan with salbutamol was superior to placebo or dextromethorphan alone in relieving cough at night (mean symptom score 0.19 versus 0.67 and 0.44, respectively on day 4, p<0.01; low quality evidence). However, more tremors were reported in the dextromethorphan with salbutamol group than in the placebo group (no figures given, p<0.05; low quality evidence).
Dextromethorphan was no more effective than placebo (in 4 RCTs) or diphenhydramine (in 1 RCT) in reducing various cough outcomes in children with an acute cough, a night cough or an upper respiratory tract infection (very low quality evidence). In 2 RCTs, there were no differences between the groups in adverse effects, which were generally mild. In another RCT, adverse events (mainly gastrointestinal and dizziness) were reported in 34% of the dextromethorphan group and 5% of the placebo group (p value not reported).
Based on Smith et al. (2014), a systematic review including 11 RCTs of adults, young people and children with an acute cough, with or without a related upper respiratory tract infection.
Over-the-counter cough medicines containing the cough suppressant dextromethorphan are subject to MHRA advice on how to use cough and cold medicines safely for children under 12 years (Drug Safety Update, April 2009). Cough medicines containing codeine have restricted use in children (Drug Safety Update, April 2015).
## Over-the-counter antihistamines and decongestants
Loratadine in combination with pseudoephedrine for 4 days was no more effective than placebo in reducing a composite cough symptom score in 1 RCT of adults with a common cold (very low quality evidence). Adverse effects (including dry mouth, headache and insomnia) were not significantly different between groups (reported in 30% of the loratadine with pseudoephedrine group compared with 21% of the placebo group; very low quality evidence).
Clemastine for 3 days was no more effective than placebo or chlorpheniramine in reducing cough scores in 1 RCT of children under 5 years with a common cold (very low quality evidence). Drowsiness and sleepiness was reported in 20% of children, with no difference between groups (p values not reported).
Diphenhydramine (as a single dose at night) was no more effective than placebo in reducing composite symptom scores, cough frequency or sleep disturbance in children and their parents in 1 RCT of children and young people aged 2 to 18 years with acute cough due to an upper respiratory tract infection (low quality evidence). No safety data were reported.
Promethazine for 3 days was no more effective than placebo in reducing a composite cough symptom scores in 1 RCT of children and young people aged 1 to 22 years with acute cough due to an upper respiratory tract infection (low quality evidence). Adverse events were reported in 32% of the promethazine group and 5% of the placebo group (p value not reported; low quality evidence).
Based on 4 RCTs from 1 systematic review (Smith et al. 2014) in adults, young people and children with cough related to a common cold or upper respiratory tract infection.
Over-the-counter cough medicines containing the antihistamines diphenhydramine and promethazine are subject to MHRA advice on how to use cough and cold medicines safely for children under 12 years (Drug Safety Update, April 2009).
Committee discussion on self-care
Overall, the committee recognised that the quality of the evidence on self‑care treatments for cough was limited. In many studies it was not clear what outcomes were being measured, or these measures were subjective. The sweet, glycerine-like consistency of many cough remedies, rather than the 'active ingredients' themselves may also have an effect, and the placebo effect of taking something rather than nothing to ease symptoms could be marked. However, promoting the role of self-care may help to reduce the amount of antibiotic prescriptions, and repeated or future consultations in general practice.
Honey
The committee agreed that there was some evidence that suggests honey reduced cough symptoms in children and young people with an acute cough caused by an upper respiratory tract infection. The clinical significance of the benefit of honey on cough symptoms is unclear, particularly because follow-up was for 1 day only.
Honey was well tolerated in the studies, and is readily available. However, it should not be given to children under 1 year of age because of concerns about infant botulism. It also contains sugars, and the committee discussed concerns about tooth decay.
In the studies, honey was given as a single 10‑g dose in 1 trial, and 2 trials reported that honey was given before bedtime. A range of types of honey were used, with no studies using the same variety.
Based on evidence, the committee agreed that that limited evidence suggests that honey may have some benefit on cough symptoms and people over 1 year of age may wish to try this for the treatment of acute cough.
Herbal medicines
The committee found that the evidence for many of the herbal medicines was limited by poorly defined populations, outcomes, length of follow-up and a lack of safety data or data on adverse outcomes.
The committee reviewed evidence for several herbal products: Andrographis paniculata, ivy, primrose and thyme as a combined product, echinacea, and pelargonium.
The committee agreed that there was some evidence that suggests Andrographis paniculata (A. paniculata) reduced cough symptoms. However, as the clinical significance of this benefit is unclear, safety data was not available, and no A. paniculata product has been granted a traditional herbal registration with the MHRA, the committee agreed that no recommendation on its use for the treatment of acute cough could be made.
The committee agreed that there was some evidence that suggests ivy, primrose or thyme as various combined or single products reduced cough symptoms. However, as the clinical significance of this benefit is unclear and safety data was not available, the committee agreed that no recommendation on the use of these herbal products for the treatment of acute cough could be made. Several combined products containing ivy, primrose or thyme have been granted traditional herbal registrations with the MHRA to relieve coughs and catarrh associated with the common cold based on traditional use only.
Most studies in a systematic review of echinacea did not report a benefit on cough symptoms, and no safety data was available. Therefore, the committee agreed that no recommendation on the use of echinacea for the treatment of acute cough could be made. Numerous echinacea products have been granted traditional herbal registrations with the MHRA to relieve the symptoms of the common cold and influenza type infections based on traditional use only.
The committee agreed that there was some evidence that suggests pelargonium (Pelargonium sidoides, P. sidoides) reduced cough symptoms in people with acute bronchitis, with a liquid preparation being more beneficial than a tablet preparation. However, P. sidoides increased the number of people with adverse events (mainly gastrointestinal). The clinical significance of the benefit of P. sidoides on cough symptoms is unclear, and the committee noted that all the RCTs were conducted in Russia or Ukraine and were initiated and funded by a single manufacturing company. However, several P. sidoides products have been granted traditional herbal registrations with the MHRA to relieve symptoms of the common cold, sore throat, cough and blocked or runny nose.
The committee agreed that limited evidence suggests that pelargonium may have some benefit on cough symptoms and people over 12 years may wish to try it for the treatment of acute cough. Because of the limited evidence of benefit, and possible adverse effects, the committee agreed not to recommend pelargonium for children.
NSAIDs
Based on evidence, the committee agreed that NSAIDs did not benefit cough symptoms and no recommendation for their use to treat acute cough should be made. Paracetamol or ibuprofen are often used to manage any associated pain.
Cough expectorant medicines
The committee agreed that there was some evidence that suggests guaifenesin reduced cough symptoms in adults and young people with an acute cough or upper respiratory tract infection, with no increase in adverse effects. The clinical significance of any benefit is unclear, but the committee agreed that people over 12 years may wish to try cough medicines containing guaifenesin for the treatment of acute cough.
Over-the-counter cough medicines containing the expectorants guaifenesin and ipecacuanha are subject to MHRA advice. They should not be used in children under 6 years of age and are only available in pharmacies for use in children from 6 to 12 years where advice can be given.
Cough suppressant (antitussive) medicines
The committee agreed that the evidence for dextromethorphan was mixed. There was some evidence that suggests a single, high dose reduced cough symptoms in adults with an acute cough but other evidence that it had no effect, and it may increase adverse effects (mainly gastrointestinal and dizziness). The clinical significance of any benefit it may have is unclear.
Based on evidence, the committee agreed that codeine had no benefit on cough symptoms.
The systematic review of over-the-counter cough medicines did not include evidence specifically on pholcodine. However, the committee recognised that a RCT comparing pholcodine with dextromethorphan is available.
Taking all the evidence, and their experience, into account the committee agreed that some people over 12 years may wish to try cough medicines containing cough suppressants (apart from codeine) for the treatment of acute cough.
Over-the-counter cough medicines containing the cough suppressants dextromethorphan and pholcodine are subject to MHRA advice. They should not be used in children under 6 years of age (pholcodine) or 12 years of age (dextromethorphan) and pholcodine is only available in pharmacies for use in children from 6 to 12 years where advice can be given. Over-the-counter cough medicines containing codeine should not be used in children under 12 years and are not recommended for young people under 18 years with breathing problems (MHRA advice).
Antihistamines and decongestants
The committee agreed that, from the limited evidence found, antihistamines (loratadine, clemastine, diphenhydramine and promethazine) and decongestants (pseudoephedrine) had no benefit on cough symptoms, and increased adverse effects (including drowsiness and dry mouth).
Over-the-counter cough medicines containing the antihistamines diphenhydramine and promethazine are subject to MHRA advice on how to use cough and cold medicines safely for children under 12 years.
# Bronchodilators
## Beta-2 agonists
Beta-2 agonists (salbutamol syrup) did not significantly reduce the presence of cough at 7 days, or mean cough score at days 1 to 7, compared with placebo in children with acute cough or acute bronchitis (low to moderate quality evidence). There were no significant differences in adverse effects (shaking or tremor or other adverse effects) between groups (very low quality evidence).
Beta-2 agonists (salbutamol tablets, salbutamol inhaler or fenoterol inhaler ) did not significantly reduce the presence of cough at 7 days, productive cough after 7 days, night cough after 7 days, not working by day 7 or mean cough score at days 1 to 7, compared with placebo in adults with acute cough or acute bronchitis (very low to moderate quality evidence).
There was a significant increase in adverse effects (shaking, tremor or nervousness) in adults with acute cough or acute bronchitis treated with beta-2 agonists compared with placebo or other treatment (55.2% versus 11.3%, number needed to harm 2 ; very low quality evidence), but not in other adverse effects.
Beta-2 agonists (salbutamol syrup) were significantly better than erythromycin ethylsuccinate syrup for cough after 7 days (41.2% versus 88.2%; number needed to treat 3 ; low quality evidence), productive cough after 7 days (35.7% versus 76.5%; NNT 2 ; low quality evidence) but not night cough after 7 days (very low quality evidence) in adults with acute cough or acute bronchitis.
Based on Becker et al. (2015), a systematic review and meta-analysis of 7 RCTs in adults and children with an acute cough or acute bronchitis.
Committee discussion on bronchodilators
Based on evidence, the committee agreed that bronchodilators, such as oral or inhaled salbutamol, did not benefit cough symptoms and increased adverse events, such as tremor. The committee agreed that there may be instances when people with an acute cough and an underlying airways disease, such as asthma, require bronchodilators. Therefore, they agreed that bronchodilators should not be offered to people (adults or children) with an acute cough unless they had underlying airways disease, such as asthma.
The committee discussed the evidence for oral salbutamol plus dextromethorphan but no recommendation was made because no such product is available in the UK.
# Corticosteroids
## Inhaled corticosteroids
Inhaled corticosteroids (fluticasone proprionate) significantly reduced the mean cough score at the end of the second week of treatment compared with placebo in adults with acute or subacute cough following respiratory tract infection (mean difference −0.50, 95% CI −0.55 to −0.45; very low quality evidence) but not at 4 weeks.
Inhaled corticosteroids (fluticasone proprionate) significantly reduced the mean cough score by at least 50% reduction at the end the second week in non-smoking adults with acute or subacute respiratory tract infection compared with placebo (53.5% versus 80.5%; NNT 4 ; very low quality evidence). The mean difference in the average daily cough score in the second week in non-smoking adults was −0.9 (95% CI −1.3 to −0.4; very low quality evidence). There was no difference in smokers. One RCT found that additional treatment sought after 2 weeks of study treatment was significantly lower with fluticasone proprionate compared with placebo (43.1% versus 62.7%, NNT 6 ; very low quality evidence).
There were no significant differences found for mean symptom scores (cough, cough frequency, symptoms associated with cough, night-time cough or the frequency of taking cough medicines), and the outcomes of little or no improvement at 7 to 14 days, severe symptoms at 11 days, and adverse effects (hoarseness) during the treatment period (very low quality evidence).
Based on El-Gohary et al. (2013), a systematic review of 4 RCTs in adults with an acute or subacute respiratory tract infection.
Systemic effects (mineralocorticoid and glucocorticoid) may occur with inhaled corticosteroids, including a range of psychological or behavioural effects (particularly in children; Drug Safety Update, September 2010).
Committee discussion on corticosteroids
The committee agreed that the evidence for inhaled corticosteroids was mixed. There was some evidence that it reduced cough symptoms in adults with an acute or subacute cough (particularly in non-smokers) but other evidence that it had no effect. No evidence for oral corticosteroids was found.
Corticosteroids have well-recognised systemic (mineralocorticoid and glucocorticoid) effects, including a range of psychological or behavioural effects (particularly in children) and the committee agreed that, weighing up the potential risks and benefits, oral or inhaled corticosteroids should not be offered for people (adults or children) with an acute cough (including acute bronchitis).
The committee discussed the evidence that inhaled corticosteroids reduced additional treatments being sought, and they could reduce the prescribing of antibiotics for acute cough. However, any prescribed alternatives to antibiotics have workload implications as people are likely to re‑consult and expect similar treatments in the future, sending the wrong message that prescribed treatment is needed for a largely self‑limiting condition.
The committee agreed that there may be instances when people with an acute cough and an underlying airways disease, such as asthma, require corticosteroids. Therefore, they agreed that an oral or inhaled corticosteroid should not be offered to people (adults or children) with an acute cough unless they had an underlying airways disease, such as asthma.
# Mucolytics
Mucolytics (oral acetylcysteine and oral carbocisteine) were significantly better than placebo for reducing cough at 6 to 7 days in children with acute upper and lower respiratory tract infection (4.1% versus 13.8%; very low quality evidence), but not at the end of treatment (28 days; very low quality evidence).
There were no significant differences between mucolytics and placebo for the outcomes of productive cough and expectoration at end of treatment (at 7 days), pulmonary function at day 3, febrile state at 6 days, dyspnoea at 6 to 7 days, bad general condition after 6 to 7 days, and appetite trouble (not defined) at the end of treatment (5 to 9 days) in children with acute upper and lower respiratory tract infection (very low quality evidence). There was also no significant difference for the outcome of abnormal chest signs (for example wheezing or rattling) after 5 days, but there was a significant difference for this outcome at the end of treatment (28 days; 2% versus 16%; very low quality evidence).
Based on Chalumeau and Duijvestijn (2013), a systematic review and meta-analysis of 6 RCTs in children with acute upper and lower respiratory tract infections.
Committee discussion on mucolytics
The committee agreed that the evidence for mucolytics (acetylcysteine and carbocisteine) was mixed. There was some evidence that a mucolytic reduced cough symptoms in children with acute upper and lower respiratory tract infections but other evidence that it had no effect.
The clinical significance of any benefit of mucolytics is unclear, and the committee agreed that they should not be offered for people (adults or children) with an acute cough. Any prescribed alternatives to antibiotics have workload implications as people are likely to re‑consult and expect similar treatments in the future, sending the wrong message that prescribed treatment is needed for a largely self‑limiting condition.
# No antibiotic
Acute cough associated with an upper respiratory tract infection or acute bronchitis is usually a self-limiting infection caused by a viral infection. Most upper respiratory tract infections, such as a common cold or flu, are viral. Acute bronchitis has been estimated to be viral in 85% to 95% of cases, although this is difficult to estimate. (NICE clinical knowledge summary on chest infections – adult and Worrall, 2008).
## Efficacy of antibiotics
Antibiotics (doxycycline, co-trimoxazole, erythromycin, cefuroxime, azithromycin, amoxicillin and co-amoxiclav) were not significantly better than placebo (or no active treatment) for clinical improvement at follow-up in people with acute bronchitis (11 RCTs, n=3,841, 73.2% versus 66.5%; low quality evidence). Clinical improvement was measured by a global assessment of improvement by clinicians at follow‑up.
In subgroup analysis by antibiotic, there was no significant difference in clinical improvement between doxycycline and placebo (3 RCTs), erythromycin and placebo (2 RCTs) or amoxicillin and placebo (2 RCTs; low to moderate quality evidence). However, cefuroxime significantly increased clinical improvement at follow-up in adults with acute bronchitis compared with placebo (1 RCT, n=343, 92.4% versus 79.1%; low quality evidence).
Antibiotics (erythromycin, cefuroxime, doxycycline or co-amoxiclav) did not significantly reduce the number of adults and children with acute bronchitis without improvement at physician follow-up compared with placebo (very low quality evidence). When a subgroup of people with non-purulent tracheo-bronchitis from an upper respiratory tract infection study was omitted, antibiotics were significantly better than placebo (5 RCTs, n=816, 7.7% versus 17.6%; NNT 11 ; moderate quality evidence). However, only 1 RCT in this analysis of cefuroxime versus placebo (accounting for 35.5% of the weight in the meta‑analysis) showed a significant improvement compared with placebo.
Antibiotics (erythromycin, cefuroxime or doxycycline) were significantly better than placebo for improving abnormal lung examination at follow-up in adults with acute bronchitis (5 RCTs, n=613, 18.5% versus 34.8%, NNT 7 ; moderate quality evidence). However, only 1 RCT in this analysis of cefuroxime versus placebo (accounting for 77.8% of the weight) had a significant reduction for this outcome in the antibiotic group.
Antibiotics (erythromycin, doxycycline or amoxicillin) significantly reduced the mean number of days feeling ill compared with placebo or no active treatment in adults and children with acute bronchitis (5 RCTs, n=809; moderate quality evidence). However, the significant effect was not maintained when a study of antibiotics compared with no active treatment (no placebo) was omitted. A subgroup analysis of RCTs of doxycycline versus placebo showed a significant reduction in the mean number of days feeling ill by about half a day compared with placebo (3 RCTs, n=383; high quality evidence).
Antibiotics (erythromycin or doxycycline) significantly reduced cough at follow-up in adults with acute bronchitis compared with placebo (4 RCTs, n=275, 32.9% versus 50.8%, NNT 6 ; moderate quality evidence). This significant reduction was seen in a subgroup of RCTs of doxycycline compared with placebo (2 RCTs, n=210, 22.9% versus 42.6%, NNT 6 ; moderate quality evidence) but not erythromycin compared with placebo (low quality evidence).
Antibiotics (erythromycin, cefuroxime or doxycycline) significantly reduced night cough at follow-up in adults with acute bronchitis compared with placebo (4 RCTs, n=538, 29.5% versus 44.6%, NNT 7 ; low quality evidence). This significant reduction was seen in a subgroup analysis of cefuroxime compared with placebo (1 RCT, n=340, 36.8% versus 56.8%; low quality evidence) but not for erythromycin or doxycycline compared with placebo (low quality evidence). Antibiotics did not make any significant difference to the presence of productive cough at follow-up in adults and children with acute bronchitis (moderate quality evidence).
Antibiotics (erythromycin, amoxicillin or doxycycline) significantly reduced the mean number of days of cough in adults and children with acute bronchitis compared with placebo or no active treatment by about half a day (7 RCTs, n=2,776; moderate quality evidence). This significant reduction was also seen in studies that compared antibiotics with placebo only (6 RCTs, n=2,350; moderate quality evidence). No significant differences were found for individual antibiotics in subgroup analyses.
Antibiotics made no significant difference to the mean number of days of productive cough in adults and children with acute bronchitis compared with placebo or no active treatment. When a subgroup of people with non-purulent tracheo-bronchitis from an upper respiratory tract infection study was omitted, antibiotics did significantly reduce the mean number of days of productive cough by about half a day (5 RCTs, n=535; moderate quality evidence). The significant difference was maintained in a subgroup of studies comparing doxycycline with placebo (4 RCTs, n=444; moderate quality evidence) but not in 2 RCTs of amoxicillin or erythromycin compared with placebo or no treatment (moderate quality evidence).
Antibiotics (erythromycin or co-amoxiclav) significantly reduced the number of children with clinical failure (not cured or substantially improved) at follow-up in children with prolonged moist cough compared with placebo or no treatment (2 RCTs, n=140, 34.3% versus 72.6%, NNT 3 ; moderate quality evidence). However, this became non-significant when children with Bordetellapertussis were excluded and in an intention-to-treat analysis using those not lost to follow-up (very low quality evidence). Antibiotics significantly reduced the need for additional treatment due to illness compared with placebo or no treatment (2 RCTs, n=125, 5.1% versus 36.4%, NNT 4 ; moderate quality evidence).
Antibiotics (co-amoxiclav) had no significant effect on the development of acute otitis media in children with undifferentiated acute respiratory tract infection compared with placebo or no treatment (3 RCTs; very low quality evidence), or in a subgroup of children from high-income countries (2 RCTs; very low quality evidence). Antibiotics (ampicillin) had no significant effect on the development of pneumonia in children aged under 11 months or those aged 12 to 58 months with undifferentiated acute respiratory infection compared with placebo or no treatment (1 RCT; very low quality evidence).
In 1 RCT in adults with an acute cough, for the outcome of resolution of symptoms rated moderately bad or worse, no pre-specified subgroup (green sputum, current smokers, significant past medical history, people with symptoms for longer than 7 days at baseline, fever at baseline or minor chest signs) was significantly more likely to benefit from antibiotics (amoxicillin). People with significant past medical history compared with those without significant past medical history (n=438, MD −0.28, 95% CI −0.46 to −0.09; very low quality evidence) had a significantly lower mean symptom severity score on days 2 to 4 after consultation. People with symptoms for less than 7 days at baseline compared with those who had symptoms for more than 7 days at baseline had a significantly lower mean symptom severity score on days 2 to 4 after consultation (n=711, MD −0.16, 95% CI −0.27 to −0.06; very low quality evidence). Non-current smokers compared with current smokers had a significantly lower mean symptom severity score on days 2 to 4 after consultation (n=483, MD −0.12, 95% CI −0.22 to −0.03; very low quality evidence). No subgroups were identified that were significantly more likely to develop new or worsening symptoms.
## Safety of antibiotics
Antibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta-lactam antibiotics (BNF, December 2018).
Macrolides should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF, December 2018).
Tetracyclines, including doxycycline, can deposit in growing bone and teeth causing staining and occasionally dental hypoplasia. Their use is cautioned in children under 12 years, for use only in acute, severe or life-threatening infections when there are no adequate alternatives, and they should not be given to pregnant or breast-feeding women. Common side effects include nausea, vomiting, diarrhoea, dysphagia, and oesophageal irritation (BNF, December 2018).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Antibiotics significantly increased the overall number of adverse effects compared with placebo or no active treatment in people with acute bronchitis (12 RCTs, n=3,496, 22.6% versus 18.7%, NNH 25 ; low quality evidence). The most commonly reported adverse effects included gastrointestinal symptoms such as nausea, vomiting, or diarrhoea. There were no significant differences in adverse effects for subgroups of different antibiotics (erythromycin, amoxicillin or co-amoxiclav, or doxycycline) versus placebo or no active treatment (very low to low quality evidence).
There were no significant differences between antibiotics and placebo or no treatment for adverse effects (vomiting, rash or diarrhoea) in children with moist cough for longer than 10 days duration.
Based on 3 systematic reviews and meta-analyses, Smith et al. (2017) which included adults and children with acute bronchitis from 17 RCTs, Marchant et al. (2005) which included children with a moist cough lasting longer than 10 days from 2 RCTs and Alves et al. (2016) which included children with undifferentiated acute respiratory infection from 4 RCTs; and 1 RCT in adults with an acute cough (Moore et al. 2014).
# Back-up antibiotics
Two RCTs included in a systematic review of adults and children with acute cough did not report data for back-up versus immediate antibiotics. However, the systematic review states that there was no difference in reported clinical outcomes.
One RCT included in a systematic review compared a back-up antibiotic prescription (either at the time of visit or requiring collection) with immediate antibiotics and a no antibiotic prescribing strategy in adults with acute cough. A back-up antibiotic prescription was not significantly different to an immediate antibiotic or no antibiotic for the outcomes of cough duration, pain duration or fever duration (low quality evidence).
Based on Spurling et al. (2017), a systematic review and meta-analysis of 11 RCTs of back-up antibiotic prescriptions for respiratory infections (including acute otitis media, pharyngitis, sore throat, common cold and other respiratory tract infections) in adults and children, 3 RCTs were in an acute cough population.
Committee discussion on no antibiotics, back-up antibiotics and immediate antibiotics
The committee discussed that acute cough, either associated with an upper respiratory tract infection or acute bronchitis, is usually a self-limiting infection. It is often a viral infection, and antibiotics are not usually needed.
Acute cough associated with an upper respiratory tract infection
No evidence was found for antibiotics to treat an acute cough specifically associated with an upper respiratory tract infection, which is usually a viral infection. Based on the lack of evidence and experience, the committee agreed that antibiotics should not be offered to people (adults or children) with an acute cough associated with an upper respiratory tract infection. People should be given advice that an acute cough can last up to 3 or 4 weeks and does not need an antibiotic. They should also be given safety netting advice to seek medical help if symptoms worsen rapidly or significantly, do not improve after 3 or 4 weeks, or they become systemically very unwell.
Acute cough associated with acute bronchitis
Based on evidence and experience, the committee agreed that antibiotics should not routinely be offered to people (adults or children) with an acute cough associated with acute bronchitis. Antibiotics had a beneficial effect on some outcomes, but not others, and any benefit from antibiotics needs to be weighed up against their potential to cause adverse effects. Even where statistically significant effects were seen, these were often difficult to interpret and may not be clinically meaningful for many people.
Antibiotics did not improve the overall clinical condition of people with acute bronchitis, or the number of people with improvement at physician follow-up. Antibiotics did improve abnormal lung examination at follow‑up, but the committee agreed this was not an important patient-orientated outcome for people with acute bronchitis, and this outcome was heavily influenced by 1 study of cefuroxime.
Antibiotics reduced the number of people who had 'any cough' or 'night cough' at follow-up, with a number needed to treat of 6 or 7. However, the timing of follow-up is unclear, varying between studies from 2 to 18 days after treatment started.
Antibiotics made little difference to how long the symptoms of acute bronchitis lasted. They reduced the mean number of days of cough by about 0.5 days (range 0 to 1 day), which the committee agreed may not be clinically meaningful for many people when an acute cough lasts up to 3 or 4 weeks.
Antibiotics have possible adverse effects, particularly diarrhoea and nausea. In people with acute bronchitis, antibiotics increased adverse effects, with a NNH of 25.
Based on experience, the committee discussed that withholding antibiotics in acute cough is unlikely to lead to complications in people who are not systemically very unwell or at higher risk of complications. However, they acknowledged the limited evidence base, which was solely for no increased risk of acute otitis media or pneumonia in children with acute undifferentiated respiratory tract infection.
The committee recognised the usefulness of back-up antibiotic prescriptions in managing self-limiting illnesses. However, from the evidence, back-up antibiotics were not significantly different to immediate antibiotics or no antibiotics for how long a cough lasts.
Based on evidence, experience and the principles of antimicrobial stewardship, the committee recommended a no antibiotic prescribing strategy (routinely) for people with acute cough associated with acute bronchitis. They recognised that antibiotics may be an option for some people on an individual patient basis, but this should not be routine practice. For most people with an acute cough (which is a condition that can persist for some weeks) they felt a back-up antibiotic prescribing strategy sent the wrong message that antibiotics may be needed at some point.
Acute cough in people who are systemically very unwell or at higher risk of complications
Based on evidence and experience, the committee agreed that an immediate antibiotic prescription should be offered to people (adults or children) with an acute cough (associated with an upper respiratory tract infection or acute bronchitis) who are identified as systemically very unwell (ideally at a face-to-face clinical examination), because these people require prompt treatment with an antibiotic.
Based on evidence and experience, the committee agreed that an immediate antibiotic prescription or a back-up antibiotic prescription could be considered for people with an acute cough (associated with an upper respiratory tract infection or acute bronchitis) who are identified as at higher risk of complications (ideally at a face-to-face clinical examination).
The committee recognised that the previous NICE guideline on upper respiratory tract infections noted that people with acute cough are likely to be at higher risk of developing complications because of pre-existing comorbidity (significant heart, lung, renal, liver or neuromuscular disease, immunosuppression, cystic fibrosis, and young children who were born prematurely) or because of older age and the presence of certain criteria (type 1 or type 2 diabetes, congestive heart failure, use of oral corticosteroids, hospitalisation in previous year). The committee agreed that for some of these people an immediate antibiotic may not be clinically required, and a back-up antibiotic could be considered.
The committee recommended that ideally antibiotics should only be considered after people have been assessed face-to-face but this may not always be possible.
The committee agreed that a back-up antibiotic prescription could be used if symptoms worsen rapidly or significantly at any time. Giving safety netting advice is also important to ensure people seek medical help if symptoms worsen rapidly or significantly despite taking the antibiotic, or they become systemically very unwell.
Based on experience, the committee agreed that people with acute cough who present with any symptoms or signs suggesting a more serious illness or condition (for example, sepsis, a pulmonary embolism or lung cancer) should be referred to hospital, or specialist advice should be sought on further investigation and management.
Antibiotics for moist cough of greater than 10 days duration in children
The committee discussed the evidence for antibiotics reducing clinical failure in children with a prolonged moist cough. However, they noted the limitations with this evidence base and did not make a recommendation specifically for this population. Many children had a cough for over 3 weeks at baseline, and therefore did not have an acute cough. Also, there was no benefit of antibiotics when children with Bordetella pertussis were excluded (9% of all children), and in an intention-to-treat analysis using those not lost to follow-up.
# Choice of antibiotic
No systematic reviews and RCTs met the inclusion criteria for this section.
Committee discussion on choice of antibiotic
There was no evidence directly comparing different antibiotics. However, subgroup analysis from a systematic review in people with acute bronchitis did find some differences between antibiotics compared with placebo.
Individually, doxycycline compared with placebo showed a significant reduction in the following outcomes: mean number of days feeling ill, cough at follow-up and mean number of days of productive cough, where other antibiotics (amoxicillin and erythromycin) did not.
Individually, cefuroxime also showed benefit over placebo for the following outcomes: clinical improvement at follow-up, improvement at physician follow-up and night cough at follow-up, where other antibiotics did not. This was based on a trial of over 300 people, which contributed much of the weight in meta-analyses. The committee discussed this finding and had some concerns that the study design of the cefuroxime study in particular influenced this result.
Cefuroxime is a broad-spectrum antibiotic (a second generation cephalosporin). The committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile.
Based on evidence, their experience and resistance data, the committee agreed to recommend doxycycline at usual dose, as the first-choice antibiotic for adults with acute cough (including acute bronchitis), where an antibiotic is appropriate. This is a tetracycline, which is only suitable for non-pregnant adults and, for acute cough, in young people over 12 years. Doxycycline was preferred over amoxicillin because there was limited evidence from subgroup analyses that showed benefits on some outcomes where amoxicillin did not. But more importantly, they agreed that amoxicillin should be reserved, when possible, for use in more serious infections where bacterial infection is more common, for example pneumonia. This is because of concerns that amoxicillin drives resistance not just in pneumococci but also in gram-negative organisms. The committee was aware of evidence that the risk of resistance to amoxicillin is significantly increased in urinary isolates of Escherichia coli following a course of amoxicillin. These effects are greatest in the first month after use, but are detectable for up to 12 months. There is a concern that using amoxicillin in conditions such as acute cough, where the benefits of antibiotics are marginal, drives resistance without adding benefit.
Alternative first-choice antibiotics (at usual doses) for adults unable to take doxycycline, which have good activity against common causal bacteria, are:
amoxicillin (a penicillin)
clarithromycin or erythromycin, which are macrolides.
The committee agreed that because the evidence of benefit of doxycycline over amoxicillin, clarithromycin or erythromycin is limited, these antibiotics should be offered as alternative first choices. This also reflects concerns that doxycycline is contraindicated in pregnancy, and this should be considered when choosing antibiotics for women of childbearing age.
The committee also discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
For children and young people, amoxicillin is recommended as the first-choice antibiotic, with clarithromycin, erythromycin or doxycycline (in young people aged 12 to 17 years only) as alternative choices.
# Antibiotic course length
No systematic reviews and RCTs met the inclusion criteria for this section.
Committee discussion on antibiotic course length
There was no evidence directly comparing different antibiotic course lengths. From a systematic review in people with acute bronchitis, antibiotic course length varied from 5 to 10 days typically depending on the antibiotics used.
The committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed.
Based on evidence, their experience and resistance data, the committee agreed that a 5-day course for all the recommended antibiotics was sufficient to treat acute cough, where an antibiotic was appropriate. This takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance. Studies in the evidence review for specific antibiotics in acute bronchitis sometimes had course lengths of more than 5 days.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people taking medicines that need frequent dosing or longer treatment duration (for example, antibiotics). See the NICE guideline on medicines adherence.
# Resource implications
Respiratory tract infections, including acute cough, are a common reason for consultations in primary care and for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for 'cough and bronchitis' accounted for 39% of all consultations for respiratory tract infections, and the median practice issued an antibiotic prescription in 48% of these.
There is potential for resource savings if a no antibiotic or a back-up antibiotic prescription strategy is used. One systematic review (Spurling et al. 2017) found significantly lower antibiotic use with a back-up antibiotic prescribing strategy compared with immediate antibiotics, both when the back-up antibiotic prescription was given at the time of consultation (38.4% versus 86.8%; very low quality evidence) and when the prescription had to be collected on a separate visit (27.3% versus 95.3%; very low quality evidence).
Recommended antibiotics are all available as generic formulations, see Drug Tariff for costs.
|
{'Recommendations': "# Managing acute cough\n\nFor guidance on managing acute cough in people with suspected or confirmed COVID-19, follow our rapid guideline on managing COVID-19.\n\nBe aware that an acute cough:\n\nis usually self-limiting and gets better within 3\xa0to 4\xa0weeks without antibiotics\n\nis most commonly caused by a viral upper respiratory tract infection, such as a cold or flu\n\ncan also be caused by acute bronchitis, a lower respiratory tract infection, which is usually a viral infection but can be bacterial\n\ncan also have other infective or non-infective causes.\n\nFor children under\xa05 with an acute cough and fever, follow the NICE guideline on fever in under\xa05s: assessment and initial management.\n\nFor adults, children and young people with an acute cough and suspected pneumonia, follow:\n\nour COVID-19 rapid guideline on managing COVID-19 for guidance on pneumonia secondary to COVID-19\n\nthe NICE guidelines on pneumonia (community-acquired): antimicrobial prescribing and pneumonia (hospital-acquired): antimicrobial prescribing for guidance on pneumonia not secondary to COVID-19. [amended 2021]\n\n## Referral and seeking specialist advice\n\nRefer people with an acute cough to hospital, or seek specialist advice on further investigation and management, if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis, a pulmonary embolism or lung cancer).\n\n## Treatment\n\nGive general advice to people about:\n\nthe usual course of acute cough (lasts up to 3\xa0or 4\xa0weeks)\n\nhow to manage their symptoms with self-care (see the recommendations on self-care)\n\nwhen to seek medical help, for example if symptoms worsen rapidly or significantly, do not improve after 3\xa0to 4\xa0weeks, or the person becomes systemically very unwell.\n\nDo not offer the following treatments to people for an acute cough associated with an upper respiratory tract infection or acute bronchitis unless the person has an underlying airways disease, such as asthma:\n\nan oral or inhaled bronchodilator (for example, salbutamol) or\n\nan oral or inhaled corticosteroid.\n\nDo not offer a mucolytic (for example acetylcysteine or carbocisteine) to treat an acute cough associated with an upper respiratory tract infection or acute bronchitis.\n\nDo not offer an antibiotic to treat an acute cough associated with an upper respiratory tract infection in people who are not systemically very unwell or at higher risk of complications (see recommendation 1.1.15). Give advice about why an antibiotic is not needed.\n\nDo not routinely offer an antibiotic to treat an acute cough associated with acute bronchitis in people who are not systemically very unwell or at higher risk of complications (see recommendation 1.1.15).\n\nBe aware that:\n\nantibiotics do not improve the overall clinical condition of people with acute bronchitis\n\nantibiotics make little difference to how long symptoms of acute bronchitis last (on average they shorten cough duration by about half a day)\n\nantibiotics have possible adverse effects, particularly diarrhoea and nausea.\n\nThis recommendation has been removed.\n\nWhen no antibiotic prescription is given, give advice about why an antibiotic is not needed.\n\nIf an antibiotic prescription is given, give advice about possible adverse effects of the antibiotic, particularly diarrhoea and nausea.\n\nFor people with an acute cough who are identified as systemically very unwell (ideally at a face‑to‑face clinical examination), offer an immediate antibiotic prescription (for choice of antibiotic, see recommendation 1.3.1).\n\nBe aware that people with an acute cough may be at higher risk of complications if they:\n\nhave a pre-existing comorbidity, such as significant heart, lung, renal, liver or neuromuscular disease, immunosuppression or cystic fibrosis\n\nare young children who were born prematurely\n\nare older than 65\xa0years with 2\xa0or more of the following criteria, or older than 80\xa0years with 1\xa0or more of the following criteria:\n\n\n\nhospitalisation in previous year\n\ntype\xa01 or type\xa02 diabetes\n\nhistory of congestive heart failure\n\ncurrent use of oral corticosteroids.\n\n\n\nFor people with an acute cough who are identified as at higher risk of complications (ideally at a face‑to‑face clinical examination), consider:\n\nan immediate antibiotic prescription (for choice of antibiotic, see recommendation 1.3.1) or\n\na back-up antibiotic prescription.\n\nWhen an immediate antibiotic prescription is given, give advice about possible adverse effects of the antibiotic, particularly diarrhoea and nausea.\n\nWhen a back-up antibiotic prescription is given, give advice about:\n\nan antibiotic not being needed immediately\n\nusing the back-up prescription if symptoms worsen rapidly or significantly at any time.\n\n## Reassessment\n\nReassess people with an acute cough if their symptoms worsen rapidly or significantly, taking account of:\n\nalternative diagnoses, such as pneumonia\n\nany symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nSee the evidence and committee discussion on bronchodilators, corticosteroids, mucolytics, no antibiotic, back-up antibiotics and choice of antibiotic.\n\n# Self-care\n\nBe aware that some people may wish to try the following self-care treatments, which have limited evidence of some benefit for the relief of cough symptoms:\n\nhoney (in people aged over 1\xa0year)\n\npelargonium (a herbal medicine; in people aged\xa012 and over)\n\nover-the-counter cough medicines containing the expectorant guaifenesin (in people aged\xa012 and over)\n\nover-the-counter cough medicines containing cough suppressants, except codeine, (in people aged\xa012 and over who do not have a persistent cough, such as in asthma, or excessive secretions).\n\nBe aware that limited evidence suggests that antihistamines, decongestants and codeine-containing cough medicines do not help cough symptoms.\n\nSee the evidence and committee discussion on self-care.\n\n# Choice of antibiotic\n\nWhen prescribing antibiotics for an acute cough follow:\n\ntable\xa01 for adults aged 18\xa0years and over\n\ntable\xa02 for children and young people under 18\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst choice\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course in total)\n\nAlternative first choices\n\nAmoxicillin:\n\nmg three times a day for 5\xa0days\n\n\n\nClarithromycin:\n\nmg to 500\xa0mg twice a day for 5\xa0days\n\n\n\nErythromycin:\n\nmg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0days\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breast-feeding.\n\nThe possibility of pregnancy should be considered in women of childbearing age. Doxycycline should not be used in pregnancy. Amoxicillin is the preferred antibiotic in pregnancy. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst choice\n\nAmoxicillin:\n\nmonth to 11\xa0months, 125\xa0mg three times a day for 5\xa0days\n\nyear to 4\xa0years, 250\xa0mg three times a day for 5\xa0days\n\nyears to 17\xa0years, 500\xa0mg three times a day for 5\xa0days\n\nAlternative first choices\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day for 5\xa0days\n\n\n\nErythromycin:\n\nmonth to 1\xa0year, 125\xa0mg four times a day or 250\xa0mg twice a day for 5\xa0days\n\nyears to 7\xa0years, 250\xa0mg four times a day or 500\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0days\n\n\n\nDoxycycline:\n\nyears to 17\xa0years, 200\xa0mg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course in total)\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.\n\nThe possibility of pregnancy should be considered in women of childbearing age. Doxycycline should not be used in pregnancy. Amoxicillin is the preferred antibiotic in pregnancy. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSee the committee discussion on choice of antibiotic and antibiotic course length.", 'Terms used in the guideline': '# Acute cough\n\nAcute cough is commonly defined as a cough that lasts less than 21\xa0days (3\xa0weeks). The average duration is 18\xa0days, although it can sometimes last for up to 29\xa0days (over 4\xa0weeks). It is most commonly caused by an upper respiratory tract infection, such as a cold or flu, which are viral infections. It can also be caused by acute bronchitis, a lower respiratory tract infection, which is usually a viral infection but can be bacterial.\n\nOther infective causes of cough include COVID-19, pneumonia, acute exacerbations of asthma, chronic obstructive pulmonary disease or bronchiectasis (which may also be non-infective exacerbations), and viral-induced wheeze, bronchiolitis, croup or whooping cough. Non-infective causes may include lung cancer, a foreign body, interstitial lung disease, pneumothorax, pulmonary embolism, heart failure, use of certain medicines (for example, an angiotensin-converting enzyme inhibitor), upper airway cough syndrome (post-nasal drip), or gastro-oesophageal reflux disease. (NICE clinical knowledge summaries on cough, chest infections – adult, cough – acute with chest signs in children and Ebell et al. 2013).\n\n# Acute bronchitis\n\nAcute bronchitis is a lower respiratory tract infection with temporary inflammation of the airways (the trachea and major bronchi) that causes cough and mucus production lasting for up to 3\xa0weeks. It is usually caused by a viral infection, but may be caused by a bacterial infection. (NICE clinical knowledge summary on chest infections – adult).\n\n# Self-care treatments\n\nSelf-care treatments available for acute cough include honey, herbal medicines and over-the-counter cough medicines (for example, expectorants and cough suppressants [also called antitussives]).', 'Summary of the evidence': "# Self-care\n\n## Honey\n\nHoney significantly reduced the frequency and severity of cough at 1\xa0day follow-up compared with placebo, no treatment or an antihistamine (diphenhydramine) by about 0.5 to 2\xa0points on a carer‑reported 7-point Likert scale in children and young people with an acute cough caused by an upper respiratory tract infection (low to moderate quality evidence). Carer responses about cough symptoms ranged from 'extremely' (6 points) to 'not at all' (0 points), but it was not clear how these responses were defined.\n\nHowever, honey did not reduce the frequency and severity of cough at 1\xa0day follow-up compared with an antitussive (dextromethorphan; very low quality evidence).\n\nHoney significantly reduced bothersome cough by about 2\xa0points on a 7‑point Likert scale compared with placebo (moderate quality evidence), but not compared with no treatment or dextromethorphan (low quality evidence).\n\nHoney had no significant effect on children's or parents' sleep quality compared with placebo or dextromethorphan, but was significantly better compared with no treatment or diphenhydramine (by about 0.5 to 1\xa0point on a 7-point Likert scale; low to moderate quality evidence).\n\nThere was no data on the effect of honey on cough duration because follow-up was for 1\xa0day only.\n\nThere was no significant difference in gastrointestinal side effects with honey compared with placebo or dextromethorphan (very low to low quality evidence). There were also no significant differences in mild adverse effects (for example, nervousness, insomnia, hyperactivity and drowsiness) compared with dextromethorphan (very low quality evidence). No significant difference in sleepiness was found when honey was compared with diphenhydramine (very low quality evidence).\n\nBased on Oduwole et al. (2014), a systematic review and meta-analysis including 3 randomised controlled trials (RCTs) in 568\xa0children and young people (aged 1 to 17\xa0years) with acute cough caused by an upper respiratory tract infection.\n\nHoney should not be given to children until they are aged over 1\xa0year because of concerns about infant botulism. It is also a sugar, and there are concerns about tooth decay. (NHS – foods to avoid giving babies and young children)\n\n## Herbal medicines\n\nA. paniculata (as liquid or tablets) significantly reduced the frequency and severity of cough compared with placebo in people with acute cough as a symptom of upper respiratory tract infection or common cold (frequency: standardised mean difference [SMD] −1.00, 95% confidence interval [CI] −1.85 to −0.15; very low quality evidence; severity: SMD −0.57, 95% CI −1.01 to −0.14; very low quality evidence).\n\nNo safety data for A. paniculata were reported.\n\nBased on Wagner et al. (2015), a systematic review and meta-analysis of 6\xa0RCTs with dosages of 31.5\xa0mg to 200\xa0mg for 3 to 10\xa0days.\n\nIvy, primrose or thyme as various combined or single preparations (as liquid or tablets) significantly reduced 'cough' (not defined and follow-up time was not reported) compared with placebo in people with an acute cough as a symptom of upper respiratory tract infection or common cold (77.4% versus 54.9%; very low quality evidence).\n\nNo safety data for ivy, primrose or thyme were reported.\n\nBased on Wagner et al. (2015), a systematic review and meta-analysis of 4\xa0RCTs.\n\nEchinacea significantly improved 'cough' (not defined) compared with placebo in people with an acute cough as a symptom of an upper respiratory tract infection or common cold (SMD −0.68, 95% CI −1.32 to −0.04; low quality evidence).\n\nHowever, this was a meta-analysis of just 2\xa0studies, and the authors reported that most studies in the systematic review did not report any significant reduction in patients' cough symptoms. It is not clear if this was due to the absence of data for this outcome, or the lack of effectiveness for echinacea.\n\nNo safety data for echinacea were reported.\n\nBased on Wagner et al. (2015), a systematic review and meta-analysis including 8\xa0RCTs with dosages of 0.3\xa0g to 6\xa0g daily for 1 to 12\xa0weeks.\n\nPelargonium sidoides (P. sidoides, as a liquid) significantly reduced 'failure to resolve all symptoms' by day 7 (61.0% versus 95.3%; very low quality evidence), 'failure to resolve cough' by day 7 (very low quality evidence) and 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in adults with acute bronchitis.\n\nP. sidoides tablets (any dosage) significantly reduced 'failure to resolve all symptoms' by day 7 (92.7% versus 99.0%; low quality evidence) and 'failure to resolve cough' by day 7 (low quality evidence) compared with placebo in adults with acute bronchitis, although, individually, only the 30‑mg dose achieved a significant reduction for 'failure to resolve cough' (low quality evidence).\n\nP. sidoides (as a liquid) significantly reduced 'failure to resolve all symptoms' by day 7 (79.9% versus 97.1%; low quality evidence), 'failure to resolve cough' by day 7 (low quality evidence) and 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in children or young people with acute bronchitis.\n\nP. sidoides tablets (any dosage) did not significantly reduce 'failure to resolve all symptoms' by day 7 (low quality evidence) or 'failure to resolve sputum' by day 7 (very low quality evidence) compared with placebo in children or young people with acute bronchitis. Only P. sidoides tablets of 20\xa0mg significantly reduced 'failure to resolve cough symptoms' by day 7 (low quality evidence) compared with placebo.\n\nP. sidoides (as a liquid or tablet) significantly increased the number of people (adults, young people and children) with adverse events (19.5% versus 15.1%; very low quality evidence) compared with placebo, which were mainly gastrointestinal. However, there was no significant difference in the number of people with adverse events which led to withdrawal (0.5% versus 1.0%; very low quality evidence).\n\nBased on 2\xa0systematic reviews and meta-analyses, Wagner et al. (2015) and Timmer et al. (2013), in adults, young people or children with an acute cough or acute bronchitis.\n\nNSAIDs (naproxen or ibuprofen) were not significantly different to placebo for a cumulative cough score at follow-up in adults with a common cold (very low quality evidence). NSAIDs significantly reduced associated individual symptoms scores for headache (very low quality evidence), joint and muscle pain (low quality evidence), earache (very low quality evidence) and sneezing (low quality evidence).\n\nNSAIDs were not significantly different to placebo for overall symptom score, severity of illness, duration of illness, throat irritation or hoarseness, malaise or fatigue, chilliness, nasal irritation, pain on swallowing, eye itching, rhinorrhoea, nasal obstruction or dryness, number of nose blows, total weight of mucous, tissue count, sense of smell or adverse effects in adults with a common cold (very low to low quality evidence).\n\nBased on Kim et al. (2015), a systematic review and meta-analysis of 9\xa0RCTs of NSAIDs in adults with a common cold.\n\nNSAIDs are associated with cardiovascular and gastrointestinal risks (Drug Safety Update, October 2012 and Drug Safety Update, December 2007).\n\n## Over-the-counter expectorants\n\nGuaifenesin significantly reduced patient reported cough frequency and intensity compared with placebo in 1\xa0RCT in adults and young people over 12\xa0years with an acute cough or upper respiratory tract infection (75% said guaifenesin was helpful compared with 31% in the placebo group, p<0.01; low quality evidence). There was no significant difference in cough frequency or severity in another RCT, but guaifenesin significantly reduced sputum thickness compared with placebo (p=0.001; low quality evidence). Extended-release guaifenesin reduced symptom severity scores at 4\xa0days (p=0.04) but not at 7\xa0days compared with placebo in 1\xa0RCT (low quality evidence).\n\nIn 2\xa0RCTs reporting adverse events, there was no difference between guaifenesin and placebo (no p\xa0values reported; very low quality evidence).\n\nBased on Smith et al. (2014), a systematic review including 3\xa0RCTs of adults and young people over 12\xa0years with an acute cough or upper respiratory tract infection.\n\nOver-the-counter cough medicines containing the expectorant guaifenesin are subject to MHRA advice on how to use cough and cold medicines safely for children under 12\xa0years (Drug Safety Update, April 2009).\n\n## Over-the-counter cough suppressants (antitussives)\n\nCodeine was no more effective than placebo, either as a single dose of 30\xa0mg or in a total daily dose of 120\xa0mg (30\xa0mg four times a day), in reducing cough symptoms in adults with acute cough (low quality evidence). A single dose of codeine (50\xa0mg) was no more effective than placebo in reducing cough symptoms at 90\xa0minutes in adults with acute cough (low quality evidence).\n\nCodeine as a single dose at bedtime (10\xa0mg in 5\xa0ml plus guaifenesin) for 3\xa0nights was no more effective than placebo in reducing cough score on day 3 in children with acute cough (p=0.70, low quality evidence).\n\nNo safety data for codeine were reported for adults. In children, adverse effects (mainly drowsiness, diarrhoea and hyperactivity) were not significantly different between codeine and placebo (very low quality evidence).\n\nDextromethorphan (as a single 30‑mg dose) was no more effective than placebo for reduction in cough frequency or reduction in cough severity in 1\xa0RCT of adults with acute cough (very low quality evidence). However, in another RCT, a single 30‑mg dose of dextromethorphan significantly reduced cough counts (not further defined) in adults (mean changes of cough counts between dextromethorphan and placebo varied from 19% to 36%, p<0.05; very low quality evidence). A third RCT found that a single 30‑mg dose of dextromethorphan significantly reduced cough bouts (average treatment difference 12% to 17%, p=0.004), cough components (p=0.003), cough effort (p=0.001) and cough latency (p=0.002) compared with placebo in adults with acute cough (very low quality evidence).\n\nOral dextromethorphan with salbutamol was no more effective than placebo or dextromethorphan alone in reducing cough frequency (very low quality evidence) or daytime cough severity (low quality evidence) in 1\xa0RCT of adults with acute cough. Dextromethorphan with salbutamol was superior to placebo or dextromethorphan alone in relieving cough at night (mean symptom score 0.19 versus 0.67 and 0.44, respectively on day 4, p<0.01; low quality evidence). However, more tremors were reported in the dextromethorphan with salbutamol group than in the placebo group (no figures given, p<0.05; low quality evidence).\n\nDextromethorphan was no more effective than placebo (in 4\xa0RCTs) or diphenhydramine (in 1\xa0RCT) in reducing various cough outcomes in children with an acute cough, a night cough or an upper respiratory tract infection (very low quality evidence). In 2\xa0RCTs, there were no differences between the groups in adverse effects, which were generally mild. In another RCT, adverse events (mainly gastrointestinal and dizziness) were reported in 34% of the dextromethorphan group and 5% of the placebo group (p\xa0value not reported).\n\nBased on Smith et al. (2014), a systematic review including 11\xa0RCTs of adults, young people and children with an acute cough, with or without a related upper respiratory tract infection.\n\nOver-the-counter cough medicines containing the cough suppressant dextromethorphan are subject to MHRA advice on how to use cough and cold medicines safely for children under 12\xa0years (Drug Safety Update, April 2009). Cough medicines containing codeine have restricted use in children (Drug Safety Update, April 2015).\n\n## Over-the-counter antihistamines and decongestants\n\nLoratadine in combination with pseudoephedrine for 4\xa0days was no more effective than placebo in reducing a composite cough symptom score in 1\xa0RCT of adults with a common cold (very low quality evidence). Adverse effects (including dry mouth, headache and insomnia) were not significantly different between groups (reported in 30% of the loratadine with pseudoephedrine group compared with 21% of the placebo group; very low quality evidence).\n\nClemastine for 3\xa0days was no more effective than placebo or chlorpheniramine in reducing cough scores in 1\xa0RCT of children under 5\xa0years with a common cold (very low quality evidence). Drowsiness and sleepiness was reported in 20% of children, with no difference between groups (p\xa0values not reported).\n\nDiphenhydramine (as a single dose at night) was no more effective than placebo in reducing composite symptom scores, cough frequency or sleep disturbance in children and their parents in 1\xa0RCT of children and young people aged 2 to 18\xa0years with acute cough due to an upper respiratory tract infection (low quality evidence). No safety data were reported.\n\nPromethazine for 3\xa0days was no more effective than placebo in reducing a composite cough symptom scores in 1\xa0RCT of children and young people aged 1 to 22\xa0years with acute cough due to an upper respiratory tract infection (low quality evidence). Adverse events were reported in 32% of the promethazine group and 5% of the placebo group (p\xa0value not reported; low quality evidence).\n\nBased on 4\xa0RCTs from 1 systematic review (Smith et al. 2014) in adults, young people and children with cough related to a common cold or upper respiratory tract infection.\n\nOver-the-counter cough medicines containing the antihistamines diphenhydramine and promethazine are subject to MHRA advice on how to use cough and cold medicines safely for children under 12\xa0years (Drug Safety Update, April 2009).\n\nCommittee discussion on self-care\n\nOverall, the committee recognised that the quality of the evidence on self‑care treatments for cough was limited. In many studies it was not clear what outcomes were being measured, or these measures were subjective. The sweet, glycerine-like consistency of many cough remedies, rather than the 'active ingredients' themselves may also have an effect, and the placebo effect of taking something rather than nothing to ease symptoms could be marked. However, promoting the role of self-care may help to reduce the amount of antibiotic prescriptions, and repeated or future consultations in general practice.\n\nHoney\n\nThe committee agreed that there was some evidence that suggests honey reduced cough symptoms in children and young people with an acute cough caused by an upper respiratory tract infection. The clinical significance of the benefit of honey on cough symptoms is unclear, particularly because follow-up was for 1\xa0day only.\n\nHoney was well tolerated in the studies, and is readily available. However, it should not be given to children under 1\xa0year of age because of concerns about infant botulism. It also contains sugars, and the committee discussed concerns about tooth decay.\n\nIn the studies, honey was given as a single 10‑g dose in 1\xa0trial, and 2\xa0trials reported that honey was given before bedtime. A range of types of honey were used, with no studies using the same variety.\n\nBased on evidence, the committee agreed that that limited evidence suggests that honey may have some benefit on cough symptoms and people over 1\xa0year of age may wish to try this for the treatment of acute cough.\n\nHerbal medicines\n\nThe committee found that the evidence for many of the herbal medicines was limited by poorly defined populations, outcomes, length of follow-up and a lack of safety data or data on adverse outcomes.\n\nThe committee reviewed evidence for several herbal products: Andrographis paniculata, ivy, primrose and thyme as a combined product, echinacea, and pelargonium.\n\nThe committee agreed that there was some evidence that suggests Andrographis paniculata (A.\xa0paniculata) reduced cough symptoms. However, as the clinical significance of this benefit is unclear, safety data was not available, and no A. paniculata product has been granted a traditional herbal registration with the MHRA, the committee agreed that no recommendation on its use for the treatment of acute cough could be made.\n\nThe committee agreed that there was some evidence that suggests ivy, primrose or thyme as various combined or single products reduced cough symptoms. However, as the clinical significance of this benefit is unclear and safety data was not available, the committee agreed that no recommendation on the use of these herbal products for the treatment of acute cough could be made. Several combined products containing ivy, primrose or thyme have been granted traditional herbal registrations with the MHRA to relieve coughs and catarrh associated with the common cold based on traditional use only.\n\nMost studies in a systematic review of echinacea did not report a benefit on cough symptoms, and no safety data was available. Therefore, the committee agreed that no recommendation on the use of echinacea for the treatment of acute cough could be made. Numerous echinacea products have been granted traditional herbal registrations with the MHRA to relieve the symptoms of the common cold and influenza type infections based on traditional use only.\n\nThe committee agreed that there was some evidence that suggests pelargonium (Pelargonium\xa0sidoides, P. sidoides) reduced cough symptoms in people with acute bronchitis, with a liquid preparation being more beneficial than a tablet preparation. However, P. sidoides increased the number of people with adverse events (mainly gastrointestinal). The clinical significance of the benefit of P. sidoides on cough symptoms is unclear, and the committee noted that all the RCTs were conducted in Russia or Ukraine and were initiated and funded by a single manufacturing company. However, several P.\xa0sidoides products have been granted traditional herbal registrations with the MHRA to relieve symptoms of the common cold, sore throat, cough and blocked or runny nose.\n\nThe committee agreed that limited evidence suggests that pelargonium may have some benefit on cough symptoms and people over 12\xa0years may wish to try it for the treatment of acute cough. Because of the limited evidence of benefit, and possible adverse effects, the committee agreed not to recommend pelargonium for children.\n\nNSAIDs\n\nBased on evidence, the committee agreed that NSAIDs did not benefit cough symptoms and no recommendation for their use to treat acute cough should be made. Paracetamol or ibuprofen are often used to manage any associated pain.\n\nCough expectorant medicines\n\nThe committee agreed that there was some evidence that suggests guaifenesin reduced cough symptoms in adults and young people with an acute cough or upper respiratory tract infection, with no increase in adverse effects. The clinical significance of any benefit is unclear, but the committee agreed that people over 12\xa0years may wish to try cough medicines containing guaifenesin for the treatment of acute cough.\n\nOver-the-counter cough medicines containing the expectorants guaifenesin and ipecacuanha are subject to MHRA advice. They should not be used in children under 6 years of age and are only available in pharmacies for use in children from 6 to 12\xa0years where advice can be given.\n\nCough suppressant (antitussive) medicines\n\nThe committee agreed that the evidence for dextromethorphan was mixed. There was some evidence that suggests a single, high dose reduced cough symptoms in adults with an acute cough but other evidence that it had no effect, and it may increase adverse effects (mainly gastrointestinal and dizziness). The clinical significance of any benefit it may have is unclear.\n\nBased on evidence, the committee agreed that codeine had no benefit on cough symptoms.\n\nThe systematic review of over-the-counter cough medicines did not include evidence specifically on pholcodine. However, the committee recognised that a RCT comparing pholcodine with dextromethorphan is available.\n\nTaking all the evidence, and their experience, into account the committee agreed that some people over 12\xa0years may wish to try cough medicines containing cough suppressants (apart from codeine) for the treatment of acute cough.\n\nOver-the-counter cough medicines containing the cough suppressants dextromethorphan and pholcodine are subject to MHRA advice. They should not be used in children under 6 years of age (pholcodine) or 12\xa0years of age (dextromethorphan) and pholcodine is only available in pharmacies for use in children from 6 to 12\xa0years where advice can be given. Over-the-counter cough medicines containing codeine should not be used in children under 12\xa0years and are not recommended for young people under 18\xa0years with breathing problems (MHRA advice).\n\nAntihistamines and decongestants\n\nThe committee agreed that, from the limited evidence found, antihistamines (loratadine, clemastine, diphenhydramine and promethazine) and decongestants (pseudoephedrine) had no benefit on cough symptoms, and increased adverse effects (including drowsiness and dry mouth).\n\nOver-the-counter cough medicines containing the antihistamines diphenhydramine and promethazine are subject to MHRA advice on how to use cough and cold medicines safely for children under 12 years.\n\n# Bronchodilators\n\n## Beta-2 agonists\n\nBeta-2 agonists (salbutamol syrup) did not significantly reduce the presence of cough at 7\xa0days, or mean cough score at days 1 to 7, compared with placebo in children with acute cough or acute bronchitis (low to moderate quality evidence). There were no significant differences in adverse effects (shaking or tremor or other adverse effects) between groups (very low quality evidence).\n\nBeta-2 agonists (salbutamol tablets, salbutamol inhaler or fenoterol inhaler [not available in the UK]) did not significantly reduce the presence of cough at 7\xa0days, productive cough after 7\xa0days, night cough after 7\xa0days, not working by day 7 or mean cough score at days 1 to 7, compared with placebo in adults with acute cough or acute bronchitis (very low to moderate quality evidence).\n\nThere was a significant increase in adverse effects (shaking, tremor or nervousness) in adults with acute cough or acute bronchitis treated with beta-2 agonists compared with placebo or other treatment (55.2% versus 11.3%, number needed to harm [NNH] 2 [range 1 to 3]; very low quality evidence), but not in other adverse effects.\n\nBeta-2 agonists (salbutamol syrup) were significantly better than erythromycin ethylsuccinate syrup for cough after 7 days (41.2% versus 88.2%; number needed to treat [NNT] 3 [range 2 to 6]; low quality evidence), productive cough after 7\xa0days (35.7% versus 76.5%; NNT 2 [range 2 to 12]; low quality evidence) but not night cough after 7\xa0days (very low quality evidence) in adults with acute cough or acute bronchitis.\n\nBased on Becker et al. (2015), a systematic review and meta-analysis of 7\xa0RCTs in adults and children with an acute cough or acute bronchitis.\n\nCommittee discussion on bronchodilators\n\nBased on evidence, the committee agreed that bronchodilators, such as oral or inhaled salbutamol, did not benefit cough symptoms and increased adverse events, such as tremor. The committee agreed that there may be instances when people with an acute cough and an underlying airways disease, such as asthma, require bronchodilators. Therefore, they agreed that bronchodilators should not be offered to people (adults or children) with an acute cough unless they had underlying airways disease, such as asthma.\n\nThe committee discussed the evidence for oral salbutamol plus dextromethorphan but no recommendation was made because no such product is available in the UK.\n\n# Corticosteroids\n\n## Inhaled corticosteroids\n\nInhaled corticosteroids (fluticasone proprionate) significantly reduced the mean cough score at the end of the second week of treatment compared with placebo in adults with acute or subacute cough following respiratory tract infection (mean difference [MD] −0.50, 95% CI −0.55 to −0.45; very low quality evidence) but not at 4\xa0weeks.\n\nInhaled corticosteroids (fluticasone proprionate) significantly reduced the mean cough score by at least 50% reduction at the end the second week in non-smoking adults with acute or subacute respiratory tract infection compared with placebo (53.5% versus 80.5%; NNT 4 [range 3 to 13]; very low quality evidence). The mean difference in the average daily cough score in the second week in non-smoking adults was −0.9 (95% CI −1.3 to −0.4; very low quality evidence). There was no difference in smokers. One RCT found that additional treatment sought after 2\xa0weeks of study treatment was significantly lower with fluticasone proprionate compared with placebo (43.1% versus 62.7%, NNT 6 [range 3 to 35]; very low quality evidence).\n\nThere were no significant differences found for mean symptom scores (cough, cough frequency, symptoms associated with cough, night-time cough or the frequency of taking cough medicines), and the outcomes of little or no improvement at 7 to 14 days, severe symptoms at 11 days, and adverse effects (hoarseness) during the treatment period (very low quality evidence).\n\nBased on El-Gohary et al. (2013), a systematic review of 4\xa0RCTs in adults with an acute or subacute respiratory tract infection.\n\nSystemic effects (mineralocorticoid and glucocorticoid) may occur with inhaled corticosteroids, including a range of psychological or behavioural effects (particularly in children; Drug Safety Update, September 2010).\n\nCommittee discussion on corticosteroids\n\nThe committee agreed that the evidence for inhaled corticosteroids was mixed. There was some evidence that it reduced cough symptoms in adults with an acute or subacute cough (particularly in non-smokers) but other evidence that it had no effect. No evidence for oral corticosteroids was found.\n\nCorticosteroids have well-recognised systemic (mineralocorticoid and glucocorticoid) effects, including a range of psychological or behavioural effects (particularly in children) and the committee agreed that, weighing up the potential risks and benefits, oral or inhaled corticosteroids should not be offered for people (adults or children) with an acute cough (including acute bronchitis).\n\nThe committee discussed the evidence that inhaled corticosteroids reduced additional treatments being sought, and they could reduce the prescribing of antibiotics for acute cough. However, any prescribed alternatives to antibiotics have workload implications as people are likely to re‑consult and expect similar treatments in the future, sending the wrong message that prescribed treatment is needed for a largely self‑limiting condition.\n\nThe committee agreed that there may be instances when people with an acute cough and an underlying airways disease, such as asthma, require corticosteroids. Therefore, they agreed that an oral or inhaled corticosteroid should not be offered to people (adults or children) with an acute cough unless they had an underlying airways disease, such as asthma.\n\n# Mucolytics\n\nMucolytics (oral acetylcysteine and oral carbocisteine) were significantly better than placebo for reducing cough at 6 to 7\xa0days in children with acute upper and lower respiratory tract infection (4.1% versus 13.8%; very low quality evidence), but not at the end of treatment (28\xa0days; very low quality evidence).\n\nThere were no significant differences between mucolytics and placebo for the outcomes of productive cough and expectoration at end of treatment (at 7\xa0days), pulmonary function at day\xa03, febrile state at 6\xa0days, dyspnoea at 6 to 7\xa0days, bad general condition after 6 to 7\xa0days, and appetite trouble (not defined) at the end of treatment (5 to 9\xa0days) in children with acute upper and lower respiratory tract infection (very low quality evidence). There was also no significant difference for the outcome of abnormal chest signs (for example wheezing or rattling) after 5\xa0days, but there was a significant difference for this outcome at the end of treatment (28\xa0days; 2% versus 16%; very low quality evidence).\n\nBased on Chalumeau and Duijvestijn (2013), a systematic review and meta-analysis of 6\xa0RCTs in children with acute upper and lower respiratory tract infections.\n\nCommittee discussion on mucolytics\n\nThe committee agreed that the evidence for mucolytics (acetylcysteine and carbocisteine) was mixed. There was some evidence that a mucolytic reduced cough symptoms in children with acute upper and lower respiratory tract infections but other evidence that it had no effect.\n\nThe clinical significance of any benefit of mucolytics is unclear, and the committee agreed that they should not be offered for people (adults or children) with an acute cough. Any prescribed alternatives to antibiotics have workload implications as people are likely to re‑consult and expect similar treatments in the future, sending the wrong message that prescribed treatment is needed for a largely self‑limiting condition.\n\n# No antibiotic\n\nAcute cough associated with an upper respiratory tract infection or acute bronchitis is usually a self-limiting infection caused by a viral infection. Most upper respiratory tract infections, such as a common cold or flu, are viral. Acute bronchitis has been estimated to be viral in 85% to 95% of cases, although this is difficult to estimate. (NICE clinical knowledge summary on chest infections – adult and Worrall, 2008).\n\n## Efficacy of antibiotics\n\nAntibiotics (doxycycline, co-trimoxazole, erythromycin, cefuroxime, azithromycin, amoxicillin and co-amoxiclav) were not significantly better than placebo (or no active treatment) for clinical improvement at follow-up in people with acute bronchitis (11\xa0RCTs, n=3,841, 73.2% versus 66.5%; low quality evidence). Clinical improvement was measured by a global assessment of improvement by clinicians at follow‑up.\n\nIn subgroup analysis by antibiotic, there was no significant difference in clinical improvement between doxycycline and placebo (3\xa0RCTs), erythromycin and placebo (2\xa0RCTs) or amoxicillin and placebo (2\xa0RCTs; low to moderate quality evidence). However, cefuroxime significantly increased clinical improvement at follow-up in adults with acute bronchitis compared with placebo (1\xa0RCT, n=343, 92.4% versus 79.1%; low quality evidence).\n\nAntibiotics (erythromycin, cefuroxime, doxycycline or co-amoxiclav) did not significantly reduce the number of adults and children with acute bronchitis without improvement at physician follow-up compared with placebo (very low quality evidence). When a subgroup of people with non-purulent tracheo-bronchitis from an upper respiratory tract infection study was omitted, antibiotics were significantly better than placebo (5 RCTs, n=816, 7.7% versus 17.6%; NNT 11 [7 to 19]; moderate quality evidence). However, only 1\xa0RCT in this analysis of cefuroxime versus placebo (accounting for 35.5% of the weight in the meta‑analysis) showed a significant improvement compared with placebo.\n\nAntibiotics (erythromycin, cefuroxime or doxycycline) were significantly better than placebo for improving abnormal lung examination at follow-up in adults with acute bronchitis (5\xa0RCTs, n=613, 18.5% versus 34.8%, NNT 7 [5 to 11]; moderate quality evidence). However, only 1\xa0RCT in this analysis of cefuroxime versus placebo (accounting for 77.8% of the weight) had a significant reduction for this outcome in the antibiotic group.\n\nAntibiotics (erythromycin, doxycycline or amoxicillin) significantly reduced the mean number of days feeling ill compared with placebo or no active treatment in adults and children with acute bronchitis (5 RCTs, n=809; moderate quality evidence). However, the significant effect was not maintained when a study of antibiotics compared with no active treatment (no placebo) was omitted. A subgroup analysis of RCTs of doxycycline versus placebo showed a significant reduction in the mean number of days feeling ill by about half a day compared with placebo (3\xa0RCTs, n=383; high quality evidence).\n\nAntibiotics (erythromycin or doxycycline) significantly reduced cough at follow-up in adults with acute bronchitis compared with placebo (4\xa0RCTs, n=275, 32.9% versus 50.8%, NNT 6 [4 to 16]; moderate quality evidence). This significant reduction was seen in a subgroup of RCTs of doxycycline compared with placebo (2\xa0RCTs, n=210, 22.9% versus 42.6%, NNT 6 [4 to 14]; moderate quality evidence) but not erythromycin compared with placebo (low quality evidence).\n\nAntibiotics (erythromycin, cefuroxime or doxycycline) significantly reduced night cough at follow-up in adults with acute bronchitis compared with placebo (4\xa0RCTs, n=538, 29.5% versus 44.6%, NNT 7 [5 to 15]; low quality evidence). This significant reduction was seen in a subgroup analysis of cefuroxime compared with placebo (1\xa0RCT, n=340, 36.8% versus 56.8%; low quality evidence) but not for erythromycin or doxycycline compared with placebo (low quality evidence). Antibiotics did not make any significant difference to the presence of productive cough at follow-up in adults and children with acute bronchitis (moderate quality evidence).\n\nAntibiotics (erythromycin, amoxicillin or doxycycline) significantly reduced the mean number of days of cough in adults and children with acute bronchitis compared with placebo or no active treatment by about half a day (7\xa0RCTs, n=2,776; moderate quality evidence). This significant reduction was also seen in studies that compared antibiotics with placebo only (6\xa0RCTs, n=2,350; moderate quality evidence). No significant differences were found for individual antibiotics in subgroup analyses.\n\nAntibiotics made no significant difference to the mean number of days of productive cough in adults and children with acute bronchitis compared with placebo or no active treatment. When a subgroup of people with non-purulent tracheo-bronchitis from an upper respiratory tract infection study was omitted, antibiotics did significantly reduce the mean number of days of productive cough by about half a day (5\xa0RCTs, n=535; moderate quality evidence). The significant difference was maintained in a subgroup of studies comparing doxycycline with placebo (4\xa0RCTs, n=444; moderate quality evidence) but not in 2\xa0RCTs of amoxicillin or erythromycin compared with placebo or no treatment (moderate quality evidence).\n\nAntibiotics (erythromycin or co-amoxiclav) significantly reduced the number of children with clinical failure (not cured or substantially improved) at follow-up in children with prolonged moist cough compared with placebo or no treatment (2\xa0RCTs, n=140, 34.3% versus 72.6%, NNT 3 [2 to 5]; moderate quality evidence). However, this became non-significant when children with Bordetellapertussis were excluded and in an intention-to-treat analysis using those not lost to follow-up (very low quality evidence). Antibiotics significantly reduced the need for additional treatment due to illness compared with placebo or no treatment (2\xa0RCTs, n=125, 5.1% versus 36.4%, NNT 4 [3\xa0to\xa06]; moderate quality evidence).\n\nAntibiotics (co-amoxiclav) had no significant effect on the development of acute otitis media in children with undifferentiated acute respiratory tract infection compared with placebo or no treatment (3 RCTs; very low quality evidence), or in a subgroup of children from high-income countries (2\xa0RCTs; very low quality evidence). Antibiotics (ampicillin) had no significant effect on the development of pneumonia in children aged under 11\xa0months or those aged 12 to 58\xa0months with undifferentiated acute respiratory infection compared with placebo or no treatment (1\xa0RCT; very low quality evidence).\n\nIn 1\xa0RCT in adults with an acute cough, for the outcome of resolution of symptoms rated moderately bad or worse, no pre-specified subgroup (green sputum, current smokers, significant past medical history, people with symptoms for longer than 7\xa0days at baseline, fever at baseline or minor chest signs) was significantly more likely to benefit from antibiotics (amoxicillin). People with significant past medical history compared with those without significant past medical history (n=438, MD −0.28, 95% CI −0.46 to −0.09; very low quality evidence) had a significantly lower mean symptom severity score on days 2 to 4 after consultation. People with symptoms for less than 7\xa0days at baseline compared with those who had symptoms for more than 7\xa0days at baseline had a significantly lower mean symptom severity score on days 2 to 4 after consultation (n=711, MD −0.16, 95% CI −0.27 to −0.06; very low quality evidence). Non-current smokers compared with current smokers had a significantly lower mean symptom severity score on days 2 to 4 after consultation (n=483, MD −0.12, 95% CI −0.22 to −0.03; very low quality evidence). No subgroups were identified that were significantly more likely to develop new or worsening symptoms.\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta-lactam antibiotics (BNF, December 2018).\n\nMacrolides should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF, December 2018).\n\nTetracyclines, including doxycycline, can deposit in growing bone and teeth causing staining and occasionally dental hypoplasia. Their use is cautioned in children under 12\xa0years, for use only in acute, severe or life-threatening infections when there are no adequate alternatives, and they should not be given to pregnant or breast-feeding women. Common side effects include nausea, vomiting, diarrhoea, dysphagia, and oesophageal irritation (BNF, December 2018).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nAntibiotics significantly increased the overall number of adverse effects compared with placebo or no active treatment in people with acute bronchitis (12\xa0RCTs, n=3,496, 22.6% versus 18.7%, NNH 25 [range 15 to 84]; low quality evidence). The most commonly reported adverse effects included gastrointestinal symptoms such as nausea, vomiting, or diarrhoea. There were no significant differences in adverse effects for subgroups of different antibiotics (erythromycin, amoxicillin or co-amoxiclav, or doxycycline) versus placebo or no active treatment (very low to low quality evidence).\n\nThere were no significant differences between antibiotics and placebo or no treatment for adverse effects (vomiting, rash or diarrhoea) in children with moist cough for longer than 10 days duration.\n\nBased on 3\xa0systematic reviews and meta-analyses, Smith et al. (2017) which included adults and children with acute bronchitis from 17\xa0RCTs, Marchant et al. (2005) which included children with a moist cough lasting longer than 10 days from 2\xa0RCTs and Alves et al. (2016) which included children with undifferentiated acute respiratory infection from 4\xa0RCTs; and 1\xa0RCT in adults with an acute cough (Moore et al. 2014).\n\n# Back-up antibiotics\n\nTwo RCTs included in a systematic review of adults and children with acute cough did not report data for back-up versus immediate antibiotics. However, the systematic review states that there was no difference in reported clinical outcomes.\n\nOne RCT included in a systematic review compared a back-up antibiotic prescription (either at the time of visit or requiring collection) with immediate antibiotics and a no antibiotic prescribing strategy in adults with acute cough. A back-up antibiotic prescription was not significantly different to an immediate antibiotic or no antibiotic for the outcomes of cough duration, pain duration or fever duration (low quality evidence).\n\nBased on Spurling et al. (2017), a systematic review and meta-analysis of 11\xa0RCTs of back-up antibiotic prescriptions for respiratory infections (including acute otitis media, pharyngitis, sore throat, common cold and other respiratory tract infections) in adults and children, 3 RCTs were in an acute cough population.\n\nCommittee discussion on no antibiotics, back-up antibiotics and immediate antibiotics\n\nThe committee discussed that acute cough, either associated with an upper respiratory tract infection or acute bronchitis, is usually a self-limiting infection. It is often a viral infection, and antibiotics are not usually needed.\n\nAcute cough associated with an upper respiratory tract infection\n\nNo evidence was found for antibiotics to treat an acute cough specifically associated with an upper respiratory tract infection, which is usually a viral infection. Based on the lack of evidence and experience, the committee agreed that antibiotics should not be offered to people (adults or children) with an acute cough associated with an upper respiratory tract infection. People should be given advice that an acute cough can last up to 3 or 4\xa0weeks and does not need an antibiotic. They should also be given safety netting advice to seek medical help if symptoms worsen rapidly or significantly, do not improve after 3 or 4\xa0weeks, or they become systemically very unwell.\n\nAcute cough associated with acute bronchitis\n\nBased on evidence and experience, the committee agreed that antibiotics should not routinely be offered to people (adults or children) with an acute cough associated with acute bronchitis. Antibiotics had a beneficial effect on some outcomes, but not others, and any benefit from antibiotics needs to be weighed up against their potential to cause adverse effects. Even where statistically significant effects were seen, these were often difficult to interpret and may not be clinically meaningful for many people.\n\nAntibiotics did not improve the overall clinical condition of people with acute bronchitis, or the number of people with improvement at physician follow-up. Antibiotics did improve abnormal lung examination at follow‑up, but the committee agreed this was not an important patient-orientated outcome for people with acute bronchitis, and this outcome was heavily influenced by 1\xa0study of cefuroxime.\n\nAntibiotics reduced the number of people who had 'any cough' or 'night cough' at follow-up, with a number needed to treat of 6 or 7. However, the timing of follow-up is unclear, varying between studies from 2 to 18\xa0days after treatment started.\n\nAntibiotics made little difference to how long the symptoms of acute bronchitis lasted. They reduced the mean number of days of cough by about 0.5\xa0days (range 0 to 1\xa0day), which the committee agreed may not be clinically meaningful for many people when an acute cough lasts up to 3 or 4 weeks.\n\nAntibiotics have possible adverse effects, particularly diarrhoea and nausea. In people with acute bronchitis, antibiotics increased adverse effects, with a NNH of 25.\n\nBased on experience, the committee discussed that withholding antibiotics in acute cough is unlikely to lead to complications in people who are not systemically very unwell or at higher risk of complications. However, they acknowledged the limited evidence base, which was solely for no increased risk of acute otitis media or pneumonia in children with acute undifferentiated respiratory tract infection.\n\nThe committee recognised the usefulness of back-up antibiotic prescriptions in managing self-limiting illnesses. However, from the evidence, back-up antibiotics were not significantly different to immediate antibiotics or no antibiotics for how long a cough lasts.\n\nBased on evidence, experience and the principles of antimicrobial stewardship, the committee recommended a no antibiotic prescribing strategy (routinely) for people with acute cough associated with acute bronchitis. They recognised that antibiotics may be an option for some people on an individual patient basis, but this should not be routine practice. For most people with an acute cough (which is a condition that can persist for some weeks) they felt a back-up antibiotic prescribing strategy sent the wrong message that antibiotics may be needed at some point.\n\nAcute cough in people who are systemically very unwell or at higher risk of complications\n\nBased on evidence and experience, the committee agreed that an immediate antibiotic prescription should be offered to people (adults or children) with an acute cough (associated with an upper respiratory tract infection or acute bronchitis) who are identified as systemically very unwell (ideally at a face-to-face clinical examination), because these people require prompt treatment with an antibiotic.\n\nBased on evidence and experience, the committee agreed that an immediate antibiotic prescription or a back-up antibiotic prescription could be considered for people with an acute cough (associated with an upper respiratory tract infection or acute bronchitis) who are identified as at higher risk of complications (ideally at a face-to-face clinical examination).\n\nThe committee recognised that the previous NICE guideline on upper respiratory tract infections noted that people with acute cough are likely to be at higher risk of developing complications because of pre-existing comorbidity (significant heart, lung, renal, liver or neuromuscular disease, immunosuppression, cystic fibrosis, and young children who were born prematurely) or because of older age and the presence of certain criteria (type 1 or type 2 diabetes, congestive heart failure, use of oral corticosteroids, hospitalisation in previous year). The committee agreed that for some of these people an immediate antibiotic may not be clinically required, and a back-up antibiotic could be considered.\n\nThe committee recommended that ideally antibiotics should only be considered after people have been assessed face-to-face but this may not always be possible.\n\nThe committee agreed that a back-up antibiotic prescription could be used if symptoms worsen rapidly or significantly at any time. Giving safety netting advice is also important to ensure people seek medical help if symptoms worsen rapidly or significantly despite taking the antibiotic, or they become systemically very unwell.\n\nBased on experience, the committee agreed that people with acute cough who present with any symptoms or signs suggesting a more serious illness or condition (for example, sepsis, a pulmonary embolism or lung cancer) should be referred to hospital, or specialist advice should be sought on further investigation and management.\n\nAntibiotics for moist cough of greater than 10\xa0days duration in children\n\nThe committee discussed the evidence for antibiotics reducing clinical failure in children with a prolonged moist cough. However, they noted the limitations with this evidence base and did not make a recommendation specifically for this population. Many children had a cough for over 3\xa0weeks at baseline, and therefore did not have an acute cough. Also, there was no benefit of antibiotics when children with Bordetella pertussis were excluded (9% of all children), and in an intention-to-treat analysis using those not lost to follow-up.\n\n# Choice of antibiotic\n\nNo systematic reviews and RCTs met the inclusion criteria for this section.\n\nCommittee discussion on choice of antibiotic\n\nThere was no evidence directly comparing different antibiotics. However, subgroup analysis from a systematic review in people with acute bronchitis did find some differences between antibiotics compared with placebo.\n\nIndividually, doxycycline compared with placebo showed a significant reduction in the following outcomes: mean number of days feeling ill, cough at follow-up and mean number of days of productive cough, where other antibiotics (amoxicillin and erythromycin) did not.\n\nIndividually, cefuroxime also showed benefit over placebo for the following outcomes: clinical improvement at follow-up, improvement at physician follow-up and night cough at follow-up, where other antibiotics did not. This was based on a trial of over 300\xa0people, which contributed much of the weight in meta-analyses. The committee discussed this finding and had some concerns that the study design of the cefuroxime study in particular influenced this result.\n\nCefuroxime is a broad-spectrum antibiotic (a second generation cephalosporin). The committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend doxycycline at usual dose, as the first-choice antibiotic for adults with acute cough (including acute bronchitis), where an antibiotic is appropriate. This is a tetracycline, which is only suitable for non-pregnant adults and, for acute cough, in young people over 12\xa0years. Doxycycline was preferred over amoxicillin because there was limited evidence from subgroup analyses that showed benefits on some outcomes where amoxicillin did not. But more importantly, they agreed that amoxicillin should be reserved, when possible, for use in more serious infections where bacterial infection is more common, for example pneumonia. This is because of concerns that amoxicillin drives resistance not just in pneumococci but also in gram-negative organisms. The committee was aware of evidence that the risk of resistance to amoxicillin is significantly increased in urinary isolates of Escherichia coli following a course of amoxicillin. These effects are greatest in the first month after use, but are detectable for up to 12\xa0months. There is a concern that using amoxicillin in conditions such as acute cough, where the benefits of antibiotics are marginal, drives resistance without adding benefit.\n\nAlternative first-choice antibiotics (at usual doses) for adults unable to take doxycycline, which have good activity against common causal bacteria, are:\n\n\n\namoxicillin (a penicillin)\n\nclarithromycin or erythromycin, which are macrolides.\n\n\n\nThe committee agreed that because the evidence of benefit of doxycycline over amoxicillin, clarithromycin or erythromycin is limited, these antibiotics should be offered as alternative first choices. This also reflects concerns that doxycycline is contraindicated in pregnancy, and this should be considered when choosing antibiotics for women of childbearing age.\n\nThe committee also discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nFor children and young people, amoxicillin is recommended as the first-choice antibiotic, with clarithromycin, erythromycin or doxycycline (in young people aged 12 to 17\xa0years only) as alternative choices.\n\n# Antibiotic course length\n\nNo systematic reviews and RCTs met the inclusion criteria for this section.\n\nCommittee discussion on antibiotic course length\n\nThere was no evidence directly comparing different antibiotic course lengths. From a systematic review in people with acute bronchitis, antibiotic course length varied from 5 to 10\xa0days typically depending on the antibiotics used.\n\nThe committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed.\n\nBased on evidence, their experience and resistance data, the committee agreed that a 5-day course for all the recommended antibiotics was sufficient to treat acute cough, where an antibiotic was appropriate. This takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance. Studies in the evidence review for specific antibiotics in acute bronchitis sometimes had course lengths of more than 5\xa0days.", 'Other considerations': "# Medicines adherence\n\nMedicines adherence may be a problem for some people taking medicines that need frequent dosing or longer treatment duration (for example, antibiotics). See the NICE guideline on medicines adherence.\n\n# Resource implications\n\nRespiratory tract infections, including acute cough, are a common reason for consultations in primary care and for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for 'cough and bronchitis' accounted for 39% of all consultations for respiratory tract infections, and the median practice issued an antibiotic prescription in 48% of these.\n\nThere is potential for resource savings if a no antibiotic or a back-up antibiotic prescription strategy is used. One systematic review (Spurling et al. 2017) found significantly lower antibiotic use with a back-up antibiotic prescribing strategy compared with immediate antibiotics, both when the back-up antibiotic prescription was given at the time of consultation (38.4% versus 86.8%; very low quality evidence) and when the prescription had to be collected on a separate visit (27.3% versus 95.3%; very low quality evidence).\n\nRecommended antibiotics are all available as generic formulations, see Drug Tariff for costs."}
|
https://www.nice.org.uk/guidance/ng120
|
This guideline sets out an antimicrobial prescribing strategy for acute cough associated with an upper respiratory tract infection or acute bronchitis in adults, young people and children. It aims to limit antibiotic use and reduce antibiotic resistance.
|
b2bebefcda6e317b6c50be780efc0348d7868f3c
|
nice
|
Electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer
|
Electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer
Evidence-based recommendations on electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer in adults. This involves using a small electrical current to improve the effect of chemotherapy given directly into the bladder.
# Recommendations
Current evidence on electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer shows there are no major safety concerns. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include randomised controlled trials compared with standard care, which should report details of patient selection.# The condition, current treatments and procedure
# The condition
The most common form of bladder cancer is transitional cell carcinoma (TCC). Non-muscle-invasive TCC is classified as stage Ta when the tumour is confined to the urothelium with no spread into the wall of the bladder or beyond, and stage T1 when there is spread into the connective tissue layer between the urothelium and the muscle wall. It is graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Another type of non-muscle-invasive cancer is carcinoma in situ, in which aggressive cancer cells spread within the surface lining of the bladder.
# Current treatments
Conventional treatment for non-muscle-invasive cancer is transurethral resection of bladder tumour (TURBT), in which malignant tissue is removed with an electrocautery device during cystoscopy. Intravesical chemotherapy with Bacillus Calmette-Guérin (BCG) vaccine or other chemotherapeutic drugs may also be used. The drug is instilled directly into the bladder, either alone or as adjuvant therapy after TURBT. The aim is to reduce the risk of cancer recurrence. Intravesical microwave hyperthermia may also be used, in combination with intravesical chemotherapy. Cystectomy may be needed in some patients.
# The procedure
Electrically stimulated intravesical chemotherapy (also known as electromotive drug administration) can be used as neoadjuvant treatment before TURBT, or as adjuvant treatment after TURBT. The procedure involves the use of a device to create an electric field across the bladder wall, with the aim of stimulating directional ionic and solute movement of the intravesical fluid. This increases absorption of the drug into the bladder lining.
The procedure is usually done using local anaesthesia. With the patient in a supine position, electrode pads are placed on the skin of the lower abdomen and a catheter (with an intravesical electrode) is inserted into the bladder through the urethra. When the catheter and electrodes are in place the chemotherapeutic drug solution (usually mitomycin C in saline or distilled water) is instilled into the bladder through the catheter. The cutaneous and intravesical electrodes are connected to a generator that creates a current of up to 25 milliamps. Treatment sessions last about 30 minutes and are repeated, often weekly, for 4 to 8 weeks or longer for adjuvant treatment. After the procedure, the bladder is drained and the catheter is removed.
|
{'Recommendations': 'Current evidence on electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer shows there are no major safety concerns. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include randomised controlled trials compared with standard care, which should report details of patient selection.', 'The condition, current treatments and procedure': '# The condition\n\nThe most common form of bladder cancer is transitional cell carcinoma (TCC). Non-muscle-invasive TCC is classified as stage\xa0Ta when the tumour is confined to the urothelium with no spread into the wall of the bladder or beyond, and stage\xa0T1 when there is spread into the connective tissue layer between the urothelium and the muscle wall. It is graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Another type of non-muscle-invasive cancer is carcinoma in situ, in which aggressive cancer cells spread within the surface lining of the bladder.\n\n# Current treatments\n\nConventional treatment for non-muscle-invasive cancer is transurethral resection of bladder tumour (TURBT), in which malignant tissue is removed with an electrocautery device during cystoscopy. Intravesical chemotherapy with Bacillus Calmette-Guérin (BCG) vaccine or other chemotherapeutic drugs may also be used. The drug is instilled directly into the bladder, either alone or as adjuvant therapy after TURBT. The aim is to reduce the risk of cancer recurrence. Intravesical microwave hyperthermia may also be used, in combination with intravesical chemotherapy. Cystectomy may be needed in some patients.\n\n# The procedure\n\nElectrically stimulated intravesical chemotherapy (also known as electromotive drug administration) can be used as neoadjuvant treatment before TURBT, or as adjuvant treatment after TURBT. The procedure involves the use of a device to create an electric field across the bladder wall, with the aim of stimulating directional ionic and solute movement of the intravesical fluid. This increases absorption of the drug into the bladder lining.\n\nThe procedure is usually done using local anaesthesia. With the patient in a supine position, electrode pads are placed on the skin of the lower abdomen and a catheter (with an intravesical electrode) is inserted into the bladder through the urethra. When the catheter and electrodes are in place the chemotherapeutic drug solution (usually mitomycin\xa0C in saline or distilled water) is instilled into the bladder through the catheter. The cutaneous and intravesical electrodes are connected to a generator that creates a current of up to 25\xa0milliamps. Treatment sessions last about 30\xa0minutes and are repeated, often weekly, for 4\xa0to\xa08 weeks or longer for adjuvant treatment. After the procedure, the bladder is drained and the catheter is removed.'}
|
https://www.nice.org.uk/guidance/ipg638
|
Evidence-based recommendations on electrically stimulated intravesical chemotherapy for non-muscle-invasive bladder cancer in adults. This involves using a small electrical current to improve the effect of chemotherapy given directly into the bladder.
|
df1a53810e50d6cd25075dc6cb325f7624471c6b
|
nice
|
Laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth
|
Laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth
Evidence-based recommendations on laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth. This involves placing a stitch around the upper part of the cervix to keep it closed.
# Recommendations
Current evidence on the safety and efficacy of laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team experienced in the management and prevention of preterm delivery.# The condition, current treatments and procedure
# The condition
Cervical incompetence may be caused by a congenital weakness of the cervix, or previous obstetric or gynaecological trauma. It is characterised by painless dilatation of the cervix in the second or third trimester, followed by second trimester miscarriage or premature rupture of the membranes and preterm delivery. The condition is usually diagnosed after 1 or more late second trimester pregnancy losses or early third trimester delivery, and after other causes have been excluded.
# Current treatments
Cervical incompetence is traditionally treated by transvaginal cervical cerclage. This involves placing a strong suture or tape around the cervix, via the vagina, and tightening it to keep the cervix closed. The procedure is typically done at the end of the first trimester or the beginning of the second trimester. The suture or tape is then usually removed at around 37 weeks of gestation to allow delivery.
Cervical cerclage using a transabdominal approach may be needed if transvaginal cerclage is technically difficult or has proved ineffective. With this approach, caesarean section is necessary to deliver the baby.
# The procedure
Laparoscopic cervical cerclage can be done during pregnancy or in women who are not pregnant. Under general anaesthesia, the peritoneal cavity is insufflated with carbon dioxide through a needle inserted into the umbilicus. Several small incisions are made to provide access for the laparoscope and surgical instruments. In women who are not pregnant, a dilator may initially be inserted into the cervix through the vagina for uterine manipulation. The bladder is dissected away from the uterus and a suture or tape is secured around the cervical isthmus, above the cardinal and uterosacral ligaments. As with the open transabdominal approach, caesarean section is necessary to deliver the baby. The suture or tape may be left in place for future pregnancies.
|
{'Recommendations': 'Current evidence on the safety and efficacy of laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team experienced in the management and prevention of preterm delivery.', 'The condition, current treatments and procedure': '# The condition\n\nCervical incompetence may be caused by a congenital weakness of the cervix, or previous obstetric or gynaecological trauma. It is characterised by painless dilatation of the cervix in the second or third trimester, followed by second trimester miscarriage or premature rupture of the membranes and preterm delivery. The condition is usually diagnosed after 1\xa0or more late second trimester pregnancy losses or early third trimester delivery, and after other causes have been excluded.\n\n# Current treatments\n\nCervical incompetence is traditionally treated by transvaginal cervical cerclage. This involves placing a strong suture or tape around the cervix, via the vagina, and tightening it to keep the cervix closed. The procedure is typically done at the end of the first trimester or the beginning of the second trimester. The suture or tape is then usually removed at around 37\xa0weeks of gestation to allow delivery.\n\nCervical cerclage using a transabdominal approach may be needed if transvaginal cerclage is technically difficult or has proved ineffective. With this approach, caesarean section is necessary to deliver the baby.\n\n# The procedure\n\nLaparoscopic cervical cerclage can be done during pregnancy or in women who are not pregnant. Under general anaesthesia, the peritoneal cavity is insufflated with carbon dioxide through a needle inserted into the umbilicus. Several small incisions are made to provide access for the laparoscope and surgical instruments. In women who are not pregnant, a dilator may initially be inserted into the cervix through the vagina for uterine manipulation. The bladder is dissected away from the uterus and a suture or tape is secured around the cervical isthmus, above the cardinal and uterosacral ligaments. As with the open transabdominal approach, caesarean section is necessary to deliver the baby. The suture or tape may be left in place for future pregnancies.'}
|
https://www.nice.org.uk/guidance/ipg639
|
Evidence-based recommendations on laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth. This involves placing a stitch around the upper part of the cervix to keep it closed.
|
2dd95156dbe207186dbd8a2bdfffe5dee5d3a20d
|
nice
|
Percutaneous venoplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis
|
Percutaneous venoplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis
Evidence-based recommendations on percutaneous venoplasty for chronic cerebrospinal venous insufficiency in people with multiple sclerosis. This involves inserting an inflatable balloon into veins in the neck and chest in an attempt to widen them.
# Recommendations
Current evidence on percutaneous venoplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis shows that there are serious complications and that it provides no benefit. Therefore, this procedure should not be used in the management of multiple sclerosis.# The condition, current treatments and procedure
# The condition
Multiple sclerosis is a disease of the central nervous system, which usually starts in early adult life. It is characterised by neurological symptoms caused by episodes of inflammation and scarring in the white matter of the brain or spinal cord. It causes a range of symptoms including problems with vision, arm or leg movement, sensation or balance. Muscle spasms, pain, fatigue, and emotional problems or depression may also occur. Symptoms may vary over time and some people become profoundly disabled. The 3 most common types of multiple sclerosis are: relapsing–remitting, in which periods of good health or remission are followed by sudden onset of symptoms or relapses; secondary progressive, in which symptoms gradually worsen with fewer remissions; and primary progressive, which involves a gradual, continuous worsening of symptoms.
# Current treatments
Current treatment for multiple sclerosis includes specialist neurological rehabilitation, and medication aimed at symptom control and preventing disease progression (see NICE's guideline on multiple sclerosis in adults).
# The procedure
The aim of percutaneous venoplasty for chronic cerebrospinal venous insufficiency is to relieve multiple sclerosis symptoms by improving cerebrospinal venous drainage. However, the full mechanism of action is not currently understood.
Percutaneous needle puncture of the femoral vein is done under local anaesthesia and a vascular sheath inserted using a standard needle, guidewire and catheter technique. The guidewire is advanced into the superior vena cava under fluoroscopic control. Selective venography of veins, including but not limited to the internal jugular and azygos, is used to identify any abnormal luminal narrowing and collateral circuits. Intravascular ultrasound may also be used. Abnormally narrowed segments are dilated with a standard angioplasty balloon. Sometimes a stent is left in place after the angioplasty. Further venography or ultrasound, or both, are used to assess the outcome of the intervention before the guidewire and sheath are removed.
|
{'Recommendations': 'Current evidence on percutaneous venoplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis shows that there are serious complications and that it provides no benefit. Therefore, this procedure should not be used in the management of multiple sclerosis.', 'The condition, current treatments and procedure': "# The condition\n\nMultiple sclerosis is a disease of the central nervous system, which usually starts in early adult life. It is characterised by neurological symptoms caused by episodes of inflammation and scarring in the white matter of the brain or spinal cord. It causes a range of symptoms including problems with vision, arm or leg movement, sensation or balance. Muscle spasms, pain, fatigue, and emotional problems or depression may also occur. Symptoms may vary over time and some people become profoundly disabled. The 3\xa0most common types of multiple sclerosis are: relapsing–remitting, in which periods of good health or remission are followed by sudden onset of symptoms or relapses; secondary progressive, in which symptoms gradually worsen with fewer remissions; and primary progressive, which involves a gradual, continuous worsening of symptoms.\n\n# Current treatments\n\nCurrent treatment for multiple sclerosis includes specialist neurological rehabilitation, and medication aimed at symptom control and preventing disease progression (see NICE's guideline on multiple sclerosis in adults).\n\n# The procedure\n\nThe aim of percutaneous venoplasty for chronic cerebrospinal venous insufficiency is to relieve multiple sclerosis symptoms by improving cerebrospinal venous drainage. However, the full mechanism of action is not currently understood.\n\nPercutaneous needle puncture of the femoral vein is done under local anaesthesia and a vascular sheath inserted using a standard needle, guidewire and catheter technique. The guidewire is advanced into the superior vena cava under fluoroscopic control. Selective venography of veins, including but not limited to the internal jugular and azygos, is used to identify any abnormal luminal narrowing and collateral circuits. Intravascular ultrasound may also be used. Abnormally narrowed segments are dilated with a standard angioplasty balloon. Sometimes a stent is left in place after the angioplasty. Further venography or ultrasound, or both, are used to assess the outcome of the intervention before the guidewire and sheath are removed."}
|
https://www.nice.org.uk/guidance/ipg640
|
Evidence-based recommendations on percutaneous venoplasty for chronic cerebrospinal venous insufficiency in people with multiple sclerosis. This involves inserting an inflatable balloon into veins in the neck and chest in an attempt to widen them.
|
4e6420ad3e9dc6a37e9b96f1a2809bc679c63cfe
|
nice
|
Platelet-rich plasma injections for knee osteoarthritis
|
Platelet-rich plasma injections for knee osteoarthritis
Evidence-based recommendations on platelet-rich plasma injections for knee osteoarthritis in adults. This involves taking plasma from a small amount of the person’s own blood and injecting it into the knee.
# Recommendations
Current evidence on platelet-rich plasma injections for knee osteoarthritis raises no major safety concerns. However, the evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to give platelet-rich plasma injections for knee osteoarthritis should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear information to support shared decision making. In addition, the use of NICE's information for the public on platelet-rich plasma injections for knee osteoarthritis is recommended.
Audit and review clinical outcomes of all patients having platelet-rich plasma injections for knee osteoarthritis, including details of the methods used to prepare and administer the platelet-rich plasma injections. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Further research should be in the form of randomised controlled trials with medium- to long-term follow‑up, including validated measures of knee function and patient-reported outcomes.# The condition, current treatments and procedure
# The condition
Osteoarthritis of the knee is the result of progressive deterioration of the articular cartilage and menisci of the joint, usually because of trauma, and wear and tear. This leads to exposure of the bone surface. Symptoms include pain, stiffness, swelling and difficulty walking.
# Current treatments
Treatment depends on the severity of the symptoms. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated: options include upper tibial osteotomy and unicompartmental or total knee replacement.
# The procedure
Platelet-rich plasma is prepared by a clinician or a technician. Blood is taken from the patient and centrifuged to obtain a concentrated suspension of platelets in plasma. Different preparation methods may affect the concentrations of platelets and the level of contamination with red and white blood cells. Different agents such as calcium chloride or thrombin may be added.
The platelet-rich plasma is injected into the joint space in the knee, usually under ultrasound guidance. Platelets contain growth factors that are thought to stimulate chondrocyte proliferation, leading to cartilage repair. The aim is to relieve symptoms, potentially delaying the need for joint replacement surgery. This guidance refers to the use of platelet-rich plasma injections alone and not as part of a combination therapy.
|
{'Recommendations': "Current evidence on platelet-rich plasma injections for knee osteoarthritis raises no major safety concerns. However, the evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to give platelet-rich plasma injections for knee osteoarthritis should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear information to support shared decision making. In addition, the use of NICE's information for the public on platelet-rich plasma injections for knee osteoarthritis is recommended.\n\nAudit and review clinical outcomes of all patients having platelet-rich plasma injections for knee osteoarthritis, including details of the methods used to prepare and administer the platelet-rich plasma injections. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nFurther research should be in the form of randomised controlled trials with medium- to long-term follow‑up, including validated measures of knee function and patient-reported outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nOsteoarthritis of the knee is the result of progressive deterioration of the articular cartilage and menisci of the joint, usually because of trauma, and wear and tear. This leads to exposure of the bone surface. Symptoms include pain, stiffness, swelling and difficulty walking.\n\n# Current treatments\n\nTreatment depends on the severity of the symptoms. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated: options include upper tibial osteotomy and unicompartmental or total knee replacement.\n\n# The procedure\n\nPlatelet-rich plasma is prepared by a clinician or a technician. Blood is taken from the patient and centrifuged to obtain a concentrated suspension of platelets in plasma. Different preparation methods may affect the concentrations of platelets and the level of contamination with red and white blood cells. Different agents such as calcium chloride or thrombin may be added.\n\nThe platelet-rich plasma is injected into the joint space in the knee, usually under ultrasound guidance. Platelets contain growth factors that are thought to stimulate chondrocyte proliferation, leading to cartilage repair. The aim is to relieve symptoms, potentially delaying the need for joint replacement surgery. This guidance refers to the use of platelet-rich plasma injections alone and not as part of a combination therapy.'}
|
https://www.nice.org.uk/guidance/ipg637
|
Evidence-based recommendations on platelet-rich plasma injections for knee osteoarthritis in adults. This involves taking plasma from a small amount of the person’s own blood and injecting it into the knee.
|
97c1ff250f8a94b0f5292c83ab9855fccb756600
|
nice
|
Senza spinal cord stimulation system for delivering HF10 therapy to treat chronic neuropathic pain
|
Senza spinal cord stimulation system for delivering HF10 therapy to treat chronic neuropathic pain
Evidence-based recommendations on the Senza spinal cord stimulation system for delivering HF10 therapy to treat chronic neuropathic pain.
# Recommendations
The case for adopting Senza spinal cord stimulation (SCS) for delivering HF10 therapy as a treatment option for chronic neuropathic back or leg pain after failed back surgery is supported by the evidence. HF10 therapy using Senza SCS is at least as effective as low‑frequency SCS in reducing pain and functional disability, and avoids the experience of tingling sensations (paraesthesia).
Senza SCS for delivering HF10 therapy should be considered for patients:
with residual chronic neuropathic back or leg pain (at least 50 mm on a 0 mm to 100 mm visual analogue scale) at least 6 months after back surgery despite conventional medical management and
who have had a successful trial of stimulation as part of a wider assessment by a multidisciplinary team.
Patients with other causes of neuropathic pain were included in the evaluation and may be considered for HF10 therapy using Senza SCS but any additional benefits compared with low‑frequency SCS are less certain. Cost modelling indicates that, over 15 years, HF10 therapy using Senza SCS has similar costs to low‑frequency SCS using either a rechargeable or non-rechargeable device.
Clinicians implanting SCS devices including Senza should submit timely and complete data to the UK Neuromodulation Registry.
When assessing the severity of pain and the trial of stimulation, the multidisciplinary team should be aware of the need to ensure equality of access to treatment with SCS. Tests to assess pain and response to SCS should take into account a person's disabilities (such as physical or sensory disabilities), or linguistic or other communication difficulties, and may need to be adapted.
Why the committee made these recommendations
The use of SCS for chronic neuropathic pain is recommended in the NICE technology appraisal guidance on spinal cord stimulation for chronic pain of neuropathic for ischaemic origin. This medical technology guidance assessed the evidence to support the additional benefits of HF10 therapy using Senza compared with low‑frequency SCS in patients with chronic neuropathic pain.
Clinical trial evidence shows that HF10 therapy using Senza SCS is at least as effective as low‑frequency SCS in relieving pain for patients with chronic back or leg pain after failed back surgery. For other patients with chronic neuropathic pain, HF10 therapy using Senza SCS remains an option alongside other SCS options because there is more uncertainty about its additional benefits compared with low‑frequency SCS.# The technology
# Description of the technology
The Senza spinal cord stimulation (SCS) system (Nevro) is a neuromodulation device that delivers electrical impulses to the spinal cord. The treatment Senza provides (known as HF10 therapy) is a combination of high-frequency (10 kHz) low-amplitude electrical pulses designed to relieve pain and not be felt by the patient, and a proprietary programming algorithm. The impulses are delivered by small electrodes, which are placed in the spinal epidural space and are connected to a small, battery-powered pulse generator that is implanted under the skin. The strength, duration and frequency of the electrical pulses can be controlled remotely. HF10 therapy using Senza SCS is referred to as Senza in the main body of this guidance.
Senza was CE marked as a class III device in May 2010 and is intended to be used only for patients who have had effective pain relief in a trial of stimulation. Patients who have a Senza device in place should not have shortwave, microwave or therapeutic ultrasound diathermy because of the risk of severe injury or death. They should only be exposed to MRI under conditions outlined in the instructions for use and the full-body MRI conditional label issued in November 2017.
The company also offers a newer system called Senza II, which delivers the same HF10 therapy. Senza II is intended for use in patients with a low BMI who need a smaller device. It has not been considered as part of this evaluation.
The acquisition cost of Senza, as stated in the company's submission, is £16,648 (excluding VAT). This includes electrodes, leads, an implantable pulse generator (with rechargeable battery), a remote control and a battery charger.
The claimed benefits in the case for adoption presented by the company are that, compared with low‑frequency SCS, Senza is associated with:
clinically superior pain relief, as well as better clinical and functional outcomes, for most people with back or leg pain
no paraesthesia, so treatment can be continued during sleep and while driving or operating machinery
sustained and long-term improvement in pain relief and function, which may reduce the need for pain medication and follow-up attendance at pain clinics
no need for paraesthesia mapping during implantation, which allows for shorter and more predictable procedure times.
# Current management
The NICE technology appraisal guidance on spinal cord stimulation for chronic pain of neuropathic or ischaemic origin recommends SCS as a treatment option for adults with chronic pain of neuropathic origin that continues for at least 6 months despite conventional medical management (including pharmacological treatment, physiotherapy and psychological support) who have had a successful trial of stimulation as part of a wider assessment by a multidisciplinary team. SCS is not recommended for adults with chronic pain of ischaemic origin, except in the context of research. The devices considered in the guidance deliver low‑frequency SCS. The guidance was last reviewed in 2013, before all the evidence on Senza considered in this evaluation was available. The review concluded that more recent evidence would be unlikely to change the recommendations, and the guidance was placed on the static list.
NICE has also produced related guidelines on neuropathic pain in adults in non-specialist settings and low back pain and sciatica in over 16s.# Evidence
# Summary of clinical evidence
The evidence for Senza considered by the external assessment centre (EAC) comprised 10 studies in adults with chronic neuropathic pain. Of these 10, 3 studies (Al-Kaisy et al. 2017b, De Andres et al. 2017 and Van Buyten et al. 2017) became available during consultation on the original draft recommendations, and 1 became available (Amirdelfan et al. 2018) after a further consultation on the second draft recommendations. The 10 studies were:
randomised controlled trials comparing Senza and low‑frequency spinal cord stimulation (SCS; Kapural et al. 2015 and 2016 and De Andres et al. 2017)
before-and-after study (Tiede et al. 2013)
single-arm observational studies (Al-Kaisy et al. 2014, Russo et al. 2016, Rapcan et al. 2015, Al-Kaisy et al. 2017a and Al-Kaisy et al. 2017b)
retrospective chart review (Van Buyten et al. 2017)
quality-of-life analysis using data from Kapural et al. 2016 (Amirdelfan et al. 2018).For full details of the clinical evidence, see section 3 of the assessment report and the supplementary EAC documents.
# Main points from the EAC's analysis of the clinical evidence
The EAC initially considered Kapural et al. (2016) to be the most relevant study providing the best quality evidence. Although it identified that the study had the potential for performance, detection and reporting bias, the EAC was satisfied that the trial's limitations did not affect the overall direction of the results.
The other 5 studies initially identified were single-arm observational studies, the results of which generally supported and corroborated the results of Kapural et al. (2016). The highest quality of these was Al-Kaisy et al. (2014), which reported results up to 2 years.
The EAC initially concluded that the evidence was strong and relevant to the decision problem, and that it showed that Senza provided substantially better pain control than low‑frequency SCS. However, it noted gaps in the evidence base, particularly the lack of long-term studies and the absence of a sham control.
## Evidence identified during consultations
Following consultation on the draft guidance, 4 additional studies were identified as being relevant to the decision problem: De Andres et al. (2017), Van Buyten et al. (2017), Al-Kaisy et al. (2017b) and Amirdelfan et al. (2018).
The EAC considered that, in addition to Kapural et al. (2016), the De Andres et al. and Van Buyten et al. studies were most relevant to the decision problem. De Andres et al. reported that Senza and low‑frequency SCS had similar benefits, conflicting with the results of Kapural et al. Van Buyten et al. is a retrospective chart review that reported the rates and reasons for removing SCS devices in 4 centres that had done 955 implantations (155 of which were Senza) in 822 patients.
Al-Kaisy et al. (2017b) reported extended follow-up data to the original study by the same author which had been included in the company submission assessed by the EAC in its original report. The new data reported that early improvements (up to 12 months) in pain, disability and quality of life were maintained until 36 months.
The Amirdelfan et al. (2018) study provided data on additional outcomes from Kapural et al. at 12 months. The EAC concluded that this study provided additional evidence that Senza may result in improved patient-reported outcome measures compared with low‑frequency SCS, but did not detect a difference in generic health-related quality-of-life outcomes.
## Further EAC review of the randomised controlled trial evidence
Kapural et al. (2016) and De Andres et al. (2017) reported randomised controlled trials comparing Senza with low‑frequency SCS, with inconsistent findings. Specifically, Kapural et al. (2016) reported a statistically significant reduction in back and leg pain with Senza compared with low‑frequency SCS whereas De Andres et al. (2017) reported no difference in pain scores. The trial design and conduct of the De Andres study was openly challenged and the authors' responses to these criticisms were summarised in a letter that was published in the same journal as the original paper (see the supplementary EAC documents for more details).
Having reviewed all of the evidence, the EAC concluded that Senza is likely to be at least as effective as low‑frequency SCS in terms of reducing pain in appropriately selected patients. However, it noted that both the Kapural et al. (2016) and particularly the De Andres et al. (2017) studies were subject to bias and had design and reporting weaknesses, significantly more so for the latter. Because of this, the EAC considered that the results should be interpreted with caution.
Because of the inconsistent trial results and because of a large number of conflicting comments received during both consultations, a second EAC reviewed the randomised controlled trial evidence. It concluded that the De Andres et al. (2017) study was methodologically worse than Kapural et al. (2016). It drew specific attention to weaknesses in terms of the trial's analysis, governance and design (see the supplementary EAC documents or more details).
# Summary of economic evidence
The company's cost model was based on a published cost-effectiveness study (Annemans et al. 2014) comparing Senza separately with conventional medical management, reoperation and low‑frequency SCS devices (both rechargeable and non-rechargeable). The model, which was also used to inform the NICE technology appraisal guidance on spinal cord stimulation (Simpson et al. 2008), was a 2-stage decision analytic model that used a decision tree for the first 6 months, followed by a Markov state transition model with a 15‑year time horizon. For full details of the economic evidence, see section 4 of the assessment report and the supplementary EAC documents.
# EAC's analysis of the economic evidence
The EAC considered Annemans et al. (2014) to be of high quality and the company's cost model to be of good methodological quality. It was therefore initially satisfied with the reported results and sensitivity analyses. However, the publication of Van Buyten et al. (2017) during the first consultation provided additional real-world data as an alternative estimate for the rate of unanticipated explantation used in the cost model. The EAC did not change the anticipated explants parameters in the model but estimated the unanticipated explantation parameters used in the cost model by extrapolating the data available from Van Buyten et al. for explantations because of inadequate pain relief (see the supplementary EAC documents for more details).
Many of the costs in the model, including the acquisition costs for Senza and its comparators, were adjusted for inflation from the original values in the Annemans et al. study. The EAC considered it inappropriate to inflate drug prices in this way because they are subject to a wide range of non-inflationary factors. The EAC explored this further with 4 hypothetical scenarios to assess how different drug costs affect the cost consequences of using Senza.
The main drivers of the cost modelling results were acquisition costs, explantation rates and device lifespan, particularly for non-rechargeable SCS devices, which need to be replaced around every 4 years. The company's base-case results showed that, over 15 years, Senza could lead to cost savings of £4,795 compared with rechargeable low‑frequency SCS devices and £7,755 compared with non-rechargeable low‑frequency SCS devices.# Committee discussion
# Clinical effectiveness
The committee considered the clinical evidence and noted the inconsistent results from the 2 randomised controlled trials (Kapural et al. 2016 and De Andres et al. 2017). In particular, the committee noted that Kapural et al. demonstrated statistically significantly better pain reduction using Senza compared with low‑frequency spinal cord stimulation (SCS), but that in De Andres et al. there was no statistically significant difference between the 2 treatments in this regard. The expert advisers explained that the low‑frequency SCS devices used as the comparator in both studies work in the same way as those used in standard clinical practice in the NHS. However, the response to low‑frequency SCS was lower than expected in De Andres et al., compared with both clinical experience and other trial results including Kapural et al. The external assessment centre (EAC) also highlighted that pain reduction was greater in Kapural et al. for both Senza and low‑frequency SCS compared with both treatment arms in De Andres et al.
The committee was concerned about the methodological quality of the De Andres et al. (2017) study, noting the conclusions of the 2 EAC reports about the reliability and robustness of the evidence. Although the committee noted the weaknesses in both randomised controlled trials, including the potential for bias and concerns about the relevance of the results to the NHS, it agreed with the EAC's conclusion that Senza is at least as effective as low‑frequency SCS in terms of relieving pain. It acknowledged that current studies are limited to 2 years' follow-up; a clinical expert explained that 3-year outcome data will soon be available, and that the ultimate intention is to collect 5-year follow-up data. The committee considered that long-term outcome data would be particularly important, given that Senza and other similar devices are used to treat a chronic condition and have a lifespan of at least 10 years. The committee concluded that, in view of these uncertainties, it would be beneficial for clinicians to routinely collect clinical and procedural outcome data on the use of SCS including Senza. It was encouraged to hear that the UK Neuromodulation Registry has well-established data collection arrangements to support the gathering of useful data.
## Avoiding paraesthesia
People having low‑frequency SCS often experience paraesthesia (or tingling sensations), but this is not the case with high-frequency SCS (such as Senza). The experts explained that people may have paraesthesia throughout the use of low‑frequency SCS devices and that this can impair day-to-day living. For example, intense paraesthesia may be distracting enough to interrupt sleep or prevent tasks such as driving or operating machinery. However, the committee heard that some patients (usually those who have had low‑frequency SCS for a long time) find the presence of paraesthesia reassuring, because it confirms that the device is still working. The committee concluded that paraesthesia after SCS device implantation is an important issue that should be discussed with patients before choosing a device.
## Patient selection
The committee noted that most of the higher quality evidence for the clinical benefits of Senza is in people who have chronic back or leg pain despite previous back surgery. The clinical experts agreed that this is the largest group of patients who are likely to benefit from Senza, but highlighted others who may benefit (for example, people for whom surgery is either not possible or unlikely to be successful and people with neuropathic pain of other causes including complex regional pain syndrome). However, the committee concluded that there is limited evidence to support the claimed benefits for Senza in these other patient groups. It noted that these patient groups are already covered by the recommendations in the NICE technology appraisal guidance on spinal cord stimulation. The committee also concluded that more evidence would be valuable about the potential role of Senza for neuropathic pain in patients who have not had previous back surgery. The committee was supportive of further research in these difficult circumstances, and would encourage SCS users to include patient data following all implantations in the UK Neuromodulation Registry.
## Mode of action
The clinical experts advised that Senza uses different physiological mechanisms to low‑frequency SCS, but these are not yet fully understood.
# NHS considerations
The clinical experts explained that because paraesthesia mapping is not needed when using Senza, implantation procedure times may be shorter and more predictable compared with those for low‑frequency SCS devices. The committee was advised that, typically, 2 electrodes are used when implanting Senza compared with 1 electrode for low‑frequency SCS devices. The EAC explained that these factors had not been quantified in the published studies and so were not included in the cost modelling. The committee concluded that it is plausible that using Senza may allow for better planning of procedure times (thereby potentially increasing the number of procedures per operating list).
The clinical experts explained that when first adopting Senza in their services, the company provided trained experts to attend procedures and support clinicians until competence had been achieved. This was confirmed by the company representatives who attended the meetings.
The clinical experts also explained that there may be further time savings when using Senza at follow-up appointments because, in their experience, programming is easier and less time-consuming than with low‑frequency SCS devices.
## Charging the device
Based on NHS Supply Chain purchase data, the committee concluded that the low‑frequency SCS devices most commonly used in the NHS are rechargeable. The clinical experts explained that although Senza is also rechargeable, it needs to be charged more often than most low‑frequency SCS devices (for 30 to 45 minutes each day). The committee concluded that the need for recharging is an important factor that should be discussed with patients before choosing a device.
## Cost savings
The committee noted that the company's cost model replicated that used to inform the NICE technology appraisal guidance on spinal cord stimulation, and that the model has also been subjected to peer review before being published elsewhere. It agreed with the EAC that supplementation of the model with data from Van Buyten et al. (2017) was appropriate.
The committee noted that the model assumed a time horizon of 15 years. This is appropriate for a long-term condition, but clinical outcome data are currently limited to 2 years after implantation. Nonetheless, it noted the EAC's conclusions that the claimed lifespan of Senza is plausible (see the supplementary EAC documents for more details). The clinical experts also explained that they had seen no evidence in their own clinical practices to suggest that the effectiveness of Senza diminishes over time.
The committee noted the uncertainties in the cost model associated with the use of drug costs adjusted for inflation. The EAC explained that additional modelling involving attempts to more accurately estimate the cost of drug management in the relevant patient groups would be difficult.
Having acknowledged that the acquisition costs of Senza and the comparators were an important driver of the cost modelling results, the committee noted that these had also been adjusted for inflation from the cost model used to inform the NICE technology appraisal guidance on spinal cord stimulation. Acquisition costs in the model were assumed to be:
Senza: £16,648, with a lifespan of 10 years.
Non-rechargeable low‑frequency SCS device: £11,281, with a lifespan of 4 years.
Rechargeable low‑frequency SCS device: £17,422, with a lifespan of 10 years.The EAC confirmed that these are an accurate reflection of current device costs.
The committee noted the results of the EAC's updated cost model (which included explantation data from Van Buyten et al. 2017), which showed that:
Over 15 years, compared with using a non-rechargeable low‑frequency SCS device, Senza is cost incurring by £351 per patient (£23.40 per year).
Over 15 years, compared with using a rechargeable low‑frequency SCS device, Senza is cost saving by £2,292 per patient (£152.80 per year).The committee concluded that, despite the uncertainties in the cost model and the extrapolations made over the 15-year time horizon, it is unlikely that using Senza will incur additional overall costs compared with using low‑frequency SCS devices.
|
{'Recommendations': "The case for adopting Senza spinal cord stimulation (SCS) for delivering HF10\xa0therapy as a treatment option for chronic neuropathic back or leg pain after failed back surgery is supported by the evidence. HF10\xa0therapy using Senza\xa0SCS is at least as effective as low‑frequency\xa0SCS in reducing pain and functional disability, and avoids the experience of tingling sensations (paraesthesia).\n\nSenza\xa0SCS for delivering HF10\xa0therapy should be considered for patients:\n\nwith residual chronic neuropathic back or leg pain (at least 50\xa0mm on a 0\xa0mm to 100\xa0mm visual analogue scale) at least 6\xa0months after back surgery despite conventional medical management and\n\nwho have had a successful trial of stimulation as part of a wider assessment by a multidisciplinary team.\n\nPatients with other causes of neuropathic pain were included in the evaluation and may be considered for HF10\xa0therapy using Senza\xa0SCS but any additional benefits compared with low‑frequency\xa0SCS are less certain. Cost modelling indicates that, over 15\xa0years, HF10\xa0therapy using Senza\xa0SCS has similar costs to low‑frequency\xa0SCS using either a rechargeable or non-rechargeable device.\n\nClinicians implanting SCS\xa0devices including Senza should submit timely and complete data to the UK Neuromodulation Registry.\n\nWhen assessing the severity of pain and the trial of stimulation, the multidisciplinary team should be aware of the need to ensure equality of access to treatment with SCS. Tests to assess pain and response to SCS should take into account a person's disabilities (such as physical or sensory disabilities), or linguistic or other communication difficulties, and may need to be adapted.\n\nWhy the committee made these recommendations\n\nThe use of SCS for chronic neuropathic pain is recommended in the NICE technology appraisal guidance on spinal cord stimulation for chronic pain of neuropathic for ischaemic origin. This medical technology guidance assessed the evidence to support the additional benefits of HF10\xa0therapy using Senza compared with low‑frequency\xa0SCS in patients with chronic neuropathic pain.\n\nClinical trial evidence shows that HF10\xa0therapy using Senza\xa0SCS is at least as effective as low‑frequency\xa0SCS in relieving pain for patients with chronic back or leg pain after failed back surgery. For other patients with chronic neuropathic pain, HF10\xa0therapy using Senza\xa0SCS remains an option alongside other SCS options because there is more uncertainty about its additional benefits compared with low‑frequency\xa0SCS.", 'The technology': "# Description of the technology\n\nThe Senza spinal cord stimulation (SCS) system (Nevro) is a neuromodulation device that delivers electrical impulses to the spinal cord. The treatment Senza provides (known as HF10\xa0therapy) is a combination of high-frequency (10\xa0kHz) low-amplitude electrical pulses designed to relieve pain and not be felt by the patient, and a proprietary programming algorithm. The impulses are delivered by small electrodes, which are placed in the spinal epidural space and are connected to a small, battery-powered pulse generator that is implanted under the skin. The strength, duration and frequency of the electrical pulses can be controlled remotely. HF10\xa0therapy using Senza\xa0SCS is referred to as Senza in the main body of this guidance.\n\nSenza was CE marked as a class III device in May 2010 and is intended to be used only for patients who have had effective pain relief in a trial of stimulation. Patients who have a Senza device in place should not have shortwave, microwave or therapeutic ultrasound diathermy because of the risk of severe injury or death. They should only be exposed to MRI under conditions outlined in the instructions for use and the full-body MRI conditional label issued in November 2017.\n\nThe company also offers a newer system called Senza II, which delivers the same HF10\xa0therapy. Senza II is intended for use in patients with a low BMI who need a smaller device. It has not been considered as part of this evaluation.\n\nThe acquisition cost of Senza, as stated in the company's submission, is £16,648 (excluding VAT). This includes electrodes, leads, an implantable pulse generator (with rechargeable battery), a remote control and a battery charger.\n\nThe claimed benefits in the case for adoption presented by the company are that, compared with low‑frequency\xa0SCS, Senza is associated with:\n\nclinically superior pain relief, as well as better clinical and functional outcomes, for most people with back or leg pain\n\nno paraesthesia, so treatment can be continued during sleep and while driving or operating machinery\n\nsustained and long-term improvement in pain relief and function, which may reduce the need for pain medication and follow-up attendance at pain clinics\n\nno need for paraesthesia mapping during implantation, which allows for shorter and more predictable procedure times.\n\n# Current management\n\nThe NICE technology appraisal guidance on spinal cord stimulation for chronic pain of neuropathic or ischaemic origin recommends SCS as a treatment option for adults with chronic pain of neuropathic origin that continues for at least 6\xa0months despite conventional medical management (including pharmacological treatment, physiotherapy and psychological support) who have had a successful trial of stimulation as part of a wider assessment by a multidisciplinary team. SCS is not recommended for adults with chronic pain of ischaemic origin, except in the context of research. The devices considered in the guidance deliver low‑frequency\xa0SCS. The guidance was last reviewed in 2013, before all the evidence on Senza considered in this evaluation was available. The review concluded that more recent evidence would be unlikely to change the recommendations, and the guidance was placed on the static list.\n\nNICE has also produced related guidelines on neuropathic pain in adults in non-specialist settings and low back pain and sciatica in over 16s.", 'Evidence': "# Summary of clinical evidence\n\nThe evidence for Senza considered by the external assessment centre (EAC) comprised 10 studies in adults with chronic neuropathic pain. Of these 10, 3 studies (Al-Kaisy et\xa0al.\xa02017b, De Andres et\xa0al.\xa02017 and Van Buyten et\xa0al.\xa02017) became available during consultation on the original draft recommendations, and 1 became available (Amirdelfan et\xa0al.\xa02018) after a further consultation on the second draft recommendations. The 10 studies were:\n\nrandomised controlled trials comparing Senza and low‑frequency\xa0spinal cord stimulation (SCS; Kapural et\xa0al.\xa02015 and 2016 and De Andres et\xa0al.\xa02017)\n\nbefore-and-after study (Tiede et\xa0al.\xa02013)\n\nsingle-arm observational studies (Al-Kaisy et\xa0al.\xa02014, Russo et\xa0al.\xa02016, Rapcan et\xa0al.\xa02015, Al-Kaisy et\xa0al.\xa02017a and Al-Kaisy et\xa0al.\xa02017b)\n\nretrospective chart review (Van Buyten et\xa0al.\xa02017)\n\nquality-of-life analysis using data from Kapural et\xa0al.\xa02016 (Amirdelfan et\xa0al.\xa02018).For full details of the clinical evidence, see section 3 of the assessment report and the supplementary EAC documents.\n\n# Main points from the EAC's analysis of the clinical evidence\n\nThe EAC initially considered Kapural et\xa0al.\xa0(2016) to be the most relevant study providing the best quality evidence. Although it identified that the study had the potential for performance, detection and reporting bias, the EAC was satisfied that the trial's limitations did not affect the overall direction of the results.\n\nThe other 5 studies initially identified were single-arm observational studies, the results of which generally supported and corroborated the results of Kapural et\xa0al.\xa0(2016). The highest quality of these was Al-Kaisy et\xa0al.\xa0(2014), which reported results up to 2\xa0years.\n\nThe EAC initially concluded that the evidence was strong and relevant to the decision problem, and that it showed that Senza provided substantially better pain control than low‑frequency\xa0SCS. However, it noted gaps in the evidence base, particularly the lack of long-term studies and the absence of a sham control.\n\n## Evidence identified during consultations\n\nFollowing consultation on the draft guidance, 4 additional studies were identified as being relevant to the decision problem: De Andres et\xa0al.\xa0(2017), Van Buyten et\xa0al.\xa0(2017), Al-Kaisy et\xa0al.\xa0(2017b) and Amirdelfan et\xa0al.\xa0(2018).\n\nThe EAC considered that, in addition to Kapural et\xa0al.\xa0(2016), the De Andres et\xa0al.\xa0and Van Buyten et\xa0al.\xa0studies were most relevant to the decision problem. De Andres et\xa0al.\xa0reported that Senza and low‑frequency\xa0SCS had similar benefits, conflicting with the results of Kapural et\xa0al.\xa0Van Buyten et\xa0al.\xa0is a retrospective chart review that reported the rates and reasons for removing SCS\xa0devices in 4 centres that had done 955 implantations (155 of which were Senza) in 822 patients.\n\nAl-Kaisy et\xa0al.\xa0(2017b) reported extended follow-up data to the original study by the same author which had been included in the company submission assessed by the EAC in its original report. The new data reported that early improvements (up to 12\xa0months) in pain, disability and quality of life were maintained until 36\xa0months.\n\nThe Amirdelfan et\xa0al.\xa0(2018) study provided data on additional outcomes from Kapural et\xa0al.\xa0at 12\xa0months. The EAC concluded that this study provided additional evidence that Senza may result in improved patient-reported outcome measures compared with low‑frequency\xa0SCS, but did not detect a difference in generic health-related quality-of-life outcomes.\n\n## Further EAC review of the randomised controlled trial evidence\n\nKapural et\xa0al.\xa0(2016) and De Andres et\xa0al.\xa0(2017) reported randomised controlled trials comparing Senza with low‑frequency\xa0SCS, with inconsistent findings. Specifically, Kapural et\xa0al.\xa0(2016) reported a statistically significant reduction in back and leg pain with Senza compared with low‑frequency\xa0SCS whereas De Andres et\xa0al.\xa0(2017) reported no difference in pain scores. The trial design and conduct of the De Andres study was openly challenged and the authors' responses to these criticisms were summarised in a letter that was published in the same journal as the original paper (see the supplementary EAC documents for more details).\n\nHaving reviewed all of the evidence, the EAC concluded that Senza is likely to be at least as effective as low‑frequency\xa0SCS in terms of reducing pain in appropriately selected patients. However, it noted that both the Kapural et\xa0al.\xa0(2016) and particularly the De Andres et\xa0al.\xa0(2017) studies were subject to bias and had design and reporting weaknesses, significantly more so for the latter. Because of this, the EAC considered that the results should be interpreted with caution.\n\nBecause of the inconsistent trial results and because of a large number of conflicting comments received during both consultations, a second EAC reviewed the randomised controlled trial evidence. It concluded that the De Andres et\xa0al.\xa0(2017) study was methodologically worse than Kapural et\xa0al.\xa0(2016). It drew specific attention to weaknesses in terms of the trial's analysis, governance and design (see the supplementary EAC documents or more details).\n\n# Summary of economic evidence\n\nThe company's cost model was based on a published cost-effectiveness study (Annemans et\xa0al.\xa02014) comparing Senza separately with conventional medical management, reoperation and low‑frequency\xa0SCS\xa0devices (both rechargeable and non-rechargeable). The model, which was also used to inform the NICE technology appraisal guidance on spinal cord stimulation (Simpson et\xa0al.\xa02008), was a 2-stage decision analytic model that used a decision tree for the first 6\xa0months, followed by a Markov state transition model with a 15‑year time horizon. For full details of the economic evidence, see section 4 of the assessment report and the supplementary EAC documents.\n\n# EAC's analysis of the economic evidence\n\nThe EAC considered Annemans et\xa0al.\xa0(2014) to be of high quality and the company's cost model to be of good methodological quality. It was therefore initially satisfied with the reported results and sensitivity analyses. However, the publication of Van Buyten et\xa0al.\xa0(2017) during the first consultation provided additional real-world data as an alternative estimate for the rate of unanticipated explantation used in the cost model. The EAC did not change the anticipated explants parameters in the model but estimated the unanticipated explantation parameters used in the cost model by extrapolating the data available from Van Buyten et\xa0al.\xa0for explantations because of inadequate pain relief (see the supplementary EAC documents for more details).\n\nMany of the costs in the model, including the acquisition costs for Senza and its comparators, were adjusted for inflation from the original values in the Annemans et\xa0al.\xa0study. The EAC considered it inappropriate to inflate drug prices in this way because they are subject to a wide range of non-inflationary factors. The EAC explored this further with 4 hypothetical scenarios to assess how different drug costs affect the cost consequences of using Senza.\n\nThe main drivers of the cost modelling results were acquisition costs, explantation rates and device lifespan, particularly for non-rechargeable SCS\xa0devices, which need to be replaced around every 4\xa0years. The company's base-case results showed that, over 15\xa0years, Senza could lead to cost savings of £4,795 compared with rechargeable low‑frequency\xa0SCS\xa0devices and £7,755 compared with non-rechargeable low‑frequency\xa0SCS\xa0devices.", 'Committee discussion': "# Clinical effectiveness\n\nThe committee considered the clinical evidence and noted the inconsistent results from the 2 randomised controlled trials (Kapural et\xa0al.\xa02016 and De Andres et\xa0al.\xa02017). In particular, the committee noted that Kapural et\xa0al.\xa0demonstrated statistically significantly better pain reduction using Senza compared with low‑frequency\xa0spinal cord stimulation (SCS), but that in De Andres et\xa0al.\xa0there was no statistically significant difference between the 2 treatments in this regard. The expert advisers explained that the low‑frequency\xa0SCS\xa0devices used as the comparator in both studies work in the same way as those used in standard clinical practice in the NHS. However, the response to low‑frequency\xa0SCS was lower than expected in De Andres et al., compared with both clinical experience and other trial results including Kapural et\xa0al.\xa0The external assessment centre (EAC) also highlighted that pain reduction was greater in Kapural et\xa0al.\xa0for both Senza and low‑frequency\xa0SCS compared with both treatment arms in De Andres et al.\n\nThe committee was concerned about the methodological quality of the De Andres et\xa0al.\xa0(2017) study, noting the conclusions of the 2 EAC reports about the reliability and robustness of the evidence. Although the committee noted the weaknesses in both randomised controlled trials, including the potential for bias and concerns about the relevance of the results to the NHS, it agreed with the EAC's conclusion that Senza is at least as effective as low‑frequency\xa0SCS in terms of relieving pain. It acknowledged that current studies are limited to 2 years' follow-up; a clinical expert explained that 3-year outcome data will soon be available, and that the ultimate intention is to collect 5-year follow-up data. The committee considered that long-term outcome data would be particularly important, given that Senza and other similar devices are used to treat a chronic condition and have a lifespan of at least 10\xa0years. The committee concluded that, in view of these uncertainties, it would be beneficial for clinicians to routinely collect clinical and procedural outcome data on the use of SCS including Senza. It was encouraged to hear that the UK Neuromodulation Registry has well-established data collection arrangements to support the gathering of useful data.\n\n## Avoiding paraesthesia\n\nPeople having low‑frequency\xa0SCS often experience paraesthesia (or tingling sensations), but this is not the case with high-frequency\xa0SCS (such as Senza). The experts explained that people may have paraesthesia throughout the use of low‑frequency\xa0SCS\xa0devices and that this can impair day-to-day living. For example, intense paraesthesia may be distracting enough to interrupt sleep or prevent tasks such as driving or operating machinery. However, the committee heard that some patients (usually those who have had low‑frequency\xa0SCS for a long time) find the presence of paraesthesia reassuring, because it confirms that the device is still working. The committee concluded that paraesthesia after SCS device implantation is an important issue that should be discussed with patients before choosing a device.\n\n## Patient selection\n\nThe committee noted that most of the higher quality evidence for the clinical benefits of Senza is in people who have chronic back or leg pain despite previous back surgery. The clinical experts agreed that this is the largest group of patients who are likely to benefit from Senza, but highlighted others who may benefit (for example, people for whom surgery is either not possible or unlikely to be successful and people with neuropathic pain of other causes including complex regional pain syndrome). However, the committee concluded that there is limited evidence to support the claimed benefits for Senza in these other patient groups. It noted that these patient groups are already covered by the recommendations in the NICE technology appraisal guidance on spinal cord stimulation. The committee also concluded that more evidence would be valuable about the potential role of Senza for neuropathic pain in patients who have not had previous back surgery. The committee was supportive of further research in these difficult circumstances, and would encourage SCS users to include patient data following all implantations in the UK Neuromodulation Registry.\n\n## Mode of action\n\nThe clinical experts advised that Senza uses different physiological mechanisms to low‑frequency\xa0SCS, but these are not yet fully understood.\n\n# NHS considerations\n\nThe clinical experts explained that because paraesthesia mapping is not needed when using Senza, implantation procedure times may be shorter and more predictable compared with those for low‑frequency\xa0SCS\xa0devices. The committee was advised that, typically, 2 electrodes are used when implanting Senza compared with 1 electrode for low‑frequency\xa0SCS\xa0devices. The EAC explained that these factors had not been quantified in the published studies and so were not included in the cost modelling. The committee concluded that it is plausible that using Senza may allow for better planning of procedure times (thereby potentially increasing the number of procedures per operating list).\n\nThe clinical experts explained that when first adopting Senza in their services, the company provided trained experts to attend procedures and support clinicians until competence had been achieved. This was confirmed by the company representatives who attended the meetings.\n\nThe clinical experts also explained that there may be further time savings when using Senza at follow-up appointments because, in their experience, programming is easier and less time-consuming than with low‑frequency\xa0SCS\xa0devices.\n\n## Charging the device\n\nBased on NHS Supply Chain purchase data, the committee concluded that the low‑frequency\xa0SCS\xa0devices most commonly used in the NHS are rechargeable. The clinical experts explained that although Senza is also rechargeable, it needs to be charged more often than most low‑frequency\xa0SCS\xa0devices (for 30 to 45 minutes each day). The committee concluded that the need for recharging is an important factor that should be discussed with patients before choosing a device.\n\n## Cost savings\n\nThe committee noted that the company's cost model replicated that used to inform the NICE technology appraisal guidance on spinal cord stimulation, and that the model has also been subjected to peer review before being published elsewhere. It agreed with the EAC that supplementation of the model with data from Van Buyten et\xa0al.\xa0(2017) was appropriate.\n\nThe committee noted that the model assumed a time horizon of 15\xa0years. This is appropriate for a long-term condition, but clinical outcome data are currently limited to 2\xa0years after implantation. Nonetheless, it noted the EAC's conclusions that the claimed lifespan of Senza is plausible (see the supplementary EAC documents for more details). The clinical experts also explained that they had seen no evidence in their own clinical practices to suggest that the effectiveness of Senza diminishes over time.\n\nThe committee noted the uncertainties in the cost model associated with the use of drug costs adjusted for inflation. The EAC explained that additional modelling involving attempts to more accurately estimate the cost of drug management in the relevant patient groups would be difficult.\n\nHaving acknowledged that the acquisition costs of Senza and the comparators were an important driver of the cost modelling results, the committee noted that these had also been adjusted for inflation from the cost model used to inform the NICE technology appraisal guidance on spinal cord stimulation. Acquisition costs in the model were assumed to be:\n\nSenza: £16,648, with a lifespan of 10\xa0years.\n\nNon-rechargeable low‑frequency\xa0SCS device: £11,281, with a lifespan of 4\xa0years.\n\nRechargeable low‑frequency\xa0SCS device: £17,422, with a lifespan of 10\xa0years.The EAC confirmed that these are an accurate reflection of current device costs.\n\nThe committee noted the results of the EAC's updated cost model (which included explantation data from Van Buyten et\xa0al.\xa02017), which showed that:\n\nOver 15\xa0years, compared with using a non-rechargeable low‑frequency\xa0SCS device, Senza is cost incurring by £351 per patient (£23.40 per year).\n\nOver 15\xa0years, compared with using a rechargeable low‑frequency\xa0SCS device, Senza is cost saving by £2,292 per patient (£152.80 per year).The committee concluded that, despite the uncertainties in the cost model and the extrapolations made over the 15-year time horizon, it is unlikely that using Senza will incur additional overall costs compared with using low‑frequency\xa0SCS\xa0devices."}
|
https://www.nice.org.uk/guidance/mtg41
|
Evidence-based recommendations on the Senza spinal cord stimulation system for delivering HF10 therapy to treat chronic neuropathic pain.
|
7db95a91254a82c5f37191511dcc99c52e99e245
|
nice
|
Ex-situ machine perfusion for extracorporeal preservation of livers for transplantation
|
Ex-situ machine perfusion for extracorporeal preservation of livers for transplantation
Evidence-based recommendations on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation in people of all ages. This involves using a machine to give an oxygenated solution to the donor liver until it is transplanted.
# Recommendations
The evidence on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do ex-situ machine perfusion for extracorporeal preservation of livers for transplantation should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients given a liver which has had ex-situ machine perfusion understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation is recommended.
Audit and review clinical outcomes of all patients given a liver which has had ex-situ machine perfusion for extracorporeal preservation of livers for transplantation. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Clinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the Human Tissue Authority.
Clinicians should enter details about all patients having this procedure into the NHS Blood and Transplant UK transplant registry.
Further research should report the exact method of perfusion used (such as hypothermic or normothermic), graft survival and the use of marginal grafts.# The condition, current treatments and procedure
# The condition
Liver transplantation is the treatment of choice for patients with end-stage liver disease. It may also be indicated in patients with some types of primary liver cancer. End-stage liver failure can be either acute (for example, from poisoning) or chronic (for example, because of cirrhosis from alcohol-related liver disease, metabolic, autoimmune or infectious conditions). In children, the most common cause of end-stage liver failure is congenital biliary atresia.
# Current treatments
Limited availability of deceased donor livers for transplantation led to the development of techniques that increase the number of recipients who can benefit from 1 available organ. These include split liver grafts (the larger right lobe is usually grafted into an adult and the left lobe into a child) and reduced (segmental) liver grafts.
Living-donor liver transplantation is also an option for patients who are deteriorating clinically while waiting for a deceased donor transplant.
# The procedure
Ex-situ machine perfusion preserves the donor liver outside the body under normothermic or hypothermic conditions. A perfusion machine is used to deliver oxygenated perfusate (which may or may not contain blood depending on the technique employed), supplemented with nutrients and metabolic substrates. The intention is to:
reduce the rate of tissue deterioration that occurs after the liver has been removed from the donor compared with that seen with conventional static cold storage
extend how long the liver can be stored to allow more flexibility in the timing of the transplant operation.Normothermic machine perfusion also allows assessment of donor liver viability and function during preservation. The aim is to improve clinical outcomes for the recipient and to enable otherwise marginal organs (such as those donated after circulatory death, steatotic livers and livers from older people) to be transplanted safely, so increasing the number of livers available for transplantation.
In this procedure, the donor liver is placed in a perfusion machine. The precise configuration of the machine depends on whether normothermic or hypothermic perfusion is being used. Typically, it comprises a reservoir, a pump, an oxygenator, a warming or cooling unit and, for normothermic machine perfusion only, monitoring equipment. Both the hepatic artery and portal vein of the liver may be perfused. For normothermic perfusion, the effluent perfusate is collected and recirculated through the liver. A donor liver can be perfused for several hours, after which it can be implanted into a recipient in the conventional way.
|
{'Recommendations': "The evidence on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do ex-situ machine perfusion for extracorporeal preservation of livers for transplantation should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients given a liver which has had ex-situ machine perfusion understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation is recommended.\n\nAudit and review clinical outcomes of all patients given a liver which has had ex-situ machine perfusion for extracorporeal preservation of livers for transplantation. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nClinicians and centres doing this procedure must follow the relevant regulatory and legal requirements of the Human Tissue Authority.\n\nClinicians should enter details about all patients having this procedure into the NHS Blood and Transplant UK transplant registry.\n\nFurther research should report the exact method of perfusion used (such as hypothermic or normothermic), graft survival and the use of marginal grafts.", 'The condition, current treatments and procedure': '# The condition\n\nLiver transplantation is the treatment of choice for patients with end-stage liver disease. It may also be indicated in patients with some types of primary liver cancer. End-stage liver failure can be either acute (for example, from poisoning) or chronic (for example, because of cirrhosis from alcohol-related liver disease, metabolic, autoimmune or infectious conditions). In children, the most common cause of end-stage liver failure is congenital biliary atresia.\n\n# Current treatments\n\nLimited availability of deceased donor livers for transplantation led to the development of techniques that increase the number of recipients who can benefit from 1\xa0available organ. These include split liver grafts (the larger right lobe is usually grafted into an adult and the left lobe into a child) and reduced (segmental) liver grafts.\n\nLiving-donor liver transplantation is also an option for patients who are deteriorating clinically while waiting for a deceased donor transplant.\n\n# The procedure\n\nEx-situ machine perfusion preserves the donor liver outside the body under normothermic or hypothermic conditions. A perfusion machine is used to deliver oxygenated perfusate (which may or may not contain blood depending on the technique employed), supplemented with nutrients and metabolic substrates. The intention is to:\n\nreduce the rate of tissue deterioration that occurs after the liver has been removed from the donor compared with that seen with conventional static cold storage\n\nextend how long the liver can be stored to allow more flexibility in the timing of the transplant operation.Normothermic machine perfusion also allows assessment of donor liver viability and function during preservation. The aim is to improve clinical outcomes for the recipient and to enable otherwise marginal organs (such as those donated after circulatory death, steatotic livers and livers from older people) to be transplanted safely, so increasing the number of livers available for transplantation.\n\nIn this procedure, the donor liver is placed in a perfusion machine. The precise configuration of the machine depends on whether normothermic or hypothermic perfusion is being used. Typically, it comprises a reservoir, a pump, an oxygenator, a warming or cooling unit and, for normothermic machine perfusion only, monitoring equipment. Both the hepatic artery and portal vein of the liver may be perfused. For normothermic perfusion, the effluent perfusate is collected and recirculated through the liver. A donor liver can be perfused for several hours, after which it can be implanted into a recipient in the conventional way.'}
|
https://www.nice.org.uk/guidance/ipg636
|
Evidence-based recommendations on ex-situ machine perfusion for extracorporeal preservation of livers for transplantation in people of all ages. This involves using a machine to give an oxygenated solution to the donor liver until it is transplanted.
|
c9ec5a82a5c096072bb6c979061f297e4029aed3
|
nice
|
Cerebral palsy in adults
|
Cerebral palsy in adults
This guideline covers care and support for adults with cerebral palsy. It aims to improve health and wellbeing, promote access to services and support participation and independent living.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Service organisation
## Access to services
Refer adults with cerebral palsy to a multidisciplinary team experienced in the management of neurological impairments if:
their ability to carry out their usual daily activities deteriorates or
a neurosurgical or orthopaedic procedure is being considered that may affect their ability to carry out their usual daily activities.
Recognise that reassessment by the multidisciplinary team may be needed by adults with cerebral palsy at different points in their lives to ensure that their changing needs are met (for example, pregnancy and parenting, decreased mobility due to hip arthritis, and loss of care and support from a parent).
Commissioners and service providers should develop pathways that allow adults with cerebral palsy access to a local network of care that includes:
advocacy support
learning disability services
mental health services
-rthopaedic surgery (and post-surgery rehabilitation)
rehabilitation engineering services
rehabilitation medicine or specialist neurology services
secondary care expertise for managing comorbidities (for example, respiratory, gastrointestinal and urology services)
social care
specialist therapy services (for example, physiotherapy, occupational therapy, speech and language therapy, and dietetics)
wheelchair services.
Ensure that adults with cerebral palsy, their families and carers, and their primary care teams are provided with information about their local network of specialist services.
Explain to the person with cerebral palsy and their family members and carers their right to a care and support needs assessment, in line with the Care Act 2014, and discuss with them the type of support available (see NICE's guideline on supporting adult carers).
For advice on access to services when adults with cerebral palsy transfer from hospital to home, refer to the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs. For the principles of social care provision, see the NICE guideline on people's experience in adult social care services.
Recognise and address any personal barriers to accessing primary and secondary care for adults with cerebral palsy. For example, this may involve:
ensuring healthcare professionals have the skills and training to overcome communication difficulties
providing treatment and support for mental health problems
ensuring that the person has an advocate, if needed
providing support to help with social and emotional factors, such as fear of stigma, lack of motivation and exhaustion.
Recognise and address any physical and organisational barriers to accessing primary and secondary care for adults with cerebral palsy. For example, this may involve:
improving physical access to buildings
providing advice and information on accessible transport services, for example, local community transport services
ensuring that appropriate equipment (for example, hoists and wheelchair weighing scales) and adequate changing and toilet facilities are available
extending appointment times, if needed.
When an adult with cerebral palsy is admitted to hospital, the staff should always offer advocacy, and health and personal care (including toileting, washing, nutrition and hydration) even if the person has a family member, carer or advocate there to support them.
Give information to people with cerebral palsy about national screening services (for example, breast, colon and cervical cancer screening) and encourage them to attend screening appointments. Explain that screening services will have to make arrangements to provide screening services that are accessible to people with cerebral palsy.
## Moving into adults' services
For young adults with cerebral palsy moving from children's services, ensure that transitions are managed in line with transition to adults' services in the NICE guideline on cerebral palsy in under 25s and the NICE guideline on transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to services and moving into adults' services .
Full details of the evidence and the committee's discussion are in evidence review F1: configuration of services for adults with cerebral palsy and evidence review F2: barriers to access to primary and secondary care.
Loading. Please wait.
## Ongoing care
Consider regular reviews for adults with cerebral palsy, tailored to their needs and preferences. Agree with the person the frequency of review and which services should be involved based on their needs and preferences.
Offer an annual review of the person's clinical and functional needs, carried out by a healthcare professional with expertise in neurodisabilities, for people with cerebral palsy who have complex needs (such as Gross Motor Function Classification System levels IV and V) and any of the following:
communication difficulties
learning disabilities
living in long-term care settings
living in the community without sufficient practical and social support (for example, being cared for by elderly, frail parents)
multiple comorbidities.
Discuss with the person with cerebral palsy (and their family and carers, if agreed) what information should inform the regular or annual review, and who should receive clinical information following review (for example, their GP).
Record details of the person's review and share the information with relevant people (for example, healthcare professionals and social care practitioners), with the person's permission.
Identify who will be the main point of contact for the person with cerebral palsy (and their family and carers, if agreed) between reviews, and provide information on how to contact them.
If an adult with cerebral palsy chooses not to have regular reviews, offer the person (and their family and carers, if agreed) information on when to contact a healthcare professional and how to access the specialist services that they may need. Ensure that the person's GP and multidisciplinary team are aware that they do not want to be reviewed regularly (with the person's permission).
For adults with cerebral palsy and learning disabilities, follow the recommendations in NICE's guideline on care and support of people growing older with learning disabilities.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on ongoing care .
Full details of the evidence and the committee's discussion are in evidence review F1: configuration of services for adults with cerebral palsy.
Loading. Please wait.
# Function and participation
## Communication
Be aware that speech and communication needs in adults with cerebral palsy may change with time and social circumstances.
At every review, ask adults with cerebral palsy (and their families and carers, if agreed) about any changes in their hearing, speech and communication.
Explore with the person with cerebral palsy who has communication difficulties whether they have a potential need for alternative and augmentative communication systems.
Ensure that training is provided for people with cerebral palsy using alternative and augmentative communication systems and their families, carers and other key communication partners in home, care, social or work environments.
Be aware that adults with cerebral palsy and poor intelligibility of speech may still prefer to use speech as their main means of communication.
Refer adults with cerebral palsy who have communication difficulties to speech and language therapy services to assess their need for intervention, which may include:
use of alternative or augmentative communication systems
intensive speech therapy to improve the intelligibility of their speech.See also communication and information in the NICE guideline on patient experience in adult NHS services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication .
Full details of the evidence and the committee's discussion are in evidence review D4: interventions to promote participation: communication.
Loading. Please wait.
## Vocational skills and independent living
Identify and address any factors that prevent people with cerebral palsy from participating in activities, including:
physical barriers, for example, access to buildings
personal barriers, for example, carers with unmet training needs
-rganisational barriers, for example, policies and situations that put people with cerebral palsy at a disadvantage.
Ask adults with cerebral palsy what they enjoy doing and if they find it difficult to participate in a chosen activity, assess their physical and mental health, and address any factors identified that may be affecting participation, if possible.
If adults with cerebral palsy have complex physical, cognitive, language or sensory needs, consider referral to occupational therapy services to assess the person's functional needs and provide individualised support.
Give adults with cerebral palsy information about assessments of vocational and independent living skills that is tailored to the person's functional abilities and goals (see NICE's guideline on patient experience in adult NHS services for advice on information giving and NICE's guideline on people's experience in adult social care services for details of the information that local authorities should provide).
Refer adults with cerebral palsy who would like to live independently to a professional with expertise in independent living (for example, an occupational therapist). Give information and advice, which could include:
adaptations to their home
housing
leisure activities
statutory welfare benefits.
Refer adults with cerebral palsy who would like to work, or who are already working, to a professional with expertise in vocational skills and independent living (for example, an occupational therapist). Give information and advice, which could include:
continued education
job seeking or access to work schemes
employment support to include workplace training and job retention
-ccupational health assessment or workplace assessment
statutory welfare benefits
supporting a planned exit from the workforce if it becomes too difficult to continue working
vocational rehabilitation
voluntary work.See also NICE's guideline on workplace health: management practices for advice on improving the health and wellbeing of employees.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vocational skills and independent living .
Full details of the evidence and the committee's discussion are in evidence review D1: interventions to promote participation – vocational and independent living skills.
Loading. Please wait.
## Electronic assistive technology
Discuss with adults with cerebral palsy the potential role of electronic assistive technology if they have problems with participation and independence.
If adults with cerebral palsy have complex physical, cognitive, language or sensory needs, consider referring them to services providing information, assessment and provision of electronic assistive technology.
Be aware that using electronic assistive technology may mean that the person with cerebral palsy needs less contact with their carers, which may reduce their social interaction.
If adults with cerebral palsy are already using electronic assistive technology, discuss at every review any:
problems or concerns they have with their equipment
potential changes in their needs.
Ensure that training is provided for adults with cerebral palsy using electronic assistive technology, and for their families or carers, if appropriate.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on electronic assistive technology .
Full details of the evidence and the committee's discussion are in evidence review D3: electronic assistive technology.
Loading. Please wait.
## Physical activity
Discuss with adults with cerebral palsy (and their families or carers, if agreed) the importance of physical activity in maintaining general fitness and physical and mental health.
Provide information on accessible local services that support people with cerebral palsy to take part in physical activity.
Consider referring people with cerebral palsy to services with experience and expertise in neurological impairments that can provide support with physical activities (including sport) and tasks of daily living. Depending on local service provision and the person's needs, this may be to any of the following services:
physiotherapy
-ccupational therapy
-rthotic and functional electronic stimulation services
rehabilitation engineering services
wheelchair services.
## Orthopaedic surgery
If people with cerebral palsy have problems participating in physical activities because of pain or joint problems that do not respond to any other treatments, consider referring them to a musculoskeletal specialist or an orthopaedic surgeon with experience and expertise in managing musculoskeletal problems in adults with cerebral palsy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity, orthopaedic surgery and orthotics .
Full details of the evidence and the committee's discussion are in evidence review D2: interventions that improve or maintain physical function and participation.
Loading. Please wait.
# Managing abnormal muscle tone
## Agreeing goals for treatment
Discuss with the adult with cerebral palsy (and their family and carers, if agreed) treatments for spasticity or dystonia, including:
personal treatment goals (which should be documented) and
the benefits and risks of treatments (for example, the risk of deterioration in function) as part of their multidisciplinary treatment strategy.See also enabling patients to actively participate in their care in the NICE guidelines on patient experience in adult NHS services and shared decision making.
Discuss with the person with cerebral palsy (and their family and carers, if agreed) the balance between the benefits and harms of treating spasticity and dystonia. In particular, explain that some people use their spasticity or dystonia to help their posture and ability to stand, walk or transfer, and that treatment may affect this.
## Initial management of spasticity and dystonia
Be aware that adults with cerebral palsy may have both spasticity and dystonia. The severity of symptoms for both conditions may fluctuate in response to health, social and emotional wellbeing, and environmental factors.
At every review, discuss with the person with cerebral palsy (and their family and carers, if agreed) factors that may exacerbate their spasticity or dystonia, such as:
bladder problems (for example, urinary tract infection or bladder stones)
constipation
emotional distress
pain
posture
pressure sores
changes in home or work environments, including seating
medication changes and side effects.
Before discussing further management options for spasticity or dystonia with a person with cerebral palsy:
address any modifiable factors identified that may be exacerbating the spasticity or dystonia and
review their physical management programme.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on agreeing goals for treatment and initial management of spasticity and dystonia .
Full details of the evidence and the committee's discussion are in evidence review A1: pharmacological treatments for spasticity and evidence review A3: interventions for dystonia.
Loading. Please wait.
## Spasticity
In January 2019, giving baclofen via an enteral feeding tube was an off-label use. See NICE's information on prescribing medicines.
Consider enteral baclofen as the first-line drug treatment for adults with cerebral palsy and generalised spasticity causing:
functional impairment or
pain or
spasms.
Start enteral baclofen treatment with a low dose and increase the dose gradually over about 4 weeks to achieve the optimum therapeutic effect.
If enteral baclofen is ineffective or not tolerated by adults with cerebral palsy and generalised spasticity:
refer the person to a tone or spasticity management service or
discuss other drug treatment options (including other enteral muscle relaxants) with a tone management specialist.
Do not offer diazepam for spasticity in adults with cerebral palsy, except in an acute situation when spasticity is causing severe pain or anxiety.
Do not rapidly withdraw muscle relaxant drugs, particularly if adults with cerebral palsy have taken them for more than 2 months or at a high dosage. Reduce the dosage gradually to avoid withdrawal symptoms.If using a benzodiazepine (such as diazepam) as a muscle relaxant for spasticity, see NICE's guideline on medicines associated with dependence or withdrawal symptoms for guidance on safe prescribing.
Consider referring adults with cerebral palsy for botulinum toxin type A treatment if:
they have spasticity in a limited number of muscle groups that is:
affecting their care (such as hygiene or dressing) or
causing pain or
impairing activity and participation, or
a tone management specialist agrees that treatment targeted to focal muscle groups is likely to improve their function and symptoms.In January 2019, there were several different preparations of botulinum toxin type A and the licensed indications varied between them. See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on drug treatments for spasticity .
Full details of the evidence and the committee's discussion are in evidence review A1: pharmacological treatments for spasticity.
Loading. Please wait.
Intrathecal baclofen
Consider referring adults with cerebral palsy to a tone or spasticity management service offering continuous pump-administered intrathecal baclofen therapy if they still have difficulties with spasticity, despite enteral muscle relaxant drug treatment or botulinum toxin type A treatment.
When considering continuous pump-administered intrathecal baclofen, give the person (and their family and carers, if agreed) information and discuss the procedure with them. This should include:
the need for an intrathecal baclofen test to ensure treatment is suitable
the surgical procedure for implanting the pump
the need for regular hospital follow‑up visits to ensure optimal dosage and pump refill
the risks of implanting a pump and pump-related complications (for example, battery failure or catheter leakage), which can result in baclofen withdrawal or overdose
a review of 24-hour postural needs.
If continuous pump-administered intrathecal baclofen is being considered for an adult with cerebral palsy, perform an intrathecal baclofen test to assess if it is suitable before implanting a pump. This should involve a test dose or doses of intrathecal baclofen given to the person by lumbar puncture or through a spinal catheter.
Assess the effect of the test dose or doses of intrathecal baclofen on:
reducing increased muscle tone
reducing pain
reducing the frequency of muscle spasms
motor function, such as sitting, standing and walking.
Discuss with the adult with cerebral palsy (and their family and carers, if agreed) their views on the response to the intrathecal baclofen test and whether treatment is likely to achieve their treatment goals.
Selective dorsal rhizotomy
Only consider selective dorsal rhizotomy for adults with cerebral palsy and spasticity if other treatments have been unsuccessful or are contraindicated, and after they have been assessed by a multidisciplinary team with:
specialist training and expertise in the care of spasticity and
access to the full range of treatment options. See also NICE interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy.
Discuss the impact of selective dorsal rhizotomy with the person (and their family and carers, if agreed) when it is a proposed treatment option and provide information. This should include:
that the procedure cannot be reversed
the possible complications
the need for prolonged physiotherapy and aftercare
the possible impact on function
that the long-term benefits are uncertain.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neurosurgical treatments to reduce spasticity .
Full details of the evidence and the committee's discussion are in evidence review A2: neurosurgical treatments for spasticity.
Loading. Please wait.
## Dystonia
Refer adults with cerebral palsy and problematic dystonia (for example, causing problems with function, pain or participation) to a tone or spasticity management service to consider treatment options.
Do not prescribe levodopa to manage dystonia in adults with cerebral palsy, except in the rare situation when it is used as a therapeutic trial to identify dopa-responsive dystonia.In January 2019, this was an off-label use of levodopa. See NICE's information on prescribing medicines.
Do not rapidly withdraw enteral drugs for treating dystonia, particularly if adults with cerebral palsy have taken them for more than 2 months or at a high dosage. Reduce the dosage gradually to avoid withdrawal symptoms. In January 2019, giving anti-dystonic drugs via an enteral feeding tube was an off-label use. See NICE's information on prescribing medicines.
In January 2019, the recommendations in this section were for an off-label use of botulinum toxin type A. See NICE's information on prescribing medicines.
Only consider botulinum toxin type A treatment for focal dystonia in adults with cerebral palsy when:
the person is under the supervision of a tone or spasticity management service, and it is part of a wider programme of therapy and
focal dystonia is:
affecting their care (such as hygiene or dressing) or
causing pain or
impairing activity and participation.
If botulinum toxin type A is a proposed treatment option, take into account and explain to the adult with cerebral palsy (and their family and carers, if agreed):
that the severity and pattern of dystonia may change after treatment and
the potential impact of treatment on function.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on drug treatments for dystonia .
Full details of the evidence and the committee's discussion are in evidence review A3: treatments to reduce dystonia.
Loading. Please wait.
Intrathecal baclofen
Only consider continuous pump-administered intrathecal baclofen if people with cerebral palsy still have difficulties with dystonia, despite having enteral anti-dystonic drug treatment or botulinum toxin type A treatment. Provide information and discuss the procedure, including intrathecal baclofen testing, with the person (and their family or carer, if agreed) as described in recommendations 1.3.13 to 1.3.16.In January 2019, this was an off-label use for intrathecal baclofen and botulinum toxin type A. See NICE's information on prescribing medicines.
Deep brain stimulation
If adults with cerebral palsy continue to have severe and painful dystonia, despite having enteral anti-dystonic drug treatment or botulinum toxin type A treatment, consider referring them to a specialised centre with experience in providing deep brain stimulation. See also NICE interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neurosurgical treatments to reduce dystonia .
Full details of the evidence and the committee's discussion are in evidence review A3: treatments to reduce dystonia.
Loading. Please wait.
# Assessment and monitoring of clinical complications and comorbidities
## Bone and joint disorders
Discuss with adults with cerebral palsy (and their families or carers, if agreed) that:
their musculoskeletal function may deteriorate gradually, and any changes should be investigated to identify treatable causes
early recognition of bone and joint disorders enables early treatment, which may improve outcomes.
Be aware that low bone mineral density is common in adults with cerebral palsy, particularly in people:
with reduced mobility or reduced weight bearing
taking anticonvulsants or proton pump inhibitors
who have had a previous low-impact fracture.
Consider assessing for risk of fractures secondary to osteoporosis in adults with cerebral palsy. Risk factors to assess include:
needing help with moving or having to be moved, for example, hoisting
history of falls
low BMI
history of low-impact fractures
-ther medical factors, for example steroid use, that may adversely affect bone health.For more information about assessment of fracture risk, see NICE's guideline on osteoporosis: assessing the risk of fragility fracture.
Consider a dual-energy X‑ray absorptiometry (DXA) assessment in adults with cerebral palsy who have 2 or more risk factors (see recommendation 1.4.3), particularly if they have had a previous low-impact fracture.
Consider referring adults with cerebral palsy for specialist assessment and management, for example, to a rheumatology, endocrinology or bone health service, if they have:
a high fracture risk or
a positive DXA result.
Be aware that, because of abnormal musculoskeletal development, adults with cerebral palsy are more likely to have bone and joint disorders.
Refer adults with cerebral palsy to a specialist orthopaedic or musculoskeletal service if a bone or joint disorder is suspected and causing pain or affecting posture or function. These may include:
-steoarthritis
cervical instability or spondylosis (including athetosis)
spinal deformity (including scoliosis, kyphosis and lordosis)
subluxation of the hips, wrist and shoulders
biomechanical knee problems
abnormalities of the foot structure.
Do not offer an X‑ray to assess for hip subluxation or curvature of the spine in adults with cerebral palsy, unless the person is in pain or their posture or function is affected.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bone and joint disorders .
Full details of the evidence and the committee's discussion are in evidence review B1: disorders of bones and joints.
Loading. Please wait.
## Mental health problems
Identify and address mental health problems alongside physical health problems. Recognise that the impact of mental health problems and emotional difficulties can be as important as physical health problems for adults with cerebral palsy.
Follow NICE guidelines on identifying and managing specific mental health problems, and psychological and neurodevelopmental disorders, in adults who have cerebral palsy, for example:
attention deficit hyperactivity disorder
depression in adults and depression in adults with a chronic physical health problem
generalised anxiety disorder and panic disorder in adults
autism spectrum disorder in adults
challenging behaviour and learning disabilities
mental health problems in people with learning disabilities.
Tailor the identification and assessment of mental health problems and emotional difficulties to the needs and abilities of the person with cerebral palsy, in particular take into account communication difficulties or learning disabilities.
At every review, explore with the adult with cerebral palsy (and their family and carers, if agreed) if they have any concerns about, for example, their:
mood
irritability
behaviour
social interaction
sleep
general level of function.
Involve families and carers, when agreed, in identifying and assessing mental health problems and emotional difficulties in adults with cerebral palsy.
Take into account the specific factors that might affect identifying, assessing and managing mental health problems and emotional difficulties in people with cerebral palsy. These may include:
adverse effects of medicines (including the effects of medicines used for managing mental health problems on motor function or those used for managing motor function on mental health)
communication difficulties
learning disabilities
impaired neuropsychological and executive functions
comorbidities, particularly epilepsy and pain
side effects and drug interactions of multiple medicines (polypharmacy).
Discuss with the adult with cerebral palsy (and their family and carers, if agreed) if physical problems, such as pain, or frustration from communication difficulties or lack of stimulation are contributing to emotional distress or challenging behaviour.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on mental health problems .
Full details of the evidence and the committee's discussion are in evidence review B2: monitoring and assessing mental health.
Loading. Please wait.
## Difficulties with eating and nutritional problems
Offer adults with cerebral palsy a regular weight check, and BMI or another anthropometric measurement, and identify people who may be at risk of undernutrition or obesity (see also the NICE guideline on obesity: identification, assessment and management).
At every review, discuss with adults with cerebral palsy (and their family and carers, if agreed) whether they have difficulties with eating or if there have been any changes in their eating habits or bowel function. Ask about issues including:
changes in appetite
changes in the person's ability to feed themselves
constipation
coughing or choking when eating
food refusal
increased frequency of chest infections (which may be related to swallowing difficulties or gastro-oesophageal reflux)
an increase in the length of meal times.
Discuss if any of the following factors might be affecting the person's appetite, eating habits or weight:
changes in carer support
depression
pain
reduced physical activity
side effects of medications.
Be aware that adults with cerebral palsy with severe spasticity and dyskinesia may have an increased metabolic rate and a higher risk of malnutrition.
Follow the recommendations on screening for malnutrition, indications for nutrition support, and education and training of staff and carers related to nutrition, in NICE's guideline on nutrition support for adults.
Refer adults with cerebral palsy to a relevant clinical specialist, such as a dietitian or speech and language therapist, if assessment suggests they have difficulties with eating or malnutrition.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on difficulties with eating and nutritional problems .
Full details of the evidence and the committee's discussion are in evidence review B3: monitoring feeding and nutritional problems.
Loading. Please wait.
## Respiratory disorders
Be aware that adults with cerebral palsy are at increased risk of respiratory failure. Symptoms may include:
breathlessness
changes in behaviour (such as irritability or inability to concentrate)
daytime drowsiness
worsening epilepsy
headaches on waking
increasing frequency of chest infections
poor sleep pattern
sleep apnoea.
Recognise that some risk factors for respiratory impairment are more common in adults with severe cerebral palsy (GMFCS level IV or V), such as:
aspiration pneumonia
chronic cardiorespiratory disorders (for example, cor pulmonale or pulmonary circulation hypertension)
chronic suppurative lung disease
kyphoscoliosis
poor saliva control
recurrent chest infections.
Refer adults with cerebral palsy and persistent or multiple signs and symptoms of respiratory impairment, or risk factors for respiratory impairment (see recommendations 1.4.22 and 1.4.23) to specialist services.
Consider assessment with spirometry for adults with cerebral palsy who are suspected to be at high risk of respiratory impairment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying and monitoring respiratory disorders .
Full details of the evidence and the committee's discussion are in evidence review C1: protocols for monitoring respiratory health.
Loading. Please wait.
Offer vaccinations to adults with cerebral palsy and their carers, in line with the national immunisation programme (see the Green Book, Public Health England for further information).
Do not offer prophylactic antibiotics for lower respiratory tract infections in adults with cerebral palsy, unless:
the person is at high risk of respiratory impairment (see recommendation 1.4.23) and
they are offered on the advice of a respiratory specialist with expertise in neurodisability management.
If an adult with cerebral palsy is at high risk of lower respiratory tract infection, consider a prophylactic physiotherapy chest care review. This may include:
postural management
advice on exercise
advice on training and care for family members and carers.
Refer adults with cerebral palsy and recurrent chest infections, if dysphagia is suspected, to a speech and language therapist with training in dysphagia to assess swallowing.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prophylactic treatments for respiratory infections .
Full details of the evidence and the committee's discussion are in evidence review C3: prophylactic treatments for respiratory disorders.
Loading. Please wait.
If a person with cerebral palsy has symptoms of respiratory failure, or is at high risk of developing respiratory failure, discuss their management plan with them (and their family or carers, if agreed), including:
assessing the effectiveness and tolerability of treatment
treatment goals and escalation plan of treatment
managing complications
-ptions for managing progressive respiratory failure.
Consider home-based non-invasive ventilation for adults with cerebral palsy and respiratory failure.
If a person with cerebral palsy is having home-based non-invasive ventilation, carry out a review with a multidisciplinary team every 3 to 6 months. Assess and discuss with the person (and their family and carers, if agreed) the effectiveness, tolerability and whether agreed goals are being met.
If a person with cerebral palsy is having non-invasive ventilation, discuss with them (and their family or carers, if agreed) their preferences for future treatment. Agree a plan for what should happen if an intercurrent infection (occurring during the progress of respiratory failure) causes an acute deterioration in respiratory function and record this in the person's advance care plan.
If the agreed treatment goals are not met by non-invasive ventilation, consider alternative treatment options, such as tracheostomy or supportive care, and discuss them with the person with cerebral palsy, taking into account their preferences for future treatment (see recommendation 1.4.33).
If an adult with cerebral palsy has sleep apnoea, follow the recommendations on continuous positive airway pressure in sections 1.5 and 1.6 of the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s for when to offer assisted ventilation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on discussing the management of respiratory failure, and assisted ventilation for respiratory failure and sleep apnoea .
Full details of the evidence and the committee's discussion are in evidence review C2: assisted ventilation for respiratory failure.
Loading. Please wait.
## Pain
Be aware that some adults with cerebral palsy have difficulty communicating or are unable to communicate that they are in pain.
Assess for the presence, severity and location of pain in adults with cerebral palsy using pain assessment tools such as:
numerical rating scales
visual analogue scales
faces pain scales
body maps.
If an adult with cerebral palsy has difficulty communicating:
discuss with their family or carers how best to identify pain and include this information in their care plan
use observational or descriptive pain scales to assess the presence, severity and location of pain.See also communication in the NICE guideline on patient experience in adult NHS services.
Ensure that health and social care staff (and families and carers, if appropriate) caring for adults with cerebral palsy have access to a range of pain assessment tools and that they have been trained in their use.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain. .
Full details of the evidence and the committee's discussion are in evidence review E: identifying pain, such as musculoskeletal and gastrointestinal pain.
Loading. Please wait.
# Terms used in this guideline
## Advance care plan
Defined by international consensus as: 'A process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences about future medical care. The goal of an advance care plan is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness.' See Defining advance care planning for adults (Sudore et al. 2017).
## Alternative and augmentative communication systems
Alternative and augmentative communication systems are a variety of methods (for example, signing, use of visual symbols and eye gaze technology) that can be used to help people with disabilities communicate with others. These systems or methods of communication can be used as an alternative to speech or to supplement it.
## Anthropometric measurements
Body measurements that include weight, height, knee height, mid-upper arm circumference, waist circumference, head circumference and skinfold thickness measurements.
## Comorbidities
In the context of cerebral palsy, comorbidities are health problems caused by the brain disorder that also caused the motor impairment that is the core problem of cerebral palsy, but are not a direct complication of the motor disorder. For example, visual impairment and epilepsy are described as comorbidities because they are caused by the brain disorder. Hip dislocation and scoliosis are complications of the motor disorder and would not be described as comorbidities.
## Electronic assistive technology
Any piece of equipment or system that is used to increase, maintain or improve function in people with disabilities, and is electronically powered (mains electricity and/or battery). These may include communication aids, environmental controls and access to computers.
## Enteral drug treatment
Drugs given by mouth (oral), or via a nasogastric tube, gastrostomy tube or jejunostomy tube.
## Escalation plan
A record of the interventions that a person would find acceptable, in line with their values, goals and preferences. It can be used to indicate that more intensive or invasive interventions would be unacceptable to the person. For example, an escalation plan of ward-based care only, indicates that the person would not want invasive monitoring, intubation and ventilation, which are undertaken as part of intensive care.
## Executive functions
Cognitive processes that are important for the control of behaviour. These include planning, organising and monitoring behaviours leading to goal attainment, inhibitory control, working memory and cognitive flexibility. As a result of injuries to the frontal lobes of the brain, these processes can be disrupted.
## Gross Motor Function Classification System
A 5‑level clinical classification system that describes the gross motor function of people with cerebral palsy based on self-initiated movement abilities. People assessed as level I are the most able and people assessed as level V are dependent on others for all their mobility needs.
The GMFCS is not validated for use in adults. However, the GMFCS level at age 12 has been shown to be a good predictor of mobility into adulthood, especially at the milder and most severe levels. It is used here in the absence of a validated system for use in adults because it is readily understood by people with cerebral palsy, their families and carers, and health professionals involved in the care of adults with cerebral palsy.
## Key communication partners
People who regularly interact with the person with cerebral palsy in any environment. Communication may be by speech, using communication aids, signing, facial expression or a combination of these.
## Rehabilitation engineering services
Centres that design, develop and adapt technological solutions to overcome challenges to function, activity and participation for individuals with disability. This includes assessment and provision of assistive devices to help with posture, mobility and communication (for example, electronic assistive technology).
## Review
A planned clinical appointment between an adult with cerebral palsy and a healthcare professional or multidisciplinary team. They may explore common concerns, physical symptoms, mental health, pain, nutrition and communication to ensure an individualised approach to care. The healthcare professional may be a GP, specialist nurse, rehabilitation specialist or therapist. This also allows the opportunity to address general health issues that affect people as they grow older.
## Review of 24‑hour postural needs
Part of a 24‑hour posture review that considers all the relevant postures that an individual has the ability to adopt over the 24 hours of any given day, including postures to allow for participation in daily activities. The 3 core postural orientations are lying, sitting and standing. An example of a postural need is support and positioning in bed.
## Supportive care
Care focused on relieving symptoms caused by serious illnesses such as respiratory failure. It can be given at any point during a person's illness to help them feel more comfortable and improve their quality of life.
## Transferring
Moving from one surface to another (for example, from a bed to a wheelchair) independently or with assistance.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Method of botulinum toxin type A injection in treating focal spasticity
Is guided botulinum toxin type A injection using electrical localisation (electrostimulation or electromyography) of muscles more clinically and cost effective than ultrasound-guided injections or clinical positioning for localisation of injections in treating focal spasticity in adults with cerebral palsy?
For a short explanation of why the committee made the recommendation for research, see the rationale on drug treatments for spasticity .
Full details of the evidence and the committee's discussion are in evidence review A1: pharmacological treatments for spasticity.
Loading. Please wait.
## Selective dorsal rhizotomy treatment to reduce spasticity
What is the clinical and cost effectiveness of selective dorsal rhizotomy compared with intrathecal baclofen to reduce spasticity in adults with cerebral palsy?
For a short explanation of why the committee made the recommendation for research, see the rationale on neurosurgical treatments to reduce spasticity .
Full details of the evidence and the committee's discussion are in evidence review A2: neurosurgical treatments for spasticity.
Loading. Please wait.
## Detection and management of respiratory disorders in primary and community care
Can detection and management of respiratory disorders in adults with cerebral palsy be improved in primary and community care?
For a short explanation of why the committee made the recommendation for research, see the rationale on identifying and monitoring respiratory disorders .
Full details of the evidence and the committee's discussion are in evidence review C1: protocols for monitoring respiratory health.
Loading. Please wait.
## Prophylactic antibiotics for respiratory disorders
Are prophylactic antibiotics clinically and cost effective in the management of respiratory symptoms in adults with cerebral palsy with significant respiratory comorbidity?
For a short explanation of why the committee made the recommendation for research, see the rationale on prophylactic treatments for respiratory infections .
Full details of the evidence and the committee's discussion are in evidence review C3: prophylactic treatments for respiratory disorders.
Loading. Please wait.
## Splinting to improve or maintain posture or function
What is the optimum regimen for splints applied to the upper limb in adults with cerebral palsy to improve or maintain posture or function?
For a short explanation of why the committee made the recommendation for research, see the rationale on physical activity, orthopaedic surgery and orthotics .
Full details of the evidence and the committee's discussion are in evidence review D2: interventions that improve or maintain physical function and participation.
Loading. Please wait.
## Augmentative and alternative communication systems
Are augmentative and alternative communication systems clinically and cost effective in promoting communication for adults with cerebral palsy who have communication difficulties?
For a short explanation of why the committee made the recommendation for research, see the rationale on communication .
Full details of the evidence and the committee's discussion are in evidence review D4: interventions to promote participation: communication.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Access to services and moving into adults' services
Recommendations 1.1.1 to 1.1.11
## Why the committee made the recommendations
Disabled people have the same rights to access healthcare services as other people. These rights are outlined in the Equality Act 2010 and the United Nations (UN) Convention on the rights of persons with disabilities. To support this, the committee highlighted that there should be local pathways to enable access to a range of services for adults with cerebral palsy. The committee agreed that referral to specialist services is needed for some treatment options. Based on their discussions about treating spasticity and dystonia (see evidence reviews A1, A2 and A3), the committee agreed that access to specialist multidisciplinary teams is particularly important when a person with cerebral palsy experiences a deterioration in their ability to carry out usual daily activities (for example, due to pain) or when a neurosurgical or orthopaedic procedure is being considered that may affect their abilities. Adults with cerebral palsy may also need reassessment by the multidisciplinary team because of changing needs at different points in their lives, for example, changes in physical, environmental, or personal care or support needs. The committee highlighted this to raise awareness that people may need access to different services if their needs change.
To achieve good access to the relevant specialists, local networks of care are needed. The committee also noted that both people with cerebral palsy and healthcare professionals often lack awareness of the services available. Based on their experience, they agreed that provision of information about local networks of services would help to improve access.
The committee also acknowledged that carers are often unaware of their right to a local authority assessment of their own needs, including physical and mental health, and to an assessment of their need for respite care under the Care Act 2014. They agreed that highlighting this would help carers to access support if needed.
The evidence showed that adults with cerebral palsy experience many obstacles to equal access to services. Some examples of how these might be addressed are highlighted in the recommendations to help raise awareness among healthcare professionals. The committee agreed that healthcare professionals should recognise and address any barriers to enable equitable access to services and provide timely care. This will improve quality of life and health outcomes for adults with cerebral palsy.
The committee also noted that access to services may be limited for adults with cerebral palsy who need practical support and advocacy. There was some evidence that lack of an advocate could disadvantage people, especially when they are admitted to hospital. In addition, some adults with cerebral palsy reported that their family members were expected to act as their carers when they were admitted to hospital. The committee agreed that it should not be assumed that family members should provide personal care in a healthcare setting and that advocacy, and health and personal care, should always be offered to people when they are admitted to hospital.
Based on their knowledge and experience, the committee noted that people with cerebral palsy experience barriers in access to national screening programmes, for example, lack of equipment for breast screening for women in wheelchairs, especially those with limited upper body strength, or lack of knowledge about how to perform cervical screening for women with lower limb spasticity. However, national screening services have an obligation to make arrangements so that screening is accessible to everyone. The committee agreed that increasing awareness about accessibility of these services and encouraging people to attend screening appointments would help to improve uptake of these services.
The committee discussed that specialist cerebral palsy services are provided for children and young people, but there is insufficient specialist service provision for adults, with variation and a lack of continuity in care. The committee highlighted that it is important that services continue to meet the people's needs when they move into adults' services, in line with recommendations in the NICE guidelines on cerebral palsy in under 25s and transition from children's to adults' services for young people using health or social care services. To ensure that needs are met for adults with cerebral palsy, the committee made recommendations about access to services and service organisation.
## How the recommendations might affect practice
The recommendations on access to services reinforce legislation and best current practice.
Service organisation for networks of care is variable, so changes to practice will depend on the availability of services within a particular local area. Providing information about local networks of care may incur an initial cost to set up.
There may be an increase in the number of referrals. Training will also be needed to ensure healthcare professionals can manage referrals rapidly because there is a limited number of healthcare professionals with expertise in neurological disorders. However, recommendations with criteria for referral will help to reduce inappropriate referrals and variation in referrals.
Full details of the evidence and the committee's discussion are in evidence review F1: configuration of services for adults with cerebral palsy and evidence review F2: barriers to access to primary and secondary care.
Return to recommendations
# Ongoing care
Recommendations 1.1.12 to 1.1.18
## Why the committee made the recommendations
There was limited evidence for the effectiveness of different service configurations. One study suggested that fewer visits to emergency departments and hospital visits were associated with having consistent outpatient care provided by a single doctor. Although the committee recognised that this may reflect the value of continuity of care, they agreed that the quality of the evidence was not good enough to make a recommendation.
Further evidence showed that changing the configuration of services to include the time and staff for an annual review could be cost effective if there is a reduction of at least 1 emergency department visit per year per person. It was not clear from the evidence that this could be achieved when offered to all people with cerebral palsy. The committee discussed the variation in the needs of people with cerebral palsy and, based on their experience and knowledge, identified groups with more severe or complex health and social care needs who would most benefit from being offered an annual review. The committee agreed that annual review is likely to prevent an emergency department visit for this group and so would be cost effective. The committee decided that the annual review should be carried out by a healthcare professional with expertise in neurodisabilities who would have the skills and experience needed to identify potential issues that could lead to an emergency department visit. It was noted that adults with learning disabilities should already be offered an annual health check in primary care.
As an example of complex needs, the Gross Motor Function Classification System (GMFCS) levels IV and V were used. The committee acknowledged that the GMFCS is not validated for use in adults. However, it has been shown that at age 12, a GMFCS level I strongly predicts that the person with cerebral palsy will retain good mobility into adult years and a GMFCS level V strongly predicts that the person will be a wheelchair user in adult life. Therefore, at the mild and severe ends of the spectrum of mobility in cerebral palsy, there is stability of GMFCS levels into adulthood. In the absence of an alternative descriptive system validated for use in adults, the GMFCS is used here because it is readily understood by people with cerebral palsy, their families and carers, and health professionals involved in the care of adults with cerebral palsy.
Although the evidence did not support annual reviews for all people with cerebral palsy, the committee agreed that regular reviews are important to check for any new problems and ensure that people's needs continue to be met. They agreed that regular reviews should be considered, tailored to the person's needs. The frequency of review was not specified because it will depend on person's needs and wishes.
It is important to discuss who should be involved in the review with the adult with cerebral palsy. Information from different healthcare professionals and social care staff may be essential to fully understand the person's clinical needs. Good record keeping and sharing of information ensures that the outcome of the review is known to all relevant people and that the appropriate actions are taken. The committee also agreed that information about the review and any changes to the person's needs should be shared to ensure integrated care.
To help maintain continuity of care between reviews, the committee agreed that there should be a single point of contact, which could be a department or service in primary or secondary care.
The committee recognised that some people may not need or wish to have regular reviews. To ensure that they still have access to specialist services when needed, the committee agreed that they should be given information on how and when to do this.
## How the recommendations might affect practice
Adults with severe impairment are already likely to have more frequent contact with services. Therefore, providing an annual review for adults with severe impairment is likely to result in a minor change in practice and reduce variation. There may be bigger changes in practice for people with less severe impairment if they are reviewed more often. However, the costs of this will be offset by the benefits of more frequent checks, such as early identification and management of new impairments or deterioration of function.
Full details of the evidence and the committee's discussion are in evidence review F1: configuration of services for adults with cerebral palsy.
Return to recommendations
# Communication
Recommendations 1.2.1 to 1.2.6
## Why the committee made the recommendations
There was limited evidence to support interventions to improve communication between adults with cerebral palsy and their communication partners. However, the committee acknowledged that communication is a basic human right and that adults with cerebral palsy should be supported to communicate, express themselves and live as independently as possible.
The committee was concerned that communication difficulties and changes to communication needs are sometimes missed. Based on the members' experience, the committee agreed that increased awareness of this and a check for any changes to speech, hearing and communication at every review would help ensure that communication needs are recognised.
Based on their experience and knowledge, the committee agreed that alternative and augmentative communication systems may help some adults with cerebral palsy to meet their communication needs, support independence and improve quality of life and social relationships. Therefore the need for these systems should be discussed with adults who have communication difficulties. The committee noted that there is variation in the availability of training in these techniques, which is vital for their effective use. They also highlighted that personal preference is important, and that some people may not wish to use alternative or augmentative communication systems in place of speech as their main means of communication.
There was some evidence that intensive speech therapy or supplemented speech (using topic and alphabet cues) improved speech intelligibility, but the committee agreed that it was not sufficient to recommend these specific interventions. However, using this evidence and their knowledge and experience, the committee agreed that referral to speech therapy services would enable adults with communication difficulties to be assessed and offered suitable interventions.
The committee also noted that the recommendations support the fundamental rights of people with disabilities to freedom of expression and opinion, and access to information as set out in Article 21 of the UN Convention on the rights of persons with disabilities.
The committee discussed that there was a need for more research on alternative and augmentative communication systems. Current practice is to offer these systems in preference to intensive speech and language therapy for people with cerebral palsy and communication difficulties. However, there is only limited evidence to support this in children with cerebral palsy and no evidence was identified for adults. The committee developed a research recommendation to determine the effectiveness of augmentative and alternative communication systems in promoting communication for adults with cerebral palsy and communication difficulties.
## How the recommendations might affect practice
There is currently variation in practice and the recommendations will help to address this and reinforce best practice.
Initially, an increase in referrals to speech therapy services and subsequent management is likely. However, this will decline as variations in practice are reduced.
There may be an increase in the use of augmentative and alternative communication equipment, and related training, which will involve additional costs. However, the benefits of being able to communicate would outweigh the additional costs of increased use of augmentative and alternative communication systems.
Full details of the evidence and the committee's discussion are in evidence review D4: interventions to promote participation: communication.
Return to recommendations
# Vocational skills and independent living
Recommendations 1.2.7 to 1.2.12
## Why the committee made the recommendations
There was very little evidence on specific interventions for vocational or independent living skills training. However, the committee acknowledged the benefits of increased independence, social and occupational integration, participation in the community and access to work for adults with cerebral palsy. Based on their experience and knowledge, the committee highlighted that people with cerebral palsy should be asked what they enjoy doing. If they have problems in participating in their chosen activity, they should have access to support. This should include assessing for and addressing any barriers to participation and support, and may involve referral to occupational therapy services, particularly for people with complex needs.
For adults who wish to work or live independently, the committee agreed that referral for specialist support to access training, work placements and leisure activities would be beneficial. Some evidence showed that people with higher educational attainment and fewer physical complications were more likely to gain paid employment, but the committee agreed that support should be an option regardless of ability, to enable all adults to reach their full potential. For adults with cerebral palsy who are in work, referral could support access to workplace and equipment assessment, and workplace and job retention training. The NICE guideline on workplace health: management practices was highlighted by the committee as an important resource to refer to.
The recommendations support compliance with the Equality Act 2010 to protect people from discrimination in employment, training and education. They also reflect the fundamental rights of people with disabilities to independence, social and occupational integration, participation in the community, access to training and to engage in work, as set out in the UN Convention on the rights of persons with disabilities.
## How the recommendations might affect practice
These recommendations are intended to reinforce good current practice. There will be a cost associated with addressing external factors (such as access to buildings). However, this must be done to comply with government policy and legislation. Where they are not currently being implemented, some services may need additional investment in resources.
Full details of the evidence and the committee's discussion are in evidence review D1: interventions to promote participation – vocational and independent living skills.
Return to recommendations
# Electronic assistive technology
Recommendations 1.2.13 to 1.2.17
## Why the committee made the recommendations
There was no evidence identified on electronic assistive technology for adults with cerebral palsy. Based on their experience, the committee agreed that adults with cerebral palsy and complex disabilities would benefit from access to electronic assisted technology, which may enhance their independence, quality of life and improve their opportunities for employment. The recommendations support legislation such as the Human Rights Act 1998 and the Equality Act 2010. The recommendation on referral to services providing electronic assistive technology is also in line with the NHS England service specifications on environmental control equipment for patients with complex disability (all ages).
The committee was unable to recommend any specific electronic assistive technology devices because of the lack of evidence. They agreed that services providing electronic assistive technology should provide devices tailored to the person's needs.
Variation in training and ongoing reviews of electronic assistive technology equipment were highlighted by the committee. Training is important for both the adult with cerebral palsy and their family and carers to ensure that the devices are used to their full benefit. By discussing the use of their equipment at each review, the healthcare professional can ensure that any problems with equipment or changes to the person's needs are identified.
The committee noted that people using electronic assistive technology may need less support from their carers and healthcare workers. This may reduce the person's social contact, which can have a negative impact. Based on their experience, the committee agreed that it is important that healthcare professionals take this into account when discussing the risks and benefits of electronic assistive technology with the adult with cerebral palsy, their family and carers.
## How the recommendations might affect practice
These recommendations are intended to reinforce good current practice, and support government policy and legislation. Where they are not currently being implemented, some services may need additional investment in resources.
Full details of the evidence and the committee's discussion are in evidence review D3: electronic assistive technology.
Return to recommendations
# Physical activity, orthopaedic surgery and orthotics
Recommendations 1.2.18 to 1.2.21
## Why the committee made the recommendations
There was limited evidence on physical activity interventions for adults with cerebral palsy, and what there was showed little or no improvements in, for example, mobility, function and participation. However, based on their experience the committee agreed that physical activity can help people with cerebral palsy with strength and range of movement, as well as maintaining their general fitness and a healthy weight. Evidence in the general population also shows that physical activity is of benefit to people's overall health and wellbeing. The evidence did show that the risk of injury or other adverse events for people with cerebral palsy was not increased by doing physical activities such as strength training.
The committee agreed that physical activity should be promoted by providing information and discussing the benefits with the adult with cerebral palsy. This would also be in line with current government strategies for the wider population (for example, the Start active, stay active report on physical activity in the UK).
Some adults with cerebral palsy may need extra support to overcome barriers to participation in physical activities. Based on their experience, the committee agreed that referral to a relevant service is likely to be helpful for some people; for example, for assessment by a physiotherapist or occupational therapist to agree suitable interventions. The recommendation also supports improved access to mobility aids, including wheelchairs. The committee noted that a referral is in line with NHS guidance on walking aids, wheelchairs and mobility scooters for people long-term or permanent difficulty with mobility.
There was little evidence on orthopaedic surgery. However, the committee recognised that some adults with cerebral palsy who have painful musculoskeletal problems might benefit from surgery if other treatments are not effective. The committee agreed that referral to an experienced orthopaedic surgeon could be considered to review possible surgical options.
There was no evidence identified on the effectiveness of orthotic devices for adults with cerebral palsy. The committee discussed that there is variation in how orthoses are used in current practice and decided that further research in this area is a priority. Orthotic devices, such as splints, are used to help improve positioning and function. They can be used alongside other treatments or separately. The committee developed a research recommendation to determine the effectiveness of different splinting regimens in improving and maintaining posture or functional abilities in the upper limb.
## How the recommendations might affect practice
The recommendations on interventions to maintain physical function reinforce current best practice and should not lead to additional resource use. Any initial costs of specialist advice would be outweighed by the potential savings from avoiding complications, injuries and maintaining a wider range of abilities.
Full details of the evidence and the committee's discussion are in evidence review D2: interventions that improve or maintain physical function and participation.
Return to recommendations
# Agreeing goals for treatment and initial management of spasticity and dystonia
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
The committee noted that there is a lack of understanding about the relationship between spasticity and dystonia. Based on their experience, they agreed that a better understanding of these conditions and the factors that affect them is likely to lead to more effective decisions about management. The committee discussed factors that commonly trigger or worsen symptoms of both spasticity and dystonia, and their concerns that these may sometimes go unrecognised.
The committee also discussed the balance of benefits and risks of treatment to reduce spasticity and dystonia. In particular, some people with cerebral palsy make functional use of their increased muscle tone from spasticity and dystonia, for example, to help them walk or transfer independently. For these people, a reduction in spasticity or dystonia could have a negative impact on function. To ensure informed decision making, the risks and benefits of treatment should be discussed with each person and specific treatment goals should be agreed.
There was limited evidence on treatments for spasticity and dystonia in adults with cerebral palsy, but based on their experience and expertise, the committee agreed on a stepwise approach to treatment dependent on tolerability and effectiveness. This is from the least invasive to the most invasive treatment option, which is reflected in the order of recommendations in the individual sections:
identifying and managing any factors that might be exacerbating a person's symptoms
reviewing their physical management programme
considering enteral (oral or via a feeding tube) drug treatment and referral if spasticity and dystonia are still inadequately managed
considering more invasive treatment options.
## How the recommendations might affect practice
The recommendations reflect current good practice and will help to eliminate variation.
Full details of the evidence and the committee's discussion are in evidence review A1: pharmacological treatments for spasticity and evidence review A3: interventions for dystonia.
Return to recommendations
# Drug treatments for spasticity
Recommendations 1.3.6 to 1.3.11
## Why the committee made the recommendations
No evidence was identified on using enteral baclofen for treating spasticity in adults with cerebral palsy. However, the committee discussed the evidence reviewed for NICE's guideline on spasticity in under 19s, and agreed that this could be extrapolated to the adult population. There was limited evidence of effectiveness in children and young people, but the committee agreed that it was sufficient, supported by their experience, for enteral baclofen to be considered as a first-line drug treatment for generalised spasticity causing functional impairment, pain or spasms. The committee were unable to make a stronger recommendation because there was no comparative clinical evidence that baclofen was the most effective option.
The evidence on enteral diazepam showed no improvement in muscle tone, and side effects such as drowsiness, vomiting and abdominal pain were recorded. The committee agreed that it should not be offered routinely to treat spasticity because of the risk of adverse events and also of dependency. However, evidence from NICE's guideline on spasticity in under 19s and the committee's experience suggested that diazepam can be beneficial in the short-term management of pain and anxiety in acute situations.
There was no evidence for any other medicines. However, based on their experience of current practice, the committee acknowledged that alternative drug treatments are available that might be beneficial for some people if enteral baclofen is ineffective or not tolerated. The committee agreed that in these situations, specialist advice or referral to specialist services is warranted to consider further treatment options.
Severe symptoms, such as life-threatening seizures, are associated with rapid withdrawal of enteral muscle relaxants, so the committee highlighted the importance of gradual withdrawal of these treatments. Based on their experience and knowledge, the committee decided that withdrawal symptoms are more likely if the person has been taking them for over 2 months or the prescribed dosage is high.
There was some evidence that botulinum toxin type A injections improved muscle tone in adults with cerebral palsy and spasticity. However, the evidence was limited, and this treatment is more invasive and costly than alternative muscle relaxant drug treatment. For these reasons, the committee agreed that it should only be considered for people with focal spasticity and difficulties with their symptoms, who might gain the most benefit from the treatment, or if a specialist agrees that it is likely to be of benefit.
The committee discussed that botulinum toxin type A injections should be given by an experienced specialist. This is important because the injections need to be accurately placed for successful treatment and to avoid side effects. They acknowledged that some healthcare professionals use ultrasound, electrical stimulation or electromyography to help guide the injections, but noted that the benefits and cost effectiveness of these techniques are uncertain. Additional resources are associated with these techniques, for example, for equipment and training. Therefore, the committee developed a research recommendation to help determine the most effective method for ensuring accurate positioning of these injections.
## How the recommendations might affect practice
Overall, the recommendations reflect current good practice and will help to eliminate variation, particularly in referrals to tone or spasticity management services.
The recommendation to consider enteral baclofen as a first-line drug treatment to manage spasticity should not lead to a large increase in costs because enteral baclofen is relatively cheap and already widely used. Despite this, the committee were unable to make a stronger recommendation because there was no comparative clinical evidence that baclofen was the most effective option.
There was clinical evidence to suggest the cost of botulinum toxin could be outweighed by its benefits when treating focal spasticity. The focus on referral for focal spasticity that is causing pain, impacting care or impairing activity is likely to reduce the number of inappropriate referrals.
Any additional costs of specialist input is expected to be balanced by a reduction in potentially inappropriate treatment and related adverse effects. There may be a change to practice because enteral diazepam will no longer be prescribed routinely, and this may result in a small cost saving.
Full details of the evidence and the committee's discussion are in evidence review A1: pharmacological treatments for spasticity.
Return to recommendations
# Neurosurgical treatments to reduce spasticity
Recommendations 1.3.12 to 1.3.18
## Why the committee made the recommendations
There was some limited evidence with high uncertainty suggesting that both intrathecal baclofen and selective dorsal rhizotomy are effective in reducing muscle tone in adults with spasticity. However, there are risks involved, both in having surgery and of long-term complications. The committee highlighted the importance of discussing the procedure with the person and their family or carers, so that they fully understand what the treatment involves and the potential risks and benefits.
Using the evidence and their experience of current practice, the committee agreed that intrathecal baclofen pumps can be beneficial for treating spasticity in some adults with cerebral palsy. However, they should only be considered by a specialist service that can safely carry out the procedure and has the expertise to assess whether it is a suitable treatment for the person. There are potential risks of intrathecal baclofen pump treatment. These include pump-related complications (for example, battery failure or catheter leakage), infections, and baclofen withdrawal or overdose. It is also more costly than other drug treatments. Taking into account these factors, the committee agreed that referral should only be considered if a person still has difficulties with spasticity after trying enteral muscle relaxant drug treatment or botulinum toxin type A injections.
Because of the complexity of this procedure, adults with cerebral palsy need sufficient information to make an informed choice. The committee noted that this is not always consistently provided in current practice. A number of issues specifically related to this surgical procedure were highlighted by the committee as important to discuss when considering this treatment.
The response to intrathecal baclofen needs to be tested before a pump can be implanted. The committee agreed that it would be useful to highlight this. However, they noted that testing is described in detail in the BNF. The committee agreed to include advice on assessing and discussing the test results to ensure that a pump is only implanted when the benefits are established in advance.
The committee were aware that there is a risk of complications with selective dorsal rhizotomy, including deterioration in walking ability and bladder function, and later spinal deformity. They also took into account NICE's interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy, published in 2010, which recommends the involvement of a multidisciplinary team. Although they noted that the evidence for the interventional procedures guidance was in children, the committee agreed that selective dorsal rhizotomy should only be considered if other treatments have been unsuccessful or are contraindicated, and after multidisciplinary assessment in a specialist spasticity service. They noted that this is an infrequent procedure and therefore recommended that the team has specialist training and expertise in the care of spasticity.
The committee were aware that some young adults are being offered selective dorsal rhizotomy for tone management, sometimes as an alternative to replacing an intrathecal baclofen pump. In the absence of evidence for selective dorsal rhizotomy in this age group, the committee agreed that they could not make a recommendation specifically for young adults.
The committee agreed that, it is important that adults with cerebral palsy (and their family or carers, if agreed) are fully informed about the procedure, including the possibility of complications and that there is uncertainty about long-term benefits of treatment.
The committee also recommended further research, comparing the safety and effectiveness of selective dorsal rhizotomy with continuous intrathecal baclofen pump treatment. Both procedures are currently used to treat spasticity in people with cerebral palsy and there is some evidence that both are effective. However, the committee noted that the procedures, and their risks and benefits, are very different. They agreed that a comparative study would be helpful to inform decision making.
The committee noted that the NICE guideline on spasticity in under 19s recommends the collection of national outcome data for all patients assessed for selective dorsal rhizotomy, which may also help to inform future guidance.
## How the recommendations might affect practice
The recommendations reinforce current best practice and should not lead to additional resource use. Specialist services already exist and neurosurgical procedures are currently available for the treatment of spasticity. Including specific criteria for referral should reduce the number of inappropriate referrals to these services.
Full details of the evidence and the committee's discussion are in evidence review A2: neurosurgical treatments for spasticity.
Return to recommendations
# Drug treatments for dystonia
Recommendations 1.3.19 to 1.3.23
## Why the committee made the recommendations
There was limited evidence on treating dystonia in adults with cerebral palsy. The committee discussed that it is a specialist clinical area and that the benefits and harms of treatments would need to be assessed by a person with expertise in tone management. Therefore, the committee agreed that adults with cerebral palsy should be referred for specialist management if they have problematic dystonia.
The evidence for levodopa was limited, although there was some evidence that it was not effective for reducing dystonia in adults with severe impairment. Taking into account the lack of evidence of effectiveness, and also the potential for side effects and the cost of long-term treatment to the NHS, the committee agreed that levodopa should not be prescribed routinely for dystonia in adults with cerebral palsy. However, the committee agreed that a trial of levodopa can sometimes be useful to identify the rare but treatable condition of dopa-responsive dystonia.
No evidence was identified for other enteral anti-dystonic drug treatments, so the committee agreed that they could not advise on their use. However, based on their experience of current practice, the committee acknowledged that there are options available that might be beneficial for some people and these could be considered by a specialist service. If enteral anti-dystonic drugs are then prescribed, they noted that severe symptoms, such as life-threatening seizures, are associated with rapid withdrawal of enteral anti-dystonic drugs, so the committee highlighted the importance of gradual withdrawal of these treatments. Based on their experience and knowledge, the committee decided that withdrawal symptoms are more likely if the person with cerebral palsy has been taking them for over 2 months or the prescribed dosage is high.
No evidence was identified on using botulinum toxin type A injections for treating dystonia in adults with cerebral palsy. However, based on their knowledge and experience, the committee agreed that it can be of benefit to some people with focal dystonia. Because there was no evidence and this treatment is more invasive and costly than enteral anti-dystonic drug treatments, the committee agreed that it should only be considered under specialist supervision for people with focal dystonia and difficulties with symptoms, who might gain the most benefit from the treatment. They also agreed that it should only be used as part of a programme of therapy. This would usually involve a physical management programme, for example, including physiotherapy and splinting.
The committee noted that botulinum toxin type A injections should be given by an experienced specialist. This is important because the injections need to be accurately placed for successful treatment and to avoid side effects.
## How the recommendations might affect practice
Overall, the recommendations reflect current good practice and will help to eliminate variation, particularly in referral. There may be a change to practice because levodopa will no longer be prescribed routinely, and this may result in a small cost saving.
Full details of the evidence and the committee's discussion are in evidence review A3: treatments to reduce dystonia.
Return to recommendations
# Neurosurgical treatments to reduce dystonia
Recommendations 1.3.24 and 1.3.25
## Why the committee made the recommendations
Despite a lack of evidence, the committee agreed that their knowledge and experience of current practice supported the use of intrathecal baclofen pumps for treating dystonia in some adults with cerebral palsy. However, they should only be considered by a specialist service that can safely carry out the procedure and has the expertise to assess whether it is a suitable treatment for the person. There are potential risks of intrathecal baclofen pump treatment. These include pump-related complications (for example, battery failure or catheter leakage), infections, and baclofen withdrawal or overdose. It is also more costly than other drug treatments. Taking into account these factors, the committee agreed that it should only be considered when a person still has difficulties with dystonia after trying enteral anti-dystonic drug treatment or botulinum toxin type A injections.
The committee also highlighted the importance of discussing the procedure with the person and their family or carer, so that they fully understand what the treatment involves and the potential risks and benefits. They agreed that the recommendations on intrathecal baclofen testing for spasticity would also apply to dystonia.
Although there was limited and sometimes incongruous evidence for deep brain stimulation, it did suggest some improvement in dystonia after treatment. However, some complications were noted, including problems with speech, pain, numbness and anxiety, as well as problems with the equipment.
Two studies, identified as part of the economic evidence, suggested that deep brain stimulation improved quality of life. However, one showed that it was likely to be cost effective whereas the other suggested it was not. The committee agreed that the study showing cost effectiveness was more relevant because it better reflected current technology. It also had a longer follow‑up and the results for quality of life matched the committee's expectations based on their clinical experience. However, it was noted that deep brain stimulation is only likely to be a treatment option when drug treatment is unsuccessful. This was more consistent with the patient group for the other study but current technology and appropriate quality of life at the outset was considered to be more important. The committee also took into account NICE's interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease) published in 2006, which supports its use with the involvement of a multidisciplinary team.
Based on the evidence on improvements in quality of life and the committee's knowledge and experience, they agreed that deep brain stimulation should be considered when drug treatment has been unsuccessful. However, because of the possible complications, it should only be an option for people who have severe and painful dystonia, and only carried out at an experienced specialised centre.
## How the recommendations might affect practice
Overall, the recommendations reflect current good practice and will help to eliminate variation.
Full details of the evidence and the committee's discussion are in evidence review A3: treatments to reduce dystonia.
Return to recommendations
# Bone and joint disorders
Recommendations 1.4.1 to 1.4.8
## Why the committee made the recommendations
Based on their experience, the committee noted that there is a lack of awareness, both among adults with cerebral palsy and healthcare professionals, that people with cerebral palsy are at increased risk of bone and joint complications, and that musculoskeletal function may worsen over time. Common complications include osteoporosis and conditions caused by abnormal musculoskeletal development, such as scoliosis and subluxation of joints, or abnormal movements leading to degenerative change, such as cervical myelopathy. Increasing awareness and discussing this with adults with cerebral palsy will enable early identification and management of these conditions.
The committee agreed that assessing fracture risk is important for adults with cerebral palsy who are at increased risk of osteoporosis to enable action to be taken to manage osteoporosis and prevent fractures. Based on their experience and knowledge, the committee identified factors that are associated with increased risk and agreed that fracture risk assessment should be considered for adults with cerebral palsy with these factors. In addition to the risk factors related to cerebral palsy (such as reduced weight bearing), risk factors for the general population also apply. These are described in NICE's guideline on osteoporosis: assessing the risk of fragility fracture along with information about assessing fracture risk.
There was some evidence that dual-energy X‑ray absorptiometry (DXA) scanning can be effective in identifying reduced bone density in adults with cerebral palsy. However, the committee noted that these scans can often be uncomfortable and the results difficult to interpret in people with cerebral palsy. The risks of treatment may also outweigh the benefits in people without symptoms. For these reasons, the committee agreed that it should only be considered for people with more than 1 risk factor, suggesting a high risk of fractures and osteoporosis.
Based on their experience, the committee agreed that assessment and management of osteoporosis in adults with cerebral palsy is highly complex, and that referral to a specialist service is often necessary. For some people this may be to a rheumatology or bone health service, for others referral to endocrinology may be considered to explore whether a hormonal condition could be affecting their bones.
Adults with cerebral palsy may develop joint abnormalities due to problems of tone, movement and posture. No evidence was identified on monitoring for these disorders. However, the committee agreed that specialist referral is needed for assessment and management if these conditions are suspected and causing problematic symptoms. They highlighted some of the more common disorders to help increase awareness and improve recognition.
The committee were aware that hip and spine X‑rays may be offered routinely to children and young people in paediatric services. However, ongoing surveillance is not necessary for adults once growth is complete, and X‑rays should not be offered unless there are new problems of pain, posture or function.
## How the recommendations might affect practice
The recommendations for risk assessment and DXA scanning are unlikely to change current practice. DXA scans should already be considered under NICE's guideline on osteoporosis.
The recommendations could increase referrals to specialist services. However, the impact of this is likely to be balanced by better treatment and prevention of hospital stays.
Full details of the evidence and the committee's discussion are in evidence review B1: disorders of bones and joints.
Return to recommendations
# Mental health problems
Recommendations 1.4.9 to 1.4.15
## Why the committee made the recommendations
No evidence was found on assessing and monitoring mental health in adults with cerebral palsy. However, from their experience, the committee acknowledged that healthcare services for adults with cerebral palsy tend to focus on physical rather than mental health. Greater awareness of mental health problems and the specific challenges of identifying and managing them in adults with cerebral palsy would help to ensure that such problems are recognised and managed. Alongside this, the committee highlighted that discussing the person's mental wellbeing at each review would help to identify any concerns and ensure that support for mental health problems is included in the person's care plan. Important insights about a person's mental health can often be gained from people close to them, so the committee agreed that (with consent from the person) family members or carers should also be asked if they have any concerns.
Physical problems and common frustrations that can affect emotional wellbeing in adults with cerebral palsy were highlighted by the committee because they are often overlooked, but can negatively affect mental health and behaviour.
The committee noted that there are many relevant NICE guidelines related to mental health conditions that would apply to adults with cerebral palsy, and other NICE guidelines relevant to those with communication difficulties or learning disabilities.
## How the recommendations might affect practice
The recommendations will reinforce current best practice and help to eliminate variation.
Full details of the evidence and the committee's discussion are in evidence review B2: monitoring and assessing mental health.
Return to recommendations
# Difficulties with eating and nutritional problems
Recommendations 1.4.16 to 1.4.21
## Why the committee made the recommendations
There was some evidence on tools for assessing nutritional status in adults with cerebral palsy, but the committee concluded that the evidence was not good enough to recommend a specific tool. In addition, many factors can affect feeding and nutrition, so they agreed that a single tool is unlikely to be suitable for everyone.
Based on their experience, the committee agreed that assessment should be individualised to reflect each adult's needs and circumstances. Current good practice includes regular weight checks and BMI or anthropometric measurement, and talking to the person and their families and carers about eating problems and other factors affecting nutrition and weight. People identified as at risk of undernutrition or with eating difficulties can then be referred to a specialist to assess for and treat specific problems. Because the recommendations focus on individualised assessment, the committee agreed that specific tools for assessing nutrition are not a priority for further research.
The committee discussed the role of people caring for adults with cerebral palsy and agreed that training should be provided in line with the NICE guideline on nutrition support for adults, to help pick up any problems between reviews.
The committee noted that adults with dyskinetic cerebral palsy or severe spasticity may have an increased metabolic rate and need to increase their calorie intake to prevent malnutrition. The committee recognised that reduction in dyskinesia or spasticity by treatment such as intrathecal baclofen may result in weight gain. They agreed that, from their experience, this can go unrecognised and that greater awareness could help people get the support they need.
## How the recommendations might affect practice
The recommendations will reinforce current best practice and help to eliminate variation.
Full details of the evidence and the committee's discussion are in evidence review B3: monitoring feeding and nutritional problems.
Return to recommendations
# Identifying and monitoring respiratory disorders
Recommendations 1.4.22 to 1.4.25
## Why the committee made the recommendations
No evidence was found on monitoring respiratory health in adults with cerebral palsy. Adults with cerebral palsy are at an increased risk of respiratory failure, which can be life threatening. However, based on their experience and knowledge, the committee agreed that the early symptoms of respiratory impairment may sometimes go unrecognised. Greater awareness and earlier recognition and treatment may result in treatment that prevents progression to respiratory failure.
Based on their experience and some limited evidence, the committee agreed that better awareness of the risk factors for respiratory impairment would help to ensure early recognition and appropriate referral. They also wanted to highlight that these are more common in adults with severe impairment, such as a high GMFCS score. They agreed that referral for specialist assessment would enable prevention or treatment of respiratory complications in people at high risk.
The committee discussed that reduced lung volume is an important factor contributing to respiratory impairment. However, there was limited evidence available on the value of spirometry in assessing respiratory function in adults with cerebral palsy. Based on their experience and expertise, the committee agreed that spirometry should be considered for people at high risk of respiratory impairment to help identify people who may need treatment.
The committee agreed that further research on identifying and managing respiratory disorders in adults with cerebral palsy would be helpful. They developed a research recommendation to determine the most effective methods of detecting and managing respiratory disorders in primary and community care.
## How the recommendations might affect practice
Better survival of children with cerebral palsy into adulthood means that this is an emerging area of practice. There are relatively few respiratory specialists with a special interest in adults with cerebral palsy. There may be an increase in referrals, which might place increased pressure on limited specialist services. However, earlier recognition and treatment will lead to improved outcomes. Respiratory conditions can often lead to hospital admission and reducing the need for this would potentially lead to cost savings.
Full details of the evidence and the committee's discussion are in evidence review C1: protocols for monitoring respiratory health.
Return to recommendations
# Prophylactic treatments for respiratory infections
Recommendations 1.4.26 to 1.4.29
## Why the committee made the recommendations
No evidence was identified on preventing respiratory infections in adults with cerebral palsy. However, adults with cerebral palsy are at an increased risk of respiratory impairments and respiratory failure, so the committee agreed that adults with cerebral palsy and their family and carers should receive vaccinations, such as the flu vaccination, as a prophylactic measure to prevent respiratory infections.
Applying their clinical expertise and experience, the committee agreed that the role of antibiotics is limited for prophylaxis of respiratory infections in adults with cerebral palsy. Taking into account potential adverse effects and the principles of antibiotic stewardship, the committee agreed that antibiotic prophylaxis should only be used in people at high risk of infection when it is advised by the respiratory specialist with expertise in neurodisability management. For example, this might be in people with recurrent chest infections and bacterial colonisation identified on sputum culture. The aim for these people would be to reduce acute antibiotic use and limit symptom burden.
The committee agreed that the prevention of respiratory infections is an important area for research. Many people with cerebral palsy have respiratory symptoms caused by sputum retention or recurrent respiratory infection, possibly related to aspiration. A smaller number have chronic bacterial airway colonisation with increased respiratory symptom burden and recurrent infections. The committee developed a research recommendation to determine the role of prophylactic antibiotics in improving quality of life and preventing hospital stays in people with or without persistent bacterial airway colonisation.
Although there was no evidence for chest physiotherapy to prevent respiratory infections, the committee discussed the potential benefits of postural management and exercise. Based on their experience and expertise, they agreed that a physiotherapy chest care review should be considered for adults with cerebral palsy who are at high risk of respiratory infection. The committee also noted that families and carers can help with ongoing chest care, but may not always receive adequate support to enable this. They agreed that it would be beneficial for this to be included as part of the chest care review. This could also include advice on posture, position change, opportunities to move, interventions to assist ventilation and secretion control management.
Effective swallowing (and saliva control) is important to prevent respiratory infections in adults with cerebral palsy. The committee agreed that assessment by a dysphagia-trained speech and language therapist should be considered for people with recurrent chest infections that may be caused by dysphagia.
## How the recommendations might affect practice
The recommendations on vaccination reinforce current best practice.
Referral to a respiratory team for adults with cerebral palsy will reinforce best practice. However, there may be an increase in referrals, which could put additional pressure on already limited specialist services.
The recommendation on prophylactic antibiotic use is not considered to be a change in practice. However, there may be a small decrease in use of prophylactic antibiotics, which could lead to cost savings.
The recommendations on chest physiotherapy review and referral to dysphagia-trained speech and language therapist are unlikely to have a big impact on current practice. There may be a small increase in the number of referrals. This is likely to be balanced by improved prevention of respiratory infections. There may also be an increase in provision of training and support for families and carers. However, this is likely to be balanced by improved ongoing chest care, which would reduce respiratory infections and the costs associated with them.
Full details of the evidence and the committee's discussion are in evidence review C3: prophylactic treatments for respiratory disorders.
Return to recommendations
# Discussing the management of respiratory failure, and assisted ventilation for respiratory failure and sleep apnoea
Recommendations 1.4.30 to 1.4.35
## Why the committee made the recommendations
The management of respiratory failure varies according to individual circumstances and preferences. The committee noted that having discussions about the effectiveness and tolerability of treatments (for example, non-invasive ventilation can be uncomfortable), as well as planning for future treatment and what to do if the person's condition worsens, helps to identify the most appropriate treatment pathway.
Although no evidence was identified on assisted ventilation for adults with cerebral palsy, the committee noted that there is evidence supporting non-invasive ventilation in people with progressive neuromuscular conditions. The committee discussed that the course and symptoms of respiratory failure may be similar across the different conditions. They agreed that non-invasive ventilation could be beneficial, based on evidence extrapolated from these populations and the committee's experience. The committee also agreed that it is important to review management every 3 to 6 months, which is consistent with standard practice.
The committee discussed that people's goals and preferences for management after acute deterioration in respiratory function will vary. Based on their experience and expertise, the committee highlighted the importance of agreeing a management plan with the person (and their family or carers, if agreed) for future care in this situation. This should be documented in the person's advance care plan. A full understanding of the options available and the person's values, preferences and goals will lead to better shared decision making and more informed choices about care.
Based on their experience and expertise, the committee discussed that when treatment goals are not met by non-invasive techniques, alternative options such as tracheostomy or supportive care could be considered. There was no evidence available in adults with cerebral palsy, but the committee agreed that tracheostomy can be effective for some patients in maintaining quality of life.
The committee recognised that sleep apnoea is common in adults with cerebral palsy. It can affect sleep quality and therefore quality of life. They agreed that treatment would be the same for adults with cerebral palsy as in the general population and cross-referred to the recommendations on continuous positive airway pressure in sections 1.5 and 1.6 of the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s for when to offer assisted ventilation.
## How the recommendations might affect practice
The recommendations in this section reinforce current best practice and will help to standardise practice.
Full details of the evidence and the committee's discussion are in evidence review C2: assisted ventilation for respiratory failure.
Return to recommendations
# Pain
Recommendations 1.4.36 to 1.4.39
## Why the committee made the recommendations
The committee acknowledged that it can be difficult to recognise pain in people with communication difficulties. They agreed that better awareness of this would help to prevent under-identification of pain.
The evidence indicated that numerical, visual analogue and faces pain scales had similarly good reliability and validity for assessing pain in adults with cerebral palsy. Although the use of body maps was not evaluated in the evidence, the committee agreed they would also be a useful way to help localise the source of any pain. The committee acknowledged that families and carers have valuable insight into identifying whether a person is in pain, and this is especially important if the person has communication difficulties. For adults with cerebral palsy who have difficulty communicating, the committee agreed that observational and descriptive pain scales would be appropriate and useful. The committee agreed that in practice, the method of pain assessment chosen would depend on the person's individual needs and circumstances, in particular, their ability to communicate.
The committee were also aware that people caring for adults with cerebral palsy do not always have access to suitable pain assessment tools or the training that is needed for their use. Based on their experience, they agreed that these are important to enable pain to be recognised, localised pain identified and treatment targeted effectively.
## How the recommendations might affect practice
The recommendations reflect the current practice of selecting an appropriate measure from a range of pain assessment methods, depending on the person's ability to communicate. The committee acknowledged that, although learning disability nurses currently train carers in generic pain assessment techniques, individualised training and documentation of how best to identify pain in the care plan would be a change in practice in some centres and may have a cost impact.
Full details of the evidence and the committee's discussion are in evidence review E: identifying pain, such as musculoskeletal and gastrointestinal pain.
Return to recommendations# Context
Cerebral palsy is a disorder of motor development caused by a non-progressive pathology that affects the developing brain. People with cerebral palsy may also have disorders of communication, learning, feeding and vision, and epilepsy. Cerebral palsy is a lifelong condition and there is not yet a cure for the underlying brain disorder.
There are now more adults living with cerebral palsy than there are children with cerebral palsy. Adults with cerebral palsy have a wide range of abilities – from full independence in everyday life to needing 24‑hour care and attention.
New interventions are coming into routine clinical practice for the management of premature babies and babies in a poor condition at birth who are at high risk of developing cerebral palsy. These may change the pattern of cerebral palsy and its related comorbidities. With improved survival, more children with severe and complex cerebral palsy are likely to live beyond childhood and into adult life. As they become young adults and transfer into adult services, this group will continue to need regular monitoring of their health and wellbeing.
Adults with cerebral palsy should be able to become as functionally independent as possible. Many may wish to go into further education, gain employment, participate in leisure activities and contribute fully to society. Barriers to these goals should be minimised so that adults with cerebral palsy have equal access to all opportunities.
Adults with cerebral palsy tend to have less fluctuation in their motor skills than children. However, their mobility may decrease because of factors such as muscle tone, weakness and pain. Comorbid symptoms, such as pain, mental health problems, communication difficulties and nutritional problems can, individually and in combination, affect participation and quality of life. These should also be a high priority for management.
As adults with cerebral palsy who have ongoing care needs grow older, there may be changes in their care arrangements. It may not be possible for their parents to continue to be the main carers and other support may be needed, either in the community or a residential setting. There is always the need for ongoing training and support for those who are caring for adults with cerebral palsy.
Adults with cerebral palsy and associated comorbidities may have difficulties with all aspects of health and daily living. However, this guideline has not been able to look at the evidence and develop recommendations for all areas of care. Areas that are not covered include bowel and bladder continence, sexual health and dental health. The principles of access to services, providing information and appropriate referral, discussed in the guideline, apply not only to areas directly addressed but also equally to other areas of care.
The care and support needs of adults with cerebral palsy depend on the severity of impairment and the presence or absence of comorbidities. There is significant variation in how services are currently provided to meet these needs. However, there is not a single system appropriate for all adults with cerebral palsy. In line with the Equality Act 2010 and the United Nations (UN) Convention on the rights of persons with disabilities, this guideline aims to ensure that adults with cerebral palsy have easy access to equitable, cost-efficient services, with a clear network of referral to more specialised services as appropriate.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Service organisation\n\n## Access to services\n\nRefer adults with cerebral palsy to a multidisciplinary team experienced in the management of neurological impairments if:\n\ntheir ability to carry out their usual daily activities deteriorates or\n\na neurosurgical or orthopaedic procedure is being considered that may affect their ability to carry out their usual daily activities.\n\nRecognise that reassessment by the multidisciplinary team may be needed by adults with cerebral palsy at different points in their lives to ensure that their changing needs are met (for example, pregnancy and parenting, decreased mobility due to hip arthritis, and loss of care and support from a parent).\n\nCommissioners and service providers should develop pathways that allow adults with cerebral palsy access to a local network of care that includes:\n\nadvocacy support\n\nlearning disability services\n\nmental health services\n\northopaedic surgery (and post-surgery rehabilitation)\n\nrehabilitation engineering services\n\nrehabilitation medicine or specialist neurology services\n\nsecondary care expertise for managing comorbidities (for example, respiratory, gastrointestinal and urology services)\n\nsocial care\n\nspecialist therapy services (for example, physiotherapy, occupational therapy, speech and language therapy, and dietetics)\n\nwheelchair services.\n\nEnsure that adults with cerebral palsy, their families and carers, and their primary care teams are provided with information about their local network of specialist services.\n\nExplain to the person with cerebral palsy and their family members and carers their right to a care and support needs assessment, in line with the Care Act 2014, and discuss with them the type of support available (see NICE's guideline on supporting adult carers).\n\nFor advice on access to services when adults with cerebral palsy transfer from hospital to home, refer to the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs. For the principles of social care provision, see the NICE guideline on people's experience in adult social care services.\n\nRecognise and address any personal barriers to accessing primary and secondary care for adults with cerebral palsy. For example, this may involve:\n\nensuring healthcare professionals have the skills and training to overcome communication difficulties\n\nproviding treatment and support for mental health problems\n\nensuring that the person has an advocate, if needed\n\nproviding support to help with social and emotional factors, such as fear of stigma, lack of motivation and exhaustion.\n\nRecognise and address any physical and organisational barriers to accessing primary and secondary care for adults with cerebral palsy. For example, this may involve:\n\nimproving physical access to buildings\n\nproviding advice and information on accessible transport services, for example, local community transport services\n\nensuring that appropriate equipment (for example, hoists and wheelchair weighing scales) and adequate changing and toilet facilities are available\n\nextending appointment times, if needed.\n\nWhen an adult with cerebral palsy is admitted to hospital, the staff should always offer advocacy, and health and personal care (including toileting, washing, nutrition and hydration) even if the person has a family member, carer or advocate there to support them.\n\nGive information to people with cerebral palsy about national screening services (for example, breast, colon and cervical cancer screening) and encourage them to attend screening appointments. Explain that screening services will have to make arrangements to provide screening services that are accessible to people with cerebral palsy.\n\n## Moving into adults' services\n\nFor young adults with cerebral palsy moving from children's services, ensure that transitions are managed in line with transition to adults' services in the NICE guideline on cerebral palsy in under 25s and the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to services and moving into adults' services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: configuration of services for adults with cerebral palsy and evidence review\xa0F2: barriers to access to primary and secondary care.\n\nLoading. Please wait.\n\n## Ongoing care\n\nConsider regular reviews for adults with cerebral palsy, tailored to their needs and preferences. Agree with the person the frequency of review and which services should be involved based on their needs and preferences.\n\nOffer an annual review of the person's clinical and functional needs, carried out by a healthcare professional with expertise in neurodisabilities, for people with cerebral palsy who have complex needs (such as Gross Motor Function Classification System [GMFCS] levels\xa0IV and\xa0V) and any of the following:\n\ncommunication difficulties\n\nlearning disabilities\n\nliving in long-term care settings\n\nliving in the community without sufficient practical and social support (for example, being cared for by elderly, frail parents)\n\nmultiple comorbidities.\n\nDiscuss with the person with cerebral palsy (and their family and carers, if agreed) what information should inform the regular or annual review, and who should receive clinical information following review (for example, their GP).\n\nRecord details of the person's review and share the information with relevant people (for example, healthcare professionals and social care practitioners), with the person's permission.\n\nIdentify who will be the main point of contact for the person with cerebral palsy (and their family and carers, if agreed) between reviews, and provide information on how to contact them.\n\nIf an adult with cerebral palsy chooses not to have regular reviews, offer the person (and their family and carers, if agreed) information on when to contact a healthcare professional and how to access the specialist services that they may need. Ensure that the person's GP and multidisciplinary team are aware that they do not want to be reviewed regularly (with the person's permission).\n\nFor adults with cerebral palsy and learning disabilities, follow the recommendations in NICE's guideline on care and support of people growing older with learning disabilities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on ongoing care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: configuration of services for adults with cerebral palsy.\n\nLoading. Please wait.\n\n# Function and participation\n\n## Communication\n\nBe aware that speech and communication needs in adults with cerebral palsy may change with time and social circumstances.\n\nAt every review, ask adults with cerebral palsy (and their families and carers, if agreed) about any changes in their hearing, speech and communication.\n\nExplore with the person with cerebral palsy who has communication difficulties whether they have a potential need for alternative and augmentative communication systems.\n\nEnsure that training is provided for people with cerebral palsy using alternative and augmentative communication systems and their families, carers and other key communication partners in home, care, social or work environments.\n\nBe aware that adults with cerebral palsy and poor intelligibility of speech may still prefer to use speech as their main means of communication.\n\nRefer adults with cerebral palsy who have communication difficulties to speech and language therapy services to assess their need for intervention, which may include:\n\nuse of alternative or augmentative communication systems\n\nintensive speech therapy to improve the intelligibility of their speech.See also communication and information in the NICE guideline on patient experience in adult NHS services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D4: interventions to promote participation: communication.\n\nLoading. Please wait.\n\n## Vocational skills and independent living\n\nIdentify and address any factors that prevent people with cerebral palsy from participating in activities, including:\n\nphysical barriers, for example, access to buildings\n\npersonal barriers, for example, carers with unmet training needs\n\norganisational barriers, for example, policies and situations that put people with cerebral palsy at a disadvantage.\n\nAsk adults with cerebral palsy what they enjoy doing and if they find it difficult to participate in a chosen activity, assess their physical and mental health, and address any factors identified that may be affecting participation, if possible.\n\nIf adults with cerebral palsy have complex physical, cognitive, language or sensory needs, consider referral to occupational therapy services to assess the person's functional needs and provide individualised support.\n\nGive adults with cerebral palsy information about assessments of vocational and independent living skills that is tailored to the person's functional abilities and goals (see NICE's guideline on patient experience in adult NHS services for advice on information giving and NICE's guideline on people's experience in adult social care services for details of the information that local authorities should provide).\n\nRefer adults with cerebral palsy who would like to live independently to a professional with expertise in independent living (for example, an occupational therapist). Give information and advice, which could include:\n\nadaptations to their home\n\nhousing\n\nleisure activities\n\nstatutory welfare benefits.\n\nRefer adults with cerebral palsy who would like to work, or who are already working, to a professional with expertise in vocational skills and independent living (for example, an occupational therapist). Give information and advice, which could include:\n\ncontinued education\n\njob seeking or access to work schemes\n\nemployment support to include workplace training and job retention\n\noccupational health assessment or workplace assessment\n\nstatutory welfare benefits\n\nsupporting a planned exit from the workforce if it becomes too difficult to continue working\n\nvocational rehabilitation\n\nvoluntary work.See also NICE's guideline on workplace health: management practices for advice on improving the health and wellbeing of employees.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on vocational skills and independent living\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D1: interventions to promote participation – vocational and independent living skills.\n\nLoading. Please wait.\n\n## Electronic assistive technology\n\nDiscuss with adults with cerebral palsy the potential role of electronic assistive technology if they have problems with participation and independence.\n\nIf adults with cerebral palsy have complex physical, cognitive, language or sensory needs, consider referring them to services providing information, assessment and provision of electronic assistive technology.\n\nBe aware that using electronic assistive technology may mean that the person with cerebral palsy needs less contact with their carers, which may reduce their social interaction.\n\nIf adults with cerebral palsy are already using electronic assistive technology, discuss at every review any:\n\nproblems or concerns they have with their equipment\n\npotential changes in their needs.\n\nEnsure that training is provided for adults with cerebral palsy using electronic assistive technology, and for their families or carers, if appropriate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on electronic assistive technology\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D3: electronic assistive technology.\n\nLoading. Please wait.\n\n## Physical activity\n\nDiscuss with adults with cerebral palsy (and their families or carers, if agreed) the importance of physical activity in maintaining general fitness and physical and mental health.\n\nProvide information on accessible local services that support people with cerebral palsy to take part in physical activity.\n\nConsider referring people with cerebral palsy to services with experience and expertise in neurological impairments that can provide support with physical activities (including sport) and tasks of daily living. Depending on local service provision and the person's needs, this may be to any of the following services:\n\nphysiotherapy\n\noccupational therapy\n\northotic and functional electronic stimulation services\n\nrehabilitation engineering services\n\nwheelchair services.\n\n## Orthopaedic surgery\n\nIf people with cerebral palsy have problems participating in physical activities because of pain or joint problems that do not respond to any other treatments, consider referring them to a musculoskeletal specialist or an orthopaedic surgeon with experience and expertise in managing musculoskeletal problems in adults with cerebral palsy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity, orthopaedic surgery and orthotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D2: interventions that improve or maintain physical function and participation.\n\nLoading. Please wait.\n\n# Managing abnormal muscle tone\n\n## Agreeing goals for treatment\n\nDiscuss with the adult with cerebral palsy (and their family and carers, if agreed) treatments for spasticity or dystonia, including:\n\npersonal treatment goals (which should be documented) and\n\nthe benefits and risks of treatments (for example, the risk of deterioration in function) as part of their multidisciplinary treatment strategy.See also enabling patients to actively participate in their care in the NICE guidelines on patient experience in adult NHS services and shared decision making.\n\nDiscuss with the person with cerebral palsy (and their family and carers, if agreed) the balance between the benefits and harms of treating spasticity and dystonia. In particular, explain that some people use their spasticity or dystonia to help their posture and ability to stand, walk or transfer, and that treatment may affect this.\n\n## Initial management of spasticity and dystonia\n\nBe aware that adults with cerebral palsy may have both spasticity and dystonia. The severity of symptoms for both conditions may fluctuate in response to health, social and emotional wellbeing, and environmental factors.\n\nAt every review, discuss with the person with cerebral palsy (and their family and carers, if agreed) factors that may exacerbate their spasticity or dystonia, such as:\n\nbladder problems (for example, urinary tract infection or bladder stones)\n\nconstipation\n\nemotional distress\n\npain\n\nposture\n\npressure sores\n\nchanges in home or work environments, including seating\n\nmedication changes and side effects.\n\nBefore discussing further management options for spasticity or dystonia with a person with cerebral palsy:\n\naddress any modifiable factors identified that may be exacerbating the spasticity or dystonia and\n\nreview their physical management programme.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on agreeing goals for treatment and initial management of spasticity and dystonia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A1: pharmacological treatments for spasticity and evidence review\xa0A3: interventions for dystonia.\n\nLoading. Please wait.\n\n## Spasticity\n\nIn January 2019, giving baclofen via an enteral feeding tube was an off-label use. See NICE's information on prescribing medicines.\n\nConsider enteral baclofen as the first-line drug treatment for adults with cerebral palsy and generalised spasticity causing:\n\nfunctional impairment or\n\npain or\n\nspasms.\n\nStart enteral baclofen treatment with a low dose and increase the dose gradually over about 4\xa0weeks to achieve the optimum therapeutic effect.\n\nIf enteral baclofen is ineffective or not tolerated by adults with cerebral palsy and generalised spasticity:\n\nrefer the person to a tone or spasticity management service or\n\ndiscuss other drug treatment options (including other enteral muscle relaxants) with a tone management specialist.\n\nDo not offer diazepam for spasticity in adults with cerebral palsy, except in an acute situation when spasticity is causing severe pain or anxiety.\n\nDo not rapidly withdraw muscle relaxant drugs, particularly if adults with cerebral palsy have taken them for more than 2\xa0months or at a high dosage. Reduce the dosage gradually to avoid withdrawal symptoms.If using a benzodiazepine (such as diazepam) as a muscle relaxant for spasticity, see NICE's guideline on medicines associated with dependence or withdrawal symptoms for guidance on safe prescribing.\n\nConsider referring adults with cerebral palsy for botulinum toxin type\xa0A treatment if:\n\nthey have spasticity in a limited number of muscle groups that is:\n\n\n\naffecting their care (such as hygiene or dressing) or\n\ncausing pain or\n\nimpairing activity and participation, or\n\n\n\na tone management specialist agrees that treatment targeted to focal muscle groups is likely to improve their function and symptoms.In January 2019, there were several different preparations of botulinum toxin type\xa0A and the licensed indications varied between them. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on drug treatments for spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A1: pharmacological treatments for spasticity.\n\nLoading. Please wait.\n\nIntrathecal baclofen\n\nConsider referring adults with cerebral palsy to a tone or spasticity management service offering continuous pump-administered intrathecal baclofen therapy if they still have difficulties with spasticity, despite enteral muscle relaxant drug treatment or botulinum toxin type\xa0A treatment.\n\nWhen considering continuous pump-administered intrathecal baclofen, give the person (and their family and carers, if agreed) information and discuss the procedure with them. This should include:\n\nthe need for an intrathecal baclofen test to ensure treatment is suitable\n\nthe surgical procedure for implanting the pump\n\nthe need for regular hospital follow‑up visits to ensure optimal dosage and pump refill\n\nthe risks of implanting a pump and pump-related complications (for example, battery failure or catheter leakage), which can result in baclofen withdrawal or overdose\n\na review of 24-hour postural needs.\n\nIf continuous pump-administered intrathecal baclofen is being considered for an adult with cerebral palsy, perform an intrathecal baclofen test to assess if it is suitable before implanting a pump. This should involve a test dose or doses of intrathecal baclofen given to the person by lumbar puncture or through a spinal catheter.\n\nAssess the effect of the test dose or doses of intrathecal baclofen on:\n\nreducing increased muscle tone\n\nreducing pain\n\nreducing the frequency of muscle spasms\n\nmotor function, such as sitting, standing and walking.\n\nDiscuss with the adult with cerebral palsy (and their family and carers, if agreed) their views on the response to the intrathecal baclofen test and whether treatment is likely to achieve their treatment goals.\n\nSelective dorsal rhizotomy\n\nOnly consider selective dorsal rhizotomy for adults with cerebral palsy and spasticity if other treatments have been unsuccessful or are contraindicated, and after they have been assessed by a multidisciplinary team with:\n\nspecialist training and expertise in the care of spasticity and\n\naccess to the full range of treatment options. See also NICE interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy.\n\nDiscuss the impact of selective dorsal rhizotomy with the person (and their family and carers, if agreed) when it is a proposed treatment option and provide information. This should include:\n\nthat the procedure cannot be reversed\n\nthe possible complications\n\nthe need for prolonged physiotherapy and aftercare\n\nthe possible impact on function\n\nthat the long-term benefits are uncertain.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neurosurgical treatments to reduce spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A2: neurosurgical treatments for spasticity.\n\nLoading. Please wait.\n\n## Dystonia\n\nRefer adults with cerebral palsy and problematic dystonia (for example, causing problems with function, pain or participation) to a tone or spasticity management service to consider treatment options.\n\nDo not prescribe levodopa to manage dystonia in adults with cerebral palsy, except in the rare situation when it is used as a therapeutic trial to identify dopa-responsive dystonia.In January 2019, this was an off-label use of levodopa. See NICE's information on prescribing medicines.\n\nDo not rapidly withdraw enteral drugs for treating dystonia, particularly if adults with cerebral palsy have taken them for more than 2\xa0months or at a high dosage. Reduce the dosage gradually to avoid withdrawal symptoms. In January 2019, giving anti-dystonic drugs via an enteral feeding tube was an off-label use. See NICE's information on prescribing medicines.\n\nIn January 2019, the recommendations in this section were for an off-label use of botulinum toxin type\xa0A. See NICE's information on prescribing medicines.\n\nOnly consider botulinum toxin type\xa0A treatment for focal dystonia in adults with cerebral palsy when:\n\nthe person is under the supervision of a tone or spasticity management service, and it is part of a wider programme of therapy and\n\nfocal dystonia is:\n\n\n\naffecting their care (such as hygiene or dressing) or\n\ncausing pain or\n\nimpairing activity and participation.\n\n\n\nIf botulinum toxin type\xa0A is a proposed treatment option, take into account and explain to the adult with cerebral palsy (and their family and carers, if agreed):\n\nthat the severity and pattern of dystonia may change after treatment and\n\nthe potential impact of treatment on function.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on drug treatments for dystonia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A3: treatments to reduce dystonia.\n\nLoading. Please wait.\n\nIntrathecal baclofen\n\nOnly consider continuous pump-administered intrathecal baclofen if people with cerebral palsy still have difficulties with dystonia, despite having enteral anti-dystonic drug treatment or botulinum toxin type\xa0A treatment. Provide information and discuss the procedure, including intrathecal baclofen testing, with the person (and their family or carer, if agreed) as described in recommendations 1.3.13 to 1.3.16.In January 2019, this was an off-label use for intrathecal baclofen and botulinum toxin type\xa0A. See NICE's information on prescribing medicines.\n\nDeep brain stimulation\n\nIf adults with cerebral palsy continue to have severe and painful dystonia, despite having enteral anti-dystonic drug treatment or botulinum toxin type\xa0A treatment, consider referring them to a specialised centre with experience in providing deep brain stimulation. See also NICE interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on neurosurgical treatments to reduce dystonia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A3: treatments to reduce dystonia.\n\nLoading. Please wait.\n\n# Assessment and monitoring of clinical complications and comorbidities\n\n## Bone and joint disorders\n\nDiscuss with adults with cerebral palsy (and their families or carers, if agreed) that:\n\ntheir musculoskeletal function may deteriorate gradually, and any changes should be investigated to identify treatable causes\n\nearly recognition of bone and joint disorders enables early treatment, which may improve outcomes.\n\nBe aware that low bone mineral density is common in adults with cerebral palsy, particularly in people:\n\nwith reduced mobility or reduced weight bearing\n\ntaking anticonvulsants or proton pump inhibitors\n\nwho have had a previous low-impact fracture.\n\nConsider assessing for risk of fractures secondary to osteoporosis in adults with cerebral palsy. Risk factors to assess include:\n\nneeding help with moving or having to be moved, for example, hoisting\n\nhistory of falls\n\nlow BMI\n\nhistory of low-impact fractures\n\nother medical factors, for example steroid use, that may adversely affect bone health.For more information about assessment of fracture risk, see NICE's guideline on osteoporosis: assessing the risk of fragility fracture.\n\nConsider a dual-energy X‑ray absorptiometry (DXA) assessment in adults with cerebral palsy who have 2\xa0or more risk factors (see recommendation 1.4.3), particularly if they have had a previous low-impact fracture.\n\nConsider referring adults with cerebral palsy for specialist assessment and management, for example, to a rheumatology, endocrinology or bone health service, if they have:\n\na high fracture risk or\n\na positive DXA result.\n\nBe aware that, because of abnormal musculoskeletal development, adults with cerebral palsy are more likely to have bone and joint disorders.\n\nRefer adults with cerebral palsy to a specialist orthopaedic or musculoskeletal service if a bone or joint disorder is suspected and causing pain or affecting posture or function. These may include:\n\nosteoarthritis\n\ncervical instability or spondylosis (including athetosis)\n\nspinal deformity (including scoliosis, kyphosis and lordosis)\n\nsubluxation of the hips, wrist and shoulders\n\nbiomechanical knee problems\n\nabnormalities of the foot structure.\n\nDo not offer an X‑ray to assess for hip subluxation or curvature of the spine in adults with cerebral palsy, unless the person is in pain or their posture or function is affected.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bone and joint disorders\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B1: disorders of bones and joints.\n\nLoading. Please wait.\n\n## Mental health problems\n\nIdentify and address mental health problems alongside physical health problems. Recognise that the impact of mental health problems and emotional difficulties can be as important as physical health problems for adults with cerebral palsy.\n\nFollow NICE guidelines on identifying and managing specific mental health problems, and psychological and neurodevelopmental disorders, in adults who have cerebral palsy, for example:\n\nattention deficit hyperactivity disorder\n\ndepression in adults and depression in adults with a chronic physical health problem\n\ngeneralised anxiety disorder and panic disorder in adults\n\nautism spectrum disorder in adults\n\nchallenging behaviour and learning disabilities\n\nmental health problems in people with learning disabilities.\n\nTailor the identification and assessment of mental health problems and emotional difficulties to the needs and abilities of the person with cerebral palsy, in particular take into account communication difficulties or learning disabilities.\n\nAt every review, explore with the adult with cerebral palsy (and their family and carers, if agreed) if they have any concerns about, for example, their:\n\nmood\n\nirritability\n\nbehaviour\n\nsocial interaction\n\nsleep\n\ngeneral level of function.\n\nInvolve families and carers, when agreed, in identifying and assessing mental health problems and emotional difficulties in adults with cerebral palsy.\n\nTake into account the specific factors that might affect identifying, assessing and managing mental health problems and emotional difficulties in people with cerebral palsy. These may include:\n\nadverse effects of medicines (including the effects of medicines used for managing mental health problems on motor function or those used for managing motor function on mental health)\n\ncommunication difficulties\n\nlearning disabilities\n\nimpaired neuropsychological and executive functions\n\ncomorbidities, particularly epilepsy and pain\n\nside effects and drug interactions of multiple medicines (polypharmacy).\n\nDiscuss with the adult with cerebral palsy (and their family and carers, if agreed) if physical problems, such as pain, or frustration from communication difficulties or lack of stimulation are contributing to emotional distress or challenging behaviour.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on mental health problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B2: monitoring and assessing mental health.\n\nLoading. Please wait.\n\n## Difficulties with eating and nutritional problems\n\nOffer adults with cerebral palsy a regular weight check, and BMI or another anthropometric measurement, and identify people who may be at risk of undernutrition or obesity (see also the NICE guideline on obesity: identification, assessment and management).\n\nAt every review, discuss with adults with cerebral palsy (and their family and carers, if agreed) whether they have difficulties with eating or if there have been any changes in their eating habits or bowel function. Ask about issues including:\n\nchanges in appetite\n\nchanges in the person's ability to feed themselves\n\nconstipation\n\ncoughing or choking when eating\n\nfood refusal\n\nincreased frequency of chest infections (which may be related to swallowing difficulties or gastro-oesophageal reflux)\n\nan increase in the length of meal times.\n\nDiscuss if any of the following factors might be affecting the person's appetite, eating habits or weight:\n\nchanges in carer support\n\ndepression\n\npain\n\nreduced physical activity\n\nside effects of medications.\n\nBe aware that adults with cerebral palsy with severe spasticity and dyskinesia may have an increased metabolic rate and a higher risk of malnutrition.\n\nFollow the recommendations on screening for malnutrition, indications for nutrition support, and education and training of staff and carers related to nutrition, in NICE's guideline on nutrition support for adults.\n\nRefer adults with cerebral palsy to a relevant clinical specialist, such as a dietitian or speech and language therapist, if assessment suggests they have difficulties with eating or malnutrition.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on difficulties with eating and nutritional problems\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B3: monitoring feeding and nutritional problems.\n\nLoading. Please wait.\n\n## Respiratory disorders\n\nBe aware that adults with cerebral palsy are at increased risk of respiratory failure. Symptoms may include:\n\nbreathlessness\n\nchanges in behaviour (such as irritability or inability to concentrate)\n\ndaytime drowsiness\n\nworsening epilepsy\n\nheadaches on waking\n\nincreasing frequency of chest infections\n\npoor sleep pattern\n\nsleep apnoea.\n\nRecognise that some risk factors for respiratory impairment are more common in adults with severe cerebral palsy (GMFCS level\xa0IV or\xa0V), such as:\n\naspiration pneumonia\n\nchronic cardiorespiratory disorders (for example, cor pulmonale or pulmonary circulation hypertension)\n\nchronic suppurative lung disease\n\nkyphoscoliosis\n\npoor saliva control\n\nrecurrent chest infections.\n\nRefer adults with cerebral palsy and persistent or multiple signs and symptoms of respiratory impairment, or risk factors for respiratory impairment (see recommendations 1.4.22 and 1.4.23) to specialist services.\n\nConsider assessment with spirometry for adults with cerebral palsy who are suspected to be at high risk of respiratory impairment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying and monitoring respiratory disorders\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C1: protocols for monitoring respiratory health.\n\nLoading. Please wait.\n\nOffer vaccinations to adults with cerebral palsy and their carers, in line with the national immunisation programme (see the Green Book, Public Health England for further information).\n\nDo not offer prophylactic antibiotics for lower respiratory tract infections in adults with cerebral palsy, unless:\n\nthe person is at high risk of respiratory impairment (see recommendation\xa01.4.23) and\n\nthey are offered on the advice of a respiratory specialist with expertise in neurodisability management.\n\nIf an adult with cerebral palsy is at high risk of lower respiratory tract infection, consider a prophylactic physiotherapy chest care review. This may include:\n\npostural management\n\nadvice on exercise\n\nadvice on training and care for family members and carers.\n\nRefer adults with cerebral palsy and recurrent chest infections, if dysphagia is suspected, to a speech and language therapist with training in dysphagia to assess swallowing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prophylactic treatments for respiratory infections \xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C3: prophylactic treatments for respiratory disorders.\n\nLoading. Please wait.\n\nIf a person with cerebral palsy has symptoms of respiratory failure, or is at high risk of developing respiratory failure, discuss their management plan with them (and their family or carers, if agreed), including:\n\nassessing the effectiveness and tolerability of treatment\n\ntreatment goals and escalation plan of treatment\n\nmanaging complications\n\noptions for managing progressive respiratory failure.\n\nConsider home-based non-invasive ventilation for adults with cerebral palsy and respiratory failure.\n\nIf a person with cerebral palsy is having home-based non-invasive ventilation, carry out a review with a multidisciplinary team every 3\xa0to 6\xa0months. Assess and discuss with the person (and their family and carers, if agreed) the effectiveness, tolerability and whether agreed goals are being met.\n\nIf a person with cerebral palsy is having non-invasive ventilation, discuss with them (and their family or carers, if agreed) their preferences for future treatment. Agree a plan for what should happen if an intercurrent infection (occurring during the progress of respiratory failure) causes an acute deterioration in respiratory function and record this in the person's advance care plan.\n\nIf the agreed treatment goals are not met by non-invasive ventilation, consider alternative treatment options, such as tracheostomy or supportive care, and discuss them with the person with cerebral palsy, taking into account their preferences for future treatment (see recommendation\xa01.4.33).\n\nIf an adult with cerebral palsy has sleep apnoea, follow the recommendations on continuous positive airway pressure in sections 1.5 and 1.6 of the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s for when to offer assisted ventilation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on discussing the management of respiratory failure, and assisted ventilation for respiratory failure and sleep apnoea\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C2: assisted ventilation for respiratory failure.\n\nLoading. Please wait.\n\n## Pain\n\nBe aware that some adults with cerebral palsy have difficulty communicating or are unable to communicate that they are in pain.\n\nAssess for the presence, severity and location of pain in adults with cerebral palsy using pain assessment tools such as:\n\nnumerical rating scales\n\nvisual analogue scales\n\nfaces pain scales\n\nbody maps.\n\nIf an adult with cerebral palsy has difficulty communicating:\n\ndiscuss with their family or carers how best to identify pain and include this information in their care plan\n\nuse observational or descriptive pain scales to assess the presence, severity and location of pain.See also communication in the NICE guideline on patient experience in adult NHS services.\n\nEnsure that health and social care staff (and families and carers, if appropriate) caring for adults with cerebral palsy have access to a range of pain assessment tools and that they have been trained in their use.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain. \xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: identifying pain, such as musculoskeletal and gastrointestinal pain.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Advance care plan\n\nDefined by international consensus as: 'A process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences about future medical care. The goal of an advance care plan is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness.' See Defining advance care planning for adults (Sudore et al. 2017).\n\n## Alternative and augmentative communication systems\n\nAlternative and augmentative communication systems are a variety of methods (for example, signing, use of visual symbols and eye gaze technology) that can be used to help people with disabilities communicate with others. These systems or methods of communication can be used as an alternative to speech or to supplement it.\n\n## Anthropometric measurements\n\nBody measurements that include weight, height, knee height, mid-upper arm circumference, waist circumference, head circumference and skinfold thickness measurements.\n\n## Comorbidities\n\nIn the context of cerebral palsy, comorbidities are health problems caused by the brain disorder that also caused the motor impairment that is the core problem of cerebral palsy, but are not a direct complication of the motor disorder. For example, visual impairment and epilepsy are described as comorbidities because they are caused by the brain disorder. Hip dislocation and scoliosis are complications of the motor disorder and would not be described as comorbidities.\n\n## Electronic assistive technology\n\nAny piece of equipment or system that is used to increase, maintain or improve function in people with disabilities, and is electronically powered (mains electricity and/or battery). These may include communication aids, environmental controls and access to computers.\n\n## Enteral drug treatment\n\nDrugs given by mouth (oral), or via a nasogastric tube, gastrostomy tube or jejunostomy tube.\n\n## Escalation plan\n\nA record of the interventions that a person would find acceptable, in line with their values, goals and preferences. It can be used to indicate that more intensive or invasive interventions would be unacceptable to the person. For example, an escalation plan of ward-based care only, indicates that the person would not want invasive monitoring, intubation and ventilation, which are undertaken as part of intensive care.\n\n## Executive functions\n\nCognitive processes that are important for the control of behaviour. These include planning, organising and monitoring behaviours leading to goal attainment, inhibitory control, working memory and cognitive flexibility. As a result of injuries to the frontal lobes of the brain, these processes can be disrupted.\n\n## Gross Motor Function Classification System\n\nA 5‑level clinical classification system that describes the gross motor function of people with cerebral palsy based on self-initiated movement abilities. People assessed as level\xa0I are the most able and people assessed as level\xa0V are dependent on others for all their mobility needs.\n\nThe GMFCS is not validated for use in adults. However, the GMFCS level at age\xa012 has been shown to be a good predictor of mobility into adulthood, especially at the milder and most severe levels. It is used here in the absence of a validated system for use in adults because it is readily understood by people with cerebral palsy, their families and carers, and health professionals involved in the care of adults with cerebral palsy.\n\n## Key communication partners\n\nPeople who regularly interact with the person with cerebral palsy in any environment. Communication may be by speech, using communication aids, signing, facial expression or a combination of these.\n\n## Rehabilitation engineering services\n\nCentres that design, develop and adapt technological solutions to overcome challenges to function, activity and participation for individuals with disability. This includes assessment and provision of assistive devices to help with posture, mobility and communication (for example, electronic assistive technology).\n\n## Review\n\nA planned clinical appointment between an adult with cerebral palsy and a healthcare professional or multidisciplinary team. They may explore common concerns, physical symptoms, mental health, pain, nutrition and communication to ensure an individualised approach to care. The healthcare professional may be a GP, specialist nurse, rehabilitation specialist or therapist. This also allows the opportunity to address general health issues that affect people as they grow older.\n\n## Review of 24‑hour postural needs\n\nPart of a 24‑hour posture review that considers all the relevant postures that an individual has the ability to adopt over the 24\xa0hours of any given day, including postures to allow for participation in daily activities. The 3\xa0core postural orientations are lying, sitting and standing. An example of a postural need is support and positioning in bed.\n\n## Supportive care\n\nCare focused on relieving symptoms caused by serious illnesses such as respiratory failure. It can be given at any point during a person's illness to help them feel more comfortable and improve their quality of life.\n\n## Transferring\n\nMoving from one surface to another (for example, from a bed to a wheelchair) independently or with assistance.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Method of botulinum toxin type\xa0A injection in treating focal spasticity\n\nIs guided botulinum toxin type\xa0A injection using electrical localisation (electrostimulation or electromyography) of muscles more clinically and cost effective than ultrasound-guided injections or clinical positioning for localisation of injections in treating focal spasticity in adults with cerebral palsy?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on drug treatments for spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A1: pharmacological treatments for spasticity.\n\nLoading. Please wait.\n\n## Selective dorsal rhizotomy treatment to reduce spasticity\n\nWhat is the clinical and cost effectiveness of selective dorsal rhizotomy compared with intrathecal baclofen to reduce spasticity in adults with cerebral palsy?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on neurosurgical treatments to reduce spasticity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A2: neurosurgical treatments for spasticity.\n\nLoading. Please wait.\n\n## Detection and management of respiratory disorders in primary and community care\n\nCan detection and management of respiratory disorders in adults with cerebral palsy be improved in primary and community care?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on identifying and monitoring respiratory disorders\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C1: protocols for monitoring respiratory health.\n\nLoading. Please wait.\n\n## Prophylactic antibiotics for respiratory disorders\n\nAre prophylactic antibiotics clinically and cost effective in the management of respiratory symptoms in adults with cerebral palsy with significant respiratory comorbidity?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on prophylactic treatments for respiratory infections \xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C3: prophylactic treatments for respiratory disorders.\n\nLoading. Please wait.\n\n## Splinting to improve or maintain posture or function\n\nWhat is the optimum regimen for splints applied to the upper limb in adults with cerebral palsy to improve or maintain posture or function?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on physical activity, orthopaedic surgery and orthotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D2: interventions that improve or maintain physical function and participation.\n\nLoading. Please wait.\n\n## Augmentative and alternative communication systems\n\nAre augmentative and alternative communication systems clinically and cost effective in promoting communication for adults with cerebral palsy who have communication difficulties?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on communication\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D4: interventions to promote participation: communication.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Access to services and moving into adults' services\n\nRecommendations 1.1.1 to 1.1.11\n\n## Why the committee made the recommendations\n\nDisabled people have the same rights to access healthcare services as other people. These rights are outlined in the Equality Act\xa02010 and the United Nations (UN) Convention on the rights of persons with disabilities. To support this, the committee highlighted that there should be local pathways to enable access to a range of services for adults with cerebral palsy. The committee agreed that referral to specialist services is needed for some treatment options. Based on their discussions about treating spasticity and dystonia (see evidence reviews A1, A2 and A3), the committee agreed that access to specialist multidisciplinary teams is particularly important when a person with cerebral palsy experiences a deterioration in their ability to carry out usual daily activities (for example, due to pain) or when a neurosurgical or orthopaedic procedure is being considered that may affect their abilities. Adults with cerebral palsy may also need reassessment by the multidisciplinary team because of changing needs at different points in their lives, for example, changes in physical, environmental, or personal care or support needs. The committee highlighted this to raise awareness that people may need access to different services if their needs change.\n\nTo achieve good access to the relevant specialists, local networks of care are needed. The committee also noted that both people with cerebral palsy and healthcare professionals often lack awareness of the services available. Based on their experience, they agreed that provision of information about local networks of services would help to improve access.\n\nThe committee also acknowledged that carers are often unaware of their right to a local authority assessment of their own needs, including physical and mental health, and to an assessment of their need for respite care under the Care Act\xa02014. They agreed that highlighting this would help carers to access support if needed.\n\nThe evidence showed that adults with cerebral palsy experience many obstacles to equal access to services. Some examples of how these might be addressed are highlighted in the recommendations to help raise awareness among healthcare professionals. The committee agreed that healthcare professionals should recognise and address any barriers to enable equitable access to services and provide timely care. This will improve quality of life and health outcomes for adults with cerebral palsy.\n\nThe committee also noted that access to services may be limited for adults with cerebral palsy who need practical support and advocacy. There was some evidence that lack of an advocate could disadvantage people, especially when they are admitted to hospital. In addition, some adults with cerebral palsy reported that their family members were expected to act as their carers when they were admitted to hospital. The committee agreed that it should not be assumed that family members should provide personal care in a healthcare setting and that advocacy, and health and personal care, should always be offered to people when they are admitted to hospital.\n\nBased on their knowledge and experience, the committee noted that people with cerebral palsy experience barriers in access to national screening programmes, for example, lack of equipment for breast screening for women in wheelchairs, especially those with limited upper body strength, or lack of knowledge about how to perform cervical screening for women with lower limb spasticity. However, national screening services have an obligation to make arrangements so that screening is accessible to everyone. The committee agreed that increasing awareness about accessibility of these services and encouraging people to attend screening appointments would help to improve uptake of these services.\n\nThe committee discussed that specialist cerebral palsy services are provided for children and young people, but there is insufficient specialist service provision for adults, with variation and a lack of continuity in care. The committee highlighted that it is important that services continue to meet the people's needs when they move into adults' services, in line with recommendations in the NICE guidelines on cerebral palsy in under\xa025s and transition from children's to adults' services for young people using health or social care services. To ensure that needs are met for adults with cerebral palsy, the committee made recommendations about access to services and service organisation.\n\n## How the recommendations might affect practice\n\nThe recommendations on access to services reinforce legislation and best current practice.\n\nService organisation for networks of care is variable, so changes to practice will depend on the availability of services within a particular local area. Providing information about local networks of care may incur an initial cost to set up.\n\nThere may be an increase in the number of referrals. Training will also be needed to ensure healthcare professionals can manage referrals rapidly because there is a limited number of healthcare professionals with expertise in neurological disorders. However, recommendations with criteria for referral will help to reduce inappropriate referrals and variation in referrals.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: configuration of services for adults with cerebral palsy and evidence review\xa0F2: barriers to access to primary and secondary care.\n\nReturn to recommendations\n\n# Ongoing care\n\nRecommendations 1.1.12 to 1.1.18\n\n## Why the committee made the recommendations\n\nThere was limited evidence for the effectiveness of different service configurations. One study suggested that fewer visits to emergency departments and hospital visits were associated with having consistent outpatient care provided by a single doctor. Although the committee recognised that this may reflect the value of continuity of care, they agreed that the quality of the evidence was not good enough to make a recommendation.\n\nFurther evidence showed that changing the configuration of services to include the time and staff for an annual review could be cost effective if there is a reduction of at least 1\xa0emergency department visit per year per person. It was not clear from the evidence that this could be achieved when offered to all people with cerebral palsy. The committee discussed the variation in the needs of people with cerebral palsy and, based on their experience and knowledge, identified groups with more severe or complex health and social care needs who would most benefit from being offered an annual review. The committee agreed that annual review is likely to prevent an emergency department visit for this group and so would be cost effective. The committee decided that the annual review should be carried out by a healthcare professional with expertise in neurodisabilities who would have the skills and experience needed to identify potential issues that could lead to an emergency department visit. It was noted that adults with learning disabilities should already be offered an annual health check in primary care.\n\nAs an example of complex needs, the Gross Motor Function Classification System (GMFCS) levels\xa0IV and\xa0V were used. The committee acknowledged that the GMFCS is not validated for use in adults. However, it has been shown that at age\xa012, a GMFCS level\xa0I strongly predicts that the person with cerebral palsy will retain good mobility into adult years and a GMFCS level\xa0V strongly predicts that the person will be a wheelchair user in adult life. Therefore, at the mild and severe ends of the spectrum of mobility in cerebral palsy, there is stability of GMFCS levels into adulthood. In the absence of an alternative descriptive system validated for use in adults, the GMFCS is used here because it is readily understood by people with cerebral palsy, their families and carers, and health professionals involved in the care of adults with cerebral palsy.\n\nAlthough the evidence did not support annual reviews for all people with cerebral palsy, the committee agreed that regular reviews are important to check for any new problems and ensure that people's needs continue to be met. They agreed that regular reviews should be considered, tailored to the person's needs. The frequency of review was not specified because it will depend on person's needs and wishes.\n\nIt is important to discuss who should be involved in the review with the adult with cerebral palsy. Information from different healthcare professionals and social care staff may be essential to fully understand the person's clinical needs. Good record keeping and sharing of information ensures that the outcome of the review is known to all relevant people and that the appropriate actions are taken. The committee also agreed that information about the review and any changes to the person's needs should be shared to ensure integrated care.\n\nTo help maintain continuity of care between reviews, the committee agreed that there should be a single point of contact, which could be a department or service in primary or secondary care.\n\nThe committee recognised that some people may not need or wish to have regular reviews. To ensure that they still have access to specialist services when needed, the committee agreed that they should be given information on how and when to do this.\n\n## How the recommendations might affect practice\n\nAdults with severe impairment are already likely to have more frequent contact with services. Therefore, providing an annual review for adults with severe impairment is likely to result in a minor change in practice and reduce variation. There may be bigger changes in practice for people with less severe impairment if they are reviewed more often. However, the costs of this will be offset by the benefits of more frequent checks, such as early identification and management of new impairments or deterioration of function.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: configuration of services for adults with cerebral palsy.\n\nReturn to recommendations\n\n# Communication\n\nRecommendations 1.2.1 to 1.2.6\n\n## Why the committee made the recommendations\n\nThere was limited evidence to support interventions to improve communication between adults with cerebral palsy and their communication partners. However, the committee acknowledged that communication is a basic human right and that adults with cerebral palsy should be supported to communicate, express themselves and live as independently as possible.\n\nThe committee was concerned that communication difficulties and changes to communication needs are sometimes missed. Based on the members' experience, the committee agreed that increased awareness of this and a check for any changes to speech, hearing and communication at every review would help ensure that communication needs are recognised.\n\nBased on their experience and knowledge, the committee agreed that alternative and augmentative communication systems may help some adults with cerebral palsy to meet their communication needs, support independence and improve quality of life and social relationships. Therefore the need for these systems should be discussed with adults who have communication difficulties. The committee noted that there is variation in the availability of training in these techniques, which is vital for their effective use. They also highlighted that personal preference is important, and that some people may not wish to use alternative or augmentative communication systems in place of speech as their main means of communication.\n\nThere was some evidence that intensive speech therapy or supplemented speech (using topic and alphabet cues) improved speech intelligibility, but the committee agreed that it was not sufficient to recommend these specific interventions. However, using this evidence and their knowledge and experience, the committee agreed that referral to speech therapy services would enable adults with communication difficulties to be assessed and offered suitable interventions.\n\nThe committee also noted that the recommendations support the fundamental rights of people with disabilities to freedom of expression and opinion, and access to information as set out in Article\xa021 of the UN Convention on the rights of persons with disabilities.\n\nThe committee discussed that there was a need for more research on alternative and augmentative communication systems. Current practice is to offer these systems in preference to intensive speech and language therapy for people with cerebral palsy and communication difficulties. However, there is only limited evidence to support this in children with cerebral palsy and no evidence was identified for adults. The committee developed a research recommendation to determine the effectiveness of augmentative and alternative communication systems in promoting communication for adults with cerebral palsy and communication difficulties.\n\n## How the recommendations might affect practice\n\nThere is currently variation in practice and the recommendations will help to address this and reinforce best practice.\n\nInitially, an increase in referrals to speech therapy services and subsequent management is likely. However, this will decline as variations in practice are reduced.\n\nThere may be an increase in the use of augmentative and alternative communication equipment, and related training, which will involve additional costs. However, the benefits of being able to communicate would outweigh the additional costs of increased use of augmentative and alternative communication systems.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D4: interventions to promote participation: communication.\n\nReturn to recommendations\n\n# Vocational skills and independent living\n\nRecommendations 1.2.7 to 1.2.12\n\n## Why the committee made the recommendations\n\nThere was very little evidence on specific interventions for vocational or independent living skills training. However, the committee acknowledged the benefits of increased independence, social and occupational integration, participation in the community and access to work for adults with cerebral palsy. Based on their experience and knowledge, the committee highlighted that people with cerebral palsy should be asked what they enjoy doing. If they have problems in participating in their chosen activity, they should have access to support. This should include assessing for and addressing any barriers to participation and support, and may involve referral to occupational therapy services, particularly for people with complex needs.\n\nFor adults who wish to work or live independently, the committee agreed that referral for specialist support to access training, work placements and leisure activities would be beneficial. Some evidence showed that people with higher educational attainment and fewer physical complications were more likely to gain paid employment, but the committee agreed that support should be an option regardless of ability, to enable all adults to reach their full potential. For adults with cerebral palsy who are in work, referral could support access to workplace and equipment assessment, and workplace and job retention training. The NICE guideline on workplace health: management practices was highlighted by the committee as an important resource to refer to.\n\nThe recommendations support compliance with the Equality Act\xa02010 to protect people from discrimination in employment, training and education. They also reflect the fundamental rights of people with disabilities to independence, social and occupational integration, participation in the community, access to training and to engage in work, as set out in the UN Convention on the rights of persons with disabilities.\n\n## How the recommendations might affect practice\n\nThese recommendations are intended to reinforce good current practice. There will be a cost associated with addressing external factors (such as access to buildings). However, this must be done to comply with government policy and legislation. Where they are not currently being implemented, some services may need additional investment in resources.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D1: interventions to promote participation – vocational and independent living skills.\n\nReturn to recommendations\n\n# Electronic assistive technology\n\nRecommendations 1.2.13 to 1.2.17\n\n## Why the committee made the recommendations\n\nThere was no evidence identified on electronic assistive technology for adults with cerebral palsy. Based on their experience, the committee agreed that adults with cerebral palsy and complex disabilities would benefit from access to electronic assisted technology, which may enhance their independence, quality of life and improve their opportunities for employment. The recommendations support legislation such as the Human Rights Act\xa01998 and the Equality Act\xa02010. The recommendation on referral to services providing electronic assistive technology is also in line with the NHS England service specifications on environmental control equipment for patients with complex disability (all ages).\n\nThe committee was unable to recommend any specific electronic assistive technology devices because of the lack of evidence. They agreed that services providing electronic assistive technology should provide devices tailored to the person's needs.\n\nVariation in training and ongoing reviews of electronic assistive technology equipment were highlighted by the committee. Training is important for both the adult with cerebral palsy and their family and carers to ensure that the devices are used to their full benefit. By discussing the use of their equipment at each review, the healthcare professional can ensure that any problems with equipment or changes to the person's needs are identified.\n\nThe committee noted that people using electronic assistive technology may need less support from their carers and healthcare workers. This may reduce the person's social contact, which can have a negative impact. Based on their experience, the committee agreed that it is important that healthcare professionals take this into account when discussing the risks and benefits of electronic assistive technology with the adult with cerebral palsy, their family and carers.\n\n## How the recommendations might affect practice\n\nThese recommendations are intended to reinforce good current practice, and support government policy and legislation. Where they are not currently being implemented, some services may need additional investment in resources.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D3: electronic assistive technology.\n\nReturn to recommendations\n\n# Physical activity, orthopaedic surgery and orthotics\n\nRecommendations 1.2.18 to 1.2.21\n\n## Why the committee made the recommendations\n\nThere was limited evidence on physical activity interventions for adults with cerebral palsy, and what there was showed little or no improvements in, for example, mobility, function and participation. However, based on their experience the committee agreed that physical activity can help people with cerebral palsy with strength and range of movement, as well as maintaining their general fitness and a healthy weight. Evidence in the general population also shows that physical activity is of benefit to people's overall health and wellbeing. The evidence did show that the risk of injury or other adverse events for people with cerebral palsy was not increased by doing physical activities such as strength training.\n\nThe committee agreed that physical activity should be promoted by providing information and discussing the benefits with the adult with cerebral palsy. This would also be in line with current government strategies for the wider population (for example, the Start active, stay active report on physical activity in the UK).\n\nSome adults with cerebral palsy may need extra support to overcome barriers to participation in physical activities. Based on their experience, the committee agreed that referral to a relevant service is likely to be helpful for some people; for example, for assessment by a physiotherapist or occupational therapist to agree suitable interventions. The recommendation also supports improved access to mobility aids, including wheelchairs. The committee noted that a referral is in line with NHS guidance on walking aids, wheelchairs and mobility scooters for people long-term or permanent difficulty with mobility.\n\nThere was little evidence on orthopaedic surgery. However, the committee recognised that some adults with cerebral palsy who have painful musculoskeletal problems might benefit from surgery if other treatments are not effective. The committee agreed that referral to an experienced orthopaedic surgeon could be considered to review possible surgical options.\n\nThere was no evidence identified on the effectiveness of orthotic devices for adults with cerebral palsy. The committee discussed that there is variation in how orthoses are used in current practice and decided that further research in this area is a priority. Orthotic devices, such as splints, are used to help improve positioning and function. They can be used alongside other treatments or separately. The committee developed a research recommendation to determine the effectiveness of different splinting regimens in improving and maintaining posture or functional abilities in the upper limb.\n\n## How the recommendations might affect practice\n\nThe recommendations on interventions to maintain physical function reinforce current best practice and should not lead to additional resource use. Any initial costs of specialist advice would be outweighed by the potential savings from avoiding complications, injuries and maintaining a wider range of abilities.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D2: interventions that improve or maintain physical function and participation.\n\nReturn to recommendations\n\n# Agreeing goals for treatment and initial management of spasticity and dystonia\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nThe committee noted that there is a lack of understanding about the relationship between spasticity and dystonia. Based on their experience, they agreed that a better understanding of these conditions and the factors that affect them is likely to lead to more effective decisions about management. The committee discussed factors that commonly trigger or worsen symptoms of both spasticity and dystonia, and their concerns that these may sometimes go unrecognised.\n\nThe committee also discussed the balance of benefits and risks of treatment to reduce spasticity and dystonia. In particular, some people with cerebral palsy make functional use of their increased muscle tone from spasticity and dystonia, for example, to help them walk or transfer independently. For these people, a reduction in spasticity or dystonia could have a negative impact on function. To ensure informed decision making, the risks and benefits of treatment should be discussed with each person and specific treatment goals should be agreed.\n\nThere was limited evidence on treatments for spasticity and dystonia in adults with cerebral palsy, but based on their experience and expertise, the committee agreed on a stepwise approach to treatment dependent on tolerability and effectiveness. This is from the least invasive to the most invasive treatment option, which is reflected in the order of recommendations in the individual sections:\n\nidentifying and managing any factors that might be exacerbating a person's symptoms\n\nreviewing their physical management programme\n\nconsidering enteral (oral or via a feeding tube) drug treatment and referral if spasticity and dystonia are still inadequately managed\n\nconsidering more invasive treatment options.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current good practice and will help to eliminate variation.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A1: pharmacological treatments for spasticity and evidence review\xa0A3: interventions for dystonia.\n\nReturn to recommendations\n\n# Drug treatments for spasticity\n\nRecommendations 1.3.6 to 1.3.11\n\n## Why the committee made the recommendations\n\nNo evidence was identified on using enteral baclofen for treating spasticity in adults with cerebral palsy. However, the committee discussed the evidence reviewed for NICE's guideline on spasticity in under\xa019s, and agreed that this could be extrapolated to the adult population. There was limited evidence of effectiveness in children and young people, but the committee agreed that it was sufficient, supported by their experience, for enteral baclofen to be considered as a first-line drug treatment for generalised spasticity causing functional impairment, pain or spasms. The committee were unable to make a stronger recommendation because there was no comparative clinical evidence that baclofen was the most effective option.\n\nThe evidence on enteral diazepam showed no improvement in muscle tone, and side effects such as drowsiness, vomiting and abdominal pain were recorded. The committee agreed that it should not be offered routinely to treat spasticity because of the risk of adverse events and also of dependency. However, evidence from NICE's guideline on spasticity in under 19s and the committee's experience suggested that diazepam can be beneficial in the short-term management of pain and anxiety in acute situations.\n\nThere was no evidence for any other medicines. However, based on their experience of current practice, the committee acknowledged that alternative drug treatments are available that might be beneficial for some people if enteral baclofen is ineffective or not tolerated. The committee agreed that in these situations, specialist advice or referral to specialist services is warranted to consider further treatment options.\n\nSevere symptoms, such as life-threatening seizures, are associated with rapid withdrawal of enteral muscle relaxants, so the committee highlighted the importance of gradual withdrawal of these treatments. Based on their experience and knowledge, the committee decided that withdrawal symptoms are more likely if the person has been taking them for over 2\xa0months or the prescribed dosage is high.\n\nThere was some evidence that botulinum toxin type\xa0A injections improved muscle tone in adults with cerebral palsy and spasticity. However, the evidence was limited, and this treatment is more invasive and costly than alternative muscle relaxant drug treatment. For these reasons, the committee agreed that it should only be considered for people with focal spasticity and difficulties with their symptoms, who might gain the most benefit from the treatment, or if a specialist agrees that it is likely to be of benefit.\n\nThe committee discussed that botulinum toxin type\xa0A injections should be given by an experienced specialist. This is important because the injections need to be accurately placed for successful treatment and to avoid side effects. They acknowledged that some healthcare professionals use ultrasound, electrical stimulation or electromyography to help guide the injections, but noted that the benefits and cost effectiveness of these techniques are uncertain. Additional resources are associated with these techniques, for example, for equipment and training. Therefore, the committee developed a research recommendation to help determine the most effective method for ensuring accurate positioning of these injections.\n\n## How the recommendations might affect practice\n\nOverall, the recommendations reflect current good practice and will help to eliminate variation, particularly in referrals to tone or spasticity management services.\n\nThe recommendation to consider enteral baclofen as a first-line drug treatment to manage spasticity should not lead to a large increase in costs because enteral baclofen is relatively cheap and already widely used. Despite this, the committee were unable to make a stronger recommendation because there was no comparative clinical evidence that baclofen was the most effective option.\n\nThere was clinical evidence to suggest the cost of botulinum toxin could be outweighed by its benefits when treating focal spasticity. The focus on referral for focal spasticity that is causing pain, impacting care or impairing activity is likely to reduce the number of inappropriate referrals.\n\nAny additional costs of specialist input is expected to be balanced by a reduction in potentially inappropriate treatment and related adverse effects. There may be a change to practice because enteral diazepam will no longer be prescribed routinely, and this may result in a small cost saving.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A1: pharmacological treatments for spasticity.\n\nReturn to recommendations\n\n# Neurosurgical treatments to reduce spasticity\n\nRecommendations 1.3.12 to 1.3.18\n\n## Why the committee made the recommendations\n\nThere was some limited evidence with high uncertainty suggesting that both intrathecal baclofen and selective dorsal rhizotomy are effective in reducing muscle tone in adults with spasticity. However, there are risks involved, both in having surgery and of long-term complications. The committee highlighted the importance of discussing the procedure with the person and their family or carers, so that they fully understand what the treatment involves and the potential risks and benefits.\n\nUsing the evidence and their experience of current practice, the committee agreed that intrathecal baclofen pumps can be beneficial for treating spasticity in some adults with cerebral palsy. However, they should only be considered by a specialist service that can safely carry out the procedure and has the expertise to assess whether it is a suitable treatment for the person. There are potential risks of intrathecal baclofen pump treatment. These include pump-related complications (for example, battery failure or catheter leakage), infections, and baclofen withdrawal or overdose. It is also more costly than other drug treatments. Taking into account these factors, the committee agreed that referral should only be considered if a person still has difficulties with spasticity after trying enteral muscle relaxant drug treatment or botulinum toxin type\xa0A injections.\n\nBecause of the complexity of this procedure, adults with cerebral palsy need sufficient information to make an informed choice. The committee noted that this is not always consistently provided in current practice. A number of issues specifically related to this surgical procedure were highlighted by the committee as important to discuss when considering this treatment.\n\nThe response to intrathecal baclofen needs to be tested before a pump can be implanted. The committee agreed that it would be useful to highlight this. However, they noted that testing is described in detail in the BNF. The committee agreed to include advice on assessing and discussing the test results to ensure that a pump is only implanted when the benefits are established in advance.\n\nThe committee were aware that there is a risk of complications with selective dorsal rhizotomy, including deterioration in walking ability and bladder function, and later spinal deformity. They also took into account NICE's interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy, published in 2010, which recommends the involvement of a multidisciplinary team. Although they noted that the evidence for the interventional procedures guidance was in children, the committee agreed that selective dorsal rhizotomy should only be considered if other treatments have been unsuccessful or are contraindicated, and after multidisciplinary assessment in a specialist spasticity service. They noted that this is an infrequent procedure and therefore recommended that the team has specialist training and expertise in the care of spasticity.\n\nThe committee were aware that some young adults are being offered selective dorsal rhizotomy for tone management, sometimes as an alternative to replacing an intrathecal baclofen pump. In the absence of evidence for selective dorsal rhizotomy in this age group, the committee agreed that they could not make a recommendation specifically for young adults.\n\nThe committee agreed that, it is important that adults with cerebral palsy (and their family or carers, if agreed) are fully informed about the procedure, including the possibility of complications and that there is uncertainty about long-term benefits of treatment.\n\nThe committee also recommended further research, comparing the safety and effectiveness of selective dorsal rhizotomy with continuous intrathecal baclofen pump treatment. Both procedures are currently used to treat spasticity in people with cerebral palsy and there is some evidence that both are effective. However, the committee noted that the procedures, and their risks and benefits, are very different. They agreed that a comparative study would be helpful to inform decision making.\n\nThe committee noted that the NICE guideline on spasticity in under\xa019s recommends the collection of national outcome data for all patients assessed for selective dorsal rhizotomy, which may also help to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice and should not lead to additional resource use. Specialist services already exist and neurosurgical procedures are currently available for the treatment of spasticity. Including specific criteria for referral should reduce the number of inappropriate referrals to these services.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A2: neurosurgical treatments for spasticity.\n\nReturn to recommendations\n\n# Drug treatments for dystonia\n\nRecommendations 1.3.19 to 1.3.23\n\n## Why the committee made the recommendations\n\nThere was limited evidence on treating dystonia in adults with cerebral palsy. The committee discussed that it is a specialist clinical area and that the benefits and harms of treatments would need to be assessed by a person with expertise in tone management. Therefore, the committee agreed that adults with cerebral palsy should be referred for specialist management if they have problematic dystonia.\n\nThe evidence for levodopa was limited, although there was some evidence that it was not effective for reducing dystonia in adults with severe impairment. Taking into account the lack of evidence of effectiveness, and also the potential for side effects and the cost of long-term treatment to the NHS, the committee agreed that levodopa should not be prescribed routinely for dystonia in adults with cerebral palsy. However, the committee agreed that a trial of levodopa can sometimes be useful to identify the rare but treatable condition of dopa-responsive dystonia.\n\nNo evidence was identified for other enteral anti-dystonic drug treatments, so the committee agreed that they could not advise on their use. However, based on their experience of current practice, the committee acknowledged that there are options available that might be beneficial for some people and these could be considered by a specialist service. If enteral anti-dystonic drugs are then prescribed, they noted that severe symptoms, such as life-threatening seizures, are associated with rapid withdrawal of enteral anti-dystonic drugs, so the committee highlighted the importance of gradual withdrawal of these treatments. Based on their experience and knowledge, the committee decided that withdrawal symptoms are more likely if the person with cerebral palsy has been taking them for over 2\xa0months or the prescribed dosage is high.\n\nNo evidence was identified on using botulinum toxin type\xa0A injections for treating dystonia in adults with cerebral palsy. However, based on their knowledge and experience, the committee agreed that it can be of benefit to some people with focal dystonia. Because there was no evidence and this treatment is more invasive and costly than enteral anti-dystonic drug treatments, the committee agreed that it should only be considered under specialist supervision for people with focal dystonia and difficulties with symptoms, who might gain the most benefit from the treatment. They also agreed that it should only be used as part of a programme of therapy. This would usually involve a physical management programme, for example, including physiotherapy and splinting.\n\nThe committee noted that botulinum toxin type\xa0A injections should be given by an experienced specialist. This is important because the injections need to be accurately placed for successful treatment and to avoid side effects.\n\n## How the recommendations might affect practice\n\nOverall, the recommendations reflect current good practice and will help to eliminate variation, particularly in referral. There may be a change to practice because levodopa will no longer be prescribed routinely, and this may result in a small cost saving.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A3: treatments to reduce dystonia.\n\nReturn to recommendations\n\n# Neurosurgical treatments to reduce dystonia\n\nRecommendations 1.3.24 and 1.3.25\n\n## Why the committee made the recommendations\n\nDespite a lack of evidence, the committee agreed that their knowledge and experience of current practice supported the use of intrathecal baclofen pumps for treating dystonia in some adults with cerebral palsy. However, they should only be considered by a specialist service that can safely carry out the procedure and has the expertise to assess whether it is a suitable treatment for the person. There are potential risks of intrathecal baclofen pump treatment. These include pump-related complications (for example, battery failure or catheter leakage), infections, and baclofen withdrawal or overdose. It is also more costly than other drug treatments. Taking into account these factors, the committee agreed that it should only be considered when a person still has difficulties with dystonia after trying enteral anti-dystonic drug treatment or botulinum toxin type\xa0A injections.\n\nThe committee also highlighted the importance of discussing the procedure with the person and their family or carer, so that they fully understand what the treatment involves and the potential risks and benefits. They agreed that the recommendations on intrathecal baclofen testing for spasticity would also apply to dystonia.\n\nAlthough there was limited and sometimes incongruous evidence for deep brain stimulation, it did suggest some improvement in dystonia after treatment. However, some complications were noted, including problems with speech, pain, numbness and anxiety, as well as problems with the equipment.\n\nTwo studies, identified as part of the economic evidence, suggested that deep brain stimulation improved quality of life. However, one showed that it was likely to be cost effective whereas the other suggested it was not. The committee agreed that the study showing cost effectiveness was more relevant because it better reflected current technology. It also had a longer follow‑up and the results for quality of life matched the committee's expectations based on their clinical experience. However, it was noted that deep brain stimulation is only likely to be a treatment option when drug treatment is unsuccessful. This was more consistent with the patient group for the other study but current technology and appropriate quality of life at the outset was considered to be more important. The committee also took into account NICE's interventional procedures guidance on deep brain stimulation for tremor and dystonia (excluding Parkinson's disease) published in 2006, which supports its use with the involvement of a multidisciplinary team.\n\nBased on the evidence on improvements in quality of life and the committee's knowledge and experience, they agreed that deep brain stimulation should be considered when drug treatment has been unsuccessful. However, because of the possible complications, it should only be an option for people who have severe and painful dystonia, and only carried out at an experienced specialised centre.\n\n## How the recommendations might affect practice\n\nOverall, the recommendations reflect current good practice and will help to eliminate variation.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A3: treatments to reduce dystonia.\n\nReturn to recommendations\n\n# Bone and joint disorders\n\nRecommendations 1.4.1 to 1.4.8\n\n## Why the committee made the recommendations\n\nBased on their experience, the committee noted that there is a lack of awareness, both among adults with cerebral palsy and healthcare professionals, that people with cerebral palsy are at increased risk of bone and joint complications, and that musculoskeletal function may worsen over time. Common complications include osteoporosis and conditions caused by abnormal musculoskeletal development, such as scoliosis and subluxation of joints, or abnormal movements leading to degenerative change, such as cervical myelopathy. Increasing awareness and discussing this with adults with cerebral palsy will enable early identification and management of these conditions.\n\nThe committee agreed that assessing fracture risk is important for adults with cerebral palsy who are at increased risk of osteoporosis to enable action to be taken to manage osteoporosis and prevent fractures. Based on their experience and knowledge, the committee identified factors that are associated with increased risk and agreed that fracture risk assessment should be considered for adults with cerebral palsy with these factors. In addition to the risk factors related to cerebral palsy (such as reduced weight bearing), risk factors for the general population also apply. These are described in NICE's guideline on osteoporosis: assessing the risk of fragility fracture along with information about assessing fracture risk.\n\nThere was some evidence that dual-energy X‑ray absorptiometry (DXA) scanning can be effective in identifying reduced bone density in adults with cerebral palsy. However, the committee noted that these scans can often be uncomfortable and the results difficult to interpret in people with cerebral palsy. The risks of treatment may also outweigh the benefits in people without symptoms. For these reasons, the committee agreed that it should only be considered for people with more than 1\xa0risk factor, suggesting a high risk of fractures and osteoporosis.\n\nBased on their experience, the committee agreed that assessment and management of osteoporosis in adults with cerebral palsy is highly complex, and that referral to a specialist service is often necessary. For some people this may be to a rheumatology or bone health service, for others referral to endocrinology may be considered to explore whether a hormonal condition could be affecting their bones.\n\nAdults with cerebral palsy may develop joint abnormalities due to problems of tone, movement and posture. No evidence was identified on monitoring for these disorders. However, the committee agreed that specialist referral is needed for assessment and management if these conditions are suspected and causing problematic symptoms. They highlighted some of the more common disorders to help increase awareness and improve recognition.\n\nThe committee were aware that hip and spine X‑rays may be offered routinely to children and young people in paediatric services. However, ongoing surveillance is not necessary for adults once growth is complete, and X‑rays should not be offered unless there are new problems of pain, posture or function.\n\n## How the recommendations might affect practice\n\nThe recommendations for risk assessment and DXA scanning are unlikely to change current practice. DXA scans should already be considered under NICE's guideline on osteoporosis.\n\nThe recommendations could increase referrals to specialist services. However, the impact of this is likely to be balanced by better treatment and prevention of hospital stays.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B1: disorders of bones and joints.\n\nReturn to recommendations\n\n# Mental health problems\n\nRecommendations 1.4.9 to 1.4.15\n\n## Why the committee made the recommendations\n\nNo evidence was found on assessing and monitoring mental health in adults with cerebral palsy. However, from their experience, the committee acknowledged that healthcare services for adults with cerebral palsy tend to focus on physical rather than mental health. Greater awareness of mental health problems and the specific challenges of identifying and managing them in adults with cerebral palsy would help to ensure that such problems are recognised and managed. Alongside this, the committee highlighted that discussing the person's mental wellbeing at each review would help to identify any concerns and ensure that support for mental health problems is included in the person's care plan. Important insights about a person's mental health can often be gained from people close to them, so the committee agreed that (with consent from the person) family members or carers should also be asked if they have any concerns.\n\nPhysical problems and common frustrations that can affect emotional wellbeing in adults with cerebral palsy were highlighted by the committee because they are often overlooked, but can negatively affect mental health and behaviour.\n\nThe committee noted that there are many relevant NICE guidelines related to mental health conditions that would apply to adults with cerebral palsy, and other NICE guidelines relevant to those with communication difficulties or learning disabilities.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current best practice and help to eliminate variation.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B2: monitoring and assessing mental health.\n\nReturn to recommendations\n\n# Difficulties with eating and nutritional problems\n\nRecommendations 1.4.16 to 1.4.21\n\n## Why the committee made the recommendations\n\nThere was some evidence on tools for assessing nutritional status in adults with cerebral palsy, but the committee concluded that the evidence was not good enough to recommend a specific tool. In addition, many factors can affect feeding and nutrition, so they agreed that a single tool is unlikely to be suitable for everyone.\n\nBased on their experience, the committee agreed that assessment should be individualised to reflect each adult's needs and circumstances. Current good practice includes regular weight checks and BMI or anthropometric measurement, and talking to the person and their families and carers about eating problems and other factors affecting nutrition and weight. People identified as at risk of undernutrition or with eating difficulties can then be referred to a specialist to assess for and treat specific problems. Because the recommendations focus on individualised assessment, the committee agreed that specific tools for assessing nutrition are not a priority for further research.\n\nThe committee discussed the role of people caring for adults with cerebral palsy and agreed that training should be provided in line with the NICE guideline on nutrition support for adults, to help pick up any problems between reviews.\n\nThe committee noted that adults with dyskinetic cerebral palsy or severe spasticity may have an increased metabolic rate and need to increase their calorie intake to prevent malnutrition. The committee recognised that reduction in dyskinesia or spasticity by treatment such as intrathecal baclofen may result in weight gain. They agreed that, from their experience, this can go unrecognised and that greater awareness could help people get the support they need.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current best practice and help to eliminate variation.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B3: monitoring feeding and nutritional problems.\n\nReturn to recommendations\n\n# Identifying and monitoring respiratory disorders\n\nRecommendations 1.4.22 to 1.4.25\n\n## Why the committee made the recommendations\n\nNo evidence was found on monitoring respiratory health in adults with cerebral palsy. Adults with cerebral palsy are at an increased risk of respiratory failure, which can be life threatening. However, based on their experience and knowledge, the committee agreed that the early symptoms of respiratory impairment may sometimes go unrecognised. Greater awareness and earlier recognition and treatment may result in treatment that prevents progression to respiratory failure.\n\nBased on their experience and some limited evidence, the committee agreed that better awareness of the risk factors for respiratory impairment would help to ensure early recognition and appropriate referral. They also wanted to highlight that these are more common in adults with severe impairment, such as a high GMFCS score. They agreed that referral for specialist assessment would enable prevention or treatment of respiratory complications in people at high risk.\n\nThe committee discussed that reduced lung volume is an important factor contributing to respiratory impairment. However, there was limited evidence available on the value of spirometry in assessing respiratory function in adults with cerebral palsy. Based on their experience and expertise, the committee agreed that spirometry should be considered for people at high risk of respiratory impairment to help identify people who may need treatment.\n\nThe committee agreed that further research on identifying and managing respiratory disorders in adults with cerebral palsy would be helpful. They developed a research recommendation to determine the most effective methods of detecting and managing respiratory disorders in primary and community care.\n\n## How the recommendations might affect practice\n\nBetter survival of children with cerebral palsy into adulthood means that this is an emerging area of practice. There are relatively few respiratory specialists with a special interest in adults with cerebral palsy. There may be an increase in referrals, which might place increased pressure on limited specialist services. However, earlier recognition and treatment will lead to improved outcomes. Respiratory conditions can often lead to hospital admission and reducing the need for this would potentially lead to cost savings.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C1: protocols for monitoring respiratory health.\n\nReturn to recommendations\n\n# Prophylactic treatments for respiratory infections\n\nRecommendations 1.4.26 to 1.4.29\n\n## Why the committee made the recommendations\n\nNo evidence was identified on preventing respiratory infections in adults with cerebral palsy. However, adults with cerebral palsy are at an increased risk of respiratory impairments and respiratory failure, so the committee agreed that adults with cerebral palsy and their family and carers should receive vaccinations, such as the flu vaccination, as a prophylactic measure to prevent respiratory infections.\n\nApplying their clinical expertise and experience, the committee agreed that the role of antibiotics is limited for prophylaxis of respiratory infections in adults with cerebral palsy. Taking into account potential adverse effects and the principles of antibiotic stewardship, the committee agreed that antibiotic prophylaxis should only be used in people at high risk of infection when it is advised by the respiratory specialist with expertise in neurodisability management. For example, this might be in people with recurrent chest infections and bacterial colonisation identified on sputum culture. The aim for these people would be to reduce acute antibiotic use and limit symptom burden.\n\nThe committee agreed that the prevention of respiratory infections is an important area for research. Many people with cerebral palsy have respiratory symptoms caused by sputum retention or recurrent respiratory infection, possibly related to aspiration. A smaller number have chronic bacterial airway colonisation with increased respiratory symptom burden and recurrent infections. The committee developed a research recommendation to determine the role of prophylactic antibiotics in improving quality of life and preventing hospital stays in people with or without persistent bacterial airway colonisation.\n\nAlthough there was no evidence for chest physiotherapy to prevent respiratory infections, the committee discussed the potential benefits of postural management and exercise. Based on their experience and expertise, they agreed that a physiotherapy chest care review should be considered for adults with cerebral palsy who are at high risk of respiratory infection. The committee also noted that families and carers can help with ongoing chest care, but may not always receive adequate support to enable this. They agreed that it would be beneficial for this to be included as part of the chest care review. This could also include advice on posture, position change, opportunities to move, interventions to assist ventilation and secretion control management.\n\nEffective swallowing (and saliva control) is important to prevent respiratory infections in adults with cerebral palsy. The committee agreed that assessment by a dysphagia-trained speech and language therapist should be considered for people with recurrent chest infections that may be caused by dysphagia.\n\n## How the recommendations might affect practice\n\nThe recommendations on vaccination reinforce current best practice.\n\nReferral to a respiratory team for adults with cerebral palsy will reinforce best practice. However, there may be an increase in referrals, which could put additional pressure on already limited specialist services.\n\nThe recommendation on prophylactic antibiotic use is not considered to be a change in practice. However, there may be a small decrease in use of prophylactic antibiotics, which could lead to cost savings.\n\nThe recommendations on chest physiotherapy review and referral to dysphagia-trained speech and language therapist are unlikely to have a big impact on current practice. There may be a small increase in the number of referrals. This is likely to be balanced by improved prevention of respiratory infections. There may also be an increase in provision of training and support for families and carers. However, this is likely to be balanced by improved ongoing chest care, which would reduce respiratory infections and the costs associated with them.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C3: prophylactic treatments for respiratory disorders.\n\nReturn to recommendations\n\n# Discussing the management of respiratory failure, and assisted ventilation for respiratory failure and sleep apnoea\n\nRecommendations 1.4.30 to 1.4.35\n\n## Why the committee made the recommendations\n\nThe management of respiratory failure varies according to individual circumstances and preferences. The committee noted that having discussions about the effectiveness and tolerability of treatments (for example, non-invasive ventilation can be uncomfortable), as well as planning for future treatment and what to do if the person's condition worsens, helps to identify the most appropriate treatment pathway.\n\nAlthough no evidence was identified on assisted ventilation for adults with cerebral palsy, the committee noted that there is evidence supporting non-invasive ventilation in people with progressive neuromuscular conditions. The committee discussed that the course and symptoms of respiratory failure may be similar across the different conditions. They agreed that non-invasive ventilation could be beneficial, based on evidence extrapolated from these populations and the committee's experience. The committee also agreed that it is important to review management every 3\xa0to 6\xa0months, which is consistent with standard practice.\n\nThe committee discussed that people's goals and preferences for management after acute deterioration in respiratory function will vary. Based on their experience and expertise, the committee highlighted the importance of agreeing a management plan with the person (and their family or carers, if agreed) for future care in this situation. This should be documented in the person's advance care plan. A full understanding of the options available and the person's values, preferences and goals will lead to better shared decision making and more informed choices about care.\n\nBased on their experience and expertise, the committee discussed that when treatment goals are not met by non-invasive techniques, alternative options such as tracheostomy or supportive care could be considered. There was no evidence available in adults with cerebral palsy, but the committee agreed that tracheostomy can be effective for some patients in maintaining quality of life.\n\nThe committee recognised that sleep apnoea is common in adults with cerebral palsy. It can affect sleep quality and therefore quality of life. They agreed that treatment would be the same for adults with cerebral palsy as in the general population and cross-referred to the recommendations on continuous positive airway pressure in sections 1.5 and 1.6 of the NICE guideline on obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in over 16s for when to offer assisted ventilation.\n\n## How the recommendations might affect practice\n\nThe recommendations in this section reinforce current best practice and will help to standardise practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C2: assisted ventilation for respiratory failure.\n\nReturn to recommendations\n\n# Pain\n\nRecommendations 1.4.36 to 1.4.39\n\n## Why the committee made the recommendations\n\nThe committee acknowledged that it can be difficult to recognise pain in people with communication difficulties. They agreed that better awareness of this would help to prevent under-identification of pain.\n\nThe evidence indicated that numerical, visual analogue and faces pain scales had similarly good reliability and validity for assessing pain in adults with cerebral palsy. Although the use of body maps was not evaluated in the evidence, the committee agreed they would also be a useful way to help localise the source of any pain. The committee acknowledged that families and carers have valuable insight into identifying whether a person is in pain, and this is especially important if the person has communication difficulties. For adults with cerebral palsy who have difficulty communicating, the committee agreed that observational and descriptive pain scales would be appropriate and useful. The committee agreed that in practice, the method of pain assessment chosen would depend on the person's individual needs and circumstances, in particular, their ability to communicate.\n\nThe committee were also aware that people caring for adults with cerebral palsy do not always have access to suitable pain assessment tools or the training that is needed for their use. Based on their experience, they agreed that these are important to enable pain to be recognised, localised pain identified and treatment targeted effectively.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect the current practice of selecting an appropriate measure from a range of pain assessment methods, depending on the person's ability to communicate. The committee acknowledged that, although learning disability nurses currently train carers in generic pain assessment techniques, individualised training and documentation of how best to identify pain in the care plan would be a change in practice in some centres and may have a cost impact.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: identifying pain, such as musculoskeletal and gastrointestinal pain.\n\nReturn to recommendations", 'Context': 'Cerebral palsy is a disorder of motor development caused by a non-progressive pathology that affects the developing brain. People with cerebral palsy may also have disorders of communication, learning, feeding and vision, and epilepsy. Cerebral palsy is a lifelong condition and there is not yet a cure for the underlying brain disorder.\n\nThere are now more adults living with cerebral palsy than there are children with cerebral palsy. Adults with cerebral palsy have a wide range of abilities – from full independence in everyday life to needing 24‑hour care and attention.\n\nNew interventions are coming into routine clinical practice for the management of premature babies and babies in a poor condition at birth who are at high risk of developing cerebral palsy. These may change the pattern of cerebral palsy and its related comorbidities. With improved survival, more children with severe and complex cerebral palsy are likely to live beyond childhood and into adult life. As they become young adults and transfer into adult services, this group will continue to need regular monitoring of their health and wellbeing.\n\nAdults with cerebral palsy should be able to become as functionally independent as possible. Many may wish to go into further education, gain employment, participate in leisure activities and contribute fully to society. Barriers to these goals should be minimised so that adults with cerebral palsy have equal access to all opportunities.\n\nAdults with cerebral palsy tend to have less fluctuation in their motor skills than children. However, their mobility may decrease because of factors such as muscle tone, weakness and pain. Comorbid symptoms, such as pain, mental health problems, communication difficulties and nutritional problems can, individually and in combination, affect participation and quality of life. These should also be a high priority for management.\n\nAs adults with cerebral palsy who have ongoing care needs grow older, there may be changes in their care arrangements. It may not be possible for their parents to continue to be the main carers and other support may be needed, either in the community or a residential setting. There is always the need for ongoing training and support for those who are caring for adults with cerebral palsy.\n\nAdults with cerebral palsy and associated comorbidities may have difficulties with all aspects of health and daily living. However, this guideline has not been able to look at the evidence and develop recommendations for all areas of care. Areas that are not covered include bowel and bladder continence, sexual health and dental health. The principles of access to services, providing information and appropriate referral, discussed in the guideline, apply not only to areas directly addressed but also equally to other areas of care.\n\nThe care and support needs of adults with cerebral palsy depend on the severity of impairment and the presence or absence of comorbidities. There is significant variation in how services are currently provided to meet these needs. However, there is not a single system appropriate for all adults with cerebral palsy. In line with the Equality Act\xa02010 and the United Nations (UN) Convention on the rights of persons with disabilities, this guideline aims to ensure that adults with cerebral palsy have easy access to equitable, cost-efficient services, with a clear network of referral to more specialised services as appropriate.'}
|
https://www.nice.org.uk/guidance/ng119
|
This guideline covers care and support for adults with cerebral palsy. It aims to improve health and wellbeing, promote access to services and support participation and independent living.
|
0f148b7f7eb901aaeb0830ce80866dbf8acd7f7e
|
nice
|
Mepilex Border Heel and Sacrum dressings for preventing pressure ulcers
|
Mepilex Border Heel and Sacrum dressings for preventing pressure ulcers
Evidence-based recommendations on Mepilex Border Heel and Sacrum dressings for preventing pressure ulcers.
# Recommendations
Mepilex Border Heel and Sacrum dressings show promise for preventing pressure ulcers in people who are considered to be at risk in acute care settings. However, there is currently insufficient evidence to support the case for routine adoption in the NHS.
Research is recommended to address uncertainties about the claimed benefits of using Mepilex Border Heel and Sacrum dressings. This research should also explore issues such as:
the incidence of heel and sacrum pressure ulcers in NHS acute care settings
criteria for patient selection to reduce pressure ulcer incidence with Mepilex Border Heel and Sacrum dressings in addition to standard care.NICE will consider reviewing this guidance when substantive new evidence becomes available.
Why the committee made these recommendations
Standard care to prevent pressure ulcers in acute care settings includes risk assessment, skin assessment, regular repositioning and the use of special devices.
Pressure ulcers are most common on the heel and sacrum. Mepilex Border Heel and Mepilex Border Sacrum dressings are designed to prevent pressure ulcers in these areas by reducing pressure, friction, shear and humidity.
There is limited evidence for the clinical effectiveness of Mepilex Border Heel dressings compared with standard care. Evidence from clinical trials suggests that Mepilex Border Sacrum dressings may reduce the incidence of pressure ulcers but it is unclear if the results are generalisable to patients in NHS acute care settings. On the basis of the published evidence and expert advice it is uncertain how patients might be selected for Mepilex Border dressings for the potential clinical benefits to be realised.
Cost modelling shows that Mepilex Border dressings may be cost saving when used with standard care, but the savings are difficult to estimate because of limitations in the evidence and uncertainty about the incidence of pressure ulcers in NHS acute care settings. The incidence rate is likely to fall over time as a result of improvements in preventative care but it will still vary across NHS trusts and it may be affected by proposed changes to the reporting arrangements.
Because of these uncertainties the case for routinely adopting Mepilex Border dressings is not supported, but further research to reduce the clinical and cost uncertainties would be helpful.# The technology
Mepilex Border Heel and Mepilex Border Sacrum dressings (Mölnlycke Health Care)
Overview
Mepilex Border dressings are self-adherent, 5-layer foam dressings that include a patented soft silicone technology (known as Safetac).
They are intended for use as part of a care bundle to prevent pressure ulcers in patients at risk of developing pressure ulcers. The current standard of care, and relevant comparators, are described in the NICE Pathway on pressure ulcers.
The company claims that the dressings reduce shear and friction and displace pressure.
Mepilex Border dressings are available in 3 variants: for use on the heel and sacrum (Mepilex Border Heel and Mepilex Border Sacrum), or as standard dressings (Mepilex Border) for use on any part of the body.
This guidance specifically considers the variants designed to prevent pressure ulcers of the heel and sacrum (Mepilex Border Heel and Mepilex Border Sacrum).
Innovative aspects
The proprietary Safetac technology allows the dressings to be easily removed and reapplied. The dressings also have a non-woven redistribution layer designed to lessen the effect of shear forces.
Costs
The costs stated in the company's submission are £6.47 to £7.21 for Mepilex Border Heel and £3.06 to £7.26 for Mepilex Border Sacrum, depending on size.
For more details, see the website for Mepilex Border Heel and Sacrum dressings.# Evidence
# Clinical evidence
## Relevant evidence comes from 13 studies, 4 of which are randomised controlled trials
Of the studies that met the inclusion criteria defined in the scope, 4 were randomised controlled trials (n=1,344) and 9 were non-randomised comparative observational studies (n=1,767). The 4 randomised controlled trials were based on the prevention of sacral pressure ulcers in adults, and none was done in the UK. For full details of the clinical evidence, see section 3 of the assessment report.
## Results of the randomised controlled trials are mixed
The 4 randomised controlled trials (Aloweni et al. 2017, Kalowes et al. 2016, Santamaria et al. 2015a and Walker et al. 2017) compared Mepilex Border Sacrum with standard care in adults at risk of developing pressure ulcers in intensive care units in Singapore, the US and Australia. The external assessment centre (EAC) considered these studies to have acceptable internal and external validity and to provide relevant evidence for the use of Mepilex Border Sacrum. Pooled treatment effect estimates from the fixed-effect meta-analysis of the 3 studies that reported pressure ulcer incidence rates as the number of patients with a pressure ulcer showed a non-significant relative risk (RR) in favour of Mepilex Border Sacrum (RR 0.51, 95% confidence interval 0.22 to 1.18; p=0.12). Based on the assumption of 1 pressure ulcer per patient in Santamaria (2015a), pooled treatment effect estimates from a fixed-effect meta-analysis of the 4 studies showed a significant relative risk in favour of Mepilex Border Sacrum (RR 0.42, 95% CI 0.20 to 0.86; p=0.02). However, a random-effects meta-analysis of the 4 studies showed a non- significant relative risk with Mepilex Border Sacrum (RR 0.45, 95% CI 0.20 to 1.04; p=0.06).
## Evidence from most observational studies is low quality and less relevant
The EAC considered 3 of the 9 observational studies (Park 2014, Richard-Denis et al. 2017a and Santamaria et al. 2015b) to have acceptable levels of both internal and external validity. However, the observational studies overall had lower internal and external validity compared with the randomised controlled trials, because of unacceptable cohort recruitment, inconsistencies in describing procedures and measurements, and unclear presentation and precision of results. Because of this, the EAC concluded that the evidence from the 9 observational studies was less relevant to the decision problem.
## There is less evidence for Mepilex Border Heel
The EAC noted that the clinical effectiveness of Mepilex Border Heel is uncertain because of the limited comparative evidence. Only 2 observational studies assessing the heel dressing were identified (Haisley et al. 2015 and Santamaria et al. 2015b), and only the Santamaria study had acceptable levels of internal and external validity. This study (n=412) showed a significant difference in the proportion of patients who developed a pressure ulcer, in favour of Mepilex Border Heel (p=<0.001).
# Cost evidence
## The company's cost model shows that the use of Mepilex Border dressings is cost saving
The company's economic evidence was a cost model comparing standard care for preventing pressure ulcers with standard care and the use of Mepilex Border dressings. The time horizon was less than 1 year. The model was a single-level decision tree comprising health states for 2 possible outcomes, specifically whether or not a patient develops a pressure ulcer. The model assumed that:
standard care and reductions in pressure ulcer incidence rates were generalisable from Santamaria et al. (2015a) to NHS practice
resource use was generalisable from Santamaria et al. (2015a) to NHS practice
the cost of pressure ulcer management in the UK is known and the estimates are reliable
the costs of implementation and managing adverse events are negligible
the treatment effect is comparable across different types of Mepilex Border dressing.The EAC agreed that the structure of the model accurately depicts the patient pathway and any possible changes that may result from the use of Mepilex Border dressings, but it considered that some of the values of the parameters used to populate the model were inappropriate. The company's model showed that using Mepilex Border Heel and Sacrum dressings results in a cost saving of £177 per patient. For full details of the cost evidence, see section 4 of the assessment report.
## The EAC's changes to the cost model parameter values make Mepilex Border dressings less cost saving
The EAC identified limitations in some of the parameter values in the company's model and made changes to better reflect NHS costs, including:
Applying baseline incidence rates of pressure ulcers from UK sources.
Calculating the cost of pressure ulcer treatment by appropriately weighting treatment cost for different pressure ulcer stages using UK sources.
Updating the number of dressing changes and the cost of nursing time.Clinical-effectiveness estimates in the EAC's model were informed by the pooled treatment effect in the meta-analysis of the 3 randomised controlled trials. These changes to the model decreased the cost savings associated with Mepilex Border Heel and Sacrum dressings to £19 per patient. For full details of the changes, see section 4 of the assessment report.# Committee discussion
# Clinical effectiveness
## The effectiveness of Mepilex Border dressings is uncertain
Having considered the various meta-analyses done by the EAC, the committee preferred the meta-analysis of the 3 randomised controlled trials and concluded that any benefit provided by Mepilex Border Sacrum in preventing sacral pressure ulcers was of borderline statistical significance. The committee also noted that there was limited robust evidence on the clinical effectiveness of Mepilex Border Heel; indeed, only 1 observational study reported positive results for the Mepilex Border dressing. The committee concluded that Mepilex Border Sacrum is at best marginally effective, and that the effectiveness of Mepilex Border Heel remains uncertain.
## Pressure ulcer incidence rates in the NHS may be lower than those in the published evidence
The incidence of pressure ulcers with standard care is an important factor in determining the potential of Mepilex Border dressings. The clinical experts highlighted that there is variation in reported pressure ulcer incidence rates across the NHS; this is likely because of variation in how best practice to prevent pressure ulcers is implemented. However, they explained that preventing pressure ulcers is a priority for all NHS trusts and the incidence of pressure ulcers seems to be reducing through the widespread use of standard bundles of care. The EAC provided estimates of pressure ulcer prevalence from NHS safety thermometer data, but the committee concluded that there remains uncertainty because of the failure to capture grade 1 pressure ulcers and the voluntary nature of data submission. Proposed changes to reporting measures will also affect the future reported incidence rates and hopefully improve the consistency and completeness of the data. Based on the available data, the committee concluded that the proportion of patients at risk of developing a new heel or sacral pressure ulcer in an acute care NHS setting is likely to be close to 3.8% (as estimated by the EAC), but that this is likely to decrease over time.
## It is unclear if the evidence is generalisable to the NHS
All 4 randomised controlled trials were done outside the UK. The clinical experts explained that because of international guidelines on preventing pressure ulcers, overall standards of care are likely to be relatively consistent across different countries. Nonetheless, there may still be differences in terms of patient selection, length of hospital stay, staff ratios and the exact composition of care bundles. The committee noted the relatively high baseline incidence rate of pressure ulcers in the control arm of the trials compared with the EAC's estimate for the incidence in the NHS. It also noted that any benefits associated with Mepilex Border dressings observed in the trial were based on a small absolute number of pressure ulcer events. Moreover, the committee was aware that assessing and grading heel and sacral pressure ulcers is subjective, and the clinical experts confirmed that this often depends on individual staff experience. Healthcare professionals will often seek a second opinion to avoid the consequence of incorrect grading, and the availability of specialist tissue viability nurses across the NHS varies. The clinical experts confirmed that NHS acute care settings include a broad range of patients at risk of pressure ulcers, and that staff across different clinical areas will have different levels of expertise in preventing and recognising early evidence of pressure ulcers. Having considered these factors, the committee concluded that there were uncertainties about the generalisability of the evidence to NHS practice.
# NHS considerations
## Healthcare professionals should use the appropriate dressing for the specific location of the pressure ulcer
The clinical experts explained that little training is needed to be able to apply Mepilex Border dressings. Some clinical experts noted that because of the cost of the specific Mepilex Border Sacrum and Heel variants, the less costly standard rectangular Mepilex Border dressings are sometimes used and instead cut to the appropriate shape. However, this may limit the effectiveness of the dressings and mean that they need to be changed more often. The committee noted that this improvised use is not included in the manufacturer's instructions for use. It concluded that healthcare professionals should use the appropriate dressing for the specific location of the pressure ulcer.
## Further research would help to inform patient selection
The clinical experts agreed that not all patients in acute care should have Mepilex Border dressings, but they described uncertainty in terms of best patient selection. They explained that it has not yet been determined how to identify patients for whom Mepilex Border dressings would be most suitable. The committee agreed that the evidence available does not allow for accurate patient selection and that further research would be helpful in this regard. The committee also noted that evidence was generated in other settings which are not covered by the scope of this evaluation.
# Cost modelling
## The EAC's updated model is more plausible than the company's model but uncertainties remain
The committee accepted the EAC's changes to the company's cost model (see section 3.6), and considered that the revised parameters better reflected costs and resource use in an NHS acute care setting. However, it noted that uncertainties remained with regard to important factors such as the incidence of pressure ulcers and how often dressings needed to be changed. The committee concluded that the cost consequences associated with Mepilex Border Heel and Sacrum were uncertain and that further research would help to inform more accurate cost modelling.
## Pressure ulcer incidence rates and frequency of dressing changes are uncertain and vary across settings
Cost savings in the updated model were mainly driven by the incidence of pressure ulcers in the standard care arm and the frequency of dressing changes. The committee recalled that pressure ulcer incidence rates may be lower in the NHS than those used in the model (see section 4.2). The committee also understood that according to the instructions for use, Mepilex Border Heel and Sacrum dressings should be changed every 3 days. However, the clinical experts explained that in certain patient groups, such as people with faecal or urinary incontinence, the dressings may need to be changed more often. The committee concluded that resource use data from clinical practice would help to inform more accurate cost modelling.
# Cost savings
## Mepilex Border Heel and Sacrum dressings may be cost saving compared with standard care
The EAC's updated cost model reported that compared with standard care, using Mepilex Border Heel and Sacrum may save around £19 per patient. However, the committee concluded that any proposed cost savings should be interpreted with caution because of the uncertainties in the cost modelling (see section 4.7).
# Further research
## Mepilex Border dressings show promise and further research would help to address the uncertainties
The committee concluded that Mepilex Border Heel and Sacrum dressings show promise, and that further research should be done to help resolve the uncertainties about clinical effectiveness and cost modelling. This research should also evaluate the incidence of pressure ulcers in patients at risk or high risk of pressure ulcers in an acute care setting, despite having standard care to prevent pressure ulcers. The research should explore any benefits that Mepilex Border dressings may offer in addition to standard care for preventing heel and sacral pressure ulcers. Data from this research, combined with data from use of dressings in clinical practice, should allow conclusions to be drawn about which patients will benefit most, as well as practical considerations such as how often the dressings should be changed.
|
{'Recommendations': 'Mepilex\xa0Border Heel and Sacrum dressings show promise for preventing pressure ulcers in people who are considered to be at risk in acute care settings. However, there is currently insufficient evidence to support the case for routine adoption in the NHS.\n\nResearch is recommended to address uncertainties about the claimed benefits of using Mepilex\xa0Border Heel and Sacrum dressings. This research should also explore issues such as:\n\nthe incidence of heel and sacrum pressure ulcers in NHS acute care settings\n\ncriteria for patient selection to reduce pressure ulcer incidence with Mepilex\xa0Border Heel and Sacrum dressings in addition to standard care.NICE will consider reviewing this guidance when substantive new evidence becomes available.\n\nWhy the committee made these recommendations\n\nStandard care to prevent pressure ulcers in acute care settings includes risk assessment, skin assessment, regular repositioning and the use of special devices.\n\nPressure ulcers are most common on the heel and sacrum. Mepilex\xa0Border Heel and Mepilex\xa0Border Sacrum dressings are designed to prevent pressure ulcers in these areas by reducing pressure, friction, shear and humidity.\n\nThere is limited evidence for the clinical effectiveness of Mepilex\xa0Border Heel dressings compared with standard care. Evidence from clinical trials suggests that Mepilex\xa0Border Sacrum dressings may reduce the incidence of pressure ulcers but it is unclear if the results are generalisable to patients in NHS acute care settings. On the basis of the published evidence and expert advice it is uncertain how patients might be selected for Mepilex\xa0Border dressings for the potential clinical benefits to be realised.\n\nCost modelling shows that Mepilex\xa0Border dressings may be cost saving when used with standard care, but the savings are difficult to estimate because of limitations in the evidence and uncertainty about the incidence of pressure ulcers in NHS acute care settings. The incidence rate is likely to fall over time as a result of improvements in preventative care but it will still vary across NHS trusts and it may be affected by proposed changes to the reporting arrangements.\n\nBecause of these uncertainties the case for routinely adopting Mepilex\xa0Border dressings is not supported, but further research to reduce the clinical and cost uncertainties would be helpful.', 'The technology': "Mepilex\xa0Border Heel and Mepilex\xa0Border Sacrum dressings (Mölnlycke Health Care)\n\nOverview\n\nMepilex\xa0Border dressings are self-adherent, 5-layer foam dressings that include a patented soft silicone technology (known as Safetac).\n\nThey are intended for use as part of a care bundle to prevent pressure ulcers in patients at risk of developing pressure ulcers. The current standard of care, and relevant comparators, are described in the NICE Pathway on pressure ulcers.\n\nThe company claims that the dressings reduce shear and friction and displace pressure.\n\nMepilex\xa0Border dressings are available in 3 variants: for use on the heel and sacrum (Mepilex\xa0Border Heel and Mepilex\xa0Border Sacrum), or as standard dressings (Mepilex\xa0Border) for use on any part of the body.\n\nThis guidance specifically considers the variants designed to prevent pressure ulcers of the heel and sacrum (Mepilex\xa0Border Heel and Mepilex\xa0Border Sacrum).\n\nInnovative aspects\n\nThe proprietary Safetac technology allows the dressings to be easily removed and reapplied. The dressings also have a non-woven redistribution layer designed to lessen the effect of shear forces.\n\nCosts\n\nThe costs stated in the company's submission are £6.47 to £7.21 for Mepilex\xa0Border Heel and £3.06 to £7.26 for Mepilex\xa0Border Sacrum, depending on size.\n\nFor more details, see the website for Mepilex\xa0Border Heel and Sacrum dressings.", 'Evidence': "# Clinical evidence\n\n## Relevant evidence comes from 13 studies, 4 of which are randomised controlled trials\n\nOf the studies that met the inclusion criteria defined in the scope, 4 were randomised controlled trials (n=1,344) and 9 were non-randomised comparative observational studies (n=1,767). The 4 randomised controlled trials were based on the prevention of sacral pressure ulcers in adults, and none was done in the UK. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n## Results of the randomised controlled trials are mixed\n\nThe 4 randomised controlled trials (Aloweni\xa0et\xa0al.\xa02017, Kalowes\xa0et\xa0al.\xa02016, Santamaria\xa0et\xa0al.\xa02015a and Walker\xa0et\xa0al.\xa02017) compared Mepilex\xa0Border Sacrum with standard care in adults at risk of developing pressure ulcers in intensive care units in Singapore, the US and Australia. The external assessment centre (EAC) considered these studies to have acceptable internal and external validity and to provide relevant evidence for the use of Mepilex\xa0Border Sacrum. Pooled treatment effect estimates from the fixed-effect meta-analysis of the 3 studies that reported pressure ulcer incidence rates as the number of patients with a pressure ulcer showed a non-significant relative risk (RR) in favour of Mepilex\xa0Border Sacrum (RR 0.51, 95% confidence interval [CI] 0.22 to 1.18; p=0.12). Based on the assumption of 1 pressure ulcer\xa0per\xa0patient in Santamaria (2015a), pooled treatment effect estimates from a fixed-effect meta-analysis of the 4 studies showed a significant relative risk in favour of Mepilex\xa0Border Sacrum (RR\xa00.42, 95%\xa0CI 0.20\xa0to\xa00.86;\xa0p=0.02). However, a random-effects meta-analysis of the 4 studies showed a non- significant relative risk with Mepilex\xa0Border Sacrum (RR\xa00.45, 95%\xa0CI 0.20\xa0to\xa01.04; p=0.06).\n\n## Evidence from most observational studies is low quality and less relevant\n\nThe EAC considered 3 of the 9 observational studies (Park 2014, Richard-Denis\xa0et\xa0al.\xa02017a and Santamaria\xa0et\xa0al.\xa02015b) to have acceptable levels of both internal and external validity. However, the observational studies overall had lower internal and external validity compared with the randomised controlled trials, because of unacceptable cohort recruitment, inconsistencies in describing procedures and measurements, and unclear presentation and precision of results. Because of this, the EAC concluded that the evidence from the 9 observational studies was less relevant to the decision problem.\n\n## There is less evidence for Mepilex\xa0Border Heel\n\nThe EAC noted that the clinical effectiveness of Mepilex\xa0Border Heel is uncertain because of the limited comparative evidence. Only 2 observational studies assessing the heel dressing were identified (Haisley\xa0et\xa0al.\xa02015 and Santamaria\xa0et\xa0al.\xa02015b), and only the Santamaria study had acceptable levels of internal and external validity. This study (n=412) showed a significant difference in the proportion of patients who developed a pressure ulcer, in favour of Mepilex\xa0Border Heel (p=<0.001).\n\n# Cost evidence\n\n## The company's cost model shows that the use of Mepilex\xa0Border dressings is cost saving\n\nThe company's economic evidence was a cost model comparing standard care for preventing pressure ulcers with standard care and the use of Mepilex\xa0Border dressings. The time horizon was less than 1\xa0year. The model was a single-level decision tree comprising health states for 2 possible outcomes, specifically whether or not a patient develops a pressure ulcer. The model assumed that:\n\nstandard care and reductions in pressure ulcer incidence rates were generalisable from Santamaria\xa0et\xa0al.\xa0(2015a) to NHS practice\n\nresource use was generalisable from Santamaria\xa0et\xa0al.\xa0(2015a) to NHS practice\n\nthe cost of pressure ulcer management in the UK is known and the estimates are reliable\n\nthe costs of implementation and managing adverse events are negligible\n\nthe treatment effect is comparable across different types of Mepilex\xa0Border dressing.The EAC agreed that the structure of the model accurately depicts the patient pathway and any possible changes that may result from the use of Mepilex\xa0Border dressings, but it considered that some of the values of the parameters used to populate the model were inappropriate. The company's model showed that using Mepilex\xa0Border Heel and Sacrum dressings results in a cost saving of £177\xa0per\xa0patient. For full details of the cost evidence, see section\xa04 of the assessment report.\n\n## The EAC's changes to the cost model parameter values make Mepilex\xa0Border dressings less cost saving\n\nThe EAC identified limitations in some of the parameter values in the company's model and made changes to better reflect NHS costs, including:\n\nApplying baseline incidence rates of pressure ulcers from UK sources.\n\nCalculating the cost of pressure ulcer treatment by appropriately weighting treatment cost for different pressure ulcer stages using UK sources.\n\nUpdating the number of dressing changes and the cost of nursing time.Clinical-effectiveness estimates in the EAC's model were informed by the pooled treatment effect in the meta-analysis of the 3 randomised controlled trials. These changes to the model decreased the cost savings associated with Mepilex\xa0Border Heel and Sacrum dressings to £19\xa0per\xa0patient. For full details of the changes, see section\xa04 of the assessment report.", 'Committee discussion': "# Clinical effectiveness\n\n## The effectiveness of Mepilex\xa0Border dressings is uncertain\n\nHaving considered the various meta-analyses done by the EAC, the committee preferred the meta-analysis of the 3 randomised controlled trials and concluded that any benefit provided by Mepilex\xa0Border Sacrum in preventing sacral pressure ulcers was of borderline statistical significance. The committee also noted that there was limited robust evidence on the clinical effectiveness of Mepilex\xa0Border Heel; indeed, only 1 observational study reported positive results for the Mepilex\xa0Border dressing. The committee concluded that Mepilex\xa0Border Sacrum is at best marginally effective, and that the effectiveness of Mepilex\xa0Border Heel remains uncertain.\n\n## Pressure ulcer incidence rates in the NHS may be lower than those in the published evidence\n\nThe incidence of pressure ulcers with standard care is an important factor in determining the potential of Mepilex\xa0Border dressings. The clinical experts highlighted that there is variation in reported pressure ulcer incidence rates across the NHS; this is likely because of variation in how best practice to prevent pressure ulcers is implemented. However, they explained that preventing pressure ulcers is a priority for all NHS trusts and the incidence of pressure ulcers seems to be reducing through the widespread use of standard bundles of care. The EAC provided estimates of pressure ulcer prevalence from NHS safety thermometer data, but the committee concluded that there remains uncertainty because of the failure to capture grade 1 pressure ulcers and the voluntary nature of data submission. Proposed changes to reporting measures will also affect the future reported incidence rates and hopefully improve the consistency and completeness of the data. Based on the available data, the committee concluded that the proportion of patients at risk of developing a new heel or sacral pressure ulcer in an acute care NHS setting is likely to be close to 3.8% (as estimated by the EAC), but that this is likely to decrease over time.\n\n## It is unclear if the evidence is generalisable to the NHS\n\nAll 4 randomised controlled trials were done outside the UK. The clinical experts explained that because of international guidelines on preventing pressure ulcers, overall standards of care are likely to be relatively consistent across different countries. Nonetheless, there may still be differences in terms of patient selection, length of hospital stay, staff ratios and the exact composition of care bundles. The committee noted the relatively high baseline incidence rate of pressure ulcers in the control arm of the trials compared with the EAC's estimate for the incidence in the NHS. It also noted that any benefits associated with Mepilex\xa0Border dressings observed in the trial were based on a small absolute number of pressure ulcer events. Moreover, the committee was aware that assessing and grading heel and sacral pressure ulcers is subjective, and the clinical experts confirmed that this often depends on individual staff experience. Healthcare professionals will often seek a second opinion to avoid the consequence of incorrect grading, and the availability of specialist tissue viability nurses across the NHS varies. The clinical experts confirmed that NHS acute care settings include a broad range of patients at risk of pressure ulcers, and that staff across different clinical areas will have different levels of expertise in preventing and recognising early evidence of pressure ulcers. Having considered these factors, the committee concluded that there were uncertainties about the generalisability of the evidence to NHS practice.\n\n# NHS considerations\n\n## Healthcare professionals should use the appropriate dressing for the specific location of the pressure ulcer\n\nThe clinical experts explained that little training is needed to be able to apply Mepilex\xa0Border dressings. Some clinical experts noted that because of the cost of the specific Mepilex\xa0Border Sacrum and Heel variants, the less costly standard rectangular Mepilex\xa0Border dressings are sometimes used and instead cut to the appropriate shape. However, this may limit the effectiveness of the dressings and mean that they need to be changed more often. The committee noted that this improvised use is not included in the manufacturer's instructions for use. It concluded that healthcare professionals should use the appropriate dressing for the specific location of the pressure ulcer.\n\n## Further research would help to inform patient selection\n\nThe clinical experts agreed that not all patients in acute care should have Mepilex\xa0Border dressings, but they described uncertainty in terms of best patient selection. They explained that it has not yet been determined how to identify patients for whom Mepilex\xa0Border dressings would be most suitable. The committee agreed that the evidence available does not allow for accurate patient selection and that further research would be helpful in this regard. The committee also noted that evidence was generated in other settings which are not covered by the scope of this evaluation.\n\n# Cost modelling\n\n## The EAC's updated model is more plausible than the company's model but uncertainties remain\n\nThe committee accepted the EAC's changes to the company's cost model (see section\xa03.6), and considered that the revised parameters better reflected costs and resource use in an NHS acute care setting. However, it noted that uncertainties remained with regard to important factors such as the incidence of pressure ulcers and how often dressings needed to be changed. The committee concluded that the cost consequences associated with Mepilex\xa0Border Heel and Sacrum were uncertain and that further research would help to inform more accurate cost modelling.\n\n## Pressure ulcer incidence rates and frequency of dressing changes are uncertain and vary across settings\n\nCost savings in the updated model were mainly driven by the incidence of pressure ulcers in the standard care arm and the frequency of dressing changes. The committee recalled that pressure ulcer incidence rates may be lower in the NHS than those used in the model (see section\xa04.2). The committee also understood that according to the instructions for use, Mepilex\xa0Border Heel and Sacrum dressings should be changed every 3\xa0days. However, the clinical experts explained that in certain patient groups, such as people with faecal or urinary incontinence, the dressings may need to be changed more often. The committee concluded that resource use data from clinical practice would help to inform more accurate cost modelling.\n\n# Cost savings\n\n## Mepilex\xa0Border Heel and Sacrum dressings may be cost saving compared with standard care\n\nThe EAC's updated cost model reported that compared with standard care, using Mepilex\xa0Border Heel and Sacrum may save around £19\xa0per\xa0patient. However, the committee concluded that any proposed cost savings should be interpreted with caution because of the uncertainties in the cost modelling (see section\xa04.7).\n\n# Further research\n\n## Mepilex\xa0Border dressings show promise and further research would help to address the uncertainties\n\nThe committee concluded that Mepilex\xa0Border Heel and Sacrum dressings show promise, and that further research should be done to help resolve the uncertainties about clinical effectiveness and cost modelling. This research should also evaluate the incidence of pressure ulcers in patients at risk or high risk of pressure ulcers in an acute care setting, despite having standard care to prevent pressure ulcers. The research should explore any benefits that Mepilex\xa0Border dressings may offer in addition to standard care for preventing heel and sacral pressure ulcers. Data from this research, combined with data from use of dressings in clinical practice, should allow conclusions to be drawn about which patients will benefit most, as well as practical considerations such as how often the dressings should be changed."}
|
https://www.nice.org.uk/guidance/mtg40
|
Evidence-based recommendations on Mepilex Border Heel and Sacrum dressings for preventing pressure ulcers.
|
56aa13d61ae0ba0d3bc5c47cde03f94331b8f7ee
|
nice
|
Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms
|
Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms
Evidence-based recommendations on the Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms.
# Recommendations
The case for adopting the Pipeline Flex embolisation device with Shield Technology in the NHS is supported by the current evidence when it is used in patients with complex giant or large intracranial aneurysms which are unsuitable for surgery and being considered for stenting, and where large numbers of coils would be needed during stent-assisted coiling.
The Pipeline Flex embolisation device with Shield Technology is estimated to be cost saving when compared with stent-assisted coiling, in patients with complex giant or large intracranial aneurysms when the number of Pipeline embolisation devices inserted does not exceed 2, and when treatment would otherwise require the use of 34 or more coils combined with 1 stent for stent-assisted coiling. If 2 Pipeline embolisation devices are used the total procedure cost is estimated as £37,625 compared with £38,320 for the use of 34 coils for stent-assisted coiling (a saving of £695 using Pipeline embolisation device).
Clinicians should submit details of all patients being treated with the Pipeline Flex embolisation device with Shield Technology to the UK Neurointerventional Radiology Group audit database, to increase the evidence base and guide future use of this technology.# The technology
# Description of the technology
The Pipeline Flex embolisation device with Shield Technology ('Pipeline'; Medtronic) is a self-expanding blood flow diverter that is placed across the neck of an intracranial aneurysm. While blood flow through the parent vessel is maintained via the device, flow within the aneurysm sac is disrupted, leading to stagnation and eventual thrombosis formation. Pipeline provides a scaffold for endothelial growth leading to the formation of a biological seal and exclusion of the aneurysm from the circulation.
Pipeline is a braided, cobalt chromium and platinum stent-like device which is loaded into and delivered via a microcatheter. It is manufactured in lengths of 10–35 mm and is available in different diameters from 2.5 to 5 mm (in 0.25 mm increments). Multiple devices can be used within each other and/or in sequence to increase the overall length of the construct or to increase the metal surface coverage within an aneurysm.
Pipeline is indicated for use in patients with unruptured, complex intracranial aneurysms, specifically large and giant, wide-necked and fusiform aneurysms. This is the group of patients covered by this guidance. Pipeline may also be used in patients whose aneurysms are unsuitable for standard coiling and/or stenting and for neurosurgical treatment; and in patients for whom previous coiling/clipping procedures have failed.
The cost of Pipeline stated in the sponsor's submission is £10,171. These costs have been updated in the latest revision of the cost model to £10,450.
The claimed benefits of Pipeline in the case for adoption presented by the sponsor are:
A higher rate of complete, permanent occlusion of large/giant intracranial aneurysms compared with coiling and stent-assisted coiling, leading to reduced rates of retreatment and a decreased risk of haemorrhage.
Increased access to treatment for patients with complex intracranial aneurysms. Pipeline offers a new option for treating patients with complex intracranial aneurysms which are not suitable for stent-assisted coiling or surgery, and patients for whom previous interventions have failed.
Patients may experience a resolution of neurological symptoms as a result of relieving pressure on surrounding areas of the brain caused by the mass effect of aneurysms.
Increased long-term vessel patency, preserving blood flow to distal tissues supplied by the aneurysmal artery.
The high rate of complete, permanent occlusion of the target aneurysm with the possibility of reduced need for retreatment and an overall decrease in use of NHS resources.
# Current management
Current options for managing complex intracranial aneurysms include coiling, often with concomitant use of stent placement (stent-assisted coiling), neurosurgical clipping requiring craniotomy (with or without bypass procedures), parent vessel occlusion (by open neurosurgery or by endovascular means) and conservative management.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the committee are available in the assessment report overview.
The key clinical outcomes for Pipeline presented in the decision problem are:
successful device deployment
successful occlusion of the aneurysm, with or without preservation of flow through the parent vessel
size of the aneurysm and its contained thrombus mass
resolution of symptoms (including headache, diplopia, nystagmus or other neurological dysfunction), relief of pain and quality of life outcomes
resource use outcomes (for example, re-admission rates, repeat interventions and duration of hospital stay)
stroke related to device insertion (any cause, but particularly due to vessel occlusion or bleeding)
delayed parent vessel occlusion
subarachnoid haemorrhage and/or other major bleeding events needing admission to hospital
neurovascular death
device-related adverse events.
The sponsor identified 13 studies relevant to the scope, but because it judged the quality of many of these to be poor and because of duplication in patient reporting, the sponsor's submission presented detailed findings on a total of 139 patients from 2 studies, with a maximum follow-up of 2 years. The studies were Pipeline for Intracranial Treatment of Aneurysms (PITA) and Pipeline for Uncoilable or Failed aneurysms (PUFS).
Nelson et al. (2011) reported outcomes up to 2 years for the PITA study: a prospective, multicentre single-arm feasibility study of 31 patients with 31 intracranial aneurysms that were small (25 mm ). An aneurysm neck width ≥4 mm was recorded in 22 patients (71%). In 12 patients (39%), other interventions for the target aneurysm had failed.
A report to the FDA by the sponsor (FDA 2011) described the clinical evidence at 1 year from the PUFS study: an ongoing prospective, multicentre, single-arm study of 108 patients with 110 intracranial aneurysms that were small (25 mm ). The mean aneurysm neck width was 8.8 mm. In 8 patients (7%), other interventions for the target aneurysm had failed.
In its literature search, the external assessment centre found 3 case reports and 1 conference abstract of 96 patients in addition to the 13 studies identified by the sponsor. It excluded 1 of the studies identified by the sponsor (Matouk et al. 2010) because it was outside the scope. The external assessment centre therefore included a total of 16 studies with 380 patients in its assessment report.
Across 13 studies with a total of 237 patients (239 complex intracranial aneurysms), successful device placement was reported in 50–100% of patients. In 8 of the 13 studies, successful device placement was reported in all patients (25 in total; Fiorella et al. 2008, 2009a, 2009b, 2010; Hartmann et al. 2010; Kilsch et al. 2011; Phillips et al. 2010; Sararols et al. 2011).
Nelson et al. (2011) reported clinical procedure success (defined as successful placement of the device without death or ipsilateral stroke) in 94% (29/31) of patients: the 2 failures were because of peri-procedural stroke. For patients in the PUFS study, the primary effectiveness end point was complete occlusion of the aneurysm and absence of parent vessel stenosis greater than 50% at 180 days. The probability of exceeding the pre-determined 'success threshold' of 50% was statistically significant (p<0.0001; FDA, 2011).
Major ipsilateral stroke or neurological death, as judged by the Clinical Events Committee, was reported in 6% (6/107) of patients at 180 days in the PUFS study (FDA 2011). Ipsilateral stroke was reported in 7% (2/31) of patients within 30 days in the PITA study (Nelson et al. 2011). Five other studies including a total of 58 patients (68 complex intracranial aneurysms) reported a stroke rate of 0% at follow-up ranging from 10 weeks to more than 52 weeks (Fiorella et al. 2009a, 2009b; Lylyk et al. 2009a; Klisch et al. 2011; Sararols et al. 2011).
In the PUFS study, 3 of the 6 patients who had a major ipsilateral stroke died (timing of events not reported). Nelson et al. (2011) reported no deaths in the PITA study.
Nelson et al. (2011) reported complete occlusion of the target aneurysm in 93% (28/30) of patients at 180 days (95% confidence interval 77.9 to 99.2); it was not possible to assess occlusion in 1 patient who had Pipeline surgically removed and the parent vessel ligated. All patients who had complete occlusion at 180 days also had complete occlusion at 2 years as assessed by either catheter angiography or MRI.
Complete occlusion without major stenosis was reported in 74% (78/106) of aneurysms at 180 days and 71% (75/106) of aneurysms at 1-year angiography (FDA 2011). Eight studies with a total of 131 patients all reported occlusion rates of 100% in patients assessed at follow-up ranging from 3 to 30 months (Fiorella et al. 2008, 2009a, 2009b, 2010; Klisch et al. 2011; Phillips et al. 2010; Sararols et al. 2011; Szikora et al. 2010b). Occlusion rates of 93%, 89% and 69% were reported by Lylyk et al. (2009a), Szikora et al. (2010a) and O'Kelly et al. (2011) respectively (absolute figures not reported).
Nelson et al. (2011) reported that 10% (3/31) of patients, 1 of whom had previously had a stroke, showed improvement in intracranial aneurysm-related symptoms at 30 days. There was no deterioration in neurological status at 30 days in the 28 patients free of stroke. The FDA report (2011) described Rankin scoring (a general measure of neurological function) for 104 patients. The scores improved from baseline in 20% (21/104) of patients, remained unchanged in 67% (70/104) and deteriorated in 10% (10/104) at 180 days follow-up. There was an improvement in visual field sensitivity (not otherwise described) from baseline in 21% (19/89) of patients, no change in 73% (65/89) of patients and deterioration in eye function in 6% (5/89) of patients at follow-up of 180 days (FDA 2011). Three case reports described complete resolution of symptoms at follow-up ranging from 10 to 26 weeks (Fiorella et al. 2009a, 2009b; Sararols et al. 2011). Szikora et al. (2010b) reported resolution of symptoms in 61% of patients at a mean follow-up of 26 weeks.
Studies of 96, 18, 8 and 5 patients reported subarachnoid haemorrhage after surgery in 1%, 5%, 13% and 20% of patients respectively (absolute figures and follow-up not reported; Hampton et al. 2011; Hartmann et al. 2010; O'Kelly et al. 2011, Szikora et al. 2010b).
## Committee considerations
The committee was advised by the experts that Pipeline is currently considered in some specialist units for patients who have symptoms caused by the mass effect of aneurysms, or a high risk of future bleeding, who are considered fit for general anaesthesia and who have an average life expectancy of at least 1 year.
The committee noted that Pipeline may be the only possible intervention for some patients who have symptoms caused by the mass effect of aneurysms, or a high risk of future bleeding, whose aneurysms are unsuitable for either stent-assisted coiling or surgical treatment and for whom parent vessel occlusion would result in stroke or death.
The committee considered that data from the studies described above provided evidence for the efficacy of Pipeline in most patients. In the context of the high risks posed to patients by untreated complex large or giant aneurysms the safety profile was judged to be acceptable.
The committee noted that the effect of the device on symptoms or on the risk of bleeding is subject to some delay.
The committee recognised that patient selection for treatment either by Pipeline or by comparator interventions is complex, and needs to be carried out by an experienced multidisciplinary team.
The committee noted that most of the clinical evidence came from the United States, where patient selection for different types of endovascular interventions may differ from the UK, in terms of the treatments selected for intracranial aneurysms based on their size and shape.
The committee noted that the clinical evidence comparing the efficacy of Pipeline with other interventions was very limited. This made evaluation difficult. The committee recognised the difficulties in conducting comparative studies, particularly randomised controlled trials, for large and giant complex intracranial aneurysms.
The committee noted that both new studies and an extension of the PUFS study are in progress.
The committee considered that data collection using a register would be an important practical way of developing evidence to guide future practice, in addition to the ongoing studies.# NHS considerations
# System impact
No secondary treatments were required at 1-year follow-up among patients in the PUFS study (FDA 2011). Need for retreatment was not reported in the PITA study (Nelson et al. 2011). Need for retreatment was not reported in the other 14 studies included in the external assessment centre's assessment report.
## Committee considerations
The committee noted that little evidence was available on the need for retreatment following treatment with Pipeline.
The committee recognised that there are a small number of patients for whom Pipeline offers the only possible means of treatment (an estimated 60 patients per year in the UK). For these patients the potential benefits offered by Pipeline are important, because they are at high risk of aneurysm rupture and because their intracranial aneurysms are unsuitable for other treatments.# Cost considerations
# Cost evidence
The sponsor submitted a de novo cost analysis for Pipeline for the treatment of complex intracranial aneurysms. Full details of all cost evidence and modelling considered by the committee are available in the assessment report overview.
The sponsor presented a decision tree (for the peri-procedural period) followed by a Markov model (for long-term outcomes) to estimate the costs and consequences associated with Pipeline against 5 comparator interventions: stent-assisted coiling, neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion and conservative management. The patient population included those with unruptured large or giant intracranial aneurysms as outlined in the scope, but did not include fusiform or wide-necked aneurysms.
The decision-tree structure separated patients who had survived initial treatment, based on a mortality rate for the procedure, into 1 of 3 occlusion categories (complete occlusion, residual neck and residual aneurysm). For each occlusion category, patients were tracked through 5 possible health states: 'no complications', 'new non-fatal rupture', 'post rupture', 'fatal rupture' and 'dead (all cause)'. It was assumed that transition probabilities for the health states would be constant over time. The time horizon of the base-case analysis was 10 years.
An NHS and personal social services perspective was used. The cost analysis included the costs associated with the duration of the procedure, staff time (surgeon, radiologist, nurse, anaesthetist), hospital costs (neurology operating or neurosurgical operating room, and recovery ward), imaging (angiography, fluoroscopy or MRI), consumables, drugs; and for conservative management only, long-term monitoring with annual MRI. The cost associated with stroke was assumed to be representative of the cost of rupture. Costs applied to each type of retreatment were assumed to be the same as the full cost if that treatment had been used initially.
The costs and consequences associated with adverse events were not included in the base-case analysis because the sponsor considered there to be insufficient reliable data for each treatment group. However, the sponsor did include costs associated with mortality at 31 days, rupture and retreatment.
In the base case the number of Pipeline embolisation devices used was 1.46, based on data submitted to the sponsor from use of the device in UK hospitals up to August 2011. The number of coils used in the base case was 40 and was derived from an estimate in an editorial review by Wehman in 2006. It was assumed that 1 stent would be needed for each stent-assisted coiling intervention.
The base case presented the total procedure costs over the 10-year time horizon associated with Pipeline as £24,341. For the comparators, the total procedure costs were £37,451 for stent-assisted coiling, £11,658 for neurosurgical clipping, £16,893 for endovascular parent vessel occlusion, £11,654 for neurosurgical parent vessel occlusion and £10,352 for conservative management. The only intervention against which Pipeline was shown to be cost saving was stent-assisted coiling, with a cost saving of £13,110 per patient.
Two scenario analyses were presented. One included costs associated with the adverse events of subarachnoid haemorrhage related to the aneurysm, thromboembolic stroke and intracranial haemorrhagic stroke remote from the aneurysm using data from the PUFS study and data from Darsault et al. (2001) for the comparators. The other scenario analysis restricted the time horizon to 6 months (short-term). Conservative management was excluded from the short-term scenario because it does not have a 'peri-procedural' mortality rate.
In both scenario analyses Pipeline was shown to be cost saving only when compared with stent-assisted coiling. When costs associated with adverse events were included in the model, Pipeline remained a cost-saving intervention compared with stent-assisted coiling, with an associated saving of £13,327. When outcomes were restricted to the short term (6 months), Pipeline remained cost saving compared with stent-assisted coiling (£10,316).
Sensitivity analyses carried out by the sponsor showed that the main factors influencing the cost analysis were the number and cost of consumables, in particular the numbers of Pipeline embolisation devices and endovascular coils. The sponsor carried out sensitivity analysis for the use of 1–3 Pipeline embolisation devices and separately for 5–100 coils.
The number of Pipeline embolisation devices used in the base case was 1.46 per patient. On receipt of more data from UK hospitals, the sponsor submitted a revised number of 1.658 in October 2011. The external assessment centre reviewed the data and concluded that when 1.658 Pipeline embolisation devices were used, Pipeline was more costly compared with stent-assisted coiling if 22 coils were used (an estimated cost increase of £19), but cost saving when 23 coils were used. The cost saving when using 1.658 Pipeline embolisation devices compared with stent-assisted coiling with 23 coils was estimated to be £588 (total procedure costs of £26,546 and £27,134 respectively). When 2 Pipeline embolisation devices were used, Pipeline was more costly by an estimated £185 than stent-assisted coiling using 28 coils, but was less costly than stent-assisted coiling when 29 coils were used. The cost saving when using 2 Pipeline embolisation devices compared with stent-assisted coiling with 29 coils was estimated to be £421 (total procedure costs of £30,354 and £30,775 respectively).
During consultation, expert advisers expressed doubts about 5 parameters in the cost model: the cost of microcatheters; the use of a balloon in stent-assisted coiling; drug costs; the procedure duration; and the cost of additional endovascular equipment. Additional exploratory analyses were carried out by the external assessment centre to examine the impact of changing these parameters, in ways which the expert advisers suggested were more appropriate.
In the sponsor's economic model, the cost of microcatheters used in stent-assisted coiling was comparable to the cost of a Marksman catheter (£1,030) used to insert Pipeline. However, the expert advisers stated that cheaper microcatheters (average cost £460.50) would be used for stent-assisted coiling than for Pipeline in UK practice. The external assessment centre's exploratory analyses demonstrated that reducing the cost of 2 microcatheters for stent-assisted coiling from £1,030 to £460.50 reduced the total procedure cost for stent-assisted coiling from £37,451 to £36,137.
The sponsor's economic modelling also assumed that a balloon is used in 50% of stent-assisted coiling procedures and is not used to insert Pipeline. However, the expert advisers stated that use of a balloon is relatively uncommon in the UK for stent-assisted coiling procedures. In the exploratory analyses carried out by the external assessment centre, removing the cost of a balloon reduced the total procedure cost for stent-assisted coiling from £36,137 to £35,725, while the total procedure cost for Pipeline (with 2 devices) remained at £30,354.
The sponsor's economic model assumed different drug use for patients having stent-assisted coiling and those having Pipeline (18,000 mg aspirin and 6,750 mg clopidogrel compared with 25,000 mg aspirin and 13,500 mg clopidogrel respectively). The expert advisers stated that in clinical practice drug use in the 2 groups is likely to be equal. The external assessment centre noted that in the sponsor's economic model drug use was calculated from 2 non-comparative studies, but that few published data are available on clinical use. The external assessment centre stated that the low cost of these drugs means that relatively small differences in drug use are unlikely to have a significant impact on the overall procedure costs for stent-assisted coiling and Pipeline. In the absence of a systematic review the external assessment centre stated that the drug costs used in the model were appropriate.
In its exploratory analysis the external assessment centre identified 2 calculation errors in the sponsor's economic model, both relating to the number of days of drug therapy. The external assessment centre stated that correcting these calculation errors made only a very small difference in the total procedure costs for both Pipeline and stent-assisted coiling, reducing them from £30,354 to £30,346 and £35,725 to £35,724 respectively.
In the sponsor's economic model, the average duration of the procedure (in hours) and therefore the use of additional endovascular equipment were different for stent-assisted coiling and insertion of Pipeline. The expert advisers stated that the procedures are likely to take the same amount of time in clinical practice. The external assessment centre noted that the time taken for stent-assisted coiling was derived from 1 non-comparative study and the time for inserting Pipeline from another. However the external assessment centre was not able to judge which study was the best source for duration of procedure and no systematic review was carried out. The external assessment centre stated that because both studies were appropriately and accurately used in the model no changes were justified with regard to procedure time for stent-assisted coiling or Pipeline. The external assessment centre also noted that the sponsor included the use of additional endovascular equipment in the model based on the duration of procedure, but provided no justification for why it was included only for stent-assisted coiling and not for Pipeline or the other comparators. Furthermore, there was no justification for why the cost of additional equipment was only included in calculating the retreatment cost but not the cost of the initial procedure. The exploratory analyses demonstrated that removing the costs of additional endovascular equipment from the model reduced the total procedure cost of stent-assisted coiling from £35,724 to £35,693 while the total procedure cost for Pipeline remained at £30,346.
## Committee considerations
The committee considered the cost consequences of using Pipeline against 5 comparators – stent-assisted coiling, neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion and conservative management.
The committee noted that in UK clinical practice, patients who might currently be considered for Pipeline would be those for whom surgery would not be possible and for whom stent-assisted coiling would be the only other potential intervention. It therefore considered that comparison of costs with those for stent-assisted coiling was of particular relevance. The committee noted that for this cost comparison, the main drivers of cost were the numbers of Pipeline embolisation devices used and the numbers of coils used during stent-assisted coiling. The committee was given advice from the experts about whether 1 or 2 Pipeline embolisation devices should be used as the most typical number on which to base its judgements about cost. It therefore considered the cost modelling for a range of scenarios – with different numbers of Pipeline embolisation devices. During its discussions the committee was informed both by expert advisers and by data from the sponsor that 2 Pipeline embolisation devices were likely to be needed for most patients treated in the UK for complex giant or large aneurysms.
There was considerable uncertainty about the number of coils likely to be used during stent-assisted coiling. The committee was advised that 40 coils was probably an overestimate of the number needed for most complex aneurysms and there were suggestions that about 25–30 coils might be more typical of the number needed for aneurysms being considered for treatment using Pipeline. The committee recognised that it is not possible to estimate accurately the number of coils which will be required to treat an aneurysm during stent-assisted coiling, but it was advised by experts that the number can usually be predicted with an accuracy of plus or minus 6 coils.
The committee discussed a number of parameters in the sponsor's economic model based on comments received during public consultation. As described in sections 5.12 to 5.17, these included: the cost of microcatheters used for stent-assisted coiling; balloon use in UK practice during stent-assisted coiling; drug costs for patients having Pipeline and those having stent-assisted coiling; the duration of the procedure and the use of additional endovascular equipment in stent-assisted coiling. These parameters were examined in additional analyses by the external assessment centre.
The committee considered that the costs for microcatheters used for stent-assisted coiling in the sponsor's base-case analysis were overestimated. It agreed with the views of the expert advisers that it was reasonable to use the average cost of the microcatheters most commonly used in UK clinical practice. This reduced the total procedure cost for stent-assisted coiling from £37,451 to £36,137.
Based on expert advice, the committee accepted that the inclusion of balloon use during stent-assisted coiling in the sponsor's base-case analysis was inappropriate and that it was reasonable to adjust this cost to zero. This reduced the total procedure cost for stent-assisted coiling from £36,137 to £35,725, while the total procedure cost for Pipeline remained at £30,354.
The committee considered the drug costs presented in the sponsor's base-case analysis. It noted the external assessment centre's view that few published data are available on clinical use and that the low cost of these drugs and the difference in drug use would not be likely to have any significant impact on the overall procedure costs for either stent-assisted coiling or Pipeline. The committee agreed that the drug cost in the sponsor's base-case analysis was appropriate
The committee considered the average duration of the procedure presented in the sponsor's base-case analysis. It noted the external assessment centre's view that both studies were appropriately and accurately used in the model and that therefore no changes were justified for the average duration of the procedure for stent-assisted coiling or inserting Pipeline. The committee agreed that the average duration of the procedure presented in the sponsor's base-case analysis was appropriate.
The committee was advised by the experts that it was not appropriate to include the cost for additional endovascular equipment for stent-assisted coiling only. This was because the cost of endovascular equipment was likely to be the same for Pipeline compared with stent-assisted coiling. The committee accepted the views of the expert advisers that removing this cost from the model for stent-assisted coiling was appropriate. This reduced the total procedure cost for stent-assisted coiling from £35,724 (this cost takes account of the drug cost calculation errors referred to in section 5.16) to £35,693 while the total procedure cost for Pipeline remained at £30,346.
With these issues in mind, the committee considered a graph showing the costs of Pipeline and of stent-assisted coiling using different numbers of Pipeline embolisation devices and coils. This indicated that the total cost of treatment using 2 Pipeline embolisation devices is greater than that of stent-assisted coiling (using 1 stent) if 31 coils or fewer are used, but Pipeline is less costly if 32 or more coils are needed. The cost saving associated with Pipeline compared with stent-assisted coiling with 32 coils was estimated to be £492 (total costs of £30,346 and £30,838 respectively).
The committee noted that using 2 Pipeline embolisation devices would incur a higher total treatment cost than neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion or conservative management for patients in whom those other options were feasible.
For the guidance review, the external assessment centre revised the model to reflect updated costs. The main parameter changes were costs associated with staff, hospital imaging equipment, drugs, rupture and adverse event costs. Further details of the revised model are in the revised model summary. # Conclusions
The committee concluded that current evidence supports the case for adoption of Pipeline when it is used in highly selected patients with complex giant or large intracranial aneurysms which are unsuitable for surgery and being considered for stenting, when the number of Pipeline embolisation devices does not exceed 2 and when 32 or more coils and 1 stent would be needed during stent-assisted coiling. For these patients use of Pipeline appears efficacious and is less costly than stent-assisted coiling.
The committee noted that standard management of intracranial aneurysms varies according to the size and type of aneurysm and the symptoms the patient experiences. This may include conservative management, for example, in patients whose complex giant or large intracranial aneurysms are unsuitable in size or shape for stent-assisted coiling or surgery, and for whom parent vessel occlusion would result in stroke or death. The recommendations in section 1 of the guidance are based on circumstances in which Pipeline releases resources, and were not framed on the basis of treating patients for whom there is no other viable option apart from conservative management. The committee saw little evidence in this patient group and this area of unmet clinical need would benefit from further research.
|
{'Recommendations': 'The case for adopting the Pipeline Flex embolisation device with Shield Technology in the NHS is supported by the current evidence when it is used in patients with complex giant or large intracranial aneurysms which are unsuitable for surgery and being considered for stenting, and where large numbers of coils would be needed during stent-assisted coiling.\n\nThe Pipeline Flex embolisation device with Shield Technology is estimated to be cost saving when compared with stent-assisted coiling, in patients with complex giant or large intracranial aneurysms when the number of Pipeline embolisation devices inserted does not exceed 2, and when treatment would otherwise require the use of 34 or more coils combined with 1 stent for stent-assisted coiling. If 2 Pipeline embolisation devices are used the total procedure cost is estimated as £37,625 compared with £38,320 for the use of 34 coils for stent-assisted coiling (a saving of £695 using Pipeline embolisation device). \n\nClinicians should submit details of all patients being treated with the Pipeline Flex embolisation device with Shield Technology to the UK Neurointerventional Radiology Group audit database, to increase the evidence base and guide future use of this technology.', 'The technology': "# Description of the technology\n\nThe Pipeline Flex embolisation device with Shield Technology ('Pipeline'; Medtronic) is a self-expanding blood flow diverter that is placed across the neck of an intracranial aneurysm. While blood flow through the parent vessel is maintained via the device, flow within the aneurysm sac is disrupted, leading to stagnation and eventual thrombosis formation. Pipeline provides a scaffold for endothelial growth leading to the formation of a biological seal and exclusion of the aneurysm from the circulation. \n\nPipeline is a braided, cobalt chromium and platinum stent-like device which is loaded into and delivered via a microcatheter. It is manufactured in lengths of 10–35\xa0mm and is available in different diameters from 2.5 to 5\xa0mm (in 0.25\xa0mm increments). Multiple devices can be used within each other and/or in sequence to increase the overall length of the construct or to increase the metal surface coverage within an aneurysm.\n\nPipeline is indicated for use in patients with unruptured, complex intracranial aneurysms, specifically large and giant, wide-necked and fusiform aneurysms. This is the group of patients covered by this guidance. Pipeline may also be used in patients whose aneurysms are unsuitable for standard coiling and/or stenting and for neurosurgical treatment; and in patients for whom previous coiling/clipping procedures have failed.\n\nThe cost of Pipeline stated in the sponsor's submission is £10,171. These costs have been updated in the latest revision of the cost model to £10,450. \n\nThe claimed benefits of Pipeline in the case for adoption presented by the sponsor are:\n\nA higher rate of complete, permanent occlusion of large/giant intracranial aneurysms compared with coiling and stent-assisted coiling, leading to reduced rates of retreatment and a decreased risk of haemorrhage.\n\nIncreased access to treatment for patients with complex intracranial aneurysms. Pipeline offers a new option for treating patients with complex intracranial aneurysms which are not suitable for stent-assisted coiling or surgery, and patients for whom previous interventions have failed.\n\nPatients may experience a resolution of neurological symptoms as a result of relieving pressure on surrounding areas of the brain caused by the mass effect of aneurysms.\n\nIncreased long-term vessel patency, preserving blood flow to distal tissues supplied by the aneurysmal artery.\n\nThe high rate of complete, permanent occlusion of the target aneurysm with the possibility of reduced need for retreatment and an overall decrease in use of NHS resources.\n\n# Current management\n\nCurrent options for managing complex intracranial aneurysms include coiling, often with concomitant use of stent placement (stent-assisted coiling), neurosurgical clipping requiring craniotomy (with or without bypass procedures), parent vessel occlusion (by open neurosurgery or by endovascular means) and conservative management.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the committee are available in the assessment report overview.\n\nThe key clinical outcomes for Pipeline presented in the decision problem are:\n\nsuccessful device deployment\n\nsuccessful occlusion of the aneurysm, with or without preservation of flow through the parent vessel\n\nsize of the aneurysm and its contained thrombus mass\n\nresolution of symptoms (including headache, diplopia, nystagmus or other neurological dysfunction), relief of pain and quality of life outcomes\n\nresource use outcomes (for example, re-admission rates, repeat interventions and duration of hospital stay)\n\nstroke related to device insertion (any cause, but particularly due to vessel occlusion or bleeding)\n\ndelayed parent vessel occlusion\n\nsubarachnoid haemorrhage and/or other major bleeding events needing admission to hospital\n\nneurovascular death\n\ndevice-related adverse events.\n\nThe sponsor identified 13 studies relevant to the scope, but because it judged the quality of many of these to be poor and because of duplication in patient reporting, the sponsor's submission presented detailed findings on a total of 139\xa0patients from 2 studies, with a maximum follow-up of 2\xa0years. The studies were Pipeline for Intracranial Treatment of Aneurysms (PITA) and Pipeline for Uncoilable or Failed aneurysms (PUFS).\n\nNelson\xa0et\xa0al. (2011) reported outcomes up to 2\xa0years for the PITA study: a prospective, multicentre single-arm feasibility study of 31\xa0patients with 31 intracranial aneurysms that were small (<10\xa0mm [20\xa0patients]), large (10–25\xa0mm [9\xa0patients]) or giant (>25\xa0mm [2\xa0patients]). An aneurysm neck width ≥4\xa0mm was recorded in 22\xa0patients (71%). In 12\xa0patients (39%), other interventions for the target aneurysm had failed.\n\nA report to the FDA by the sponsor (FDA 2011) described the clinical evidence at 1\xa0year from the PUFS study: an ongoing prospective, multicentre, single-arm study of 108\xa0patients with 110 intracranial aneurysms that were small (<10\xa0mm [1 patient]), large (10–25\xa0mm [85\xa0patients]) or giant (>25\xa0mm [22\xa0patients]). The mean aneurysm neck width was 8.8\xa0mm. In 8\xa0patients (7%), other interventions for the target aneurysm had failed.\n\nIn its literature search, the external assessment centre found 3 case reports and 1 conference abstract of 96\xa0patients in addition to the 13 studies identified by the sponsor. It excluded 1 of the studies identified by the sponsor (Matouk\xa0et\xa0al. 2010) because it was outside the scope. The external assessment centre therefore included a total of 16 studies with 380\xa0patients in its assessment report.\n\nAcross 13 studies with a total of 237\xa0patients (239 complex intracranial aneurysms), successful device placement was reported in 50–100% of patients. In 8 of the 13 studies, successful device placement was reported in all patients (25 in total; Fiorella\xa0et\xa0al. 2008, 2009a, 2009b, 2010; Hartmann\xa0et\xa0al. 2010; Kilsch\xa0et\xa0al. 2011; Phillips\xa0et\xa0al. 2010; Sararols\xa0et\xa0al. 2011).\n\nNelson\xa0et\xa0al. (2011) reported clinical procedure success (defined as successful placement of the device without death or ipsilateral stroke) in 94% (29/31) of patients: the 2 failures were because of peri-procedural stroke. For patients in the PUFS study, the primary effectiveness end point was complete occlusion of the aneurysm and absence of parent vessel stenosis greater than 50% at 180\xa0days. The probability of exceeding the pre-determined 'success threshold' of 50% was statistically significant (p<0.0001; FDA, 2011).\n\nMajor ipsilateral stroke or neurological death, as judged by the Clinical Events Committee, was reported in 6% (6/107) of patients at 180\xa0days in the PUFS study (FDA 2011). Ipsilateral stroke was reported in 7% (2/31) of patients within 30\xa0days in the PITA study (Nelson\xa0et\xa0al. 2011). Five other studies including a total of 58\xa0patients (68 complex intracranial aneurysms) reported a stroke rate of 0% at follow-up ranging from 10\xa0weeks to more than 52\xa0weeks (Fiorella\xa0et\xa0al. 2009a, 2009b; Lylyk\xa0et\xa0al. 2009a; Klisch\xa0et\xa0al. 2011; Sararols\xa0et\xa0al. 2011).\n\nIn the PUFS study, 3 of the 6\xa0patients who had a major ipsilateral stroke died (timing of events not reported). Nelson\xa0et\xa0al. (2011) reported no deaths in the PITA study.\n\nNelson\xa0et\xa0al. (2011) reported complete occlusion of the target aneurysm in 93% (28/30) of patients at 180\xa0days (95% confidence interval [CI] 77.9 to 99.2); it was not possible to assess occlusion in 1 patient who had Pipeline surgically removed and the parent vessel ligated. All patients who had complete occlusion at 180\xa0days also had complete occlusion at 2\xa0years as assessed by either catheter angiography or MRI.\n\nComplete occlusion without major stenosis was reported in 74% (78/106) of aneurysms at 180\xa0days and 71% (75/106) of aneurysms at 1-year angiography (FDA 2011). Eight studies with a total of 131\xa0patients all reported occlusion rates of 100% in patients assessed at follow-up ranging from 3 to 30\xa0months (Fiorella\xa0et\xa0al. 2008, 2009a, 2009b, 2010; Klisch\xa0et\xa0al. 2011; Phillips\xa0et\xa0al. 2010; Sararols\xa0et\xa0al. 2011; Szikora\xa0et\xa0al. 2010b). Occlusion rates of 93%, 89% and 69% were reported by Lylyk\xa0et\xa0al. (2009a), Szikora\xa0et\xa0al. (2010a) and O'Kelly\xa0et\xa0al. (2011) respectively (absolute figures not reported).\n\nNelson\xa0et\xa0al. (2011) reported that 10% (3/31) of patients, 1 of whom had previously had a stroke, showed improvement in intracranial aneurysm-related symptoms at 30\xa0days. There was no deterioration in neurological status at 30\xa0days in the 28\xa0patients free of stroke. The FDA report (2011) described Rankin scoring (a general measure of neurological function) for 104\xa0patients. The scores improved from baseline in 20% (21/104) of patients, remained unchanged in 67% (70/104) and deteriorated in 10% (10/104) at 180\xa0days follow-up. There was an improvement in visual field sensitivity (not otherwise described) from baseline in 21% (19/89) of patients, no change in 73% (65/89) of patients and deterioration in eye function in 6% (5/89) of patients at follow-up of 180\xa0days (FDA 2011). Three case reports described complete resolution of symptoms at follow-up ranging from 10 to 26\xa0weeks (Fiorella\xa0et\xa0al. 2009a, 2009b; Sararols\xa0et\xa0al. 2011). Szikora\xa0et\xa0al. (2010b) reported resolution of symptoms in 61% of patients at a mean follow-up of 26\xa0weeks.\n\nStudies of 96, 18, 8 and 5\xa0patients reported subarachnoid haemorrhage after surgery in 1%, 5%, 13% and 20% of patients respectively (absolute figures and follow-up not reported; Hampton\xa0et\xa0al. 2011; Hartmann\xa0et\xa0al. 2010; O'Kelly\xa0et\xa0al. 2011, Szikora\xa0et\xa0al. 2010b).\n\n## Committee considerations\n\nThe committee was advised by the experts that Pipeline is currently considered in some specialist units for patients who have symptoms caused by the mass effect of aneurysms, or a high risk of future bleeding, who are considered fit for general anaesthesia and who have an average life expectancy of at least 1\xa0year.\n\nThe committee noted that Pipeline may be the only possible intervention for some patients who have symptoms caused by the mass effect of aneurysms, or a high risk of future bleeding, whose aneurysms are unsuitable for either stent-assisted coiling or surgical treatment and for whom parent vessel occlusion would result in stroke or death.\n\nThe committee considered that data from the studies described above provided evidence for the efficacy of Pipeline in most patients. In the context of the high risks posed to patients by untreated complex large or giant aneurysms the safety profile was judged to be acceptable.\n\nThe committee noted that the effect of the device on symptoms or on the risk of bleeding is subject to some delay.\n\nThe committee recognised that patient selection for treatment either by Pipeline or by comparator interventions is complex, and needs to be carried out by an experienced multidisciplinary team.\n\nThe committee noted that most of the clinical evidence came from the United States, where patient selection for different types of endovascular interventions may differ from the UK, in terms of the treatments selected for intracranial aneurysms based on their size and shape.\n\nThe committee noted that the clinical evidence comparing the efficacy of Pipeline with other interventions was very limited. This made evaluation difficult. The committee recognised the difficulties in conducting comparative studies, particularly randomised controlled trials, for large and giant complex intracranial aneurysms.\n\nThe committee noted that both new studies and an extension of the PUFS study are in progress.\n\nThe committee considered that data collection using a register would be an important practical way of developing evidence to guide future practice, in addition to the ongoing studies.", 'NHS considerations': "# System impact\n\nNo secondary treatments were required at 1-year follow-up among patients in the PUFS study (FDA 2011). Need for retreatment was not reported in the PITA study (Nelson\xa0et\xa0al. 2011). Need for retreatment was not reported in the other 14 studies included in the external assessment centre's assessment report.\n\n## Committee considerations\n\nThe committee noted that little evidence was available on the need for retreatment following treatment with Pipeline.\n\nThe committee recognised that there are a small number of patients for whom Pipeline offers the only possible means of treatment (an estimated 60\xa0patients per year in the UK). For these patients the potential benefits offered by Pipeline are important, because they are at high risk of aneurysm rupture and because their intracranial aneurysms are unsuitable for other treatments.", 'Cost considerations': "# Cost evidence\n\nThe sponsor submitted a de novo cost analysis for Pipeline for the treatment of complex intracranial aneurysms. Full details of all cost evidence and modelling considered by the committee are available in the assessment report overview.\n\nThe sponsor presented a decision tree (for the peri-procedural period) followed by a Markov model (for long-term outcomes) to estimate the costs and consequences associated with Pipeline against 5 comparator interventions: stent-assisted coiling, neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion and conservative management. The patient population included those with unruptured large or giant intracranial aneurysms as outlined in the scope, but did not include fusiform or wide-necked aneurysms.\n\nThe decision-tree structure separated patients who had survived initial treatment, based on a mortality rate for the procedure, into 1 of 3 occlusion categories (complete occlusion, residual neck and residual aneurysm). For each occlusion category, patients were tracked through 5 possible health states: 'no complications', 'new non-fatal rupture', 'post rupture', 'fatal rupture' and 'dead (all cause)'. It was assumed that transition probabilities for the health states would be constant over time. The time horizon of the base-case analysis was 10\xa0years.\n\nAn NHS and personal social services perspective was used. The cost analysis included the costs associated with the duration of the procedure, staff time (surgeon, radiologist, nurse, anaesthetist), hospital costs (neurology operating or neurosurgical operating room, and recovery ward), imaging (angiography, fluoroscopy or MRI), consumables, drugs; and for conservative management only, long-term monitoring with annual MRI. The cost associated with stroke was assumed to be representative of the cost of rupture. Costs applied to each type of retreatment were assumed to be the same as the full cost if that treatment had been used initially.\n\nThe costs and consequences associated with adverse events were not included in the base-case analysis because the sponsor considered there to be insufficient reliable data for each treatment group. However, the sponsor did include costs associated with mortality at 31\xa0days, rupture and retreatment.\n\nIn the base case the number of Pipeline embolisation devices used was 1.46, based on data submitted to the sponsor from use of the device in UK hospitals up to August 2011. The number of coils used in the base case was 40 and was derived from an estimate in an editorial review by Wehman in 2006. It was assumed that 1 stent would be needed for each stent-assisted coiling intervention.\n\nThe base case presented the total procedure costs over the 10-year time horizon associated with Pipeline as £24,341. For the comparators, the total procedure costs were £37,451 for stent-assisted coiling, £11,658 for neurosurgical clipping, £16,893 for endovascular parent vessel occlusion, £11,654 for neurosurgical parent vessel occlusion and £10,352 for conservative management. The only intervention against which Pipeline was shown to be cost saving was stent-assisted coiling, with a cost saving of £13,110 per patient.\n\nTwo scenario analyses were presented. One included costs associated with the adverse events of subarachnoid haemorrhage related to the aneurysm, thromboembolic stroke and intracranial haemorrhagic stroke remote from the aneurysm using data from the PUFS study and data from Darsault\xa0et\xa0al. (2001) for the comparators. The other scenario analysis restricted the time horizon to 6\xa0months (short-term). Conservative management was excluded from the short-term scenario because it does not have a 'peri-procedural' mortality rate.\n\nIn both scenario analyses Pipeline was shown to be cost saving only when compared with stent-assisted coiling. When costs associated with adverse events were included in the model, Pipeline remained a cost-saving intervention compared with stent-assisted coiling, with an associated saving of £13,327. When outcomes were restricted to the short term (6\xa0months), Pipeline remained cost saving compared with stent-assisted coiling (£10,316).\n\nSensitivity analyses carried out by the sponsor showed that the main factors influencing the cost analysis were the number and cost of consumables, in particular the numbers of Pipeline embolisation devices and endovascular coils. The sponsor carried out sensitivity analysis for the use of 1–3 Pipeline embolisation devices and separately for 5–100 coils.\n\nThe number of Pipeline embolisation devices used in the base case was 1.46 per patient. On receipt of more data from UK hospitals, the sponsor submitted a revised number of 1.658 in October 2011. The external assessment centre reviewed the data and concluded that when 1.658 Pipeline embolisation devices were used, Pipeline was more costly compared with stent-assisted coiling if 22 coils were used (an estimated cost increase of £19), but cost saving when 23 coils were used. The cost saving when using 1.658 Pipeline embolisation devices compared with stent-assisted coiling with 23 coils was estimated to be £588 (total procedure costs of £26,546 and £27,134 respectively). When 2 Pipeline embolisation devices were used, Pipeline was more costly by an estimated £185 than stent-assisted coiling using 28 coils, but was less costly than stent-assisted coiling when 29 coils were used. The cost saving when using 2 Pipeline embolisation devices compared with stent-assisted coiling with 29 coils was estimated to be £421 (total procedure costs of £30,354 and £30,775 respectively).\n\nDuring consultation, expert advisers expressed doubts about 5 parameters in the cost model: the cost of microcatheters; the use of a balloon in stent-assisted coiling; drug costs; the procedure duration; and the cost of additional endovascular equipment. Additional exploratory analyses were carried out by the external assessment centre to examine the impact of changing these parameters, in ways which the expert advisers suggested were more appropriate.\n\nIn the sponsor's economic model, the cost of microcatheters used in stent-assisted coiling was comparable to the cost of a Marksman catheter (£1,030) used to insert Pipeline. However, the expert advisers stated that cheaper microcatheters (average cost £460.50) would be used for stent-assisted coiling than for Pipeline in UK practice. The external assessment centre's exploratory analyses demonstrated that reducing the cost of 2 microcatheters for stent-assisted coiling from £1,030 to £460.50 reduced the total procedure cost for stent-assisted coiling from £37,451 to £36,137.\n\nThe sponsor's economic modelling also assumed that a balloon is used in 50% of stent-assisted coiling procedures and is not used to insert Pipeline. However, the expert advisers stated that use of a balloon is relatively uncommon in the UK for stent-assisted coiling procedures. In the exploratory analyses carried out by the external assessment centre, removing the cost of a balloon reduced the total procedure cost for stent-assisted coiling from £36,137 to £35,725, while the total procedure cost for Pipeline (with 2 devices) remained at £30,354.\n\nThe sponsor's economic model assumed different drug use for patients having stent-assisted coiling and those having Pipeline (18,000\xa0mg aspirin and 6,750\xa0mg clopidogrel compared with 25,000\xa0mg aspirin and 13,500\xa0mg clopidogrel respectively). The expert advisers stated that in clinical practice drug use in the 2 groups is likely to be equal. The external assessment centre noted that in the sponsor's economic model drug use was calculated from 2 non-comparative studies, but that few published data are available on clinical use. The external assessment centre stated that the low cost of these drugs means that relatively small differences in drug use are unlikely to have a significant impact on the overall procedure costs for stent-assisted coiling and Pipeline. In the absence of a systematic review the external assessment centre stated that the drug costs used in the model were appropriate.\n\nIn its exploratory analysis the external assessment centre identified 2 calculation errors in the sponsor's economic model, both relating to the number of days of drug therapy. The external assessment centre stated that correcting these calculation errors made only a very small difference in the total procedure costs for both Pipeline and stent-assisted coiling, reducing them from £30,354 to £30,346 and £35,725 to £35,724 respectively.\n\nIn the sponsor's economic model, the average duration of the procedure (in hours) and therefore the use of additional endovascular equipment were different for stent-assisted coiling and insertion of Pipeline. The expert advisers stated that the procedures are likely to take the same amount of time in clinical practice. The external assessment centre noted that the time taken for stent-assisted coiling was derived from 1 non-comparative study and the time for inserting Pipeline from another. However the external assessment centre was not able to judge which study was the best source for duration of procedure and no systematic review was carried out. The external assessment centre stated that because both studies were appropriately and accurately used in the model no changes were justified with regard to procedure time for stent-assisted coiling or Pipeline. The external assessment centre also noted that the sponsor included the use of additional endovascular equipment in the model based on the duration of procedure, but provided no justification for why it was included only for stent-assisted coiling and not for Pipeline or the other comparators. Furthermore, there was no justification for why the cost of additional equipment was only included in calculating the retreatment cost but not the cost of the initial procedure. The exploratory analyses demonstrated that removing the costs of additional endovascular equipment from the model reduced the total procedure cost of stent-assisted coiling from £35,724 to £35,693 while the total procedure cost for Pipeline remained at £30,346.\n\n## Committee considerations\n\nThe committee considered the cost consequences of using Pipeline against 5 comparators – stent-assisted coiling, neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion and conservative management.\n\nThe committee noted that in UK clinical practice, patients who might currently be considered for Pipeline would be those for whom surgery would not be possible and for whom stent-assisted coiling would be the only other potential intervention. It therefore considered that comparison of costs with those for stent-assisted coiling was of particular relevance. The committee noted that for this cost comparison, the main drivers of cost were the numbers of Pipeline embolisation devices used and the numbers of coils used during stent-assisted coiling. The committee was given advice from the experts about whether 1 or 2 Pipeline embolisation devices should be used as the most typical number on which to base its judgements about cost. It therefore considered the cost modelling for a range of scenarios – with different numbers of Pipeline embolisation devices. During its discussions the committee was informed both by expert advisers and by data from the sponsor that 2 Pipeline embolisation devices were likely to be needed for most patients treated in the UK for complex giant or large aneurysms.\n\nThere was considerable uncertainty about the number of coils likely to be used during stent-assisted coiling. The committee was advised that 40 coils was probably an overestimate of the number needed for most complex aneurysms and there were suggestions that about 25–30 coils might be more typical of the number needed for aneurysms being considered for treatment using Pipeline. The committee recognised that it is not possible to estimate accurately the number of coils which will be required to treat an aneurysm during stent-assisted coiling, but it was advised by experts that the number can usually be predicted with an accuracy of plus or minus 6 coils.\n\nThe committee discussed a number of parameters in the sponsor's economic model based on comments received during public consultation. As described in sections 5.12 to 5.17, these included: the cost of microcatheters used for stent-assisted coiling; balloon use in UK practice during stent-assisted coiling; drug costs for patients having Pipeline and those having stent-assisted coiling; the duration of the procedure and the use of additional endovascular equipment in stent-assisted coiling. These parameters were examined in additional analyses by the external assessment centre.\n\nThe committee considered that the costs for microcatheters used for stent-assisted coiling in the sponsor's base-case analysis were overestimated. It agreed with the views of the expert advisers that it was reasonable to use the average cost of the microcatheters most commonly used in UK clinical practice. This reduced the total procedure cost for stent-assisted coiling from £37,451 to £36,137.\n\nBased on expert advice, the committee accepted that the inclusion of balloon use during stent-assisted coiling in the sponsor's base-case analysis was inappropriate and that it was reasonable to adjust this cost to zero. This reduced the total procedure cost for stent-assisted coiling from £36,137 to £35,725, while the total procedure cost for Pipeline remained at £30,354.\n\nThe committee considered the drug costs presented in the sponsor's base-case analysis. It noted the external assessment centre's view that few published data are available on clinical use and that the low cost of these drugs and the difference in drug use would not be likely to have any significant impact on the overall procedure costs for either stent-assisted coiling or Pipeline. The committee agreed that the drug cost in the sponsor's base-case analysis was appropriate\n\nThe committee considered the average duration of the procedure presented in the sponsor's base-case analysis. It noted the external assessment centre's view that both studies were appropriately and accurately used in the model and that therefore no changes were justified for the average duration of the procedure for stent-assisted coiling or inserting Pipeline. The committee agreed that the average duration of the procedure presented in the sponsor's base-case analysis was appropriate.\n\nThe committee was advised by the experts that it was not appropriate to include the cost for additional endovascular equipment for stent-assisted coiling only. This was because the cost of endovascular equipment was likely to be the same for Pipeline compared with stent-assisted coiling. The committee accepted the views of the expert advisers that removing this cost from the model for stent-assisted coiling was appropriate. This reduced the total procedure cost for stent-assisted coiling from £35,724 (this cost takes account of the drug cost calculation errors referred to in section 5.16) to £35,693 while the total procedure cost for Pipeline remained at £30,346.\n\nWith these issues in mind, the committee considered a graph showing the costs of Pipeline and of stent-assisted coiling using different numbers of Pipeline embolisation devices and coils. This indicated that the total cost of treatment using 2 Pipeline embolisation devices is greater than that of stent-assisted coiling (using 1 stent) if 31 coils or fewer are used, but Pipeline is less costly if 32 or more coils are needed. The cost saving associated with Pipeline compared with stent-assisted coiling with 32 coils was estimated to be £492 (total costs of £30,346 and £30,838 respectively).\n\nThe committee noted that using 2 Pipeline embolisation devices would incur a higher total treatment cost than neurosurgical clipping, endovascular parent vessel occlusion, neurosurgical parent vessel occlusion or conservative management for patients in whom those other options were feasible.\n\nFor the guidance review, the external assessment centre revised the model to reflect updated costs. The main parameter changes were costs associated with staff, hospital imaging equipment, drugs, rupture and adverse event costs. Further details of the revised model are in the revised model summary. ", 'Conclusions': 'The committee concluded that current evidence supports the case for adoption of Pipeline when it is used in highly selected patients with complex giant or large intracranial aneurysms which are unsuitable for surgery and being considered for stenting, when the number of Pipeline embolisation devices does not exceed 2 and when 32 or more coils and 1 stent would be needed during stent-assisted coiling. For these patients use of Pipeline appears efficacious and is less costly than stent-assisted coiling.\n\nThe committee noted that standard management of intracranial aneurysms varies according to the size and type of aneurysm and the symptoms the patient experiences. This may include conservative management, for example, in patients whose complex giant or large intracranial aneurysms are unsuitable in size or shape for stent-assisted coiling or surgery, and for whom parent vessel occlusion would result in stroke or death. The recommendations in section 1 of the guidance are based on circumstances in which Pipeline releases resources, and were not framed on the basis of treating patients for whom there is no other viable option apart from conservative management. The committee saw little evidence in this patient group and this area of unmet clinical need would benefit from further research.'}
|
https://www.nice.org.uk/guidance/mtg10
|
Evidence-based recommendations on the Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms.
|
4ff4d8553f7a3aeda230513f5f92ce91d830b427
|
nice
|
Darvadstrocel for treating complex perianal fistulas in Crohn's disease
|
Darvadstrocel for treating complex perianal fistulas in Crohn's disease
Evidence-based recommendations on darvadstrocel (Alofisel) for previously treated complex perianal fistulas in adults with non-active or mildly active luminal Crohn’s disease.
# Recommendations
Darvadstrocel is not recommended, within its marketing authorisation, for previously treated complex perianal fistulas in adults with non-active or mildly active luminal Crohn's disease.
Why the committee made these recommendations
In a single clinical trial comparing remission rates for darvadstrocel and placebo, only an additional 14% of people showed a beneficial effect from darvadstrocel over and above placebo. Reliable follow‑up results are only available for up to 1 year during which time more than 50% of patients who had remission subsequently relapsed in both the darvadstrocel and placebo arms, so it is unclear how long the treatment benefit will last. The additional evidence submitted after consultation did not clarify the uncertainties around long-term benefits of darvadstrocel. The committee considered that further research in this area would be beneficial (see section 4 for further details). The cost-effectiveness estimates are therefore highly uncertain and the committee was unable to decide on the most plausible cost-effectiveness estimate. Because of this, darvadstrocel cannot be recommended for routine commissioning for treating complex perianal fistulas in people with Crohn's disease.# Information about darvadstrocel
# Marketing authorisation
Darvadstrocel (Alofisel, Takeda) is indicated for the 'treatment of complex perianal fistulae in adult patients with non-active/mildly active luminal Crohn's disease, when fistulae have shown an inadequate response to at least 1 conventional or biologic therapy'.
# Dosage in the marketing authorisation
A single dose of darvadstrocel consists of 120 million cells distributed in 4 vials. Each vial contains 30 million cells in 6 ml of suspension. The full content of the 4 vials must be administered for the treatment of up to 2 internal openings and up to 3 external openings. This means that, with a dose of 120 million cells, it is possible to treat up to 3 fistula tracts that open to the perianal area. There is currently limited experience with the efficacy or safety of repeat administration of darvadstrocel.
# Price
The list price of darvadstrocel is £13,500 per vial. One course of treatment (4 vials) costs £54,000 (company submission). The company has a commercial arrangement, which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Management of the disease
## There are no targeted interventions for complex perianal fistulas in people who have Crohn's disease
Perianal fistulas are abnormal passages between the lower parts of the gut and the skin near the anus. Complex perianal fistulas have several abnormal passages and openings, or passages that go deep inside the body, or have other complications such as abscesses. In adults with non-active or mildly active luminal Crohn's disease, perianal fistulas are managed with medical therapies including antibiotics, immunosuppressants and biological therapy. If the fistula and any associated abscesses do not heal, surgery is needed. Using general anaesthesia, the abscesses are drained and a seton (piece of thread) is passed through the fistula. This keeps the fistula open so that it can drain. The clinical experts explained that setons are not usually curative, but aim to reduce the risk of abscess formation. Long-term remission rates are relatively low (about 10%). The success rate of seton placement also depends on the surgeon's experience in treating complex perianal fistulas with multiple tracts. Because setons are not usually curative and remission rates are low, people may need to have defunctioning surgery (a temporary diversion of the bowel to allow healing of the perianal fistula) or a proctectomy (permanent removal of part of the bowel to bypass the perianal fistula).
# New treatment option
## Perianal fistulas are chronic and debilitating, and a new treatment option would be welcome
The patient experts explained that perianal fistulas are highly debilitating, have a big effect on the person's everyday life and greatly reduce their quality of life. People can experience excruciating pain and are limited in their everyday activities. The availability of systemic biological treatments has improved people's quality of life, but these treatments can have serious side effects and do not specifically treat the perianal fistula. Darvadstrocel is injected directly into the perianal fistula. It is the first stem-cell treatment that is specifically developed to promote healing of fistulas caused by Crohn's disease and, if curative, would be a life-changing intervention. At the second committee meeting, patient experts explained that any relief from the symptoms would be considered a huge benefit, even if it is only maintained for a short period of time (such as 24 to 52 weeks). This would allow people to reduce the amount of other concomitant therapies used in managing perianal fistulas (such as antibiotics and painkillers). In response to consultation, patients also expressed that seton placement can be very painful, uncomfortable and associated with faecal incontinence. It also negatively affects the patient's self-esteem, sexual activity and everyday functions. But, the subsequent therapies often involve multiple surgical treatments to achieve healing. They can be life-changing interventions that have an even bigger effect on a person's daily life, self-esteem and sexual activity. They also reduce fertility and are potentially stigmatising interventions. Darvadstrocel has the potential to offer a more favourable outcome for patients and to raise the standards and expertise in treating perianal fistulas. The committee understood that patients and clinicians would welcome a new treatment option that is targeted to heal the perianal fistula rather than to reduce complications such as abscesses, even if the treatment benefits are only maintained for a few months before relapse.
# The method of administration of darvadstrocel
## Using darvadstrocel needs training of the multidisciplinary team and careful planning and scheduling of treatment
Darvadstrocel is a suspension of allogeneic expanded human adipose-derived stem cells. Administration involves re‑suspension of the cells, which need to be used within 48 hours. Because of its short shelf life, careful planning and scheduling is necessary to avoid procedures being cancelled and darvadstrocel being wasted. The clinical experts explained that the pharmacist and surgeon would need training in its preparation and administration. They also emphasised that patients should be seen by a multidisciplinary team who are experienced in treating complex perianal fistulas. Not all fistulas would be considered suitable for this treatment (see section 3.4). The committee noted that darvadstrocel needs an additional procedure compared with current management. Standard examination under anaesthesia, with conditioning of the fistula is done first, then another procedure is done 2 weeks later to administer darvadstrocel. The clinical experts explained that the outcome of the intervention is highly dependent on the appropriate conditioning of the fistula and optimal placement of the darvadstrocel injection. They suggested that it should only be used in specialist centres where a multidisciplinary team is available, who could gain appropriate experience in the use of this technology. However, the clinical experts did not consider this to be a barrier to implement darvadstrocel in the NHS. The company also explained in its response to consultation that training would be funded and provided by the company in collaboration with research groups in this area. The committee concluded that because darvadstrocel is the first stem-cell treatment in this disease area, and keeping in mind the logistics of administration of darvadstrocel, it would only be used in specialist centres, after further training.
# Clinical evidence
## Darvadstrocel would only be appropriate for a specific group of people with complex perianal fistulas, in line with the population enrolled into ADMIRE‑CD trial
Clinical evidence comes from ADMIRE‑CD, a randomised controlled trial. This included adults with Crohn's disease who had a complex perianal fistula with up to 2 internal openings and up to 3 external openings, which had not responded to treatment with antibiotics, immune-modulators, tumour necrosis factor (TNF) alpha inhibitors, or a combination of these treatments. The clinical experts explained that the trial excluded people with the most severe and the least severe fistulas (that is, people with multiple complex fistulas, and those with simple fistulas). The clinical experts noted that the benefit for people with multiple fistulas would be limited because of the restrictions around the volume of darvadstrocel that can be used for a single administration. Therefore in NHS practice, it would only be used in the fistula types specified in ADMIRE‑CD, and patients would be carefully selected to achieve the best outcomes. The committee noted that people with proctitis were excluded from the clinical trial, because this condition makes perianal fistula healing unlikely. The clinical experts agreed that these patients are unlikely to benefit from darvadstrocel. The committee concluded that if darvadstrocel were recommended, it should only be used in a population similar to people who were enrolled in ADMIRE‑CD.
## The evidence on the natural history of the disease and outcome of current practice in the UK is limited
ADMIRE‑CD was a multicentre trial but it did not include patients from the UK. To show that the data are generalisable to people in the UK, the company presented the results of a study from St Mark's Hospital in London. This was a retrospective cohort study that collected data from January 2008 until July 2017. It included people with complex perianal fistulas that would have met the eligibility criteria of ADMIRE‑CD. It was used to externally validate the results from ADMIRE‑CD and calculate the transition to the proctectomy state. The ERG also used the data for adjusting the probabilities in the model and updating it with missing transitions (see section 3.15). The committee noted that people in the St Mark's study were more likely to be male and had a different medication history than the people in ADMIRE‑CD. In particular, a higher percentage had had biological treatments. Clinical experts explained that, because the St Mark's study reported previous and current treatment together, the data are of limited usefulness and would not help the committee to decide who would be eligible for darvadstrocel in the NHS. It also noted that the St Mark's study did not report on the outcome of treatments, so it provided no evidence about the success rates of current NHS practice. The clinical experts also explained that evidence on the natural history of Crohn's disease with perianal fistulas is limited. The committee considered the St Mark's study useful for understanding the patient population in the NHS, but concluded that it does not contribute substantially to predicting the natural history of the disease and outcome of current UK clinical practice.
## Clinical-effectiveness data for darvadstrocel is from only 1 trial with a relatively short time-frame
ADMIRE‑CD compared darvadstrocel with placebo (saline solution injection). The primary outcome of the trial was remission after 24 weeks, with clinical and MRI confirmation of fistula healing. Results from longer-term follow‑up are also available (at 52 weeks and 104 weeks). The company and the ERG stated that the results are only reliable up to 52 weeks, because of a protocol change at that time, and the longer-term results are highly uncertain. The committee would have liked to have seen longer follow‑up, given that darvadstrocel after a single use is expected to have lifelong benefit.
## Using clinical and patient-centric assessment of remission is appropriate
Although the primary outcome of ADMIRE‑CD was combined remission (assessed both clinically and by MRI), the company also did a post-hoc analysis of an alternative outcome. This had been suggested by clinicians who advised that, as well as clinically assessed remission, the outcome should include a component of patient-assessed pain and discharge (that is, clinical and patient-centric remission). The time to CPC remission, and time to relapse after CPC remission, were considered to be indicators of the clinical effectiveness of darvadstrocel compared with placebo. The committee noted that the trial was not powered to detect changes in CPC remission and relapse. However, the ERG and the clinical experts explained that this outcome would be the most relevant to clinicians and patients. The committee concluded that using CPC remission and relapse was appropriate, but remained concerned that these outcomes were defined post hoc and that the trial was not powered to detect changes in these outcomes.
## ADMIRE‑CD shows a statistically significant benefit of darvadstrocel compared with placebo but by 1 year more than 50% of patients with remission had relapsed
ADMIRE‑CD showed a statistically significant difference in combined remission for darvadstrocel compared with placebo at week 24 (49.5% and 34.3% respectively; difference 15.2%, p=0.024). This statistically significant difference was maintained at week 52 (54.2% compared with 37.1% respectively; difference 17.1%, p=0.012). The committee also considered the results of the post-hoc analysis, which showed that a statistically significantly higher number of people's disease responded to darvadstrocel and achieved CPC remission compared with placebo (55.1% and 41.0% respectively, p=0.014). It noted that only around 14.1% (n=16) more patients experienced CPC remission with darvadstrocel, compared with placebo. The committee understood the benefit to patients of achieving complete remission. However, it considered that this additional remission rate is disappointing for a highly complex, one‑off treatment, which is associated with high upfront costs. Darvadstrocel retained a higher remission rate than placebo during the 1 year of the trial, but during that time there were also high relapse rates seen in both arms (50.8% for darvadstrocel and 59.6% for placebo; p=0.0262). In both arms, patients who were in remission were relapsing, and the patient numbers who were still in remission at 1 year were low (29 for darvadstrocel and 19 for placebo). It also noted that the data are only reliable up to 52 weeks (see section 3.6) and the number of patients who were followed up between 52 and 104 weeks was extremely low. The committee concluded that ADMIRE‑CD shows a benefit of darvadstrocel compared with placebo, but this is not large, and there are uncertainties about how long the benefit will be maintained.
## There is an ongoing clinical trial, which will provide further results on the clinical effectiveness of darvadstrocel
The committee noted that an ongoing clinical trial (ADMIRE‑CD II) is expected to provide more evidence on the clinical effectiveness of darvadstrocel for a complex perianal fistula in people who have Crohn's disease. The study is planning to recruit more people (n=326) than were included in ADMIRE‑CD (n=212). However, the committee noted that it will not collect data on health-related quality of life and at the time of the discussion, there was no plan to collect longer-term data beyond 52 weeks. The company also explained in its response to consultation that a global registry (INSPIRE) has been set up by Takeda to collect data about patients having darvadstrocel therapy across the world. But long-term outcomes are not likely to be available in the near future. The committee considered that the results of the 2 studies together and from the registry will form a more robust evidence base. It also noted that the European Medicines Agency considers that the results of ADMIRE‑CD II should be submitted to the agency as post-authorisation measures.
# Generalisability of ADMIRE‑CD data to UK clinical practice
## The treatment effect seen in the placebo group of ADMIRE‑CD is better than achieved in UK clinical practice
The clinical and patient experts explained that standard care for complex perianal fistulas in people with Crohn's disease is surgical intervention and seton placement, which allows free drainage to prevent deep abscess formation. Because the ADMIRE‑CD trial did not include patients from the UK, it is unclear to what extent the outcomes seen in the placebo group of the trial reflect the outcome of clinical practice in the UK. In ADMIRE‑CD, the interventions given in the placebo arm resulted in a much higher rate of remission than would be expected with standard care in the UK. The reasons for this are unclear. It may be a placebo effect or it may reflect differences between the trial setting and real-life clinical practice. The clinical experts indicated that careful conditioning of the fistula and thorough abscess drainage and curettage is key to successful treatment and that perhaps more experienced surgeons were involved in the trial, which may have increased the remission rate with placebo. They explained that there is variability in the level of service across the NHS. The clinical expert at the second committee meeting also explained that in clinical trials for Crohn's disease, a high placebo effect is usually seen because of the more careful management of the disease in a clinical trial setting. The committee considered that this might have underestimated the benefits of darvadstrocel compared with placebo seen at 1 time point (24 or 52 weeks), but this does not indicate if the response to darvadstrocel therapy is maintained in the longer term. The committee reiterated its previous conclusion that darvadstrocel would only be suitable for use in specialist centres (see section 3.3). It concluded that there was uncertainty in the generalisability of the placebo arm of the ADMIRE‑CD trial to UK clinical practice, and therefore it is uncertain whether the benefit shown for darvadstrocel in the trial would translate to the same benefit compared with standard care in the NHS.
## ADMIRE‑CD did not collect patient-reported health-related quality-of-life data
ADMIRE‑CD collected disease severity scores as secondary outcomes (Perianal Disease Activity Index and Van Assche Score). The clinical experts explained that although the Perianal Disease Activity Index is a patient-reported outcome measure, it does not capture health-related quality of life. The committee noted that the reference case in section 5.3.1 of NICE's guide to the methods of technology appraisal (2013) specifies that health-related quality-of-life data should be obtained from patients using the EQ‑5D questionnaire. The committee concluded that it would have welcomed the collection of health-related quality-of-life outcomes in the trial, particularly using EQ‑5D.
## The new evidence does not clarify the uncertainties around long-term benefits of darvadstrocel compared with placebo
In response to consultation, the company did a literature search to determine long-term relapse rates in patients with Crohn's disease with perianal fistulas (both complex and simple). It identified 6 potentially relevant studies. However, there were some key differences between the ADMIRE‑CD trial and these studies:
definition of remission among studies
maintenance use of biological treatments
time points for outcome assessments
populations and countries where the studies were conducted
methodology of the study (prospective or retrospective).Comparing the Kaplan–Meier curves showed more rapid relapse rates in the ADMIRE‑CD trial than in the other studies, regardless of treatment arm. According to the company, this suggests that the population of the studies reflects a subgroup with a more sustained remission than the population in ADMIRE‑CD. The company considered that the results showed a 'plateau' effect once remission is reached at 2 years and that therefore remission is likely to be maintained in the long term. The committee noted that relapse may be less frequent the longer remission is maintained, but did not consider a 'plateau' effect had been proven. Moreover, there was a high relapse rate during year 1 and no reliable trial data for year 2 after which a plateau effect was suggested. Therefore, the number of relapses that would have happened before the rate plateaued was unknown. Using the results from 2 of the studies that according to the company best reflected UK clinical practice and were most comparable with ADMIRE‑CD (Bouguen et al. 2013 and Gottens et al. 2017), the company presented scenario analyses. In these analyses, the 4‑weekly constant relapse rate was adjusted (also see section 3.19). The ERG explained that as well as the differences listed above, there were differences in types of fistulas (simple or complex) that were included in the studies, and it was unclear what proportion of the different type of fistulas responded to treatment. The ERG considered these differences to be important and did not think that the studies were comparable with the ADMIRE‑CD trial and would be suitable to inform the analyses on long-term extrapolation methods. The committee considered the new evidence from the company and also understood the ERG's concerns. It concluded that the new evidence does not clarify the uncertainties around the long-term benefits of darvadstrocel compared with placebo.
The company also did a Delphi-panel survey, which sought expert opinion from 20 clinicians across the UK, including gastroenterologists, surgeons and nurses. Experts were asked to give a view on long-term outcomes with darvadstrocel and the natural history of fistulising Crohn's disease. Their initial response noted a higher rate of relapse in the ADMIRE‑CD trial than has previously been reported in the literature. There was a consensus that relapse rates would reduce the longer the remission was maintained, particularly because maintenance TNF‑alpha inhibitor therapy would be continued after a patient had had darvadstrocel. However, it was only possible to get qualitative evidence from the results of the survey and no consensus was reached when the company tried to quantify the results. The responses also indicated differences in the definition of true healing of fistula and remission. The committee found the results from the literature review and the survey informative but concluded that they did not consider it robust evidence that would alter their decision.
# The company's economic model
## The company's model structure is appropriate and suitable for decision making
The company presented a semi-Markov state transition cohort model, which assumed a single administration of darvadstrocel (the committee noted no evidence had been presented by the company for repeated treatments with darvadstrocel), and a lifetime benefit for patients. It used a 40‑year time horizon and a 4‑week cycle length. The committee agreed with the structure of the model and considered it suitable for decision making.
# Discounting future costs and benefits
## A reference case discount rate of 3.5% should be used for both benefits and costs
The company deviated from the reference case in its base-case analysis, using a 1.5% discount rate for future benefits and a 3.5% discount rate for costs, because it considered that section 6.2.19 of NICE's guide to the methods of technology appraisal applies. This states that in cases when treatment restores people who would otherwise die or have a very severely impaired life to full or near-full health, and when this is sustained over a very long period, a non-reference case discount rate of 1.5% for costs and benefits may be considered. The ERG commented that evidence does not support the suggestion that darvadstrocel restores quality of life to full or near-full health for a prolonged period (at least 30 years, as defined by section 6.2.19 of NICE's guide to the methods of technology appraisal). The committee agreed that it has not been shown that darvadstrocel restores a patient's quality of life to full or nearly-full health (partly because it does not treat the underlying condition, Crohn's disease). It also noted the lack of evidence on the long-term benefits of darvadstrocel. Also, the committee noted that NICE's guide to the methods of technology appraisal does not support using different discount rates for costs and benefits. The committee concluded that a reference case discount rate of 3.5% should be used for both costs and benefits in the economic model.
# Time horizon of the model
## Using a 60‑year time horizon in the economic model is in line with the NICE reference case
The company's model used a 40‑year time horizon. The ERG explained that at 40 years, only 31.7% of patients will have died, so the time horizon might be too short to capture differences in costs and benefits for darvadstrocel compared with standard care. The ERG explored the impact of using a 60‑year time horizon. The committee noted this had a minimal impact on the incremental cost-effectiveness ratio (ICER) and concluded that time horizon was not a driver of cost effectiveness.
## Base-case cost-effectiveness estimates
The company presented a deterministic base-case cost-effectiveness estimate of £20,591 per quality-adjusted life year (QALY) gained (incremental costs £21,639; incremental QALYs 1.05), using the following assumptions: the reference case discount rate of 3.5% for both costs and QALYs; a 40‑year time horizon; and applying the patient access scheme for the treatment costs of darvadstrocel. The committee noted that the ERG's preferred inputs into the company's base-case analysis produced an ICER of £23,176 (incremental costs £23,978; incremental QALYs 1.01), using the following corrections and assumptions:
correcting for programming errors in the model
updating the model structure with adding the missing transitions of successful defunctioning surgery to unsuccessful defunctioning surgery, successful proctectomy to unsuccessful proctectomy, and unsuccessful proctectomy to successful proctectomy to reflect the evidence from the St Mark's study
adjusting the probabilities of moving to the proctectomy and defunctioning surgery health states in the model, so that the data matched the evidence from the Mueller et al. and Bell et al. studies
amending the long-term remission rates for subsequent therapies in the standard-care group, based on the time-to-event functions of subsequent therapies and the methods used in the darvadstrocel group
using a 60‑year time horizon.The committee considered the ERG's corrections and assumptions to be appropriate.
# Modelling the long-term benefits of darvadstrocel
## The long-term benefit of darvadstrocel is highly uncertain, and the model is highly sensitive to the choice of parametric curve for long-term extrapolation of relapse rate
To model the long-term clinical effectiveness of darvadstrocel, the company used a Gompertz curve to extrapolate both time to CPC remission and time to relapse after CPC remission. The ERG explained that the choice of curve is a key driver of the model and that the cost-effectiveness results are very sensitive to the extrapolation method used, particularly the time to relapse. The ERG presented a scenario analysis, similar to that presented by the company, but including the ERG's preferred base-case assumptions and using the second-best options according to the Akaike Information Criterion and Bayesian Information Criterion statistics, which were the generalised gamma curve for extrapolating time to CPC remission, and the log-normal curve for time to relapse following CPC remission. This results in a substantially higher ICER (£143,131 per QALY gained) compared with the company's base case (see section 3.15). The committee discussed the clinical plausibility of the different curves with the clinical experts, particularly the choice of curve for time to relapse after CPC remission. The clinical experts explained that without more evidence on the natural history of the disease, it is difficult to predict the relapse rate after the time horizon of the trial. However, the experts highlighted that if the fistula is healed and remission is maintained until 2 years, and there is no underlying risk for future recurrence, recurrence rates are likely to be very low after this time (around 10 to 20%), but it is not eliminated. They also explained that relapse tends to happen soon after treatment, rather than later. The committee noted that it had no reliable figures for the number of patients in remission at 2 years from the ADMIRE‑CD trial. The company stated that its model assumes 40% of people remain relapse free, with a low ongoing risk of relapse, after remission has been maintained with darvadstrocel for 2 years. The committee concluded that the risk of relapse over time (hence the method of extrapolation from the trial to the long term) is a key driver of the model. It was unable to select the most appropriate method for modelling the long-term effectiveness of darvadstrocel. The committee expressed concern that no reliable data on the number of people in remission at 2 years is available, and that the choice of curves has a large effect on the ICER (with a difference of more than £100,000 per QALY gained between the best and second-best fitting curves). It concluded that only better data on long-term outcomes from the ongoing trial, or more robust information on the natural history of the disease, would make it possible to decide which is the most plausible ICER.
## The new scenarios were not based on robust evidence and the committee did not consider these any more plausible than the original assumptions
In response to consultation, the company also presented the results of scenario analyses, where it altered the rate of 4‑weekly constant relapse rate that was applied from 2 years onwards in the model. In scenario 1, it assumed that 16.92% of people who had not relapsed at 2 years would relapse at 5 years. The corresponding rate at 10 years was 39.01%. This resulted in an ICER of £36,235 per QALY gained. In scenario 2, it assumed that 24.02% of people who had not relapsed at 2 years would relapse at 10 years, and the corresponding rate at 5 years was 9.72%. This resulted in an ICER of £28,370 per QALY gained. The committee also noted the ERG's alternative cost-effectiveness results using their base-case assumptions, which resulted in £40,900 for scenario 1 and £31,925 for scenario 2. The committee considered the scenario analyses results by the company and the ERG, but did not consider that they were based on more robust evidence or more plausible assumptions than the original base-case cost-effectiveness results.
## There is limited evidence available on health-related quality of life for Crohn's disease with complex perianal fistula
ADMIRE‑CD did not include a direct health-related quality-of-life measurement, and there are no published utility values for this disease area. To calculate the health-related quality-of-life benefits of darvadstrocel, the company did a vignette study to derive utility values for each health state in the model. The committee noted that this is not in line with the NICE reference case. The ERG's clinical experts considered that the utility value after successful defunctioning (0.567) or proctectomy surgery (0.564) may be underestimated in the company's base case, as well as the utility value for the 'mild chronic symptomatic fistulae' health state (0.578). The ERG explored the impact of using the same utility value (0.865) for remission (for a mild chronic symptomatic fistula and for successful defunctioning and successful proctectomy surgery), to establish the direction and maximum size of any changes in the ICER because of the possible under-prediction of utility in these 3 health states. The resulting ICER was £63,721 per QALY gained. The committee discussed this scenario with the patient and clinical experts at the meeting. They explained that a patient's quality of life after defunctioning surgery is expected to be substantially lower than the quality of life of a patient in remission. At the second meeting and in response to consultation, patient experts also explained the devastating symptoms of Crohn's disease with perianal fistulas, especially if they have severe symptoms. They explained that having mild symptoms, even if the fistula is not completely healed, is a relief and allows them to maintain a relatively normal life. But this is conditional on the seton being placed carefully and not causing pain, and that they do not experience major adverse events from the underlying medical treatments. The committee considered that the utilities in some heath states might be too low, and that correctly derived utility values for these 3 health states could result in higher ICERs. However, it concluded that the ERG's suggested scenario is extreme and not plausible, but found that it was informative because it showed the impact that the utility values had on the cost-effectiveness results.
# Most plausible cost-effectiveness estimate
## The most plausible cost-effectiveness estimate is uncertain, and darvadstrocel is unlikely to be a cost-effective use of NHS resources
The key factors affecting the ICER are the parametric curve chosen for extrapolating the time to CPC remission and particularly time to relapse after CPC remission. To a smaller extent, the utility values for a mild chronic symptomatic fistula and for successful defunctioning and successful proctectomy surgery also affect the ICER. Using a generalised gamma curve to extrapolate time to CPC remission, and log-normal curve to extrapolate time to CPC relapse, resulted in an ICER of £143,131 per QALY gained. The committee noted that this ICER is considerably higher than the company's base case and, given the reasonable fit of the curves, it could be correct. The very large difference in the ICERs, depending on the curves chosen, emphasises how sensitive the cost-effectiveness estimate is to the duration of remission. The lack of long-term evidence from the trial and limited evidence on the natural history of the disease, particularly on long-term relapse rates after successful treatment, make it very difficult to decide the most plausible estimate of cost effectiveness. Therefore the committee was unable to conclude on the most plausible cost-effectiveness estimate.
# Other factors
In response to consultation, a patient group stated that some equality issues needed to be considered by the committee in terms of leaving patients with no option but to have defunctioning surgery or a proctectomy. It was noted that having pelvic surgery may be an issue for people who have not completed their family and whose fertility may be affected, and that the condition and potentially having defunctioning surgery or a proctectomy may raise particular issues for certain religious groups. The committee acknowledged that having Crohn's disease presents certain difficulties for some groups. But because of the lack of clear evidence on long-term clinical effectiveness of darvadstrocel, the committee considered that not recommending darvadstrocel does not exclude or impact differently on any populations. It also discussed that it is not proven by the clinical evidence that subsequent surgery will be avoided in any of the patient groups as an outcome of treatment with darvadstrocel. Therefore the committee concluded that this did not represent an equalities issue and that there was no need to alter its recommendations.
The company stated that darvadstrocel is innovative and the first licensed allogenic stem-cell treatment in the UK for this disease. The clinical experts explained that this is the first targeted treatment option for complex perianal fistulas in Crohn's disease, and that it represents a step‑change in the management of the disease. The committee considered these factors to be important and concluded that darvadstrocel is potentially innovative in the short term, but its long-term benefit is uncertain.
# Conclusion
The committee understood the huge disease burden that patients experience and how severely impaired quality of life is for patients with this condition. Data on clinical effectiveness of darvadstrocel show only modest benefit over and above placebo, and data are only available for up to 1 year, so the duration of this benefit is also uncertain. The committee concluded that the clinical benefit to patients in the NHS is not known. The cost-effectiveness estimates are therefore highly uncertain. This reflects the uncertainty about how long treatment benefit will last and the most appropriate extrapolation method for time to CPC remission and particularly time to relapse after CPC remission. Taking all the uncertainties into account, the committee concluded that darvadstrocel was not a clinically or cost-effective use of NHS resources and could not be recommended for routine commissioning.# Recommendations for research
The results of ADMIRE‑CD showed that most patients tend to relapse within the first year after achieving remission and healing of the fistula in both arms of the trial. Unfortunately, there are limited data between year 1 and year 2 for data on relapse, and no data on relapse are available for year 2 and beyond. The committee considered that the outcomes of the ADMIRE‑CD and the ongoing ADMIRE‑CD II trial did not capture fully the relapsing-remitting nature of Crohn's disease with perianal fistulas. The new evidence submitted after consultation did not clarify the uncertainties around the long-term benefits of darvadstrocel compared with placebo either, because the results from the literature were very different from the results of ADMIRE‑CD.
Further research is recommended to resolve the uncertainties about the long-term clinical effectiveness of darvadstrocel compared with standard care. In particular, estimates of long-term remission rates (minimum of 2 years' follow‑up) in Crohn's disease with perianal fistulas are needed.
The health-related quality-of-life evidence of patients with perianal fistulas is also lacking, therefore further research is recommended. Any research should measure the effect of treatment using preference-based measures (such as use of the EQ‑5D questionnaire).
|
{'Recommendations': "Darvadstrocel is not recommended, within its marketing authorisation, for previously treated complex perianal fistulas in adults with non-active or mildly active luminal Crohn's disease.\n\nWhy the committee made these recommendations\n\nIn a single clinical trial comparing remission rates for darvadstrocel and placebo, only an additional 14% of people showed a beneficial effect from darvadstrocel over and above placebo. Reliable follow‑up results are only available for up to 1\xa0year during which time more than 50% of patients who had remission subsequently relapsed in both the darvadstrocel and placebo arms, so it is unclear how long the treatment benefit will last. The additional evidence submitted after consultation did not clarify the uncertainties around long-term benefits of darvadstrocel. The committee considered that further research in this area would be beneficial (see section\xa04 for further details). The cost-effectiveness estimates are therefore highly uncertain and the committee was unable to decide on the most plausible cost-effectiveness estimate. Because of this, darvadstrocel cannot be recommended for routine commissioning for treating complex perianal fistulas in people with Crohn's disease.", 'Information about darvadstrocel': "# Marketing authorisation\n\nDarvadstrocel (Alofisel, Takeda) is indicated for the 'treatment of complex perianal fistulae in adult patients with non-active/mildly active luminal Crohn's disease, when fistulae have shown an inadequate response to at least 1\xa0conventional or biologic therapy'.\n\n# Dosage in the marketing authorisation\n\nA single dose of darvadstrocel consists of 120\xa0million cells distributed in 4\xa0vials. Each vial contains 30\xa0million cells in 6\xa0ml of suspension. The full content of the 4\xa0vials must be administered for the treatment of up to 2\xa0internal openings and up to 3\xa0external openings. This means that, with a dose of 120\xa0million cells, it is possible to treat up to 3\xa0fistula tracts that open to the perianal area. There is currently limited experience with the efficacy or safety of repeat administration of darvadstrocel.\n\n# Price\n\nThe list price of darvadstrocel is £13,500 per vial. One course of treatment (4\xa0vials) costs £54,000 (company submission). The company has a commercial arrangement, which would apply if the technology had been recommended.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Management of the disease\n\n## There are no targeted interventions for complex perianal fistulas in people who have Crohn's disease\n\nPerianal fistulas are abnormal passages between the lower parts of the gut and the skin near the anus. Complex perianal fistulas have several abnormal passages and openings, or passages that go deep inside the body, or have other complications such as abscesses. In adults with non-active or mildly active luminal Crohn's disease, perianal fistulas are managed with medical therapies including antibiotics, immunosuppressants and biological therapy. If the fistula and any associated abscesses do not heal, surgery is needed. Using general anaesthesia, the abscesses are drained and a seton (piece of thread) is passed through the fistula. This keeps the fistula open so that it can drain. The clinical experts explained that setons are not usually curative, but aim to reduce the risk of abscess formation. Long-term remission rates are relatively low (about\xa010%). The success rate of seton placement also depends on the surgeon's experience in treating complex perianal fistulas with multiple tracts. Because setons are not usually curative and remission rates are low, people may need to have defunctioning surgery (a temporary diversion of the bowel to allow healing of the perianal fistula) or a proctectomy (permanent removal of part of the bowel to bypass the perianal fistula).\n\n# New treatment option\n\n## Perianal fistulas are chronic and debilitating, and a new treatment option would be welcome\n\nThe patient experts explained that perianal fistulas are highly debilitating, have a big effect on the person's everyday life and greatly reduce their quality of life. People can experience excruciating pain and are limited in their everyday activities. The availability of systemic biological treatments has improved people's quality of life, but these treatments can have serious side effects and do not specifically treat the perianal fistula. Darvadstrocel is injected directly into the perianal fistula. It is the first stem-cell treatment that is specifically developed to promote healing of fistulas caused by Crohn's disease and, if curative, would be a life-changing intervention. At the second committee meeting, patient experts explained that any relief from the symptoms would be considered a huge benefit, even if it is only maintained for a short period of time (such as 24\xa0to 52\xa0weeks). This would allow people to reduce the amount of other concomitant therapies used in managing perianal fistulas (such as antibiotics and painkillers). In response to consultation, patients also expressed that seton placement can be very painful, uncomfortable and associated with faecal incontinence. It also negatively affects the patient's self-esteem, sexual activity and everyday functions. But, the subsequent therapies often involve multiple surgical treatments to achieve healing. They can be life-changing interventions that have an even bigger effect on a person's daily life, self-esteem and sexual activity. They also reduce fertility and are potentially stigmatising interventions. Darvadstrocel has the potential to offer a more favourable outcome for patients and to raise the standards and expertise in treating perianal fistulas. The committee understood that patients and clinicians would welcome a new treatment option that is targeted to heal the perianal fistula rather than to reduce complications such as abscesses, even if the treatment benefits are only maintained for a few months before relapse.\n\n# The method of administration of darvadstrocel\n\n## Using darvadstrocel needs training of the multidisciplinary team and careful planning and scheduling of treatment\n\nDarvadstrocel is a suspension of allogeneic expanded human adipose-derived stem cells. Administration involves re‑suspension of the cells, which need to be used within 48\xa0hours. Because of its short shelf life, careful planning and scheduling is necessary to avoid procedures being cancelled and darvadstrocel being wasted. The clinical experts explained that the pharmacist and surgeon would need training in its preparation and administration. They also emphasised that patients should be seen by a multidisciplinary team who are experienced in treating complex perianal fistulas. Not all fistulas would be considered suitable for this treatment (see section\xa03.4). The committee noted that darvadstrocel needs an additional procedure compared with current management. Standard examination under anaesthesia, with conditioning of the fistula is done first, then another procedure is done 2\xa0weeks later to administer darvadstrocel. The clinical experts explained that the outcome of the intervention is highly dependent on the appropriate conditioning of the fistula and optimal placement of the darvadstrocel injection. They suggested that it should only be used in specialist centres where a multidisciplinary team is available, who could gain appropriate experience in the use of this technology. However, the clinical experts did not consider this to be a barrier to implement darvadstrocel in the NHS. The company also explained in its response to consultation that training would be funded and provided by the company in collaboration with research groups in this area. The committee concluded that because darvadstrocel is the first stem-cell treatment in this disease area, and keeping in mind the logistics of administration of darvadstrocel, it would only be used in specialist centres, after further training.\n\n# Clinical evidence\n\n## Darvadstrocel would only be appropriate for a specific group of people with complex perianal fistulas, in line with the population enrolled into ADMIRE‑CD trial\n\nClinical evidence comes from ADMIRE‑CD, a randomised controlled trial. This included adults with Crohn's disease who had a complex perianal fistula with up to 2\xa0internal openings and up to 3\xa0external openings, which had not responded to treatment with antibiotics, immune-modulators, tumour necrosis factor (TNF) alpha inhibitors, or a combination of these treatments. The clinical experts explained that the trial excluded people with the most severe and the least severe fistulas (that is, people with multiple complex fistulas, and those with simple fistulas). The clinical experts noted that the benefit for people with multiple fistulas would be limited because of the restrictions around the volume of darvadstrocel that can be used for a single administration. Therefore in NHS practice, it would only be used in the fistula types specified in ADMIRE‑CD, and patients would be carefully selected to achieve the best outcomes. The committee noted that people with proctitis were excluded from the clinical trial, because this condition makes perianal fistula healing unlikely. The clinical experts agreed that these patients are unlikely to benefit from darvadstrocel. The committee concluded that if darvadstrocel were recommended, it should only be used in a population similar to people who were enrolled in ADMIRE‑CD.\n\n## The evidence on the natural history of the disease and outcome of current practice in the UK is limited\n\nADMIRE‑CD was a multicentre trial but it did not include patients from the UK. To show that the data are generalisable to people in the UK, the company presented the results of a study from St\xa0Mark's Hospital in London. This was a retrospective cohort study that collected data from January 2008 until July 2017. It included people with complex perianal fistulas that would have met the eligibility criteria of ADMIRE‑CD. It was used to externally validate the results from ADMIRE‑CD and calculate the transition to the proctectomy state. The ERG also used the data for adjusting the probabilities in the model and updating it with missing transitions (see section\xa03.15). The committee noted that people in the St Mark's study were more likely to be male and had a different medication history than the people in ADMIRE‑CD. In particular, a higher percentage had had biological treatments. Clinical experts explained that, because the St\xa0Mark's study reported previous and current treatment together, the data are of limited usefulness and would not help the committee to decide who would be eligible for darvadstrocel in the NHS. It also noted that the St\xa0Mark's study did not report on the outcome of treatments, so it provided no evidence about the success rates of current NHS practice. The clinical experts also explained that evidence on the natural history of Crohn's disease with perianal fistulas is limited. The committee considered the St\xa0Mark's study useful for understanding the patient population in the NHS, but concluded that it does not contribute substantially to predicting the natural history of the disease and outcome of current UK clinical practice.\n\n## Clinical-effectiveness data for darvadstrocel is from only 1\xa0trial with a relatively short time-frame\n\nADMIRE‑CD compared darvadstrocel with placebo (saline solution injection). The primary outcome of the trial was remission after 24\xa0weeks, with clinical and MRI confirmation of fistula healing. Results from longer-term follow‑up are also available (at 52\xa0weeks and 104\xa0weeks). The company and the ERG stated that the results are only reliable up to 52\xa0weeks, because of a protocol change at that time, and the longer-term results are highly uncertain. The committee would have liked to have seen longer follow‑up, given that darvadstrocel after a single use is expected to have lifelong benefit.\n\n## Using clinical and patient-centric assessment of remission is appropriate\n\nAlthough the primary outcome of ADMIRE‑CD was combined remission (assessed both clinically and by MRI), the company also did a post-hoc analysis of an alternative outcome. This had been suggested by clinicians who advised that, as well as clinically assessed remission, the outcome should include a component of patient-assessed pain and discharge (that is, clinical and patient-centric [CPC] remission). The time to CPC remission, and time to relapse after CPC remission, were considered to be indicators of the clinical effectiveness of darvadstrocel compared with placebo. The committee noted that the trial was not powered to detect changes in CPC remission and relapse. However, the ERG and the clinical experts explained that this outcome would be the most relevant to clinicians and patients. The committee concluded that using CPC remission and relapse was appropriate, but remained concerned that these outcomes were defined post hoc and that the trial was not powered to detect changes in these outcomes.\n\n## ADMIRE‑CD shows a statistically significant benefit of darvadstrocel compared with placebo but by 1\xa0year more than 50% of patients with remission had relapsed\n\nADMIRE‑CD showed a statistically significant difference in combined remission for darvadstrocel compared with placebo at week\xa024 (49.5% and 34.3% respectively; difference 15.2%, p=0.024). This statistically significant difference was maintained at week\xa052 (54.2% compared with 37.1% respectively; difference 17.1%, p=0.012). The committee also considered the results of the post-hoc analysis, which showed that a statistically significantly higher number of people's disease responded to darvadstrocel and achieved CPC remission compared with placebo (55.1% and 41.0% respectively, p=0.014). It noted that only around 14.1% (n=16) more patients experienced CPC remission with darvadstrocel, compared with placebo. The committee understood the benefit to patients of achieving complete remission. However, it considered that this additional remission rate is disappointing for a highly complex, one‑off treatment, which is associated with high upfront costs. Darvadstrocel retained a higher remission rate than placebo during the 1\xa0year of the trial, but during that time there were also high relapse rates seen in both arms (50.8% for darvadstrocel and 59.6% for placebo; p=0.0262). In both arms, patients who were in remission were relapsing, and the patient numbers who were still in remission at 1\xa0year were low (29 [27.1%] for darvadstrocel and 19 [18.1%] for placebo). It also noted that the data are only reliable up to 52\xa0weeks (see section\xa03.6) and the number of patients who were followed up between 52\xa0and 104\xa0weeks was extremely low. The committee concluded that ADMIRE‑CD shows a benefit of darvadstrocel compared with placebo, but this is not large, and there are uncertainties about how long the benefit will be maintained.\n\n## There is an ongoing clinical trial, which will provide further results on the clinical effectiveness of darvadstrocel\n\nThe committee noted that an ongoing clinical trial (ADMIRE‑CD\xa0II) is expected to provide more evidence on the clinical effectiveness of darvadstrocel for a complex perianal fistula in people who have Crohn's disease. The study is planning to recruit more people (n=326) than were included in ADMIRE‑CD (n=212). However, the committee noted that it will not collect data on health-related quality of life and at the time of the discussion, there was no plan to collect longer-term data beyond 52\xa0weeks. The company also explained in its response to consultation that a global registry (INSPIRE) has been set up by Takeda to collect data about patients having darvadstrocel therapy across the world. But long-term outcomes are not likely to be available in the near future. The committee considered that the results of the 2\xa0studies together and from the registry will form a more robust evidence base. It also noted that the European Medicines Agency considers that the results of ADMIRE‑CD\xa0II should be submitted to the agency as post-authorisation measures.\n\n# Generalisability of ADMIRE‑CD data to UK clinical practice\n\n## The treatment effect seen in the placebo group of ADMIRE‑CD is better than achieved in UK clinical practice\n\nThe clinical and patient experts explained that standard care for complex perianal fistulas in people with Crohn's disease is surgical intervention and seton placement, which allows free drainage to prevent deep abscess formation. Because the ADMIRE‑CD trial did not include patients from the UK, it is unclear to what extent the outcomes seen in the placebo group of the trial reflect the outcome of clinical practice in the UK. In ADMIRE‑CD, the interventions given in the placebo arm resulted in a much higher rate of remission than would be expected with standard care in the UK. The reasons for this are unclear. It may be a placebo effect or it may reflect differences between the trial setting and real-life clinical practice. The clinical experts indicated that careful conditioning of the fistula and thorough abscess drainage and curettage is key to successful treatment and that perhaps more experienced surgeons were involved in the trial, which may have increased the remission rate with placebo. They explained that there is variability in the level of service across the NHS. The clinical expert at the second committee meeting also explained that in clinical trials for Crohn's disease, a high placebo effect is usually seen because of the more careful management of the disease in a clinical trial setting. The committee considered that this might have underestimated the benefits of darvadstrocel compared with placebo seen at 1\xa0time point (24\xa0or 52\xa0weeks), but this does not indicate if the response to darvadstrocel therapy is maintained in the longer term. The committee reiterated its previous conclusion that darvadstrocel would only be suitable for use in specialist centres (see section\xa03.3). It concluded that there was uncertainty in the generalisability of the placebo arm of the ADMIRE‑CD trial to UK clinical practice, and therefore it is uncertain whether the benefit shown for darvadstrocel in the trial would translate to the same benefit compared with standard care in the NHS.\n\n## ADMIRE‑CD did not collect patient-reported health-related quality-of-life data\n\nADMIRE‑CD collected disease severity scores as secondary outcomes (Perianal Disease Activity Index and Van Assche Score). The clinical experts explained that although the Perianal Disease Activity Index is a patient-reported outcome measure, it does not capture health-related quality of life. The committee noted that the reference case in section\xa05.3.1 of NICE's guide to the methods of technology appraisal (2013) specifies that health-related quality-of-life data should be obtained from patients using the EQ‑5D questionnaire. The committee concluded that it would have welcomed the collection of health-related quality-of-life outcomes in the trial, particularly using EQ‑5D.\n\n## The new evidence does not clarify the uncertainties around long-term benefits of darvadstrocel compared with placebo\n\nIn response to consultation, the company did a literature search to determine long-term relapse rates in patients with Crohn's disease with perianal fistulas (both complex and simple). It identified 6\xa0potentially relevant studies. However, there were some key differences between the ADMIRE‑CD trial and these studies:\n\ndefinition of remission among studies\n\nmaintenance use of biological treatments\n\ntime points for outcome assessments\n\npopulations and countries where the studies were conducted\n\nmethodology of the study (prospective or retrospective).Comparing the Kaplan–Meier curves showed more rapid relapse rates in the ADMIRE‑CD trial than in the other studies, regardless of treatment arm. According to the company, this suggests that the population of the studies reflects a subgroup with a more sustained remission than the population in ADMIRE‑CD. The company considered that the results showed a 'plateau' effect once remission is reached at 2\xa0years and that therefore remission is likely to be maintained in the long term. The committee noted that relapse may be less frequent the longer remission is maintained, but did not consider a 'plateau' effect had been proven. Moreover, there was a high relapse rate during year\xa01 and no reliable trial data for year\xa02 after which a plateau effect was suggested. Therefore, the number of relapses that would have happened before the rate plateaued was unknown. Using the results from 2\xa0of the studies that according to the company best reflected UK clinical practice and were most comparable with ADMIRE‑CD (Bouguen et al. 2013 and Gottens et al. 2017), the company presented scenario analyses. In these analyses, the 4‑weekly constant relapse rate was adjusted (also see section\xa03.19). The ERG explained that as well as the differences listed above, there were differences in types of fistulas (simple or complex) that were included in the studies, and it was unclear what proportion of the different type of fistulas responded to treatment. The ERG considered these differences to be important and did not think that the studies were comparable with the ADMIRE‑CD trial and would be suitable to inform the analyses on long-term extrapolation methods. The committee considered the new evidence from the company and also understood the ERG's concerns. It concluded that the new evidence does not clarify the uncertainties around the long-term benefits of darvadstrocel compared with placebo.\n\nThe company also did a Delphi-panel survey, which sought expert opinion from 20\xa0clinicians across the UK, including gastroenterologists, surgeons and nurses. Experts were asked to give a view on long-term outcomes with darvadstrocel and the natural history of fistulising Crohn's disease. Their initial response noted a higher rate of relapse in the ADMIRE‑CD trial than has previously been reported in the literature. There was a consensus that relapse rates would reduce the longer the remission was maintained, particularly because maintenance TNF‑alpha inhibitor therapy would be continued after a patient had had darvadstrocel. However, it was only possible to get qualitative evidence from the results of the survey and no consensus was reached when the company tried to quantify the results. The responses also indicated differences in the definition of true healing of fistula and remission. The committee found the results from the literature review and the survey informative but concluded that they did not consider it robust evidence that would alter their decision.\n\n# The company's economic model\n\n## The company's model structure is appropriate and suitable for decision making\n\nThe company presented a semi-Markov state transition cohort model, which assumed a single administration of darvadstrocel (the committee noted no evidence had been presented by the company for repeated treatments with darvadstrocel), and a lifetime benefit for patients. It used a 40‑year time horizon and a 4‑week cycle length. The committee agreed with the structure of the model and considered it suitable for decision making.\n\n# Discounting future costs and benefits\n\n## A reference case discount rate of 3.5% should be used for both benefits and costs\n\nThe company deviated from the reference case in its base-case analysis, using a 1.5% discount rate for future benefits and a 3.5% discount rate for costs, because it considered that section\xa06.2.19 of NICE's guide to the methods of technology appraisal applies. This states that in cases when treatment restores people who would otherwise die or have a very severely impaired life to full or near-full health, and when this is sustained over a very long period, a non-reference case discount rate of 1.5% for costs and benefits may be considered. The ERG commented that evidence does not support the suggestion that darvadstrocel restores quality of life to full or near-full health for a prolonged period (at least 30\xa0years, as defined by section\xa06.2.19 of NICE's guide to the methods of technology appraisal). The committee agreed that it has not been shown that darvadstrocel restores a patient's quality of life to full or nearly-full health (partly because it does not treat the underlying condition, Crohn's disease). It also noted the lack of evidence on the long-term benefits of darvadstrocel. Also, the committee noted that NICE's guide to the methods of technology appraisal does not support using different discount rates for costs and benefits. The committee concluded that a reference case discount rate of 3.5% should be used for both costs and benefits in the economic model.\n\n# Time horizon of the model\n\n## Using a 60‑year time horizon in the economic model is in line with the NICE reference case\n\nThe company's model used a 40‑year time horizon. The ERG explained that at 40\xa0years, only 31.7% of patients will have died, so the time horizon might be too short to capture differences in costs and benefits for darvadstrocel compared with standard care. The ERG explored the impact of using a 60‑year time horizon. The committee noted this had a minimal impact on the incremental cost-effectiveness ratio (ICER) and concluded that time horizon was not a driver of cost effectiveness.\n\n## Base-case cost-effectiveness estimates\n\nThe company presented a deterministic base-case cost-effectiveness estimate of £20,591 per quality-adjusted life year (QALY) gained (incremental costs £21,639; incremental QALYs 1.05), using the following assumptions: the reference case discount rate of 3.5% for both costs and QALYs; a 40‑year time horizon; and applying the patient access scheme for the treatment costs of darvadstrocel. The committee noted that the ERG's preferred inputs into the company's base-case analysis produced an ICER of £23,176 (incremental costs £23,978; incremental QALYs 1.01), using the following corrections and assumptions:\n\ncorrecting for programming errors in the model\n\nupdating the model structure with adding the missing transitions of successful defunctioning surgery to unsuccessful defunctioning surgery, successful proctectomy to unsuccessful proctectomy, and unsuccessful proctectomy to successful proctectomy to reflect the evidence from the St\xa0Mark's study\n\nadjusting the probabilities of moving to the proctectomy and defunctioning surgery health states in the model, so that the data matched the evidence from the Mueller et al. and Bell et al. studies\n\namending the long-term remission rates for subsequent therapies in the standard-care group, based on the time-to-event functions of subsequent therapies and the methods used in the darvadstrocel group\n\nusing a 60‑year time horizon.The committee considered the ERG's corrections and assumptions to be appropriate.\n\n# Modelling the long-term benefits of darvadstrocel\n\n## The long-term benefit of darvadstrocel is highly uncertain, and the model is highly sensitive to the choice of parametric curve for long-term extrapolation of relapse rate\n\nTo model the long-term clinical effectiveness of darvadstrocel, the company used a Gompertz curve to extrapolate both time to CPC remission and time to relapse after CPC remission. The ERG explained that the choice of curve is a key driver of the model and that the cost-effectiveness results are very sensitive to the extrapolation method used, particularly the time to relapse. The ERG presented a scenario analysis, similar to that presented by the company, but including the ERG's preferred base-case assumptions and using the second-best options according to the Akaike Information Criterion and Bayesian Information Criterion statistics, which were the generalised gamma curve for extrapolating time to CPC remission, and the log-normal curve for time to relapse following CPC remission. This results in a substantially higher ICER (£143,131 per QALY gained) compared with the company's base case (see section\xa03.15). The committee discussed the clinical plausibility of the different curves with the clinical experts, particularly the choice of curve for time to relapse after CPC remission. The clinical experts explained that without more evidence on the natural history of the disease, it is difficult to predict the relapse rate after the time horizon of the trial. However, the experts highlighted that if the fistula is healed and remission is maintained until 2\xa0years, and there is no underlying risk for future recurrence, recurrence rates are likely to be very low after this time (around 10\xa0to\xa020%), but it is not eliminated. They also explained that relapse tends to happen soon after treatment, rather than later. The committee noted that it had no reliable figures for the number of patients in remission at 2\xa0years from the ADMIRE‑CD trial. The company stated that its model assumes 40% of people remain relapse free, with a low ongoing risk of relapse, after remission has been maintained with darvadstrocel for 2\xa0years. The committee concluded that the risk of relapse over time (hence the method of extrapolation from the trial to the long term) is a key driver of the model. It was unable to select the most appropriate method for modelling the long-term effectiveness of darvadstrocel. The committee expressed concern that no reliable data on the number of people in remission at 2\xa0years is available, and that the choice of curves has a large effect on the ICER (with a difference of more than £100,000 per QALY gained between the best and second-best fitting curves). It concluded that only better data on long-term outcomes from the ongoing trial, or more robust information on the natural history of the disease, would make it possible to decide which is the most plausible ICER.\n\n## The new scenarios were not based on robust evidence and the committee did not consider these any more plausible than the original assumptions\n\nIn response to consultation, the company also presented the results of scenario analyses, where it altered the rate of 4‑weekly constant relapse rate that was applied from 2\xa0years onwards in the model. In scenario\xa01, it assumed that 16.92% of people who had not relapsed at 2\xa0years would relapse at 5\xa0years. The corresponding rate at 10\xa0years was 39.01%. This resulted in an ICER of £36,235 per QALY gained. In scenario\xa02, it assumed that 24.02% of people who had not relapsed at 2\xa0years would relapse at 10\xa0years, and the corresponding rate at 5\xa0years was 9.72%. This resulted in an ICER of £28,370 per QALY gained. The committee also noted the ERG's alternative cost-effectiveness results using their base-case assumptions, which resulted in £40,900 for scenario\xa01 and £31,925 for scenario\xa02. The committee considered the scenario analyses results by the company and the ERG, but did not consider that they were based on more robust evidence or more plausible assumptions than the original base-case cost-effectiveness results.\n\n## There is limited evidence available on health-related quality of life for Crohn's disease with complex perianal fistula\n\nADMIRE‑CD did not include a direct health-related quality-of-life measurement, and there are no published utility values for this disease area. To calculate the health-related quality-of-life benefits of darvadstrocel, the company did a vignette study to derive utility values for each health state in the model. The committee noted that this is not in line with the NICE reference case. The ERG's clinical experts considered that the utility value after successful defunctioning (0.567) or proctectomy surgery (0.564) may be underestimated in the company's base case, as well as the utility value for the 'mild chronic symptomatic fistulae' health state (0.578). The ERG explored the impact of using the same utility value (0.865) for remission (for a mild chronic symptomatic fistula and for successful defunctioning and successful proctectomy surgery), to establish the direction and maximum size of any changes in the ICER because of the possible under-prediction of utility in these 3\xa0health states. The resulting ICER was £63,721 per QALY gained. The committee discussed this scenario with the patient and clinical experts at the meeting. They explained that a patient's quality of life after defunctioning surgery is expected to be substantially lower than the quality of life of a patient in remission. At the second meeting and in response to consultation, patient experts also explained the devastating symptoms of Crohn's disease with perianal fistulas, especially if they have severe symptoms. They explained that having mild symptoms, even if the fistula is not completely healed, is a relief and allows them to maintain a relatively normal life. But this is conditional on the seton being placed carefully and not causing pain, and that they do not experience major adverse events from the underlying medical treatments. The committee considered that the utilities in some heath states might be too low, and that correctly derived utility values for these 3\xa0health states could result in higher ICERs. However, it concluded that the ERG's suggested scenario is extreme and not plausible, but found that it was informative because it showed the impact that the utility values had on the cost-effectiveness results.\n\n# Most plausible cost-effectiveness estimate\n\n## The most plausible cost-effectiveness estimate is uncertain, and darvadstrocel is unlikely to be a cost-effective use of NHS resources\n\nThe key factors affecting the ICER are the parametric curve chosen for extrapolating the time to CPC remission and particularly time to relapse after CPC remission. To a smaller extent, the utility values for a mild chronic symptomatic fistula and for successful defunctioning and successful proctectomy surgery also affect the ICER. Using a generalised gamma curve to extrapolate time to CPC remission, and log-normal curve to extrapolate time to CPC relapse, resulted in an ICER of £143,131 per QALY gained. The committee noted that this ICER is considerably higher than the company's base case and, given the reasonable fit of the curves, it could be correct. The very large difference in the ICERs, depending on the curves chosen, emphasises how sensitive the cost-effectiveness estimate is to the duration of remission. The lack of long-term evidence from the trial and limited evidence on the natural history of the disease, particularly on long-term relapse rates after successful treatment, make it very difficult to decide the most plausible estimate of cost effectiveness. Therefore the committee was unable to conclude on the most plausible cost-effectiveness estimate.\n\n# Other factors\n\nIn response to consultation, a patient group stated that some equality issues needed to be considered by the committee in terms of leaving patients with no option but to have defunctioning surgery or a proctectomy. It was noted that having pelvic surgery may be an issue for people who have not completed their family and whose fertility may be affected, and that the condition and potentially having defunctioning surgery or a proctectomy may raise particular issues for certain religious groups. The committee acknowledged that having Crohn's disease presents certain difficulties for some groups. But because of the lack of clear evidence on long-term clinical effectiveness of darvadstrocel, the committee considered that not recommending darvadstrocel does not exclude or impact differently on any populations. It also discussed that it is not proven by the clinical evidence that subsequent surgery will be avoided in any of the patient groups as an outcome of treatment with darvadstrocel. Therefore the committee concluded that this did not represent an equalities issue and that there was no need to alter its recommendations.\n\nThe company stated that darvadstrocel is innovative and the first licensed allogenic stem-cell treatment in the UK for this disease. The clinical experts explained that this is the first targeted treatment option for complex perianal fistulas in Crohn's disease, and that it represents a step‑change in the management of the disease. The committee considered these factors to be important and concluded that darvadstrocel is potentially innovative in the short term, but its long-term benefit is uncertain.\n\n# Conclusion\n\nThe committee understood the huge disease burden that patients experience and how severely impaired quality of life is for patients with this condition. Data on clinical effectiveness of darvadstrocel show only modest benefit over and above placebo, and data are only available for up to 1\xa0year, so the duration of this benefit is also uncertain. The committee concluded that the clinical benefit to patients in the NHS is not known. The cost-effectiveness estimates are therefore highly uncertain. This reflects the uncertainty about how long treatment benefit will last and the most appropriate extrapolation method for time to CPC remission and particularly time to relapse after CPC remission. Taking all the uncertainties into account, the committee concluded that darvadstrocel was not a clinically or cost-effective use of NHS resources and could not be recommended for routine commissioning.", 'Recommendations for research': "The results of ADMIRE‑CD showed that most patients tend to relapse within the first year after achieving remission and healing of the fistula in both arms of the trial. Unfortunately, there are limited data between year\xa01 and year\xa02 for data on relapse, and no data on relapse are available for year\xa02 and beyond. The committee considered that the outcomes of the ADMIRE‑CD and the ongoing ADMIRE‑CD\xa0II trial did not capture fully the relapsing-remitting nature of Crohn's disease with perianal fistulas. The new evidence submitted after consultation did not clarify the uncertainties around the long-term benefits of darvadstrocel compared with placebo either, because the results from the literature were very different from the results of ADMIRE‑CD.\n\nFurther research is recommended to resolve the uncertainties about the long-term clinical effectiveness of darvadstrocel compared with standard care. In particular, estimates of long-term remission rates (minimum of 2\xa0years' follow‑up) in Crohn's disease with perianal fistulas are needed.\n\nThe health-related quality-of-life evidence of patients with perianal fistulas is also lacking, therefore further research is recommended. Any research should measure the effect of treatment using preference-based measures (such as use of the EQ‑5D questionnaire)."}
|
https://www.nice.org.uk/guidance/ta556
|
Evidence-based recommendations on darvadstrocel (Alofisel) for previously treated complex perianal fistulas in adults with non-active or mildly active luminal Crohn’s disease.
|
09f1117afef7d3c07dbd23e1d6c3579640ff3834
|
nice
|
Regorafenib for previously treated advanced hepatocellular carcinoma
|
Regorafenib for previously treated advanced hepatocellular carcinoma
Evidence-based recommendations on regorafenib (Stivarga) for treating advanced hepatocellular carcinoma in adults who have had sorafenib.
# Recommendations
Regorafenib is recommended as an option for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib, only if:
they have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and
the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with regorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Advanced unresectable hepatocellular carcinoma is mostly treated with sorafenib in the NHS. For people who cannot tolerate sorafenib, or whose disease progresses on sorafenib, the only current option is best supportive care. Regorafenib is a possible treatment option after sorafenib instead of best supportive care.
Clinical trial evidence comes from people who have advanced hepatocellular carcinoma that has been treated with sorafenib, and who have an ECOG performance status of 0 or 1 and Child–Pugh grade A liver impairment. This shows that people having regorafenib live longer than people having best supportive care. However, the trial does not include people who cannot tolerate sorafenib, or who have more severe liver disease or a poorer performance status. So it can't be assumed that these people would get the same benefits from regorafenib as the people in the trial.
Regorafenib meets NICE's criteria to be considered a life-extending treatment at the end of life. The most plausible cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore it is recommended for people with hepatocellular carcinoma who have had sorafenib, and have an ECOG performance status of 0 or 1 and Child–Pugh grade A liver impairment.# Information about regorafenib
# Marketing authorisation indication
Regorafenib (Stivarga, Bayer) is indicated as 'monotherapy for the treatment of adult patients with hepatocellular carcinoma who have been previously treated with sorafenib'.
# Dosage in the marketing authorisation
160 mg (4×40 mg tablets) orally once daily for 3 weeks followed by 1 week off therapy. A 4‑week period is considered a treatment cycle.
# Price
The list price per treatment cycle for 160 mg of regorafenib is £3,744.00 (excluding VAT; British national formulary online ). The company has a commercial arrangement. This makes regorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Unmet need
## People with advanced hepatocellular carcinoma would welcome a new treatment option
Advanced unresectable hepatocellular carcinoma is often diagnosed late in life and has a poor survival prognosis. It is a debilitating condition with many distressing symptoms. The clinical and patient experts noted that people with advanced unresectable hepatocellular carcinoma have limited treatment options and will have been through many unsuccessful treatments in a long treatment pathway. They noted that improving quality of life and even small extensions to length of life are of considerable importance to this patient group. The committee agreed that people with advanced unresectable hepatocellular carcinoma who have already had sorafenib have an unmet clinical need, and would welcome other treatment options.
# Treatment pathway
## Regorafenib is a potential option for advanced unresectable hepatocellular carcinoma after sorafenib
If surgical or locoregional treatments fail or are unsuitable, systemic therapy with sorafenib is the most often used treatment option for people with hepatocellular carcinoma. NICE's technology appraisal guidance on sorafenib recommends it as an option for treating advanced hepatocellular carcinoma only for people with Child–Pugh grade A liver impairment. During the appraisal of sorafenib, the committee noted that current clinical experience suggests that people need both adequate liver function and performance status to have sorafenib in clinical practice in England, and concluded that treatment should be restricted to people with Child–Pugh grade A liver function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The clinical expert explained that best supportive care or clinical trials are the only options for people whose disease progresses despite taking sorafenib, or who cannot tolerate it. There are no second-line therapies available and a palliative care approach is taken for these patients. The committee noted that regorafenib offered a potential second-line treatment option for people who cannot tolerate, or whose disease progresses on, sorafenib.
# Clinical evidence
## Regorafenib is more clinically effective than best supportive care in the clinical trial population
The company's clinical evidence came from 1 trial. RESORCE (n=573) was an international, phase III, multicentre, randomised, double-blind, placebo-controlled trial comparing regorafenib (plus best supportive care) with placebo (plus best supportive care). The trial included people whose disease had progressed on sorafenib, who had either 160 mg regorafenib orally once daily for weeks 1 to 3 of each 4‑week treatment cycle, or best supportive care. Up to 2 regorafenib dose reductions because of toxicity were allowed (from 160 mg to 120 mg to 80 mg). The primary outcome was overall survival, with secondary outcomes including progression-free survival. The committee noted that the results showed a small and statistically significant median overall survival gain of 2.8 months for regorafenib (10.6 months; 95% confidence interval 9.1 to 12.1) compared with best supportive care (7.8 months; 95% CI 6.3 to 8.8). The committee noted that the hazard ratio for overall survival for regorafenib compared with best supportive care was 0.63 (95% CI 0.50 to 0.79) and that regorafenib offered an important survival benefit for people with advanced hepatocellular carcinoma. Median progression-free survival was statistically significantly better for regorafenib (3.1 months, 95% CI 2.8 to 4.2) than for best supportive care (1.5 months, 95% CI 1.4 to 1.6). The committee noted that the hazard ratio for progression-free survival for regorafenib compared with best supportive care was 0.46 (95% CI 0.37 to 0.56), which represented a clinically relevant reduced risk of progression for the regorafenib group. It also heard that quality-of-life scores were generally similar across treatment arms with different measures, including EQ‑5D. Scores were slightly worse for regorafenib than for best supportive care but these differences did not pass the 'minimally important difference' threshold established in the literature. The committee noted that there were 5 clinical trial centres in the UK, with 20 patients randomised to treatment in 4 of the centres. The ERG noted that RESORCE was a high-quality randomised controlled trial, with a low risk of selection, performance, attrition and reporting bias. Therefore, the committee concluded that regorafenib offered an important gain in progression-free and overall survival compared with best supportive care.
## The benefits of regorafenib cannot be generalised outside the trial population
RESORCE included people with advanced unresectable hepatocellular carcinoma who:
previously tolerated treatment with sorafenib
mostly had Child–Pugh grade A liver impairment
had an ECOG performance status of either 0 or 1.The committee noted that regorafenib's marketing authorisation is broader than the trial population, because the trial did not include people who:
had Child–Pugh grade B liver impairment
had an ECOG performance status of 2 or more
could not tolerate sorafenib.In RESORCE, tolerating sorafenib was defined as having had at least 400 mg a day for 20 days or more, in the 28 days before stopping treatment with sorafenib. The clinical expert noted that RESORCE included a highly selected population who could tolerate sorafenib well. They also highlighted that post-trial studies investigating survival outcomes for sorafenib, which included patients outside of the strict trial criteria, showed lower survival than predicted in the main sorafenib trial. The clinical expert stated that the toxicity and efficacy of regorafenib in people who could not tolerate sorafenib, with Child–Pugh grade B liver impairment and with an ECOG performance status of 2 or more, was unknown. The committee therefore concluded that benefits could not be extrapolated outside the trial population because of the uncertainty in survival benefit for people excluded from RESORCE but covered by the marketing authorisation for regorafenib.
## An audit of sorafenib use shows differences between the RESORCE trial population and the population in clinical practice in England
A 2017 audit of sorafenib use in the UK by King et al. found that sorafenib is used in patients who have an ECOG performance status of 2 or more and Child–Pugh grade B liver impairment (21 and 16% of the audit population respectively). The committee noted that sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child–Pugh grade A liver impairment, but that people progressing on sorafenib are likely to have further deterioration in liver impairment (Child–Pugh status) and ECOG performance status. The clinical expert explained that because sorafenib and regorafenib are both tyrosine kinase inhibitors with similar mechanisms of action, people who cannot tolerate sorafenib may also be unable to tolerate regorafenib (although there are no data to support this). Therefore, an estimated 30 to 50% of the population whose disease progressed on sorafenib would be eligible for regorafenib. The committee also noted that all patients had a treatment-related adverse event, and that quality of life was only maintained rather than improved with regorafenib treatment. The committee acknowledged comments received during consultation that use of regorafenib should be restricted based on the eligibility criteria in the RESORCE trial. It concluded that given the lack of evidence in people with an ECOG performance status of 2 or more, or with Child–Pugh B liver impairment or who cannot tolerate sorafenib, there was considerable uncertainty in the efficacy of regorafenib in populations not included in RESORCE but covered by its marketing authorisation.
# The company's economic model
## The model structure is appropriate for decision making
The company used a partitioned survival model with 3 health states (progression free, progressed disease and death). The committee noted the uncertainty in the model about people covered by the marketing authorisation for regorafenib who were excluded from RESORCE. The committee understood that all efficacy and clinical parameters in the model were derived using patient-level data from RESORCE. The committee noted that data for progression-free survival from RESORCE represented a full pattern of progression, so no extrapolation was needed and the progression-free survival curve was taken directly from the observed trial's Kaplan–Meier data. The committee accepted that standard parametric curve fitting was done using patient-level data from RESORCE for overall survival.
# Overall survival extrapolation in the economic model
## The Weibull distribution is preferred but is associated with uncertainty
In the company's original base case, a dependent log-normal curve was used to model overall survival. The ERG disagreed with this choice of curve and the fitting of dependent models because the log-normal function is an accelerated failure time model. The ERG also considered the choice of the log-normal curve to be inappropriate, based on its clinical expert's advice that the model-predicted sustained difference in overall survival between the regorafenib and best supportive care curves beyond 35 cycles was unrealistic in a population with progressed hepatocellular carcinoma. At the appraisal committee meeting, the clinical expert explained that the 5‑year survival suggested by the log-normal curve was implausible because the modelled population was elderly, with advanced disease refractory to most previous treatments. NICE's reference case places most significance on clinical plausibility and so the ERG preferred the Weibull curve based on clinical opinion and goodness-of-fit to observed data. The Cancer Drugs Fund clinical lead highlighted a recent study reporting mature follow‑up data for people having sorafenib (plus other treatments) in specialist centres. This showed relatively high 5‑year survival rates of 5 to 8%, suggesting that some people may have indolent disease. The committee noted that this study included people having sorafenib and that the population having regorafenib are likely to have lower 5‑year survival rates because they are further along the treatment pathway. The committee concluded that the company's preferred dependent log-normal curves were technically incorrect and overly optimistic. It preferred the use of independent Weibull curves, but recognised that these were associated with uncertainty.
## The Weibull distribution is the most appropriate for extrapolating overall survival
The committee considered that the Weibull distribution remained the most appropriate choice for extrapolating overall survival because no new evidence was provided during consultation. However, in its updated analyses, the company extrapolated overall survival with independently fitted Gompertz and exponential distributions, as well as the Weibull distribution. The company noted that the ERG's clinical expert also considered the Gompertz and exponential extrapolations to be clinically plausible, so it provided cost-effectiveness results for these 3 distributions individually combined with its updated assumptions. The ERG explained that its preference for the Weibull distribution was not based only on clinical opinion of its plausibility, but also on goodness-of-fit to the observed data and the empirical hazards. The committee noted that based on the empirical hazards (particularly in the best supportive care arm), an exponential curve was not appropriate and that the Akaike information criterion/Bayesian information criterion for Weibull fitted better than Gompertz by more than 5 points. The committee noted that no further information was provided by the company to support the use of an exponential or Gompertz curve. The committee reiterated that the Weibull was the most appropriate distribution for extrapolating overall survival, in preference to the Gompertz and exponential curves.
# Time-to-treatment discontinuation in the economic model
## Treatment discontinuation in RESORCE may not represent NHS clinical practice
The committee noted that the number of people continuing treatment with regorafenib despite disease progression was high in RESORCE and that time-to-treatment discontinuation did not equate to time to progression. The clinical expert explained that this did not represent clinical practice in England because 80% of patients would stop treatment on progression. They highlighted that the number of people continuing treatment despite disease progression and the efficacy of treatment in these patients was uncertain. The committee concluded that the rate of treatment discontinuation in RESORCE was unlikely to represent NHS clinical practice.
## Including the survival benefits but excluding the costs of post-progression treatment is not appropriate
The company agreed that most people would stop treatment if their disease progressed, and accepted that people would have less treatment in practice than in RESORCE. The company did a new survey, which investigated post-progression treatment, and found that 8 of the 9 respondents would stop treatment at progression. In response to consultation, the company presented a scenario whereby an area under the log-logistic, time-to-treatment discontinuation curve was applied. This was adjusted for 80% of patients stopping treatment at or before progression and 20% having treatment post-progression. This resulted in people having an average of approximately 1 cycle of post-progression treatment. The ERG explained that although current practice in England may differ from that in RESORCE, the survival estimates observed in RESORCE may have been influenced by the post-progression treatment. Therefore it was inappropriate to include health benefits associated with post-progression treatment, but to exclude a proportion of the costs associated with generating those health gains. The committee concluded that adjusting for cost alone for 20% of people having treatment post-progression was not appropriate.
# Costs in the economic model
## Assuming additional days of drug wastage to model drug cost is arbitrary and associated with uncertainty
The company's original base case included cost savings from dose reductions and treatment interruptions for regorafenib. The ERG's clinical advisers noted that NHS prescribing practices do not account for reduced frequency of individual prescriptions for patients with leftover tablets. Cost reductions included in the company's model would therefore probably not be fully realised in clinical practice. The clinical expert explained that despite efficiency measures in the NHS, it would be reasonable to assume some drug wastage in clinical practice even if the patient's dose were reduced. This was also supported by the Cancer Drugs Fund clinical lead who stated that people are normally given a month's supply of a drug, and any leftover tablets cannot be used for other patients. Therefore, a month's supply should be modelled to take wastage into account. The company provided evidence from pharmacists from 2 of the largest tertiary centres in the UK supporting pack splitting to minimise wastage of sorafenib and other oral tyrosine kinase inhibitors. Healthcare at Home, which distributes sorafenib in England, also provided a supportive statement after consultation. The committee acknowledged that although wastage could be minimised, the pharmacists' evidence provided by the company suggested that it could not be eliminated entirely. In response to consultation, the company presented a scenario whereby costs for the actual treatment taken (as average doses in RESORCE) were modelled but with an assumption that every patient wastes additional days of medicine at the maximum daily dose over the course of their treatment. This wastage was applied as a one‑off cost to every patient and reflected an assumption in between the original company base case and committee-preferred analysis. The committee considered the assumption of drug wastage to be arbitrary and therefore associated with significant uncertainty. The ERG did 2 exploratory analyses: a pessimistic scenario in which drug costs were assumed to be 160 mg per day (full pack dose), and an optimistic scenario in which drug costs were assumed to be 160 mg multiplied by relative dose intensity to account for this uncertainty (see section 3.15). The ERG also highlighted 2 further concerns with the company's modelling of drug costs. It noted that the projected log-logistic, time-to-treatment discontinuation curve and the Weibull overall survival curves crossed at around 4 years. This is not logical because it indicates that patients are still incurring drug costs after they have died. In addition, the modelled relative dose intensity followed an unusual pattern for which no rationale was provided. The committee concluded that the company's approach to modelling drug wastage was associated with uncertainty.
## Pooling estimates from the 2007 and 2015 surveys is appropriate for health state resource use costs
In its original base case, the company used clinician surveys to estimate resource use associated with sorafenib and best supportive care. It assumed that the sorafenib results would also apply to regorafenib. The committee noted that the company used a survey from 2015 with 3 clinical experts to inform resource use in its original base case. The ERG highlighted that the company did not reference an earlier survey done in 2007 using 4 UK clinicians. The company reiterated its preference for the 2015 survey because estimates from 2007 preceded the availability of sorafenib and were not based on clinical experience. The committee considered that the new survey might have produced better estimates for the sorafenib arm because it would take into account experience with sorafenib. But it noted that estimates for the best supportive care arm from the original survey should be equally valid when compared with those of the new survey. The committee was not convinced of the robustness of the surveys and noted the small number of clinicians involved and the variability in the clinicians' responses. Without any better quality data, the committee concluded that it would be more appropriate to pool estimates from the 2007 and 2015 surveys for health state resource use costs.
## The hospital admission rate derived from the new survey is appropriate
In response to consultation, the company provided results from a new survey designed to better understand the rate of hospitalisations in the NHS, and to address the ERG's concerns with how questions in the original surveys may have been interpreted. The results supported the statement from the clinical expert in the appraisal consultation document that few people are admitted to hospital. These results related to hospitalisations were then incorporated in the company's updated model. The ERG noted that in the new survey, resources associated with patients who have post-progression treatment with regorafenib are unlikely to be generalisable to those associated with people who stop regorafenib after progression. Nevertheless, the committee concluded that the hospital admission rates derived from the new survey were the best available data to be used in its decision making.
# Utility values in the economic model
## Utility values derived from RESORCE using EQ‑5D data are too high for a population with progressed disease
The Cancer Drugs Fund clinical lead noted that the utility values appear high for a population of patients who enter the model after progressing on sorafenib even if the patients have an ECOG performance status of 0 or 1 at entry. The clinical expert said that most patients tend to have side effects from treatment that have a serious impact on their quality of life, which did not appear to be reflected in the utility values. There were concerns about the face validity of the utility values collected in RESORCE using EQ‑5D data because the utility decrement for progression (–0.048) appeared low for an advanced hepatocellular population with progressed disease. The company obtained EQ‑5D data directly from the trial as recommended in NICE's methods guide. However, the ERG explained that the EQ‑5D questionnaire was completed on the first day of each treatment cycle, when a patient had not had treatment for a week. So any adverse effects of regorafenib treatment may not have been fully captured. The committee noted that reducing the health state utility values would increase the incremental cost-effectiveness ratio (ICER), although an exact figure was not provided. The committee concluded that the high utility values used in the model did not seem clinically plausible despite EQ‑5D data from the trial being used. This was likely to have resulted in an underestimate of the ICER.
# Cost-effectiveness results
## The most plausible ICER is below £50,000 per QALY gained
After consultation, the company submitted a further model using the committee's preferred assumptions, specifically:
extrapolating overall survival using a Weibull distribution (see section 3.7)
pooling resource use estimates from the 2015 and 2007 surveys (see section 3.12) and
fully extrapolating time-to-treatment discontinuation (see section 3.9).The company also:
used a revised rate of hospitalisations based on the new survey (see section 3.13)
assumed that 80% of people stop treatment at or before progression, with only 20% having treatment post-progression (see section 3.9) and
included a confidential commercial arrangement.The ERG did 4 exploratory analyses that investigated the effect of individual assumptions on the ICER for regorafenib compared with best supportive care. All 4 analyses extrapolated overall survival using a Weibull distribution and corrected errors in the company model (specifically when additional progression-free survival data points had erroneously been excluded from calculations, and when emergency department visits accrued no cost):
Analysis 1: using costs of full pack (160 mg) dosing.
Analysis 2: analysis 1, using costs based on patients having the mean dose in RESORCE instead of full pack dosing.
Analysis 3: analysis 2, plus incorporating a logical consistency constraint to account for the projected log-logistic, time-to-treatment discontinuation curve and the Weibull overall survival curve crossing at around 4 years.
Analysis 4: analysis 3, plus using last observation carried forward relative dose intensity extrapolation instead of modelling relative dose intensity for regorafenib as in the company's model.The committee noted that the ERG's most optimistic (analysis 4) and pessimistic (analysis 1) scenarios (in terms of drug wastage), using the committee-preferred Weibull distribution, and with the commercial arrangement, produced ICERs for regorafenib compared with best supportive care of £44,296 and £51,868 per quality-adjusted life year (QALY) gained respectively. The committee agreed that analysis 1 was unlikely to reflect clinical practice, because the dose reductions in the trial were planned, so it was more likely that wastage would be minimised in clinical practice. It agreed that the most plausible ICER would be between the 2 figures and likely closer to £44,296 than to £51,868 per QALY gained. The committee concluded that the most plausible ICER, incorporating the confidential commercial arrangement for regorafenib compared with best supportive care, was below £50,000 per QALY gained.
# End of life
## Regorafenib for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib meets both NICE's end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee discussed whether life expectancy without regorafenib would be less than 24 months. It noted that median overall survival was 7.8 months for best supportive care in RESORCE and that the mean modelled overall survival from the company model was 10.8 months. The ERG explained that any changes relating to parametric overall survival functions would not change the conclusions for this end‑of‑life criterion. The committee concluded that the short life expectancy criterion was met. The committee discussed whether a survival benefit of over 3 months could be expected for regorafenib compared with best supportive care. It noted that the median survival in the regorafenib arm of RESORCE was extended by 2.8 months. It also recalled that the average number of months of life gained with regorafenib, as estimated by the company's economic model, was 6.24 months compared with best supportive care. On balance, the committee agreed that it was reasonable to assume that the survival benefit of regorafenib is likely to exceed 3 months and concluded that the extension-to-life criterion was met.
# Innovation
## There is no evidence of additional benefits of regorafenib
The patient and clinical experts explained that there was a significant unmet need for people with advanced unresectable hepatocellular carcinoma because of the limited treatment options available to them. The committee noted that best supportive care was currently the only treatment option available for people whose disease progresses with sorafenib, or who cannot tolerate it, and that regorafenib offered a valuable second-line treatment option. It concluded that regorafenib would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# Conclusion
## Regorafenib is recommended for routine NHS use
The committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICER was within the range that NICE normally considers an acceptable use of NHS resources for a life-extending treatment at the end of life. It therefore recommended regorafenib for use in the NHS, for the population in RESORCE. That is, for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib, only if they have Child–Pugh grade A liver impairment and an ECOG performances status of 0 or 1 (see section 3.4).
|
{'Recommendations': "Regorafenib is recommended as an option for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib, only if:\n\n\n\nthey have Child–Pugh grade\xa0A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01 and\n\n\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with regorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nAdvanced unresectable hepatocellular carcinoma is mostly treated with sorafenib in the NHS. For people who cannot tolerate sorafenib, or whose disease progresses on sorafenib, the only current option is best supportive care. Regorafenib is a possible treatment option after sorafenib instead of best supportive care.\n\nClinical trial evidence comes from people who have advanced hepatocellular carcinoma that has been treated with sorafenib, and who have an ECOG performance status of 0\xa0or\xa01 and Child–Pugh grade\xa0A liver impairment. This shows that people having regorafenib live longer than people having best supportive care. However, the trial does not include people who cannot tolerate sorafenib, or who have more severe liver disease or a poorer performance status. So it can't be assumed that these people would get the same benefits from regorafenib as the people in the trial.\n\nRegorafenib meets NICE's criteria to be considered a life-extending treatment at the end of life. The most plausible cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore it is recommended for people with hepatocellular carcinoma who have had sorafenib, and have an ECOG performance status of 0\xa0or\xa01 and Child–Pugh grade\xa0A liver impairment.", 'Information about regorafenib': "# Marketing authorisation indication\n\nRegorafenib (Stivarga, Bayer) is indicated as 'monotherapy for the treatment of adult patients with hepatocellular carcinoma who have been previously treated with sorafenib'.\n\n# Dosage in the marketing authorisation\n\n160\xa0mg (4×40\xa0mg tablets) orally once daily for 3\xa0weeks followed by 1\xa0week off therapy. A 4‑week period is considered a treatment cycle.\n\n# Price\n\nThe list price per treatment cycle for 160\xa0mg of regorafenib is £3,744.00 (excluding VAT; British national formulary online [accessed October\xa02018]). The company has a commercial arrangement. This makes regorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Unmet need\n\n## People with advanced hepatocellular carcinoma would welcome a new treatment option\n\nAdvanced unresectable hepatocellular carcinoma is often diagnosed late in life and has a poor survival prognosis. It is a debilitating condition with many distressing symptoms. The clinical and patient experts noted that people with advanced unresectable hepatocellular carcinoma have limited treatment options and will have been through many unsuccessful treatments in a long treatment pathway. They noted that improving quality of life and even small extensions to length of life are of considerable importance to this patient group. The committee agreed that people with advanced unresectable hepatocellular carcinoma who have already had sorafenib have an unmet clinical need, and would welcome other treatment options.\n\n# Treatment pathway\n\n## Regorafenib is a potential option for advanced unresectable hepatocellular carcinoma after sorafenib\n\nIf surgical or locoregional treatments fail or are unsuitable, systemic therapy with sorafenib is the most often used treatment option for people with hepatocellular carcinoma. NICE's technology appraisal guidance on sorafenib recommends it as an option for treating advanced hepatocellular carcinoma only for people with Child–Pugh grade\xa0A liver impairment. During the appraisal of sorafenib, the committee noted that current clinical experience suggests that people need both adequate liver function and performance status to have sorafenib in clinical practice in England, and concluded that treatment should be restricted to people with Child–Pugh grade\xa0A liver function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0to\xa02. The clinical expert explained that best supportive care or clinical trials are the only options for people whose disease progresses despite taking sorafenib, or who cannot tolerate it. There are no second-line therapies available and a palliative care approach is taken for these patients. The committee noted that regorafenib offered a potential second-line treatment option for people who cannot tolerate, or whose disease progresses on, sorafenib.\n\n# Clinical evidence\n\n## Regorafenib is more clinically effective than best supportive care in the clinical trial population\n\nThe company's clinical evidence came from 1\xa0trial. RESORCE (n=573) was an international, phase\xa0III, multicentre, randomised, double-blind, placebo-controlled trial comparing regorafenib (plus best supportive care) with placebo (plus best supportive care). The trial included people whose disease had progressed on sorafenib, who had either 160\xa0mg regorafenib orally once daily for weeks 1\xa0to\xa03 of each 4‑week treatment cycle, or best supportive care. Up to 2\xa0regorafenib dose reductions because of toxicity were allowed (from 160\xa0mg to 120\xa0mg to 80\xa0mg). The primary outcome was overall survival, with secondary outcomes including progression-free survival. The committee noted that the results showed a small and statistically significant median overall survival gain of 2.8\xa0months for regorafenib (10.6\xa0months; 95% confidence interval [CI] 9.1\xa0to\xa012.1) compared with best supportive care (7.8\xa0months; 95%\xa0CI 6.3\xa0to\xa08.8). The committee noted that the hazard ratio for overall survival for regorafenib compared with best supportive care was 0.63 (95%\xa0CI 0.50\xa0to\xa00.79) and that regorafenib offered an important survival benefit for people with advanced hepatocellular carcinoma. Median progression-free survival was statistically significantly better for regorafenib (3.1\xa0months, 95%\xa0CI 2.8\xa0to\xa04.2) than for best supportive care (1.5\xa0months, 95%\xa0CI 1.4\xa0to\xa01.6). The committee noted that the hazard ratio for progression-free survival for regorafenib compared with best supportive care was 0.46 (95%\xa0CI 0.37\xa0to\xa00.56), which represented a clinically relevant reduced risk of progression for the regorafenib group. It also heard that quality-of-life scores were generally similar across treatment arms with different measures, including EQ‑5D. Scores were slightly worse for regorafenib than for best supportive care but these differences did not pass the 'minimally important difference' threshold established in the literature. The committee noted that there were 5\xa0clinical trial centres in the UK, with 20\xa0patients randomised to treatment in 4\xa0of the centres. The ERG noted that RESORCE was a high-quality randomised controlled trial, with a low risk of selection, performance, attrition and reporting bias. Therefore, the committee concluded that regorafenib offered an important gain in progression-free and overall survival compared with best supportive care.\n\n## The benefits of regorafenib cannot be generalised outside the trial population\n\nRESORCE included people with advanced unresectable hepatocellular carcinoma who:\n\n\n\npreviously tolerated treatment with sorafenib\n\nmostly had Child–Pugh grade\xa0A liver impairment\n\n\n\nhad an ECOG performance status of either 0\xa0or\xa01.The committee noted that regorafenib's marketing authorisation is broader than the trial population, because the trial did not include people who:\n\nhad Child–Pugh grade\xa0B liver impairment\n\nhad an ECOG performance status of 2\xa0or more\n\ncould not tolerate sorafenib.In RESORCE, tolerating sorafenib was defined as having had at least 400\xa0mg a day for 20\xa0days or more, in the 28\xa0days before stopping treatment with sorafenib. The clinical expert noted that RESORCE included a highly selected population who could tolerate sorafenib well. They also highlighted that post-trial studies investigating survival outcomes for sorafenib, which included patients outside of the strict trial criteria, showed lower survival than predicted in the main sorafenib trial. The clinical expert stated that the toxicity and efficacy of regorafenib in people who could not tolerate sorafenib, with Child–Pugh grade\xa0B liver impairment and with an ECOG performance status of 2\xa0or more, was unknown. The committee therefore concluded that benefits could not be extrapolated outside the trial population because of the uncertainty in survival benefit for people excluded from RESORCE but covered by the marketing authorisation for regorafenib.\n\n## An audit of sorafenib use shows differences between the RESORCE trial population and the population in clinical practice in England\n\nA 2017 audit of sorafenib use in the UK by King et al. found that sorafenib is used in patients who have an ECOG performance status of 2\xa0or more and Child–Pugh grade\xa0B liver impairment (21 and 16% of the audit population respectively). The committee noted that sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child–Pugh grade\xa0A liver impairment, but that people progressing on sorafenib are likely to have further deterioration in liver impairment (Child–Pugh status) and ECOG performance status. The clinical expert explained that because sorafenib and regorafenib are both tyrosine kinase inhibitors with similar mechanisms of action, people who cannot tolerate sorafenib may also be unable to tolerate regorafenib (although there are no data to support this). Therefore, an estimated 30 to 50% of the population whose disease progressed on sorafenib would be eligible for regorafenib. The committee also noted that all patients had a treatment-related adverse event, and that quality of life was only maintained rather than improved with regorafenib treatment. The committee acknowledged comments received during consultation that use of regorafenib should be restricted based on the eligibility criteria in the RESORCE trial. It concluded that given the lack of evidence in people with an ECOG performance status of 2\xa0or more, or with Child–Pugh\xa0B liver impairment or who cannot tolerate sorafenib, there was considerable uncertainty in the efficacy of regorafenib in populations not included in RESORCE but covered by its marketing authorisation.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company used a partitioned survival model with 3\xa0health states (progression free, progressed disease and death). The committee noted the uncertainty in the model about people covered by the marketing authorisation for regorafenib who were excluded from RESORCE. The committee understood that all efficacy and clinical parameters in the model were derived using patient-level data from RESORCE. The committee noted that data for progression-free survival from RESORCE represented a full pattern of progression, so no extrapolation was needed and the progression-free survival curve was taken directly from the observed trial's Kaplan–Meier data. The committee accepted that standard parametric curve fitting was done using patient-level data from RESORCE for overall survival.\n\n# Overall survival extrapolation in the economic model\n\n## The Weibull distribution is preferred but is associated with uncertainty\n\nIn the company's original base case, a dependent log-normal curve was used to model overall survival. The ERG disagreed with this choice of curve and the fitting of dependent models because the log-normal function is an accelerated failure time model. The ERG also considered the choice of the log-normal curve to be inappropriate, based on its clinical expert's advice that the model-predicted sustained difference in overall survival between the regorafenib and best supportive care curves beyond 35\xa0cycles was unrealistic in a population with progressed hepatocellular carcinoma. At the appraisal committee meeting, the clinical expert explained that the 5‑year survival suggested by the log-normal curve was implausible because the modelled population was elderly, with advanced disease refractory to most previous treatments. NICE's reference case places most significance on clinical plausibility and so the ERG preferred the Weibull curve based on clinical opinion and goodness-of-fit to observed data. The Cancer Drugs Fund clinical lead highlighted a recent study reporting mature follow‑up data for people having sorafenib (plus other treatments) in specialist centres. This showed relatively high 5‑year survival rates of 5 to 8%, suggesting that some people may have indolent disease. The committee noted that this study included people having sorafenib and that the population having regorafenib are likely to have lower 5‑year survival rates because they are further along the treatment pathway. The committee concluded that the company's preferred dependent log-normal curves were technically incorrect and overly optimistic. It preferred the use of independent Weibull curves, but recognised that these were associated with uncertainty.\n\n## The Weibull distribution is the most appropriate for extrapolating overall survival\n\nThe committee considered that the Weibull distribution remained the most appropriate choice for extrapolating overall survival because no new evidence was provided during consultation. However, in its updated analyses, the company extrapolated overall survival with independently fitted Gompertz and exponential distributions, as well as the Weibull distribution. The company noted that the ERG's clinical expert also considered the Gompertz and exponential extrapolations to be clinically plausible, so it provided cost-effectiveness results for these 3\xa0distributions individually combined with its updated assumptions. The ERG explained that its preference for the Weibull distribution was not based only on clinical opinion of its plausibility, but also on goodness-of-fit to the observed data and the empirical hazards. The committee noted that based on the empirical hazards (particularly in the best supportive care arm), an exponential curve was not appropriate and that the Akaike information criterion/Bayesian information criterion for Weibull fitted better than Gompertz by more than 5\xa0points. The committee noted that no further information was provided by the company to support the use of an exponential or Gompertz curve. The committee reiterated that the Weibull was the most appropriate distribution for extrapolating overall survival, in preference to the Gompertz and exponential curves.\n\n# Time-to-treatment discontinuation in the economic model\n\n## Treatment discontinuation in RESORCE may not represent NHS clinical practice\n\nThe committee noted that the number of people continuing treatment with regorafenib despite disease progression was high in RESORCE and that time-to-treatment discontinuation did not equate to time to progression. The clinical expert explained that this did not represent clinical practice in England because 80% of patients would stop treatment on progression. They highlighted that the number of people continuing treatment despite disease progression and the efficacy of treatment in these patients was uncertain. The committee concluded that the rate of treatment discontinuation in RESORCE was unlikely to represent NHS clinical practice.\n\n## Including the survival benefits but excluding the costs of post-progression treatment is not appropriate\n\nThe company agreed that most people would stop treatment if their disease progressed, and accepted that people would have less treatment in practice than in RESORCE. The company did a new survey, which investigated post-progression treatment, and found that 8\xa0of the 9\xa0respondents would stop treatment at progression. In response to consultation, the company presented a scenario whereby an area under the log-logistic, time-to-treatment discontinuation curve was applied. This was adjusted for 80% of patients stopping treatment at or before progression and 20% having treatment post-progression. This resulted in people having an average of approximately 1\xa0cycle of post-progression treatment. The ERG explained that although current practice in England may differ from that in RESORCE, the survival estimates observed in RESORCE may have been influenced by the post-progression treatment. Therefore it was inappropriate to include health benefits associated with post-progression treatment, but to exclude a proportion of the costs associated with generating those health gains. The committee concluded that adjusting for cost alone for 20% of people having treatment post-progression was not appropriate.\n\n# Costs in the economic model\n\n## Assuming additional days of drug wastage to model drug cost is arbitrary and associated with uncertainty\n\nThe company's original base case included cost savings from dose reductions and treatment interruptions for regorafenib. The ERG's clinical advisers noted that NHS prescribing practices do not account for reduced frequency of individual prescriptions for patients with leftover tablets. Cost reductions included in the company's model would therefore probably not be fully realised in clinical practice. The clinical expert explained that despite efficiency measures in the NHS, it would be reasonable to assume some drug wastage in clinical practice even if the patient's dose were reduced. This was also supported by the Cancer Drugs Fund clinical lead who stated that people are normally given a month's supply of a drug, and any leftover tablets cannot be used for other patients. Therefore, a month's supply should be modelled to take wastage into account. The company provided evidence from pharmacists from 2\xa0of the largest tertiary centres in the UK supporting pack splitting to minimise wastage of sorafenib and other oral tyrosine kinase inhibitors. Healthcare at Home, which distributes sorafenib in England, also provided a supportive statement after consultation. The committee acknowledged that although wastage could be minimised, the pharmacists' evidence provided by the company suggested that it could not be eliminated entirely. In response to consultation, the company presented a scenario whereby costs for the actual treatment taken (as average doses in RESORCE) were modelled but with an assumption that every patient wastes additional days of medicine at the maximum daily dose over the course of their treatment. This wastage was applied as a one‑off cost to every patient and reflected an assumption in between the original company base case and committee-preferred analysis. The committee considered the assumption of drug wastage to be arbitrary and therefore associated with significant uncertainty. The ERG did 2\xa0exploratory analyses: a pessimistic scenario in which drug costs were assumed to be 160\xa0mg per day (full pack dose), and an optimistic scenario in which drug costs were assumed to be 160\xa0mg multiplied by relative dose intensity to account for this uncertainty (see section\xa03.15). The ERG also highlighted 2\xa0further concerns with the company's modelling of drug costs. It noted that the projected log-logistic, time-to-treatment discontinuation curve and the Weibull overall survival curves crossed at around 4\xa0years. This is not logical because it indicates that patients are still incurring drug costs after they have died. In addition, the modelled relative dose intensity followed an unusual pattern for which no rationale was provided. The committee concluded that the company's approach to modelling drug wastage was associated with uncertainty.\n\n## Pooling estimates from the 2007 and 2015 surveys is appropriate for health state resource use costs\n\nIn its original base case, the company used clinician surveys to estimate resource use associated with sorafenib and best supportive care. It assumed that the sorafenib results would also apply to regorafenib. The committee noted that the company used a survey from 2015 with 3\xa0clinical experts to inform resource use in its original base case. The ERG highlighted that the company did not reference an earlier survey done in 2007 using 4\xa0UK clinicians. The company reiterated its preference for the 2015 survey because estimates from 2007 preceded the availability of sorafenib and were not based on clinical experience. The committee considered that the new survey might have produced better estimates for the sorafenib arm because it would take into account experience with sorafenib. But it noted that estimates for the best supportive care arm from the original survey should be equally valid when compared with those of the new survey. The committee was not convinced of the robustness of the surveys and noted the small number of clinicians involved and the variability in the clinicians' responses. Without any better quality data, the committee concluded that it would be more appropriate to pool estimates from the 2007 and 2015 surveys for health state resource use costs.\n\n## The hospital admission rate derived from the new survey is appropriate\n\nIn response to consultation, the company provided results from a new survey designed to better understand the rate of hospitalisations in the NHS, and to address the ERG's concerns with how questions in the original surveys may have been interpreted. The results supported the statement from the clinical expert in the appraisal consultation document that few people are admitted to hospital. These results related to hospitalisations were then incorporated in the company's updated model. The ERG noted that in the new survey, resources associated with patients who have post-progression treatment with regorafenib are unlikely to be generalisable to those associated with people who stop regorafenib after progression. Nevertheless, the committee concluded that the hospital admission rates derived from the new survey were the best available data to be used in its decision making.\n\n# Utility values in the economic model\n\n## Utility values derived from RESORCE using EQ‑5D data are too high for a population with progressed disease\n\nThe Cancer Drugs Fund clinical lead noted that the utility values appear high for a population of patients who enter the model after progressing on sorafenib even if the patients have an ECOG performance status of 0\xa0or\xa01 at entry. The clinical expert said that most patients tend to have side effects from treatment that have a serious impact on their quality of life, which did not appear to be reflected in the utility values. There were concerns about the face validity of the utility values collected in RESORCE using EQ‑5D data because the utility decrement for progression (–0.048) appeared low for an advanced hepatocellular population with progressed disease. The company obtained EQ‑5D data directly from the trial as recommended in NICE's methods guide. However, the ERG explained that the EQ‑5D questionnaire was completed on the first day of each treatment cycle, when a patient had not had treatment for a week. So any adverse effects of regorafenib treatment may not have been fully captured. The committee noted that reducing the health state utility values would increase the incremental cost-effectiveness ratio (ICER), although an exact figure was not provided. The committee concluded that the high utility values used in the model did not seem clinically plausible despite EQ‑5D data from the trial being used. This was likely to have resulted in an underestimate of the ICER.\n\n# Cost-effectiveness results\n\n## The most plausible ICER is below £50,000 per QALY gained\n\nAfter consultation, the company submitted a further model using the committee's preferred assumptions, specifically:\n\n\n\nextrapolating overall survival using a Weibull distribution (see section\xa03.7)\n\npooling resource use estimates from the 2015 and 2007 surveys (see section\xa03.12) and\n\n\n\nfully extrapolating time-to-treatment discontinuation (see section\xa03.9).The company also:\n\nused a revised rate of hospitalisations based on the new survey (see section\xa03.13)\n\nassumed that 80% of people stop treatment at or before progression, with only 20% having treatment post-progression (see section\xa03.9) and\n\nincluded a confidential commercial arrangement.The ERG did 4\xa0exploratory analyses that investigated the effect of individual assumptions on the ICER for regorafenib compared with best supportive care. All 4\xa0analyses extrapolated overall survival using a Weibull distribution and corrected errors in the company model (specifically when additional progression-free survival data points had erroneously been excluded from calculations, and when emergency department visits accrued no cost):\n\nAnalysis 1: using costs of full pack (160\xa0mg) dosing.\n\nAnalysis 2: analysis 1, using costs based on patients having the mean dose in RESORCE instead of full pack dosing.\n\nAnalysis 3: analysis 2, plus incorporating a logical consistency constraint to account for the projected log-logistic, time-to-treatment discontinuation curve and the Weibull overall survival curve crossing at around 4\xa0years.\n\nAnalysis 4: analysis 3, plus using last observation carried forward relative dose intensity extrapolation instead of modelling relative dose intensity for regorafenib as in the company's model.The committee noted that the ERG's most optimistic (analysis\xa04) and pessimistic (analysis\xa01) scenarios (in terms of drug wastage), using the committee-preferred Weibull distribution, and with the commercial arrangement, produced ICERs for regorafenib compared with best supportive care of £44,296 and £51,868 per quality-adjusted life year (QALY) gained respectively. The committee agreed that analysis\xa01 was unlikely to reflect clinical practice, because the dose reductions in the trial were planned, so it was more likely that wastage would be minimised in clinical practice. It agreed that the most plausible ICER would be between the 2\xa0figures and likely closer to £44,296 than to £51,868 per QALY gained. The committee concluded that the most plausible ICER, incorporating the confidential commercial arrangement for regorafenib compared with best supportive care, was below £50,000 per QALY gained.\n\n# End of life\n\n## Regorafenib for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib meets both NICE's end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee discussed whether life expectancy without regorafenib would be less than 24\xa0months. It noted that median overall survival was 7.8\xa0months for best supportive care in RESORCE and that the mean modelled overall survival from the company model was 10.8\xa0months. The ERG explained that any changes relating to parametric overall survival functions would not change the conclusions for this end‑of‑life criterion. The committee concluded that the short life expectancy criterion was met. The committee discussed whether a survival benefit of over 3\xa0months could be expected for regorafenib compared with best supportive care. It noted that the median survival in the regorafenib arm of RESORCE was extended by 2.8\xa0months. It also recalled that the average number of months of life gained with regorafenib, as estimated by the company's economic model, was 6.24\xa0months compared with best supportive care. On balance, the committee agreed that it was reasonable to assume that the survival benefit of regorafenib is likely to exceed 3\xa0months and concluded that the extension-to-life criterion was met.\n\n# Innovation\n\n## There is no evidence of additional benefits of regorafenib\n\nThe patient and clinical experts explained that there was a significant unmet need for people with advanced unresectable hepatocellular carcinoma because of the limited treatment options available to them. The committee noted that best supportive care was currently the only treatment option available for people whose disease progresses with sorafenib, or who cannot tolerate it, and that regorafenib offered a valuable second-line treatment option. It concluded that regorafenib would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# Conclusion\n\n## Regorafenib is recommended for routine NHS use\n\nThe committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICER was within the range that NICE normally considers an acceptable use of NHS resources for a life-extending treatment at the end of life. It therefore recommended regorafenib for use in the NHS, for the population in RESORCE. That is, for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib, only if they have Child–Pugh grade\xa0A liver impairment and an ECOG performances status of 0\xa0or\xa01 (see section\xa03.4)."}
|
https://www.nice.org.uk/guidance/ta555
|
Evidence-based recommendations on regorafenib (Stivarga) for treating advanced hepatocellular carcinoma in adults who have had sorafenib.
|
847ac502a79a5efc9302d821c25b9272839efcb9
|
nice
|
Renal and ureteric stones: assessment and management
|
Renal and ureteric stones: assessment and management
This guideline covers assessing and managing renal and ureteric stones. It aims to improve the detection, clearance and prevention of stones, so reducing pain and anxiety, and improving quality of life.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnostic imaging
Offer urgent (within 24 hours of presentation) low-dose non-contrast CT to adults with suspected renal colic. If a woman is pregnant, offer ultrasound instead of CT.
Offer urgent (within 24 hours of presentation) ultrasound as first-line imaging for children and young people with suspected renal colic.
If there is still uncertainty about the diagnosis of renal colic after ultrasound for children and young people, consider low-dose non-contrast CT.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic imaging .
Full details of the evidence and the committee's discussion are in evidence review B: imaging for diagnosis.
Loading. Please wait.
# Pain management
Offer a non-steroidal anti-inflammatory drug (NSAID) by any route as first-line treatment for adults, children and young people with suspected renal colic.
Offer intravenous paracetamol to adults, children and young people with suspected renal colic if NSAIDs are contraindicated or are not giving sufficient pain relief.
Consider opioids for adults, children and young people with suspected renal colic if both NSAIDs and intravenous paracetamol are contraindicated or are not giving sufficient pain relief.
Do not offer antispasmodics to adults, children and young people with suspected renal colic.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management .
Full details of the evidence and the committee's discussion are in evidence review E: pain management.
Loading. Please wait.
# Medical expulsive therapy
Consider alpha blockers for adults, children and young people with distal ureteric stones less than 10 mm.In January 2019, this was an off-label use of alpha blockers. See NICE's information on prescribing medicines.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on medical expulsive therapy .
Full details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.
Loading. Please wait.
# Stenting before shockwave lithotripsy
Do not offer pre-treatment stenting to adults having shockwave lithotripsy (SWL) for ureteric or renal stones.
Consider pre-treatment stenting for children and young people having SWL for renal staghorn stones.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stenting before shockwave lithotripsy .
Full details of the evidence and the committee's discussion are in evidence review H: stents before surgery.
Loading. Please wait.
# Surgical treatments (including shockwave lithotripsy)
## Renal stones
Consider watchful waiting for asymptomatic renal stones in adults, children and young people if:
the stone is less than 5 mm or
the stone is larger than 5 mm and the person (or their family or carers, as appropriate) agrees to watchful waiting after an informed discussion of the possible risks and benefits.
Follow the recommendations in table 1 for surgical treatment (including SWL) of renal stones in adults, children and young people.
Stone type and size
Treatment for adults (16 years and over)
Treatment for children and young people (under 16 years)
Renal stone less than 10 mm
Offer SWL
Consider URS:
if there are contraindications for SWL or
if a previous course of SWL has failed or
because of anatomical reasons, SWL is not indicated
Consider PCNL if SWL and URS have failed to treat the current stone or they are not an option
Consider URS or SWL
Consider PCNL if:
URS or SWL have failed or
for anatomical reasons, PCNL is the more favourable option
Renal stone 10 to 20 mm
Consider URS or SWL
Consider PCNL if URS or SWL have failed
Consider URS, SWL or PCNL
Renal stone larger than 20 mm, including staghorn stones
Offer PCNL
Consider URS if PCNL is not an option
Consider URS, SWL or PCNL
Abbreviations: PCNL, percutaneous nephrolithotomy; SWL, shockwave lithotripsy; URS, ureteroscopy.
Use clinical judgement when considering mini or standard PCNL for children and young people under 16 years with renal stones greater than 10 mm, including staghorn stones.
Use clinical judgement when considering tubeless, mini or standard PCNL, and supine and prone positions for adults (16 years and over) with renal stones greater than 20 mm, including staghorn stones.
## Ureteric stones
Follow the recommendations in table 2 for surgical treatment (including SWL) of ureteric stones in adults, children and young people.
Stone type and size
Treatment for adults (16 years and over)
Treatment for children and young people (under 16 years)
Ureteric stone less than 10 mm
Offer SWL
Consider URS if:
stone clearance is not possible within 4 weeks with SWL or
there are contraindications for SWL or
the stone is not targetable with SWL or
a previous course of SWL has failed
Consider URS or SWL
Ureteric stone 10 to 20 mm
Offer URS
Consider SWL if local facilities allow stone clearance within 4 weeks
Consider PCNL for impacted proximal stones when URS has failed
Consider URS or SWL
Abbreviations: PCNL, percutaneous nephrolithotomy; SWL, shockwave lithotripsy; URS, ureteroscopy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical treatments (including shockwave lithotripsy) .
Full details of the evidence and the committee's discussion are in evidence review F: surgical treatments.
Loading. Please wait.
Offer surgical treatment (including SWL) to adults with ureteric stones and renal colic within 48 hours of diagnosis or readmission, if:
pain is ongoing and not tolerated or
the stone is unlikely to pass.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on timing of surgical treatment .
Full details of the evidence and the committee's discussion are in evidence review G: timing of surgery.
Loading. Please wait.
Consider alpha blockers as adjunctive therapy for adults having SWL for ureteric stones less than 10 mm.In January 2019, this was an off-label use of alpha blockers. See NICE's information on prescribing medicines.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on medical expulsive therapy as adjunctive to shockwave lithotripsy .
Full details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.
Loading. Please wait.
# Stenting after ureteroscopy for adults with ureteric stones less than 20 mm
Do not routinely offer post-treatment stenting to adults who have had ureteroscopy for ureteric stones less than 20 mm.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on stenting after ureteroscopy .
Full details of the evidence and the committee's discussion are in evidence review I: stents after surgery.
Loading. Please wait.
# Metabolic testing
Consider stone analysis for adults with ureteric or renal stones.
Measure serum calcium for adults with ureteric or renal stones.
Consider referring children and young people with ureteric or renal stones to a paediatric nephrologist or paediatric urologist with expertise in this area for assessment and metabolic investigations.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metabolic testing .
Full details of the evidence and the committee's discussion are in evidence review A: metabolic investigations.
Loading. Please wait.
# Preventing recurrence
## Dietary and lifestyle advice
Discuss diet and fluid intake with the person (and their family or carers, as appropriate), and advise:
adults to drink 2.5 to 3 litres of water per day, and children and young people (depending on their age) 1 to 2 litres
adding fresh lemon juice to drinking water
avoiding carbonated drinks
adults to have a daily salt intake of no more than 6 g, and children and young people (depending on their age) 2 to 6 g
not restricting daily calcium intake, but maintaining a normal calcium intake of 700 to 1,200 mg for adults, and 350 to 1,000 mg per day for children and young people (depending on their age).
Follow the recommendations on maintaining a healthy lifestyle in the NICE guideline on preventing excess weight gain.
## Potassium citrate
The following recommendations apply alongside the recommendations on dietary and lifestyle advice.
Consider potassium citrate for adults with a recurrence of stones that are predominantly (more than 50%) calcium oxalate. In January 2019, this was an off-label use of potassium citrate. See NICE's information on prescribing medicines.
Consider potassium citrate for children and young people with a recurrence of stones that are predominantly (more than 50%) calcium oxalate, and with hypercalciuria or hypocitraturia.
## Thiazides
The following recommendation applies alongside the recommendations on dietary and lifestyle advice.
Consider thiazides for adults with a recurrence of stones that are predominantly (more than 50%) calcium oxalate and hypercalciuria, after restricting their sodium intake to no more than 6 g a day.In January 2019, this was an off-label use of thiazides. See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing recurrence .
Full details of the evidence and the committee's discussion are in evidence review C: dietary interventions and evidence review K: prevention of recurrence.
Loading. Please wait.
# Terms used in this guideline
## Children and young people
People under 16 years.# Recommendations for research
The guideline committee has made the following key recommendations for research.
# Metabolic assessment
What is the clinical and cost effectiveness of full metabolic assessment compared with standard advice alone, in people with recurrent calcium oxalate stones?
For a short explanation of why the committee made the recommendation for research, see the rationale on metabolic testing .
Full details of the evidence and the committee's discussion are in evidence review A: metabolic investigations.
Loading. Please wait.
# Alpha blockers and ureteroscopy
What is the clinical and cost effectiveness of tamsulosin as an adjunct to ureteroscopy?
For a short explanation of why the committee made the recommendation for research, see the rationale on medical expulsive therapy as adjunctive to shockwave lithotripsy .
Full details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.
Loading. Please wait.
# Preventive treatment following shockwave lithotripsy
What is the clinical and cost effectiveness of empirical potassium citrate or bendroflumethiazide as preventive treatment for people with small residual fragments following shockwave lithotripsy for renal and ureteric stones?
For a short explanation of why the committee made the recommendation for research, see the rationale on preventing recurrence .
Full details of the evidence and the committee's discussion are in evidence review C: dietary interventions and evidence review K: prevention of recurrence.
Loading. Please wait.
# Frequency of follow‑up imaging
What is the clinical and cost effectiveness of 6‑monthly imaging for 3 years for people with recurrent calcium renal or ureteric stones?
For a short explanation of why the committee made the recommendation for research, see the rationale on frequency of follow-up imaging .
Full details of the evidence and the committee's discussion are in evidence review J: imaging for follow-up.
Loading. Please wait.
# Non-steroidal anti-inflammatory drugs (NSAIDs) – route of administration
What is the most clinically and cost effective route of administration for NSAIDs in the management of acute pain thought to be due to renal or ureteric stones?
For a short explanation of why the committee made the recommendation for research, see the rationale on pain management .
Full details of the evidence and the committee's discussion are in evidence review E: pain management.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Diagnostic imaging
Recommendations 1.1.1 to 1.1.3
## Why the committee made the recommendations
Limited evidence showed that MRI, ultrasound and plain abdominal radiograph were not as good as non-contrast CT for detecting renal and ureteric stones in adults. CT is more expensive than ultrasound or plain abdominal radiograph but the extra cost is likely to be outweighed by avoiding additional investigations when a first test misses the diagnosis. The committee agreed that CT should be performed as soon as possible because renal function can decline quickly. However, they acknowledged that it could be delayed for up to 24 hours if needed (for example, in some locations and when first presentation is out of hours). The committee agreed that CT should not be offered to everyone with abdominal pain, only those with suspected renal colic. They also noted that CT should not be used for pregnant women because of the radiation exposure, and agreed that ultrasound is the preferred imaging modality in this group.
Limited evidence on the use of ultrasound showed that it was not as good as CT for detecting renal and ureteric stones in children and young people. There is known to be widespread variation in the quality of ultrasound. The committee acknowledged that although CT is a better test, there is serious concern about radiation exposure in children and young people and they were keen to minimise this. They agreed that ultrasound should be offered first, and that low-dose non-contrast CT should only be considered if there is still uncertainty about the diagnosis after ultrasound.
## How the recommendations might affect practice
The recommendations reflect current practice so the committee agreed there should be no change.
Return to recommendations
# Pain management
Recommendations 1.2.1 to 1.2.4
## Why the committee made the recommendations
Evidence showed that non-steroidal anti-inflammatory drugs (NSAIDs) reduced the need for rescue medication compared with opioids, antispasmodics and intravenous paracetamol. NSAIDs also reduced pain and had fewer adverse effects. NSAIDs had a better balance of benefits and costs, so the committee agreed that these should be offered as a first-line treatment for people with suspected renal colic.
The committee discussed the route of administration for NSAIDs and noted that most studies used intravenous or intramuscular NSAIDs. They agreed that oral or rectal NSAIDs are more commonly used in UK practice. The committee were concerned that there was very little evidence that oral or rectal NSAIDs were as effective as intravenous or intramuscular NSAIDs, and were reluctant to recommend a significant change in practice that would have resource implications. Therefore, they were not able to specify a particular route of administration of NSAIDs, but did agree to make a research recommendation on route of administration to inform future practice.
Some evidence showed a benefit of paracetamol for pain relief when compared with opioids. The committee noted that most of the evidence was based on intravenous paracetamol, which differs from other routes of administration in terms of potency and speed of action. They agreed this benefit could not be generalised to other routes of administration, such as oral. This difference in mechanism of action was not believed to be as strong for other drugs such as NSAIDs. They recommended that intravenous paracetamol should be offered if NSAIDs cannot be used or have not been effective.
There was no benefit of opioids for pain relief over NSAIDs or paracetamol. The committee noted concerns around opioid use in terms of dependency and misuse. However, opioids showed a benefit compared with antispasmodics in terms of pain relief, and there was no difference between opioids and most comparators in terms of adverse events. The committee agreed that opioids could only be considered if both NSAIDs and intravenous paracetamol were contraindicated or not effective.
Antispasmodics offered no benefit in terms of pain relief when compared with NSAIDs. The committee also highlighted that in the studies antispasmodics were given intravenously, whereas in clinical practice an oral route is often used. The committee discussed how antispasmodics can be more difficult to administer intravenously, because of an increased risk of adverse events and a need for intensive monitoring. They agreed that antispasmodics should not be offered to people with suspected renal colic.
Very limited evidence from small single studies showed some benefit of a combination of NSAIDs and oral paracetamol, for pain relief, and no increase in adverse events. The committee noted that in practice, 2 drugs would not be given at the same time, but a second would usually be given in a staged manner if the first drug hadn't worked. They noted that people with recurrent stones may self-manage with both oral paracetamol and NSAIDs and so it is important to ask people presenting with suspected renal colic about previous analgesia use. Overall, they agreed that there was not enough convincing evidence for any of the combination treatments.
All the identified evidence was for adults with renal or ureteric stones. However, the committee agreed that it would be reasonable to extrapolate the evidence on pain relief to children and young people and to include this age group in the recommendations.
## How the recommendations might affect practice
Currently, intravenous paracetamol is not used routinely for managing pain in people with acute renal colic, but is used in other areas of secondary care (for example, analgesia during surgery). Extending its use into other clinical areas (for example, emergency departments and surgical assessment units) will mean changes in policy and additional training for staff. Therefore, this recommendation will require a change from current practice by most or all providers. The use of intravenous paracetamol may also have some implications for practice if more hospital attendances are required to administer the treatment.
Return to recommendations
# Medical expulsive therapy
Recommendation 1.3.1
## Why the committee made the recommendation
Evidence showed that in adults, both alpha blockers and calcium channel blockers improved passage of distal ureteric stones of less than 10 mm compared with no treatment. Alpha blockers also improved stone passage when compared with placebo. Alpha blockers offered more benefit than calcium channel blockers in terms of stone passage, and had some benefits in terms of hospital stay and pain, but there was no difference in time to stone passage and quality of life. Evidence was mixed in terms of adverse events. The committee agreed that alpha blockers could be considered for adults with small (less than 10 mm) distal ureteric stones.
Limited evidence in children showed that alpha blockers improved stone passage and time to stone passage, and decreased pain compared with no treatment or placebo. They were not associated with any more adverse events so the committee agreed that alpha blockers could be considered for children and young people with distal ureteric stones less than 10 mm.
There was not enough evidence for the committee to make recommendations for proximal or mid-ureteric stones in adults, children and young people.
Medical expulsive therapy (MET) is low cost, and the savings from interventions avoided because of this therapy, are likely to offset the cost of the therapy.
## How the recommendation might affect practice
Current practice is varied, but many healthcare professionals do not offer alpha blockers for managing symptomatic ureteric stones. Up to 2015, MET was recommended practice in the UK to aid the passage of small ureteric stones. This changed after the SUSPEND trial (Pickard et al. 2015), the largest randomised controlled trial on this subject, concluded that there was no benefit in using alpha blockers. The committee reviewed all the available evidence, some of which was more recent than the SUSPEND trial, and agreed that alpha blockers can help the passage of small ureteric stones and the management of pain.
Return to recommendation
# Stenting before shockwave lithotripsy
Recommendations 1.4.1 and 1.4.2
## Why the committee made the recommendations
No evidence was found for the use of stents before ureteroscopy or percutaneous nephrolithotomy.
The committee reviewed evidence for the use of stents before treating renal and ureteric stones with shockwave lithotripsy (SWL). No benefits were identified in the use of pre-treatment stents and there were adverse events associated with stent use. These included frequency, urgency and dysuria. The committee agreed that having a stent in place may impede treatment by stopping shockwaves from reaching the stone. They agreed that pre-treatment stenting is not needed for people having SWL, because it does not significantly improve outcomes.
There was no evidence for ureteric or renal stones less than 10 mm, and no evidence for ureteric stones greater than 20 mm. The committee agreed that stone size should not be specified in the recommendation because for small renal stones, current practice is not to stent, and for small ureteric stones, although current practice does sometimes include stenting for reasons such as ongoing pain and obstruction, evidence has shown that treatment within 48 hours is beneficial, and this would avoid the use of stents. Ureteric stones greater than 20 mm are unlikely to be treated with SWL and therefore the recommendation would not apply to this group.
Limited evidence from 1 non-randomised study showed a benefit of pre-treatment stenting for children having SWL for renal stones less than 10 mm. However, the committee had concerns about the methods used in the study. They also agreed that the evidence was inconsistent with clinical practice. The committee decided that the evidence was not convincing enough to make a recommendation.
Limited evidence from 1 non-randomised study showed an overall benefit of pre-treatment stenting for children having SWL for renal staghorn stones. Rates of readmission and other procedures were significantly lower in children who had had a stent. They agreed that the evidence was not strong enough to recommend that this should be offered to all children with renal staghorn stones, but it could be considered.
## How the recommendations might affect practice
The recommendations broadly reflect current practice.
Return to recommendations
# Surgical treatments (including shockwave lithotripsy)
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
The committee noted that in current practice, watchful waiting may be used for people with asymptomatic renal stones, because these stones are not likely to affect quality of life and may pass spontaneously without intervention. This is particularly the case for stones less than 5 mm, but may also apply to larger stones. The committee noted that larger stones are more likely to have risks associated with watchful waiting. For example, the stone's location may change and cause obstruction, there may be infection or bleeding, or the person may become symptomatic. The committee agreed that watchful waiting may be particularly beneficial for people with complex comorbidities that make surgery a higher risk. They agreed that watchful waiting should be considered for those with asymptomatic renal stones less than 5 mm, and for stones larger than 5 mm as long as the possible risks and benefits have been discussed with the patient.
Some evidence showed a small benefit of ureteroscopy (URS) over SWL for stone removal, the number of repeat treatments needed and quality of life, but there was a shorter hospital stay, less pain and fewer major adverse events with SWL. Economic analysis showed that SWL offered a better balance of benefits and costs than URS, even when the possible need for repeat treatment was taken into account. The cost differences were substantial, and sensitivity analysis showed economic benefit for SWL even with lower SWL success rates. The committee therefore agreed to offer the less-invasive procedure of SWL to treat small ureteric stones (less than 10 mm) in adults.
However, they acknowledged that prompt treatment of these stones is needed because of the risk of obstruction and kidney damage. URS may be considered as an alternative treatment if, for example, stone clearance is not possible within 4 weeks with SWL, there are contraindications to SWL, the stone is not targetable, or a course of SWL has previously failed (because patients tend to form the same type of stones).
Evidence showed a benefit of URS over SWL for stone removal and the number of repeat treatments needed, but there was a shorter hospital stay, less pain and fewer major adverse events with SWL.
Prompt treatment of ureteric stones is needed because of the risk of obstruction and kidney damage. The risk is even greater with larger stones.
The committee acknowledged that in terms of costs, SWL may offer better value; however, the committee were very concerned about the risks in using SWL for larger ureteric stones. SWL may be delayed because of availability of a lithotripter and the total time to clear the stone will increase if multiple sessions are needed. Additionally, the effectiveness of SWL can vary with the type of machine used (fixed/mobile) and operator skill. The committee agreed to recommend URS for adults with ureteric stones of 10 to 20 mm, but SWL can be considered if local facilities allow stone clearance within 4 weeks.
Evidence (mainly in a group with impacted stones) suggested a benefit of percutaneous nephrolithotomy (PCNL) for stone removal compared with URS, but there was a shorter hospital stay with URS. The committee agreed that PCNL is not usually performed in the UK for this indication, but that it could be considered for larger impacted stones, particularly in the proximal ureter.
No evidence was identified, and the committee agreed that this is a very small group. Usual practice depends on local availability of treatments and expertise. The committee decided that they could not make a recommendation for this group.
There was evidence comparing SWL with URS, SWL with PCNL and surgical treatment including SWL with non-surgical treatment (observation or MET). The evidence suggested a benefit of URS in terms of retreatment rate and ancillary procedures, and a benefit of SWL in terms of readmission, failed technology and major adverse events. Limited evidence from 1 small study suggested a benefit of PCNL over SWL in terms of stone-free state and ancillary procedures. There was also evidence of a benefit of surgery compared with non-surgical treatment (observation or MET).
Because SWL offered a better balance of benefits and costs, the committee agreed that it should be offered in the first instance, and that URS should be considered if there are contraindications for SWL, or anatomical reasons or multiple stones, or a previous course of SWL has failed. Because of concerns around the limited evidence for PCNL, this should only be considered as an option when both SWL and URS have failed or are not an option.
Some evidence showed a benefit of SWL in terms of length of stay, quality of life and some major adverse events, compared with URS and PCNL. Both URS and PCNL had clinical benefits in terms of stone-free state, retreatment rate and ancillary procedures, compared with SWL. There was no difference between PCNL and URS for most outcomes. One study showed a benefit of surgery in terms of ancillary procedures and stone-free state compared with non-surgical treatment (observation), and 1 study showed a benefit of tubeless compared with standard PCNL in terms of stone-free state.
The committee agreed that URS or SWL offered a better balance of benefits and costs compared with PCNL, and this intervention should be considered only if URS or SWL have failed. In terms of a choice between URS and SWL, the size of the stone was a concern for the committee; however, factors such as quality of life and the risks associated with larger stones were difficult to quantify in any costing work. The committee agreed that the stone size itself would be a factor in the treatment decision, because effectiveness of SWL can also vary by stone size, and a stone nearer to the lower end of the range (10 to 20 mm) could be an appropriate candidate for SWL. Overall, the committee felt that a recommendation to consider URS or SWL would allow flexibility for clinicians in choosing a treatment option. The committee agreed that they did not have enough confidence in the evidence to recommend tubeless over standard PCNL, but agreed that either approach could be used, according to clinical judgement.
Current practice for renal stones greater than 20 mm is PCNL, and the committee agreed that there was insufficient evidence to change this. However, the committee considered that PCNL may not always be an option (for example, for people with high comorbidity, anaesthetic risks or anatomical considerations), and so URS could be considered in these circumstances. The committee agreed that all evidence for types of PCNL was based on small studies, and there was no difference between them for many outcomes. Therefore, any approach should be available and considered based on clinical judgement.
There was no evidence for renal staghorn stones in adults. Current practice for these stones is to use PCNL. The committee agreed that staghorn stones are all over 20 mm and so would be treated as renal stones larger than 20 mm.
Limited evidence from a single, small study showed a benefit of URS over SWL in terms of stone-free state, retreatment rate and ancillary procedures. The committee agreed to recommend SWL as the first treatment for these stones in adults because of the better balance of benefits and costs. However, they noted that evidence for children and young people was much more limited. They also discussed that unlike adults, children usually require a general anaesthetic for each session of SWL. Because both URS and SWL are used in current practice, the committee agreed that either could be considered for children and young people with stones less than 10 mm.
No evidence was identified so the committee made a recommendation based on their knowledge and experience. They noted that there is a perception that children have a higher incidence of spontaneous passage of larger stones than adults. The committee agreed that unlike the adult population where URS should be offered in the first instance and SWL considered if facilities allow quick stone clearance, for children and young people, both SWL and URS could be treatment options so allowing clinical flexibility.
No evidence was identified and the committee agreed that currently these stones are treated on a case-by-case basis. They decided that they could not make a recommendation for this group.
No evidence was identified. The committee discussed current practice and agreed that URS or SWL should be considered in the first instance, and PCNL when other treatment has failed.
Very limited evidence from a single study showed a benefit of URS in terms of stone-free state, retreatment and significant residual stones when compared with SWL. Limited evidence from another single study showed benefits of PCNL in terms of stone-free state, retreatment rate and ancillary procedures when compared with SWL. The only evidence showing a benefit for SWL was for fewer minor adverse events, when SWL was compared with PCNL. Two non-randomised studies comparing URS and PCNL had inconclusive results. The committee agreed that clinical judgement should be used when deciding which treatment to use (URS, SWL or PCNL).
Evidence from a single study showed a benefit of URS compared with PCNL in terms of length of stay and adverse events, but a benefit of PCNL in terms of stone-free state and retreatment rate. Evidence from 2 small studies showed a benefit of tubeless PCNL compared with standard PCNL in terms of length of stay, ancillary procedures and minor adverse events, but a benefit of standard PCNL in terms of retreatment. One non-randomised study showed a benefit of PCNL compared with SWL for stone-free state and retreatment, but a benefit of SWL for length of stay.
The committee agreed that PCNL may be effective, but carries more risks than URS. They decided that either URS or PCNL could be considered, and that SWL should not be ruled out.
No evidence was identified. The committee agreed that staghorn stones in children would be treated in the same way as stones greater than 20 mm.
## How the recommendations might affect practice
Changes in practice are likely for adults with ureteric stones smaller than 10 mm because SWL is recommended, whereas currently URS is more frequently used. Economic analysis showed there will be a saving from using SWL over URS, although this may be more longer term because of short-term implementation costs required. Having good referral systems may mean that additional lithotripters are not needed. Alternatively, more investment in mobile or fixed lithotripters could be an option, or networks of mobile or fixed-site lithotripters allowing patients timely access to treatment. However, more staff may be needed to undertake SWL (for example, ultrasonographers) to meet the additional demand. Additional training to maximise the effectiveness of lithotripsy may also be needed. Increases in staffing can provide benefits to other areas of the NHS because it is likely that not all their time will be spent treating renal and ureteric stones.
In adults with ureteric stones of 10 to 20 mm, URS tends to be used, so recommendations to consider SWL could lead to a change in practice, with potential longer-term savings, depending on uptake.
In adults with renal stones of 10 to 20 mm, PCNL tends to be used, so recommendations to consider URS or SWL as first line could lead to a change in practice, with likely savings, depending on uptake.
Other recommendations for adults reflect current practice. In children, multiple treatment options have been recommended to allow for clinical judgement, and therefore a change in practice is unlikely.
Return to recommendations
# Timing of surgical treatment for ureteric stones
Recommendation 1.5.4
## Why the committee made the recommendation
Evidence showed a benefit of early intervention (within 48 hours) in terms of stone removal, repeated or ancillary procedures, and stent insertion. This could lead to substantial cost savings on a population level from stents and further treatment avoided. The committee agreed that ureteric stones can be extremely painful and if left untreated can lead to a loss of kidney function. Surgical treatment should be offered within 48 hours of diagnosis or readmission, to people presenting with ureteric stones and renal colic, if the pain is ongoing and not tolerated or the stone is unlikely to pass.
Although the evidence was from people with stones less than 20 mm, the committee agreed that ureteric stones of all sizes should be treated within this timeframe. There was no evidence for people with renal stones, and the committee considered that the timing of treatment for these stones should be prioritised according to the nature and severity of symptoms. There was also no evidence found for children and young people, and so the committee agreed that the recommendations should only apply to adults.
## How the recommendation might affect practice
Current practice is to aim to treat ureteric stones in adults with an elective surgical procedure within 4 to 6 weeks, although practice can vary and is influenced by the availability of services. People are likely to have a stent inserted while waiting for surgery.
To implement these recommendations for URS, services would need to be reconfigured to allocate more theatre time for emergency surgery. More equipment would also be needed for SWL, such as more responsive networks of mobile lithotripters, more fixed-site machines or better organised referral systems. Early intervention is likely to lead to substantial savings by avoiding the need for further treatments and the use of stents. These savings are likely to outweigh the implementation costs, and therefore this recommendation is not expected to have a cost impact overall.
Return to recommendation
# Medical expulsive therapy as adjunctive to shockwave lithotripsy
Recommendation 1.5.5
## Why the committee made the recommendation
Evidence showed a benefit in terms of stone passage when alpha blockers were used as adjunctive therapy for adults having SWL for small distal or proximal ureteric stones (less than 10 mm). There was no difference in adverse events. The evidence focused on distal or proximal ureteric stones but the committee agreed that alpha blockers could be considered as adjunctive therapy to SWL for adults with small ureteric stones in any location. There was no evidence for mid-ureteric stones less than 10 mm; however, the committee agreed that this is a small group of people and usual clinical practice often involves waiting to see if the stone progresses to the distal ureter. There was not enough evidence for the committee to make a recommendation for adjunctive therapy for other interventions or for larger ureteric stones of 10 to 20 mm.
Evidence showed that the use of alpha blockers in conjunction with URS improved stone passage and some adults with small distal ureteric stones (less than 10 mm) and proximal ureteric stones (10 to 20 mm) experienced reduced pain. The committee agreed that this is not usual practice and also noted that the evidence was based on single studies. They agreed that further research on the use of alpha blockers, particularly tamsulosin, as adjunctive therapy to URS for any stone less than 20 mm would be beneficial to inform future practice, so decided to make a research recommendation on alpha blockers and ureteroscopy.
## How the recommendation might affect practice
Alpha blockers are not widely used as an adjunct to SWL for ureteric stones so this will represent a change in practice. The small cost of the alpha blockers is likely to be outweighed by savings related to improved stone clearance (reduced use of surgical interventions).
Return to recommendation
# Stenting after ureteroscopy
Recommendation 1.6.1
## Why the committee made the recommendation
No evidence was found for the use of stents after SWL or PCNL, or for people with renal stones, or for children and young people.
Evidence showed that there was no benefit of routine stenting after URS for adults with ureteric stones less than 20 mm. Stents were associated with a number of adverse symptoms (dysuria, haematuria, irritative symptoms, frequency and urgency). People with a stent also had more abdominal and bladder pain, which the committee agreed were likely to be stent related. The committee agreed that because there was no benefit of stents, and they cause adverse events that negatively affect quality of life, stents should not be routinely offered to adults who have had URS for ureteric stones less than 20 mm. There may be instances when stents might be considered (such as more treatment anticipated, evidence of infection or obstruction, or a solitary kidney).
There was no evidence for stones larger than 20 mm. The committee agreed that this is a small group and the surgical treatment used varies. They noted that the decision to use a stent would be based on clinical judgement and so agreed not to make a recommendation for this group.
## How the recommendation might affect practice
Currently around 70% of people overall receive a stent after URS and many of these are being used to avoid future problems that are unlikely to occur. Stents may still be needed in some cases, for example, when further treatment is anticipated, or there is evidence of infection or obstruction, a solitary kidney or for a Clavien–Dindo grade 3 complication. A few urologists currently advocate the routine placement of stents after all URS procedures. The recommendation is likely to mean that fewer people receive stents, which may be cost saving.
Return to recommendation
# Metabolic testing
Recommendations 1.7.1 to 1.7.3
## Why the committee made the recommendations
Stone analysis and blood testing (serum calcium) allows the diagnosis of treatable conditions such as cystinuria, uric acid stones and primary hyperparathyroidism. Urine testing allows for the identification of metabolic abnormalities that can be treated, and so reduces the risk of future stones.
Evidence showed that there is effective treatment for hypercalciuria and hypocitraturia, and the committee noted that these conditions would be diagnosed with a 24‑hour urine test. This suggests that understanding underlying metabolic diseases can lead to prevention of stone recurrence. However, no evidence for 24‑hour urine testing was identified, so the committee agreed that they could not make a practice recommendation. They agreed to make a research recommendation on the clinical and cost effectiveness of a full metabolic investigation to inform future guidance.
No evidence was found on stone analysis or blood tests in people who have or have had renal or ureteric stones. It is not clear which tests are most useful and whether tests should be offered to all people with a stone or just those at high risk of stone recurrence. However, the committee also considered the high prevalence of primary hyperparathyroidism in people with renal stones and noted that this could be identified with serum calcium testing, which is an inexpensive test. Therefore, the committee agreed that serum calcium should be measured for adults and stone analysis considered.
The committee agreed that current practice for children and young people is variable. All paediatric patients should have a metabolic assessment. The nature of this assessment varies nationally. Referral to a paediatric nephrologist or urologist with expertise in testing for metabolic conditions should be considered.
## How the recommendations might affect practice
Current practice is varied with a full range of metabolic tests being done in some areas and fewer tests in others. Therefore, the recommendations may mean a change in practice for some providers. However, the committee agreed that existing centres should have the resources to cope with an increased demand for stone analysis, which is relatively easy to do and is not urgent.
Return to recommendations
# Frequency of follow‑up imaging
## Why the committee made the research recommendation
No evidence was found on the optimum frequency of imaging in people who have or have had renal or ureteric stones. The committee agreed that there is variation in current practice, with frequency often depending on factors such as whether the person has had 1 stone or recurrent stones. The committee was not able to make a recommendation for practice because their experience differed, but they did agree to make a research recommendation on the frequency of follow-up imaging to inform future guidance.
Full details of the evidence and the committee's discussion are in evidence review J: imaging for follow-up.
# Preventing recurrence
Recommendations 1.8.1 to 1.8.5
## Why the committee made the recommendations
Some evidence showed a benefit of a high water intake in reducing stone recurrence in adults. Limited evidence from a single study in adults showed a benefit of lemon juice in terms of urine calcium and pH but no difference in urine oxalate. Lemon juice is high in citrate leading to higher concentrations of citrate in urine. This may stop calcium from binding to other stone constituents and so prevent stone formation and recurrence. The committee agreed to recommend a high water intake and the addition of lemon juice to water. Evidence showed a benefit of avoiding carbonated drinks in terms of stone recurrence, and so the committee agreed to recommend that these should be avoided.
Evidence on diet was mixed but the committee agreed that a normal calcium intake and a low salt intake may help to prevent stone recurrence. Evidence on avoiding a high protein diet was inconclusive, but the committee acknowledged that this is the advice currently given.
Evidence showed that potassium citrate could reduce the recurrence of calcium oxalate and calcium oxalate/calcium phosphate stones in adults. However, there were adverse events associated with the use of potassium citrate and the committee agreed that there may be concerns about high levels of potassium in the blood (hyperkalaemia) in some groups. Despite this, the committee agreed that the benefits in terms of stones avoided are likely to outweigh any harms. Potassium citrate is currently used in UK practice and so the committee agreed it could be considered to prevent stone recurrence in adults with calcium oxalate stones.
Limited evidence in children showed that potassium citrate reduced stone recurrence after PCNL and SWL. There was no information on adverse events or on the type of stone or results of urine testing. The committee noted that in UK practice, potassium citrate is used for children based on the levels of calcium or citrate in urine. They agreed that it could be considered for children with recurrence of calcium oxalate stones and with hypercalciuria or hypocitraturia.
Limited evidence showed that thiazides reduced stone recurrence in adults with high levels of calcium in urine (hypercalciuria) compared with no intervention. There was no benefit for adults with normal levels of urinary calcium, and evidence was mixed when the biochemical abnormality was mixed or not defined. The committee agreed that thiazides tend to be well tolerated but should only be used after salt has been restricted. They agreed that thiazides could be considered for adults with hypercalciuria and recurrent calcium oxalate stones, but only after reducing salt intake to recommended levels.
There was not enough evidence for the committee to make recommendations on allopurinol or combined therapy of allopurinol and thiazides. Although limited evidence suggested a potential benefit of magnesium, the committee knew from their experience that magnesium may cause adverse effects. The committee agreed that the limited evidence and potential for adverse events did not justify a recommendation.
Limited evidence from a single study of thiazides compared with placebo in people who had had previous SWL showed some benefit of thiazides in reducing the need for further SWL and for stone growth. The committee agreed that this is not usual practice and that further research would be beneficial. The committee agreed to make a research recommendation on preventative treatment following SWL.
## How the recommendations might affect practice
The recommendations on diet broadly reflect current practice. They emphasise the importance of dietary advice in preventing further stone episodes. Dietary advice should be given in conjunction with lifestyle advice.
The committee considered the impact the recommendations would have on practice, including metabolic laboratory testing. Identifying stone composition or metabolic abnormalities would be a prerequisite to the recommendations and this would have a cost as well as potential service impact.
Recommending the interventions also has a monitoring impact. There is variation in current practice in terms of the use of thiazides and potassium citrate for people with renal or ureteric stones.
Return to recommendations# Context
Renal and ureteric stones usually present as an acute episode with severe pain, although some stones are picked up incidentally during imaging or may present as a history of infection. The initial diagnosis is made by taking a clinical history and examination and carrying out imaging; initial management is with painkillers and treatment of any infection.
Ongoing treatment of renal and ureteric stones depends on the site of the stone and size of the stone (less than 10 mm, 10 to 20 mm, greater than 20 mm; staghorn stones). Options for treatment range from observation with pain relief to surgical intervention. Open surgery is performed very infrequently; most surgical stone management is minimally invasive and the interventions include shockwave lithotripsy (SWL), ureteroscopy (URS) and percutaneous stone removal (surgery). As well as the site and size of the stone, treatment also depends on local facilities and expertise. Most centres have access to SWL, but many use a mobile machine on a sessional basis rather than a fixed-site machine, which has easier access during the working week. The use of a mobile machine may affect options for emergency treatment, but may also add to waiting times for non-emergency treatment.
Although URS for renal and ureteric stones is increasing (there has been a 49% increase from 12,062 treatments in 2009/10, to 18,066 in 2014/15 ), there is a trend towards day-case/ambulatory care, with this increasing by 10% to 31,000 cases a year between 2010 and 2015. The total number of bed-days used for renal stone disease has fallen by 15% since 2009/10. However, waiting times for treatment are increasing and this means that patient satisfaction is likely to be lower.
Because the incidence of renal and ureteric stones and the rate of intervention are increasing, there is a need to reduce recurrences through patient education and lifestyle changes. Assessing dietary factors and changing lifestyle have been shown to reduce the number of episodes in people with renal stone disease.
Adults, children and young people using services, their families and carers, and the public will be able to use the guideline to find out more about what NICE recommends, and help them make decisions. These recommendations apply to all settings in which NHS-commissioned care is provided.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnostic imaging\n\nOffer urgent (within 24\xa0hours of presentation) low-dose non-contrast CT to adults with suspected renal colic. If a woman is pregnant, offer ultrasound instead of\xa0CT.\n\nOffer urgent (within 24\xa0hours of presentation) ultrasound as first-line imaging for children and young people with suspected renal colic.\n\nIf there is still uncertainty about the diagnosis of renal colic after ultrasound for children and young people, consider low-dose non-contrast\xa0CT.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnostic imaging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: imaging for diagnosis.\n\nLoading. Please wait.\n\n# Pain management\n\nOffer a non-steroidal anti-inflammatory drug (NSAID) by any route as first-line treatment for adults, children and young people with suspected renal colic.\n\nOffer intravenous paracetamol to adults, children and young people with suspected renal colic if NSAIDs are contraindicated or are not giving sufficient pain relief.\n\nConsider opioids for adults, children and young people with suspected renal colic if both NSAIDs and intravenous paracetamol are contraindicated or are not giving sufficient pain relief.\n\nDo not offer antispasmodics to adults, children and young people with suspected renal colic.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: pain management.\n\nLoading. Please wait.\n\n# Medical expulsive therapy\n\nConsider alpha blockers for adults, children and young people with distal ureteric stones less than 10\xa0mm.In January 2019, this was an off-label use of alpha blockers. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on medical expulsive therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.\n\nLoading. Please wait.\n\n# Stenting before shockwave lithotripsy\n\nDo not offer pre-treatment stenting to adults having shockwave lithotripsy (SWL) for ureteric or renal stones.\n\nConsider pre-treatment stenting for children and young people having SWL for renal staghorn stones.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stenting before shockwave lithotripsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: stents before surgery.\n\nLoading. Please wait.\n\n# Surgical treatments (including shockwave lithotripsy)\n\n## Renal stones\n\nConsider watchful waiting for asymptomatic renal stones in adults, children and young people if:\n\nthe stone is less than 5\xa0mm or\n\nthe stone is larger than 5\xa0mm and the person (or their family or carers, as appropriate) agrees to watchful waiting after an informed discussion of the possible risks and benefits.\n\nFollow the recommendations in table\xa01 for surgical treatment (including SWL) of renal stones in adults, children and young people.\n\nStone type and size\n\nTreatment for adults (16\xa0years and over)\n\nTreatment for children and young people (under 16\xa0years)\n\nRenal stone less than 10\xa0mm\n\nOffer SWL\n\nConsider URS:\n\nif there are contraindications for SWL or\n\nif a previous course of SWL has failed or\n\nbecause of anatomical reasons, SWL is not indicated\n\nConsider PCNL if SWL and URS have failed to treat the current stone or they are not an option\n\nConsider URS or SWL\n\nConsider PCNL if:\n\nURS or SWL have failed or\n\nfor anatomical reasons, PCNL is the more favourable option\n\nRenal stone 10 to 20\xa0mm\n\nConsider URS or SWL\n\nConsider PCNL if URS or SWL have failed\n\nConsider URS, SWL or PCNL\n\nRenal stone larger than 20\xa0mm, including staghorn stones\n\nOffer PCNL\n\nConsider URS if PCNL is not an option\n\nConsider URS, SWL or PCNL\n\nAbbreviations: PCNL, percutaneous nephrolithotomy; SWL, shockwave lithotripsy; URS, ureteroscopy.\n\nUse clinical judgement when considering mini or standard PCNL for children and young people under 16\xa0years with renal stones greater than 10\xa0mm, including staghorn stones.\n\nUse clinical judgement when considering tubeless, mini or standard PCNL, and supine and prone positions for adults (16\xa0years and over) with renal stones greater than 20\xa0mm, including staghorn stones.\n\n## Ureteric stones\n\nFollow the recommendations in table\xa02 for surgical treatment (including SWL) of ureteric stones in adults, children and young people.\n\nStone type and size\n\nTreatment for adults (16\xa0years and over)\n\nTreatment for children and young people (under 16\xa0years)\n\nUreteric stone less than 10\xa0mm\n\nOffer SWL\n\nConsider URS if:\n\nstone clearance is not possible within 4\xa0weeks with SWL or\n\nthere are contraindications for SWL or\n\nthe stone is not targetable with SWL or\n\na previous course of SWL has failed\n\nConsider URS or SWL\n\nUreteric stone 10 to 20\xa0mm\n\nOffer URS\n\nConsider SWL if local facilities allow stone clearance within 4\xa0weeks\n\nConsider PCNL for impacted proximal stones when URS has failed\n\nConsider URS or SWL\n\n\n\nAbbreviations: PCNL, percutaneous nephrolithotomy; SWL, shockwave lithotripsy; URS, ureteroscopy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical treatments (including shockwave lithotripsy)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: surgical treatments.\n\nLoading. Please wait.\n\nOffer surgical treatment (including SWL) to adults with ureteric stones and renal colic within 48\xa0hours of diagnosis or readmission, if:\n\npain is ongoing and not tolerated or\n\nthe stone is unlikely to pass.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on timing of surgical treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: timing of surgery.\n\nLoading. Please wait.\n\nConsider alpha blockers as adjunctive therapy for adults having SWL for ureteric stones less than 10\xa0mm.In January 2019, this was an off-label use of alpha blockers. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on medical expulsive therapy as adjunctive to shockwave lithotripsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.\n\nLoading. Please wait.\n\n# Stenting after ureteroscopy for adults with ureteric stones less than 20\xa0mm\n\nDo not routinely offer post-treatment stenting to adults who have had ureteroscopy for ureteric stones less than 20\xa0mm.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on stenting after ureteroscopy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: stents after surgery.\n\nLoading. Please wait.\n\n# Metabolic testing\n\nConsider stone analysis for adults with ureteric or renal stones.\n\nMeasure serum calcium for adults with ureteric or renal stones.\n\nConsider referring children and young people with ureteric or renal stones to a paediatric nephrologist or paediatric urologist with expertise in this area for assessment and metabolic investigations.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metabolic testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: metabolic investigations.\n\nLoading. Please wait.\n\n# Preventing recurrence\n\n## Dietary and lifestyle advice\n\nDiscuss diet and fluid intake with the person (and their family or carers, as appropriate), and advise:\n\nadults to drink 2.5\xa0to\xa03\xa0litres of water per day, and children and young people (depending on their age) 1\xa0to\xa02\xa0litres\n\nadding fresh lemon juice to drinking water\n\navoiding carbonated drinks\n\nadults to have a daily salt intake of no more than 6\xa0g, and children and young people (depending on their age) 2\xa0to\xa06\xa0g\n\nnot restricting daily calcium intake, but maintaining a normal calcium intake of 700\xa0to 1,200\xa0mg for adults, and 350\xa0to 1,000\xa0mg per day for children and young people (depending on their age).\n\nFollow the recommendations on maintaining a healthy lifestyle in the NICE guideline on preventing excess weight gain.\n\n## Potassium citrate\n\nThe following recommendations apply alongside the recommendations on dietary and lifestyle advice.\n\nConsider potassium citrate for adults with a recurrence of stones that are predominantly (more than 50%) calcium oxalate. In January 2019, this was an off-label use of potassium citrate. See NICE's information on prescribing medicines.\n\nConsider potassium citrate for children and young people with a recurrence of stones that are predominantly (more than 50%) calcium oxalate, and with hypercalciuria or hypocitraturia.\n\n## Thiazides\n\nThe following recommendation applies alongside the recommendations on dietary and lifestyle advice.\n\nConsider thiazides for adults with a recurrence of stones that are predominantly (more than 50%) calcium oxalate and hypercalciuria, after restricting their sodium intake to no more than 6\xa0g a day.In January 2019, this was an off-label use of thiazides. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing recurrence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: dietary interventions and evidence review K: prevention of recurrence.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Children and young people\n\nPeople under 16\xa0years.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Metabolic assessment\n\nWhat is the clinical and cost effectiveness of full metabolic assessment compared with standard advice alone, in people with recurrent calcium oxalate stones?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on metabolic testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: metabolic investigations.\n\nLoading. Please wait.\n\n# Alpha blockers and ureteroscopy\n\nWhat is the clinical and cost effectiveness of tamsulosin as an adjunct to ureteroscopy?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on medical expulsive therapy as adjunctive to shockwave lithotripsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical expulsive therapy.\n\nLoading. Please wait.\n\n# Preventive treatment following shockwave lithotripsy\n\nWhat is the clinical and cost effectiveness of empirical potassium citrate or bendroflumethiazide as preventive treatment for people with small residual fragments following shockwave lithotripsy for renal and ureteric stones?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on preventing recurrence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: dietary interventions and evidence review K: prevention of recurrence.\n\nLoading. Please wait.\n\n# Frequency of follow‑up imaging\n\nWhat is the clinical and cost effectiveness of 6‑monthly imaging for 3\xa0years for people with recurrent calcium renal or ureteric stones?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on frequency of follow-up imaging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: imaging for follow-up.\n\nLoading. Please wait.\n\n# Non-steroidal anti-inflammatory drugs (NSAIDs) – route of administration\n\nWhat is the most clinically and cost effective route of administration for NSAIDs in the management of acute pain thought to be due to renal or ureteric stones?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on pain management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: pain management.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Diagnostic imaging\n\nRecommendations 1.1.1 to\xa01.1.3\n\n## Why the committee made the recommendations\n\nLimited evidence showed that MRI, ultrasound and plain abdominal radiograph were not as good as non-contrast CT for detecting renal and ureteric stones in adults. CT is more expensive than ultrasound or plain abdominal radiograph but the extra cost is likely to be outweighed by avoiding additional investigations when a first test misses the diagnosis. The committee agreed that CT should be performed as soon as possible because renal function can decline quickly. However, they acknowledged that it could be delayed for up to 24\xa0hours if needed (for example, in some locations and when first presentation is out of hours). The committee agreed that CT should not be offered to everyone with abdominal pain, only those with suspected renal colic. They also noted that CT should not be used for pregnant women because of the radiation exposure, and agreed that ultrasound is the preferred imaging modality in this group.\n\nLimited evidence on the use of ultrasound showed that it was not as good as CT for detecting renal and ureteric stones in children and young people. There is known to be widespread variation in the quality of ultrasound. The committee acknowledged that although CT is a better test, there is serious concern about radiation exposure in children and young people and they were keen to minimise this. They agreed that ultrasound should be offered first, and that low-dose non-contrast CT should only be considered if there is still uncertainty about the diagnosis after ultrasound.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice so the committee agreed there should be no change.\n\nReturn to recommendations\n\n# Pain management\n\nRecommendations 1.2.1 to\xa01.2.4\n\n## Why the committee made the recommendations\n\nEvidence showed that non-steroidal anti-inflammatory drugs (NSAIDs) reduced the need for rescue medication compared with opioids, antispasmodics and intravenous paracetamol. NSAIDs also reduced pain and had fewer adverse effects. NSAIDs had a better balance of benefits and costs, so the committee agreed that these should be offered as a first-line treatment for people with suspected renal colic.\n\nThe committee discussed the route of administration for NSAIDs and noted that most studies used intravenous or intramuscular NSAIDs. They agreed that oral or rectal NSAIDs are more commonly used in UK practice. The committee were concerned that there was very little evidence that oral or rectal NSAIDs were as effective as intravenous or intramuscular NSAIDs, and were reluctant to recommend a significant change in practice that would have resource implications. Therefore, they were not able to specify a particular route of administration of NSAIDs, but did agree to make a research recommendation on route of administration to inform future practice.\n\nSome evidence showed a benefit of paracetamol for pain relief when compared with opioids. The committee noted that most of the evidence was based on intravenous paracetamol, which differs from other routes of administration in terms of potency and speed of action. They agreed this benefit could not be generalised to other routes of administration, such as oral. This difference in mechanism of action was not believed to be as strong for other drugs such as NSAIDs. They recommended that intravenous paracetamol should be offered if NSAIDs cannot be used or have not been effective.\n\nThere was no benefit of opioids for pain relief over NSAIDs or paracetamol. The committee noted concerns around opioid use in terms of dependency and misuse. However, opioids showed a benefit compared with antispasmodics in terms of pain relief, and there was no difference between opioids and most comparators in terms of adverse events. The committee agreed that opioids could only be considered if both NSAIDs and intravenous paracetamol were contraindicated or not effective.\n\nAntispasmodics offered no benefit in terms of pain relief when compared with NSAIDs. The committee also highlighted that in the studies antispasmodics were given intravenously, whereas in clinical practice an oral route is often used. The committee discussed how antispasmodics can be more difficult to administer intravenously, because of an increased risk of adverse events and a need for intensive monitoring. They agreed that antispasmodics should not be offered to people with suspected renal colic.\n\nVery limited evidence from small single studies showed some benefit of a combination of NSAIDs and oral paracetamol, for pain relief, and no increase in adverse events. The committee noted that in practice, 2\xa0drugs would not be given at the same time, but a second would usually be given in a staged manner if the first drug hadn't worked. They noted that people with recurrent stones may self-manage with both oral paracetamol and NSAIDs and so it is important to ask people presenting with suspected renal colic about previous analgesia use. Overall, they agreed that there was not enough convincing evidence for any of the combination treatments.\n\nAll the identified evidence was for adults with renal or ureteric stones. However, the committee agreed that it would be reasonable to extrapolate the evidence on pain relief to children and young people and to include this age group in the recommendations.\n\n## How the recommendations might affect practice\n\nCurrently, intravenous paracetamol is not used routinely for managing pain in people with acute renal colic, but is used in other areas of secondary care (for example, analgesia during surgery). Extending its use into other clinical areas (for example, emergency departments and surgical assessment units) will mean changes in policy and additional training for staff. Therefore, this recommendation will require a change from current practice by most or all providers. The use of intravenous paracetamol may also have some implications for practice if more hospital attendances are required to administer the treatment.\n\nReturn to recommendations\n\n# Medical expulsive therapy\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nEvidence showed that in adults, both alpha blockers and calcium channel blockers improved passage of distal ureteric stones of less than 10\xa0mm compared with no treatment. Alpha blockers also improved stone passage when compared with placebo. Alpha blockers offered more benefit than calcium channel blockers in terms of stone passage, and had some benefits in terms of hospital stay and pain, but there was no difference in time to stone passage and quality of life. Evidence was mixed in terms of adverse events. The committee agreed that alpha blockers could be considered for adults with small (less than 10\xa0mm) distal ureteric stones.\n\nLimited evidence in children showed that alpha blockers improved stone passage and time to stone passage, and decreased pain compared with no treatment or placebo. They were not associated with any more adverse events so the committee agreed that alpha blockers could be considered for children and young people with distal ureteric stones less than 10\xa0mm.\n\nThere was not enough evidence for the committee to make recommendations for proximal or mid-ureteric stones in adults, children and young people.\n\nMedical expulsive therapy (MET) is low cost, and the savings from interventions avoided because of this therapy, are likely to offset the cost of the therapy.\n\n## How the recommendation might affect practice\n\nCurrent practice is varied, but many healthcare professionals do not offer alpha blockers for managing symptomatic ureteric stones. Up to 2015, MET was recommended practice in the UK to aid the passage of small ureteric stones. This changed after the SUSPEND trial (Pickard et al. 2015), the largest randomised controlled trial on this subject, concluded that there was no benefit in using alpha blockers. The committee reviewed all the available evidence, some of which was more recent than the SUSPEND trial, and agreed that alpha blockers can help the passage of small ureteric stones and the management of pain.\n\nReturn to recommendation\n\n# Stenting before shockwave lithotripsy\n\nRecommendations 1.4.1 and\xa01.4.2\n\n## Why the committee made the recommendations\n\nNo evidence was found for the use of stents before ureteroscopy or percutaneous nephrolithotomy.\n\nThe committee reviewed evidence for the use of stents before treating renal and ureteric stones with shockwave lithotripsy (SWL). No benefits were identified in the use of pre-treatment stents and there were adverse events associated with stent use. These included frequency, urgency and dysuria. The committee agreed that having a stent in place may impede treatment by stopping shockwaves from reaching the stone. They agreed that pre-treatment stenting is not needed for people having SWL, because it does not significantly improve outcomes.\n\nThere was no evidence for ureteric or renal stones less than 10\xa0mm, and no evidence for ureteric stones greater than 20\xa0mm. The committee agreed that stone size should not be specified in the recommendation because for small renal stones, current practice is not to stent, and for small ureteric stones, although current practice does sometimes include stenting for reasons such as ongoing pain and obstruction, evidence has shown that treatment within 48\xa0hours is beneficial, and this would avoid the use of stents. Ureteric stones greater than 20\xa0mm are unlikely to be treated with SWL and therefore the recommendation would not apply to this group.\n\nLimited evidence from 1\xa0non-randomised study showed a benefit of pre-treatment stenting for children having SWL for renal stones less than 10\xa0mm. However, the committee had concerns about the methods used in the study. They also agreed that the evidence was inconsistent with clinical practice. The committee decided that the evidence was not convincing enough to make a recommendation.\n\nLimited evidence from 1\xa0non-randomised study showed an overall benefit of pre-treatment stenting for children having SWL for renal staghorn stones. Rates of readmission and other procedures were significantly lower in children who had had a stent. They agreed that the evidence was not strong enough to recommend that this should be offered to all children with renal staghorn stones, but it could be considered.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current practice.\n\nReturn to recommendations\n\n# Surgical treatments (including shockwave lithotripsy)\n\nRecommendations 1.5.1 to\xa01.5.3\n\n## Why the committee made the recommendations\n\nThe committee noted that in current practice, watchful waiting may be used for people with asymptomatic renal stones, because these stones are not likely to affect quality of life and may pass spontaneously without intervention. This is particularly the case for stones less than 5\xa0mm, but may also apply to larger stones. The committee noted that larger stones are more likely to have risks associated with watchful waiting. For example, the stone's location may change and cause obstruction, there may be infection or bleeding, or the person may become symptomatic. The committee agreed that watchful waiting may be particularly beneficial for people with complex comorbidities that make surgery a higher risk. They agreed that watchful waiting should be considered for those with asymptomatic renal stones less than 5\xa0mm, and for stones larger than 5\xa0mm as long as the possible risks and benefits have been discussed with the patient.\n\nSome evidence showed a small benefit of ureteroscopy (URS) over SWL for stone removal, the number of repeat treatments needed and quality of life, but there was a shorter hospital stay, less pain and fewer major adverse events with SWL. Economic analysis showed that SWL offered a better balance of benefits and costs than URS, even when the possible need for repeat treatment was taken into account. The cost differences were substantial, and sensitivity analysis showed economic benefit for SWL even with lower SWL success rates. The committee therefore agreed to offer the less-invasive procedure of SWL to treat small ureteric stones (less than 10\xa0mm) in adults.\n\nHowever, they acknowledged that prompt treatment of these stones is needed because of the risk of obstruction and kidney damage. URS may be considered as an alternative treatment if, for example, stone clearance is not possible within 4\xa0weeks with SWL, there are contraindications to SWL, the stone is not targetable, or a course of SWL has previously failed (because patients tend to form the same type of stones).\n\nEvidence showed a benefit of URS over SWL for stone removal and the number of repeat treatments needed, but there was a shorter hospital stay, less pain and fewer major adverse events with SWL.\n\nPrompt treatment of ureteric stones is needed because of the risk of obstruction and kidney damage. The risk is even greater with larger stones.\n\nThe committee acknowledged that in terms of costs, SWL may offer better value; however, the committee were very concerned about the risks in using SWL for larger ureteric stones. SWL may be delayed because of availability of a lithotripter and the total time to clear the stone will increase if multiple sessions are needed. Additionally, the effectiveness of SWL can vary with the type of machine used (fixed/mobile) and operator skill. The committee agreed to recommend URS for adults with ureteric stones of 10\xa0to\xa020\xa0mm, but SWL can be considered if local facilities allow stone clearance within 4\xa0weeks.\n\nEvidence (mainly in a group with impacted stones) suggested a benefit of percutaneous nephrolithotomy (PCNL) for stone removal compared with URS, but there was a shorter hospital stay with URS. The committee agreed that PCNL is not usually performed in the UK for this indication, but that it could be considered for larger impacted stones, particularly in the proximal ureter.\n\nNo evidence was identified, and the committee agreed that this is a very small group. Usual practice depends on local availability of treatments and expertise. The committee decided that they could not make a recommendation for this group.\n\nThere was evidence comparing SWL with URS, SWL with PCNL and surgical treatment including SWL with non-surgical treatment (observation or MET). The evidence suggested a benefit of URS in terms of retreatment rate and ancillary procedures, and a benefit of SWL in terms of readmission, failed technology and major adverse events. Limited evidence from 1\xa0small study suggested a benefit of PCNL over SWL in terms of stone-free state and ancillary procedures. There was also evidence of a benefit of surgery compared with non-surgical treatment (observation or MET).\n\nBecause SWL offered a better balance of benefits and costs, the committee agreed that it should be offered in the first instance, and that URS should be considered if there are contraindications for SWL, or anatomical reasons or multiple stones, or a previous course of SWL has failed. Because of concerns around the limited evidence for PCNL, this should only be considered as an option when both SWL and URS have failed or are not an option.\n\nSome evidence showed a benefit of SWL in terms of length of stay, quality of life and some major adverse events, compared with URS and PCNL. Both URS and PCNL had clinical benefits in terms of stone-free state, retreatment rate and ancillary procedures, compared with SWL. There was no difference between PCNL and URS for most outcomes. One study showed a benefit of surgery in terms of ancillary procedures and stone-free state compared with non-surgical treatment (observation), and 1\xa0study showed a benefit of tubeless compared with standard PCNL in terms of stone-free state.\n\nThe committee agreed that URS or SWL offered a better balance of benefits and costs compared with PCNL, and this intervention should be considered only if URS or SWL have failed. In terms of a choice between URS and SWL, the size of the stone was a concern for the committee; however, factors such as quality of life and the risks associated with larger stones were difficult to quantify in any costing work. The committee agreed that the stone size itself would be a factor in the treatment decision, because effectiveness of SWL can also vary by stone size, and a stone nearer to the lower end of the range (10\xa0to\xa020\xa0mm) could be an appropriate candidate for SWL. Overall, the committee felt that a recommendation to consider URS or SWL would allow flexibility for clinicians in choosing a treatment option. The committee agreed that they did not have enough confidence in the evidence to recommend tubeless over standard PCNL, but agreed that either approach could be used, according to clinical judgement.\n\nCurrent practice for renal stones greater than 20\xa0mm is PCNL, and the committee agreed that there was insufficient evidence to change this. However, the committee considered that PCNL may not always be an option (for example, for people with high comorbidity, anaesthetic risks or anatomical considerations), and so URS could be considered in these circumstances. The committee agreed that all evidence for types of PCNL was based on small studies, and there was no difference between them for many outcomes. Therefore, any approach should be available and considered based on clinical judgement.\n\nThere was no evidence for renal staghorn stones in adults. Current practice for these stones is to use PCNL. The committee agreed that staghorn stones are all over 20\xa0mm and so would be treated as renal stones larger than 20\xa0mm.\n\nLimited evidence from a single, small study showed a benefit of URS over SWL in terms of stone-free state, retreatment rate and ancillary procedures. The committee agreed to recommend SWL as the first treatment for these stones in adults because of the better balance of benefits and costs. However, they noted that evidence for children and young people was much more limited. They also discussed that unlike adults, children usually require a general anaesthetic for each session of SWL. Because both URS and SWL are used in current practice, the committee agreed that either could be considered for children and young people with stones less than 10\xa0mm.\n\nNo evidence was identified so the committee made a recommendation based on their knowledge and experience. They noted that there is a perception that children have a higher incidence of spontaneous passage of larger stones than adults. The committee agreed that unlike the adult population where URS should be offered in the first instance and SWL considered if facilities allow quick stone clearance, for children and young people, both SWL and URS could be treatment options so allowing clinical flexibility.\n\nNo evidence was identified and the committee agreed that currently these stones are treated on a case-by-case basis. They decided that they could not make a recommendation for this group.\n\nNo evidence was identified. The committee discussed current practice and agreed that URS or SWL should be considered in the first instance, and PCNL when other treatment has failed.\n\nVery limited evidence from a single study showed a benefit of URS in terms of stone-free state, retreatment and significant residual stones when compared with SWL. Limited evidence from another single study showed benefits of PCNL in terms of stone-free state, retreatment rate and ancillary procedures when compared with SWL. The only evidence showing a benefit for SWL was for fewer minor adverse events, when SWL was compared with PCNL. Two non-randomised studies comparing URS and PCNL had inconclusive results. The committee agreed that clinical judgement should be used when deciding which treatment to use (URS, SWL or PCNL).\n\nEvidence from a single study showed a benefit of URS compared with PCNL in terms of length of stay and adverse events, but a benefit of PCNL in terms of stone-free state and retreatment rate. Evidence from 2\xa0small studies showed a benefit of tubeless PCNL compared with standard PCNL in terms of length of stay, ancillary procedures and minor adverse events, but a benefit of standard PCNL in terms of retreatment. One non-randomised study showed a benefit of PCNL compared with SWL for stone-free state and retreatment, but a benefit of SWL for length of stay.\n\nThe committee agreed that PCNL may be effective, but carries more risks than URS. They decided that either URS or PCNL could be considered, and that SWL should not be ruled out.\n\nNo evidence was identified. The committee agreed that staghorn stones in children would be treated in the same way as stones greater than 20\xa0mm.\n\n## How the recommendations might affect practice\n\nChanges in practice are likely for adults with ureteric stones smaller than 10\xa0mm because SWL is recommended, whereas currently URS is more frequently used. Economic analysis showed there will be a saving from using SWL over URS, although this may be more longer term because of short-term implementation costs required. Having good referral systems may mean that additional lithotripters are not needed. Alternatively, more investment in mobile or fixed lithotripters could be an option, or networks of mobile or fixed-site lithotripters allowing patients timely access to treatment. However, more staff may be needed to undertake SWL (for example, ultrasonographers) to meet the additional demand. Additional training to maximise the effectiveness of lithotripsy may also be needed. Increases in staffing can provide benefits to other areas of the NHS because it is likely that not all their time will be spent treating renal and ureteric stones.\n\nIn adults with ureteric stones of 10\xa0to\xa020\xa0mm, URS tends to be used, so recommendations to consider SWL could lead to a change in practice, with potential longer-term savings, depending on uptake.\n\nIn adults with renal stones of 10\xa0to\xa020\xa0mm, PCNL tends to be used, so recommendations to consider URS or SWL as first line could lead to a change in practice, with likely savings, depending on uptake.\n\nOther recommendations for adults reflect current practice. In children, multiple treatment options have been recommended to allow for clinical judgement, and therefore a change in practice is unlikely.\n\nReturn to recommendations\n\n# Timing of surgical treatment for ureteric stones\n\nRecommendation 1.5.4\n\n## Why the committee made the recommendation\n\nEvidence showed a benefit of early intervention (within 48\xa0hours) in terms of stone removal, repeated or ancillary procedures, and stent insertion. This could lead to substantial cost savings on a population level from stents and further treatment avoided. The committee agreed that ureteric stones can be extremely painful and if left untreated can lead to a loss of kidney function. Surgical treatment should be offered within 48\xa0hours of diagnosis or readmission, to people presenting with ureteric stones and renal colic, if the pain is ongoing and not tolerated or the stone is unlikely to pass.\n\nAlthough the evidence was from people with stones less than 20\xa0mm, the committee agreed that ureteric stones of all sizes should be treated within this timeframe. There was no evidence for people with renal stones, and the committee considered that the timing of treatment for these stones should be prioritised according to the nature and severity of symptoms. There was also no evidence found for children and young people, and so the committee agreed that the recommendations should only apply to adults.\n\n## How the recommendation might affect practice\n\nCurrent practice is to aim to treat ureteric stones in adults with an elective surgical procedure within 4\xa0to\xa06\xa0weeks, although practice can vary and is influenced by the availability of services. People are likely to have a stent inserted while waiting for surgery.\n\nTo implement these recommendations for URS, services would need to be reconfigured to allocate more theatre time for emergency surgery. More equipment would also be needed for SWL, such as more responsive networks of mobile lithotripters, more fixed-site machines or better organised referral systems. Early intervention is likely to lead to substantial savings by avoiding the need for further treatments and the use of stents. These savings are likely to outweigh the implementation costs, and therefore this recommendation is not expected to have a cost impact overall.\n\nReturn to recommendation\n\n# Medical expulsive therapy as adjunctive to shockwave lithotripsy\n\nRecommendation 1.5.5\n\n## Why the committee made the recommendation\n\nEvidence showed a benefit in terms of stone passage when alpha blockers were used as adjunctive therapy for adults having SWL for small distal or proximal ureteric stones (less than 10\xa0mm). There was no difference in adverse events. The evidence focused on distal or proximal ureteric stones but the committee agreed that alpha blockers could be considered as adjunctive therapy to SWL for adults with small ureteric stones in any location. There was no evidence for mid-ureteric stones less than 10\xa0mm; however, the committee agreed that this is a small group of people and usual clinical practice often involves waiting to see if the stone progresses to the distal ureter. There was not enough evidence for the committee to make a recommendation for adjunctive therapy for other interventions or for larger ureteric stones of 10\xa0to\xa020\xa0mm.\n\nEvidence showed that the use of alpha blockers in conjunction with URS improved stone passage and some adults with small distal ureteric stones (less than 10\xa0mm) and proximal ureteric stones (10\xa0to\xa020\xa0mm) experienced reduced pain. The committee agreed that this is not usual practice and also noted that the evidence was based on single studies. They agreed that further research on the use of alpha blockers, particularly tamsulosin, as adjunctive therapy to URS for any stone less than 20\xa0mm would be beneficial to inform future practice, so decided to make a research recommendation on alpha blockers and ureteroscopy.\n\n## How the recommendation might affect practice\n\nAlpha blockers are not widely used as an adjunct to SWL for ureteric stones so this will represent a change in practice. The small cost of the alpha blockers is likely to be outweighed by savings related to improved stone clearance (reduced use of surgical interventions).\n\nReturn to recommendation\n\n# Stenting after ureteroscopy\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendation\n\nNo evidence was found for the use of stents after SWL or PCNL, or for people with renal stones, or for children and young people.\n\nEvidence showed that there was no benefit of routine stenting after URS for adults with ureteric stones less than 20\xa0mm. Stents were associated with a number of adverse symptoms (dysuria, haematuria, irritative symptoms, frequency and urgency). People with a stent also had more abdominal and bladder pain, which the committee agreed were likely to be stent related. The committee agreed that because there was no benefit of stents, and they cause adverse events that negatively affect quality of life, stents should not be routinely offered to adults who have had URS for ureteric stones less than 20\xa0mm. There may be instances when stents might be considered (such as more treatment anticipated, evidence of infection or obstruction, or a solitary kidney).\n\nThere was no evidence for stones larger than 20\xa0mm. The committee agreed that this is a small group and the surgical treatment used varies. They noted that the decision to use a stent would be based on clinical judgement and so agreed not to make a recommendation for this group.\n\n## How the recommendation might affect practice\n\nCurrently around 70% of people overall receive a stent after URS and many of these are being used to avoid future problems that are unlikely to occur. Stents may still be needed in some cases, for example, when further treatment is anticipated, or there is evidence of infection or obstruction, a solitary kidney or for a Clavien–Dindo grade\xa03 complication. A few urologists currently advocate the routine placement of stents after all URS procedures. The recommendation is likely to mean that fewer people receive stents, which may be cost saving.\n\nReturn to recommendation\n\n# Metabolic testing\n\nRecommendations 1.7.1 to\xa01.7.3\n\n## Why the committee made the recommendations\n\nStone analysis and blood testing (serum calcium) allows the diagnosis of treatable conditions such as cystinuria, uric acid stones and primary hyperparathyroidism. Urine testing allows for the identification of metabolic abnormalities that can be treated, and so reduces the risk of future stones.\n\nEvidence showed that there is effective treatment for hypercalciuria and hypocitraturia, and the committee noted that these conditions would be diagnosed with a 24‑hour urine test. This suggests that understanding underlying metabolic diseases can lead to prevention of stone recurrence. However, no evidence for 24‑hour urine testing was identified, so the committee agreed that they could not make a practice recommendation. They agreed to make a research recommendation on the clinical and cost effectiveness of a full metabolic investigation to inform future guidance.\n\nNo evidence was found on stone analysis or blood tests in people who have or have had renal or ureteric stones. It is not clear which tests are most useful and whether tests should be offered to all people with a stone or just those at high risk of stone recurrence. However, the committee also considered the high prevalence of primary hyperparathyroidism in people with renal stones and noted that this could be identified with serum calcium testing, which is an inexpensive test. Therefore, the committee agreed that serum calcium should be measured for adults and stone analysis considered.\n\nThe committee agreed that current practice for children and young people is variable. All paediatric patients should have a metabolic assessment. The nature of this assessment varies nationally. Referral to a paediatric nephrologist or urologist with expertise in testing for metabolic conditions should be considered.\n\n## How the recommendations might affect practice\n\nCurrent practice is varied with a full range of metabolic tests being done in some areas and fewer tests in others. Therefore, the recommendations may mean a change in practice for some providers. However, the committee agreed that existing centres should have the resources to cope with an increased demand for stone analysis, which is relatively easy to do and is not urgent.\n\nReturn to recommendations\n\n# Frequency of follow‑up imaging\n\n## Why the committee made the research recommendation\n\nNo evidence was found on the optimum frequency of imaging in people who have or have had renal or ureteric stones. The committee agreed that there is variation in current practice, with frequency often depending on factors such as whether the person has had 1\xa0stone or recurrent stones. The committee was not able to make a recommendation for practice because their experience differed, but they did agree to make a research recommendation on the frequency of follow-up imaging to inform future guidance.\n\nFull details of the evidence and the committee's discussion are in evidence review J: imaging for follow-up.\n\n# Preventing recurrence\n\nRecommendations 1.8.1 to\xa01.8.5\n\n## Why the committee made the recommendations\n\nSome evidence showed a benefit of a high water intake in reducing stone recurrence in adults. Limited evidence from a single study in adults showed a benefit of lemon juice in terms of urine calcium and pH but no difference in urine oxalate. Lemon juice is high in citrate leading to higher concentrations of citrate in urine. This may stop calcium from binding to other stone constituents and so prevent stone formation and recurrence. The committee agreed to recommend a high water intake and the addition of lemon juice to water. Evidence showed a benefit of avoiding carbonated drinks in terms of stone recurrence, and so the committee agreed to recommend that these should be avoided.\n\nEvidence on diet was mixed but the committee agreed that a normal calcium intake and a low salt intake may help to prevent stone recurrence. Evidence on avoiding a high protein diet was inconclusive, but the committee acknowledged that this is the advice currently given.\n\nEvidence showed that potassium citrate could reduce the recurrence of calcium oxalate and calcium oxalate/calcium phosphate stones in adults. However, there were adverse events associated with the use of potassium citrate and the committee agreed that there may be concerns about high levels of potassium in the blood (hyperkalaemia) in some groups. Despite this, the committee agreed that the benefits in terms of stones avoided are likely to outweigh any harms. Potassium citrate is currently used in UK practice and so the committee agreed it could be considered to prevent stone recurrence in adults with calcium oxalate stones.\n\nLimited evidence in children showed that potassium citrate reduced stone recurrence after PCNL and SWL. There was no information on adverse events or on the type of stone or results of urine testing. The committee noted that in UK practice, potassium citrate is used for children based on the levels of calcium or citrate in urine. They agreed that it could be considered for children with recurrence of calcium oxalate stones and with hypercalciuria or hypocitraturia.\n\nLimited evidence showed that thiazides reduced stone recurrence in adults with high levels of calcium in urine (hypercalciuria) compared with no intervention. There was no benefit for adults with normal levels of urinary calcium, and evidence was mixed when the biochemical abnormality was mixed or not defined. The committee agreed that thiazides tend to be well tolerated but should only be used after salt has been restricted. They agreed that thiazides could be considered for adults with hypercalciuria and recurrent calcium oxalate stones, but only after reducing salt intake to recommended levels.\n\nThere was not enough evidence for the committee to make recommendations on allopurinol or combined therapy of allopurinol and thiazides. Although limited evidence suggested a potential benefit of magnesium, the committee knew from their experience that magnesium may cause adverse effects. The committee agreed that the limited evidence and potential for adverse events did not justify a recommendation.\n\nLimited evidence from a single study of thiazides compared with placebo in people who had had previous SWL showed some benefit of thiazides in reducing the need for further SWL and for stone growth. The committee agreed that this is not usual practice and that further research would be beneficial. The committee agreed to make a research recommendation on preventative treatment following SWL.\n\n## How the recommendations might affect practice\n\nThe recommendations on diet broadly reflect current practice. They emphasise the importance of dietary advice in preventing further stone episodes. Dietary advice should be given in conjunction with lifestyle advice.\n\nThe committee considered the impact the recommendations would have on practice, including metabolic laboratory testing. Identifying stone composition or metabolic abnormalities would be a prerequisite to the recommendations and this would have a cost as well as potential service impact.\n\nRecommending the interventions also has a monitoring impact. There is variation in current practice in terms of the use of thiazides and potassium citrate for people with renal or ureteric stones.\n\nReturn to recommendations", 'Context': 'Renal and ureteric stones usually present as an acute episode with severe pain, although some stones are picked up incidentally during imaging or may present as a history of infection. The initial diagnosis is made by taking a clinical history and examination and carrying out imaging; initial management is with painkillers and treatment of any infection.\n\nOngoing treatment of renal and ureteric stones depends on the site of the stone and size of the stone (less than 10\xa0mm, 10\xa0to\xa020\xa0mm, greater than 20\xa0mm; staghorn stones). Options for treatment range from observation with pain relief to surgical intervention. Open surgery is performed very infrequently; most surgical stone management is minimally invasive and the interventions include shockwave lithotripsy (SWL), ureteroscopy (URS) and percutaneous stone removal (surgery). As well as the site and size of the stone, treatment also depends on local facilities and expertise. Most centres have access to SWL, but many use a mobile machine on a sessional basis rather than a fixed-site machine, which has easier access during the working week. The use of a mobile machine may affect options for emergency treatment, but may also add to waiting times for non-emergency treatment.\n\nAlthough URS for renal and ureteric stones is increasing (there has been a 49% increase from 12,062\xa0treatments in 2009/10, to 18,066\xa0in 2014/15 [Hospital Episode Statistics data]), there is a trend towards day-case/ambulatory care, with this increasing by 10% to 31,000\xa0cases a year between 2010 and\xa02015. The total number of bed-days used for renal stone disease has fallen by 15% since 2009/10. However, waiting times for treatment are increasing and this means that patient satisfaction is likely to be lower.\n\nBecause the incidence of renal and ureteric stones and the rate of intervention are increasing, there is a need to reduce recurrences through patient education and lifestyle changes. Assessing dietary factors and changing lifestyle have been shown to reduce the number of episodes in people with renal stone disease.\n\nAdults, children and young people using services, their families and carers, and the public will be able to use the guideline to find out more about what NICE recommends, and help them make decisions. These recommendations apply to all settings in which NHS-commissioned care is provided.'}
|
https://www.nice.org.uk/guidance/ng118
|
This guideline covers assessing and managing renal and ureteric stones. It aims to improve the detection, clearance and prevention of stones, so reducing pain and anxiety, and improving quality of life.
|
d1e748f276a17e9b7daff7635dd9bc8fccfde663
|
nice
|
Tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years
|
Tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years
Evidence-based recommendations on tisagenlecleucel therapy (Kymriah) for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years.
# Recommendations
Tisagenlecleucel therapy is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25 years, only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect both treatment in preparation for and treatment with tisagenlecleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people aged under 18 years, this decision should be made jointly by the clinician and the young person, or the young person's parents or carers.
Why the committee made these recommendations
Current treatment for relapsed or refractory acute lymphoblastic leukaemia is usually blinatumomab or salvage chemotherapy. Tisagenlecleucel is a chimeric antigen receptor (CAR) T‑cell therapy. It contains the patient's own T cells that have been modified to attach to and kill cancer cells.
Clinical trial evidence suggests that compared with current treatment, people having tisagenlecleucel may live for longer, or have more time before their disease relapses. However, the evidence is uncertain and it is not known whether tisagenlecleucel can cure acute lymphoblastic leukaemia.
There is also not enough evidence to determine the costs of treating side effects and whether people will need a subsequent stem cell transplant.
The most plausible cost‑effectiveness estimates for tisagenlecleucel are higher than what NICE normally considers acceptable. The life expectancy of people with relapsed or refractory acute lymphoblastic leukaemia is uncertain. It does not meet both of NICE's criteria to be a life-extending treatment at the end of life. Therefore tisagenlecleucel cannot be recommended for routine use in the NHS.
Collecting more data on overall survival, subsequent stem cell transplant rates, and immunoglobulin usage will reduce the uncertainty in the clinical‑ and cost‑effectiveness evidence. Therefore tisagenlecleucel is recommended for use in the Cancer Drugs Fund.# Information about tisagenlecleucel
# Marketing authorisation indication
Tisagenlecleucel (Kymriah, Novartis) is indicated for treating 'paediatric and young adult patients up to 25 years of age with B‑cell acute lymphoblastic leukaemia that is refractory, in relapse post‑transplant or in second or later relapse'. Tisagenlecleucel is an immunocellular CAR T‑cell therapy. It contains the patient's own T cells (a type of white blood cell) that have been modified genetically in the laboratory so that they make a protein called chimeric antigen receptor (CAR). CAR can attach to another protein on the surface of cancer cells called CD-19. When tisagenlecleucel is given to the patient, the modified T cells attach to and kill cancer cells, thereby helping to clear the cancer from the body.
# Dosage in the marketing authorisation
Treatment with tisagenlecleucel comprises a single‑dose intravenous infusion of tisagenlecleucel. It is intended for autologous use only and at the following dosage:
For patients ≤50 kg: 0.2 to 5.0×106 CAR‑positive viable T cells per kg body weight.
For patients >50 kg: 0.1 to 2.5×108 CAR‑positive viable T cells (non-weight based).
# Price
The list price for tisagenlecleucel is £282,000 per infusion (company submission). The company has a commercial arrangement. This makes tisagenlecleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with relapsed or refractory B‑cell acute lymphoblastic leukaemia would welcome a new treatment option
Outcomes for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia are poor. The disease has low levels of response to treatment, and is associated with limited survival. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. The patient experts explained that the cycle of remission and relapse when having successive treatments has a substantial psychological and physical effect on people with the disease and the people caring for them. They further explained that stem cell transplants are associated with a slow and laborious recovery over the course of around a year. The committee understood that chimeric antigen receptor (CAR) T‑cell therapies (such as tisagenlecleucel) are advanced treatments for cancer and belong to a new generation of personalised cancer immunotherapies that are based on collecting and modifying patients' own immune cells to treat their cancer. The committee heard from the patient experts that treatment with CAR T‑cell therapies involves intense and challenging side effects immediately after infusion, but can enable recovery within a few months. The committee concluded that people with relapsed or refractory acute lymphoblastic leukaemia would welcome new treatment options such as CAR T‑cell therapies that improve the chance of survival.
# Treatment pathway
## The company's positioning of tisagenlecleucel in the pathway is appropriate
The company proposed 4 potential positions for tisagenlecleucel in the treatment pathway for this indication. Specifically, for use in people aged up to 25 years with B‑cell acute lymphoblastic leukaemia:
whose disease was refractory after 1 systemic chemotherapy ('primary refractory')
whose disease was refractory after 2 systemic chemotherapies ('chemo‑refractory')
whose disease had relapsed after an allogeneic stem cell transplant
whose disease had relapsed after 2 or more systemic chemotherapies.The clinical experts indicated that survival outcomes for these groups of people were poor and agreed that they could potentially benefit from tisagenlecleucel. The committee accepted that the company's 4 proposed positions for tisagenlecleucel were consistent with its marketing authorisation. It noted that the marketing authorisation did not specify treatment based on Philadelphia chromosome status: having discussed this, the committee agreed that the marketing authorisation included both people with and without the Philadelphia chromosome. It agreed that the treatment pathways for Philadelphia chromosome‑negative and Philadelphia chromosome‑positive B‑cell acute lymphoblastic leukaemia should be considered in more detail.
## Blinatumomab and salvage chemotherapy are both appropriate comparators and blinatumomab is the main comparator
The clinical experts stated that the treatment pathway for B‑cell acute lymphoblastic leukaemia was evolving, and that NICE's technology appraisal guidance on inotuzumab ozogamicin as an option for treating B-cell acute lymphoblastic leukaemia may change the treatment pathway. The committee noted that this was not included in the scope of this appraisal because it was not established clinical practice in the NHS when the final scope was issued. Patients with primary refractory Philadelphia chromosome‑negative B‑cell acute lymphoblastic leukaemia would currently have blinatumomab or salvage chemotherapy, with the aim of bridging to an allogeneic stem cell transplant. Salvage chemotherapy includes FLA(G)-IDA (fludarabine, cytarabine and idarubicin, with or without granulocyte‑colony stimulating factor). For patients whose disease responds to initial therapy and then relapses, or who have a second or further relapse, the aim of treatment is a further remission which can then be consolidated with an allogeneic stem cell transplant. As for patients with primary refractory disease, treatment options are blinatumomab and salvage chemotherapy with FLA(G)-IDA. The clinical experts stated that treatment with blinatumomab was more likely to enable a subsequent stem cell transplant than treatment with salvage chemotherapy, so blinatumomab was the preferred treatment option providing it had not already been used (for example, after first relapse for adults). If blinatumomab cannot be offered then salvage chemotherapy would be offered. The clinical experts also stated that in their opinion inotuzumab ozogamicin was likely to replace blinatumomab as a treatment option after first relapse in the treatment pathway, with blinatumomab likely to become the preferred subsequent treatment option for patients who have a second relapse. However, the committee accepted that there are little data on the use of blinatumomab after inotuzumab ozogamicin, and it noted that this lack of evidence may affect the choice of treatment. The committee also accepted that there is no biologically plausible reason why blinatumomab should not be effective when used after inotuzumab ozogamicin. It agreed that blinatumomab was the main treatment option for relapsed or refractory Philadelphia chromosome‑negative B‑cell acute lymphoma, and that some people would be offered salvage chemotherapy. The committee concluded that blinatumomab and salvage chemotherapy were both appropriate comparators and that blinatumomab was the main comparator.
## Patient numbers are too small to analyse the clinical and cost effectiveness of tisagenlecleucel for Philadelphia chromosome‑positive disease separately
Philadelphia chromosome‑positive disease accounts for around 3% of B‑cell acute lymphoblastic leukaemia. It is associated with poor outcomes and is treated differently to Philadelphia chromosome‑negative disease: most people have at least 2 tyrosine kinase inhibitors (TKIs), before then having salvage chemotherapy or best supportive care. The clinical and patient experts explained that patients with Philadelphia chromosome‑positive acute lymphoblastic leukaemia whose disease relapses after treatment TKIs could benefit from tisagenlecleucel and that outcomes were expected to be similar to patients with Philadelphia chromosome‑negative disease. The committee noted that although the company did not present a treatment pathway for Philadelphia chromosome‑positive disease, it stated in its submission that in clinical studies, patients could only have tisagenlecleucel if their disease had already relapsed after 2 TKIs, or they had stopped taking them. The committee also noted that the company did not present a separate clinical‑ and cost‑effectiveness analysis for Philadelphia chromosome‑positive disease because of the small population size; the tisagenlecleucel clinical studies included only 5 patients with Philadelphia chromosome‑positive disease, and there are expected to be only 1 or 2 patients per year in England. The committee concluded that the company's positioning of tisagenlecleucel for Philadelphia chromosome‑positive disease based on clinical study eligibility was appropriate and acknowledged that patient numbers were too small for clinical and cost effectiveness in this population to be analysed separately.
# Clinical evidence
## Tisagenlecleucel is clinically effective but the lack of comparator data means the benefit compared with blinatumomab or salvage chemotherapy is unknown
The main evidence on the clinical effectiveness of tisagenlecleucel came from 3 single-arm studies:
ELIANA, an international, multicentre, phase II study (n=97)
ENSIGN, a US, multicentre, phase II study (n=73)
B2101J, a US, single-centre, phase I/IIa study (n=66).The company pooled results from all patients in the studies who had tisagenlecleucel (n=193). The clinical experts indicated that although patient numbers in the primary refractory and Philadelphia chromosome‑positive populations were small, outcomes were expected to be similar to the overall pooled study population. Outcomes of each study included overall remission rate, overall survival, event-free survival and adverse events of treatment. The pooled analysis and full results from the ELIANA and B2101J studies are considered to be academic in confidence by the company and cannot be reported here. However, results from earlier analyses of the trials have been reported (ELIANA: Maude, Laetsch et al. 2018; B2101J: Maude, Grupp et al. 2018) so these results are reported here. Results from the individual studies showed that tisagenlecleucel was effective in inducing remission and improving survival for patients with B‑cell acute lymphoblastic leukaemia (see table 1, below). The committee heard from clinical experts that the results of the studies were generalisable to clinical practice, although the experts noted that clinicians were more likely to offer tisagenlecleucel to patients with a higher Karnofsky/Lansky performance status, who would be more likely to tolerate the bridging chemotherapy regimen and the potential adverse effects. The committee noted that there was no clinical evidence directly comparing tisagenlecleucel with blinatumomab or salvage chemotherapy because all 3 trials were single‑arm studies. It concluded that tisagenlecleucel was clinically effective, but agreed that the lack of comparative data made the assessment of comparative effectiveness (and any cost‑effectiveness analyses) more challenging.
Source and data
ELIANA
number=75
ENSIGN
number=58 (42 for overall remission rate)
B2101J
number=59
Source
Maude, Laetsch et al. 2018
Company submission
Maude, Grupp et al. 2018
Overall remission rate: proportion of patients (95% confidence interval)
(71 to 89)
(53 to 82)
(not recorded)
Median overall survival: months (95% confidence interval)
Not estimable
(9 to not estimable)
Not recorded
Survival at 12 months: proportion of patients (95% confidence interval)
(63 to 86)
(46 to 76)
(69 to 91)
## Clinical evidence for tisagenlecleucel beyond 30 months is very uncertain because of small patient numbers and differences in the trial populations
The median follow‑up in each study was less than 3 years, and after around 30 months survival estimates were based on less than 15 patients at risk, who were exclusively from the B2101J study. The committee noted that the patient population in B2101J was different to those in ELIANA and ENSIGN: patients in B2101J typically had a higher Karnofsky/Lansky performance status (that is, were in better health), were more likely to have already had an allogeneic stem cell transplant and were eligible for up to 3 infusions of tisagenlecleucel instead of 1. The committee concluded that because of the small patient numbers and the differences between study populations, the clinical evidence for tisagenlecleucel beyond 30 months was very uncertain.
## There is no robust evidence that tisagenlecleucel has a curative effect
The clinical experts explained that tisagenlecleucel would be offered with the intent of curing relapsed or refractory B‑cell acute lymphoblastic leukaemia. It was aware that a common assumption in oncology clinical trials of treatments given with curative intent is that people who survive for an arbitrary time period (typically 5 years) could be considered to be long‑term survivors, and effectively cured. The clinical experts considered that it may be appropriate to assume that patients in the population under consideration who survive for 3 years could be considered to be cured. Having acknowledged that survival estimates beyond 30 months were highly uncertain (see section 3.6) the committee concluded that with an assumed cure point of either 3 or 5 years, there was not robust evidence that tisagenlecleucel has a curative effect.
## There is no clinical evidence on the efficacy of tisagenlecleucel after treatment with blinatumomab
The committee was aware that all 3 tisagenlecleucel studies excluded patients who had already had blinatumomab, and that in NHS clinical practice patients may have blinatumomab after first disease relapse (see section 3.3). The clinical experts explained that up to 20% of patients who relapse after having blinatumomab may become CD‑19‑negative, meaning they would be unlikely to benefit from tisagenlecleucel after second disease relapse. However, they noted that in clinical practice patients would have blinatumomab for up to 2 cycles: this means that CD‑19‑negative relapse would be unlikely, and so treatment with tisagenlecleucel after blinatumomab may be effective. The committee was aware that the summary of product characteristics for tisagenlecleucel states that tisagenlecleucel is not recommended if the disease has relapsed with CD-19-negative leukaemia after previous anti-CD-19 therapy (such as blinatumomab). The committee concluded that there was no clinical evidence to determine if tisagenlecleucel would be effective after treatment with blinatumomab, and that this added uncertainty around the generalisability of the results to clinical practice.
## Despite limitations, the von Stackelberg et al. (2016) study is an appropriate source of data for the efficacy of blinatumomab
The evidence for the efficacy of blinatumomab came from a phase II trial in 70 patients aged under 18 years with relapsed or refractory B‑cell acute lymphoblastic leukaemia (von Stackelberg et al. 2016). The study population consisted of patients who were primary refractory, in first relapse after full salvage induction regimen, in second or later relapse or in any relapse after allogeneic stem cell transplantation. The patient population differed from that of the tisagenlecleucel studies: the tisagenlecleucel studies recruited patients up to the age of 25 years, whereas von Stackelberg et al. only recruited patients aged under 18 years. The committee noted that the 2 studies differed in several important prognostic factors, including the proportion of primary refractory patients, percentage of bone marrow blasts, number of previous treatments and time since last relapse. The committee acknowledged that patients in von Stackelberg et al. may therefore have had more progressive disease at baseline than patients in the tisagenlecleucel studies. The committee also noted that the median overall survival of 7.5 months in von Stackelberg et al. was lower than the overall survival of 9.9 months reported for patients aged 18 to 35 years (n=123) in the TOWER study of blinatumomab (the TOWER study was the main source of evidence used to inform NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia chromosome-negative acute lymphoblastic leukaemia). The committee acknowledged that this may indicate that patients in von Stackelberg et al. may have worse outcomes than would be expected for blinatumomab in clinical practice. It also noted that patients were followed up for 2 years and that no survival data were available beyond this point. Despite these limitations, the committee concluded that because neither the ERG nor the company presented a suitable alternative data source for the efficacy of blinatumomab, it was appropriate to consider von Stackelberg et al. in its decision-making.
## Jeha et al. (2006) and Kuhlen et al. (2017) should both be considered as sources of data for the efficacy of salvage chemotherapy
The company's systematic literature review did not identify any evidence for the efficacy of FLA(G)-IDA salvage chemotherapy. Instead, the company used clofarabine monotherapy as a proxy for salvage chemotherapy. It provided evidence from a phase II study of clofarabine monotherapy in 61 patients aged under 21 years with relapsed or refractory B‑cell acute lymphoblastic leukaemia (Jeha et al. 2006). The study reported an overall remission rate of 20% and median overall survival of 13 weeks. The clinical experts explained that clofarabine monotherapy was not used in clinical practice in the NHS because of concerns over increased toxicity compared with other treatment options. However, they noted that the efficacy of clofarabine was similar to that of FLA(G)-IDA, so it was plausible that data from Jeha et al. for clofarabine could be used as a proxy for salvage chemotherapy. The committee was aware of a submission from NHS England which stated that clinical practice had changed since the publication of Jeha et al., and that outcomes in the study were likely to be worse than in clinical practice because supportive care and the availability and speed of access to stem cell donors have since improved. The ERG identified 2 studies, published after the company's submission, which contained evidence on the efficacy of FLA-IDA. The most recent of these was a retrospective analysis of 242 UK children with B‑cell acute lymphoblastic leukaemia in first relapse after allogeneic stem cell transplant (Kuhlen et al. 2017). The committee noted that the 3‑year probability of overall survival reported in Kuhlen et al. was 20%. The committee also noted that the ERG considered that the much larger sample size and longer follow‑up provided a more reliable and robust dataset compared with Jeha et al. However, the committee recalled that the ERG had highlighted several differences in prognostic factors between the tisagenlecleucel studies and Kuhlen et al. Factors which may underestimate survival for salvage chemotherapy compared with tisagenlecleucel include: a higher rate of previous allogeneic stem cell transplant; a higher rate of patients having only palliative care; and the inclusion of patients with T‑cell acute lymphoblastic leukaemia or whose disease has relapsed less than 6 months after allogeneic stem cell transplant. Factors which may overestimate survival for salvage chemotherapy compared with tisagenlecleucel include: a higher proportion of patients in first relapse and the inclusion of patients with extramedullary relapse. The committee accepted that both Jeha et al. and Kuhlen et al. had a number of limitations, but concluded that that it was appropriate to consider both studies in its decision-making.
## The efficacy of tisagenlecleucel compared with blinatumomab and salvage chemotherapy is based on naive indirect comparisons which are uncertain
The company did a matching adjusted indirect treatment comparison to attempt to adjust prognostic factors in the pooled population of the 3 single-arm tisagenlecleucel studies to match those in the von Stackelberg et al. and Jeha et al. studies. Factors adjusted for were the number of previous relapses, median number of months since last relapse and proportion of patients with previous allogeneic stem cell transplant. The ERG highlighted that several other important prognostic factors could not be adjusted for, including median age, geographic region, genetic abnormalities and proportion of primary refractory patients. How adjusting these factors (had it been possible) may have affected the outcome of the matching adjusted treatment comparison was unclear. The results of the comparison are academic in confidence and cannot be reported here. However, the committee noted that the company did not use the data from the matching adjusted treatment comparison in its base‑case economic analysis. The committee concluded that using a naive indirect treatment comparison was appropriate, but was subject to uncertainty as a result of the differences in the trial populations.
# Subsequent stem cell transplant
## The number of patients who would have an allogeneic stem cell transplant after having tisagenlecleucel is highly uncertain
The clinical experts explained that in current NHS practice, patients in first or second relapse have allogeneic stem cell transplants if they are considered eligible. The NHS England clinical commissioning expert confirmed that patients who have had a previous allogeneic stem cell transplant and go on to relapse can be offered a second allogeneic stem cell transplant if they are in remission and their relapse occurred more than 1 year after their first transplant. NHS England estimated that the rate of allogeneic stem cell transplant was 15% to 20% after salvage chemotherapy and at least 24% after blinatumomab. Treatment with tisagenlecleucel is intended to be curative: that is, patients whose disease responds to treatment with tisagenlecleucel would not be expected to need a subsequent stem cell transplant. However, some patients in the tisagenlecleucel studies had subsequent allogeneic stem cell transplants; for example, interim analyses of the ELIANA study showed that of patients having tisagenlecleucel, 11% had a subsequent allogeneic stem cell transplant. The company provided an estimate of the rate of allogeneic stem cell transplant based on pooled data from the most recent data cuts of the tisagenlecleucel studies (the data are considered confidential and cannot be reported here), but this may not reflect clinical practice in the NHS. The committee concluded that the number of patients who would need an allogeneic stem cell transplant after tisagenlecleucel is highly uncertain.
# Adverse events
## The most common adverse reaction is cytokine release syndrome
The company provided an analysis of the adverse events for each of the 3 tisagenlecleucel studies. The analyses were considered to be academic in confidence by the company and cannot be reported here, but the summary of product characteristics includes details of some adverse events. The most common non-haematological adverse reactions were cytokine release syndrome (77%), infections (65%), hypogammaglobulinaemia (47%), pyrexia (40%) and decreased appetite (39%). Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common grade 3 and 4 non-haematological adverse reaction was cytokine release syndrome (47%). NHS England's clinical lead for the Cancer Drugs Fund explained that cytokine release syndrome occurs soon after treatment with tisagenlecleucel. Mild or moderate cytokine release syndrome needs considerable observation and supportive care but more severe cytokine release syndrome needs full intensive care and treatment with tocilizumab and steroids. It noted that treatment strategies for these side effects are described in tisagenlecleucel's summary of product characteristics and in the risk management plan that is part of the marketing authorisation. The committee was also aware that tocilizumab has a marketing authorisation for treating CAR T‑cell-induced severe or life-threatening cytokine release syndrome in people aged 2 years and older. NHS England's clinical lead for the Cancer Drugs Fund explained that there is great need for staff training because the symptoms of cytokine release syndrome are so diverse and unexpected. The committee concluded that cytokine release syndrome is a common toxicity associated with tisagenlecleucel and the costs associated with managing and treating it should be reflected in the cost-effectiveness modelling.
## It is unknown how many patients will need intravenous immunoglobulin treatment for B‑cell aplasia and for how long
The committee noted that most people having tisagenlecleucel in clinical trials would have B‑cell aplasia. The clinical experts noted that current practice in clinical trials was for prophylactic treatment with intravenous immunoglobulin (IVIG) for B‑cell aplasia, but that the clinical effectiveness of this approach had not been studied. Long‑term treatment for B‑cell aplasia with IVIG would only be considered for patients with concurrent infections, but there are not enough data on the rate of infections to determine how often long-term treatment is needed. The clinical experts indicated that an assumption of 50% of patients having IVIG over 1 to 2 years as proposed by NHS England was reasonable, but was based on current practice rather than clinical evidence. One expert suggested that treatment may only last for 3 to 12 months. The committee concluded that it was unknown how many patients would need IVIG treatment for B‑cell aplasia and for how long.
# The company's economic model
## The structure of the company's model is appropriate for decision‑making
The company used a partitioned‑survival economic model for all treatments that included 3 states: event-free, progressed disease and death. Before entering the partitioned-survival part of the model, patients having tisagenlecleucel also progressed through a decision tree to capture outcomes for patients who discontinued treatment or died before having tisagenlecleucel. The model contained a structural assumption that after 5 years, general population health‑related quality‑of‑life and costs were applied. The committee concluded that the structure of the company's model was appropriate for its decision-making.
## Blinatumomab is the main comparator to consider in the economic modelling
The committee recalled that blinatumomab and salvage chemotherapy were both appropriate comparators and that blinatumomab is preferred to salvage chemotherapy for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia (see section 3.3). The committee therefore concluded that blinatumomab and salvage chemotherapy should both be considered as comparators in the economic model and that blinatumomab was the main comparator.
# Survival modelling in the economic model
## The extrapolation of overall survival for tisagenlecleucel is an important source of uncertainty in the economic model
The company stated in its submission that using simple parametric survival curves or spline models to model overall survival for tisagenlecleucel produced curves with poor statistical and visual fit. The committee considered the company's preferred extrapolation of overall survival for tisagenlecleucel. It noted the use of a mixture cure model with the exponential distribution to estimate a cure fraction (that is, the proportion of patients cured). After infusion, the cured patients were immediately restored to the age- and gender-matched mortality of the general UK population adjusted for increased mortality in the acute lymphoblastic leukaemia population using a multiplier of 9.05 from MacArthur et al. (2007). Uncured patients followed the parametric survival curve from the time of infusion. The committee noted that the cure fraction for overall survival was a major driver of the cost-effectiveness estimates, and that it varied by approximately 35% in the company's exploratory analyses (the cure fractions are considered confidential and cannot be reported here). The committee was aware that the ERG used the log-logistic distribution in its base case, because the cure fraction for overall survival estimated by the exponential function exceeded the percentage of event‑free survival events in the tisagenlecleucel trials and was therefore a less plausible assumption. It also noted that when the ERG did a scenario analysis using the log-normal distribution, which estimated the lowest cure fraction, the incremental cost-effectiveness ratio (ICER) compared with the ERG's deterministic base-case results increased by £16,567 per quality-adjusted life year (QALY) gained for the comparison with blinatumomab and £28,925 for the comparison with salvage chemotherapy. The committee noted that the variance in cure fraction reflected the lack of long-term survival data (see section 3.6). It also recalled that there was no robust evidence to support the underlying assumption of tisagenlecleucel having a curative effect (see section 3.7). It concluded that the extrapolation of overall survival for tisagenlecleucel is an important source of uncertainty in the economic model.
## Estimates of long-term survival with blinatumomab are subject to uncertainty
The company also used the mixture cure method to extrapolate the overall survival curve for blinatumomab, and chose a log-normal distribution in its analysis. The ERG noted that, as with tisagenlecleucel (see section 3.17), modelling overall survival using this approach is subject to uncertainty and produced cure fractions ranging from 4% to 22%. It preferred the log-logistic distribution because this more closely matched the survival curve in the appraisal of blinatumomab. The committee was also aware that a naive comparison of the blinatumomab curve with the tisagenlecleucel curve was subject to uncertainty because of differences between the trial populations (see section 3.11). The committee accepted the ERG's approach but concluded that estimates of long-term survival with blinatumomab are subject to uncertainty.
## Long-term overall survival with salvage chemotherapy is underestimated by the company's approach and overestimated by the ERG's approach
The company's extrapolation of overall survival used a standard parametric model with a generalised gamma distribution based on data from Jeha et al. (2006). The ERG preferred to base its extrapolation on data from Kuhlen et al. (2017; see section 3.10). It also preferred to use a mixture cure model because this was consistent with the method of extrapolation used for tisagenlecleucel and blinatumomab. The ERG chose the log-normal distribution as the best fitting distribution. When the ERG did a scenario analysis using the log-normal distribution and incorporating adverse event and allogeneic stem cell transplant rates from Kuhlen et al. (2017), the ICER compared with the company's deterministic base‑case result for salvage chemotherapy increased by £8,758 per QALY gained. The clinical experts and the Cancer Drugs Fund clinical lead both indicated that the estimated long-term survival would likely be between the values predicted by the base-case modelling assumptions of the company and ERG. The committee concluded that there was a substantial degree of uncertainty in the extrapolation of overall survival for salvage chemotherapy and that it was underestimated by the company's approach and overestimated by the ERG's approach. It agreed that the most plausible estimate for long‑term overall survival would be somewhere between the values predicted by the 2 models.
## The ERG's correction to the company's approach to modelling long‑term mortality in the mixture cure model is appropriate
The ERG noted an apparent error in the company's model whereby the modelled overall survival could not deviate from the curve predicted by the mixture cure model. This implied that the long-term mortality of patients was lower than that of the general population and lower than observed in epidemiological studies of long‑term survivors of acute lymphoblastic leukaemia in some periods of the model. In a small number of scenarios it also led the model to make inconsistent predictions; for example, patients would come back to life. The company stated that its approach was intended and that it reflected the most appropriate estimates of survival in both the cured and uncured fractions. The committee considered that the long‑term mortality curve predicted by the ERG's model was more plausible and therefore concluded that the ERG's correction to the company's model was appropriate.
# Costs in the economic model
## It is appropriate to assume that patients would have 2 cycles of blinatumomab
The company's model included the assumption that patients could have up to 5 cycles of blinatumomab. However, clinical advice to the ERG indicated that in clinical practice, patients would only have 2 cycles of blinatumomab and the ERG preferred to incorporate this assumption into its model. The committee recalled that it too had heard expert advice that patients would usually only have 2 cycles of blinatumomab (see section 3.8). It concluded that it was appropriate to assume patients would have 2 cycles of blinatumomab.
## The rate of allogeneic stem cell transplant after tisagenlecleucel has a substantial effect on the cost-effectiveness estimates
The rate of subsequent allogeneic stem cell transplant in the company's base-case model was taken from pooled results of the tisagenlecleucel studies (see section 3.12). The company considered that this may be higher than the rate in NHS clinical practice. The committee recalled its previous conclusions that the rate of allogeneic stem cell transplant in clinical practice is highly uncertain and would depend on whether tisagenlecleucel was a curative therapy. It noted that an ERG scenario analysis decreased the ICERs for tisagenlecleucel in the ERG's deterministic base‑case compared with both blinatumomab and salvage chemotherapy by around £4,000 per QALY gained when it was assumed that no patients had a subsequent allogeneic stem cell transplant. It also noted that if tisagenlecleucel were considered as a bridge to allogeneic stem cell transplant (that is, assuming that all patients have a subsequent allogeneic stem cell transplant), the ICERs increased by around £20,000 per QALY gained. The committee was aware that this represented the maximum possible increase in the ICER based on rate of subsequent stem cell transplant and that any increase could be substantially lower. Based on this, it concluded that the rate potentially has a substantial effect on the cost-effectiveness estimates.
## The cost of intravenous immunoglobulin treatment for B‑cell aplasia is uncertain
The company's economic model assumed that patients having IVIG for B‑cell aplasia would have treatment for around 1 year. The ERG considered that this was an overestimate, because not all patients with B‑cell aplasia would have IVIG. It also considered that patients may be treated for longer than 1 year. Therefore, the ERG's base‑case assumed that a smaller proportion of patients (that is, only those with hypogammaglobulinaemia) had IVIG. It also examined different lengths of treatment in scenario analyses, with ICERs increasing by around £3,000 per QALY gained for a treatment length of 3 years. The committee also considered a scenario analysis in which all patients in the event‑free survival state in the model with hypogammaglobulinaemia had IVIG treatment indefinitely, which increased the ICERs by around £13,000 per QALY gained. It agreed that this scenario was likely to overestimate the costs of IVIG treatment because it resulted in a mean treatment length of 6.5 years, which was longer than that anticipated by both NHS England and the clinical experts. The committee noted that the ERG's base case was more closely aligned with assumptions proposed by NHS England and concluded that the ERG's assumptions were more plausible than the company's. It also recalled its previous conclusion that the extent of IVIG treatment in NHS clinical practice was unknown (see section 3.14). It therefore concluded that the cost of IVIG treatment for B‑cell aplasia after tisagenlecleucel was uncertain, but that it would affect the cost-effectiveness estimates.
# Cost‑effectiveness estimate
## The assumptions in the ERG's base case are more appropriate than those in the company's
The committee noted that the ERG's base-case model was more closely aligned with several of its preferred assumptions, specifically:
choosing an overall survival extrapolation for tisagenlecleucel in which the cure fraction in the mixture cure model did not exceed the probability of event-free survival from the clinical trials (see section 3.17)
incorporating the ERG's correction to the long-term mortality rate (see section 3.20)
assuming that patients have 2 cycles of blinatumomab (see section 3.21)
assuming that IVIG treatment for B‑cell aplasia is only given to patients with hypogammaglobulinaemia (see section 3.23).The committee concluded that the ERG's base case was more appropriate for its decision-making than the company's.
## The most plausible ICERs compared with blinatumomab are above £30,000 per QALY gained
The committee recalled that there was a high degree in uncertainty in the estimates of overall survival for tisagenlecleucel and blinatumomab because of the length of follow‑up in the tisagenlecleucel studies (see section 3.6 and section 3.7), use of a naive indirect treatment comparison (see section 3.11) and choice of overall survival extrapolations for both tisagenlecleucel and blinatumomab (see section 3.17 and section 3.18). It also recalled that it preferred the ERG's base case for decision-making (see section 3.24). The committee noted that the ERG's probabilistic base-case ICER for tisagenlecleucel (incorporating the patient access scheme) compared with blinatumomab was £29,501 per QALY gained, whereas the company's probabilistic base-case ICER was £20,046 per QALY gained. The committee recalled that the extrapolation of overall survival for tisagenlecleucel was an important source of uncertainty in the model (see section 3.17). It agreed that the ERG's exploratory scenario analysis which used a log-normal cure model for overall survival for tisagenlecleucel was plausible, and noted that the deterministic ICER for tisagenlecleucel increased to £44,299 per QALY gained in this scenario. It was also aware that the ICER was likely to increase by around £2,000 per QALY gained if a probabilistic analysis was used. It noted that all ICERs increased when the commercial arrangements for blinatumomab (the comparator) and tocilizumab (used to treat cytokine release syndrome) were taken into account. These ICERs cannot be reported as the simple discounts on the list price of blinatumomab and tocilizumab are commercial in confidence. The committee concluded the most plausible ICERs for tisagenlecleucel compared with blinatumomab when taking into account all the patient access scheme discounts were over £30,000 per QALY gained.
## The most plausible ICERs compared with salvage chemotherapy are above £45,000 per QALY gained
The committee recalled that there was a high degree in uncertainty in the estimates of overall survival for tisagenlecleucel and salvage chemotherapy because of the length of follow‑up in the tisagenlecleucel studies, use of a naive indirect treatment comparison and choice of overall survival extrapolations for both tisagenlecleucel and salvage chemotherapy. It recalled that it preferred the ERG's base case and in particular its preference for use of a mixture cure model for consistency with the modelling of the other comparators (see section 3.20). It therefore only considered alternative extrapolations using the mixture cure model. The committee noted that the ERG's probabilistic base-case ICER for tisagenlecleucel (incorporating the patient access scheme) compared with salvage chemotherapy was £48,265 per QALY gained and that this was higher than the company's probabilistic base case of £27,066 per QALY gained. The committee recalled that the extrapolation of overall survival for tisagenlecleucel was an important source of uncertainty in the model (see section 3.17). The committee agreed that the ERG's exploratory scenario analysis which used a log-normal cure model for overall survival for tisagenlecleucel was plausible and noted that the deterministic ICER for tisagenlecleucel increased to £74,322 per QALY gained in this scenario. It was also aware that the ICER was likely to increase by around £3,000 per QALY gained if a probabilistic analysis was used. It noted that the ICERs slightly decreased when the commercial arrangement for tocilizumab (used to treat cytokine release syndrome) was taken into account. These ICERs cannot be reported as the simple discount on the list price of tocilizumab is commercial in confidence. The committee concluded that the most plausible ICERs for tisagenlecleucel compared with salvage chemotherapy, when taking into account all patient access scheme discounts, were over £45,000 per QALY gained.
## Costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia are uncertain and may have a substantial impact on cost-effectiveness estimates
The committee recalled that the likely costs of subsequent allogeneic stem cell transplants and B‑cell aplasia after treatment with tisagenlecleucel were both uncertain (see section 3.22 and section 3.23). It noted that changes to the assumptions that underpin these costs could have a substantial effect on the ICERs. The committee concluded that in addition to survival estimates, the costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia were important sources of uncertainty in the model.
# Innovation
## Tisagenlecleucel is innovative but there are no additional benefits that have not been captured in the analysis
The committee considered tisagenlecleucel to be innovative because it represents a step‑change in the treatment of relapsed or refractory B‑cell acute lymphoblastic leukaemia. The company's submission stated that substantial positive effects for patients and caregivers, such as allowing return to work or employment, had not been captured in the economic analysis. The committee was mindful that the effect of tisagenlecleucel on employment were outside NICE's reference case, which specifies that the costs and benefits of a technology should be considered from the perspective of the NHS and personal social services. It noted that tisagenlecleucel was granted eligibility as a priority medicine through the European Medicines Agency's PRIME scheme. The committee concluded that there are no additional benefits that had not been captured in the economic analysis.
# Discount rate
## A discount rate of 3.5% should be applied for costs and benefits
The committee discussed the use of the alternative discount rate. A discount rate of 1.5% for costs and benefits may be considered by the committee when treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), and if the committee is satisfied that the introduction of the technology does not commit the NHS to substantial irrecoverable costs. The committee noted that tisagenlecleucel appeared clinically effective, but recalled its previous conclusion that there was no robust evidence that tisagenlecleucel was a curative therapy (see section 3.7). The committee concluded that the reference case should use a discount rate of 3.5% for both costs and benefits.
# End of life
## Tisagenlecleucel does not meet both criteria to be considered a life-extending treatment at the end of life because the life expectancy evidence is uncertain
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee considered whether the life expectancy of people having standard care for relapsed or refractory B‑cell acute lymphoblastic leukaemia was less than 24 months. It recalled that treatment was offered with the expectation that some patients would have a subsequent allogeneic stem cell transplant and potentially be cured. The median overall survival for this patient population was 7.5 months in the study of blinatumomab (von Stackelberg et al. 2016) and 13 weeks in the study used as a proxy for salvage chemotherapy (Jeha et al. 2006). It noted the company's and ERG's base-case results for undiscounted mean overall survival (results are considered commercial in confidence by the company and cannot be reported here). The committee was aware that the mean survival estimates from the economic model were driven by the proportion of long-term survivors (that is, patients alive after 5 years in the model). The clinical experts explained that the life expectancy of people who were not long‑term survivors after having blinatumomab or salvage chemotherapy would be close to the median life expectancy from the clinical studies. The committee noted that around 15% of patients having blinatumomab were long-term survivors in both the company's and ERG's base-case analyses. For salvage chemotherapy, the proportions of long-term survivors were 16% in the ERG's model and 8% in the company's model. Both the company's and the ERG's models predicted a mean overall survival of much longer than 24 months for blinatumomab. The committee noted that the company's model predicted a mean overall survival of less than 24 months for people having salvage chemotherapy, whereas the ERG model predicted a mean overall survival of much longer than 24 months. The committee agreed that there was a high degree of uncertainty around the overall survival extrapolations for both blinatumomab and salvage chemotherapy (see section 3.17 and section 3.18). It also recalled further uncertainties around the short survival follow‑up for blinatumomab and the choice of data source for the efficacy of salvage chemotherapy (see section 3.9 and section 3.10). Taking into account the undiscounted mean overall survival estimates, the high degree of uncertainty around the estimates and its conclusion that most patients would have blinatumomab, the committee concluded that the life expectancy criterion was not met but acknowledged that there was considerable uncertainty around this estimate. The committee then considered if tisagenlecleucel met the criterion for providing an extension to life of more than 3 months. It noted that the median overall survival for tisagenlecleucel was over 23 months in all 3 tisagenlecleucel trials. Furthermore, both the company's and the ERG's modelling suggested that tisagenlecleucel was associated with a gain in overall survival of over 8 years compared with both blinatumomab and salvage chemotherapy (irrespective of the choice of salvage chemotherapy data). The committee concluded that although tisagenlecleucel met this criterion, it did not meet both of NICE's criteria to be considered a life-extending treatment at the end of life when compared with blinatumomab and salvage chemotherapy.
# Conclusion
## Tisagenlecleucel is not recommended for routine use for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25 years
The committee recalled that although the precise life expectancy of people with relapsed or refractory B‑cell acute lymphoblastic leukaemia was uncertain, tisagenlecleucel did not meet the end-of-life criteria (see section 3.30). It also recalled that the size of the clinical benefit compared with blinatumomab or salvage chemotherapy was uncertain (see section 3.5) and that it is not yet known whether tisagenlecleucel is a curative therapy (see section 3.7). The most plausible ICERs for tisagenlecleucel compared with both blinatumomab and salvage chemotherapy were above £30,000 per QALY gained (see section 3.25 and section 3.26). The committee therefore concluded that it could not recommend tisagenlecleucel for routine use in the NHS to treat relapsed or refractory B‑cell acute lymphoblastic leukaemia.
# Cancer Drugs Fund
## Further data collection could address uncertainties in the clinical and cost‑effectiveness evidence
Having concluded that tisagenlecleucel could not be recommended for routine use, the committee then considered if it could be recommended for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee recognised that tisagenlecleucel is an innovative treatment and therefore it considered whether clinical uncertainty associated with tisagenlecleucel could be addressed through collecting more data. The committee was aware that more data from ELIANA, ENSIGN and B2101J will become available for tisagenlecleucel over time. It agreed that:
Further data on overall survival would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around length of overall survival and if tisagenlecleucel could be considered a curative treatment.
With further evidence, it may be possible to gain a more complete understanding of the costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia.
Using tisagenlecleucel in the NHS would allow data to be collected which more accurately reflect the costs and benefits of its use in clinical practice.
## Tisagenlecleucel meets the criteria for use in the Cancer Drugs Fund for this indication in people who would have blinatumomab
Having acknowledged that blinatumomab was the most common treatment option for relapsed or refractory B‑cell acute lymphoblastic leukaemia, the committee first considered if tisagenlecleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund when compared with blinatumomab. It noted that the most plausible ICER for tisagenlecleucel compared with blinatumomab was over £30,000 per QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with blinatumomab were associated with a high degree of uncertainty, and concluded that tisagenlecleucel had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more long-term survival data for tisagenlecleucel and further data on the rate of subsequent allogeneic stem cell transplants would allow for a more robust cost-effectiveness estimate. It noted that if the rate of allogeneic stem cell transplant was lower in clinical practice then the ICERs would decrease. The committee agreed that tisagenlecleucel met the criteria to be included in the Cancer Drugs Fund for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25 years who would have blinatumomab.
## The use of salvage chemotherapy is likely to decline so a recommendation in patients who would currently have salvage chemotherapy is not needed
The committee considered whether tisagenlecleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund when compared with salvage chemotherapy. It recalled that the most plausible ICERs for tisagenlecleucel compared with salvage chemotherapy were above £45,000 per QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with salvage chemotherapy were associated with a high degree of uncertainty, and concluded that tisagenlecleucel did not have the plausible potential to satisfy the criteria for routine use. The committee recalled that inotuzumab ozogamicin will likely replace blinatumomab after first disease relapse, and that blinatumomab will replace salvage chemotherapy after second disease relapse (see section 3.3). The committee therefore agreed that it would not make a distinction between people who would currently have blinatumomab or salvage chemotherapy in its recommendations, because the use of salvage chemotherapy as a treatment for relapsed or refractory disease was likely to decline over time.
## It is reasonable to include people with Philadelphia chromosome‑positive disease from the recommendations
The committee recalled that the company did not present a separate cost‑effectiveness analysis for tisagenlecleucel's use for Philadelphia chromosome‑positive disease (see section 3.4). The committee was aware that the that the proportion of patients with Philadelphia chromosome‑positive disease within the population specified in the marketing authorisation is very small, and there will likely only be 1 or 2 patients per year in England. It was also aware that for these patients, treatment options are limited and prognosis is poor. The committee accepted that excluding this population from its recommendation would leave an unmet need and recalled that treatment benefits with tisagenlecleucel were expected to be similar regardless of Philadelphia chromosome status. The committee agreed that more uncertainty was acceptable given the very small size of the patient population. It considered it reasonable to include people with Philadelphia chromosome‑negative disease, and therefore agreed that it would not make a distinction based on Philadelphia chromosome status in its recommendations.
## Tisagenlecleucel is recommended for use in the Cancer Drugs Fund for relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25
Based on its considerations for all populations covered by the marketing authorisation (see section 3.33 to section 3.35), the committee concluded that it could recommend tisagenlecleucel for use as an option within the Cancer Drugs Fund to treat relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25 years, only if the conditions in the managed access agreement are followed.
## Use in the NHS
The committee was aware of statements from clinical experts and NHS England that introducing CAR T‑cell therapies to the NHS needs the provision of a new service. Infrastructure for transporting and storing the treatment, accreditation to administer the treatment, training of staff and access to intensive care units to manage adverse events all need to be included. The committee also noted that NHS England and the company consider a cautious approach is needed because these technologies are associated with severe side effects such as cytokine release syndrome (see section 3.13). Working collaboratively, NHS England and the company aim to manage the risks associated with introducing tisagenlecleucel by adopting a cautious approach to treatment planning, particularly concerning the management of adverse events (for further information see the summary of product characteristics). NHS England and the company agreed that phased implementation to the NHS is necessary to deliver this treatment.
## Potential equalities issue
The committee noted a potential equality issue raised during the scoping process that blood support or haematopoietic stem cell transplant are not acceptable to some religious groups such as Jehovah's witnesses. These patients would normally instead have best supportive care. The committee agreed that if tisagenlecleucel does become an available treatment option, people can choose whether or not they wish to have it. Accordingly, this is not viewed as an equality issue.
|
{'Recommendations': "Tisagenlecleucel therapy is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25\xa0years, only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect both treatment in preparation for and treatment with tisagenlecleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people aged under 18\xa0years, this decision should be made jointly by the clinician and the young person, or the young person's parents or carers.\n\nWhy the committee made these recommendations\n\nCurrent treatment for relapsed or refractory acute lymphoblastic leukaemia is usually blinatumomab or salvage chemotherapy. Tisagenlecleucel is a chimeric antigen receptor (CAR)\xa0T‑cell therapy. It contains the patient's own T\xa0cells that have been modified to attach to and kill cancer cells.\n\nClinical trial evidence suggests that compared with current treatment, people having tisagenlecleucel may live for longer, or have more time before their disease relapses. However, the evidence is uncertain and it is not known whether tisagenlecleucel can cure acute lymphoblastic leukaemia.\n\nThere is also not enough evidence to determine the costs of treating side effects and whether people will need a subsequent stem cell transplant.\n\nThe most plausible cost‑effectiveness estimates for tisagenlecleucel are higher than what NICE normally considers acceptable. The life expectancy of people with relapsed or refractory acute lymphoblastic leukaemia is uncertain. It does not meet both of NICE's criteria to be a life-extending treatment at the end of life. Therefore tisagenlecleucel cannot be recommended for routine use in the NHS.\n\nCollecting more data on overall survival, subsequent stem cell transplant rates, and immunoglobulin usage will reduce the uncertainty in the clinical‑ and cost‑effectiveness evidence. Therefore tisagenlecleucel is recommended for use in the Cancer Drugs Fund.", 'Information about tisagenlecleucel': "# Marketing authorisation indication\n\nTisagenlecleucel (Kymriah, Novartis) is indicated for treating 'paediatric and young adult patients up to 25\xa0years of age with B‑cell acute lymphoblastic leukaemia that is refractory, in relapse post‑transplant or in second or later relapse'. Tisagenlecleucel is an immunocellular CAR\xa0T‑cell therapy. It contains the patient's own T\xa0cells (a type of white blood cell) that have been modified genetically in the laboratory so that they make a protein called chimeric antigen receptor (CAR). CAR can attach to another protein on the surface of cancer cells called CD-19. When tisagenlecleucel is given to the patient, the modified T\xa0cells attach to and kill cancer cells, thereby helping to clear the cancer from the body.\n\n# Dosage in the marketing authorisation\n\nTreatment with tisagenlecleucel comprises a single‑dose intravenous infusion of tisagenlecleucel. It is intended for autologous use only and at the following dosage:\n\nFor patients ≤50\xa0kg: 0.2 to 5.0×106 CAR‑positive viable T\xa0cells\xa0per\xa0kg body weight.\n\nFor patients >50\xa0kg: 0.1 to 2.5×108 CAR‑positive viable T\xa0cells (non-weight based).\n\n# Price\n\nThe list price for tisagenlecleucel is £282,000\xa0per\xa0infusion (company submission). The company has a commercial arrangement. This makes tisagenlecleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with relapsed or refractory B‑cell acute lymphoblastic leukaemia would welcome a new treatment option\n\nOutcomes for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia are poor. The disease has low levels of response to treatment, and is associated with limited survival. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. The patient experts explained that the cycle of remission and relapse when having successive treatments has a substantial psychological and physical effect on people with the disease and the people caring for them. They further explained that stem cell transplants are associated with a slow and laborious recovery over the course of around a year. The committee understood that chimeric antigen receptor (CAR)\xa0T‑cell therapies (such as tisagenlecleucel) are advanced treatments for cancer and belong to a new generation of personalised cancer immunotherapies that are based on collecting and modifying patients' own immune cells to treat their cancer. The committee heard from the patient experts that treatment with CAR\xa0T‑cell therapies involves intense and challenging side effects immediately after infusion, but can enable recovery within a few\xa0months. The committee concluded that people with relapsed or refractory acute lymphoblastic leukaemia would welcome new treatment options such as CAR\xa0T‑cell therapies that improve the chance of survival.\n\n# Treatment pathway\n\n## The company's positioning of tisagenlecleucel in the pathway is appropriate\n\nThe company proposed 4 potential positions for tisagenlecleucel in the treatment pathway for this indication. Specifically, for use in people aged up to 25\xa0years with B‑cell acute lymphoblastic leukaemia:\n\nwhose disease was refractory after 1 systemic chemotherapy ('primary refractory')\n\nwhose disease was refractory after 2 systemic chemotherapies ('chemo‑refractory')\n\nwhose disease had relapsed after an allogeneic stem cell transplant\n\nwhose disease had relapsed after 2 or more systemic chemotherapies.The clinical experts indicated that survival outcomes for these groups of people were poor and agreed that they could potentially benefit from tisagenlecleucel. The committee accepted that the company's 4 proposed positions for tisagenlecleucel were consistent with its marketing authorisation. It noted that the marketing authorisation did not specify treatment based on Philadelphia chromosome status: having discussed this, the committee agreed that the marketing authorisation included both people with and without the Philadelphia chromosome. It agreed that the treatment pathways for Philadelphia chromosome‑negative and Philadelphia chromosome‑positive B‑cell acute lymphoblastic leukaemia should be considered in more detail.\n\n## Blinatumomab and salvage chemotherapy are both appropriate comparators and blinatumomab is the main comparator\n\nThe clinical experts stated that the treatment pathway for B‑cell acute lymphoblastic leukaemia was evolving, and that NICE's technology appraisal guidance on inotuzumab ozogamicin as an option for treating B-cell acute lymphoblastic leukaemia may change the treatment pathway. The committee noted that this was not included in the scope of this appraisal because it was not established clinical practice in the NHS when the final scope was issued. Patients with primary refractory Philadelphia chromosome‑negative B‑cell acute lymphoblastic leukaemia would currently have blinatumomab or salvage chemotherapy, with the aim of bridging to an allogeneic stem cell transplant. Salvage chemotherapy includes FLA(G)-IDA (fludarabine, cytarabine and idarubicin, with or without granulocyte‑colony stimulating factor). For patients whose disease responds to initial therapy and then relapses, or who have a second or further relapse, the aim of treatment is a further remission which can then be consolidated with an allogeneic stem cell transplant. As for patients with primary refractory disease, treatment options are blinatumomab and salvage chemotherapy with FLA(G)-IDA. The clinical experts stated that treatment with blinatumomab was more likely to enable a subsequent stem cell transplant than treatment with salvage chemotherapy, so blinatumomab was the preferred treatment option providing it had not already been used (for example, after first relapse for adults). If blinatumomab cannot be offered then salvage chemotherapy would be offered. The clinical experts also stated that in their opinion inotuzumab ozogamicin was likely to replace blinatumomab as a treatment option after first relapse in the treatment pathway, with blinatumomab likely to become the preferred subsequent treatment option for patients who have a second relapse. However, the committee accepted that there are little data on the use of blinatumomab after inotuzumab ozogamicin, and it noted that this lack of evidence may affect the choice of treatment. The committee also accepted that there is no biologically plausible reason why blinatumomab should not be effective when used after inotuzumab ozogamicin. It agreed that blinatumomab was the main treatment option for relapsed or refractory Philadelphia chromosome‑negative B‑cell acute lymphoma, and that some people would be offered salvage chemotherapy. The committee concluded that blinatumomab and salvage chemotherapy were both appropriate comparators and that blinatumomab was the main comparator.\n\n## Patient numbers are too small to analyse the clinical and cost effectiveness of tisagenlecleucel for Philadelphia chromosome‑positive disease separately\n\nPhiladelphia chromosome‑positive disease accounts for around 3% of B‑cell acute lymphoblastic leukaemia. It is associated with poor outcomes and is treated differently to Philadelphia chromosome‑negative disease: most people have at least 2 tyrosine kinase inhibitors (TKIs), before then having salvage chemotherapy or best supportive care. The clinical and patient experts explained that patients with Philadelphia chromosome‑positive acute lymphoblastic leukaemia whose disease relapses after treatment TKIs could benefit from tisagenlecleucel and that outcomes were expected to be similar to patients with Philadelphia chromosome‑negative disease. The committee noted that although the company did not present a treatment pathway for Philadelphia chromosome‑positive disease, it stated in its submission that in clinical studies, patients could only have tisagenlecleucel if their disease had already relapsed after 2 TKIs, or they had stopped taking them. The committee also noted that the company did not present a separate clinical‑ and cost‑effectiveness analysis for Philadelphia chromosome‑positive disease because of the small population size; the tisagenlecleucel clinical studies included only 5 patients with Philadelphia chromosome‑positive disease, and there are expected to be only 1 or 2 patients\xa0per\xa0year in England. The committee concluded that the company's positioning of tisagenlecleucel for Philadelphia chromosome‑positive disease based on clinical study eligibility was appropriate and acknowledged that patient numbers were too small for clinical and cost effectiveness in this population to be analysed separately.\n\n# Clinical evidence\n\n## Tisagenlecleucel is clinically effective but the lack of comparator data means the benefit compared with blinatumomab or salvage chemotherapy is unknown\n\nThe main evidence on the clinical effectiveness of tisagenlecleucel came from 3 single-arm studies:\n\nELIANA, an international, multicentre, phase II study (n=97)\n\nENSIGN, a US, multicentre, phase II study (n=73)\n\nB2101J, a US, single-centre, phase I/IIa study (n=66).The company pooled results from all patients in the studies who had tisagenlecleucel (n=193). The clinical experts indicated that although patient numbers in the primary refractory and Philadelphia chromosome‑positive populations were small, outcomes were expected to be similar to the overall pooled study population. Outcomes of each study included overall remission rate, overall survival, event-free survival and adverse events of treatment. The pooled analysis and full results from the ELIANA and B2101J studies are considered to be academic in confidence by the company and cannot be reported here. However, results from earlier analyses of the trials have been reported (ELIANA: Maude, Laetsch\xa0et\xa0al.\xa02018; B2101J: Maude, Grupp\xa0et\xa0al.\xa02018) so these results are reported here. Results from the individual studies showed that tisagenlecleucel was effective in inducing remission and improving survival for patients with B‑cell acute lymphoblastic leukaemia (see table 1, below). The committee heard from clinical experts that the results of the studies were generalisable to clinical practice, although the experts noted that clinicians were more likely to offer tisagenlecleucel to patients with a higher Karnofsky/Lansky performance status, who would be more likely to tolerate the bridging chemotherapy regimen and the potential adverse effects. The committee noted that there was no clinical evidence directly comparing tisagenlecleucel with blinatumomab or salvage chemotherapy because all 3 trials were single‑arm studies. It concluded that tisagenlecleucel was clinically effective, but agreed that the lack of comparative data made the assessment of comparative effectiveness (and any cost‑effectiveness analyses) more challenging.\n\nSource and data\n\nELIANA\n\nnumber=75\n\n\n\nENSIGN\n\nnumber=58 (42 for overall remission rate)\n\nB2101J\n\nnumber=59\n\nSource\n\nMaude, Laetsch\xa0et\xa0al.\xa02018\n\nCompany submission\n\nMaude, Grupp\xa0et\xa0al.\xa02018\n\nOverall remission rate: proportion of patients (95%\xa0confidence interval)\n\n\n\n(71 to 89)\n\n\n\n(53 to 82)\n\n\n\n(not recorded)\n\nMedian overall survival:\xa0months (95%\xa0confidence interval)\n\nNot estimable\n\n\n\n(9 to not estimable)\n\nNot recorded\n\nSurvival at 12\xa0months: proportion of patients (95%\xa0confidence interval)\n\n\n\n(63 to 86)\n\n\n\n(46 to 76)\n\n\n\n(69 to 91)\n\n## Clinical evidence for tisagenlecleucel beyond 30\xa0months is very uncertain because of small patient numbers and differences in the trial populations\n\nThe median follow‑up in each study was less than 3\xa0years, and after around 30\xa0months survival estimates were based on less than 15 patients at risk, who were exclusively from the B2101J study. The committee noted that the patient population in B2101J was different to those in ELIANA and ENSIGN: patients in B2101J typically had a higher Karnofsky/Lansky performance status (that is, were in better health), were more likely to have already had an allogeneic stem cell transplant and were eligible for up to 3 infusions of tisagenlecleucel instead of 1. The committee concluded that because of the small patient numbers and the differences between study populations, the clinical evidence for tisagenlecleucel beyond 30\xa0months was very uncertain.\n\n## There is no robust evidence that tisagenlecleucel has a curative effect\n\nThe clinical experts explained that tisagenlecleucel would be offered with the intent of curing relapsed or refractory B‑cell acute lymphoblastic leukaemia. It was aware that a common assumption in oncology clinical trials of treatments given with curative intent is that people who survive for an arbitrary time period (typically 5\xa0years) could be considered to be long‑term survivors, and effectively cured. The clinical experts considered that it may be appropriate to assume that patients in the population under consideration who survive for 3\xa0years could be considered to be cured. Having acknowledged that survival estimates beyond 30\xa0months were highly uncertain (see section\xa03.6) the committee concluded that with an assumed cure point of either 3 or 5\xa0years, there was not robust evidence that tisagenlecleucel has a curative effect.\n\n## There is no clinical evidence on the efficacy of tisagenlecleucel after treatment with blinatumomab\n\nThe committee was aware that all 3 tisagenlecleucel studies excluded patients who had already had blinatumomab, and that in NHS clinical practice patients may have blinatumomab after first disease relapse (see section\xa03.3). The clinical experts explained that up to 20% of patients who relapse after having blinatumomab may become CD‑19‑negative, meaning they would be unlikely to benefit from tisagenlecleucel after second disease relapse. However, they noted that in clinical practice patients would have blinatumomab for up to 2 cycles: this means that CD‑19‑negative relapse would be unlikely, and so treatment with tisagenlecleucel after blinatumomab may be effective. The committee was aware that the summary of product characteristics for tisagenlecleucel states that tisagenlecleucel is not recommended if the disease has relapsed with CD-19-negative leukaemia after previous anti-CD-19 therapy (such as blinatumomab). The committee concluded that there was no clinical evidence to determine if tisagenlecleucel would be effective after treatment with blinatumomab, and that this added uncertainty around the generalisability of the results to clinical practice.\n\n## Despite limitations, the von Stackelberg\xa0et\xa0al. (2016) study is an appropriate source of data for the efficacy of blinatumomab\n\nThe evidence for the efficacy of blinatumomab came from a phase II trial in 70 patients aged under 18\xa0years with relapsed or refractory B‑cell acute lymphoblastic leukaemia (von Stackelberg\xa0et\xa0al.\xa02016). The study population consisted of patients who were primary refractory, in first relapse after full salvage induction regimen, in second or later relapse or in any relapse after allogeneic stem cell transplantation. The patient population differed from that of the tisagenlecleucel studies: the tisagenlecleucel studies recruited patients up to the age of 25\xa0years, whereas von Stackelberg\xa0et\xa0al.\xa0only recruited patients aged under 18\xa0years. The committee noted that the 2 studies differed in several important prognostic factors, including the proportion of primary refractory patients, percentage of bone marrow blasts, number of previous treatments and time since last relapse. The committee acknowledged that patients in von Stackelberg\xa0et\xa0al.\xa0may therefore have had more progressive disease at baseline than patients in the tisagenlecleucel studies. The committee also noted that the median overall survival of 7.5\xa0months in von Stackelberg\xa0et\xa0al.\xa0was lower than the overall survival of 9.9\xa0months reported for patients aged 18 to 35\xa0years (n=123) in the TOWER study of blinatumomab (the TOWER study was the main source of evidence used to inform NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia chromosome-negative acute lymphoblastic leukaemia). The committee acknowledged that this may indicate that patients in von Stackelberg\xa0et\xa0al.\xa0may have worse outcomes than would be expected for blinatumomab in clinical practice. It also noted that patients were followed up for 2\xa0years and that no survival data were available beyond this point. Despite these limitations, the committee concluded that because neither the ERG nor the company presented a suitable alternative data source for the efficacy of blinatumomab, it was appropriate to consider von Stackelberg\xa0et\xa0al.\xa0in its decision-making.\n\n## Jeha\xa0et\xa0al.\xa0(2006) and Kuhlen\xa0et\xa0al.\xa0(2017) should both be considered as sources of data for the efficacy of salvage chemotherapy\n\nThe company's systematic literature review did not identify any evidence for the efficacy of FLA(G)-IDA salvage chemotherapy. Instead, the company used clofarabine monotherapy as a proxy for salvage chemotherapy. It provided evidence from a phase II study of clofarabine monotherapy in 61 patients aged under 21\xa0years with relapsed or refractory B‑cell acute lymphoblastic leukaemia (Jeha\xa0et\xa0al.\xa02006). The study reported an overall remission rate of 20% and median overall survival of 13\xa0weeks. The clinical experts explained that clofarabine monotherapy was not used in clinical practice in the NHS because of concerns over increased toxicity compared with other treatment options. However, they noted that the efficacy of clofarabine was similar to that of FLA(G)-IDA, so it was plausible that data from Jeha\xa0et\xa0al.\xa0for clofarabine could be used as a proxy for salvage chemotherapy. The committee was aware of a submission from NHS England which stated that clinical practice had changed since the publication of Jeha et al., and that outcomes in the study were likely to be worse than in clinical practice because supportive care and the availability and speed of access to stem cell donors have since improved. The ERG identified 2 studies, published after the company's submission, which contained evidence on the efficacy of FLA-IDA. The most recent of these was a retrospective analysis of 242 UK children with B‑cell acute lymphoblastic leukaemia in first relapse after allogeneic stem cell transplant (Kuhlen\xa0et\xa0al.\xa02017). The committee noted that the 3‑year probability of overall survival reported in Kuhlen\xa0et\xa0al.\xa0was 20%. The committee also noted that the ERG considered that the much larger sample size and longer follow‑up provided a more reliable and robust dataset compared with Jeha\xa0et\xa0al.\xa0However, the committee recalled that the ERG had highlighted several differences in prognostic factors between the tisagenlecleucel studies and Kuhlen\xa0et\xa0al.\xa0Factors which may underestimate survival for salvage chemotherapy compared with tisagenlecleucel include: a higher rate of previous allogeneic stem cell transplant; a higher rate of patients having only palliative care; and the inclusion of patients with T‑cell acute lymphoblastic leukaemia or whose disease has relapsed less than 6\xa0months after allogeneic stem cell transplant. Factors which may overestimate survival for salvage chemotherapy compared with tisagenlecleucel include: a higher proportion of patients in first relapse and the inclusion of patients with extramedullary relapse. The committee accepted that both Jeha\xa0et\xa0al.\xa0and Kuhlen\xa0et\xa0al.\xa0had a number of limitations, but concluded that that it was appropriate to consider both studies in its decision-making.\n\n## The efficacy of tisagenlecleucel compared with blinatumomab and salvage chemotherapy is based on naive indirect comparisons which are uncertain\n\nThe company did a matching adjusted indirect treatment comparison to attempt to adjust prognostic factors in the pooled population of the 3 single-arm tisagenlecleucel studies to match those in the von Stackelberg\xa0et\xa0al.\xa0and Jeha\xa0et\xa0al.\xa0studies. Factors adjusted for were the number of previous relapses, median number of\xa0months since last relapse and proportion of patients with previous allogeneic stem cell transplant. The ERG highlighted that several other important prognostic factors could not be adjusted for, including median age, geographic region, genetic abnormalities and proportion of primary refractory patients. How adjusting these factors (had it been possible) may have affected the outcome of the matching adjusted treatment comparison was unclear. The results of the comparison are academic in confidence and cannot be reported here. However, the committee noted that the company did not use the data from the matching adjusted treatment comparison in its base‑case economic analysis. The committee concluded that using a naive indirect treatment comparison was appropriate, but was subject to uncertainty as a result of the differences in the trial populations.\n\n# Subsequent stem cell transplant\n\n## The number of patients who would have an allogeneic stem cell transplant after having tisagenlecleucel is highly uncertain\n\nThe clinical experts explained that in current NHS practice, patients in first or second relapse have allogeneic stem cell transplants if they are considered eligible. The NHS England clinical commissioning expert confirmed that patients who have had a previous allogeneic stem cell transplant and go on to relapse can be offered a second allogeneic stem cell transplant if they are in remission and their relapse occurred more than 1 year after their first transplant. NHS England estimated that the rate of allogeneic stem cell transplant was 15% to 20% after salvage chemotherapy and at least 24% after blinatumomab. Treatment with tisagenlecleucel is intended to be curative: that is, patients whose disease responds to treatment with tisagenlecleucel would not be expected to need a subsequent stem cell transplant. However, some patients in the tisagenlecleucel studies had subsequent allogeneic stem cell transplants; for example, interim analyses of the ELIANA study showed that of patients having tisagenlecleucel, 11% had a subsequent allogeneic stem cell transplant. The company provided an estimate of the rate of allogeneic stem cell transplant based on pooled data from the most recent data cuts of the tisagenlecleucel studies (the data are considered confidential and cannot be reported here), but this may not reflect clinical practice in the NHS. The committee concluded that the number of patients who would need an allogeneic stem cell transplant after tisagenlecleucel is highly uncertain.\n\n# Adverse events\n\n## The most common adverse reaction is cytokine release syndrome\n\nThe company provided an analysis of the adverse events for each of the 3 tisagenlecleucel studies. The analyses were considered to be academic in confidence by the company and cannot be reported here, but the summary of product characteristics includes details of some adverse events. The most common non-haematological adverse reactions were cytokine release syndrome (77%), infections (65%), hypogammaglobulinaemia (47%), pyrexia (40%) and decreased appetite (39%). Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common grade 3 and 4 non-haematological adverse reaction was cytokine release syndrome (47%). NHS England's clinical lead for the Cancer Drugs Fund explained that cytokine release syndrome occurs soon after treatment with tisagenlecleucel. Mild or moderate cytokine release syndrome needs considerable observation and supportive care but more severe cytokine release syndrome needs full intensive care and treatment with tocilizumab and steroids. It noted that treatment strategies for these side effects are described in tisagenlecleucel's summary of product characteristics and in the risk management plan that is part of the marketing authorisation. The committee was also aware that tocilizumab has a marketing authorisation for treating CAR\xa0T‑cell-induced severe or life-threatening cytokine release syndrome in people aged 2\xa0years and older. NHS England's clinical lead for the Cancer Drugs Fund explained that there is great need for staff training because the symptoms of cytokine release syndrome are so diverse and unexpected. The committee concluded that cytokine release syndrome is a common toxicity associated with tisagenlecleucel and the costs associated with managing and treating it should be reflected in the cost-effectiveness modelling.\n\n## It is unknown how many patients will need intravenous immunoglobulin treatment for B‑cell aplasia and for how long\n\nThe committee noted that most people having tisagenlecleucel in clinical trials would have B‑cell aplasia. The clinical experts noted that current practice in clinical trials was for prophylactic treatment with intravenous immunoglobulin (IVIG) for B‑cell aplasia, but that the clinical effectiveness of this approach had not been studied. Long‑term treatment for B‑cell aplasia with IVIG would only be considered for patients with concurrent infections, but there are not enough data on the rate of infections to determine how often long-term treatment is needed. The clinical experts indicated that an assumption of 50% of patients having IVIG over 1 to 2\xa0years as proposed by NHS England was reasonable, but was based on current practice rather than clinical evidence. One expert suggested that treatment may only last for 3 to 12\xa0months. The committee concluded that it was unknown how many patients would need IVIG treatment for B‑cell aplasia and for how long.\n\n# The company's economic model\n\n## The structure of the company's model is appropriate for decision‑making\n\nThe company used a partitioned‑survival economic model for all treatments that included 3\xa0states: event-free, progressed disease and death. Before entering the partitioned-survival part of the model, patients having tisagenlecleucel also progressed through a decision tree to capture outcomes for patients who discontinued treatment or died before having tisagenlecleucel. The model contained a structural assumption that after 5\xa0years, general population health‑related quality‑of‑life and costs were applied. The committee concluded that the structure of the company's model was appropriate for its decision-making.\n\n## Blinatumomab is the main comparator to consider in the economic modelling\n\nThe committee recalled that blinatumomab and salvage chemotherapy were both appropriate comparators and that blinatumomab is preferred to salvage chemotherapy for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia (see section\xa03.3). The committee therefore concluded that blinatumomab and salvage chemotherapy should both be considered as comparators in the economic model and that blinatumomab was the main comparator.\n\n# Survival modelling in the economic model\n\n## The extrapolation of overall survival for tisagenlecleucel is an important source of uncertainty in the economic model\n\nThe company stated in its submission that using simple parametric survival curves or spline models to model overall survival for tisagenlecleucel produced curves with poor statistical and visual fit. The committee considered the company's preferred extrapolation of overall survival for tisagenlecleucel. It noted the use of a mixture cure model with the exponential distribution to estimate a cure fraction (that is, the proportion of patients cured). After infusion, the cured patients were immediately restored to the age- and gender-matched mortality of the general UK population adjusted for increased mortality in the acute lymphoblastic leukaemia population using a multiplier of 9.05 from MacArthur\xa0et\xa0al.\xa0(2007). Uncured patients followed the parametric survival curve from the time of infusion. The committee noted that the cure fraction for overall survival was a major driver of the cost-effectiveness estimates, and that it varied by approximately 35% in the company's exploratory analyses (the cure fractions are considered confidential and cannot be reported here). The committee was aware that the ERG used the log-logistic distribution in its base case, because the cure fraction for overall survival estimated by the exponential function exceeded the percentage of event‑free survival events in the tisagenlecleucel trials and was therefore a less plausible assumption. It also noted that when the ERG did a scenario analysis using the log-normal distribution, which estimated the lowest cure fraction, the incremental cost-effectiveness ratio (ICER) compared with the ERG's deterministic base-case results increased by £16,567\xa0per\xa0quality-adjusted life year (QALY) gained for the comparison with blinatumomab and £28,925 for the comparison with salvage chemotherapy. The committee noted that the variance in cure fraction reflected the lack of long-term survival data (see section\xa03.6). It also recalled that there was no robust evidence to support the underlying assumption of tisagenlecleucel having a curative effect (see section\xa03.7). It concluded that the extrapolation of overall survival for tisagenlecleucel is an important source of uncertainty in the economic model.\n\n## Estimates of long-term survival with blinatumomab are subject to uncertainty\n\nThe company also used the mixture cure method to extrapolate the overall survival curve for blinatumomab, and chose a log-normal distribution in its analysis. The ERG noted that, as with tisagenlecleucel (see section\xa03.17), modelling overall survival using this approach is subject to uncertainty and produced cure fractions ranging from 4% to 22%. It preferred the log-logistic distribution because this more closely matched the survival curve in the appraisal of blinatumomab. The committee was also aware that a naive comparison of the blinatumomab curve with the tisagenlecleucel curve was subject to uncertainty because of differences between the trial populations (see section\xa03.11). The committee accepted the ERG's approach but concluded that estimates of long-term survival with blinatumomab are subject to uncertainty.\n\n## Long-term overall survival with salvage chemotherapy is underestimated by the company's approach and overestimated by the ERG's approach\n\nThe company's extrapolation of overall survival used a standard parametric model with a generalised gamma distribution based on data from Jeha\xa0et\xa0al.\xa0(2006). The ERG preferred to base its extrapolation on data from Kuhlen\xa0et\xa0al.\xa0(2017; see section\xa03.10). It also preferred to use a mixture cure model because this was consistent with the method of extrapolation used for tisagenlecleucel and blinatumomab. The ERG chose the log-normal distribution as the best fitting distribution. When the ERG did a scenario analysis using the log-normal distribution and incorporating adverse event and allogeneic stem cell transplant rates from Kuhlen\xa0et\xa0al.\xa0(2017), the ICER compared with the company's deterministic base‑case result for salvage chemotherapy increased by £8,758\xa0per\xa0QALY gained. The clinical experts and the Cancer Drugs Fund clinical lead both indicated that the estimated long-term survival would likely be between the values predicted by the base-case modelling assumptions of the company and ERG. The committee concluded that there was a substantial degree of uncertainty in the extrapolation of overall survival for salvage chemotherapy and that it was underestimated by the company's approach and overestimated by the ERG's approach. It agreed that the most plausible estimate for long‑term overall survival would be somewhere between the values predicted by the 2 models.\n\n## The ERG's correction to the company's approach to modelling long‑term mortality in the mixture cure model is appropriate\n\nThe ERG noted an apparent error in the company's model whereby the modelled overall survival could not deviate from the curve predicted by the mixture cure model. This implied that the long-term mortality of patients was lower than that of the general population and lower than observed in epidemiological studies of long‑term survivors of acute lymphoblastic leukaemia in some periods of the model. In a small number of scenarios it also led the model to make inconsistent predictions; for example, patients would come back to life. The company stated that its approach was intended and that it reflected the most appropriate estimates of survival in both the cured and uncured fractions. The committee considered that the long‑term mortality curve predicted by the ERG's model was more plausible and therefore concluded that the ERG's correction to the company's model was appropriate.\n\n# Costs in the economic model\n\n## It is appropriate to assume that patients would have 2 cycles of blinatumomab\n\nThe company's model included the assumption that patients could have up to 5 cycles of blinatumomab. However, clinical advice to the ERG indicated that in clinical practice, patients would only have 2 cycles of blinatumomab and the ERG preferred to incorporate this assumption into its model. The committee recalled that it too had heard expert advice that patients would usually only have 2 cycles of blinatumomab (see section\xa03.8). It concluded that it was appropriate to assume patients would have 2 cycles of blinatumomab.\n\n## The rate of allogeneic stem cell transplant after tisagenlecleucel has a substantial effect on the cost-effectiveness estimates\n\nThe rate of subsequent allogeneic stem cell transplant in the company's base-case model was taken from pooled results of the tisagenlecleucel studies (see section\xa03.12). The company considered that this may be higher than the rate in NHS clinical practice. The committee recalled its previous conclusions that the rate of allogeneic stem cell transplant in clinical practice is highly uncertain and would depend on whether tisagenlecleucel was a curative therapy. It noted that an ERG scenario analysis decreased the ICERs for tisagenlecleucel in the ERG's deterministic base‑case compared with both blinatumomab and salvage chemotherapy by around £4,000\xa0per\xa0QALY gained when it was assumed that no patients had a subsequent allogeneic stem cell transplant. It also noted that if tisagenlecleucel were considered as a bridge to allogeneic stem cell transplant (that is, assuming that all patients have a subsequent allogeneic stem cell transplant), the ICERs increased by around £20,000\xa0per\xa0QALY gained. The committee was aware that this represented the maximum possible increase in the ICER based on rate of subsequent stem cell transplant and that any increase could be substantially lower. Based on this, it concluded that the rate potentially has a substantial effect on the cost-effectiveness estimates.\n\n## The cost of intravenous immunoglobulin treatment for B‑cell aplasia is uncertain\n\nThe company's economic model assumed that patients having IVIG for B‑cell aplasia would have treatment for around 1 year. The ERG considered that this was an overestimate, because not all patients with B‑cell aplasia would have IVIG. It also considered that patients may be treated for longer than 1 year. Therefore, the ERG's base‑case assumed that a smaller proportion of patients (that is, only those with hypogammaglobulinaemia) had IVIG. It also examined different lengths of treatment in scenario analyses, with ICERs increasing by around £3,000\xa0per\xa0QALY gained for a treatment length of 3\xa0years. The committee also considered a scenario analysis in which all patients in the event‑free survival state in the model with hypogammaglobulinaemia had IVIG treatment indefinitely, which increased the ICERs by around £13,000\xa0per\xa0QALY gained. It agreed that this scenario was likely to overestimate the costs of IVIG treatment because it resulted in a mean treatment length of 6.5\xa0years, which was longer than that anticipated by both NHS England and the clinical experts. The committee noted that the ERG's base case was more closely aligned with assumptions proposed by NHS England and concluded that the ERG's assumptions were more plausible than the company's. It also recalled its previous conclusion that the extent of IVIG treatment in NHS clinical practice was unknown (see section\xa03.14). It therefore concluded that the cost of IVIG treatment for B‑cell aplasia after tisagenlecleucel was uncertain, but that it would affect the cost-effectiveness estimates.\n\n# Cost‑effectiveness estimate\n\n## The assumptions in the ERG's base case are more appropriate than those in the company's\n\nThe committee noted that the ERG's base-case model was more closely aligned with several of its preferred assumptions, specifically:\n\nchoosing an overall survival extrapolation for tisagenlecleucel in which the cure fraction in the mixture cure model did not exceed the probability of event-free survival from the clinical trials (see section\xa03.17)\n\nincorporating the ERG's correction to the long-term mortality rate (see section\xa03.20)\n\nassuming that patients have 2 cycles of blinatumomab (see section\xa03.21)\n\nassuming that IVIG treatment for B‑cell aplasia is only given to patients with hypogammaglobulinaemia (see section\xa03.23).The committee concluded that the ERG's base case was more appropriate for its decision-making than the company's.\n\n## The most plausible ICERs compared with blinatumomab are above £30,000\xa0per\xa0QALY gained\n\nThe committee recalled that there was a high degree in uncertainty in the estimates of overall survival for tisagenlecleucel and blinatumomab because of the length of follow‑up in the tisagenlecleucel studies (see section 3.6 and section 3.7), use of a naive indirect treatment comparison (see section\xa03.11) and choice of overall survival extrapolations for both tisagenlecleucel and blinatumomab (see section 3.17 and section 3.18). It also recalled that it preferred the ERG's base case for decision-making (see section\xa03.24). The committee noted that the ERG's probabilistic base-case ICER for tisagenlecleucel (incorporating the patient access scheme) compared with blinatumomab was £29,501\xa0per\xa0QALY gained, whereas the company's probabilistic base-case ICER was £20,046\xa0per\xa0QALY gained. The committee recalled that the extrapolation of overall survival for tisagenlecleucel was an important source of uncertainty in the model (see section\xa03.17). It agreed that the ERG's exploratory scenario analysis which used a log-normal cure model for overall survival for tisagenlecleucel was plausible, and noted that the deterministic ICER for tisagenlecleucel increased to £44,299\xa0per\xa0QALY gained in this scenario. It was also aware that the ICER was likely to increase by around £2,000\xa0per\xa0QALY gained if a probabilistic analysis was used. It noted that all ICERs increased when the commercial arrangements for blinatumomab (the comparator) and tocilizumab (used to treat cytokine release syndrome) were taken into account. These ICERs cannot be reported as the simple discounts on the list price of blinatumomab and tocilizumab are commercial in confidence. The committee concluded the most plausible ICERs for tisagenlecleucel compared with blinatumomab when taking into account all the patient access scheme discounts were over £30,000\xa0per\xa0QALY gained.\n\n## The most plausible ICERs compared with salvage chemotherapy are above £45,000\xa0per\xa0QALY gained\n\nThe committee recalled that there was a high degree in uncertainty in the estimates of overall survival for tisagenlecleucel and salvage chemotherapy because of the length of follow‑up in the tisagenlecleucel studies, use of a naive indirect treatment comparison and choice of overall survival extrapolations for both tisagenlecleucel and salvage chemotherapy. It recalled that it preferred the ERG's base case and in particular its preference for use of a mixture cure model for consistency with the modelling of the other comparators (see section\xa03.20). It therefore only considered alternative extrapolations using the mixture cure model. The committee noted that the ERG's probabilistic base-case ICER for tisagenlecleucel (incorporating the patient access scheme) compared with salvage chemotherapy was £48,265\xa0per\xa0QALY gained and that this was higher than the company's probabilistic base case of £27,066\xa0per\xa0QALY gained. The committee recalled that the extrapolation of overall survival for tisagenlecleucel was an important source of uncertainty in the model (see section\xa03.17). The committee agreed that the ERG's exploratory scenario analysis which used a log-normal cure model for overall survival for tisagenlecleucel was plausible and noted that the deterministic ICER for tisagenlecleucel increased to £74,322\xa0per\xa0QALY gained in this scenario. It was also aware that the ICER was likely to increase by around £3,000\xa0per\xa0QALY gained if a probabilistic analysis was used. It noted that the ICERs slightly decreased when the commercial arrangement for tocilizumab (used to treat cytokine release syndrome) was taken into account. These ICERs cannot be reported as the simple discount on the list price of tocilizumab is commercial in confidence. The committee concluded that the most plausible ICERs for tisagenlecleucel compared with salvage chemotherapy, when taking into account all patient access scheme discounts, were over £45,000\xa0per\xa0QALY gained.\n\n## Costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia are uncertain and may have a substantial impact on cost-effectiveness estimates\n\nThe committee recalled that the likely costs of subsequent allogeneic stem cell transplants and B‑cell aplasia after treatment with tisagenlecleucel were both uncertain (see section 3.22 and section 3.23). It noted that changes to the assumptions that underpin these costs could have a substantial effect on the ICERs. The committee concluded that in addition to survival estimates, the costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia were important sources of uncertainty in the model.\n\n# Innovation\n\n## Tisagenlecleucel is innovative but there are no additional benefits that have not been captured in the analysis\n\nThe committee considered tisagenlecleucel to be innovative because it represents a step‑change in the treatment of relapsed or refractory B‑cell acute lymphoblastic leukaemia. The company's submission stated that substantial positive effects for patients and caregivers, such as allowing return to work or employment, had not been captured in the economic analysis. The committee was mindful that the effect of tisagenlecleucel on employment were outside NICE's reference case, which specifies that the costs and benefits of a technology should be considered from the perspective of the NHS and personal social services. It noted that tisagenlecleucel was granted eligibility as a priority medicine through the European Medicines Agency's PRIME scheme. The committee concluded that there are no additional benefits that had not been captured in the economic analysis.\n\n# Discount rate\n\n## A discount rate of 3.5% should be applied for costs and benefits\n\nThe committee discussed the use of the alternative discount rate. A discount rate of 1.5% for costs and benefits may be considered by the committee when treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30\xa0years), and if the committee is satisfied that the introduction of the technology does not commit the NHS to substantial irrecoverable costs. The committee noted that tisagenlecleucel appeared clinically effective, but recalled its previous conclusion that there was no robust evidence that tisagenlecleucel was a curative therapy (see section\xa03.7). The committee concluded that the reference case should use a discount rate of 3.5% for both costs and benefits.\n\n# End of life\n\n## Tisagenlecleucel does not meet both criteria to be considered a life-extending treatment at the end of life because the life expectancy evidence is uncertain\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee considered whether the life expectancy of people having standard care for relapsed or refractory B‑cell acute lymphoblastic leukaemia was less than 24\xa0months. It recalled that treatment was offered with the expectation that some patients would have a subsequent allogeneic stem cell transplant and potentially be cured. The median overall survival for this patient population was 7.5\xa0months in the study of blinatumomab (von Stackelberg\xa0et\xa0al.\xa02016) and 13\xa0weeks in the study used as a proxy for salvage chemotherapy (Jeha\xa0et\xa0al.\xa02006). It noted the company's and ERG's base-case results for undiscounted mean overall survival (results are considered commercial in confidence by the company and cannot be reported here). The committee was aware that the mean survival estimates from the economic model were driven by the proportion of long-term survivors (that is, patients alive after 5\xa0years in the model). The clinical experts explained that the life expectancy of people who were not long‑term survivors after having blinatumomab or salvage chemotherapy would be close to the median life expectancy from the clinical studies. The committee noted that around 15% of patients having blinatumomab were long-term survivors in both the company's and ERG's base-case analyses. For salvage chemotherapy, the proportions of long-term survivors were 16% in the ERG's model and 8% in the company's model. Both the company's and the ERG's models predicted a mean overall survival of much longer than 24\xa0months for blinatumomab. The committee noted that the company's model predicted a mean overall survival of less than 24\xa0months for people having salvage chemotherapy, whereas the ERG model predicted a mean overall survival of much longer than 24\xa0months. The committee agreed that there was a high degree of uncertainty around the overall survival extrapolations for both blinatumomab and salvage chemotherapy (see section 3.17 and section 3.18). It also recalled further uncertainties around the short survival follow‑up for blinatumomab and the choice of data source for the efficacy of salvage chemotherapy (see section 3.9 and section 3.10). Taking into account the undiscounted mean overall survival estimates, the high degree of uncertainty around the estimates and its conclusion that most patients would have blinatumomab, the committee concluded that the life expectancy criterion was not met but acknowledged that there was considerable uncertainty around this estimate. The committee then considered if tisagenlecleucel met the criterion for providing an extension to life of more than 3\xa0months. It noted that the median overall survival for tisagenlecleucel was over 23\xa0months in all 3 tisagenlecleucel trials. Furthermore, both the company's and the ERG's modelling suggested that tisagenlecleucel was associated with a gain in overall survival of over 8\xa0years compared with both blinatumomab and salvage chemotherapy (irrespective of the choice of salvage chemotherapy data). The committee concluded that although tisagenlecleucel met this criterion, it did not meet both of NICE's criteria to be considered a life-extending treatment at the end of life when compared with blinatumomab and salvage chemotherapy.\n\n# Conclusion\n\n## Tisagenlecleucel is not recommended for routine use for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25\xa0years\n\nThe committee recalled that although the precise life expectancy of people with relapsed or refractory B‑cell acute lymphoblastic leukaemia was uncertain, tisagenlecleucel did not meet the end-of-life criteria (see section\xa03.30). It also recalled that the size of the clinical benefit compared with blinatumomab or salvage chemotherapy was uncertain (see section\xa03.5) and that it is not yet known whether tisagenlecleucel is a curative therapy (see section\xa03.7). The most plausible ICERs for tisagenlecleucel compared with both blinatumomab and salvage chemotherapy were above £30,000\xa0per\xa0QALY gained (see section 3.25 and section 3.26). The committee therefore concluded that it could not recommend tisagenlecleucel for routine use in the NHS to treat relapsed or refractory B‑cell acute lymphoblastic leukaemia.\n\n# Cancer Drugs Fund\n\n## Further data collection could address uncertainties in the clinical and cost‑effectiveness evidence\n\nHaving concluded that tisagenlecleucel could not be recommended for routine use, the committee then considered if it could be recommended for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee recognised that tisagenlecleucel is an innovative treatment and therefore it considered whether clinical uncertainty associated with tisagenlecleucel could be addressed through collecting more data. The committee was aware that more data from ELIANA, ENSIGN and B2101J will become available for tisagenlecleucel over time. It agreed that:\n\nFurther data on overall survival would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around length of overall survival and if tisagenlecleucel could be considered a curative treatment.\n\nWith further evidence, it may be possible to gain a more complete understanding of the costs of subsequent allogeneic stem cell transplant and treatment for B‑cell aplasia.\n\nUsing tisagenlecleucel in the NHS would allow data to be collected which more accurately reflect the costs and benefits of its use in clinical practice.\n\n## Tisagenlecleucel meets the criteria for use in the Cancer Drugs Fund for this indication in people who would have blinatumomab\n\nHaving acknowledged that blinatumomab was the most common treatment option for relapsed or refractory B‑cell acute lymphoblastic leukaemia, the committee first considered if tisagenlecleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund when compared with blinatumomab. It noted that the most plausible ICER for tisagenlecleucel compared with blinatumomab was over £30,000\xa0per\xa0QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with blinatumomab were associated with a high degree of uncertainty, and concluded that tisagenlecleucel had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more long-term survival data for tisagenlecleucel and further data on the rate of subsequent allogeneic stem cell transplants would allow for a more robust cost-effectiveness estimate. It noted that if the rate of allogeneic stem cell transplant was lower in clinical practice then the ICERs would decrease. The committee agreed that tisagenlecleucel met the criteria to be included in the Cancer Drugs Fund for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25\xa0years who would have blinatumomab.\n\n## The use of salvage chemotherapy is likely to decline so a recommendation in patients who would currently have salvage chemotherapy is not needed\n\nThe committee considered whether tisagenlecleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund when compared with salvage chemotherapy. It recalled that the most plausible ICERs for tisagenlecleucel compared with salvage chemotherapy were above £45,000\xa0per\xa0QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with salvage chemotherapy were associated with a high degree of uncertainty, and concluded that tisagenlecleucel did not have the plausible potential to satisfy the criteria for routine use. The committee recalled that inotuzumab ozogamicin will likely replace blinatumomab after first disease relapse, and that blinatumomab will replace salvage chemotherapy after second disease relapse (see section\xa03.3). The committee therefore agreed that it would not make a distinction between people who would currently have blinatumomab or salvage chemotherapy in its recommendations, because the use of salvage chemotherapy as a treatment for relapsed or refractory disease was likely to decline over time.\n\n## It is reasonable to include people with Philadelphia chromosome‑positive disease from the recommendations\n\nThe committee recalled that the company did not present a separate cost‑effectiveness analysis for tisagenlecleucel's use for Philadelphia chromosome‑positive disease (see section\xa03.4). The committee was aware that the that the proportion of patients with Philadelphia chromosome‑positive disease within the population specified in the marketing authorisation is very small, and there will likely only be 1 or 2 patients\xa0per\xa0year in England. It was also aware that for these patients, treatment options are limited and prognosis is poor. The committee accepted that excluding this population from its recommendation would leave an unmet need and recalled that treatment benefits with tisagenlecleucel were expected to be similar regardless of Philadelphia chromosome status. The committee agreed that more uncertainty was acceptable given the very small size of the patient population. It considered it reasonable to include people with Philadelphia chromosome‑negative disease, and therefore agreed that it would not make a distinction based on Philadelphia chromosome status in its recommendations.\n\n## Tisagenlecleucel is recommended for use in the Cancer Drugs Fund for relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25\n\nBased on its considerations for all populations covered by the marketing authorisation (see section 3.33 to section 3.35), the committee concluded that it could recommend tisagenlecleucel for use as an option within the Cancer Drugs Fund to treat relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25\xa0years, only if the conditions in the managed access agreement are followed.\n\n## Use in the NHS\n\nThe committee was aware of statements from clinical experts and NHS England that introducing CAR\xa0T‑cell therapies to the NHS needs the provision of a new service. Infrastructure for transporting and storing the treatment, accreditation to administer the treatment, training of staff and access to intensive care units to manage adverse events all need to be included. The committee also noted that NHS England and the company consider a cautious approach is needed because these technologies are associated with severe side effects such as cytokine release syndrome (see section\xa03.13). Working collaboratively, NHS England and the company aim to manage the risks associated with introducing tisagenlecleucel by adopting a cautious approach to treatment planning, particularly concerning the management of adverse events (for further information see the summary of product characteristics). NHS England and the company agreed that phased implementation to the NHS is necessary to deliver this treatment.\n\n## Potential equalities issue\n\nThe committee noted a potential equality issue raised during the scoping process that blood support or haematopoietic stem cell transplant are not acceptable to some religious groups such as Jehovah's witnesses. These patients would normally instead have best supportive care. The committee agreed that if tisagenlecleucel does become an available treatment option, people can choose whether or not they wish to have it. Accordingly, this is not viewed as an equality issue."}
|
https://www.nice.org.uk/guidance/ta554
|
Evidence-based recommendations on tisagenlecleucel therapy (Kymriah) for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years.
|
7f48aa4fc947ee29448e17b73bde702b2aacd475
|
nice
|
Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer
|
Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer
Evidence-based recommendations on tumour profiling tests to guide adjuvant chemotherapy decisions for people with early breast cancer. The tests are EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score, Prosigna, MammaPrint and IHC4+C.
# Recommendations
EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score and Prosigna are recommended as options for guiding adjuvant chemotherapy decisions for people with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and lymph node (LN)-negative (including micrometastatic disease; see section 5.4) early breast cancer, only if:
they have an intermediate risk of distant recurrence using a validated tool such as PREDICT or the Nottingham Prognostic Index
information provided by the test would help them choose, with their clinician, whether or not to have adjuvant chemotherapy taking into account their preference
the companies provide the tests to the NHS with the discounts agreed in the access proposals and
clinicians and companies make timely, complete and linkable record-level test data available to the National Cancer Registration and Analysis Service as described in the data collection arrangements agreed with NICE (see section 5.29).
MammaPrint is not recommended for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2‑negative and LN-negative early breast cancer because it is not cost effective.
IHC4+C is not recommended for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2-negative and LN‑negative early breast cancer because the analytical validity of the test is uncertain.
Why the committee made these recommendations
People with early and locally advanced breast cancer may need further treatment (adjuvant treatment) after they have surgery. Tools such as PREDICT, which is used by many NHS trusts, provide prognostic information to help guide the selection of adjuvant treatment. Additional information from tumour profiling tests may be helpful for people whose cancer has an intermediate risk of distant recurrence when the decision to offer chemotherapy is unclear.
Evidence suggests that EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score, MammaPrint and Prosigna can predict the risk of distant recurrence in people who have ER-positive, HER2-negative, early breast cancer. This evidence is strongest in the group with LN-negative disease, which is likely to include people with micrometastatic disease. Also, Oncotype DX Breast Recurrence Score may be able to predict who will respond to chemotherapy, but the evidence for this is uncertain.
There are uncertainties in the economic modelling, particularly around the pre- and post-test chemotherapy decisions and the effect of adjuvant chemotherapy on distant recurrence. Also, there are no data available to compare the tumour profiling tests with PREDICT, or to define the clinical risk groups using PREDICT.
Using the access proposal test costs for EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score and Prosigna, all 3 tests would provide value for money in people with LN-negative disease and an intermediate risk of distant recurrence. But because of the uncertainty about their effects on clinical decision making and clinical outcomes, the tests are recommended as options for guiding adjuvant chemotherapy decisions only if the criteria in section 1.1 are met, which includes collecting data on their use. Discussion about treatment options within the multidisciplinary team may be particularly helpful for people who have micrometastatic disease.
In people with an intermediate to high risk of distant recurrence, MammaPrint is less clinically effective and costs more than current practice, which does not use tumour profiling tests. It is therefore not recommended for use in the NHS.
IHC4+C appears to be cost effective, but there are concerns about its analytical validity, for example the reproducibility of test results. It is therefore not recommended for use in the NHS.# Clinical need and practice
# The problem addressed
The tumour profiling tests EndoPredict, MammaPrint, Oncotype DX Breast Recurrence Score, Prosigna and IHC4+C provide information on the activity of genes in tumour samples from people with early breast cancer. The results provide a risk profile of a person's breast cancer, which can be used with other routinely assessed clinical risk factors, such as nodal status and tumour size. It is claimed that the risk profile can be used to better predict the risk of disease recurrence. Some tests also claim to predict relative treatment effects for chemotherapy. This information is intended to help decision making about adjuvant chemotherapy use.
It is also claimed that people with early breast cancer identified as having a low risk of distant recurrence by a tumour profiling test may not need to have adjuvant chemotherapy. For these people, unnecessary treatment and therefore the comorbidities and negative effects on quality of life associated with chemotherapy could be avoided. Also, for people with early breast cancer at low risk of disease recurrence based on clinical and pathological features, the tests could confirm whether their risk is correct. If reclassified as being at high risk of recurrence, these people may benefit from chemotherapy. People with breast cancer and clinicians may also have more confidence that the treatment they are having or recommending is appropriate.
This assessment evaluates the clinical and cost effectiveness of EndoPredict, MammaPrint, Oncotype DX Breast Recurrence Score, Prosigna and IHC4+C when used to guide adjuvant chemotherapy decisions. The population was people with oestrogen receptor (ER)-positive (or progesterone receptor-positive or both), human epidermal growth factor receptor 2 (HER2)‑negative early breast cancer (stages 1 or 2) with 0 to 3 positive lymph nodes.
This is a full update of NICE's diagnostics guidance on gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat (DG10), which was published in 2013. This recommended Oncotype DX as an option for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2-negative and lymph node-negative early breast cancer if the person was assessed as being at intermediate risk and the company provided Oncotype DX to NHS organisations according to the confidential arrangement agreed with NICE. The guidance also encouraged data collection on the use of Oncotype DX in the NHS, and further research on MammaPrint, IHC4 and Mammostrat. Since publication of the original guidance, Mammostrat is no longer available. Also, a new test, EndoPredict, has become available and PAM50 has been further developed into the Prosigna test.
# The condition
Breast cancer is the most common cancer and the third most common cause of UK cancer-related deaths. One in 8 women and 1 in 870 men will be diagnosed with breast cancer during their lifetime (Cancer Research UK 2016). In 2014, 46,085 women and 332 men were newly diagnosed with breast cancer in England (Office for National Statistics 2016). Most breast cancer develops in women who are over the age of 50 (Cancer Research UK 2016).
Breast cancer survival depends on the stage of the disease at diagnosis, the treatment received and the biology of the tumour. More than 90% of women diagnosed with early breast cancer survive for at least 5 years, and 78% survive for 10 years (Cancer Research UK 2016). In contrast, only 13% of those diagnosed with advanced disease survive for more than 5 years.
# The diagnostics and care pathways
## Diagnosis
Breast cancer may be diagnosed following an abnormal result in the NHS breast cancer screening programme, or after referral for further investigation because of signs or symptoms that could be associated with breast cancer. The referral criteria are described in NICE's guideline on suspected cancer.
When cancer cells have been detected in a biopsy sample, further tests are done to provide more information on the characteristics of the tumour. The results of these tests are used to categorise breast cancer into molecular subtypes and determine which types of treatment it is most likely to respond to. Recommendations on tumour testing are in NICE's guideline on early and locally advanced breast cancer. Tumour tests can include hormone receptor and HER2 tests. Although not routinely done, some laboratories may also test for Ki67, a marker of cell proliferation.
## Care
NICE's guideline on early and locally advanced breast cancer describes the care pathway. Surgery is often the initial treatment. Neoadjuvant treatment may be used before surgery, to reduce the size of the tumour and enable breast-conserving surgery.
After surgery, further treatment (adjuvant treatment) may be needed and this can include radiotherapy, chemotherapy, hormone therapy, biological therapy or a combination of these. The decision to offer adjuvant therapy, and the treatments to use, is made taking into account the clinical history, the stage and grade of disease, the likely course of the disease (prognosis), the molecular characteristics of the tumour and the person's preferences.
A variety of tools are available that can help to predict the likelihood of breast cancer recurrence based on clinical and pathological features. These may be used to provide prognostic information for patients and to guide the selection of adjuvant therapy. Expert advice suggests that the PREDICT tool version 2.0, an online prognostic and treatment benefit calculator, is the most widely used tool in the NHS in England to calculate risk of recurrence. Adjuvant! Online is not currently available online because it is being updated. It is not certain when it will be reinstated, and the website directs people to the PREDICT tool. Adjuvant! Online is described in the supplementary appendix of Cardoso et al. 2016. PREDICT is recommended in NICE's guideline on early and locally advanced breast cancer.# The diagnostic tests
The assessment compared 5 intervention tests with 1 comparator.
# The interventions
## EndoPredict (Myriad Genetics)
EndoPredict is a CE-marked assay that is designed to predict the likelihood of metastases developing within 10 years of an initial breast cancer diagnosis. The test is for pre and postmenopausal people with early breast cancer with oestrogen receptor (ER)‑positive, human epidermal growth factor 2 (HER2)-negative and lymph node (LN)-negative or LN-positive disease (up to 3 positive nodes).
EndoPredict measures the expression of 12 genes: 3 proliferation‑associated genes, 5 hormone receptor-associated genes, 3 reference (normalisation) genes and 1 control gene.
EndoPredict needs RNA extracted from a formalin-fixed, paraffin‑embedded (FFPE) breast cancer tissue sample. The test can be done in a local laboratory or the Myriad Genetics pathology laboratory in Germany. It takes approximately 2 days from receipt of the tissue sample to get the results from a local laboratory, although the turnaround time may be longer if samples are tested in full batches. The turnaround time is also longer if samples are sent to Germany.
The test involves a reverse transcription-quantitative polymerase chain reaction. Online evaluation software calculates an EP score and an EPclin score. An EP score of 0 to less than 5 indicates low risk of distant disease recurrence in the next 10 years. An EP score of 5 to 15 indicates high risk of distant disease recurrence in the next 10 years.
The EPclin score estimates the probability of metastases developing within 10 years (assuming 5 years of endocrine therapy). It is calculated by adding clinical data about tumour size and nodal status to the EP score. An EPclin score of less than 3.3 indicates low risk (less than 10%) of metastases in the next 10 years. An EPclin score of 3.3 or more indicates high risk of metastases in the next 10 years.
During consultation on the first diagnostics consultation document, NICE accepted an access proposal from the company in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of EndoPredict, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
## MammaPrint (Agendia)
MammaPrint is a CE-marked assay that is designed to assess the risk of distant recurrence within 5 and 10 years and whether a person would benefit from chemotherapy. The test is for pre and postmenopausal people with stage 1 or 2 breast cancer, with a tumour size of 5 cm or less, and LN-negative or LN-positive disease (up to 3 positive nodes). The test can be used irrespective of ER and HER2 status.
MammaPrint measures the expression of 70 genes, including genes associated with 7 different parts of the metastatic pathway: growth and proliferation, angiogenesis, local invasion, entering the circulation, survival in the circulation, entering organs from the circulation, and adaption to the microenvironment at a secondary site.
The MammaPrint test needs RNA extracted from an FFPE breast cancer tissue sample. The test is offered as an off-site service. In Europe, samples are analysed at the Agendia laboratory in the Netherlands. Results are available within 10 days of submitting the sample.
The test is based on diagnostic microarray. Software is used to calculate the MammaPrint result on a scale of −1 to +1. The score indicates the risk of developing distant metastases over the next 10 years without any adjuvant endocrine therapy or chemotherapy. A MammaPrint result of 0 or less indicates high risk of metastases in the next 10 years and a result of more than 0 indicates low risk (10% or less) of metastases in the next 10 years.
## Oncotype DX Breast Recurrence Score (Genomic Health)
Oncotype DX Breast Recurrence Score (hereafter referred to as Oncotype DX) is designed to quantify the 10-year risk of distant recurrence and predict relative treatment effects for chemotherapy. The test also reports the underlying tumour biology: ER, progesterone receptor and HER2 status. The test is for pre and postmenopausal people with stage 1 or 2 breast cancer and ER‑positive, HER2-negative, LN-negative or LN-positive disease (up to 3 positive nodes). The assay does not have a CE mark because it is provided as a service by Genomic Health in an accredited laboratory in the US.
Oncotype DX quantifies the expression of 21 genes: 16 cancer-related genes correlated with distant recurrence-free survival, and 5 reference (normalisation) genes.
The Oncotype DX test needs RNA extracted from a FFPE breast cancer tissue sample. Samples are processed centrally at a Genomic Health laboratory in the US. Results are usually available 7 to 10 days after the sample is received.
The test is based on a reverse transcription-quantitative polymerase chain reaction. It gives a Recurrence Score result of between 0 and 100, which is used to quantify the 10-year risk of distant recurrence, assuming 5 years of endocrine therapy. A result below 18 indicates low risk of distant recurrence and claims to predict little to no effect of chemotherapy on patient outcomes. A result between 18 and 30 indicates intermediate risk of recurrence and claims to predict no substantial effect of chemotherapy on patient outcomes. A result of 31 or more indicates high risk of recurrence and claims to predict a large effect of chemotherapy on patient outcomes. NICE is aware that the cut-offs may change in light of the results from the TAILORx study.
The breast Recurrence Score result can be combined with clinical and pathological factors using the recurrence score-pathology-clinical (RSPC) calculator. However, this calculator has not been validated in a cohort independent of that used to derive Oncotype DX.
During consultation on the first diagnostics consultation document NICE accepted the company's commitment to maintain the current confidential discount, which is in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of Oncotype DX, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
## Prosigna (NanoString Technologies)
Prosigna is a CE-marked assay designed to provide information on breast cancer subtype and to predict distant recurrence-free survival at 10 years. The test is for postmenopausal people with early breast cancer that is ER-positive, HER2-negative and LN‑negative or LN-positive (up to 3 positive nodes).
Prosigna measures the expression of 50 genes used for intrinsic subtype classification, 8 housekeeping genes used for signal normalisation, 6 positive controls, and 8 negative controls.
The test needs RNA extracted from a FFPE breast tumour tissue sample. It is based on direct mRNA counting using fluorescent probes and an nCounter Digital Analyser.
Prosigna classifies the risk of distant recurrence within 10 years, assuming 5 years of endocrine therapy, based on the PAM50 gene signature, breast cancer subtype, tumour size, nodal status and proliferation score. The proliferation score is determined by evaluating multiple genes associated with the proliferation pathway. The test gives a score between 0 and 100. Based on this score and the nodal status, samples are classified into risk categories:
LN-negative: low risk (0 to 40), intermediate risk (41 to 60) or high risk (61 to 100)
LN-positive (up to 3 positive nodes): low risk (0 to 15), intermediate risk (16 to 40), or high risk (41 to 100).
During consultation on the first diagnostics consultation document, NICE accepted an access proposal from the company in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of Prosigna, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
## IHC4 and IHC4+C
The IHC4 test is a laboratory developed test that combines the results of 4 immunohistochemistry (IHC) measurements. The IHC4+C test combines the results of the 4 IHC4 tests with clinical and pathological features such as age, nodal status, tumour size, and grade. Both versions are designed to quantify the 10-year risk of distant disease recurrence, assuming 5 years of endocrine therapy. The test is for postmenopausal people with early breast cancer that is ER-positive and LN-negative or LN-positive (up to 3 positive nodes).
The IHC4+C test needs an FFPE breast tumour tissue sample. The 4 immunohistochemistry tests are: ER, progesterone receptor (PR), HER2 and the proliferation marker Ki67. ER and HER2 markers are commonly measured in NHS laboratories, but PR and Ki67 markers are not.
The IHC4+C test is in clinical use at 1 NHS centre (the Royal Marsden NHS Foundation Trust), which carries out the test with an average turnaround time of 1 week. The test could be run in local NHS laboratories providing that training and quality assurance programmes for the individual assays were in place.
The IHC4+C test uses a published algorithm to calculate a risk score for distant recurrence based on the results of the 4 assays and clinical factors. A calculator is available for use on request. A score of less than 10% is categorised as low risk for distant recurrence at 10 years. A score of more than 10% but less than 20% is intermediate risk, and a score of 20% or more is high risk for distant recurrence at 10 years.
# The comparator
The comparator is decision making for adjuvant chemotherapy prescribing, based on clinical and pathological features or the results of tools used to assess risk without the tumour profiling tests. Features may include the stage and grade of the disease, nodal status, ER or PR status, HER2 status and any previous treatment (for example, neoadjuvant therapy). Risk assessment tools include PREDICT, the Nottingham Prognostic Index (NPI) and Adjuvant! Online.
These risk assessment tools can be used to define the level of clinical risk. For example, in LN-negative disease a NPI of 3.4 or less is classed as low risk, and a NPI of more than 3.4 and up to or equal to 5.4 is classed as intermediate risk. If using the PREDICT tool, an absolute 10-year survival benefit from chemotherapy of less than 3% is classed as low risk; between 3% and 5% is classed as intermediate risk; and more than 5% is classed as high risk.# Evidence
The diagnostics advisory committee (section 7) considered evidence on EndoPredict (EP score and EPclin score), MammaPrint, Oncotype DX (with and without the recurrence score-pathology-clinical calculator), Prosigna and IHC4 or IHC4+C from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
Evidence on the following outcomes was of interest in the clinical effectiveness review:
Prognostic ability – the degree to which the test can accurately predict the risk of an outcome such as disease recurrence.
Prediction of relative treatment effect – the ability of the test to predict which patients have disease that will respond to chemotherapy. It can be assessed by considering whether the relative treatment effect of chemotherapy or no chemotherapy on patient outcomes differs according to the test score.
Clinical utility – the ability of the prospective use of the test to affect patient outcomes such as recurrence and survival compared with current practice.
Decision impact – how the test influences decision making in terms of which patients will be offered chemotherapy.
A total of 153 references were included in the review. Studies assessing prognostic ability and prediction of relative treatment effect were quality assessed using relevant criteria from the draft prediction model study risk of bias assessment tool (PROBAST). Clinical utility studies were quality assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs).
## Prognostic ability
Studies providing information on prognostic ability were retrospective analyses of RCT data or routinely collected data. Most of the studies excluded patients who did not have a large enough tissue sample for testing, which leaves the evidence base at potential risk of spectrum bias, because patients with smaller tumours (who may be systematically different to those with large tumours) are likely to be under-represented. In many studies patients had chemotherapy, which could affect event rates and therefore potentially reduce the apparent prognostic performance of a test. In other studies, patients who had chemotherapy were excluded from analyses, which may also lead to spectrum bias. Therefore studies in which all patients had endocrine monotherapy were preferable.
Results for prognostic ability were generally presented as unadjusted or adjusted analyses. Unadjusted analyses look at differences in the event rates among low, intermediate and high‑risk groups without adjusting for clinical and pathological variables. Adjusted analyses show whether the test has prognostic value over clinical and pathological variables.
Among studies of patients with lymph node (LN)-negative disease who had endocrine monotherapy, in each group around 70% to 80% had disease that was categorised as low or low/intermediate risk across all tests (11 studies). Most MammaPrint studies had mixed endocrine and chemotherapy use, mixed hormone receptor status with or without mixed human epidermal growth factor receptor 2 (HER2) status, so results may not be comparable with results from other tests. In these studies 20% to 61% of patients had disease that was categorised as low risk (6 studies). Most IHC4 or IHC4+C studies used quartiles or tertiles to define risk groups. These studies do not provide useful information on the distribution of patients across risk categories.
The proportion of patients with low and intermediate risk was generally much lower in groups with LN-positive disease than in groups with LN-negative disease who had endocrine monotherapy (7 LN-positive studies). For Oncotype DX, however, the proportion of patients with low and intermediate risk was only slightly lower in the LN-negative group than in the LN-positive group. Studies of MammaPrint in patients with LN-positive disease were all done in groups with mixed hormone receptor status and mixed or unknown HER2 status, so results may not be comparable with results from other tests. In these studies 38% to 41% of patients had disease that was categorised as low risk (2 studies).
There were 11 data sets that provided information on the prognostic ability of Oncotype DX: 7 reanalyses of RCT data and 4 retrospective studies of routinely collected data. All studies were validation studies, and in 4 RCTs patients had endocrine monotherapy. Three of the studies were done in East Asia and it is uncertain whether the commercial version of Oncotype DX was used in these studies. Also, they may not be generalisable to England because usual clinical practice may differ between countries enough to affect prognostic outcomes. In addition, it is possible that people of different ethnicities have different underlying risk profiles and natural history of disease.
Unadjusted analyses indicated that Oncotype DX had prognostic accuracy (there were statistically significant differences between low-risk and high-risk groups) across various recurrence outcomes, regardless of lymph node status. However, hazard ratios between the intermediate-risk group and the high or low-risk groups were not always statistically significant, particularly in the group with LN‑positive disease.
In adjusted analyses, Oncotype DX provided statistically significant additional prognostic information over most commonly used clinical and pathological variables (age, grade, size, nodal status), regardless of lymph node status. A bespoke analysis of TransATAC study data also showed that Oncotype DX provided additional prognostic information over clinical and pathological tools to assess risk.
There were 10 data sets that provided information on the prognostic ability of MammaPrint: 1 reanalysis of RCT data and 9 retrospective studies of routinely collected data. In addition, a further 4 studies pooled data on specific patients from the same 10 data sets. All studies were validation studies, and in 2 studies patients had endocrine monotherapy. Most studies included some patients who were out of scope (with HER2-positive or hormone receptor-negative disease or both).
In 6 of 7 unadjusted analyses, MammaPrint had prognostic accuracy (there were statistically significant differences between low-risk and high-risk groups) for 10 year distant recurrence-free survival or interval, regardless of LN status.
In adjusted analyses, a pooled analysis of patients with LN‑negative and LN-positive disease showed that MammaPrint had statistically significant prognostic accuracy for 10-year distant recurrence-free survival after adjusting for clinical and pathological variables. In patients with LN-negative disease, MammaPrint had statistically significant prognostic accuracy for 10-year distant recurrence-free interval when adjusted for Adjuvant! Online, Nottingham Prognostic Index (NPI) or clinical and pathological variables. In patients with LN-positive disease, MammaPrint had borderline statistically significant prognostic accuracy for 10-year distant metastasis-free survival when adjusted for clinical and pathological variables.
There were 8 data sets that provided information on the prognostic ability of Prosigna: 6 reanalyses of RCT data and 3 retrospective analyses of 2 prospective cohort studies. All studies were validation studies, and in 5 studies patients had endocrine monotherapy. Some studies included some patients who were out of scope (with HER2-positive or hormone receptor-negative disease or both).
Prosigna had statistically significant prognostic accuracy for 10‑year distant recurrence-free survival and interval in all unadjusted analyses of patients with LN-negative and LN-positive disease.
In analyses adjusted for clinical and pathological variables or tools, Prosigna had prognostic accuracy for 10-year distant metastasis‑free survival and distant recurrence-free survival. In patients with LN-negative disease the results were statistically significant. In patients with LN-positive disease the results were statistically or borderline significant.
There were 3 data sets that provided information on the prognostic ability of EndoPredict; all were reanalyses of RCT data. All studies were validation studies, and in 2 of the 3 studies patients had endocrine monotherapy.
In unadjusted analyses, EndoPredict (EPclin) had statistically significant prognostic accuracy for 10-year distant recurrence-free survival and interval in patients with LN-negative and LN-positive disease.
Adjusted analyses of TransATAC data show that EndoPredict (EPclin) had statistically significant increases in likelihood ratio for 10-year distant recurrence-free interval over clinical and pathological variables or tools, regardless of LN status.
There were 12 data sets that provided information on the prognostic ability of IHC4 and IHC4+C: 6 reanalyses of RCT data and 6 reanalyses of routinely collected data. Most of the data related to the IHC4 score alone, without including clinical factors. One of the studies was based on the derivation cohort for IHC4, and therefore may have overestimated prognostic ability. The remaining studies were validation studies. Patients had endocrine monotherapy in only 2 studies, 1 of which was the derivation cohort study.
In unadjusted analyses, IHC4 had statistically significantly better prognostic performance in groups with high risk than in groups with low risk (defined by quartiles or tertiles), regardless of lymph node status. However, no studies reported survival or recurrence outcomes by risk group. Also, many used laboratory methods that differed from the derivation study methodology. In adjusted analyses, IHC4 had additional prognostic value over clinical and pathological factors in 3 studies, but patients had endocrine monotherapy in only 1 of these studies.
Data on IHC4+C came from the derivation cohort and 1 validation cohort. These studies showed that IHC4+C had prognostic value in unadjusted analyses. In adjusted analyses IHC4+C provided statistically significantly more information than the NPI in LN‑negative, but not LN-positive, disease.
## Prediction of relative treatment effect
In addition to estimating the risk of recurrence, the ability of Oncotype DX and MammaPrint to predict which patients have disease that will respond to chemotherapy was explored in 7 data sets. The external assessment group (EAG) reviewed evidence in support of this.
In 5 data sets (2 reanalyses of RCT data and 3 observational studies) reported across 11 published references and 1 confidential manuscript, analyses assessed the ability of Oncotype DX to predict relative treatment effects for chemotherapy.
The 2 reanalyses of RCTs suggest that Oncotype DX may predict differences in relative treatment effects for chemotherapy. Hazard ratios for disease-free survival for patients having chemotherapy compared with those having no chemotherapy suggested that the greatest relative treatment effect was for patients in the Oncotype DX high-risk category. Unadjusted interaction tests between Oncotype DX risk group and relative treatment effects were mainly statistically significant. Adjusted interaction tests were statistically significant in an analysis of patients with HER2-negative, LN‑negative disease, but in patients with LN-positive disease the interaction test was not significant when hormone receptor status was adjusted for. However, the data for the population with LN‑negative disease came from the derivation cohort for Oncotype DX and may overestimate predictive performance.
Results from the 3 observational studies were mixed and at high risk from confounding. One reported a statistically significant interaction test but this was only adjusted for a limited number of factors. Two others reported hazard ratios for chemotherapy compared with no chemotherapy; 1 study in patients with intermediate Recurrence Score results, and another in patients with high Recurrence Score results. Both of these studies reported statistically non-significant results.
The RSPC algorithm incorporates Oncotype DX plus age, tumour size and grade. There was a non-significant interaction test result between relative chemotherapy treatment effects and RSPC risk group.
Two studies reported the ability of MammaPrint to predict the relative treatment effects for chemotherapy. In a pooled analysis including patients with LN-negative and LN-positive disease, the effect of chemotherapy compared with no chemotherapy was statistically significant in the MammaPrint high-risk group but not in the low-risk group in unadjusted and adjusted analyses. Further, the interaction test for chemotherapy treatment and risk group was non-significant. In a pooled analysis of patients with LN-positive disease, there was a non-significant interaction between chemotherapy treatment and risk group.
## Clinical utility
The EAG noted that the best evidence for clinical utility was an RCT of treatment guided by the test compared with treatment guided by the comparator. There were no clinical utility data available for EndoPredict, Prosigna or IHC4+C.
Five data sets, reported across 9 published references and 1 confidential manuscript, reported evidence on the clinical utility of Oncotype DX. These studies included the low-risk group from TAILORx. One further study did not meet the inclusion criteria (because of insufficient follow-up length), but presented subgroup data according to age, lymph node status and ethnicity, and was therefore discussed by the EAG. Studies generally reported different outcomes, making comparisons across studies difficult. All studies were judged to be of poor quality using the Cochrane risk of bias tool for RCTs.
In patients with LN-negative disease, using the test in clinical practice appeared to result in low rates of chemotherapy in patients with low risk (2% to 12%), with acceptable outcomes (distant recurrence-free survival, distant recurrence-free interval or invasive disease-free survival 96% to 99.6%). Rates of chemotherapy increased with increasing risk category, and were generally higher in patients with LN-positive disease. It was not possible to conclude whether patients in intermediate and high-risk categories had better outcomes as a result of using Oncotype DX to guide treatment because there were no comparator groups (patients who had treatment without Oncotype DX testing).
One study (TAILORx; Sparano et al. 2018) reporting evidence on clinical utility was published after completion of the diagnostics assessment report. This study was a prospective, partially randomised study in which patients with an Oncotype DX Recurrence Score result of 0 to 10 had endocrine therapy, patients with Recurrence Score results of 26 and above had endocrine therapy plus chemotherapy, and those with Recurrence Score results of 11 to 25 were randomised to have either endocrine therapy alone, or endocrine therapy plus chemotherapy. The cut‑offs in this study were different to the cut-offs recommended by the company (less than 18, 18 to 30 and greater than 30; see section 3.15). The 2018 publication focused on the results from patients in the intermediate-risk group who were randomised to treatment. It reported that across all patients with Recurrence Score results of 11 to 25, there were no clinically relevant or statistically significant differences between those who had endocrine therapy alone and those who had chemotherapy plus endocrine therapy. Results for the primary end point of 9-year invasive disease-free survival were 84.3% with chemotherapy and 83.3% without chemotherapy; an absolute difference of 1.0% (hazard ratio 1.08, 95% confidence interval 0.94 to 1.24, p=0.26). The upper confidence interval was within the pre-specified non-inferiority margin (HR 1.322). Results for freedom from distant recurrence at 9 years were 95% with chemotherapy and 94.5% without chemotherapy; an absolute difference of 0.5% (HR 1.10, 95% CI 0.85 to 1.41, p=0.48). However, exploratory subgroup analyses suggested that chemotherapy may have an effect in some subgroups, such as those with Recurrence Score results of 21 to 25 and possibly Recurrence Score results of 16 to 20, particularly in people aged 50 or under. The EAG noted that no analysis was available for the subgroup of patients with Recurrence Score results of 11 to 25 and a modified Adjuvant! Online high risk score.
Two studies reported evidence relating to the clinical utility of MammaPrint. MINDACT was a prospective, partially randomised study in which clinical risk was determined using a modified version of Adjuvant! Online. Patients with risk scores that disagreed from MammaPrint and modified Adjuvant! Online were randomised to chemotherapy or no chemotherapy. Of patients included in the study, 88% had HR-positive disease and 90% HER2-negative disease, therefore some patients were outside of the scope for this assessment. For the group who were high risk with modified Adjuvant! Online and low risk with MammaPrint, 5-year distant metastasis-free survival was 95.9% with chemotherapy and 94.4% without chemotherapy, a non-statistically significant absolute difference of 1.5% (adjusted hazard ratio for distant metastasis or death with chemotherapy compared with no chemotherapy, 0.78; 95% CI 0.50 to 1.21; p=0.27). For the group who were low risk with modified Adjuvant! Online and high risk with MammaPrint, 5-year distant metastasis-free survival was 95.8% with chemotherapy and 95.0% without chemotherapy, a non-statistically significant absolute difference of 0.8% (adjusted hazard ratio for distant metastasis or death with chemotherapy compared with no chemotherapy, 1.17; 95% CI 0.59 to 2.28; p=0.66). The EAG judged MINDACT to be at low risk of bias in terms of randomisation, allocation concealment and reporting. However, no details of blinding were reported.
Results from the RASTER study suggested that distant recurrence‑free interval rates were sufficiently low in the MammaPrint low-risk group for these patients to avoid chemotherapy. The 5-year distant recurrence-free interval rate for LN-negative disease was 97.0% for patients with low risk (15% had chemotherapy) and 91.7% for patients with high risk (81% had chemotherapy). In addition, MammaPrint provided additional prognostic information over Adjuvant! Online and the NPI, but not over the NHS PREDICT tool. The EAG judged RASTER to be at high risk of bias using the Cochrane risk of bias tool for RCTs.
## Comparison of the tests with each other
There were 6 studies that compared more than 1 test: 4 reanalyses of RCTs and 2 observational studies. Evidence shows that generally when a test placed more patients in a low-risk category than another test, the event-free survival in the low-risk group was reduced. Also, the tests generally performed differently in patients with LN-negative and LN-positive disease.
Thirteen studies reported data from microarray analyses on more than 1 test, however, these studies had methodological limitations. The comparability of test algorithms applied to microarray data with the commercial assays was unknown, so the generalisability of findings from microarray studies to the decision problem was uncertain. All the studies reported data on Oncotype DX and MammaPrint, and 2 also reported data on EndoPredict. No studies reported data on Prosigna or IHC4+C. The microarray studies generally supported the conclusions from studies using the commercial versions of the assays in suggesting that Oncotype DX, MammaPrint and EndoPredict can discriminate between patients with high and low risk regardless of LN status. In terms of additional prognostic performance of the tests over clinical and pathological variables, EndoPredict appeared to have the greatest benefit, followed by Oncotype DX and then MammaPrint. However, because of the methodological limitations, the EAG judged that these studies did not provide conclusive evidence of the superiority of 1 test over others.
The OPTIMA Prelim study, a UK-based feasibility phase of an RCT, analysed concordance between different tests. The study included Oncotype DX, MammaPrint, Prosigna and IHC4 plus 2 other tests. Out of the 4 in-scope tests, MammaPrint assigned the most patients to the low-risk category, but unlike the other 3 tests it does not have an intermediate category. When the low and intermediate categories were treated as 1 category for the 3 tests that have 3 risk groups, Oncotype DX assigned the most patients to this category, and MammaPrint the least. Kappa statistics indicated modest agreement between tests, ranging from 0.33 to 0.53. Also, across 5 tests in the study, only 39% of tumours were uniformly classified as either low/intermediate risk or high risk by all 5 tests. Of these, 31% were classified as low/intermediate risk by all tests and 8% were high risk by all tests. The study authors concluded that although the tests assigned similar proportions of patients to low/intermediate-risk and high-risk categories, test results for an individual patient could differ markedly depending on which test was used.
## Decision impact
The review of decision impact focused on studies done in the UK or the rest of Europe:
Oncotype DX: 6 UK studies and 12 other European studies
EndoPredict: 1 UK study and 3 other European studies
IHC4+C: 1 UK study and 0 other European studies
Prosigna: 0 UK studies and 3 other European studies
MammaPrint: 0 UK studies and 8 other European studies.
The percentage of patients with any change in treatment recommendation or decision (either to or from chemotherapy) in UK studies was 29% to 49% across 4 Oncotype DX studies, 37% in 1 EndoPredict study and 27% in 1 IHC4+C study. Ranges across European (non-UK) studies were 5% to 70% for Oncotype DX, 38% to 41% for EndoPredict, 14% to 41% for Prosigna and 13% to 51% for MammaPrint.
The net change in the percentage of patients with a chemotherapy recommendation or decision (pre-test to post-test) among UK studies was a reduction of 8% to 23% across 4 Oncotype DX studies, an increase of 1% in 1 EndoPredict study, and a reduction of between 2% and 26% in 1 IHC4+C study. Net changes across European (non-UK) studies were a reduction of 0% to 64% for Oncotype DX, a reduction of 13% to 26% for EndoPredict, a reduction of 2% to an increase of 9% for Prosigna, and a reduction of 31% to an increase of 8% for MammaPrint.
## Anxiety and health-related quality of life
There were 6 studies that reported outcomes relating to anxiety (including worry and distress) and health-related quality of life. The lack of a comparator in the studies made it difficult to tell whether changes in anxiety experienced with the use of tumour profiling tests would also have occurred if patients received a definitive decision based on clinical risk factors alone. Overall, evidence suggests that tumour profile testing may reduce anxiety in some patients in some contexts, but generally there was little effect on health-related quality of life.
# Cost effectiveness
## Review of economic evidence
The EAG reviewed existing studies investigating the cost effectiveness of tumour profiling tests to guide treatment decisions in people with early breast cancer, and also did a detailed critique of the economic models and analyses provided by Agendia (MammaPrint), Genomic Health (Oncotype DX), and the chief investigator of a UK decision impact study (EndoPredict).
From the review, 26 studies were identified that had been published since the original assessment for diagnostics guidance 10. The models reported in the studies assessed the cost effectiveness of tumour profiling tests across different countries including the UK, the US, Canada, Mexico, Japan, Austria, Germany, France and the Netherlands. Most studies compared Oncotype DX (18 studies), MammaPrint (8 studies) or EndoPredict (1 study) with comparators such as Adjuvant! Online, the St Gallen guidelines, standard practice or other conventional diagnostic tools. There was variation between the analyses in the populations evaluated, the disease type and other patient characteristics.
There was a high level of consistency in the general modelling approach and structure, and several studies were based on a previously published model. Most of the models used a Markov or hybrid decision tree–Markov approach, 2 studies used a partitioned survival approach and 1 study used a discrete event simulation approach. The time horizons ranged from 10 years to the patient's remaining lifetime, with cycle lengths ranging from 1 month to 1 year when reported. Most of the models that evaluated Oncotype DX assumed that the test could predict relative treatment effects for chemotherapy.
## Economic evaluation
None of the models identified in the literature review included all of the tests identified in the scope. Therefore, the EAG developed a de novo economic model designed to assess the cost effectiveness of Oncotype DX, MammaPrint, Prosigna, IHC4+C and EndoPredict compared with current practice without the use of the tumour profiling tests. The model used a lifetime time horizon (42 years) from the perspective of the UK NHS and personal social services. All costs and health outcomes were discounted at a rate of 3.5% per year. Unit costs were valued at 2015/16 prices. The main source of evidence used to inform the analyses of Oncotype DX, Prosigna, IHC4+C and EndoPredict was a bespoke analysis of TransATAC provided by the study investigators. This was limited to UK data on patients with hormone receptor-positive, HER2‑negative disease with 0 to 3 positive lymph nodes to match the scope for this assessment. Because this study did not include MammaPrint, MINDACT was used as the basis for evaluating the cost effectiveness of MammaPrint. PREDICT scores were not available in either data set, and so this tool could not be considered as a comparator or used to determine different risk subgroups. Therefore, the comparator for Oncotype DX, Prosigna, IHC4+C and EndoPredict was current practice (various tools and algorithms), and the comparator for MammaPrint was a modified version of Adjuvant! Online.
The hybrid decision tree–Markov model was based on the model previously developed by Ward et al. (2013). The decision tree component of the model classified patients in the current practice group (no test) and the tumour profiling test group as high, intermediate and low risk. For EndoPredict and MammaPrint, the intermediate-risk category was excluded because the test provides results in terms of high and low risk only. In both the test group and the current practice group, the decision tree determined the probability that a patient would be in 1 of 6 groups: low risk, chemotherapy; low risk, no chemotherapy; intermediate risk, chemotherapy; intermediate risk, no chemotherapy; high risk, chemotherapy, and high risk, no chemotherapy. For EndoPredict and MammaPrint, 4 groups were used because there was no intermediate-risk category. Each group was linked to a Markov model which predicted lifetime quality-adjusted life years (QALYs) and costs according to the patient's risk of distant recurrence and whether or not they had chemotherapy.
Each Markov node included 4 health states: distant recurrence‑free; distant recurrence; long-term adverse events (acute myeloid leukaemia ); and dead. Patients entered the model in the distant recurrence-free health state. A health-related quality of life decrement was applied during the first model cycle to account for health losses associated with short-term adverse events for patients having adjuvant chemotherapy. The treatment effect for adjuvant chemotherapy was modelled using a relative risk reduction for distant recurrence within each risk classification group. The benefit of the test was therefore captured in the model by changing the probability that patients with each test risk classification had adjuvant chemotherapy.
The risk classification probabilities used in the model for Oncotype DX, Prosigna, IHC4+C and EndoPredict were from the bespoke data analysis of TransATAC, which only included postmenopausal women. For MammaPrint, they were from MINDACT.
The probability of developing distant metastases in each group and risk category was based on 10-year recurrence-free interval data from the bespoke data analysis of TransATAC for Oncotype DX, Prosigna, IHC4+C and EndoPredict. For MammaPrint the probability of developing distant metastases was based on an adjusted analysis of 5-year distant metastasis-free survival data from MINDACT. The model assumed that the risk of distant metastases between 10 and 15 years was halved, and after 15 years was 0.
The probability of having chemotherapy in the current practice group and in the tumour profiling test groups was taken from the sources in table 1.
Population
Source
Proportion of patients having chemotherapy
LN-negative, NPI≤3.4
NCRAS data set
LN-negative, NPI>3.4
Genomic Health access scheme data set
LN-positive (1−3 nodes)
NCRAS data set
Overall population (MammaPrint)
Expert opinion
Abbreviations: LN, lymph node; NCRAS, National Cancer Registration and Analysis Service; NPI, Nottingham Prognostic Index; UKBCG, UK breast cancer group.
The Genomic Health access scheme data set is based on the access scheme operated by NHS England and is a result of the research recommendation from NICE's original diagnostics guidance 10.
For the proportion of patients having chemotherapy, the low, intermediate and high risks are combined.
Population
Source
Proportion of patients having chemotherapy (low risk)
Proportion of patients having chemotherapy (intermediate risk)
Proportion of patients having chemotherapy (high risk)
LN-negative, NPI≤3.4
UKBCG survey data
LN-negative, NPI>3.4
Genomic Health access scheme data set
LN-positive (1−3 nodes)
Loncaster et al. (2017) node-positive estimates
Abbreviations: LN, lymph node; NPI, Nottingham Prognostic Index; UKBCG, UK breast cancer group.
Population
Source
Proportion of patients having chemotherapy (low risk)
Proportion of patients having chemotherapy (intermediate risk)
Proportion of patients having chemotherapy (high risk)
EndoPredict: all 3 subgroups
Bloomfield et al. (2017) study
MammaPrint: all subgroups
Bloomfield et al. (2017) study
In the base-case analysis, the relative treatment effect for chemotherapy was assumed to be the same across all test risk groups, that is, all tests were assumed to be associated with prognostic benefit only. For Oncotype DX, Prosigna, IHC4+C and EndoPredict a 10-year relative risk of distant recurrence was estimated as 0.76 for chemotherapy compared with no chemotherapy (Early breast cancer trialists' collaborative group 2012), and was assumed to apply to the groups with LN-negative and LN-positive disease. For MammaPrint the 10-year relative risk of distant recurrence was estimated to be 0.77 (MINDACT) for chemotherapy compared with no chemotherapy.
In sensitivity analyses the effect of assuming that Oncotype DX could predict relative treatment effects for chemotherapy was explored, based on the B20 study by Paik et al. (2006) and the SWOG-8814 study by Albain et al. (2010). For the group with LN‑negative disease, the 10-year relative risks of distant recurrence with chemotherapy compared with no chemotherapy were 1.31, 0.61 and 0.26 for the low, intermediate and high-risk categories respectively. For the group with LN-positive disease, the 10-year relative risks of relapse with chemotherapy compared with no chemotherapy were 1.02, 0.72 and 0.59 respectively. It is possible that the no-chemotherapy arm of B20 may have overestimated the difference in response rates between low and high-risk patients, because this arm was the derivation set for Oncotype DX. Therefore, additional sensitivity analyses in the group with LN‑negative disease explored the impact of varying the relative chemotherapy treatment effect between risk groups on the incremental cost-effectiveness ratios (ICERs). Hazard ratios were based on naive indirect comparisons of the chemotherapy arms from the B20 study and the no-chemotherapy arms from the B14 study (estimated hazard ratios for treatment effects with chemotherapy compared with no chemotherapy were 0.64, 0.75 and 0.35 for the low, intermediate and high-risk categories respectively), and the chemotherapy arms of the B20 study and the no-chemotherapy arms of the TransATAC study (hazard ratios for treatment effects with chemotherapy compared with no chemotherapy were 0.86, 0.88 and 0.49 for the low, intermediate and high-risk categories respectively).
Survival following distant recurrence was based on a median of 40.1 months from Thomas et al. (2009). From this, the 6-month probability of death following distant recurrence was estimated to be 0.098, assuming a constant rate. The rate of death following distant metastases was assumed to be the same across the different subgroups and across each test risk group.
The model assumed that 10.5% of patients entering the distant recurrence health state had previously had local recurrence, based on de Bock et al. (2009). The 6-month probability of developing AML was estimated to be 0.00025, based on Wolff et al. (2015). Survival following the onset of AML was estimated to be approximately 8 months; assuming a constant event rate gave a 6‑month probability of death following AML of 0.53. Additional sensitivity analyses explored the effect of including congestive heart failure (average net lifetime QALY loss of 0.0385 and average net lifetime cost saving of £2 from Hall et al. 2017, using an excess congestive heart failure risk relative to that of the general population), permanent hair loss (disutility of 0.04495 from Nafees et al. 2008 applied to 15% of all patients having chemotherapy) and peripheral neuropathy (disutility of 0.02 from Shiroiwa et al. 2009 applied to 12% of all patients having chemotherapy) in the model.
The costs of the tumour profiling tests were based on company prices (see table 2).
Test
List price
Comments
Oncotype DX
Tests carried out in Genomic Health laboratory in US. Cost includes sample handling and customer service. A commercial-in-confidence discounted test cost was used in the model.
Prosigna
Based on doing the test in an NHS laboratory, which includes the laboratory costs (£240), the Prosigna kit (£1,650) and the nCounter system (£194,600) and is based on 2,500 samples per lifetime of the nCounter system).
Commercial-in-confidence discounted test costs were used in scenario analyses to account for the access proposal.
EndoPredict
Tests carried out in Myriad's laboratory in Munich.
Commercial-in-confidence discounted test costs were used in scenario analyses to account for the access proposal.
IHC4
The cost was based on 2014 prices. The total cost of the test (£198) was uplifted to current prices using the hospital and community health services indices.
MammaPrint
Converted from Euros to UK pounds sterling, assuming an exchange rate of 1 British pound to 1.15 Euros.
The costs associated with adjuvant chemotherapy were from a previous costing analysis of the OPTIMA Prelim trial (Hall et al. 2017). The weighted mean cost of adjuvant chemotherapy acquisition, delivery and toxicity was estimated to be £3,145 per course.
All surviving patients had endocrine therapy for a period of between 5 and 8 years. Costs of endocrine therapy were taken from the British national formulary (2017). In addition, 30% of women with early breast cancer had 4 mg of bisphosphonates (zoledronic acid) by intravenous infusion every 6 months for up to 3 years, at a cost of £58.50, excluding administration.
All patients had 2 routine follow-up visits during the first year after surgery, with annual visits thereafter for 5 years. Patients were also assumed to have a routine annual mammogram for up to 5 years. The cost of a routine follow-up visit was estimated to be £162.84, and the cost of a mammogram was estimated to be £46.37.
Costs associated with treating local recurrence were taken from Karnon et al. (2007) and uplifted to current prices (£13,913). This was applied as a once-only cost to distant recurrence. Costs associated with treating distant metastases were derived from Thomas et al. (2009), and included visits, drugs, pharmacy, hospital admission and intervention, imaging, radiotherapy, pathology and transport. Cost components specifically associated with terminal care were excluded. The 6-monthly cost of treating metastatic breast cancer was estimated to be £4,541.
Health utilities were taken from published studies (see table 3).
Health state / event
Duration applied in model
Mean
Standard error
Source
Recurrence-free
Indefinite
Lidgren et al. 2007
Disutility distant metastases
Indefinite
Calculated from Lidgren et al. 2007
Local recurrence
Once-only QALY loss applied on transition to distant recurrence state
(assumed)
Campbell et al. 2011
Chemotherapy AEs
Once-only QALY loss applied in first cycle
Campbell et al. 2011
AML
Indefinite
(assumed)
Younis et al. 2008
Abbreviations: AEs, adverse events; AML, acute myeloid leukaemia; QALY, quality-adjusted life year.
The following key assumptions were applied in the base-case analysis:
Clinicians interpreted each of the 3-level tests in the same way (for example, an Oncotype DX high-risk Recurrence Score result would lead to the same chemotherapy decision as a Prosigna high-risk score).
Clinicians interpreted each of the 2-level tests in the same way (for example, a MammaPrint high-risk score would lead to the same chemotherapy decision as an EndoPredict high-risk score).
The treatment effect for adjuvant chemotherapy was the same across all risk score categories for all tests.
The prognosis of patients with AML and the costs and QALYs accrued within the AML state were independent of whether they had previously developed distant metastases.
A disutility associated with adjuvant chemotherapy was applied once during the first model cycle only (while the patient is taking the regimen).
Costs associated with endocrine therapy, bisphosphonates, follow-up appointments and mammograms were assumed to differ according to time since model entry.
The model assumed that people entered at an age of around 60 years.
In the subgroup with LN-negative disease and a NPI of 3.4 or less, compared with current practice, the probabilistic model gave ICERs of:
£147,419 per QALY gained (EndoPredict)
£122,725 per QALY gained (Oncotype DX)
£91,028 per QALY gained (Prosigna)
£2,654 per QALY gained (IHC4+C).
In the subgroup with LN-negative disease and a NPI of more than 3.4, compared with current practice, the probabilistic model gave ICERs of:
£46,788 per QALY gained (EndoPredict)
£26,058 per QALY gained (Prosigna)
Oncotype DX was dominated by current practice (that is, it was more expensive and less effective)
IHC4+C was dominant over current practice (that is, it was less expensive and more effective).
In the population with LN-positive disease, compared with current practice, the probabilistic model gave ICERs of:
£28,731 per QALY gained (Prosigna)
£21,458 per QALY gained (EndoPredict)
Oncotype DX was dominated by current practice
IHC4+C was dominant over current practice.
In the overall MINDACT population, MammaPrint compared with modified Adjuvant! Online had an ICER of £131,482 per QALY gained. In the modified Adjuvant! Online high-risk subgroup, MammaPrint was dominated by current practice, and in the modified Adjuvant! Online low-risk subgroup, MammaPrint compared with current practice had an ICER of £414,202 per QALY gained.
The risk classification probabilities and the probability of having chemotherapy were combined in the model to estimate chemotherapy use with and without tumour profiling. The modelled chemotherapy use in the base case is shown in table 4.
Test, subgroup compared with current practice
Chemotherapy use with tumour profiling
Chemotherapy use with no tumour profiling
Net change
LN0 NPI≤3.4
LN0 NPI>3.4
LN+ (1–3 nodes)
Abbreviations: LN0, lymph node negative; LN+, lymph node positive, mAOL, modified Adjuvant! Online; NPI, Nottingham Prognostic Index.
Test, subgroup compared with current practice
Chemotherapy use with tumour profiling
Chemotherapy use with no tumour profiling
Net change
LN0 NPI≤3.4
LN0 NPI>3.4
LN+ (1–3 nodes)
Test, subgroup compared with current practice
Chemotherapy use with tumour profiling
Chemotherapy use with no tumour profiling
Net change
LN0 NPI≤3.4
LN0 NPI>3.4
LN+ (1–3 nodes)
Test, subgroup compared with current practice
Chemotherapy use with tumour profiling
Chemotherapy use with no tumour profiling
Net change
LN0 NPI≤3.4
LN0 NPI>3.4
LN+ (1–3 nodes)
Test, subgroup compared with current practice
Chemotherapy use with tumour profiling
Chemotherapy use with no tumour profiling
Net change
MINDACT overall population
mAOL high risk
mAOL low risk
The cost-effectiveness planes from the probabilistic sensitivity analyses showed considerable uncertainty in the cost-effectiveness estimates.
In the subgroup with LN-negative disease and a NPI of 3.4 or less, the only test with a non-zero probability of producing more net benefit than current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was IHC4+C.
In the subgroup with LN-negative disease and a NPI of more than 3.4, at a maximum acceptable ICER of £20,000 per QALY gained, IHC4+C had a probability of 0.69 of being cost effective compared with current practice. For EndoPredict, Oncotype DX and Prosigna, the probability that the test was cost effective compared with current practice at this threshold was 0.24 or less. In the same subgroup, at a maximum acceptable ICER of £30,000 per QALY gained, IHC4+C had a probability of 0.67 and Prosigna had a probability of 0.60 of being cost effective compared with current practice. Oncotype DX had a probability of 0.04 and EndoPredict had a probability of 0.26 of being cost effective compared with current practice.
In the subgroup with LN-positive disease, IHC4+C had probabilities of 0.95 and 0.94 of being cost effective compared with current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained respectively. In the same subgroup, the probabilities of EndoPredict producing more net benefit than current practice were 0.44 and 0.73, at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained respectively. For Prosigna the probabilities were 0.24 and 0.55. In this subgroup Oncotype DX had very low probabilities of producing more net benefit than current practice at the same maximum acceptable ICERs (0.01 or lower).
In the overall MINDACT population and in the subgroups, the probability that MammaPrint would be cost effective compared with current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was approximately 0.
The EAG did deterministic sensitivity analyses, testing a wide range of plausible values of key parameters.
Deterministic sensitivity analysis results for Oncotype DX compared with current practice were:
Subgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained over £34,000 per QALY gained across all analyses.
Subgroup with LN-negative disease and a NPI of more than 3.4: Oncotype DX was either dominated or had an ICER of more than £35,000 per QALY gained across almost all analyses. The only exception was when Oncotype DX was assumed to predict relative treatment effects for chemotherapy. In this analysis, Oncotype DX dominated current practice.
Population with LN-positive disease: Oncotype DX remained dominated across most analyses. The exceptions were when Oncotype DX was assumed to predict relative treatment effects for chemotherapy (it was dominant), and when the cost of chemotherapy was doubled (£3,700 saved per QALY lost).
Deterministic sensitivity analysis results for IHC4+C compared with current practice were:
Subgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained below £16,000 per QALY gained across all analyses, except when post-test chemotherapy probabilities were derived from Holt et al. (2011; £36,259 per QALY gained). Also, IHC4+C dominated current practice when the cost of chemotherapy was doubled.
Subgroup with LN-negative disease and a NPI of more than 3.4: IHC4+C dominated current practice or had an ICER below £6,000 per QALY gained across all scenarios.
Population with LN-positive disease: IHC4+C dominated current practice across all but 1 scenario. When the probability of having chemotherapy was based on the UK breast cancer group (UKBCG) survey the ICER was £1,929 per QALY gained.
Deterministic sensitivity analysis results for Prosigna compared with current practice were:
Subgroup with LN-negative disease and a NPI of 3.4 or less: ICERs were greater than £71,000 per QALY gained across all analyses.
Subgroup with LN-negative disease and a NPI of more than 3.4: ICERs were below £34,000 per QALY gained across all analyses.
Population with LN-positive disease: ICERs were below £38,000 per QALY gained across all analyses.
Deterministic sensitivity analysis results for EndoPredict compared with current practice were:
Subgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained greater than £91,000 per QALY gained across all analyses.
Subgroup with LN-negative disease and a NPI of more than 3.4: ICERs remained greater than £30,000 per QALY gained across all but 2 of the analyses. Exceptions were when the UKBCG survey was used to inform the probability of having chemotherapy (£25,250 per QALY gained), and when Cusumano et al. (2014) was used to inform the probability of having chemotherapy based on the EndoPredict test result (£26,689 per QALY gained).
Population with LN-positive disease: ICERs remained below £30,000 per QALY gained across all scenarios.
Deterministic sensitivity analysis results for MammaPrint compared with current practice were:
Overall MINDACT population: ICERs were estimated to be greater than £76,000 per QALY gained across all scenarios.
Modified Adjuvant! Online high-risk subgroup: MammaPrint was dominated by current practice across almost all scenarios.
Modified Adjuvant! Online low-risk subgroup: ICERs were greater than £161,000 per QALY gained across all analyses.
After consultation, the EAG did more deterministic sensitivity analyses varying the estimated relative risk of distant recurrence associated with chemotherapy, which was assumed to be 0.76 in the base case. Results showed that as the relative risk moved from 0.6 to 0.9, the tests became less cost effective.# Committee discussion
The committee discussed current practice for making adjuvant chemotherapy prescribing decisions. The clinical experts explained that NHS clinical practice has changed since NICE's diagnostics guidance 10 was published in 2013. The PREDICT tool is now used by many NHS trusts rather than the Nottingham Prognostic Index (NPI). Adjuvant! Online is not currently available. The committee also heard that Oncotype DX is currently used in NHS clinical practice and may be used for a broader group than the population defined in the original diagnostics guidance 10, that is, people with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and lymph node (LN)‑negative early breast cancer who are assessed as being at intermediate risk using existing risk assessment tools.
The committee discussed the potential benefits of the tumour profiling tests for people with early breast cancer who are deciding whether to have adjuvant chemotherapy. It acknowledged that chemotherapy is an unpleasant treatment associated with short‑term physical, emotional and financial effects, and also long-term consequences such as infertility and increased risk of cardiomyopathy and leukaemia. The committee heard that there is potential benefit for people with cancer identified as being at low clinical risk, when test results suggest a high risk of distant recurrence. These people could potentially benefit from chemotherapy. It also heard that there is potential benefit for people with cancer categorised as high clinical risk, when test results suggest a low risk of distant recurrence. The committee heard that these people could decide not to have chemotherapy, therefore avoiding toxic side effects and effects on fertility. They could potentially resume normal daily activities earlier, although some may wish to have chemotherapy regardless of the test result. However, the committee noted that the claimed benefits of the tests depend on them having sufficient accuracy and discrimination to correctly classify risk and provide valid clinical information. The clinical experts explained that the additional clinical information provided by the tests may help people discuss further treatment options. This information is particularly helpful for people with cancers identified as intermediate clinical risk when the decision to offer chemotherapy is unclear. However, the final decision to recommend a course of adjuvant chemotherapy would always take into account the person's circumstances and preferences.
# Clinical effectiveness
The committee considered the prognostic ability of the tumour profiling tests. It noted that for people with LN-negative disease, all the tests had statistically significant prognostic accuracy over clinical and pathological features or risk assessment tools such as the NPI. It also noted that for people with LN-positive disease, results for prognostic ability were more variable but all tests except IHC4+C showed statistically significant or borderline statistically significant prognostic ability over clinical and pathological features or risk assessment tools. The external assessment group (EAG) explained that there were concerns about bias in all studies reporting prognostic ability. This was because in many of the studies some or all patients had chemotherapy or patients who had not had chemotherapy were selected for analyses. Also, most studies excluded tumour samples with insufficient tissue or missing clinical and pathological data, and some studies included patients who had hormone receptor-negative or HER2-positive disease. The committee concluded that despite the potential spectrum bias, the evidence suggested that all the tumour profiling tests have the ability to predict the risk of distant recurrence in the population included in the assessment. It also concluded that the evidence was weaker in the group with LN-positive disease than in the group with LN-negative disease.
The committee considered the evidence on micrometastases. The EAG explained that 2 studies with Oncotype DX reported subgroup data on people with micrometastases, but no studies with the other tests reported such data. The EAG noted that in patients with micrometastases and a Recurrence Score result of less than 18, outcomes were more similar to those in patients with LN-negative disease than in those with LN-positive disease. However, in patients with micrometastases and a Recurrence Score result of more than 30, outcomes were more similar to those in patients with LN-positive disease. Results were variable in patients with Recurrence Score results between 18 and 30. The EAG noted that the data were uncertain because of the high risk of confounding. The clinical experts explained that micrometastatic disease is classified as LN-positive disease but treated as LN-negative disease for clinical and shared decision making. In clinical practice some centres send samples from patients with micrometastases for Oncotype DX testing, but others do not. A clinical expert also explained that for patients with micrometastatic disease who have reasons to avoid chemotherapy, such as being older or having comorbidities, tumour profiling tests would be helpful. The committee noted that the ongoing OPTIMA study in LN-positive disease excludes patients with micrometastases, unless the tumour size is 20 mm or more. The EAG reviewed whether all studies in the diagnostics assessment report included or excluded patients with micrometastatic disease. It found that in TransATAC micrometastases were not assessed and therefore the disease was treated as LN-negative, but other studies did not report whether patients with micrometastatic disease were included or not. A company representative explained that in the MINDACT study, micrometastases measuring 0.2 mm to 2 mm were classified as LN-positive and isolated tumour cells were classified as LN‑negative. The clinical experts judged that, on balance, patients with micrometastases were likely to have been included in the studies as having LN-negative disease. The committee concluded that tumour profiling tests should be available as an option for people fulfilling the recommendation requirements and who have micrometastatic disease. Discussion within the multidisciplinary team may be particularly helpful for this group.
The committee considered the evidence on whether the tumour profiling tests can predict relative treatment effects associated with chemotherapy. The clinical experts stated that it is likely some patients could have a greater relative treatment effect from chemotherapy than others, for example, patients with hormone receptor-positive cancer that is not sensitive to endocrine therapy, but evidence is not available to support this. The EAG explained that the only evidence available to show a relative treatment effect for chemotherapy across different risk groups was for Oncotype DX, and the evidence included in the diagnostics assessment report was weak because it was at high risk of bias from potential confounding. The results of interaction tests (which show whether the tumour profiling test was able to predict a different treatment effect by risk group) in the adjusted analysis in the B20 study by Paik et al. (2006; LN-negative disease) remained statistically significant when adjusting simultaneously for clinical and pathological variables. However, the EAG also explained that the difference in relative treatment effects for chemotherapy in the B20 study may be overestimated because this was the Oncotype DX derivation data set. In the SWOG-8814 study by Albain et al. (2010; LN-positive disease) the results of the interaction tests remained statistically significant when adjusting for some individual clinical and pathological variables, but there was no analysis that adjusted for these simultaneously, and the test was non-significant when adjusted for Allred-quantified ER status. The clinical experts explained that hormone receptor status may also predict relative treatment effects for chemotherapy. The committee considered that if all known clinical and pathological variables were included in the analyses of SWOG-8814 then it was likely that the results of the interaction test would no longer be statistically significant. This suggested highly uncertain relative treatment effects for chemotherapy according to the results of the tumour profiling tests for this group with LN-positive disease. The committee concluded that the evidence on the extent to which tumour profiling tests are able to predict relative treatment effects for chemotherapy is highly uncertain, but there may be some differences between Oncotype DX risk groups. The committee noted that no data were available to assess a difference in relative treatment effects for chemotherapy for EndoPredict, IHC4+C and Prosigna risk groups. However, it considered that it would be unethical to do a randomised controlled trial looking at the benefit of chemotherapy compared with endocrine therapy in patients with a clinically low or high risk of distant recurrence. It also noted that data on MammaPrint suggested no difference in relative treatment effects for chemotherapy.
The committee considered the evidence on clinical utility, that is, data from studies which assessed the ability of the tumour profiling tests to affect patient outcomes. It discussed the recently published results from TAILORx on Oncotype DX (see section 4.31), which showed that across all patients with Recurrence Score results of 11 to 25, there were no clinically relevant or statistically significant differences between those who had endocrine therapy alone and those who had chemotherapy plus endocrine therapy. The EAG noted that some subgroups, such as those with Recurrence Score results of 21 to 25 and those aged 50 or under, had results with confidence intervals above the non-inferiority margin, which suggested that there could be a clinically relevant difference in these subgroups. The EAG noted that patients included in TAILORx had hormone receptor-positive, HER2-negative and LN‑negative disease, and met National Comprehensive Cancer Network guidelines for recommendation or consideration of chemotherapy. In the group with Recurrence Score results of 11 to 25, 73% to 74% were clinically low risk according to modified Adjuvant! Online. The committee acknowledged that the results from TAILORx may not be generalisable to clinical practice in the UK because the population who had chemotherapy in the study would not be routinely offered chemotherapy in an NHS pathway. It noted that, to fully understand the implications of the study for UK practice, a subgroup analysis of the TAILORx data would be needed investigating the performance of the test in predicting chemotherapy benefit for patients eligible for chemotherapy in the UK. The EAG explained that this had been requested but was not made available. The committee concluded that in principle TAILORx is an important piece of evidence showing the effectiveness of gene profiling to guide adjuvant chemotherapy decisions in breast cancer. But it is uncertain how applicable it is to people with breast cancer in the UK who are considering adjuvant chemotherapy treatment.
The committee considered the evidence on clinical utility for the other tests. It noted that the only other test with evidence from randomised controlled trials was MammaPrint (the MINDACT study). The committee noted that none of the other tumour profiling tests (EndoPredict, IHC4+C and Prosigna) had similar evidence of clinical utility, but it was aware that this evidence was being collected for Prosigna (see section 5.27). The committee noted that MINDACT (see section 4.32) was a well-designed study. The results suggested that patients with high clinical risk and MammaPrint low-risk scores can forgo chemotherapy without a statistically significant increase in the 5-year risk of distant recurrence. However, a clinical expert explained that the risk of recurrence often continues beyond 5 years and noted that the MINDACT authors (Cardoso et al. 2016) stated that long-term follow-up and outcome data will be essential. These data are being collected and a 10-year follow-up analysis is planned. The committee concluded that none of these tests had strong enough evidence to demonstrate an effect on subsequent patient outcomes.
The committee was encouraged by the availability of the data set provided in confidence to NICE by Genomic Health. The data set was based on the access scheme operated by NHS England, which provided real world evidence on the use of adjuvant chemotherapy in the NHS following testing with Oncotype DX for the population included in the scope for this assessment. The committee noted that the total number of patients in the data set appeared to be much larger than the number of patients with complete data in the population of interest, and that the advice from clinical experts (see section 5.1) was that the test had been used on a wider group of patients in practice. The committee also noted that the publication on TAILORx (Sparano et al. 2018) may influence chemotherapy decision making in people with a Recurrence Score result of 11 to 25, and therefore the data set may not represent clinical decision making in this group. The committee concluded that the access scheme data set was an important piece of real world evidence for use in the economic model, but that more complete data could have been collected and reported, and that it will be important to continue the data collection to capture the influence of TAILORx. It also concluded that future data collection should be done as part of a national database, rather than by individual companies, to increase transparency and enable it to be linked to outcome data (see section 5.29).
The committee discussed the analytical validity of IHC4+C. The EAG explained that the evidence has developed since diagnostics guidance 10 was published. The committee noted that the data showed good correlation between different centres when scoring and staining were assessed separately for measurement of the Ki67 marker, which had been achieved with training. But it also noted that when studies looked at staining and scoring combined, the correlation between centres decreased substantially. A clinical expert noted that different antibody clones are available for testing Ki67, ER and progesterone receptor (PR) status. Different studies used different antibody clones which means that the studies are not directly comparable. The committee heard that different methods of assessing ER and PR receptors may be needed for IHC4+C compared with those already used routinely, which may introduce additional complexity. The committee concluded that because of these issues, the reproducibility of IHC4+C was poor. It also concluded that if this test were to be developed further, the antibody clones used in the assays for ER, PR and Ki67 should be specified, and there would need to be substantial investment in staff training and quality assurance.
# Cost effectiveness
The committee discussed the assumptions and inputs used in the model, and considered the extensive stakeholder comments on the model and the EAG responses to these comments. It noted that a specific analysis of the TransATAC data was used for risk classification probabilities and for distant recurrence rates based on test result for Oncotype DX, EndoPredict (EPclin), Prosigna and IHC4+C. The results from this specific analysis of the data set have now been published (Sestak et al. 2018). The EAG explained that this data source was chosen because it included data on 4 of the 5 tests of interest and was specific to the population included in the scope (patients with hormone receptor-positive, HER2-negative disease). The committee heard that although the TransATAC data were slightly older and some patients were not candidates for chemotherapy, the patient characteristics matched well with the more recent MINDACT study. The alternative would be to use different data sources for each test, which would have introduced additional uncertainty and complexity. Also, the group with LN‑negative disease could not have been split according to level of clinical risk. The EAG described the limitations of using data from the TAILORx study (Sparano et al. 2018) for the health economic analysis. It also explained that the distant recurrence-free rates from the TransATAC analysis used in the model were consistent with results from other studies (B14, B20, TAILORx, MD Anderson, Clalit, Memorial Sloan Kettering, SEER and WSG PlanB) both when grouped separately by clinical risk and when all clinical risk groups were pooled together. The committee concluded that the TransATAC analysis had some limitations, but was the best available data for use in the model.
The committee considered the data on pre- and post-test chemotherapy decisions used in the model. The EAG explained that for 3-level tests (tests with low, intermediate and high-risk categories ), data on pre- and post-test chemotherapy decisions for the group with LN-negative disease and a NPI of more than 3.4 were taken from the Genomic Health access scheme data set (see section 5.8). For other clinical risk subgroups with the 3-level tests, and for all clinical risk subgroups with 2-level tests (tests with low and high-risk categories; EndoPredict, MammaPrint), data on pre-test chemotherapy decisions were taken from different sources to data on post-test chemotherapy decisions. There were also very limited UK data for these groups. The committee considered the modelled impact of these data on chemotherapy use, and noted that although clinical and patient experts thought that the main benefit of the tests was in avoiding unnecessary chemotherapy, most tests were estimated to increase chemotherapy use at least in some subgroups (see section 4.49). The committee concluded that there was much more uncertainty around chemotherapy decision making for the 2-level tests, and for the subgroups who were not included in the original NICE recommendation on tumour profiling tests (LN‑negative disease and a NPI of 3.4 or less, and LN-positive disease).
The committee considered how adjuvant chemotherapy treatment effects had been applied in the economic model, particularly the relative treatment effects of chemotherapy between the risk groups predicted by the tumour profiling tests. It noted its earlier conclusion that the evidence on whether tumour profiling tests can predict relative treatment effects for chemotherapy is highly uncertain, but that there may be some differences between Oncotype DX risk groups (see section 5.5). It agreed that for EndoPredict, IHC4+C and Prosigna, no evidence was available to show a difference in relative treatment effects of chemotherapy across risk groups, and that data on MammaPrint suggested no difference in relative treatment effects. Therefore for these tests it was appropriate to assume the same relative risk of distant recurrence across all test risk categories. The EAG noted that a relative risk of distant recurrence for chemotherapy compared with no chemotherapy of 0.76 estimated from data reported in a large meta-analysis by the Early Breast Cancer Trialists' Collaborative Group was used in the base case, and that this value had been varied between 0.6 and 0.9 in sensitivity analyses. The committee acknowledged that the ICERs were sensitive to this assumption, increasing as the relative risk moved from 0.6 to 0.9. It concluded that, although the true treatment effect is unknown, the relative risk was unlikely to be 0.9 or more.
The committee considered stakeholder comments submitted during the first consultation suggesting that Oncotype DX has the ability to predict which patients have disease that will respond to chemotherapy. The EAG noted that in response to the comments it had done additional exploratory analyses for Oncotype DX to show the impact on the incremental cost-effectiveness ratios (ICERs) if a smaller relative treatment effect than that taken from the B20 study (Paik et al. 2006) was applied in the model in the group with LN‑negative disease and a NPI of more than 3.4 (see section 4.51). The EAG noted that the hazard ratios used in these analyses were from comparisons of independent arms of trials and were therefore very uncertain. The EAG also said that using hazard ratios calculated from the B20 and the B14 (Paik et al. 2004) studies resulted in an ICER of around £24,000 per quality-adjusted life year (QALY) gained for Oncotype DX compared with current practice. Using hazard ratios calculated from the B20 and TransATAC studies resulted in an ICER of around £8,000 per QALY gained. Based on the results of the Sparano et al. 2018 publication on TAILORx, the EAG repeated the analysis incorporating an additional assumption of 0 chemotherapy benefit for patients in the Oncotype DX low Recurrence Score result category. It noted that this analysis was based on the strong assumption that Oncotype DX not only identifies patients who will not relapse, but also identifies patients who will relapse but will not respond to chemotherapy. When this assumption was included in the analysis using B20, the analysis using B20 and B14, and the analysis using B20 and TransATAC, the ICERs were below £4,000 per QALY gained. The committee concluded that although these analyses were associated with considerable uncertainty, they gave an indication of Oncotype DX's likely cost effectiveness if the relative treatment effects for chemotherapy did differ between Oncotype DX risk groups, but not to the extent reported in the Paik et al. (2006) study.
The committee considered stakeholder comments submitted during the first consultation suggesting that chemotherapy adverse events had not been adequately captured in the economic model; in particular, congestive heart failure, permanent hair loss and peripheral neuropathy. The EAG noted that in response to the comments it had done additional exploratory analyses to include these adverse events in the model. Congestive heart failure was added into the model by incorporating estimated lifetime QALY losses and costs taken from an alternative model (Hall et al. 2017). Hair loss and peripheral neuropathy were incorporated using a disutility applied to a proportion of the population for the lifetime of the model. The EAG highlighted the considerable limitations of these analyses, and noted that for tests that increased chemotherapy use in some subgroups, the ICERs became less favourable. The committee noted that including additional adverse events in the model did reduce some of the ICERs, but not enough to change the conclusions. It also noted a further EAG analysis, which suggested that for tests that reduced chemotherapy use but were not cost effective, the QALY gain from avoiding adverse events would have to be in the range of 1.1 to 1.3 to result in cost‑effective ICERs. The committee concluded that it was important to consider potential adverse events that could be caused by chemotherapy. However, the reduction in adverse events from reduced chemotherapy use, although beneficial for patients, was unlikely to affect its conclusions on the cost effectiveness of the tumour profiling tests based on the EAG's analysis.
The committee considered other assumptions used in the model such as the cost of chemotherapy and how the risk of distant recurrence was applied over time. The EAG explained that there was some uncertainty around these inputs, but all had been tested in sensitivity analyses. The committee concluded that the assumptions and inputs used in the model were reasonable, but they were associated with considerable uncertainty because of the limitations in the data that underpinned them.
The committee noted its discussion on current practice (see section 5.1) and considered the absence of comparisons of the tumour profiling tests with the PREDICT tool. The EAG explained that in the model it was not possible to compare the tumour profiling tests with PREDICT, or to define the clinical risk groups using PREDICT, because relevant data were not available. The committee noted that the comparisons in the model did not fully reflect current NHS clinical practice, which led to uncaptured uncertainty in the model results. The committee concluded that research on tumour profiling tests should include comparisons with PREDICT (see section 5.26) so that the cost effectiveness of the tests relative to current practice can be fully assessed in future.
The committee considered the subgroups that were included in the model, that is, people with LN-negative disease and a NPI of 3.4 or less, people with LN-negative disease and a NPI of more then 3.4, and people with LN-positive disease. It noted its earlier conclusion that the evidence suggested that all the tumour profiling tests have the ability to predict risk of distant recurrence (prognosis), but this ability was less certain in the group with LN-positive disease (see section 5.3). The committee also recalled that the test results were particularly helpful for people with cancers identified as intermediate clinical risk when the decision to offer chemotherapy is unclear (see section 5.2). The clinical experts explained that tumour profiling tests were also helpful for people with LN-positive cancer who have comorbidities and therefore an additional reason to want to avoid chemotherapy. The EAG noted that this subgroup of the LN-positive population could not be modelled because of a lack of data. In addition, the committee noted that the EAG's systematic review had highlighted substantial lack of agreement between the tests in risk categorising the group with LN-positive disease. The committee decided to consider the ICERs in the group with LN-negative disease only, but noted that further studies would be helpful to assess the clinical effectiveness of the tests in the group with LN-positive disease (see section 5.27).
The committee considered the results from the model. It noted that the differences in the QALYs were small, and that the ICERs for all tumour profiling tests were highly uncertain because of the available clinical data and the assumptions used in the modelling (see section 5.10 to section 5.15). It also noted that the base-case ICERs for many of the tumour profiling tests were higher than those normally considered to be cost effective. However, it heard that access proposals had been made by Myriad Genetics (for EndoPredict) and NanoString Technologies (for Prosigna). Genomic Health confirmed that the confidential discount for Oncotype DX would continue in the NHS. The committee concluded that the availability of the access proposals for EndoPredict and Prosigna may reduce the ICERs to a range that could be considered plausibly cost effective despite the clinical uncertainties.
The committee considered the EndoPredict and Prosigna access proposals. Compared with current practice, the ICERs for EndoPredict and Prosigna in the group with LN-negative disease and a NPI of 3.4 or less were still higher than those normally considered to be a cost-effective use of NHS resources. In the group with LN-negative disease and a NPI of more than 3.4, Prosigna compared with current practice had an ICER of less than £20,000 per QALY gained, and therefore could be considered cost effective. In the same group, EndoPredict compared with current practice had ICERs between £20,000 and £30,000 per QALY gained, which varied depending on whether the testing was done at a local or a central laboratory. The committee noted that local testing was more cost effective than central testing, and that testing became more cost effective as test throughput increased. It also recalled its conclusion that the data on post-chemotherapy decisions were more uncertain for 2-level tests than for 3-level tests (see section 5.11), and noted that the EAG's sensitivity analyses using plausible alternative sources for post-chemotherapy decisions resulted in ICERs that were lower than £20,000 per QALY gained. The committee noted that in sensitivity analyses, when the relative risk of distant recurrence for chemotherapy compared with no chemotherapy was changed to 0.9 from the base‑case value of 0.76, the ICERs increased for both EndoPredict and Prosigna to more than £30,000 per QALY gained. It considered that a relative risk of 0.9 or more across all genomic risk groups was unlikely, but accepted the uncertainty around this parameter (see section 5.12). The committee decided that although there is uncertainty around the ICERs for EndoPredict compared with current practice, sensitivity analyses suggested that the ICER will be around £20,000 per QALY gained, and therefore it could be considered cost effective. The committee concluded that EndoPredict (EPclin) and Prosigna, when provided at the costs stated in the access proposals, were likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be important to confirm this (see section 5.29).
The committee considered the ICERs for Oncotype DX compared with current practice. It heard that the proposed confidential test cost for Oncotype DX was the same as in current NHS practice, and that this cost had been used in the EAG's economic model. It noted that compared with current practice, the ICERs for Oncotype DX in the group with LN-negative disease and a NPI of 3.4 or less were higher than those normally considered to be a cost-effective use of NHS resources. In the group with LN-negative disease and a NPI of more than 3.4, the committee noted that in the base-case analyses Oncotype DX was dominated by the comparator. The committee recalled its earlier conclusions; Oncotype DX may be able to predict relative treatment effects for chemotherapy, and the ICERs for Oncotype DX compared with current practice when some relative treatment effect across different risk groups was applied in the model were most likely to be between £2,000 and £25,000 per QALY gained (see section 5.5 and section 5.13). However, it noted that this was very uncertain. The committee concluded that Oncotype DX, when provided at the test cost stated in the access proposal, was likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be important to confirm this (see section 5.29).
The committee considered how EndoPredict, Oncotype DX and Prosigna compare with each other. It noted that only pairwise ICERs of each tumour profiling test compared with no testing had been presented, rather than a fully incremental analysis. The EAG explained that a fully incremental analysis could not be done because there was no clinical evidence which directly compared the tests. The committee noted that since the publication of TAILORx (Sparano et al. 2018) evidence on clinical utility was strongest for Oncotype DX. It also noted that it was not possible to determine which test was the most cost-effective use of NHS resources, and that it may not be the test with the lowest acquisition price.
The committee considered the ICERs for MammaPrint compared with modified Adjuvant! Online. It noted that in the base-case analyses, MammaPrint was dominated by the comparator in the modified Adjuvant! Online high-risk subgroup. In the modified Adjuvant! Online low-risk subgroup, the ICERs were much higher than those normally considered to be cost effective. The committee concluded that MammaPrint would not be a cost-effective use of NHS resources.
The committee considered the ICERs for IHC4+C compared with current practice. It noted that the ICERs were low or that IHC4+C dominated current practice in all subgroups. The committee felt that the test cost had been underestimated because it did not include any costs for training or for setting up a quality assurance programme. But even if these costs were included, IHC4+C may still be cost effective. However, the committee noted its earlier conclusion on the analytical validity of IHC4+C (see section 5.9) and concluded that it could not be recommended for use in the NHS until issues around reproducibility and implementation had been resolved.
The committee noted that the model for EndoPredict, IHC4+C, Oncotype DX and Prosigna related only to a postmenopausal population because TransATAC was used as the data source for these tests. It considered whether the model results could also apply to a premenopausal population. A clinical expert explained that the biology of a cancer and its molecular subtype, for example hormone receptor status and HER2 status, is more influential in determining the risk of distant recurrence than menopausal status. Therefore the committee concluded that the model results apply to premenopausal and postmenopausal populations, but noted that clinicians wishing to use a tumour profiling test should first check which populations the test is indicated for (see section 3).
The committee discussed the generalisability of the data to men. It acknowledged that men make up a small proportion of people with breast cancer. The committee noted that all the clinical and economic evidence was based on trials with women, but that the general subtypes of breast cancer are identical in men and women, and in clinical practice men would have treatment in the same way as women. The committee concluded that the recommendations in this guidance should also apply to men.
# Research considerations
The committee noted that there are several ongoing studies which will provide evidence of long-term patient outcomes: further data collection from the MINDACT study on MammaPrint and the OPTIMA trial on Prosigna. The committee concluded that these studies are relevant to this assessment and data from them may be important when the guidance is considered for updating in the future. It also recalled its earlier conclusion that a subgroup analysis of TAILORx would be welcomed (see section 5.6). But it noted that not all studies would provide UK-specific data and comparisons with the PREDICT tool, which would be important for future updates to fully assess the cost effectiveness of the tests compared with current practice.
The committee also recalled its previous conclusion on the potential utility of the tests in the group with LN-positive disease (see section 5.17), particularly for people who have comorbidities and who may be particularly affected by the side effects of adjuvant chemotherapy. It noted that further research in this group would be welcome and heard from clinical experts that the ongoing OPTIMA trial may help to reduce some of the uncertainties identified during this assessment.
The committee considered consultation comments from the Cancer and Society in the 21st century research team about their qualitative research on women's experiences of gene expression profiling for chemotherapy decision making, and noted the importance of this work.
# Data collection arrangements
The committee recalled its previous conclusions on the uncertainties associated with both the clinical and cost effectiveness of EndoPredict (EPclin), Oncotype DX and Prosigna. It had identified clinical uncertainties associated with the effect of the technologies on patient outcomes (see section 5.6 and 5.7) and also on clinical decision making (see section 5.8 and section 5.11). These limitations meant that the estimated cost effectiveness of the technologies in the NHS was highly uncertain (see section 5.18 to section 5.20). On balance the committee concluded that EndoPredict (EPclin), Oncotype DX and Prosigna, when provided at the test cost stated in the access proposal, were likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be needed to confirm this in the NHS. Further, it considered that this should be addressed through data collection using the National Cancer Registration and Analysis Service which would provide data on NHS use. It also believed that it is necessary that data is collected as part of a national database, rather than by individual companies, to increase transparency, enable the data to be linked to clinical outcomes and ensure evidence is available that can be considered in future updates of this guidance. It therefore decided that its recommendations for EndoPredict (EPclin), Oncotype DX and Prosigna are conditional on data collection arrangements agreed with NICE being put in place. It is anticipated that arrangements will be made to collect timely and complete record-level test data, which can be submitted to the National Cancer Registration and Analysis Service, with the aim of linking test data to chemotherapy use, recurrence and survival outcomes.
|
{'Recommendations': 'EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score and Prosigna are recommended as options for guiding adjuvant chemotherapy decisions for people with oestrogen receptor (ER)-positive, human epidermal growth factor receptor\xa02 (HER2)-negative and lymph node (LN)-negative (including micrometastatic disease; see section\xa05.4) early breast cancer, only if:\n\nthey have an intermediate risk of distant recurrence using a validated tool such as PREDICT or the Nottingham Prognostic Index\n\ninformation provided by the test would help them choose, with their clinician, whether or not to have adjuvant chemotherapy taking into account their preference\n\nthe companies provide the tests to the NHS with the discounts agreed in the access proposals and\n\nclinicians and companies make timely, complete and linkable record-level test data available to the National Cancer Registration and Analysis Service as described in the data collection arrangements agreed with NICE (see section 5.29).\n\nMammaPrint is not recommended for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2‑negative and LN-negative early breast cancer because it is not cost effective.\n\nIHC4+C is not recommended for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2-negative and LN‑negative early breast cancer because the analytical validity of the test is uncertain.\n\nWhy the committee made these recommendations\n\nPeople with early and locally advanced breast cancer may need further treatment (adjuvant treatment) after they have surgery. Tools such as PREDICT, which is used by many NHS trusts, provide prognostic information to help guide the selection of adjuvant treatment. Additional information from tumour profiling tests may be helpful for people whose cancer has an intermediate risk of distant recurrence when the decision to offer chemotherapy is unclear.\n\nEvidence suggests that EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score, MammaPrint and Prosigna can predict the risk of distant recurrence in people who have ER-positive, HER2-negative, early breast cancer. This evidence is strongest in the group with LN-negative disease, which is likely to include people with micrometastatic disease. Also, Oncotype DX Breast Recurrence Score may be able to predict who will respond to chemotherapy, but the evidence for this is uncertain.\n\nThere are uncertainties in the economic modelling, particularly around the pre- and post-test chemotherapy decisions and the effect of adjuvant chemotherapy on distant recurrence. Also, there are no data available to compare the tumour profiling tests with PREDICT, or to define the clinical risk groups using PREDICT.\n\nUsing the access proposal test costs for EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score and Prosigna, all 3\xa0tests would provide value for money in people with LN-negative disease and an intermediate risk of distant recurrence. But because of the uncertainty about their effects on clinical decision making and clinical outcomes, the tests are recommended as options for guiding adjuvant chemotherapy decisions only if the criteria in section 1.1 are met, which includes collecting data on their use. Discussion about treatment options within the multidisciplinary team may be particularly helpful for people who have micrometastatic disease.\n\nIn people with an intermediate to high risk of distant recurrence, MammaPrint is less clinically effective and costs more than current practice, which does not use tumour profiling tests. It is therefore not recommended for use in the NHS.\n\nIHC4+C appears to be cost effective, but there are concerns about its analytical validity, for example the reproducibility of test results. It is therefore not recommended for use in the NHS.', 'Clinical need and practice': "# The problem addressed\n\nThe tumour profiling tests EndoPredict, MammaPrint, Oncotype DX Breast Recurrence Score, Prosigna and IHC4+C provide information on the activity of genes in tumour samples from people with early breast cancer. The results provide a risk profile of a person's breast cancer, which can be used with other routinely assessed clinical risk factors, such as nodal status and tumour size. It is claimed that the risk profile can be used to better predict the risk of disease recurrence. Some tests also claim to predict relative treatment effects for chemotherapy. This information is intended to help decision making about adjuvant chemotherapy use.\n\nIt is also claimed that people with early breast cancer identified as having a low risk of distant recurrence by a tumour profiling test may not need to have adjuvant chemotherapy. For these people, unnecessary treatment and therefore the comorbidities and negative effects on quality of life associated with chemotherapy could be avoided. Also, for people with early breast cancer at low risk of disease recurrence based on clinical and pathological features, the tests could confirm whether their risk is correct. If reclassified as being at high risk of recurrence, these people may benefit from chemotherapy. People with breast cancer and clinicians may also have more confidence that the treatment they are having or recommending is appropriate.\n\nThis assessment evaluates the clinical and cost effectiveness of EndoPredict, MammaPrint, Oncotype DX Breast Recurrence Score, Prosigna and IHC4+C when used to guide adjuvant chemotherapy decisions. The population was people with oestrogen receptor (ER)-positive (or progesterone receptor-positive or both), human epidermal growth factor receptor\xa02 (HER2)‑negative early breast cancer (stages\xa01 or 2) with 0\xa0to\xa03 positive lymph nodes.\n\nThis is a full update of NICE's diagnostics guidance on gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat (DG10), which was published in 2013. This recommended Oncotype DX as an option for guiding adjuvant chemotherapy decisions for people with ER-positive, HER2-negative and lymph node-negative early breast cancer if the person was assessed as being at intermediate risk and the company provided Oncotype DX to NHS organisations according to the confidential arrangement agreed with NICE. The guidance also encouraged data collection on the use of Oncotype DX in the NHS, and further research on MammaPrint, IHC4 and Mammostrat. Since publication of the original guidance, Mammostrat is no longer available. Also, a new test, EndoPredict, has become available and PAM50 has been further developed into the Prosigna test.\n\n# The condition\n\nBreast cancer is the most common cancer and the third most common cause of UK cancer-related deaths. One in 8\xa0women and 1\xa0in 870\xa0men will be diagnosed with breast cancer during their lifetime (Cancer Research UK 2016). In 2014, 46,085\xa0women and 332\xa0men were newly diagnosed with breast cancer in England (Office for National Statistics 2016). Most breast cancer develops in women who are over the age of\xa050 (Cancer Research UK 2016).\n\nBreast cancer survival depends on the stage of the disease at diagnosis, the treatment received and the biology of the tumour. More than 90% of women diagnosed with early breast cancer survive for at least 5\xa0years, and 78% survive for 10\xa0years (Cancer Research UK 2016). In contrast, only 13% of those diagnosed with advanced disease survive for more than 5\xa0years.\n\n# The diagnostics and care pathways\n\n## Diagnosis\n\nBreast cancer may be diagnosed following an abnormal result in the NHS breast cancer screening programme, or after referral for further investigation because of signs or symptoms that could be associated with breast cancer. The referral criteria are described in NICE's guideline on suspected cancer.\n\nWhen cancer cells have been detected in a biopsy sample, further tests are done to provide more information on the characteristics of the tumour. The results of these tests are used to categorise breast cancer into molecular subtypes and determine which types of treatment it is most likely to respond to. Recommendations on tumour testing are in NICE's guideline on early and locally advanced breast cancer. Tumour tests can include hormone receptor and HER2 tests. Although not routinely done, some laboratories may also test for Ki67, a marker of cell proliferation.\n\n## Care\n\nNICE's guideline on early and locally advanced breast cancer describes the care pathway. Surgery is often the initial treatment. Neoadjuvant treatment may be used before surgery, to reduce the size of the tumour and enable breast-conserving surgery.\n\nAfter surgery, further treatment (adjuvant treatment) may be needed and this can include radiotherapy, chemotherapy, hormone therapy, biological therapy or a combination of these. The decision to offer adjuvant therapy, and the treatments to use, is made taking into account the clinical history, the stage and grade of disease, the likely course of the disease (prognosis), the molecular characteristics of the tumour and the person's preferences.\n\nA variety of tools are available that can help to predict the likelihood of breast cancer recurrence based on clinical and pathological features. These may be used to provide prognostic information for patients and to guide the selection of adjuvant therapy. Expert advice suggests that the PREDICT tool version\xa02.0, an online prognostic and treatment benefit calculator, is the most widely used tool in the NHS in England to calculate risk of recurrence. Adjuvant! Online is not currently available online because it is being updated. It is not certain when it will be reinstated, and the website directs people to the PREDICT tool. Adjuvant! Online is described in the supplementary appendix of Cardoso et al. 2016. PREDICT is recommended in NICE's guideline on early and locally advanced breast cancer.", 'The diagnostic tests': "The assessment compared 5\xa0intervention tests with 1\xa0comparator.\n\n# The interventions\n\n## EndoPredict (Myriad Genetics)\n\nEndoPredict is a CE-marked assay that is designed to predict the likelihood of metastases developing within 10\xa0years of an initial breast cancer diagnosis. The test is for pre and postmenopausal people with early breast cancer with oestrogen receptor (ER)‑positive, human epidermal growth factor 2 (HER2)-negative and lymph node (LN)-negative or LN-positive disease (up to 3\xa0positive nodes).\n\nEndoPredict measures the expression of 12\xa0genes: 3\xa0proliferation‑associated genes, 5\xa0hormone receptor-associated genes, 3\xa0reference (normalisation) genes and 1\xa0control gene.\n\nEndoPredict needs RNA extracted from a formalin-fixed, paraffin‑embedded (FFPE) breast cancer tissue sample. The test can be done in a local laboratory or the Myriad Genetics pathology laboratory in Germany. It takes approximately 2\xa0days from receipt of the tissue sample to get the results from a local laboratory, although the turnaround time may be longer if samples are tested in full batches. The turnaround time is also longer if samples are sent to Germany.\n\nThe test involves a reverse transcription-quantitative polymerase chain reaction. Online evaluation software calculates an EP score and an EPclin score. An EP score of\xa00 to less than\xa05 indicates low risk of distant disease recurrence in the next 10\xa0years. An EP score of 5\xa0to\xa015 indicates high risk of distant disease recurrence in the next 10\xa0years.\n\nThe EPclin score estimates the probability of metastases developing within 10\xa0years (assuming 5\xa0years of endocrine therapy). It is calculated by adding clinical data about tumour size and nodal status to the EP score. An EPclin score of less than\xa03.3 indicates low risk (less than 10%) of metastases in the next 10\xa0years. An EPclin score of\xa03.3 or more indicates high risk of metastases in the next 10\xa0years.\n\nDuring consultation on the first diagnostics consultation document, NICE accepted an access proposal from the company in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of EndoPredict, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n## MammaPrint (Agendia)\n\nMammaPrint is a CE-marked assay that is designed to assess the risk of distant recurrence within 5 and 10\xa0years and whether a person would benefit from chemotherapy. The test is for pre and postmenopausal people with stage\xa01 or 2 breast cancer, with a tumour size of 5\xa0cm or less, and LN-negative or LN-positive disease (up to 3\xa0positive nodes). The test can be used irrespective of ER and HER2 status.\n\nMammaPrint measures the expression of 70\xa0genes, including genes associated with 7\xa0different parts of the metastatic pathway: growth and proliferation, angiogenesis, local invasion, entering the circulation, survival in the circulation, entering organs from the circulation, and adaption to the microenvironment at a secondary site.\n\nThe MammaPrint test needs RNA extracted from an FFPE breast cancer tissue sample. The test is offered as an off-site service. In Europe, samples are analysed at the Agendia laboratory in the Netherlands. Results are available within 10\xa0days of submitting the sample.\n\nThe test is based on diagnostic microarray. Software is used to calculate the MammaPrint result on a scale of −1 to +1. The score indicates the risk of developing distant metastases over the next 10\xa0years without any adjuvant endocrine therapy or chemotherapy. A MammaPrint result of 0 or less indicates high risk of metastases in the next 10\xa0years and a result of more than 0 indicates low risk (10% or less) of metastases in the next 10\xa0years.\n\n## Oncotype DX Breast Recurrence Score (Genomic Health)\n\nOncotype DX Breast Recurrence Score (hereafter referred to as Oncotype DX) is designed to quantify the 10-year risk of distant recurrence and predict relative treatment effects for chemotherapy. The test also reports the underlying tumour biology: ER, progesterone receptor and HER2 status. The test is for pre and postmenopausal people with stage\xa01 or 2 breast cancer and ER‑positive, HER2-negative, LN-negative or LN-positive disease (up to 3\xa0positive nodes). The assay does not have a CE mark because it is provided as a service by Genomic Health in an accredited laboratory in the US.\n\nOncotype DX quantifies the expression of 21\xa0genes: 16\xa0cancer-related genes correlated with distant recurrence-free survival, and 5\xa0reference (normalisation) genes.\n\nThe Oncotype DX test needs RNA extracted from a FFPE breast cancer tissue sample. Samples are processed centrally at a Genomic Health laboratory in the US. Results are usually available 7 to 10\xa0days after the sample is received.\n\nThe test is based on a reverse transcription-quantitative polymerase chain reaction. It gives a Recurrence Score result of between 0 and 100, which is used to quantify the 10-year risk of distant recurrence, assuming 5\xa0years of endocrine therapy. A result below 18 indicates low risk of distant recurrence and claims to predict little to no effect of chemotherapy on patient outcomes. A result between 18 and 30 indicates intermediate risk of recurrence and claims to predict no substantial effect of chemotherapy on patient outcomes. A result of 31 or more indicates high risk of recurrence and claims to predict a large effect of chemotherapy on patient outcomes. NICE is aware that the cut-offs may change in light of the results from the TAILORx study.\n\nThe breast Recurrence Score result can be combined with clinical and pathological factors using the recurrence score-pathology-clinical (RSPC) calculator. However, this calculator has not been validated in a cohort independent of that used to derive Oncotype DX.\n\nDuring consultation on the first diagnostics consultation document NICE accepted the company's commitment to maintain the current confidential discount, which is in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of Oncotype DX, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n## Prosigna (NanoString Technologies)\n\nProsigna is a CE-marked assay designed to provide information on breast cancer subtype and to predict distant recurrence-free survival at 10\xa0years. The test is for postmenopausal people with early breast cancer that is ER-positive, HER2-negative and LN‑negative or LN-positive (up to 3\xa0positive nodes).\n\nProsigna measures the expression of 50\xa0genes used for intrinsic subtype classification, 8\xa0housekeeping genes used for signal normalisation, 6\xa0positive controls, and 8\xa0negative controls.\n\nThe test needs RNA extracted from a FFPE breast tumour tissue sample. It is based on direct mRNA counting using fluorescent probes and an nCounter Digital Analyser.\n\nProsigna classifies the risk of distant recurrence within 10\xa0years, assuming 5\xa0years of endocrine therapy, based on the PAM50 gene signature, breast cancer subtype, tumour size, nodal status and proliferation score. The proliferation score is determined by evaluating multiple genes associated with the proliferation pathway. The test gives a score between 0 and 100. Based on this score and the nodal status, samples are classified into risk categories:\n\nLN-negative: low risk (0 to 40), intermediate risk (41 to 60) or high risk (61 to 100)\n\nLN-positive (up to 3\xa0positive nodes): low risk (0 to 15), intermediate risk (16 to 40), or high risk (41 to 100).\n\nDuring consultation on the first diagnostics consultation document, NICE accepted an access proposal from the company in line with the Diagnostics Assessment Programme's interim addendum on access proposals. This provides a simple discount to the list price of Prosigna, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n## IHC4 and IHC4+C\n\nThe IHC4 test is a laboratory developed test that combines the results of 4\xa0immunohistochemistry (IHC) measurements. The IHC4+C test combines the results of the 4\xa0IHC4 tests with clinical and pathological features such as age, nodal status, tumour size, and grade. Both versions are designed to quantify the 10-year risk of distant disease recurrence, assuming 5\xa0years of endocrine therapy. The test is for postmenopausal people with early breast cancer that is ER-positive and LN-negative or LN-positive (up to 3\xa0positive nodes).\n\nThe IHC4+C test needs an FFPE breast tumour tissue sample. The 4\xa0immunohistochemistry tests are: ER, progesterone receptor (PR), HER2 and the proliferation marker Ki67. ER and HER2 markers are commonly measured in NHS laboratories, but PR and Ki67 markers are not.\n\nThe IHC4+C test is in clinical use at 1\xa0NHS centre (the Royal Marsden NHS Foundation Trust), which carries out the test with an average turnaround time of 1\xa0week. The test could be run in local NHS laboratories providing that training and quality assurance programmes for the individual assays were in place.\n\nThe IHC4+C test uses a published algorithm to calculate a risk score for distant recurrence based on the results of the 4\xa0assays and clinical factors. A calculator is available for use on request. A score of less than 10% is categorised as low risk for distant recurrence at 10\xa0years. A score of more than 10% but less than 20% is intermediate risk, and a score of 20% or more is high risk for distant recurrence at 10\xa0years.\n\n# The comparator\n\nThe comparator is decision making for adjuvant chemotherapy prescribing, based on clinical and pathological features or the results of tools used to assess risk without the tumour profiling tests. Features may include the stage and grade of the disease, nodal status, ER or PR status, HER2 status and any previous treatment (for example, neoadjuvant therapy). Risk assessment tools include PREDICT, the Nottingham Prognostic Index (NPI) and Adjuvant! Online.\n\nThese risk assessment tools can be used to define the level of clinical risk. For example, in LN-negative disease a NPI of 3.4 or less is classed as low risk, and a NPI of more than 3.4 and up to or equal to 5.4 is classed as intermediate risk. If using the PREDICT tool, an absolute 10-year survival benefit from chemotherapy of less than 3% is classed as low risk; between 3% and 5% is classed as intermediate risk; and more than 5% is classed as high risk.", 'Evidence': "The diagnostics advisory committee (section\xa07) considered evidence on EndoPredict (EP score and EPclin score), MammaPrint, Oncotype DX (with and without the recurrence score-pathology-clinical [RSPC] calculator), Prosigna and IHC4 or IHC4+C from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nEvidence on the following outcomes was of interest in the clinical effectiveness review:\n\nPrognostic ability – the degree to which the test can accurately predict the risk of an outcome such as disease recurrence.\n\nPrediction of relative treatment effect – the ability of the test to predict which patients have disease that will respond to chemotherapy. It can be assessed by considering whether the relative treatment effect of chemotherapy or no chemotherapy on patient outcomes differs according to the test score.\n\nClinical utility – the ability of the prospective use of the test to affect patient outcomes such as recurrence and survival compared with current practice.\n\nDecision impact – how the test influences decision making in terms of which patients will be offered chemotherapy.\n\nA total of 153\xa0references were included in the review. Studies assessing prognostic ability and prediction of relative treatment effect were quality assessed using relevant criteria from the draft prediction model study risk of bias assessment tool (PROBAST). Clinical utility studies were quality assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs).\n\n## Prognostic ability\n\nStudies providing information on prognostic ability were retrospective analyses of RCT data or routinely collected data. Most of the studies excluded patients who did not have a large enough tissue sample for testing, which leaves the evidence base at potential risk of spectrum bias, because patients with smaller tumours (who may be systematically different to those with large tumours) are likely to be under-represented. In many studies patients had chemotherapy, which could affect event rates and therefore potentially reduce the apparent prognostic performance of a test. In other studies, patients who had chemotherapy were excluded from analyses, which may also lead to spectrum bias. Therefore studies in which all patients had endocrine monotherapy were preferable.\n\nResults for prognostic ability were generally presented as unadjusted or adjusted analyses. Unadjusted analyses look at differences in the event rates among low, intermediate and high‑risk groups without adjusting for clinical and pathological variables. Adjusted analyses show whether the test has prognostic value over clinical and pathological variables.\n\nAmong studies of patients with lymph node (LN)-negative disease who had endocrine monotherapy, in each group around 70% to 80% had disease that was categorised as low or low/intermediate risk across all tests (11\xa0studies). Most MammaPrint studies had mixed endocrine and chemotherapy use, mixed hormone receptor status with or without mixed human epidermal growth factor receptor\xa02 (HER2) status, so results may not be comparable with results from other tests. In these studies 20% to 61% of patients had disease that was categorised as low risk (6\xa0studies). Most IHC4 or IHC4+C studies used quartiles or tertiles to define risk groups. These studies do not provide useful information on the distribution of patients across risk categories.\n\nThe proportion of patients with low and intermediate risk was generally much lower in groups with LN-positive disease than in groups with LN-negative disease who had endocrine monotherapy (7\xa0LN-positive studies). For Oncotype DX, however, the proportion of patients with low and intermediate risk was only slightly lower in the LN-negative group than in the LN-positive group. Studies of MammaPrint in patients with LN-positive disease were all done in groups with mixed hormone receptor status and mixed or unknown HER2 status, so results may not be comparable with results from other tests. In these studies 38% to 41% of patients had disease that was categorised as low risk (2\xa0studies).\n\nThere were 11\xa0data sets that provided information on the prognostic ability of Oncotype DX: 7\xa0reanalyses of RCT data and 4\xa0retrospective studies of routinely collected data. All studies were validation studies, and in 4\xa0RCTs patients had endocrine monotherapy. Three of the studies were done in East Asia and it is uncertain whether the commercial version of Oncotype DX was used in these studies. Also, they may not be generalisable to England because usual clinical practice may differ between countries enough to affect prognostic outcomes. In addition, it is possible that people of different ethnicities have different underlying risk profiles and natural history of disease.\n\nUnadjusted analyses indicated that Oncotype DX had prognostic accuracy (there were statistically significant differences between low-risk and high-risk groups) across various recurrence outcomes, regardless of lymph node status. However, hazard ratios between the intermediate-risk group and the high or low-risk groups were not always statistically significant, particularly in the group with LN‑positive disease.\n\nIn adjusted analyses, Oncotype DX provided statistically significant additional prognostic information over most commonly used clinical and pathological variables (age, grade, size, nodal status), regardless of lymph node status. A bespoke analysis of TransATAC study data also showed that Oncotype DX provided additional prognostic information over clinical and pathological tools to assess risk.\n\nThere were 10\xa0data sets that provided information on the prognostic ability of MammaPrint: 1\xa0reanalysis of RCT data and 9\xa0retrospective studies of routinely collected data. In addition, a further 4\xa0studies pooled data on specific patients from the same 10\xa0data sets. All studies were validation studies, and in 2\xa0studies patients had endocrine monotherapy. Most studies included some patients who were out of scope (with HER2-positive or hormone receptor-negative disease or both).\n\nIn 6 of 7\xa0unadjusted analyses, MammaPrint had prognostic accuracy (there were statistically significant differences between low-risk and high-risk groups) for 10\xa0year distant recurrence-free survival or interval, regardless of LN status.\n\nIn adjusted analyses, a pooled analysis of patients with LN‑negative and LN-positive disease showed that MammaPrint had statistically significant prognostic accuracy for 10-year distant recurrence-free survival after adjusting for clinical and pathological variables. In patients with LN-negative disease, MammaPrint had statistically significant prognostic accuracy for 10-year distant recurrence-free interval when adjusted for Adjuvant! Online, Nottingham Prognostic Index (NPI) or clinical and pathological variables. In patients with LN-positive disease, MammaPrint had borderline statistically significant prognostic accuracy for 10-year distant metastasis-free survival when adjusted for clinical and pathological variables.\n\nThere were 8\xa0data sets that provided information on the prognostic ability of Prosigna: 6\xa0reanalyses of RCT data and 3\xa0retrospective analyses of 2\xa0prospective cohort studies. All studies were validation studies, and in\xa05 studies patients had endocrine monotherapy. Some studies included some patients who were out of scope (with HER2-positive or hormone receptor-negative disease or both).\n\nProsigna had statistically significant prognostic accuracy for 10‑year distant recurrence-free survival and interval in all unadjusted analyses of patients with LN-negative and LN-positive disease.\n\nIn analyses adjusted for clinical and pathological variables or tools, Prosigna had prognostic accuracy for 10-year distant metastasis‑free survival and distant recurrence-free survival. In patients with LN-negative disease the results were statistically significant. In patients with LN-positive disease the results were statistically or borderline significant.\n\nThere were 3\xa0data sets that provided information on the prognostic ability of EndoPredict; all were reanalyses of RCT data. All studies were validation studies, and in 2 of the 3\xa0studies patients had endocrine monotherapy.\n\nIn unadjusted analyses, EndoPredict (EPclin) had statistically significant prognostic accuracy for 10-year distant recurrence-free survival and interval in patients with LN-negative and LN-positive disease.\n\nAdjusted analyses of TransATAC data show that EndoPredict (EPclin) had statistically significant increases in likelihood ratio for 10-year distant recurrence-free interval over clinical and pathological variables or tools, regardless of LN status.\n\nThere were 12\xa0data sets that provided information on the prognostic ability of IHC4 and IHC4+C: 6\xa0reanalyses of RCT data and 6\xa0reanalyses of routinely collected data. Most of the data related to the IHC4 score alone, without including clinical factors. One of the studies was based on the derivation cohort for IHC4, and therefore may have overestimated prognostic ability. The remaining studies were validation studies. Patients had endocrine monotherapy in only 2\xa0studies, 1\xa0of which was the derivation cohort study.\n\nIn unadjusted analyses, IHC4 had statistically significantly better prognostic performance in groups with high risk than in groups with low risk (defined by quartiles or tertiles), regardless of lymph node status. However, no studies reported survival or recurrence outcomes by risk group. Also, many used laboratory methods that differed from the derivation study methodology. In adjusted analyses, IHC4 had additional prognostic value over clinical and pathological factors in 3\xa0studies, but patients had endocrine monotherapy in only 1\xa0of these studies.\n\nData on IHC4+C came from the derivation cohort and 1\xa0validation cohort. These studies showed that IHC4+C had prognostic value in unadjusted analyses. In adjusted analyses IHC4+C provided statistically significantly more information than the NPI in LN‑negative, but not LN-positive, disease.\n\n## Prediction of relative treatment effect\n\nIn addition to estimating the risk of recurrence, the ability of Oncotype DX and MammaPrint to predict which patients have disease that will respond to chemotherapy was explored in 7\xa0data sets. The external assessment group (EAG) reviewed evidence in support of this.\n\nIn 5\xa0data sets (2\xa0reanalyses of RCT data and 3\xa0observational studies) reported across 11\xa0published references and 1\xa0confidential manuscript, analyses assessed the ability of Oncotype DX to predict relative treatment effects for chemotherapy.\n\nThe 2\xa0reanalyses of RCTs suggest that Oncotype DX may predict differences in relative treatment effects for chemotherapy. Hazard ratios for disease-free survival for patients having chemotherapy compared with those having no chemotherapy suggested that the greatest relative treatment effect was for patients in the Oncotype DX high-risk category. Unadjusted interaction tests between Oncotype DX risk group and relative treatment effects were mainly statistically significant. Adjusted interaction tests were statistically significant in an analysis of patients with HER2-negative, LN‑negative disease, but in patients with LN-positive disease the interaction test was not significant when hormone receptor status was adjusted for. However, the data for the population with LN‑negative disease came from the derivation cohort for Oncotype DX and may overestimate predictive performance.\n\nResults from the 3\xa0observational studies were mixed and at high risk from confounding. One reported a statistically significant interaction test but this was only adjusted for a limited number of factors. Two others reported hazard ratios for chemotherapy compared with no chemotherapy; 1\xa0study in patients with intermediate Recurrence Score results, and another in patients with high Recurrence Score results. Both of these studies reported statistically non-significant results.\n\nThe RSPC algorithm incorporates Oncotype DX plus age, tumour size and grade. There was a non-significant interaction test result between relative chemotherapy treatment effects and RSPC risk group.\n\nTwo studies reported the ability of MammaPrint to predict the relative treatment effects for chemotherapy. In a pooled analysis including patients with LN-negative and LN-positive disease, the effect of chemotherapy compared with no chemotherapy was statistically significant in the MammaPrint high-risk group but not in the low-risk group in unadjusted and adjusted analyses. Further, the interaction test for chemotherapy treatment and risk group was non-significant. In a pooled analysis of patients with LN-positive disease, there was a non-significant interaction between chemotherapy treatment and risk group.\n\n## Clinical utility\n\nThe EAG noted that the best evidence for clinical utility was an RCT of treatment guided by the test compared with treatment guided by the comparator. There were no clinical utility data available for EndoPredict, Prosigna or IHC4+C.\n\nFive data sets, reported across 9\xa0published references and 1\xa0confidential manuscript, reported evidence on the clinical utility of Oncotype DX. These studies included the low-risk group from TAILORx. One further study did not meet the inclusion criteria (because of insufficient follow-up length), but presented subgroup data according to age, lymph node status and ethnicity, and was therefore discussed by the EAG. Studies generally reported different outcomes, making comparisons across studies difficult. All studies were judged to be of poor quality using the Cochrane risk of bias tool for RCTs.\n\nIn patients with LN-negative disease, using the test in clinical practice appeared to result in low rates of chemotherapy in patients with low risk (2% to 12%), with acceptable outcomes (distant recurrence-free survival, distant recurrence-free interval or invasive disease-free survival 96% to 99.6%). Rates of chemotherapy increased with increasing risk category, and were generally higher in patients with LN-positive disease. It was not possible to conclude whether patients in intermediate and high-risk categories had better outcomes as a result of using Oncotype DX to guide treatment because there were no comparator groups (patients who had treatment without Oncotype DX testing).\n\nOne study (TAILORx; Sparano et al. 2018) reporting evidence on clinical utility was published after completion of the diagnostics assessment report. This study was a prospective, partially randomised study in which patients with an Oncotype DX Recurrence Score result of 0 to 10 had endocrine therapy, patients with Recurrence Score results of 26 and above had endocrine therapy plus chemotherapy, and those with Recurrence Score results of 11 to 25 were randomised to have either endocrine therapy alone, or endocrine therapy plus chemotherapy. The cut‑offs in this study were different to the cut-offs recommended by the company (less than 18, 18 to 30 and greater than 30; see section 3.15). The 2018 publication focused on the results from patients in the intermediate-risk group who were randomised to treatment. It reported that across all patients with Recurrence Score results of 11 to 25, there were no clinically relevant or statistically significant differences between those who had endocrine therapy alone and those who had chemotherapy plus endocrine therapy. Results for the primary end point of 9-year invasive disease-free survival were 84.3% with chemotherapy and 83.3% without chemotherapy; an absolute difference of 1.0% (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.94 to 1.24, p=0.26). The upper confidence interval was within the pre-specified non-inferiority margin (HR 1.322). Results for freedom from distant recurrence at 9\xa0years were 95% with chemotherapy and 94.5% without chemotherapy; an absolute difference of 0.5% (HR 1.10, 95% CI 0.85 to 1.41, p=0.48). However, exploratory subgroup analyses suggested that chemotherapy may have an effect in some subgroups, such as those with Recurrence Score results of 21 to 25 and possibly Recurrence Score results of 16 to 20, particularly in people aged 50 or under. The EAG noted that no analysis was available for the subgroup of patients with Recurrence Score results of 11 to 25 and a modified Adjuvant! Online high risk score.\n\nTwo studies reported evidence relating to the clinical utility of MammaPrint. MINDACT was a prospective, partially randomised study in which clinical risk was determined using a modified version of Adjuvant! Online. Patients with risk scores that disagreed from MammaPrint and modified Adjuvant! Online were randomised to chemotherapy or no chemotherapy. Of patients included in the study, 88% had HR-positive disease and 90% HER2-negative disease, therefore some patients were outside of the scope for this assessment. For the group who were high risk with modified Adjuvant! Online and low risk with MammaPrint, 5-year distant metastasis-free survival was 95.9% with chemotherapy and 94.4% without chemotherapy, a non-statistically significant absolute difference of 1.5% (adjusted hazard ratio for distant metastasis or death with chemotherapy compared with no chemotherapy, 0.78; 95% CI 0.50 to 1.21; p=0.27). For the group who were low risk with modified Adjuvant! Online and high risk with MammaPrint, 5-year distant metastasis-free survival was 95.8% with chemotherapy and 95.0% without chemotherapy, a non-statistically significant absolute difference of 0.8% (adjusted hazard ratio for distant metastasis or death with chemotherapy compared with no chemotherapy, 1.17; 95% CI 0.59 to 2.28; p=0.66). The EAG judged MINDACT to be at low risk of bias in terms of randomisation, allocation concealment and reporting. However, no details of blinding were reported.\n\nResults from the RASTER study suggested that distant recurrence‑free interval rates were sufficiently low in the MammaPrint low-risk group for these patients to avoid chemotherapy. The 5-year distant recurrence-free interval rate for LN-negative disease was 97.0% for patients with low risk (15% had chemotherapy) and 91.7% for patients with high risk (81% had chemotherapy). In addition, MammaPrint provided additional prognostic information over Adjuvant! Online and the NPI, but not over the NHS PREDICT tool. The EAG judged RASTER to be at high risk of bias using the Cochrane risk of bias tool for RCTs.\n\n## Comparison of the tests with each other\n\nThere were 6\xa0studies that compared more than 1\xa0test: 4\xa0reanalyses of RCTs and 2\xa0observational studies. Evidence shows that generally when a test placed more patients in a low-risk category than another test, the event-free survival in the low-risk group was reduced. Also, the tests generally performed differently in patients with LN-negative and LN-positive disease.\n\nThirteen studies reported data from microarray analyses on more than 1\xa0test, however, these studies had methodological limitations. The comparability of test algorithms applied to microarray data with the commercial assays was unknown, so the generalisability of findings from microarray studies to the decision problem was uncertain. All the studies reported data on Oncotype DX and MammaPrint, and 2\xa0also reported data on EndoPredict. No studies reported data on Prosigna or IHC4+C. The microarray studies generally supported the conclusions from studies using the commercial versions of the assays in suggesting that Oncotype DX, MammaPrint and EndoPredict can discriminate between patients with high and low risk regardless of LN status. In terms of additional prognostic performance of the tests over clinical and pathological variables, EndoPredict appeared to have the greatest benefit, followed by Oncotype DX and then MammaPrint. However, because of the methodological limitations, the EAG judged that these studies did not provide conclusive evidence of the superiority of 1\xa0test over others.\n\nThe OPTIMA Prelim study, a UK-based feasibility phase of an RCT, analysed concordance between different tests. The study included Oncotype DX, MammaPrint, Prosigna and IHC4 plus 2\xa0other tests. Out of the 4\xa0in-scope tests, MammaPrint assigned the most patients to the low-risk category, but unlike the other 3\xa0tests it does not have an intermediate category. When the low and intermediate categories were treated as 1\xa0category for the 3\xa0tests that have 3\xa0risk groups, Oncotype DX assigned the most patients to this category, and MammaPrint the least. Kappa statistics indicated modest agreement between tests, ranging from 0.33 to 0.53. Also, across 5\xa0tests in the study, only 39% of tumours were uniformly classified as either low/intermediate risk or high risk by all 5\xa0tests. Of these, 31% were classified as low/intermediate risk by all tests and 8% were high risk by all tests. The study authors concluded that although the tests assigned similar proportions of patients to low/intermediate-risk and high-risk categories, test results for an individual patient could differ markedly depending on which test was used.\n\n## Decision impact\n\nThe review of decision impact focused on studies done in the UK or the rest of Europe:\n\nOncotype DX: 6\xa0UK studies and 12\xa0other European studies\n\nEndoPredict: 1\xa0UK study and 3\xa0other European studies\n\nIHC4+C: 1\xa0UK study and 0\xa0other European studies\n\nProsigna: 0\xa0UK studies and 3\xa0other European studies\n\nMammaPrint: 0\xa0UK studies and 8\xa0other European studies.\n\nThe percentage of patients with any change in treatment recommendation or decision (either to or from chemotherapy) in UK studies was 29% to 49% across 4\xa0Oncotype DX studies, 37% in 1\xa0EndoPredict study and 27% in 1\xa0IHC4+C study. Ranges across European (non-UK) studies were 5% to 70% for Oncotype DX, 38% to 41% for EndoPredict, 14% to 41% for Prosigna and 13% to 51% for MammaPrint.\n\nThe net change in the percentage of patients with a chemotherapy recommendation or decision (pre-test to post-test) among UK studies was a reduction of 8% to 23% across 4\xa0Oncotype DX studies, an increase of 1% in 1\xa0EndoPredict study, and a reduction of between 2% and 26% in 1\xa0IHC4+C study. Net changes across European (non-UK) studies were a reduction of 0% to 64% for Oncotype DX, a reduction of 13% to 26% for EndoPredict, a reduction of 2% to an increase of 9% for Prosigna, and a reduction of 31% to an increase of 8% for MammaPrint.\n\n## Anxiety and health-related quality of life\n\nThere were 6\xa0studies that reported outcomes relating to anxiety (including worry and distress) and health-related quality of life. The lack of a comparator in the studies made it difficult to tell whether changes in anxiety experienced with the use of tumour profiling tests would also have occurred if patients received a definitive decision based on clinical risk factors alone. Overall, evidence suggests that tumour profile testing may reduce anxiety in some patients in some contexts, but generally there was little effect on health-related quality of life.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nThe EAG reviewed existing studies investigating the cost effectiveness of tumour profiling tests to guide treatment decisions in people with early breast cancer, and also did a detailed critique of the economic models and analyses provided by Agendia (MammaPrint), Genomic Health (Oncotype DX), and the chief investigator of a UK decision impact study (EndoPredict).\n\nFrom the review, 26\xa0studies were identified that had been published since the original assessment for diagnostics guidance\xa010. The models reported in the studies assessed the cost effectiveness of tumour profiling tests across different countries including the UK, the US, Canada, Mexico, Japan, Austria, Germany, France and the Netherlands. Most studies compared Oncotype DX (18\xa0studies), MammaPrint (8\xa0studies) or EndoPredict (1\xa0study) with comparators such as Adjuvant! Online, the St Gallen guidelines, standard practice or other conventional diagnostic tools. There was variation between the analyses in the populations evaluated, the disease type and other patient characteristics.\n\nThere was a high level of consistency in the general modelling approach and structure, and several studies were based on a previously published model. Most of the models used a Markov or hybrid decision tree–Markov approach, 2\xa0studies used a partitioned survival approach and 1\xa0study used a discrete event simulation approach. The time horizons ranged from 10\xa0years to the patient's remaining lifetime, with cycle lengths ranging from 1\xa0month to 1\xa0year when reported. Most of the models that evaluated Oncotype DX assumed that the test could predict relative treatment effects for chemotherapy.\n\n## Economic evaluation\n\nNone of the models identified in the literature review included all of the tests identified in the scope. Therefore, the EAG developed a de novo economic model designed to assess the cost effectiveness of Oncotype DX, MammaPrint, Prosigna, IHC4+C and EndoPredict compared with current practice without the use of the tumour profiling tests. The model used a lifetime time horizon (42\xa0years) from the perspective of the UK NHS and personal social services. All costs and health outcomes were discounted at a rate of 3.5% per year. Unit costs were valued at 2015/16 prices. The main source of evidence used to inform the analyses of Oncotype DX, Prosigna, IHC4+C and EndoPredict was a bespoke analysis of TransATAC provided by the study investigators. This was limited to UK data on patients with hormone receptor-positive, HER2‑negative disease with 0\xa0to\xa03 positive lymph nodes to match the scope for this assessment. Because this study did not include MammaPrint, MINDACT was used as the basis for evaluating the cost effectiveness of MammaPrint. PREDICT scores were not available in either data set, and so this tool could not be considered as a comparator or used to determine different risk subgroups. Therefore, the comparator for Oncotype DX, Prosigna, IHC4+C and EndoPredict was current practice (various tools and algorithms), and the comparator for MammaPrint was a modified version of Adjuvant! Online.\n\nThe hybrid decision tree–Markov model was based on the model previously developed by Ward et al. (2013). The decision tree component of the model classified patients in the current practice group (no test) and the tumour profiling test group as high, intermediate and low risk. For EndoPredict and MammaPrint, the intermediate-risk category was excluded because the test provides results in terms of high and low risk only. In both the test group and the current practice group, the decision tree determined the probability that a patient would be in 1\xa0of\xa06 groups: low risk, chemotherapy; low risk, no chemotherapy; intermediate risk, chemotherapy; intermediate risk, no chemotherapy; high risk, chemotherapy, and high risk, no chemotherapy. For EndoPredict and MammaPrint, 4\xa0groups were used because there was no intermediate-risk category. Each group was linked to a Markov model which predicted lifetime quality-adjusted life years (QALYs) and costs according to the patient's risk of distant recurrence and whether or not they had chemotherapy.\n\nEach Markov node included 4\xa0health states: distant recurrence‑free; distant recurrence; long-term adverse events (acute myeloid leukaemia [AML]); and dead. Patients entered the model in the distant recurrence-free health state. A health-related quality of life decrement was applied during the first model cycle to account for health losses associated with short-term adverse events for patients having adjuvant chemotherapy. The treatment effect for adjuvant chemotherapy was modelled using a relative risk reduction for distant recurrence within each risk classification group. The benefit of the test was therefore captured in the model by changing the probability that patients with each test risk classification had adjuvant chemotherapy.\n\nThe risk classification probabilities used in the model for Oncotype DX, Prosigna, IHC4+C and EndoPredict were from the bespoke data analysis of TransATAC, which only included postmenopausal women. For MammaPrint, they were from MINDACT.\n\nThe probability of developing distant metastases in each group and risk category was based on 10-year recurrence-free interval data from the bespoke data analysis of TransATAC for Oncotype DX, Prosigna, IHC4+C and EndoPredict. For MammaPrint the probability of developing distant metastases was based on an adjusted analysis of 5-year distant metastasis-free survival data from MINDACT. The model assumed that the risk of distant metastases between 10\xa0and 15\xa0years was halved, and after 15\xa0years was 0.\n\nThe probability of having chemotherapy in the current practice group and in the tumour profiling test groups was taken from the sources in table\xa01.\n\nPopulation\n\nSource\n\nProportion of patients having chemotherapy\n\nLN-negative, NPI≤3.4\n\nNCRAS data set\n\n\n\nLN-negative, NPI>3.4\n\nGenomic Health access scheme data set\n\n\n\nLN-positive (1−3\xa0nodes)\n\nNCRAS data set\n\n\n\nOverall population (MammaPrint)\n\nExpert opinion\n\n\n\nAbbreviations: LN, lymph node; NCRAS, National Cancer Registration and Analysis Service; NPI, Nottingham Prognostic Index; UKBCG, UK breast cancer group.\n\nThe Genomic Health access scheme data set is based on the access scheme operated by NHS England and is a result of the research recommendation from NICE's original diagnostics guidance 10.\n\nFor the proportion of patients having chemotherapy, the low, intermediate and high risks are combined.\n\nPopulation\n\nSource\n\nProportion of patients having chemotherapy (low risk)\n\nProportion of patients having chemotherapy (intermediate risk)\n\nProportion of patients having chemotherapy (high risk)\n\nLN-negative, NPI≤3.4\n\nUKBCG survey data\n\n\n\n\n\n\n\nLN-negative, NPI>3.4\n\nGenomic Health access scheme data set\n\n\n\n\n\n\n\nLN-positive (1−3\xa0nodes)\n\nLoncaster et al. (2017) node-positive estimates\n\n\n\n\n\n\n\nAbbreviations: LN, lymph node; NPI, Nottingham Prognostic Index; UKBCG, UK breast cancer group.\n\nPopulation\n\nSource\n\nProportion of patients having chemotherapy (low risk)\n\nProportion of patients having chemotherapy (intermediate risk)\n\nProportion of patients having chemotherapy (high risk)\n\nEndoPredict: all 3\xa0subgroups\n\nBloomfield et al. (2017) study\n\n\n\n–\n\n\n\nMammaPrint: all subgroups\n\nBloomfield et al. (2017) study\n\n\n\n–\n\n\n\nIn the base-case analysis, the relative treatment effect for chemotherapy was assumed to be the same across all test risk groups, that is, all tests were assumed to be associated with prognostic benefit only. For Oncotype DX, Prosigna, IHC4+C and EndoPredict a 10-year relative risk of distant recurrence was estimated as 0.76 for chemotherapy compared with no chemotherapy (Early breast cancer trialists' collaborative group 2012), and was assumed to apply to the groups with LN-negative and LN-positive disease. For MammaPrint the 10-year relative risk of distant recurrence was estimated to be 0.77 (MINDACT) for chemotherapy compared with no chemotherapy.\n\nIn sensitivity analyses the effect of assuming that Oncotype DX could predict relative treatment effects for chemotherapy was explored, based on the B20 study by Paik et al. (2006) and the SWOG-8814 study by Albain et al. (2010). For the group with LN‑negative disease, the 10-year relative risks of distant recurrence with chemotherapy compared with no chemotherapy were 1.31, 0.61 and 0.26 for the low, intermediate and high-risk categories respectively. For the group with LN-positive disease, the 10-year relative risks of relapse with chemotherapy compared with no chemotherapy were 1.02, 0.72 and 0.59 respectively. It is possible that the no-chemotherapy arm of B20 may have overestimated the difference in response rates between low and high-risk patients, because this arm was the derivation set for Oncotype DX. Therefore, additional sensitivity analyses in the group with LN‑negative disease explored the impact of varying the relative chemotherapy treatment effect between risk groups on the incremental cost-effectiveness ratios (ICERs). Hazard ratios were based on naive indirect comparisons of the chemotherapy arms from the B20 study and the no-chemotherapy arms from the B14 study (estimated hazard ratios for treatment effects with chemotherapy compared with no chemotherapy were 0.64, 0.75 and 0.35 for the low, intermediate and high-risk categories respectively), and the chemotherapy arms of the B20 study and the no-chemotherapy arms of the TransATAC study (hazard ratios for treatment effects with chemotherapy compared with no chemotherapy were 0.86, 0.88 and 0.49 for the low, intermediate and high-risk categories respectively).\n\nSurvival following distant recurrence was based on a median of 40.1\xa0months from Thomas et al. (2009). From this, the 6-month probability of death following distant recurrence was estimated to be 0.098, assuming a constant rate. The rate of death following distant metastases was assumed to be the same across the different subgroups and across each test risk group.\n\nThe model assumed that 10.5% of patients entering the distant recurrence health state had previously had local recurrence, based on de Bock et al. (2009). The 6-month probability of developing AML was estimated to be 0.00025, based on Wolff et al. (2015). Survival following the onset of AML was estimated to be approximately 8\xa0months; assuming a constant event rate gave a 6‑month probability of death following AML of 0.53. Additional sensitivity analyses explored the effect of including congestive heart failure (average net lifetime QALY loss of 0.0385 and average net lifetime cost saving of £2 from Hall et al. 2017, using an excess congestive heart failure risk relative to that of the general population), permanent hair loss (disutility of 0.04495 from Nafees et al. 2008 applied to 15% of all patients having chemotherapy) and peripheral neuropathy (disutility of 0.02 from Shiroiwa et al. 2009 applied to 12% of all patients having chemotherapy) in the model.\n\nThe costs of the tumour profiling tests were based on company prices (see table\xa02).\n\nTest\n\nList price\n\nComments\n\nOncotype DX\n\n£2,580\n\nTests carried out in Genomic Health laboratory in US. Cost includes sample handling and customer service. A commercial-in-confidence discounted test cost was used in the model.\n\nProsigna\n\n£1,970\n\nBased on doing the test in an NHS laboratory, which includes the laboratory costs (£240), the Prosigna kit (£1,650) and the nCounter system (£194,600) and is based on 2,500\xa0samples per lifetime of the nCounter system).\n\nCommercial-in-confidence discounted test costs were used in scenario analyses to account for the access proposal.\n\nEndoPredict\n\n£1,500\n\nTests carried out in Myriad's laboratory in Munich.\n\nCommercial-in-confidence discounted test costs were used in scenario analyses to account for the access proposal.\n\nIHC4\n\n£203\n\nThe cost was based on 2014 prices. The total cost of the test (£198) was uplifted to current prices using the hospital and community health services indices.\n\nMammaPrint\n\n£2,326\n\nConverted from Euros to UK pounds sterling, assuming an exchange rate of 1\xa0British pound to 1.15\xa0Euros.\n\nThe costs associated with adjuvant chemotherapy were from a previous costing analysis of the OPTIMA Prelim trial (Hall et al. 2017). The weighted mean cost of adjuvant chemotherapy acquisition, delivery and toxicity was estimated to be £3,145 per course.\n\nAll surviving patients had endocrine therapy for a period of between 5\xa0and\xa08 years. Costs of endocrine therapy were taken from the British national formulary (2017). In addition, 30% of women with early breast cancer had 4\xa0mg of bisphosphonates (zoledronic acid) by intravenous infusion every 6\xa0months for up to 3\xa0years, at a cost of £58.50, excluding administration.\n\nAll patients had 2\xa0routine follow-up visits during the first year after surgery, with annual visits thereafter for 5\xa0years. Patients were also assumed to have a routine annual mammogram for up to 5\xa0years. The cost of a routine follow-up visit was estimated to be £162.84, and the cost of a mammogram was estimated to be £46.37.\n\nCosts associated with treating local recurrence were taken from Karnon et al. (2007) and uplifted to current prices (£13,913). This was applied as a once-only cost to distant recurrence. Costs associated with treating distant metastases were derived from Thomas et al. (2009), and included visits, drugs, pharmacy, hospital admission and intervention, imaging, radiotherapy, pathology and transport. Cost components specifically associated with terminal care were excluded. The 6-monthly cost of treating metastatic breast cancer was estimated to be £4,541.\n\nHealth utilities were taken from published studies (see table\xa03).\n\nHealth state / event\n\nDuration applied in model\n\nMean\n\nStandard error\n\nSource\n\nRecurrence-free\n\nIndefinite\n\n\n\n\n\nLidgren et al. 2007\n\nDisutility distant metastases\n\nIndefinite\n\n\n\n\n\nCalculated from Lidgren et al. 2007\n\nLocal recurrence\n\nOnce-only QALY loss applied on transition to distant recurrence state\n\n−0.108\n\n(assumed)\n\nCampbell et al. 2011\n\nChemotherapy AEs\n\nOnce-only QALY loss applied in first cycle\n\n−0.038\n\n\n\nCampbell et al. 2011\n\nAML\n\nIndefinite\n\n\n\n(assumed)\n\nYounis et al. 2008\n\nAbbreviations: AEs, adverse events; AML, acute myeloid leukaemia; QALY, quality-adjusted life year.\n\nThe following key assumptions were applied in the base-case analysis:\n\nClinicians interpreted each of the 3-level tests in the same way (for example, an Oncotype DX high-risk Recurrence Score result would lead to the same chemotherapy decision as a Prosigna high-risk score).\n\nClinicians interpreted each of the 2-level tests in the same way (for example, a MammaPrint high-risk score would lead to the same chemotherapy decision as an EndoPredict high-risk score).\n\nThe treatment effect for adjuvant chemotherapy was the same across all risk score categories for all tests.\n\nThe prognosis of patients with AML and the costs and QALYs accrued within the AML state were independent of whether they had previously developed distant metastases.\n\nA disutility associated with adjuvant chemotherapy was applied once during the first model cycle only (while the patient is taking the regimen).\n\nCosts associated with endocrine therapy, bisphosphonates, follow-up appointments and mammograms were assumed to differ according to time since model entry.\n\nThe model assumed that people entered at an age of around 60\xa0years.\n\nIn the subgroup with LN-negative disease and a NPI of 3.4 or less, compared with current practice, the probabilistic model gave ICERs of:\n\n£147,419 per QALY gained (EndoPredict)\n\n£122,725 per QALY gained (Oncotype DX)\n\n£91,028 per QALY gained (Prosigna)\n\n£2,654 per QALY gained (IHC4+C).\n\nIn the subgroup with LN-negative disease and a NPI of more than 3.4, compared with current practice, the probabilistic model gave ICERs of:\n\n£46,788 per QALY gained (EndoPredict)\n\n£26,058 per QALY gained (Prosigna)\n\nOncotype DX was dominated by current practice (that is, it was more expensive and less effective)\n\nIHC4+C was dominant over current practice (that is, it was less expensive and more effective).\n\nIn the population with LN-positive disease, compared with current practice, the probabilistic model gave ICERs of:\n\n£28,731 per QALY gained (Prosigna)\n\n£21,458 per QALY gained (EndoPredict)\n\nOncotype DX was dominated by current practice\n\nIHC4+C was dominant over current practice.\n\nIn the overall MINDACT population, MammaPrint compared with modified Adjuvant! Online had an ICER of £131,482 per QALY gained. In the modified Adjuvant! Online high-risk subgroup, MammaPrint was dominated by current practice, and in the modified Adjuvant! Online low-risk subgroup, MammaPrint compared with current practice had an ICER of £414,202 per QALY gained.\n\nThe risk classification probabilities and the probability of having chemotherapy were combined in the model to estimate chemotherapy use with and without tumour profiling. The modelled chemotherapy use in the base case is shown in table\xa04.\n\nTest, subgroup compared with current practice\n\nChemotherapy use with tumour profiling\n\nChemotherapy use with no tumour profiling\n\nNet change\n\nLN0 NPI≤3.4\n\n\n\n\n\n\n\nLN0 NPI>3.4\n\n\n\n\n\n−0.157\n\nLN+ (1–3 nodes)\n\n\n\n\n\n−0.290\n\nAbbreviations: LN0, lymph node negative; LN+, lymph node positive, mAOL, modified Adjuvant! Online; NPI, Nottingham Prognostic Index.\n\nTest, subgroup compared with current practice\n\nChemotherapy use with tumour profiling\n\nChemotherapy use with no tumour profiling\n\nNet change\n\nLN0 NPI≤3.4\n\n\n\n\n\n−0.042\n\nLN0 NPI>3.4\n\n\n\n\n\n−0.075\n\nLN+ (1–3 nodes)\n\n\n\n\n\n−0.073\n\nTest, subgroup compared with current practice\n\nChemotherapy use with tumour profiling\n\nChemotherapy use with no tumour profiling\n\nNet change\n\nLN0 NPI≤3.4\n\n\n\n\n\n\n\nLN0 NPI>3.4\n\n\n\n\n\n\n\nLN+ (1–3 nodes)\n\n\n\n\n\n\n\nTest, subgroup compared with current practice\n\nChemotherapy use with tumour profiling\n\nChemotherapy use with no tumour profiling\n\nNet change\n\nLN0 NPI≤3.4\n\n\n\n\n\n\n\nLN0 NPI>3.4\n\n\n\n\n\n\n\nLN+ (1–3 nodes)\n\n\n\n\n\n−0.024\n\nTest, subgroup compared with current practice\n\nChemotherapy use with tumour profiling\n\nChemotherapy use with no tumour profiling\n\nNet change\n\nMINDACT overall population\n\n\n\n\n\n−0.148\n\nmAOL high risk\n\n\n\n\n\n−0.327\n\nmAOL low risk\n\n\n\n\n\n\n\nThe cost-effectiveness planes from the probabilistic sensitivity analyses showed considerable uncertainty in the cost-effectiveness estimates.\n\nIn the subgroup with LN-negative disease and a NPI of 3.4 or less, the only test with a non-zero probability of producing more net benefit than current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was IHC4+C.\n\nIn the subgroup with LN-negative disease and a NPI of more than 3.4, at a maximum acceptable ICER of £20,000 per QALY gained, IHC4+C had a probability of 0.69 of being cost effective compared with current practice. For EndoPredict, Oncotype DX and Prosigna, the probability that the test was cost effective compared with current practice at this threshold was 0.24 or less. In the same subgroup, at a maximum acceptable ICER of £30,000 per QALY gained, IHC4+C had a probability of 0.67 and Prosigna had a probability of 0.60 of being cost effective compared with current practice. Oncotype DX had a probability of 0.04 and EndoPredict had a probability of 0.26 of being cost effective compared with current practice.\n\nIn the subgroup with LN-positive disease, IHC4+C had probabilities of 0.95 and 0.94 of being cost effective compared with current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained respectively. In the same subgroup, the probabilities of EndoPredict producing more net benefit than current practice were 0.44 and 0.73, at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained respectively. For Prosigna the probabilities were 0.24 and 0.55. In this subgroup Oncotype DX had very low probabilities of producing more net benefit than current practice at the same maximum acceptable ICERs (0.01 or lower).\n\nIn the overall MINDACT population and in the subgroups, the probability that MammaPrint would be cost effective compared with current practice at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was approximately 0.\n\nThe EAG did deterministic sensitivity analyses, testing a wide range of plausible values of key parameters.\n\nDeterministic sensitivity analysis results for Oncotype DX compared with current practice were:\n\nSubgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained over £34,000 per QALY gained across all analyses.\n\nSubgroup with LN-negative disease and a NPI of more than 3.4: Oncotype DX was either dominated or had an ICER of more than £35,000 per QALY gained across almost all analyses. The only exception was when Oncotype DX was assumed to predict relative treatment effects for chemotherapy. In this analysis, Oncotype DX dominated current practice.\n\nPopulation with LN-positive disease: Oncotype DX remained dominated across most analyses. The exceptions were when Oncotype DX was assumed to predict relative treatment effects for chemotherapy (it was dominant), and when the cost of chemotherapy was doubled (£3,700 saved per QALY lost).\n\nDeterministic sensitivity analysis results for IHC4+C compared with current practice were:\n\nSubgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained below £16,000 per QALY gained across all analyses, except when post-test chemotherapy probabilities were derived from Holt et al. (2011; £36,259 per QALY gained). Also, IHC4+C dominated current practice when the cost of chemotherapy was doubled.\n\nSubgroup with LN-negative disease and a NPI of more than 3.4: IHC4+C dominated current practice or had an ICER below £6,000 per QALY gained across all scenarios.\n\nPopulation with LN-positive disease: IHC4+C dominated current practice across all but 1\xa0scenario. When the probability of having chemotherapy was based on the UK breast cancer group (UKBCG) survey the ICER was £1,929 per QALY gained.\n\nDeterministic sensitivity analysis results for Prosigna compared with current practice were:\n\nSubgroup with LN-negative disease and a NPI of 3.4 or less: ICERs were greater than £71,000 per QALY gained across all analyses.\n\nSubgroup with LN-negative disease and a NPI of more than 3.4: ICERs were below £34,000 per QALY gained across all analyses.\n\nPopulation with LN-positive disease: ICERs were below £38,000 per QALY gained across all analyses.\n\nDeterministic sensitivity analysis results for EndoPredict compared with current practice were:\n\nSubgroup with LN-negative disease and a NPI of 3.4 or less: ICERs remained greater than £91,000 per QALY gained across all analyses.\n\nSubgroup with LN-negative disease and a NPI of more than 3.4: ICERs remained greater than £30,000 per QALY gained across all but 2\xa0of the analyses. Exceptions were when the UKBCG survey was used to inform the probability of having chemotherapy (£25,250 per QALY gained), and when Cusumano et al. (2014) was used to inform the probability of having chemotherapy based on the EndoPredict test result (£26,689 per QALY gained).\n\nPopulation with LN-positive disease: ICERs remained below £30,000 per QALY gained across all scenarios.\n\nDeterministic sensitivity analysis results for MammaPrint compared with current practice were:\n\nOverall MINDACT population: ICERs were estimated to be greater than £76,000 per QALY gained across all scenarios.\n\nModified Adjuvant! Online high-risk subgroup: MammaPrint was dominated by current practice across almost all scenarios.\n\nModified Adjuvant! Online low-risk subgroup: ICERs were greater than £161,000 per QALY gained across all analyses.\n\nAfter consultation, the EAG did more deterministic sensitivity analyses varying the estimated relative risk of distant recurrence associated with chemotherapy, which was assumed to be 0.76 in the base case. Results showed that as the relative risk moved from 0.6 to 0.9, the tests became less cost effective.", 'Committee discussion': "The committee discussed current practice for making adjuvant chemotherapy prescribing decisions. The clinical experts explained that NHS clinical practice has changed since NICE's diagnostics guidance\xa010 was published in 2013. The PREDICT tool is now used by many NHS trusts rather than the Nottingham Prognostic Index (NPI). Adjuvant! Online is not currently available. The committee also heard that Oncotype DX is currently used in NHS clinical practice and may be used for a broader group than the population defined in the original diagnostics guidance\xa010, that is, people with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and lymph node (LN)‑negative early breast cancer who are assessed as being at intermediate risk using existing risk assessment tools.\n\nThe committee discussed the potential benefits of the tumour profiling tests for people with early breast cancer who are deciding whether to have adjuvant chemotherapy. It acknowledged that chemotherapy is an unpleasant treatment associated with short‑term physical, emotional and financial effects, and also long-term consequences such as infertility and increased risk of cardiomyopathy and leukaemia. The committee heard that there is potential benefit for people with cancer identified as being at low clinical risk, when test results suggest a high risk of distant recurrence. These people could potentially benefit from chemotherapy. It also heard that there is potential benefit for people with cancer categorised as high clinical risk, when test results suggest a low risk of distant recurrence. The committee heard that these people could decide not to have chemotherapy, therefore avoiding toxic side effects and effects on fertility. They could potentially resume normal daily activities earlier, although some may wish to have chemotherapy regardless of the test result. However, the committee noted that the claimed benefits of the tests depend on them having sufficient accuracy and discrimination to correctly classify risk and provide valid clinical information. The clinical experts explained that the additional clinical information provided by the tests may help people discuss further treatment options. This information is particularly helpful for people with cancers identified as intermediate clinical risk when the decision to offer chemotherapy is unclear. However, the final decision to recommend a course of adjuvant chemotherapy would always take into account the person's circumstances and preferences.\n\n# Clinical effectiveness\n\nThe committee considered the prognostic ability of the tumour profiling tests. It noted that for people with LN-negative disease, all the tests had statistically significant prognostic accuracy over clinical and pathological features or risk assessment tools such as the NPI. It also noted that for people with LN-positive disease, results for prognostic ability were more variable but all tests except IHC4+C showed statistically significant or borderline statistically significant prognostic ability over clinical and pathological features or risk assessment tools. The external assessment group (EAG) explained that there were concerns about bias in all studies reporting prognostic ability. This was because in many of the studies some or all patients had chemotherapy or patients who had not had chemotherapy were selected for analyses. Also, most studies excluded tumour samples with insufficient tissue or missing clinical and pathological data, and some studies included patients who had hormone receptor-negative or HER2-positive disease. The committee concluded that despite the potential spectrum bias, the evidence suggested that all the tumour profiling tests have the ability to predict the risk of distant recurrence in the population included in the assessment. It also concluded that the evidence was weaker in the group with LN-positive disease than in the group with LN-negative disease.\n\nThe committee considered the evidence on micrometastases. The EAG explained that 2\xa0studies with Oncotype DX reported subgroup data on people with micrometastases, but no studies with the other tests reported such data. The EAG noted that in patients with micrometastases and a Recurrence Score result of less than 18, outcomes were more similar to those in patients with LN-negative disease than in those with LN-positive disease. However, in patients with micrometastases and a Recurrence Score result of more than 30, outcomes were more similar to those in patients with LN-positive disease. Results were variable in patients with Recurrence Score results between 18 and 30. The EAG noted that the data were uncertain because of the high risk of confounding. The clinical experts explained that micrometastatic disease is classified as LN-positive disease but treated as LN-negative disease for clinical and shared decision making. In clinical practice some centres send samples from patients with micrometastases for Oncotype DX testing, but others do not. A clinical expert also explained that for patients with micrometastatic disease who have reasons to avoid chemotherapy, such as being older or having comorbidities, tumour profiling tests would be helpful. The committee noted that the ongoing OPTIMA study in LN-positive disease excludes patients with micrometastases, unless the tumour size is 20\xa0mm or more. The EAG reviewed whether all studies in the diagnostics assessment report included or excluded patients with micrometastatic disease. It found that in TransATAC micrometastases were not assessed and therefore the disease was treated as LN-negative, but other studies did not report whether patients with micrometastatic disease were included or not. A company representative explained that in the MINDACT study, micrometastases measuring 0.2\xa0mm to 2\xa0mm were classified as LN-positive and isolated tumour cells were classified as LN‑negative. The clinical experts judged that, on balance, patients with micrometastases were likely to have been included in the studies as having LN-negative disease. The committee concluded that tumour profiling tests should be available as an option for people fulfilling the recommendation requirements and who have micrometastatic disease. Discussion within the multidisciplinary team may be particularly helpful for this group.\n\nThe committee considered the evidence on whether the tumour profiling tests can predict relative treatment effects associated with chemotherapy. The clinical experts stated that it is likely some patients could have a greater relative treatment effect from chemotherapy than others, for example, patients with hormone receptor-positive cancer that is not sensitive to endocrine therapy, but evidence is not available to support this. The EAG explained that the only evidence available to show a relative treatment effect for chemotherapy across different risk groups was for Oncotype DX, and the evidence included in the diagnostics assessment report was weak because it was at high risk of bias from potential confounding. The results of interaction tests (which show whether the tumour profiling test was able to predict a different treatment effect by risk group) in the adjusted analysis in the B20 study by Paik et al. (2006; LN-negative disease) remained statistically significant when adjusting simultaneously for clinical and pathological variables. However, the EAG also explained that the difference in relative treatment effects for chemotherapy in the B20 study may be overestimated because this was the Oncotype DX derivation data set. In the SWOG-8814 study by Albain et al. (2010; LN-positive disease) the results of the interaction tests remained statistically significant when adjusting for some individual clinical and pathological variables, but there was no analysis that adjusted for these simultaneously, and the test was non-significant when adjusted for Allred-quantified ER status. The clinical experts explained that hormone receptor status may also predict relative treatment effects for chemotherapy. The committee considered that if all known clinical and pathological variables were included in the analyses of SWOG-8814 then it was likely that the results of the interaction test would no longer be statistically significant. This suggested highly uncertain relative treatment effects for chemotherapy according to the results of the tumour profiling tests for this group with LN-positive disease. The committee concluded that the evidence on the extent to which tumour profiling tests are able to predict relative treatment effects for chemotherapy is highly uncertain, but there may be some differences between Oncotype DX risk groups. The committee noted that no data were available to assess a difference in relative treatment effects for chemotherapy for EndoPredict, IHC4+C and Prosigna risk groups. However, it considered that it would be unethical to do a randomised controlled trial looking at the benefit of chemotherapy compared with endocrine therapy in patients with a clinically low or high risk of distant recurrence. It also noted that data on MammaPrint suggested no difference in relative treatment effects for chemotherapy.\n\nThe committee considered the evidence on clinical utility, that is, data from studies which assessed the ability of the tumour profiling tests to affect patient outcomes. It discussed the recently published results from TAILORx on Oncotype DX (see section 4.31), which showed that across all patients with Recurrence Score results of 11 to 25, there were no clinically relevant or statistically significant differences between those who had endocrine therapy alone and those who had chemotherapy plus endocrine therapy. The EAG noted that some subgroups, such as those with Recurrence Score results of 21 to 25 and those aged 50 or under, had results with confidence intervals above the non-inferiority margin, which suggested that there could be a clinically relevant difference in these subgroups. The EAG noted that patients included in TAILORx had hormone receptor-positive, HER2-negative and LN‑negative disease, and met National Comprehensive Cancer Network guidelines for recommendation or consideration of chemotherapy. In the group with Recurrence Score results of 11 to 25, 73% to 74% were clinically low risk according to modified Adjuvant! Online. The committee acknowledged that the results from TAILORx may not be generalisable to clinical practice in the UK because the population who had chemotherapy in the study would not be routinely offered chemotherapy in an NHS pathway. It noted that, to fully understand the implications of the study for UK practice, a subgroup analysis of the TAILORx data would be needed investigating the performance of the test in predicting chemotherapy benefit for patients eligible for chemotherapy in the UK. The EAG explained that this had been requested but was not made available. The committee concluded that in principle TAILORx is an important piece of evidence showing the effectiveness of gene profiling to guide adjuvant chemotherapy decisions in breast cancer. But it is uncertain how applicable it is to people with breast cancer in the UK who are considering adjuvant chemotherapy treatment.\n\nThe committee considered the evidence on clinical utility for the other tests. It noted that the only other test with evidence from randomised controlled trials was MammaPrint (the MINDACT study). The committee noted that none of the other tumour profiling tests (EndoPredict, IHC4+C and Prosigna) had similar evidence of clinical utility, but it was aware that this evidence was being collected for Prosigna (see section 5.27). The committee noted that MINDACT (see section 4.32) was a well-designed study. The results suggested that patients with high clinical risk and MammaPrint low-risk scores can forgo chemotherapy without a statistically significant increase in the 5-year risk of distant recurrence. However, a clinical expert explained that the risk of recurrence often continues beyond 5\xa0years and noted that the MINDACT authors (Cardoso et al. 2016) stated that long-term follow-up and outcome data will be essential. These data are being collected and a 10-year follow-up analysis is planned. The committee concluded that none of these tests had strong enough evidence to demonstrate an effect on subsequent patient outcomes.\n\nThe committee was encouraged by the availability of the data set provided in confidence to NICE by Genomic Health. The data set was based on the access scheme operated by NHS England, which provided real world evidence on the use of adjuvant chemotherapy in the NHS following testing with Oncotype DX for the population included in the scope for this assessment. The committee noted that the total number of patients in the data set appeared to be much larger than the number of patients with complete data in the population of interest, and that the advice from clinical experts (see section 5.1) was that the test had been used on a wider group of patients in practice. The committee also noted that the publication on TAILORx (Sparano et al. 2018) may influence chemotherapy decision making in people with a Recurrence Score result of 11 to 25, and therefore the data set may not represent clinical decision making in this group. The committee concluded that the access scheme data set was an important piece of real world evidence for use in the economic model, but that more complete data could have been collected and reported, and that it will be important to continue the data collection to capture the influence of TAILORx. It also concluded that future data collection should be done as part of a national database, rather than by individual companies, to increase transparency and enable it to be linked to outcome data (see section 5.29).\n\nThe committee discussed the analytical validity of IHC4+C. The EAG explained that the evidence has developed since diagnostics guidance\xa010 was published. The committee noted that the data showed good correlation between different centres when scoring and staining were assessed separately for measurement of the Ki67 marker, which had been achieved with training. But it also noted that when studies looked at staining and scoring combined, the correlation between centres decreased substantially. A clinical expert noted that different antibody clones are available for testing Ki67, ER and progesterone receptor (PR) status. Different studies used different antibody clones which means that the studies are not directly comparable. The committee heard that different methods of assessing ER and PR receptors may be needed for IHC4+C compared with those already used routinely, which may introduce additional complexity. The committee concluded that because of these issues, the reproducibility of IHC4+C was poor. It also concluded that if this test were to be developed further, the antibody clones used in the assays for ER, PR and Ki67 should be specified, and there would need to be substantial investment in staff training and quality assurance.\n\n# Cost effectiveness\n\nThe committee discussed the assumptions and inputs used in the model, and considered the extensive stakeholder comments on the model and the EAG responses to these comments. It noted that a specific analysis of the TransATAC data was used for risk classification probabilities and for distant recurrence rates based on test result for Oncotype DX, EndoPredict (EPclin), Prosigna and IHC4+C. The results from this specific analysis of the data set have now been published (Sestak et al. 2018). The EAG explained that this data source was chosen because it included data on 4 of the 5\xa0tests of interest and was specific to the population included in the scope (patients with hormone receptor-positive, HER2-negative disease). The committee heard that although the TransATAC data were slightly older and some patients were not candidates for chemotherapy, the patient characteristics matched well with the more recent MINDACT study. The alternative would be to use different data sources for each test, which would have introduced additional uncertainty and complexity. Also, the group with LN‑negative disease could not have been split according to level of clinical risk. The EAG described the limitations of using data from the TAILORx study (Sparano et al. 2018) for the health economic analysis. It also explained that the distant recurrence-free rates from the TransATAC analysis used in the model were consistent with results from other studies (B14, B20, TAILORx, MD Anderson, Clalit, Memorial Sloan Kettering, SEER and WSG PlanB) both when grouped separately by clinical risk and when all clinical risk groups were pooled together. The committee concluded that the TransATAC analysis had some limitations, but was the best available data for use in the model.\n\nThe committee considered the data on pre- and post-test chemotherapy decisions used in the model. The EAG explained that for 3-level tests (tests with low, intermediate and high-risk categories [IHC4+C, Oncotype DX, Prosigna]), data on pre- and post-test chemotherapy decisions for the group with LN-negative disease and a NPI of more than 3.4 were taken from the Genomic Health access scheme data set (see section 5.8). For other clinical risk subgroups with the 3-level tests, and for all clinical risk subgroups with 2-level tests (tests with low and high-risk categories; EndoPredict, MammaPrint), data on pre-test chemotherapy decisions were taken from different sources to data on post-test chemotherapy decisions. There were also very limited UK data for these groups. The committee considered the modelled impact of these data on chemotherapy use, and noted that although clinical and patient experts thought that the main benefit of the tests was in avoiding unnecessary chemotherapy, most tests were estimated to increase chemotherapy use at least in some subgroups (see section 4.49). The committee concluded that there was much more uncertainty around chemotherapy decision making for the 2-level tests, and for the subgroups who were not included in the original NICE recommendation on tumour profiling tests (LN‑negative disease and a NPI of 3.4 or less, and LN-positive disease).\n\nThe committee considered how adjuvant chemotherapy treatment effects had been applied in the economic model, particularly the relative treatment effects of chemotherapy between the risk groups predicted by the tumour profiling tests. It noted its earlier conclusion that the evidence on whether tumour profiling tests can predict relative treatment effects for chemotherapy is highly uncertain, but that there may be some differences between Oncotype DX risk groups (see section 5.5). It agreed that for EndoPredict, IHC4+C and Prosigna, no evidence was available to show a difference in relative treatment effects of chemotherapy across risk groups, and that data on MammaPrint suggested no difference in relative treatment effects. Therefore for these tests it was appropriate to assume the same relative risk of distant recurrence across all test risk categories. The EAG noted that a relative risk of distant recurrence for chemotherapy compared with no chemotherapy of 0.76 estimated from data reported in a large meta-analysis by the Early Breast Cancer Trialists' Collaborative Group was used in the base case, and that this value had been varied between 0.6 and 0.9 in sensitivity analyses. The committee acknowledged that the ICERs were sensitive to this assumption, increasing as the relative risk moved from 0.6 to 0.9. It concluded that, although the true treatment effect is unknown, the relative risk was unlikely to be 0.9 or more.\n\nThe committee considered stakeholder comments submitted during the first consultation suggesting that Oncotype DX has the ability to predict which patients have disease that will respond to chemotherapy. The EAG noted that in response to the comments it had done additional exploratory analyses for Oncotype DX to show the impact on the incremental cost-effectiveness ratios (ICERs) if a smaller relative treatment effect than that taken from the B20 study (Paik et al. 2006) was applied in the model in the group with LN‑negative disease and a NPI of more than 3.4 (see section 4.51). The EAG noted that the hazard ratios used in these analyses were from comparisons of independent arms of trials and were therefore very uncertain. The EAG also said that using hazard ratios calculated from the B20 and the B14 (Paik et al. 2004) studies resulted in an ICER of around £24,000 per quality-adjusted life year (QALY) gained for Oncotype DX compared with current practice. Using hazard ratios calculated from the B20 and TransATAC studies resulted in an ICER of around £8,000 per QALY gained. Based on the results of the Sparano et al. 2018 publication on TAILORx, the EAG repeated the analysis incorporating an additional assumption of 0 chemotherapy benefit for patients in the Oncotype DX low Recurrence Score result category. It noted that this analysis was based on the strong assumption that Oncotype DX not only identifies patients who will not relapse, but also identifies patients who will relapse but will not respond to chemotherapy. When this assumption was included in the analysis using B20, the analysis using B20 and B14, and the analysis using B20 and TransATAC, the ICERs were below £4,000 per QALY gained. The committee concluded that although these analyses were associated with considerable uncertainty, they gave an indication of Oncotype DX's likely cost effectiveness if the relative treatment effects for chemotherapy did differ between Oncotype DX risk groups, but not to the extent reported in the Paik et al. (2006) study.\n\nThe committee considered stakeholder comments submitted during the first consultation suggesting that chemotherapy adverse events had not been adequately captured in the economic model; in particular, congestive heart failure, permanent hair loss and peripheral neuropathy. The EAG noted that in response to the comments it had done additional exploratory analyses to include these adverse events in the model. Congestive heart failure was added into the model by incorporating estimated lifetime QALY losses and costs taken from an alternative model (Hall et al. 2017). Hair loss and peripheral neuropathy were incorporated using a disutility applied to a proportion of the population for the lifetime of the model. The EAG highlighted the considerable limitations of these analyses, and noted that for tests that increased chemotherapy use in some subgroups, the ICERs became less favourable. The committee noted that including additional adverse events in the model did reduce some of the ICERs, but not enough to change the conclusions. It also noted a further EAG analysis, which suggested that for tests that reduced chemotherapy use but were not cost effective, the QALY gain from avoiding adverse events would have to be in the range of 1.1 to 1.3 to result in cost‑effective ICERs. The committee concluded that it was important to consider potential adverse events that could be caused by chemotherapy. However, the reduction in adverse events from reduced chemotherapy use, although beneficial for patients, was unlikely to affect its conclusions on the cost effectiveness of the tumour profiling tests based on the EAG's analysis.\n\nThe committee considered other assumptions used in the model such as the cost of chemotherapy and how the risk of distant recurrence was applied over time. The EAG explained that there was some uncertainty around these inputs, but all had been tested in sensitivity analyses. The committee concluded that the assumptions and inputs used in the model were reasonable, but they were associated with considerable uncertainty because of the limitations in the data that underpinned them.\n\nThe committee noted its discussion on current practice (see section\xa05.1) and considered the absence of comparisons of the tumour profiling tests with the PREDICT tool. The EAG explained that in the model it was not possible to compare the tumour profiling tests with PREDICT, or to define the clinical risk groups using PREDICT, because relevant data were not available. The committee noted that the comparisons in the model did not fully reflect current NHS clinical practice, which led to uncaptured uncertainty in the model results. The committee concluded that research on tumour profiling tests should include comparisons with PREDICT (see section\xa05.26) so that the cost effectiveness of the tests relative to current practice can be fully assessed in future.\n\nThe committee considered the subgroups that were included in the model, that is, people with LN-negative disease and a NPI of 3.4 or less, people with LN-negative disease and a NPI of more then 3.4, and people with LN-positive disease. It noted its earlier conclusion that the evidence suggested that all the tumour profiling tests have the ability to predict risk of distant recurrence (prognosis), but this ability was less certain in the group with LN-positive disease (see section\xa05.3). The committee also recalled that the test results were particularly helpful for people with cancers identified as intermediate clinical risk when the decision to offer chemotherapy is unclear (see section\xa05.2). The clinical experts explained that tumour profiling tests were also helpful for people with LN-positive cancer who have comorbidities and therefore an additional reason to want to avoid chemotherapy. The EAG noted that this subgroup of the LN-positive population could not be modelled because of a lack of data. In addition, the committee noted that the EAG's systematic review had highlighted substantial lack of agreement between the tests in risk categorising the group with LN-positive disease. The committee decided to consider the ICERs in the group with LN-negative disease only, but noted that further studies would be helpful to assess the clinical effectiveness of the tests in the group with LN-positive disease (see section\xa05.27).\n\nThe committee considered the results from the model. It noted that the differences in the QALYs were small, and that the ICERs for all tumour profiling tests were highly uncertain because of the available clinical data and the assumptions used in the modelling (see section\xa05.10 to section 5.15). It also noted that the base-case ICERs for many of the tumour profiling tests were higher than those normally considered to be cost effective. However, it heard that access proposals had been made by Myriad Genetics (for EndoPredict) and NanoString Technologies (for Prosigna). Genomic Health confirmed that the confidential discount for Oncotype DX would continue in the NHS. The committee concluded that the availability of the access proposals for EndoPredict and Prosigna may reduce the ICERs to a range that could be considered plausibly cost effective despite the clinical uncertainties.\n\nThe committee considered the EndoPredict and Prosigna access proposals. Compared with current practice, the ICERs for EndoPredict and Prosigna in the group with LN-negative disease and a NPI of 3.4 or less were still higher than those normally considered to be a cost-effective use of NHS resources. In the group with LN-negative disease and a NPI of more than 3.4, Prosigna compared with current practice had an ICER of less than £20,000 per QALY gained, and therefore could be considered cost effective. In the same group, EndoPredict compared with current practice had ICERs between £20,000 and £30,000 per QALY gained, which varied depending on whether the testing was done at a local or a central laboratory. The committee noted that local testing was more cost effective than central testing, and that testing became more cost effective as test throughput increased. It also recalled its conclusion that the data on post-chemotherapy decisions were more uncertain for 2-level tests than for 3-level tests (see section\xa05.11), and noted that the EAG's sensitivity analyses using plausible alternative sources for post-chemotherapy decisions resulted in ICERs that were lower than £20,000 per QALY gained. The committee noted that in sensitivity analyses, when the relative risk of distant recurrence for chemotherapy compared with no chemotherapy was changed to 0.9 from the base‑case value of 0.76, the ICERs increased for both EndoPredict and Prosigna to more than £30,000 per QALY gained. It considered that a relative risk of 0.9 or more across all genomic risk groups was unlikely, but accepted the uncertainty around this parameter (see section\xa05.12). The committee decided that although there is uncertainty around the ICERs for EndoPredict compared with current practice, sensitivity analyses suggested that the ICER will be around £20,000 per QALY gained, and therefore it could be considered cost effective. The committee concluded that EndoPredict (EPclin) and Prosigna, when provided at the costs stated in the access proposals, were likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be important to confirm this (see section 5.29).\n\nThe committee considered the ICERs for Oncotype DX compared with current practice. It heard that the proposed confidential test cost for Oncotype DX was the same as in current NHS practice, and that this cost had been used in the EAG's economic model. It noted that compared with current practice, the ICERs for Oncotype DX in the group with LN-negative disease and a NPI of 3.4 or less were higher than those normally considered to be a cost-effective use of NHS resources. In the group with LN-negative disease and a NPI of more than 3.4, the committee noted that in the base-case analyses Oncotype DX was dominated by the comparator. The committee recalled its earlier conclusions; Oncotype DX may be able to predict relative treatment effects for chemotherapy, and the ICERs for Oncotype DX compared with current practice when some relative treatment effect across different risk groups was applied in the model were most likely to be between £2,000 and £25,000 per QALY gained (see section\xa05.5 and section\xa05.13). However, it noted that this was very uncertain. The committee concluded that Oncotype DX, when provided at the test cost stated in the access proposal, was likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be important to confirm this (see section\xa05.29).\n\nThe committee considered how EndoPredict, Oncotype DX and Prosigna compare with each other. It noted that only pairwise ICERs of each tumour profiling test compared with no testing had been presented, rather than a fully incremental analysis. The EAG explained that a fully incremental analysis could not be done because there was no clinical evidence which directly compared the tests. The committee noted that since the publication of TAILORx (Sparano et al. 2018) evidence on clinical utility was strongest for Oncotype DX. It also noted that it was not possible to determine which test was the most cost-effective use of NHS resources, and that it may not be the test with the lowest acquisition price.\n\nThe committee considered the ICERs for MammaPrint compared with modified Adjuvant! Online. It noted that in the base-case analyses, MammaPrint was dominated by the comparator in the modified Adjuvant! Online high-risk subgroup. In the modified Adjuvant! Online low-risk subgroup, the ICERs were much higher than those normally considered to be cost effective. The committee concluded that MammaPrint would not be a cost-effective use of NHS resources.\n\nThe committee considered the ICERs for IHC4+C compared with current practice. It noted that the ICERs were low or that IHC4+C dominated current practice in all subgroups. The committee felt that the test cost had been underestimated because it did not include any costs for training or for setting up a quality assurance programme. But even if these costs were included, IHC4+C may still be cost effective. However, the committee noted its earlier conclusion on the analytical validity of IHC4+C (see section\xa05.9) and concluded that it could not be recommended for use in the NHS until issues around reproducibility and implementation had been resolved.\n\nThe committee noted that the model for EndoPredict, IHC4+C, Oncotype DX and Prosigna related only to a postmenopausal population because TransATAC was used as the data source for these tests. It considered whether the model results could also apply to a premenopausal population. A clinical expert explained that the biology of a cancer and its molecular subtype, for example hormone receptor status and HER2 status, is more influential in determining the risk of distant recurrence than menopausal status. Therefore the committee concluded that the model results apply to premenopausal and postmenopausal populations, but noted that clinicians wishing to use a tumour profiling test should first check which populations the test is indicated for (see section\xa03).\n\nThe committee discussed the generalisability of the data to men. It acknowledged that men make up a small proportion of people with breast cancer. The committee noted that all the clinical and economic evidence was based on trials with women, but that the general subtypes of breast cancer are identical in men and women, and in clinical practice men would have treatment in the same way as women. The committee concluded that the recommendations in this guidance should also apply to men.\n\n# Research considerations\n\nThe committee noted that there are several ongoing studies which will provide evidence of long-term patient outcomes: further data collection from the MINDACT study on MammaPrint and the OPTIMA trial on Prosigna. The committee concluded that these studies are relevant to this assessment and data from them may be important when the guidance is considered for updating in the future. It also recalled its earlier conclusion that a subgroup analysis of TAILORx would be welcomed (see section\xa05.6). But it noted that not all studies would provide UK-specific data and comparisons with the PREDICT tool, which would be important for future updates to fully assess the cost effectiveness of the tests compared with current practice.\n\nThe committee also recalled its previous conclusion on the potential utility of the tests in the group with LN-positive disease (see section\xa05.17), particularly for people who have comorbidities and who may be particularly affected by the side effects of adjuvant chemotherapy. It noted that further research in this group would be welcome and heard from clinical experts that the ongoing OPTIMA trial may help to reduce some of the uncertainties identified during this assessment.\n\nThe committee considered consultation comments from the Cancer and Society in the 21st century research team about their qualitative research on women's experiences of gene expression profiling for chemotherapy decision making, and noted the importance of this work.\n\n# Data collection arrangements\n\nThe committee recalled its previous conclusions on the uncertainties associated with both the clinical and cost effectiveness of EndoPredict (EPclin), Oncotype DX and Prosigna. It had identified clinical uncertainties associated with the effect of the technologies on patient outcomes (see section\xa05.6 and 5.7) and also on clinical decision making (see section\xa05.8 and section\xa05.11). These limitations meant that the estimated cost effectiveness of the technologies in the NHS was highly uncertain (see section\xa05.18 to\xa0section 5.20). On balance the committee concluded that EndoPredict (EPclin), Oncotype DX and Prosigna, when provided at the test cost stated in the access proposal, were likely to be cost effective in the group with LN-negative disease and a NPI of more than 3.4, but evidence on clinical outcomes will be needed to confirm this in the NHS. Further, it considered that this should be addressed through data collection using the National Cancer Registration and Analysis Service which would provide data on NHS use. It also believed that it is necessary that data is collected as part of a national database, rather than by individual companies, to increase transparency, enable the data to be linked to clinical outcomes and ensure evidence is available that can be considered in future updates of this guidance. It therefore decided that its recommendations for EndoPredict (EPclin), Oncotype DX and Prosigna are conditional on data collection arrangements agreed with NICE being put in place. It is anticipated that arrangements will be made to collect timely and complete record-level test data, which can be submitted to the National Cancer Registration and Analysis Service, with the aim of linking test data to chemotherapy use, recurrence and survival outcomes."}
|
https://www.nice.org.uk/guidance/dg34
|
Evidence-based recommendations on tumour profiling tests to guide adjuvant chemotherapy decisions for people with early breast cancer. The tests are EndoPredict (EPclin score), Oncotype DX Breast Recurrence Score, Prosigna, MammaPrint and IHC4+C.
|
f7cdf77f216d0b60b39e5a927c454adaef8530ea
|
nice
|
Transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults
|
Transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults
Evidence-based recommendations on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults. This involves electrically stimulating nerves in the throat or neck, while the person swallows. The aim is to strengthen the muscles involved in swallowing.
# Recommendations
Current evidence on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults shows there are no major safety concerns.
For adults with dysphagia after a stroke, the evidence on efficacy suggests a potential benefit, but is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
For adults with dysphagia not caused by a stroke, there is insufficient evidence on efficacy to support the use of this procedure. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians wishing to do transcutaneous neuromuscular electrical stimulation for adults with oropharyngeal dysphagia after a stroke should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on transcutaneous neuromuscular electrical stimulation is recommended.
Audit and review clinical outcomes of all patients having transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Further research on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults should address patient selection, variations in technique, the need for retreatments and long-term outcomes.# The condition, current treatments and procedure
# The condition
Difficulty in swallowing (dysphagia) can be caused by neurological impairment affecting the muscles of the oropharynx. It can happen because of a stroke, traumatic brain injury, disorders of cerebral development, neurodegenerative conditions and major head and neck surgery (for example, to remove cancer). Dysphagia may lead to malnutrition, dehydration and aspiration pneumonia.
# Current treatments
Treatment options depend on the cause and severity of the dysphagia. Conservative treatments involve swallowing therapy to help the patient relearn swallowing techniques and strengthen oropharyngeal muscles. In severe cases, nasogastric tubes or percutaneous endoscopic gastrostomy tubes may be used to provide nutritional support.
# The procedure
Transcutaneous neuromuscular electrical stimulation (NMES) is usually used as well as traditional swallowing therapy for treating oropharyngeal dysphagia. Swallowing therapy uses exercises to improve muscle function. The aim of NMES is to increase the effectiveness of swallowing therapy by strengthening the muscles involved in swallowing. It also promotes recovery of cortical control of swallowing.
NMES is usually done by a speech and language therapist after appropriate diagnosis and patient selection. Therapists need appropriate training to use the procedure. The speech and language therapist places electrodes in selected positions on the patient's neck. Small electrical currents are then passed through the electrodes to stimulate the peripheral nerve supply of the pharyngeal or laryngeal muscles. Stimulus intensity may be at a low sensory level, or at a higher motor level to trigger muscle contractions. Under the supervision of the therapist, the patient exercises their swallowing muscles while having concurrent electrical stimulation. Treatment duration recommendations vary by device, but can be up to 1 hour. The mild electrical stimulation can produce feelings ranging from tingling and warmth, to a 'grabbing' sensation.
The position of the electrodes and levels of current used vary from patient to patient. There is a range of NMES devices that use different electrode designs, positions and stimulus intensities. At an initial assessment, videofluoroscopy or clinical observation may be used to optimise the placement of treatment electrodes and to determine an appropriate stimulus intensity.
|
{'Recommendations': "Current evidence on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults shows there are no major safety concerns.\n\nFor adults with dysphagia after a stroke, the evidence on efficacy suggests a potential benefit, but is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor adults with dysphagia not caused by a stroke, there is insufficient evidence on efficacy to support the use of this procedure. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transcutaneous neuromuscular electrical stimulation for adults with oropharyngeal dysphagia after a stroke should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on transcutaneous neuromuscular electrical stimulation is recommended.\n\nAudit and review clinical outcomes of all patients having transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nFurther research on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults should address patient selection, variations in technique, the need for retreatments and long-term outcomes.", 'The condition, current treatments and procedure': "# The condition\n\nDifficulty in swallowing (dysphagia) can be caused by neurological impairment affecting the muscles of the oropharynx. It can happen because of a stroke, traumatic brain injury, disorders of cerebral development, neurodegenerative conditions and major head and neck surgery (for example, to remove cancer). Dysphagia may lead to malnutrition, dehydration and aspiration pneumonia.\n\n# Current treatments\n\nTreatment options depend on the cause and severity of the dysphagia. Conservative treatments involve swallowing therapy to help the patient relearn swallowing techniques and strengthen oropharyngeal muscles. In severe cases, nasogastric tubes or percutaneous endoscopic gastrostomy tubes may be used to provide nutritional support.\n\n# The procedure\n\nTranscutaneous neuromuscular electrical stimulation (NMES) is usually used as well as traditional swallowing therapy for treating oropharyngeal dysphagia. Swallowing therapy uses exercises to improve muscle function. The aim of NMES is to increase the effectiveness of swallowing therapy by strengthening the muscles involved in swallowing. It also promotes recovery of cortical control of swallowing.\n\nNMES is usually done by a speech and language therapist after appropriate diagnosis and patient selection. Therapists need appropriate training to use the procedure. The speech and language therapist places electrodes in selected positions on the patient's neck. Small electrical currents are then passed through the electrodes to stimulate the peripheral nerve supply of the pharyngeal or laryngeal muscles. Stimulus intensity may be at a low sensory level, or at a higher motor level to trigger muscle contractions. Under the supervision of the therapist, the patient exercises their swallowing muscles while having concurrent electrical stimulation. Treatment duration recommendations vary by device, but can be up to 1\xa0hour. The mild electrical stimulation can produce feelings ranging from tingling and warmth, to a 'grabbing' sensation.\n\nThe position of the electrodes and levels of current used vary from patient to patient. There is a range of NMES devices that use different electrode designs, positions and stimulus intensities. At an initial assessment, videofluoroscopy or clinical observation may be used to optimise the placement of treatment electrodes and to determine an appropriate stimulus intensity."}
|
https://www.nice.org.uk/guidance/ipg634
|
Evidence-based recommendations on transcutaneous neuromuscular electrical stimulation for oropharyngeal dysphagia in adults. This involves electrically stimulating nerves in the throat or neck, while the person swallows. The aim is to strengthen the muscles involved in swallowing.
|
f5b829b5fe7b4c14ad60d1db0fe665455545912b
|
nice
|
Bronchial thermoplasty for severe asthma
|
Bronchial thermoplasty for severe asthma
Evidence-based recommendations on bronchial thermoplasty for severe asthma in adults. This involves applying heat to the inside walls of the airways.
# Recommendations
Current evidence on the safety and efficacy of bronchial thermoplasty for severe asthma is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
The procedure should only be done by a multidisciplinary team in specialist centres with on-site access to intensive care. It should only be done by clinicians with training in the procedure and experience in managing severe asthma.
Clinicians should enter details of all patients who have the procedure onto the UK Severe Asthma Registry.
Further research should report details of patient selection and long‑term safety and efficacy outcomes.# The condition, current treatments and procedure
# The condition
Asthma is a long-term condition of the airways in the lungs that affects children, young people and adults. It consists of inflammation and constriction of the smooth muscle in the airway walls (bronchoconstriction). This is triggered by increased responsiveness of the airways to various allergic stimuli, leading to airflow obstruction. Symptoms include recurring episodes of wheezing, breathlessness, chest-tightness and coughing.
Asthma is diagnosed and its severity assessed on the basis of symptoms and objective tests of lung function.
# Current treatments
Treatment, including advice about lifestyle changes, aims to reduce the frequency and severity of attacks, allowing the person to lead a normal and active life. In the UK, treatment for asthma follows NICE's guideline on asthma and guidelines from the Global Initiative for Asthma.
# The procedure
The aim of bronchial thermoplasty for severe asthma is to reduce the smooth muscle mass lining the airways, decreasing their ability to constrict.
The procedure is usually done using sedation or general anaesthesia. A catheter is introduced into the bronchial tree. Short pulses of radiofrequency energy are applied circumferentially to sequential portions of the airway wall, moving from the distal to the proximal bronchi. Treatment is usually delivered in 3 sessions with an interval of at least 3 weeks between each session. After the first session, treated airways are evaluated by bronchoscopy before proceeding with further treatment.
|
{'Recommendations': 'Current evidence on the safety and efficacy of bronchial thermoplasty for severe asthma is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThe procedure should only be done by a multidisciplinary team in specialist centres with on-site access to intensive care. It should only be done by clinicians with training in the procedure and experience in managing severe asthma.\n\nClinicians should enter details of all patients who have the procedure onto the UK Severe Asthma Registry.\n\nFurther research should report details of patient selection and long‑term safety and efficacy outcomes.', 'The condition, current treatments and procedure': "# The condition\n\nAsthma is a long-term condition of the airways in the lungs that affects children, young people and adults. It consists of inflammation and constriction of the smooth muscle in the airway walls (bronchoconstriction). This is triggered by increased responsiveness of the airways to various allergic stimuli, leading to airflow obstruction. Symptoms include recurring episodes of wheezing, breathlessness, chest-tightness and coughing.\n\nAsthma is diagnosed and its severity assessed on the basis of symptoms and objective tests of lung function.\n\n# Current treatments\n\nTreatment, including advice about lifestyle changes, aims to reduce the frequency and severity of attacks, allowing the person to lead a normal and active life. In the UK, treatment for asthma follows NICE's guideline on asthma and guidelines from the Global Initiative for Asthma.\n\n# The procedure\n\nThe aim of bronchial thermoplasty for severe asthma is to reduce the smooth muscle mass lining the airways, decreasing their ability to constrict.\n\nThe procedure is usually done using sedation or general anaesthesia. A catheter is introduced into the bronchial tree. Short pulses of radiofrequency energy are applied circumferentially to sequential portions of the airway wall, moving from the distal to the proximal bronchi. Treatment is usually delivered in 3\xa0sessions with an interval of at least 3\xa0weeks between each session. After the first session, treated airways are evaluated by bronchoscopy before proceeding with further treatment."}
|
https://www.nice.org.uk/guidance/ipg635
|
Evidence-based recommendations on bronchial thermoplasty for severe asthma in adults. This involves applying heat to the inside walls of the airways.
|
d182768ba272e5f86ba750372b9cf3952afe382b
|
nice
|
Lenvatinib for untreated advanced hepatocellular carcinoma
|
Lenvatinib for untreated advanced hepatocellular carcinoma
Evidence-based recommendations on lenvatinib (Lenvima) for untreated advanced hepatocellular carcinoma in adults.
# Recommendations
Lenvatinib is recommended as an option for untreated, advanced, unresectable hepatocellular carcinoma in adults, only if:
they have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and
the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with lenvatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Advanced unresectable hepatocellular carcinoma is treated with sorafenib, but some people cannot tolerate it because of side effects.
Clinical trial evidence shows that lenvatinib slows disease progression and causes more tumours to shrink than sorafenib. The evidence also shows that people having lenvatinib live for about as long as those having sorafenib. Lenvatinib has different side effects to sorafenib and this would benefit some people.
Using the most plausible assumptions and including the commercial arrangement, the cost-effectiveness estimates for lenvatinib compared with sorafenib are within the range NICE normally considers acceptable. Therefore, lenvatinib is recommended for untreated, advanced, unresectable hepatocellular carcinoma in adults with Child–Pugh grade A liver impairment and an ECOG performance status of 0 or 1.# Information about lenvatinib
# Marketing authorisation indication
Lenvatinib (Lenvima, Eisai) is indicated as monotherapy for 'the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy'.
# Dosage in the marketing authorisation
The daily dose of lenvatinib in the summary of product characteristics is 8 mg (2×4 mg capsules) given orally for patients who weigh less than 60 kg, and 12 mg (3×4 mg capsules) orally for patients who weigh 60 kg or over (based on company submission). The summary of product characteristics advises that dose adjustments are not needed on the basis of hepatic function in people with Child–Pugh grade A liver impairment. It advises that the available data are not sufficient to make a dosing recommendation for people with Child–Pugh grade B liver impairment; safety should be closely monitored in these patients. Because lenvatinib has not been studied in patients with Child–Pugh grade C liver impairment, the summary of product characteristics does not advise use in these patients.
# Price
£1,437 for 30×4 mg capsules (excluding VAT; British national formulary online ). The company has a commercial agreement (patient access scheme). This makes lenvatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Unmet need
## People with advanced hepatocellular carcinoma would welcome an alternative treatment option
Advanced unresectable hepatocellular carcinoma is often diagnosed late in life and has a poor prognosis. It is a debilitating condition with many distressing symptoms, including pain, digestive problems and weight loss. The patient experts noted that people with advanced unresectable hepatocellular carcinoma consider improving their quality of life to be particularly important. Sorafenib is currently the only licensed option for people who have not already had systemic treatment. The committee understood that an alternative first-line treatment option would be valuable to patients with the condition.
# Treatment pathway
## Lenvatinib may offer benefits over current treatment options
The clinical experts explained that there is a low response rate with sorafenib and around 25% of patients stop treatment because they cannot tolerate it. They added that hand-foot syndrome is more common with sorafenib, which can be very unpleasant for patients. The committee was aware that lenvatinib also has common side effects, such as hypertension. It considered that lenvatinib and sorafenib have different side-effect profiles, and that tolerability of each drug would depend on the patient. A patient expert noted that lenvatinib offers a longer time to disease progression compared with sorafenib, although there is no evidence showing a difference in overall survival. The clinical experts indicated that they may use lenvatinib instead of sorafenib based on individual patient characteristics, but also because of the improvements it offers in side-effect profile, time to disease progression and response rates. The committee agreed that lenvatinib may offer improved benefits for people with advanced unresectable hepatocellular carcinoma who have not had systemic treatment.
# Population
## The company positioned lenvatinib in line with the REFLECT trial
The company positioned lenvatinib in line with the REFLECT trial (that is, for adults with advanced unresectable hepatocellular carcinoma who have not already had systemic treatment and who have Child–Pugh grade A liver impairment). This was narrower than both the marketing authorisation and the final scope issued by NICE, but was in line with the REFLECT trial population and previous NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma. The clinical experts explained that treatment may not be clinically effective in people with more impaired liver function (for example, people with Child–Pugh grade B liver impairment). The committee accepted the company's positioning of lenvatinib for adults with advanced unresectable hepatocellular carcinoma who have not already had systemic treatment and who have Child–Pugh grade A liver impairment.
# Comparator
## Sorafenib is the most relevant comparator
The company did not consider best supportive care to be an appropriate comparator because it is only used in clinical practice if systemic treatment is not appropriate. The company's clinical expert estimated that less than 5% of patients have best supportive care; most people instead have sorafenib. The clinical experts stated that most people would be eligible for systemic therapy and would have sorafenib. The committee concluded that sorafenib was the most relevant comparator.
# Clinical evidence
## REFLECT included a clinically appropriate population with Child–Pugh grade A liver impairment and ECOG performance status of 0 or 1
The clinical evidence came from a phase III, open-label randomised controlled trial (REFLECT) comparing lenvatinib with sorafenib for untreated, advanced hepatocellular carcinoma in 954 adults with Child–Pugh grade A liver impairment and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial excluded people with Child–Pugh grade B liver impairment or worse and people with an ECOG performance status of 2 or more, and the committee understood the results may not be generalisable to these groups. The clinical experts explained that lenvatinib may not be clinically effective in these groups, and that these criteria are also used in clinical practice to decide the most appropriate treatment options. The Cancer Drugs Fund clinical lead confirmed that the NHS England treatment criteria would reflect these eligibility criteria. The committee concluded that people with both Child–Pugh grade A liver impairment and ECOG performance status 0 to 1 was the most clinically appropriate population, and agreed to consider the trial inclusion criteria when making its recommendations.
## Baseline characteristics were imbalanced but the clinical-effectiveness results are relevant to NHS practice
The company highlighted that in REFLECT, more people in the lenvatinib group had alpha-fetoprotein levels of 200 ng/ml or above compared with the sorafenib group, and there were differences in the pre-existing liver conditions associated with hepatocellular carcinoma (hepatitis C, hepatitis B or alcohol) across the 2 groups. The company explained that these variables were not included as randomisation stratification factors. It considered that these imbalances in baseline characteristics may affect the treatment benefit seen with lenvatinib because they were potentially important prognostic factors. However, the clinical experts explained that a similar treatment benefit was likely regardless of pre-existing liver conditions. The ERG's clinical expert agreed that although alpha-fetoprotein level was a prognostic factor, they did not consider the cut-off value of 200 ng/ml to be clinically relevant. The committee understood that the company had made adjustments to account for the imbalances in baseline characteristics (see section 3.12) and that the difference in alpha-fetoprotein levels may not be clinically meaningful. The committee concluded that although there may be some imbalances in the baseline characteristics, the REFLECT trial was relevant to clinical practice in the NHS.
## It is appropriate to use clinical data from the full trial population
Around two thirds of the trial population were from the Asia-Pacific region and the rest were from Western countries including the UK. The ERG noted important differences between the Western subgroup and the full trial population (the Western subgroup was heavier, had more heart disease, less underlying cirrhosis, less hepatitis B and more pre-existing hepatitis C or alcohol-related conditions), but explained that these differences may not have changed the relative treatment effect. The ERG also noted that baseline characteristics in the full population were more balanced than those in the Western subgroup, and the clinical experts agreed that the overall population reflected clinical practice in England. The committee was aware that the imbalance in post-progression treatment was larger in the Western subgroup compared with the full trial population. It understood that after adjusting for post-progression treatment (see section 3.13), the overall survival results were similar for both the Western subgroup and the full trial population. The committee agreed that there was no sufficient justification for using results from the Western subgroup instead of the full trial population because it was not more clinically relevant and had a relatively small sample size. It agreed that the baseline characteristics for the full trial population were generally in line with clinical practice in England, and it preferred to use these results.
## The company's updated approach to censoring is appropriate
In the company's original submission, progression-free survival results were censored if there was no disease progression when treatment is stopped (because not all patients were followed up until the end of the trial). The ERG explained that this could be considered to be informative censoring (that is, reasons for drop-out may potentially be related to disease progression or survival time) and that it may lead to inaccurate conclusions about the size of the treatment difference between lenvatinib and sorafenib. Based on the clinical evidence presented, the ERG explained that the company's method of censoring would likely favour lenvatinib because more people stopped lenvatinib either through choice or because of adverse effects. More events may therefore be missed because of censoring in the lenvatinib group. In response to consultation, the company updated its censoring approach to include all events in the analysis and only censored if there were missing assessments or no disease progression at the last assessment. Progression-free survival was lower with the updated censoring approach, but the results still showed a statistically significant improvement for lenvatinib compared with sorafenib. The committee concluded that the company's updated approach to censoring (that is, including all events in the analysis and only censoring missing assessments or patients with no disease progression at last assessment) was appropriate.
## More patients had post-progression treatment in the sorafenib arm than in the lenvatinib arm and the overall survival results may favour sorafenib
In REFLECT, treatment after disease progression was allowed in both the lenvatinib and sorafenib arms. In the lenvatinib arm, patients could switch to sorafenib but were not eligible for trials using second-line treatment. In the sorafenib arm, patients could continue sorafenib and were eligible for trials using second-line treatments such as regorafenib. Regorafenib is not used in England because it is not currently recommended by NICE (see the NICE technology appraisal guidance on regorafenib for previously treated advanced hepatocellular carcinoma). The committee understood that 51% of patients in the sorafenib group had post-progression treatment compared with only 43% in the lenvatinib group. It noted that longer overall survival may be expected for people having post-progression treatment, so the overall survival results may favour patients randomised to sorafenib. The committee concluded that more patients having post-progression treatment in the sorafenib arm may affect the estimates of treatment effect for overall survival.
## Overall survival with lenvatinib is non-inferior compared with sorafenib
The primary end point of REFLECT was overall survival and the study was powered to demonstrate non-inferiority. There was no statistically significant difference in overall survival (see table 1, below). However, the results for overall survival met the pre-specified criteria for non-inferiority (that is, the upper limit of the 95% confidence interval was less than 1.08). There was also a statistically significant improvement in median investigator-assessed progression-free survival with lenvatinib (7.4 months) compared with sorafenib (3.7 months). Similar results were reported for independently assessed progression-free survival using standard response evaluation criteria in solid tumours (RECIST) to measure disease progression, and a modified version of RECIST that evaluates change more accurately in hepatocellular carcinoma. The committee understood that the proportional hazards assumption (that is, there is a constant treatment effect over time) was not met for the overall and progression-free survival results, so these should be interpreted with caution. The committee noted the consistency in the progression-free survival results using the 2 different censoring rules (see section 3.8), and agreed there was robust evidence of a progression-free survival benefit, although there is some uncertainty around the size of this benefit (see section 3.15). Lenvatinib also improved response rates compared with sorafenib. The committee concluded that overall survival with lenvatinib was non-inferior compared with sorafenib.
Outcome
Lenvatinib – median (range)
Sorafenib – median (range)
Result – (95% confidence interval)
Unadjusted overall survival
(12.1 to 14.9)
(10.4 to 13.9)
Hazard ratio 0.92 (0.79 to 1.06)
Overall survival adjusted for post-progression treatment
Confidential and cannot be reported here
Investigator-assessed progression-free survival using modified response evaluation criteria in solid tumours (RECIST)
(6.9 to 8.8)
(3.6 to 4.6)
Hazard ratio 0.66 (0.57 to 0.77)
Investigator-assessed progression-free survival using modified RECIST and committee's preferred censoring rules
Confidential and cannot be reported here
Independently assessed progression-free survival using modified RECIST
(5.6 to 7.5)
(3.6 to 3.7)
Hazard ratio 0.64 (0.55 to 0.75)
Independently assessed progression-free survival using standard RECIST (1.1)
(5.6 to 7.5)
(3.6 to 3.9)
Hazard ratio 0.65 (0.56 to 0.77)
Objective response rate
Odds ratio 3.13 (2.15 to 4.56)
# The company's model
## The model structure is appropriate for decision-making
The company used a partitioned survival model with 3 health states (progression free, progressed disease and death). The committee noted that although progression-free and overall survival data were relatively mature in the REFLECT trial, extrapolations were needed for both to model effects over a lifetime horizon. The ERG considered the model structure to be appropriate but identified an inconsistency in the half-cycle correction because it was not fully applied to all costs and quality-adjusted life years (QALYs). The ERG corrected this in its own preferred base case. At clarification, the company did not consider this to be an error and so did not correct it. Ultimately these corrections had little effect on the cost-effectiveness estimates, and the committee concluded that the model structure was appropriate for decision-making.
# Survival estimates in the model
## The company's adjustment for baseline characteristics using the corrected group prognosis method is acceptable
In its original submission, the company adjusted the treatment estimates used in the model to account for imbalances in baseline characteristics of patients in REFLECT. The company fitted multivariable parametric survival models to the progression-free and overall survival data and adjusted for covariates using the mean of covariates approach. The committee was aware that the company's model contained categorical variables (such as Child–Pugh grade) and that interpreting these variables using the mean of covariates approach is problematic. The committee considered the corrected group prognosis method to be more appropriate for adjusting for categorical variables. In response to consultation, the company revised its analyses to use the corrected group prognosis method to adjust for baseline imbalances. However, the committee considered that there was still some uncertainty in the revised analyses; proportional hazards were not tested for all potential covariates, and choice of adjustment covariates was based on the pre-consultation overall survival model. However, on balance, the committee concluded that the company's adjustment for baseline characteristics using the corrected group prognosis method was acceptable.
## It is appropriate to include post-progression benefit in line with REFLECT
The company's base case included the clinical benefit of post-progression treatment. The committee recalled that in REFLECT, fewer people in the lenvatinib arm had post-progression treatment compared with the sorafenib arm (see section 3.9). The ERG explained that this may bias overall survival estimates in favour of sorafenib, because people who have post-progression treatment may have longer overall survival. The committee understood that the company used a simple binary adjustment for post-progression treatment (patients either had or did not have post-progression treatment). The committee considered that there was some uncertainty in the company's adjustment; there were missing data about the types of post-progression treatments people had, and the company did not explore alternative statistical adjustments for post-progression treatment (for example, by including post-progression treatment as a time-varying covariate). However, mindful of the risk of bias from the post-progression treatment distribution in the trial, the committee concluded that it could accept the inclusion of post-progression treatment benefit in line with REFLECT.
## A log-logistic distribution is appropriate for extrapolating overall survival
The company used a log-logistic model in its base case to extrapolate overall survival for both lenvatinib and sorafenib. The committee understood that this model provided a good fit to data from both treatment groups and concluded that a log-logistic distribution was appropriate for extrapolating overall survival for both lenvatinib and sorafenib.
## Gamma extrapolation of the progression-free survival data predicts lower survival than log-normal extrapolation but both are reasonable
In its original base case, the company used a log-normal distribution to extrapolate progression-free survival for both lenvatinib and sorafenib. At the first meeting, the committee considered that the gamma distribution was a better fit to the treatment groups. However, the committee was aware that both extrapolations were based on Kaplan–Meier data that had not been adjusted or censored in line with its preferences. In response to consultation, the company presented updated progression-free survival analyses based on the committee's preferred censoring approach (see section 3.8) and the corrected group prognosis method of adjusting for baseline characteristics (see section 3.12). In its updated base case, the company extrapolated progression-free survival using a gamma distribution and presented a log-normal distribution as an exploratory analysis. However, the company did not provide statistical indications of goodness of fit for the updated models. The committee visually assessed the model fit of both extrapolations compared with the updated Kaplan–Meier data and noted that both distributions appeared to be a reasonable fit to the adjusted trial data. However, it considered that evaluating the models without a statistical assessment of fit introduced some uncertainty about the choice of extrapolation. The committee concluded that both the gamma and log-normal extrapolations of progression-free survival were reasonable.
# Costs in the model
## Including drug wastage does not have a large effect on total costs
The company did not include drug wastage costs in its base-case analysis. The committee understood that in a previous NICE technology appraisal on sorafenib for treating advanced hepatocellular carcinoma, it was considered appropriate to include drug wastage for up to 7 days. However, in a more recent NICE technology appraisal on regorafenib for previously treated advanced hepatocellular carcinoma, the committee considered 7 days to be arbitrary and associated with some uncertainty. The ERG did a scenario analysis using drug costs based on the planned number of capsules and tablets needed each day. This led to only a modest reduction in total costs. The committee concluded that drug wastage did not have a large effect on the total costs.
## It is acceptable to include the costs of post-progression treatment in line with REFLECT
In its original submission, the company's base case only included the costs of sorafenib and regorafenib after disease progression because these are the only licensed treatments for advanced hepatocellular carcinoma. The committee was aware that other treatments and procedures were also used after disease progression in REFLECT, but these costs had not been included in the company's base case. In response to consultation, the company included in its model the costs of all post-progression treatments and procedures used in REFLECT. The committee considered that because the model included the benefit of post-progression treatments, it was also appropriate to include the costs. Because of this, the committee concluded that the company's updated modelling of post-progression treatment costs was acceptable.
# Utility values in the economic model
## Utility values in the progressed state are acceptable
In its base case, the company used utility values from the full population in REFLECT for both lenvatinib and sorafenib because there was only a small difference in mean utility values. The company used a value of 0.745 in the progression-free state and 0.678 in the progressed state, although the company's clinical experts noted that the utility value in the progressed state was higher than would be expected given that advanced hepatocellular carcinoma can severely affect functioning and wellbeing. The committee noted that the final measurement in the post-progression stage was 30 days after the final dose of lenvatinib or sorafenib so these measurements may not include the full effect of disease progression on health-related quality of life. The ERG did a scenario analysis using a utility value of 0.50 in the progressed disease state. The committee observed that this led to only a small increase in the cost-effectiveness estimates, and concluded that the utility values used in the company's analysis were acceptable.
# Cost-effectiveness estimate
## The company's updated base-case ICER is above the range normally considered to be an acceptable use of NHS resources
The committee considered the incremental cost-effectiveness ratios (ICERs) from the company's updated base case after consultation. This was recalculated by the ERG to include the confidential commercial arrangements for lenvatinib and sorafenib. The company's model assumptions included:
a larger discount as part of the patient access scheme
updated censoring rules for progression-free survival that include all events in the analysis and only censor missing assessments or patients with no disease progression at last assessment
adjustment for baseline characteristic imbalances using the corrected group prognosis method
progression-free survival extrapolated using the gamma distribution
post-progression treatment costs and benefits modelled in line with REFLECT.The committee concluded that the company's base-case ICER for lenvatinib compared with sorafenib was higher than the range normally considered to be an acceptable use of NHS resources.
## The most plausible ICER for lenvatinib compared with sorafenib is within the range normally considered to be an acceptable use of NHS resources
The committee considered that the company's updated model had captured its preferred assumptions. However, it was aware that there was still some uncertainty in the model because there was no statistical goodness-of-fit assessment of the progression-free survival extrapolation, and no exploration of alternative statistical adjustments for post-progression treatment. The committee recalled that the log-normal extrapolation gave substantially lower ICER estimates than the gamma extrapolation. It also recognised that although it had accepted the company's modelling of post-progression treatment costs and benefits, there were still flaws with the company's method of adjustment, and uncertainty from missing data on post-progression treatment (see section 3.13). Having considered all these factors, the committee concluded that the most plausible ICER for lenvatinib compared with sorafenib (including the confidential commercial arrangements for both drugs) is within the range normally considered to be an acceptable use of NHS resources (the exact ICER is confidential and cannot be reported here). The committee concluded to recommend lenvatinib for untreated, advanced, unresectable hepatocellular carcinoma in adults with Child–Pugh grade A liver impairment and an ECOG performance status of 0 or 1.
# End of life
## End-of-life considerations are not relevant because lenvatinib is recommended for routine commissioning
In the first committee meeting, the committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It concluded that lenvatinib met the short life expectancy criterion, but that it was uncertain whether lenvatinib met the extension to life criterion. In the second committee meeting, the committee considered that the end-of-life considerations were no longer relevant to the appraisal decision because the most plausible ICER was within the range normally considered to be an acceptable use of NHS resources.
# Equality
## There are no equality issues relevant to the recommendations
The committee considered whether its recommendations were associated with any potential issues related to equality. The committee noted comments from patient and clinical expert submissions that hepatocellular carcinoma is more common in men and people of some ethnicities. The committee did not consider this to be an equality issue because its recommendations apply to everyone with advanced, unresectable hepatocellular carcinoma.
# Innovation
## There is no evidence of any additional benefits with lenvatinib
The company considered lenvatinib to be innovative because there is an unmet need for treatment options other than sorafenib that delay disease progression and improve survival without decreasing health-related quality of life. The clinical experts acknowledged that lenvatinib is the only alternative first-line treatment option for advanced hepatocellular carcinoma in over 10 years, and they were not aware of any benefits that were not already captured in the model. The committee concluded that lenvatinib would be beneficial for patients (see section 3.2) but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
|
{'Recommendations': 'Lenvatinib is recommended as an option for untreated, advanced, unresectable hepatocellular carcinoma in adults, only if:\n\nthey have Child–Pugh grade\xa0A\xa0liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01 and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lenvatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nAdvanced unresectable hepatocellular carcinoma is treated with sorafenib, but some people cannot tolerate it because of side effects.\n\nClinical trial evidence shows that lenvatinib slows disease progression and causes more tumours to shrink than sorafenib. The evidence also shows that people having lenvatinib live for about as long as those having sorafenib. Lenvatinib has different side effects to sorafenib and this would benefit some people.\n\nUsing the most plausible assumptions and including the commercial arrangement, the cost-effectiveness estimates for lenvatinib compared with sorafenib are within the range NICE normally considers acceptable. Therefore, lenvatinib is recommended for untreated, advanced, unresectable hepatocellular carcinoma in adults with Child–Pugh grade\xa0A\xa0liver impairment and an ECOG performance status of 0\xa0or\xa01.', 'Information about lenvatinib': "# Marketing authorisation indication\n\nLenvatinib (Lenvima, Eisai) is indicated as monotherapy for 'the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe daily dose of lenvatinib in the summary of product characteristics is 8\xa0mg (2×4\xa0mg capsules) given orally for patients who weigh less than 60\xa0kg, and 12\xa0mg (3×4\xa0mg capsules) orally for patients who weigh 60\xa0kg or over (based on company submission). The summary of product characteristics advises that dose adjustments are not needed on the basis of hepatic function in people with Child–Pugh grade\xa0A\xa0liver impairment. It advises that the available data are not sufficient to make a dosing recommendation for people with Child–Pugh grade\xa0B\xa0liver impairment; safety should be closely monitored in these patients. Because lenvatinib has not been studied in patients with Child–Pugh grade\xa0C\xa0liver impairment, the summary of product characteristics does not advise use in these patients.\n\n# Price\n\n£1,437 for 30×4\xa0mg capsules (excluding VAT; British national formulary [BNF] online [accessed May 2018]). The company has a commercial agreement (patient access scheme). This makes lenvatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Unmet need\n\n## People with advanced hepatocellular carcinoma would welcome an alternative treatment option\n\nAdvanced unresectable hepatocellular carcinoma is often diagnosed late in life and has a poor prognosis. It is a debilitating condition with many distressing symptoms, including pain, digestive problems and weight loss. The patient experts noted that people with advanced unresectable hepatocellular carcinoma consider improving their quality of life to be particularly important. Sorafenib is currently the only licensed option for people who have not already had systemic treatment. The committee understood that an alternative first-line treatment option would be valuable to patients with the condition.\n\n# Treatment pathway\n\n## Lenvatinib may offer benefits over current treatment options\n\nThe clinical experts explained that there is a low response rate with sorafenib and around 25% of patients stop treatment because they cannot tolerate it. They added that hand-foot syndrome is more common with sorafenib, which can be very unpleasant for patients. The committee was aware that lenvatinib also has common side effects, such as hypertension. It considered that lenvatinib and sorafenib have different side-effect profiles, and that tolerability of each drug would depend on the patient. A patient expert noted that lenvatinib offers a longer time to disease progression compared with sorafenib, although there is no evidence showing a difference in overall survival. The clinical experts indicated that they may use lenvatinib instead of sorafenib based on individual patient characteristics, but also because of the improvements it offers in side-effect profile, time to disease progression and response rates. The committee agreed that lenvatinib may offer improved benefits for people with advanced unresectable hepatocellular carcinoma who have not had systemic treatment.\n\n# Population\n\n## The company positioned lenvatinib in line with the REFLECT trial\n\nThe company positioned lenvatinib in line with the REFLECT trial (that is, for adults with advanced unresectable hepatocellular carcinoma who have not already had systemic treatment and who have Child–Pugh grade\xa0A\xa0liver impairment). This was narrower than both the marketing authorisation and the final scope issued by NICE, but was in line with the REFLECT trial population and previous NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma. The clinical experts explained that treatment may not be clinically effective in people with more impaired liver function (for example, people with Child–Pugh grade\xa0B\xa0liver impairment). The committee accepted the company's positioning of lenvatinib for adults with advanced unresectable hepatocellular carcinoma who have not already had systemic treatment and who have Child–Pugh grade\xa0A\xa0liver impairment.\n\n# Comparator\n\n## Sorafenib is the most relevant comparator\n\nThe company did not consider best supportive care to be an appropriate comparator because it is only used in clinical practice if systemic treatment is not appropriate. The company's clinical expert estimated that less than 5% of patients have best supportive care; most people instead have sorafenib. The clinical experts stated that most people would be eligible for systemic therapy and would have sorafenib. The committee concluded that sorafenib was the most relevant comparator.\n\n# Clinical evidence\n\n## REFLECT included a clinically appropriate population with Child–Pugh grade\xa0A\xa0liver impairment and ECOG performance status of 0\xa0or\xa01\n\nThe clinical evidence came from a phase\xa0III, open-label randomised controlled trial (REFLECT) comparing lenvatinib with sorafenib for untreated, advanced hepatocellular carcinoma in 954 adults with Child–Pugh grade\xa0A\xa0liver impairment and Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01. The trial excluded people with Child–Pugh grade\xa0B\xa0liver impairment or worse and people with an ECOG performance status of 2 or more, and the committee understood the results may not be generalisable to these groups. The clinical experts explained that lenvatinib may not be clinically effective in these groups, and that these criteria are also used in clinical practice to decide the most appropriate treatment options. The Cancer Drugs Fund clinical lead confirmed that the NHS England treatment criteria would reflect these eligibility criteria. The committee concluded that people with both Child–Pugh grade\xa0A\xa0liver impairment and ECOG performance status 0\xa0to 1 was the most clinically appropriate population, and agreed to consider the trial inclusion criteria when making its recommendations.\n\n## Baseline characteristics were imbalanced but the clinical-effectiveness results are relevant to NHS practice\n\nThe company highlighted that in REFLECT, more people in the lenvatinib group had alpha-fetoprotein levels of 200\xa0ng/ml or above compared with the sorafenib group, and there were differences in the pre-existing liver conditions associated with hepatocellular carcinoma (hepatitis\xa0C, hepatitis\xa0B or alcohol) across the 2\xa0groups. The company explained that these variables were not included as randomisation stratification factors. It considered that these imbalances in baseline characteristics may affect the treatment benefit seen with lenvatinib because they were potentially important prognostic factors. However, the clinical experts explained that a similar treatment benefit was likely regardless of pre-existing liver conditions. The ERG's clinical expert agreed that although alpha-fetoprotein level was a prognostic factor, they did not consider the cut-off value of 200\xa0ng/ml to be clinically relevant. The committee understood that the company had made adjustments to account for the imbalances in baseline characteristics (see section\xa03.12) and that the difference in alpha-fetoprotein levels may not be clinically meaningful. The committee concluded that although there may be some imbalances in the baseline characteristics, the REFLECT trial was relevant to clinical practice in the NHS.\n\n## It is appropriate to use clinical data from the full trial population\n\nAround two thirds of the trial population were from the Asia-Pacific region and the rest were from Western countries including the UK. The ERG noted important differences between the Western subgroup and the full trial population (the Western subgroup was heavier, had more heart disease, less underlying cirrhosis, less hepatitis\xa0B and more pre-existing hepatitis\xa0C or alcohol-related conditions), but explained that these differences may not have changed the relative treatment effect. The ERG also noted that baseline characteristics in the full population were more balanced than those in the Western subgroup, and the clinical experts agreed that the overall population reflected clinical practice in England. The committee was aware that the imbalance in post-progression treatment was larger in the Western subgroup compared with the full trial population. It understood that after adjusting for post-progression treatment (see section\xa03.13), the overall survival results were similar for both the Western subgroup and the full trial population. The committee agreed that there was no sufficient justification for using results from the Western subgroup instead of the full trial population because it was not more clinically relevant and had a relatively small sample size. It agreed that the baseline characteristics for the full trial population were generally in line with clinical practice in England, and it preferred to use these results.\n\n## The company's updated approach to censoring is appropriate\n\nIn the company's original submission, progression-free survival results were censored if there was no disease progression when treatment is stopped (because not all patients were followed up until the end of the trial). The ERG explained that this could be considered to be informative censoring (that is, reasons for drop-out may potentially be related to disease progression or survival time) and that it may lead to inaccurate conclusions about the size of the treatment difference between lenvatinib and sorafenib. Based on the clinical evidence presented, the ERG explained that the company's method of censoring would likely favour lenvatinib because more people stopped lenvatinib either through choice or because of adverse effects. More events may therefore be missed because of censoring in the lenvatinib group. In response to consultation, the company updated its censoring approach to include all events in the analysis and only censored if there were missing assessments or no disease progression at the last assessment. Progression-free survival was lower with the updated censoring approach, but the results still showed a statistically significant improvement for lenvatinib compared with sorafenib. The committee concluded that the company's updated approach to censoring (that is, including all events in the analysis and only censoring missing assessments or patients with no disease progression at last assessment) was appropriate.\n\n## More patients had post-progression treatment in the sorafenib arm than in the lenvatinib arm and the overall survival results may favour sorafenib\n\nIn REFLECT, treatment after disease progression was allowed in both the lenvatinib and sorafenib arms. In the lenvatinib arm, patients could switch to sorafenib but were not eligible for trials using second-line treatment. In the sorafenib arm, patients could continue sorafenib and were eligible for trials using second-line treatments such as regorafenib. Regorafenib is not used in England because it is not currently recommended by NICE (see the NICE technology appraisal guidance on regorafenib for previously treated advanced hepatocellular carcinoma). The committee understood that 51% of patients in the sorafenib group had post-progression treatment compared with only 43% in the lenvatinib group. It noted that longer overall survival may be expected for people having post-progression treatment, so the overall survival results may favour patients randomised to sorafenib. The committee concluded that more patients having post-progression treatment in the sorafenib arm may affect the estimates of treatment effect for overall survival.\n\n## Overall survival with lenvatinib is non-inferior compared with sorafenib\n\nThe primary end point of REFLECT was overall survival and the study was powered to demonstrate non-inferiority. There was no statistically significant difference in overall survival (see table 1, below). However, the results for overall survival met the pre-specified criteria for non-inferiority (that is, the upper limit of the 95% confidence interval was less than 1.08). There was also a statistically significant improvement in median investigator-assessed progression-free survival with lenvatinib (7.4\xa0months) compared with sorafenib (3.7\xa0months). Similar results were reported for independently assessed progression-free survival using standard response evaluation criteria in solid tumours (RECIST) to measure disease progression, and a modified version of RECIST that evaluates change more accurately in hepatocellular carcinoma. The committee understood that the proportional hazards assumption (that is, there is a constant treatment effect over time) was not met for the overall and progression-free survival results, so these should be interpreted with caution. The committee noted the consistency in the progression-free survival results using the 2 different censoring rules (see section\xa03.8), and agreed there was robust evidence of a progression-free survival benefit, although there is some uncertainty around the size of this benefit (see section\xa03.15). Lenvatinib also improved response rates compared with sorafenib. The committee concluded that overall survival with lenvatinib was non-inferior compared with sorafenib.\n\nOutcome\n\nLenvatinib – median (range)\n\nSorafenib – median (range)\n\nResult – (95% confidence interval)\n\nUnadjusted overall survival\n\n(12.1 to 14.9)\n\n(10.4 to 13.9)\n\nHazard ratio 0.92 (0.79 to 1.06)\n\nOverall survival adjusted for post-progression treatment\n\n–\n\n–\n\nConfidential and cannot be reported here\n\nInvestigator-assessed progression-free survival using modified response evaluation criteria in solid tumours (RECIST)\n\n(6.9 to 8.8)\n\n(3.6 to 4.6)\n\nHazard ratio 0.66 (0.57 to 0.77)\n\nInvestigator-assessed progression-free survival using modified RECIST and committee's preferred censoring rules\n\n–\n\n–\n\nConfidential and cannot be reported here\n\nIndependently assessed progression-free survival using modified RECIST\n\n(5.6 to 7.5)\n\n(3.6 to 3.7)\n\nHazard ratio 0.64 (0.55 to 0.75)\n\nIndependently assessed progression-free survival using standard RECIST (1.1)\n\n(5.6 to 7.5)\n\n(3.6 to 3.9)\n\nHazard ratio 0.65 (0.56 to 0.77)\n\nObjective response rate\n\n%\n\n%\n\nOdds ratio 3.13 (2.15 to 4.56)\n\n# The company's model\n\n## The model structure is appropriate for decision-making\n\nThe company used a partitioned survival model with 3 health states (progression free, progressed disease and death). The committee noted that although progression-free and overall survival data were relatively mature in the REFLECT trial, extrapolations were needed for both to model effects over a lifetime horizon. The ERG considered the model structure to be appropriate but identified an inconsistency in the half-cycle correction because it was not fully applied to all costs and quality-adjusted life years (QALYs). The ERG corrected this in its own preferred base case. At clarification, the company did not consider this to be an error and so did not correct it. Ultimately these corrections had little effect on the cost-effectiveness estimates, and the committee concluded that the model structure was appropriate for decision-making.\n\n# Survival estimates in the model\n\n## The company's adjustment for baseline characteristics using the corrected group prognosis method is acceptable\n\nIn its original submission, the company adjusted the treatment estimates used in the model to account for imbalances in baseline characteristics of patients in REFLECT. The company fitted multivariable parametric survival models to the progression-free and overall survival data and adjusted for covariates using the mean of covariates approach. The committee was aware that the company's model contained categorical variables (such as Child–Pugh grade) and that interpreting these variables using the mean of covariates approach is problematic. The committee considered the corrected group prognosis method to be more appropriate for adjusting for categorical variables. In response to consultation, the company revised its analyses to use the corrected group prognosis method to adjust for baseline imbalances. However, the committee considered that there was still some uncertainty in the revised analyses; proportional hazards were not tested for all potential covariates, and choice of adjustment covariates was based on the pre-consultation overall survival model. However, on balance, the committee concluded that the company's adjustment for baseline characteristics using the corrected group prognosis method was acceptable.\n\n## It is appropriate to include post-progression benefit in line with REFLECT\n\nThe company's base case included the clinical benefit of post-progression treatment. The committee recalled that in REFLECT, fewer people in the lenvatinib arm had post-progression treatment compared with the sorafenib arm (see section\xa03.9). The ERG explained that this may bias overall survival estimates in favour of sorafenib, because people who have post-progression treatment may have longer overall survival. The committee understood that the company used a simple binary adjustment for post-progression treatment (patients either had or did not have post-progression treatment). The committee considered that there was some uncertainty in the company's adjustment; there were missing data about the types of post-progression treatments people had, and the company did not explore alternative statistical adjustments for post-progression treatment (for example, by including post-progression treatment as a time-varying covariate). However, mindful of the risk of bias from the post-progression treatment distribution in the trial, the committee concluded that it could accept the inclusion of post-progression treatment benefit in line with REFLECT.\n\n## A log-logistic distribution is appropriate for extrapolating overall survival\n\nThe company used a log-logistic model in its base case to extrapolate overall survival for both lenvatinib and sorafenib. The committee understood that this model provided a good fit to data from both treatment groups and concluded that a log-logistic distribution was appropriate for extrapolating overall survival for both lenvatinib and sorafenib.\n\n## Gamma extrapolation of the progression-free survival data predicts lower survival than log-normal extrapolation but both are reasonable\n\nIn its original base case, the company used a log-normal distribution to extrapolate progression-free survival for both lenvatinib and sorafenib. At the first meeting, the committee considered that the gamma distribution was a better fit to the treatment groups. However, the committee was aware that both extrapolations were based on Kaplan–Meier data that had not been adjusted or censored in line with its preferences. In response to consultation, the company presented updated progression-free survival analyses based on the committee's preferred censoring approach (see section 3.8) and the corrected group prognosis method of adjusting for baseline characteristics (see section 3.12). In its updated base case, the company extrapolated progression-free survival using a gamma distribution and presented a log-normal distribution as an exploratory analysis. However, the company did not provide statistical indications of goodness of fit for the updated models. The committee visually assessed the model fit of both extrapolations compared with the updated Kaplan–Meier data and noted that both distributions appeared to be a reasonable fit to the adjusted trial data. However, it considered that evaluating the models without a statistical assessment of fit introduced some uncertainty about the choice of extrapolation. The committee concluded that both the gamma and log-normal extrapolations of progression-free survival were reasonable.\n\n# Costs in the model\n\n## Including drug wastage does not have a large effect on total costs\n\nThe company did not include drug wastage costs in its base-case analysis. The committee understood that in a previous NICE technology appraisal on sorafenib for treating advanced hepatocellular carcinoma, it was considered appropriate to include drug wastage for up to 7\xa0days. However, in a more recent NICE technology appraisal on regorafenib for previously treated advanced hepatocellular carcinoma, the committee considered 7\xa0days to be arbitrary and associated with some uncertainty. The ERG did a scenario analysis using drug costs based on the planned number of capsules and tablets needed each day. This led to only a modest reduction in total costs. The committee concluded that drug wastage did not have a large effect on the total costs.\n\n## It is acceptable to include the costs of post-progression treatment in line with REFLECT\n\nIn its original submission, the company's base case only included the costs of sorafenib and regorafenib after disease progression because these are the only licensed treatments for advanced hepatocellular carcinoma. The committee was aware that other treatments and procedures were also used after disease progression in REFLECT, but these costs had not been included in the company's base case. In response to consultation, the company included in its model the costs of all post-progression treatments and procedures used in REFLECT. The committee considered that because the model included the benefit of post-progression treatments, it was also appropriate to include the costs. Because of this, the committee concluded that the company's updated modelling of post-progression treatment costs was acceptable.\n\n# Utility values in the economic model\n\n## Utility values in the progressed state are acceptable\n\nIn its base case, the company used utility values from the full population in REFLECT for both lenvatinib and sorafenib because there was only a small difference in mean utility values. The company used a value of 0.745 in the progression-free state and 0.678 in the progressed state, although the company's clinical experts noted that the utility value in the progressed state was higher than would be expected given that advanced hepatocellular carcinoma can severely affect functioning and wellbeing. The committee noted that the final measurement in the post-progression stage was 30\xa0days after the final dose of lenvatinib or sorafenib so these measurements may not include the full effect of disease progression on health-related quality of life. The ERG did a scenario analysis using a utility value of 0.50\xa0in the progressed disease state. The committee observed that this led to only a small increase in the cost-effectiveness estimates, and concluded that the utility values used in the company's analysis were acceptable.\n\n# Cost-effectiveness estimate\n\n## The company's updated base-case ICER is above the range normally considered to be an acceptable use of NHS resources\n\nThe committee considered the incremental cost-effectiveness ratios (ICERs) from the company's updated base case after consultation. This was recalculated by the ERG to include the confidential commercial arrangements for lenvatinib and sorafenib. The company's model assumptions included:\n\na larger discount as part of the patient access scheme\n\nupdated censoring rules for progression-free survival that include all events in the analysis and only censor missing assessments or patients with no disease progression at last assessment\n\nadjustment for baseline characteristic imbalances using the corrected group prognosis method\n\nprogression-free survival extrapolated using the gamma distribution\n\npost-progression treatment costs and benefits modelled in line with REFLECT.The committee concluded that the company's base-case ICER for lenvatinib compared with sorafenib was higher than the range normally considered to be an acceptable use of NHS resources.\n\n## The most plausible ICER for lenvatinib compared with sorafenib is within the range normally considered to be an acceptable use of NHS resources\n\nThe committee considered that the company's updated model had captured its preferred assumptions. However, it was aware that there was still some uncertainty in the model because there was no statistical goodness-of-fit assessment of the progression-free survival extrapolation, and no exploration of alternative statistical adjustments for post-progression treatment. The committee recalled that the log-normal extrapolation gave substantially lower ICER estimates than the gamma extrapolation. It also recognised that although it had accepted the company's modelling of post-progression treatment costs and benefits, there were still flaws with the company's method of adjustment, and uncertainty from missing data on post-progression treatment (see\xa0section 3.13). Having considered all these factors, the committee concluded that the most plausible ICER for lenvatinib compared with sorafenib (including the confidential commercial arrangements for both drugs) is within the range normally considered to be an acceptable use of NHS resources (the exact ICER is confidential and cannot be reported here). The committee concluded to recommend lenvatinib for untreated, advanced, unresectable hepatocellular carcinoma in adults with Child–Pugh grade\xa0A\xa0liver impairment and an ECOG performance status of 0\xa0or\xa01.\n\n# End of life\n\n## End-of-life considerations are not relevant because lenvatinib is recommended for routine commissioning\n\nIn the first committee meeting, the committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It concluded that lenvatinib met the short life expectancy criterion, but that it was uncertain whether lenvatinib met the extension to life criterion. In the second committee meeting, the committee considered that the end-of-life considerations were no longer relevant to the appraisal decision because the most plausible ICER was within the range normally considered to be an acceptable use of NHS resources.\n\n# Equality\n\n## There are no equality issues relevant to the recommendations\n\nThe committee considered whether its recommendations were associated with any potential issues related to equality. The committee noted comments from patient and clinical expert submissions that hepatocellular carcinoma is more common in men and people of some ethnicities. The committee did not consider this to be an equality issue because its recommendations apply to everyone with advanced, unresectable hepatocellular carcinoma.\n\n# Innovation\n\n## There is no evidence of any additional benefits with lenvatinib\n\nThe company considered lenvatinib to be innovative because there is an unmet need for treatment options other than sorafenib that delay disease progression and improve survival without decreasing health-related quality of life. The clinical experts acknowledged that lenvatinib is the only alternative first-line treatment option for advanced hepatocellular carcinoma in over 10\xa0years, and they were not aware of any benefits that were not already captured in the model. The committee concluded that lenvatinib would be beneficial for patients (see section 3.2) but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs."}
|
https://www.nice.org.uk/guidance/ta551
|
Evidence-based recommendations on lenvatinib (Lenvima) for untreated advanced hepatocellular carcinoma in adults.
|
8d3aa6f07591ed7bd51a8bec5b7545579604815b
|
nice
|
Liposomal cytarabine–daunorubicin for untreated acute myeloid leukaemia
|
Liposomal cytarabine–daunorubicin for untreated acute myeloid leukaemia
Evidence-based recommendations on liposomal cytarabine–daunorubicin (Vyxeos) for untreated acute myeloid leukaemia in adults.
# Recommendations
Liposomal cytarabine–daunorubicin is recommended, within its marketing authorisation, as an option for untreated therapy-related acute myeloid leukaemia or acute myeloid leukaemia with myelodysplasia-related changes in adults. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes is chemotherapy. Clinical trial evidence shows that people having liposomal cytarabine–daunorubicin live longer than people having standard chemotherapy.
Liposomal cytarabine–daunorubicin meets NICE's criteria for being a life-extending treatment at the end of life. Using the most plausible assumptions and the price discount, the cost-effectiveness estimates of liposomal cytarabine–daunorubicin compared with standard chemotherapy are within the range that NICE normally considers a cost-effective use of NHS resources for end-of-life treatments. So liposomal cytarabine–daunorubicin is recommended.# Information about liposomal cytarabine–daunorubicin
# Marketing authorisation indication
Liposomal cytarabine–daunorubicin (Vyxeos, Jazz Pharmaceuticals) is indicated for 'the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t‑AML) or AML with myelodysplasia-related changes (AML‑MRC)'.
# Dosage in the marketing authorisation
The company's submission states that liposomal cytarabine–daunorubicin is given by intravenous infusion over 90 minutes. The dose is based on the patient's body surface area, according to the following schedule:
For induction of remission: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3 and 5 for the first course and on days 1 and 3 for subsequent courses, if needed.
For consolidation (5 to 8 weeks after the start of the last induction): daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 on days 1 and 3. A subsequent course of consolidation may be given when there is no disease progression or unacceptable toxicity.
# Price
The company stated that the list price of liposomal cytarabine–daunorubicin is £4,581 per 50-ml vial. The company has a commercial arrangement. This makes liposomal cytarabine–daunorubicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Jazz Pharmaceuticals and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Potential new treatment option
## People with acute myeloid leukaemia that is therapy-related or with myelodysplasia-related changes would welcome a new treatment option
Therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes are high-risk types of acute myeloid leukaemia with poor survival outcomes. Patient experts described that the most common symptoms include fatigue, feeling weak or breathless, loss of memory and concentration, bruising and bleeding, and nausea or vomiting. They also highlighted that the diagnosis has an emotional and financial effect on patients, and their families and carers. Both the patient and clinical experts explained that patients would welcome a treatment that helps them be well enough to have a stem cell transplant, which is potentially a curative treatment. The committee concluded that people with therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes would welcome a new treatment that could improve survival, quality of life, and the chance of getting a stem cell transplant.
# Clinical management
## Current treatment is chemotherapy
Current treatment for therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes is intensive chemotherapy, for people who are well enough to have it. This usually involves a first induction course, and 2 or 3 further courses of standard daunorubicin and cytarabine to treat any remaining cancer cells (consolidation therapy). In the NHS, the first induction course is usually given as 3 days of daunorubicin and 10 days of cytarabine (known as DA 3+10). The clinical experts highlighted that some younger patients may have FLAG‑Ida (fludarabine, cytarabine, granulocyte-colony stimulating factor and idarubicin) chemotherapy instead. The committee understood that liposomal cytarabine–daunorubicin is a liposomal formulation of standard cytarabine and daunorubicin chemotherapy. This could be used as an alternative in clinical practice. The committee was aware that diagnosing some types of high-risk acute myeloid leukaemia, particularly de novo acute myeloid leukaemia with myelodysplastic syndrome-associated karyotypic changes, involves genetic testing. In England, genetic test results may not be available for 7 to 10 days. The clinical experts advised that it is becoming more common for clinicians to wait for these test results before starting treatment. A small number of patients with more aggressive disease would need to start treatment sooner. The committee agreed that no change in practice would be needed for most people who would be eligible for liposomal cytarabine–daunorubicin, if it were to recommend the treatment. The committee concluded that standard cytarabine and daunorubicin chemotherapy is the relevant comparator for this appraisal.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS clinical practice in England
The evidence for liposomal cytarabine–daunorubicin came from Study 301. This was a phase 3, multicentre, open-label, randomised trial. It included 309 adults aged 60 to 75 years with high-risk acute myeloid leukaemia. High-risk acute myeloid leukaemia was defined as therapy-related acute myeloid leukaemia, acute myeloid leukaemia with myelodysplastic syndrome, de novo acute myeloid leukaemia with myelodysplastic syndrome-associated karyotypic changes and chronic myelomonocytic leukaemia. The trial compared liposomal cytarabine–daunorubicin (n=153) with standard cytarabine and daunorubicin chemotherapy (n=156), in a 3+7 schedule (3 days of cytarabine then 7 days of daunorubicin). The clinical experts confirmed that it was reasonable to assume equivalence between the 3+7 schedule in the trial and the 3+10 schedule normally used in the UK. They also confirmed that, although the trial was done in the US and Canada, the baseline characteristics of people in the trial were representative of people in the UK who would be eligible for liposomal cytarabine–daunorubicin. The clinical experts explained that about a quarter of patients who would be eligible for treatment in England would be under 60 years. There was no biological reason to expect treatment benefit to be any different to that seen in people aged 65 to 70 years in the trial. The committee concluded that the clinical-effectiveness evidence from Study 301 was relevant to clinical practice in England.
## Liposomal cytarabine–daunorubicin improves overall survival compared with standard cytarabine and daunorubicin
The primary outcome measure in Study 301 was overall survival. Treatment with liposomal cytarabine–daunorubicin increased median overall survival compared with standard cytarabine and daunorubicin, from 5.95 months to 9.56 months (hazard ratio 0.69; 95% confidence interval 0.52 to 0.90, p=0.005). The company also presented results from a post-hoc analysis of overall survival from the time of stem cell transplant. Fifty-two people in the liposomal cytarabine–daunorubicin group and 39 people in the standard cytarabine and daunorubicin group had a stem cell transplant and were included in this analysis. Median overall survival was 10.25 months in the standard cytarabine and daunorubicin group and was not reached in the liposomal cytarabine–daunorubicin group (HR 0.46; 95% CI 0.24 to 0.89, p=0.0046). The committee noted that there was a plateau in the Kaplan–Meier graphs for the liposomal cytarabine–daunorubicin group at around 6 months after transplant, but not for the standard cytarabine and daunorubicin group. The clinical experts stated that response to transplant may differ depending on the person's health when they had the transplant, but that they would expect to see a plateau from the same time point in both groups. The committee noted that the post-hoc analysis included a small number of patients. It also noted that, in the trial, the decision to transplant was not randomised and therefore there could be bias in the results of the post-hoc analysis. The committee also noted that the results presented by the company were from a data cut in December 2015, 3 years after the first patient was randomised, although the company stated that trial follow-up was continuing for 5 years after randomisation. Also, after 1 year, a substantial number of patients were censored in the analysis, which the committee agreed made the long-term results more uncertain. In response to consultation, the company presented updated Kaplan–Meier graphs, using safety data up to August 2018. It presented graphs both for overall survival in the full population and from the time of stem cell transplant. The committee agreed that the updated graphs were more reliable because there was less censoring and there was a plateau in both treatment groups. The company suggested that the difference between groups in response to transplant was because people in the liposomal cytarabine–daunorubicin group were in better health before transplant or had less residual leukaemia going into transplant, or both. However, minimal residual disease status before transplant was not collected in the trial. The committee concluded that there was some uncertainty about how much survival was improved after stem cell transplant, but that liposomal cytarabine–daunorubicin improved overall survival in the whole population compared with standard cytarabine and daunorubicin.
# Adverse effects
## Liposomal cytarabine–daunorubicin is well tolerated
The committee noted that the adverse effects reported in Study 301 were broadly comparable between the 2 groups. The patient expert noted that liposomal cytarabine–daunorubicin had been more tolerable for them than other treatments. The clinical experts suggested that people in the liposomal cytarabine–daunorubicin group of Study 301 may have taken the active treatment for longer, leading to similar rates of adverse effects in the 2 groups, rather than lower rates in the liposomal cytarabine–daunorubicin group as they may have expected. The committee concluded that liposomal cytarabine–daunorubicin was generally well tolerated.
# The company's economic model
## The model is appropriate for decision making but there is uncertainty in extrapolating overall survival after transplant and the cure fraction used
The company presented an economic model in 2 parts: an initial decision tree to determine if patients were in remission after induction therapy, and whether they had a stem cell transplant or not, and then subsequent partitioned survival models. The model had a 30 year time horizon. This was assumed to be a lifetime time horizon because patients in the model were 60 to 75 years, as in Study 301. To extrapolate beyond the trial period, the company modelled parametric curves separately by treatment group. Overall survival and relapse-free survival outcomes were modelled separately for 3 groups based on data from Study 301: people in remission who had a stem cell transplant, people in remission who did not have a transplant and people who were not in remission. For people in the liposomal cytarabine–daunorubicin group who were in remission and had a stem cell transplant, the company chose a Gompertz distribution to extrapolate overall survival. This was based on clinical plausibility and because it was the best fit to the trial data. The committee considered that, although the Gompertz distribution produced a plateau, which would be expected after transplant, the plateau seemed overly optimistic. The committee agreed that the Study 301 data were not mature enough to justify this extrapolation, particularly with the amount of censoring (see section 3.4). At the first committee meeting, the committee noted that the modelled curve for the comparator group did not reach a plateau. The company stated that, after around 2 years, general population mortality rates would be applied for most people in the liposomal cytarabine–daunorubicin group in its base-case model because these rates were used when the modelled mortality rates would otherwise be lower. The ERG explored several parametric curves for extrapolating overall survival after transplant for the liposomal cytarabine–daunorubicin group. It noted that the choice of curve had a large effect on the predicted benefit and therefore the cost-effectiveness results. So, the ERG used a model averaging approach to address the uncertainty. The committee considered that this approach did not address the clinical implausibility of the extrapolation. The committee stated that it would prefer to see a cure model for the whole population, whether or not they had a stem cell transplant. The committee agreed that a plateau, or 'cure', should be accounted for in the standard cytarabine and daunorubicin survival extrapolation (see section 3.4). It also agreed that it would prefer to see overall survival analysis based on a more mature data cut (see section 3.4) to make the long-term extrapolation more reliable. In response to consultation, the company presented statistical cure model extrapolations for the whole population. However, the company did not use these models in the cost-effectiveness results because it stated that the cure model for the whole liposomal cytarabine–daunorubicin group overestimated survival compared with the Kaplan–Meier data and gave overly favourable cost-effectiveness results. Instead, the company used cure models for overall survival after stem cell transplant, which it stated matched the updated Kaplan–Meier data well. The cure models were based on the original trial data (December 2015 data cut) because the company only had a limited dataset of updated individual patient level data, which did not include event-free status. The committee agreed that it would have preferred to have seen the whole population modelled together. The company manually set a cure fraction of 20% in the standard cytarabine and daunorubicin group. The ERG noted that this figure seemed to have been taken from a visual inspection of the Kaplan–Meier curve and that a 25% cure fraction could also be considered as a plausible upper limit. The company presented a scenario analysis that included a 25% cure fraction in the standard cytarabine and daunorubicin group. This reduced the cost effectiveness of liposomal cytarabine–daunorubicin compared with standard cytarabine and daunorubicin. The committee concluded that the model was appropriate for decision making. However, it agreed that there was still uncertainty in the difference in overall survival between the 2 treatment groups after stem cell transplant and in the cure fraction assumed for the standard cytarabine and daunorubicin group.
## Event-free survival analysis for patients who had a complete response is unreliable because of small patient numbers
The company and ERG agreed that the analysis used to model event-free survival after transplant for patients who had a complete response in the model was uncertain because of small patient numbers. The ERG also suggested that it lacked face validity. This was because there was little difference between the 2 treatment groups, unlike for overall survival after transplant. Therefore the ERG excluded these data from the model and used the overall survival analysis to inform a 2‑state model. In this model, patients were either in remission or dead. This change increased the cost effectiveness of liposomal cytarabine–daunorubicin. In response to consultation, the company adopted the ERG's approach to modelling event-free survival. The committee would have preferred the whole population to be modelled together (whether or not they had a stem cell transplant) but concluded that the company's approach was appropriate for decision making.
# Mortality after transplant in the economic model
## Mortality rates are higher after stem cell transplant than in the general population and should be included in the model
In its base-case economic model, the company applied general population mortality rates when the modelled mortality rates would otherwise have been lower. In a scenario analysis, the company increased mortality rates after stem cell transplant compared with the general population mortality rates by applying a standardised mortality ratio of 2.34. This reduced the cost effectiveness of liposomal cytarabine–daunorubicin. The ERG considered that this scenario had face validity and therefore included it in its preferred analysis. The clinical experts stated that it was generally accepted that survival would be shorter for people who had a stem cell transplant than for the general population. The committee concluded that it was appropriate to increase the mortality rate after stem cell transplant in the model to higher than that of the general population.
# Utility values in the economic model
## The utility values do not have a big effect on the cost-effectiveness results
Because health-related quality-of-life data were not collected in Study 301, the company used a time-trade-off study to derive utility values for the economic model. The treatment-related disutilities included in the model were based on descriptions of the side effects of treatment provided by clinicians for the time-trade-off study. These described a more favourable side-effect profile for liposomal cytarabine–daunorubicin than for standard cytarabine and daunorubicin. Therefore a smaller disutility was applied to the liposomal cytarabine–daunorubicin group than the standard cytarabine and daunorubicin group. The ERG highlighted that this did not reflect the data from Study 301. Therefore it estimated the mean utility value for each treatment phase and applied this to both treatment groups. The ERG also noted that the utility value used by the company for the remission after transplant health state was higher than usually reported for the general population. The company also did a scenario analysis using utility values from a study by Hensen et al. (2017). In this scenario, the utility value for the remission after transplant health state was 0.75, and the ERG used this value in its preferred analysis. The ERG also adjusted the utility values for age. The committee noted that these changes did not have a big effect on the cost-effectiveness results. It concluded that it was plausible to assume the disutilities were the same in both treatment groups, to use a utility value of 0.75 for the remission health state and to adjust the utility values for age.
# Costs and resource use in the economic model
## Costs and resource use in the economic model do not have a big effect on the cost-effectiveness results
The company calculated treatment doses and vial use including wastage, based on a mean body surface area of 1.79 m2, calculated from a UK study of adults with cancer (Sacco et al. 2010). The ERG used a different method to calculate vial use. It accounted for the distribution of body surface area in the population, and also calculated a mean body surface area of 1.83 m2 by applying the gender weighting from Study 301 to the data from the Sacco study. The ERG considered that hospital length of stay was overestimated in the model compared with that seen in Study 301. Therefore in its preferred analysis, it reduced the number of hospital days in the consolidation period. The ERG used a lower cost of stem cell transplant than the company, based on using the costs of transplants from sibling donors instead of from unrelated adult donors. It also increased the follow-up cost to reflect a 2‑year follow-up, instead of 6 months. The clinical experts stated that, although sibling donors had been more common, it was now more likely that unrelated adult stem cells would be used for transplants. The committee noted that these changes to costs and resource use in the model had little effect on the cost-effectiveness results. It concluded that it was reasonable to use the ERG's method of calculating vial use, for the length of hospital stay in the model to match that in the trial and to include transplant follow-up costs for 2 years. However, it agreed that stem cells for transplant would likely come from unrelated matched donors.
# Cost-effectiveness results
## The most plausible incremental cost-effectiveness ratio compared with standard cytarabine and daunorubicin is lower than £50,000 per quality-adjusted life year gained
The company updated its economic model after consultation. This included the committee's preferred assumptions, specifically:
correcting some errors identified by the ERG
basing outcomes after transplant only on overall survival (see section 3.7)
adjusting mortality rates after transplant (see section 3.8)
using some alternative utility values (see section 3.9)
using a different method to calculate vial use (see section 3.10)
reducing the number of hospital days in the consolidation period (see section 3.10).The company used cure models after stem cell transplant (see section 3.6) and also increased the discount in the commercial arrangement. This resulted in an incremental cost-effectiveness ratio (ICER) for liposomal cytarabine–daunorubicin of £45,055 per quality-adjusted life year (QALY) gained. When the company used a 25% cure fraction for the standard cytarabine and daunorubicin group (see section 3.6), the ICER increased to £48,127 per QALY gained. When the ERG reproduced the analyses to include the confidential commercial arrangement discount for azacitidine (included in the model as a subsequent treatment), both ICERs were below £50,000 per QALY gained. The committee concluded that the most plausible ICER was lower than £50,000 per QALY gained.
# Innovation
## The benefits of liposomal cytarabine–daunorubicin are captured in the cost-effectiveness analysis
The company considered that liposomal cytarabine–daunorubicin was an innovative treatment because of its formulation. The drug accumulates in the bone marrow and is released inside the cells. The company also highlighted that infusion time is reduced and that people can have it as outpatients. It also noted that liposomal cytarabine–daunorubicin is the only new treatment in recent years to show a survival benefit for people with high-risk acute myeloid leukaemia. Patient and professional groups highlighted that liposomal cytarabine–daunorubicin is the first example of this type of technology in acute myeloid leukaemia, and that it is more targeted than standard chemotherapy. The committee concluded that liposomal cytarabine–daunorubicin would be beneficial for patients but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# End of life
## Liposomal cytarabine–daunorubicin qualifies as a life-extending treatment for people with a short life expectancy
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that the median overall survival reported in Study 301 for the comparator group was 5.95 months. It also noted that the mean modelled survival was less than 24 months in the company's model. Therefore the short life expectancy criterion of less than 24 months was met. In Study 301, overall survival in the liposomal cytarabine–daunorubicin group was higher than in the standard cytarabine and daunorubicin group by a median of 3.61 months. The mean increase in overall survival predicted by the company's model was over 2 years (undiscounted life years). Even when the ERG's least optimistic estimate of overall survival after transplant for liposomal cytarabine–daunorubicin was modelled, the mean increase in overall survival predicted by the model was more than 3 months. Therefore liposomal cytarabine–daunorubicin met the criterion of extension to life of at least an additional 3 months. The committee concluded that liposomal cytarabine–daunorubicin met NICE's criteria for being considered a life-extending treatment at the end of life.
# Equalities
## There are no equality issues relevant to the recommendations
Stakeholders highlighted that liposomal cytarabine–daunorubicin was more likely to be used for younger people than for older people. Because the recommendation for liposomal cytarabine–daunorubicin is for the whole population covered by the marketing authorisation, the committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues.
# Conclusion
## Liposomal cytarabine–daunorubicin is recommended for routine NHS use
The committee concluded that, with the discount agreed in the commercial arrangement, the ICERs were within the range that NICE usually considers an acceptable use of NHS resources for a life-extending treatment at the end of life. The committee recommended liposomal cytarabine–daunorubicin within its marketing authorisation for treating newly diagnosed, therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes.
|
{'Recommendations': "Liposomal cytarabine–daunorubicin is recommended, within its marketing authorisation, as an option for untreated therapy-related acute myeloid leukaemia or acute myeloid leukaemia with myelodysplasia-related changes in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes is chemotherapy. Clinical trial evidence shows that people having liposomal cytarabine–daunorubicin live longer than people having standard chemotherapy.\n\nLiposomal cytarabine–daunorubicin meets NICE's criteria for being a life-extending treatment at the end of life. Using the most plausible assumptions and the price discount, the cost-effectiveness estimates of liposomal cytarabine–daunorubicin compared with standard chemotherapy are within the range that NICE normally considers a cost-effective use of NHS resources for end-of-life treatments. So liposomal cytarabine–daunorubicin is recommended.", 'Information about liposomal cytarabine–daunorubicin': "# Marketing authorisation indication\n\nLiposomal cytarabine–daunorubicin (Vyxeos, Jazz Pharmaceuticals) is indicated for 'the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t‑AML) or AML with myelodysplasia-related changes (AML‑MRC)'.\n\n# Dosage in the marketing authorisation\n\nThe company's submission states that liposomal cytarabine–daunorubicin is given by intravenous infusion over 90\xa0minutes. The dose is based on the patient's body surface area, according to the following schedule:\n\nFor induction of remission: daunorubicin 44\xa0mg/m2 and cytarabine 100\xa0mg/m2 on days\xa01,\xa03 and\xa05 for the first course and on days\xa01 and\xa03 for subsequent courses, if needed.\n\nFor consolidation (5\xa0to 8\xa0weeks after the start of the last induction): daunorubicin 29\xa0mg/m2 and cytarabine 65\xa0mg/m2 on days\xa01 and\xa03. A subsequent course of consolidation may be given when there is no disease progression or unacceptable toxicity.\n\n# Price\n\nThe company stated that the list price of liposomal cytarabine–daunorubicin is £4,581 per 50-ml vial. The company has a commercial arrangement. This makes liposomal cytarabine–daunorubicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Jazz Pharmaceuticals and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Potential new treatment option\n\n## People with acute myeloid leukaemia that is therapy-related or with myelodysplasia-related changes would welcome a new treatment option\n\nTherapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes are high-risk types of acute myeloid leukaemia with poor survival outcomes. Patient experts described that the most common symptoms include fatigue, feeling weak or breathless, loss of memory and concentration, bruising and bleeding, and nausea or vomiting. They also highlighted that the diagnosis has an emotional and financial effect on patients, and their families and carers. Both the patient and clinical experts explained that patients would welcome a treatment that helps them be well enough to have a stem cell transplant, which is potentially a curative treatment. The committee concluded that people with therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes would welcome a new treatment that could improve survival, quality of life, and the chance of getting a stem cell transplant.\n\n# Clinical management\n\n## Current treatment is chemotherapy\n\nCurrent treatment for therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes is intensive chemotherapy, for people who are well enough to have it. This usually involves a first induction course, and 2\xa0or\xa03 further courses of standard daunorubicin and cytarabine to treat any remaining cancer cells (consolidation therapy). In the NHS, the first induction course is usually given as 3\xa0days of daunorubicin and 10\xa0days of cytarabine (known as DA\xa03+10). The clinical experts highlighted that some younger patients may have FLAG‑Ida (fludarabine, cytarabine, granulocyte-colony stimulating factor and idarubicin) chemotherapy instead. The committee understood that liposomal cytarabine–daunorubicin is a liposomal formulation of standard cytarabine and daunorubicin chemotherapy. This could be used as an alternative in clinical practice. The committee was aware that diagnosing some types of high-risk acute myeloid leukaemia, particularly de novo acute myeloid leukaemia with myelodysplastic syndrome-associated karyotypic changes, involves genetic testing. In England, genetic test results may not be available for 7\xa0to 10\xa0days. The clinical experts advised that it is becoming more common for clinicians to wait for these test results before starting treatment. A small number of patients with more aggressive disease would need to start treatment sooner. The committee agreed that no change in practice would be needed for most people who would be eligible for liposomal cytarabine–daunorubicin, if it were to recommend the treatment. The committee concluded that standard cytarabine and daunorubicin chemotherapy is the relevant comparator for this appraisal.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS clinical practice in England\n\nThe evidence for liposomal cytarabine–daunorubicin came from Study\xa0301. This was a phase\xa03, multicentre, open-label, randomised trial. It included 309\xa0adults aged 60\xa0to 75\xa0years with high-risk acute myeloid leukaemia. High-risk acute myeloid leukaemia was defined as therapy-related acute myeloid leukaemia, acute myeloid leukaemia with myelodysplastic syndrome, de novo acute myeloid leukaemia with myelodysplastic syndrome-associated karyotypic changes and chronic myelomonocytic leukaemia. The trial compared liposomal cytarabine–daunorubicin (n=153) with standard cytarabine and daunorubicin chemotherapy (n=156), in a 3+7 schedule (3\xa0days of cytarabine then 7\xa0days of daunorubicin). The clinical experts confirmed that it was reasonable to assume equivalence between the 3+7 schedule in the trial and the 3+10 schedule normally used in the UK. They also confirmed that, although the trial was done in the US and Canada, the baseline characteristics of people in the trial were representative of people in the UK who would be eligible for liposomal cytarabine–daunorubicin. The clinical experts explained that about a quarter of patients who would be eligible for treatment in England would be under 60\xa0years. There was no biological reason to expect treatment benefit to be any different to that seen in people aged 65\xa0to 70\xa0years in the trial. The committee concluded that the clinical-effectiveness evidence from Study\xa0301 was relevant to clinical practice in England.\n\n## Liposomal cytarabine–daunorubicin improves overall survival compared with standard cytarabine and daunorubicin\n\nThe primary outcome measure in Study\xa0301 was overall survival. Treatment with liposomal cytarabine–daunorubicin increased median overall survival compared with standard cytarabine and daunorubicin, from 5.95\xa0months to 9.56\xa0months (hazard ratio [HR]\xa00.69; 95% confidence interval [CI] 0.52\xa0to\xa00.90, p=0.005). The company also presented results from a post-hoc analysis of overall survival from the time of stem cell transplant. Fifty-two people in the liposomal cytarabine–daunorubicin group and 39\xa0people in the standard cytarabine and daunorubicin group had a stem cell transplant and were included in this analysis. Median overall survival was 10.25\xa0months in the standard cytarabine and daunorubicin group and was not reached in the liposomal cytarabine–daunorubicin group (HR\xa00.46; 95%\xa0CI 0.24\xa0to\xa00.89, p=0.0046). The committee noted that there was a plateau in the Kaplan–Meier graphs for the liposomal cytarabine–daunorubicin group at around 6\xa0months after transplant, but not for the standard cytarabine and daunorubicin group. The clinical experts stated that response to transplant may differ depending on the person's health when they had the transplant, but that they would expect to see a plateau from the same time point in both groups. The committee noted that the post-hoc analysis included a small number of patients. It also noted that, in the trial, the decision to transplant was not randomised and therefore there could be bias in the results of the post-hoc analysis. The committee also noted that the results presented by the company were from a data cut in December\xa02015, 3\xa0years after the first patient was randomised, although the company stated that trial follow-up was continuing for 5\xa0years after randomisation. Also, after 1\xa0year, a substantial number of patients were censored in the analysis, which the committee agreed made the long-term results more uncertain. In response to consultation, the company presented updated Kaplan–Meier graphs, using safety data up to August\xa02018. It presented graphs both for overall survival in the full population and from the time of stem cell transplant. The committee agreed that the updated graphs were more reliable because there was less censoring and there was a plateau in both treatment groups. The company suggested that the difference between groups in response to transplant was because people in the liposomal cytarabine–daunorubicin group were in better health before transplant or had less residual leukaemia going into transplant, or both. However, minimal residual disease status before transplant was not collected in the trial. The committee concluded that there was some uncertainty about how much survival was improved after stem cell transplant, but that liposomal cytarabine–daunorubicin improved overall survival in the whole population compared with standard cytarabine and daunorubicin.\n\n# Adverse effects\n\n## Liposomal cytarabine–daunorubicin is well tolerated\n\nThe committee noted that the adverse effects reported in Study\xa0301 were broadly comparable between the 2\xa0groups. The patient expert noted that liposomal cytarabine–daunorubicin had been more tolerable for them than other treatments. The clinical experts suggested that people in the liposomal cytarabine–daunorubicin group of Study\xa0301 may have taken the active treatment for longer, leading to similar rates of adverse effects in the 2\xa0groups, rather than lower rates in the liposomal cytarabine–daunorubicin group as they may have expected. The committee concluded that liposomal cytarabine–daunorubicin was generally well tolerated.\n\n# The company's economic model\n\n## The model is appropriate for decision making but there is uncertainty in extrapolating overall survival after transplant and the cure fraction used\n\nThe company presented an economic model in 2\xa0parts: an initial decision tree to determine if patients were in remission after induction therapy, and whether they had a stem cell transplant or not, and then subsequent partitioned survival models. The model had a 30\xa0year time horizon. This was assumed to be a lifetime time horizon because patients in the model were 60\xa0to 75\xa0years, as in Study\xa0301. To extrapolate beyond the trial period, the company modelled parametric curves separately by treatment group. Overall survival and relapse-free survival outcomes were modelled separately for 3\xa0groups based on data from Study\xa0301: people in remission who had a stem cell transplant, people in remission who did not have a transplant and people who were not in remission. For people in the liposomal cytarabine–daunorubicin group who were in remission and had a stem cell transplant, the company chose a Gompertz distribution to extrapolate overall survival. This was based on clinical plausibility and because it was the best fit to the trial data. The committee considered that, although the Gompertz distribution produced a plateau, which would be expected after transplant, the plateau seemed overly optimistic. The committee agreed that the Study\xa0301 data were not mature enough to justify this extrapolation, particularly with the amount of censoring (see section\xa03.4). At the first committee meeting, the committee noted that the modelled curve for the comparator group did not reach a plateau. The company stated that, after around 2\xa0years, general population mortality rates would be applied for most people in the liposomal cytarabine–daunorubicin group in its base-case model because these rates were used when the modelled mortality rates would otherwise be lower. The ERG explored several parametric curves for extrapolating overall survival after transplant for the liposomal cytarabine–daunorubicin group. It noted that the choice of curve had a large effect on the predicted benefit and therefore the cost-effectiveness results. So, the ERG used a model averaging approach to address the uncertainty. The committee considered that this approach did not address the clinical implausibility of the extrapolation. The committee stated that it would prefer to see a cure model for the whole population, whether or not they had a stem cell transplant. The committee agreed that a plateau, or 'cure', should be accounted for in the standard cytarabine and daunorubicin survival extrapolation (see section\xa03.4). It also agreed that it would prefer to see overall survival analysis based on a more mature data cut (see section\xa03.4) to make the long-term extrapolation more reliable. In response to consultation, the company presented statistical cure model extrapolations for the whole population. However, the company did not use these models in the cost-effectiveness results because it stated that the cure model for the whole liposomal cytarabine–daunorubicin group overestimated survival compared with the Kaplan–Meier data and gave overly favourable cost-effectiveness results. Instead, the company used cure models for overall survival after stem cell transplant, which it stated matched the updated Kaplan–Meier data well. The cure models were based on the original trial data (December\xa02015 data cut) because the company only had a limited dataset of updated individual patient level data, which did not include event-free status. The committee agreed that it would have preferred to have seen the whole population modelled together. The company manually set a cure fraction of 20% in the standard cytarabine and daunorubicin group. The ERG noted that this figure seemed to have been taken from a visual inspection of the Kaplan–Meier curve and that a 25% cure fraction could also be considered as a plausible upper limit. The company presented a scenario analysis that included a 25% cure fraction in the standard cytarabine and daunorubicin group. This reduced the cost effectiveness of liposomal cytarabine–daunorubicin compared with standard cytarabine and daunorubicin. The committee concluded that the model was appropriate for decision making. However, it agreed that there was still uncertainty in the difference in overall survival between the 2\xa0treatment groups after stem cell transplant and in the cure fraction assumed for the standard cytarabine and daunorubicin group.\n\n## Event-free survival analysis for patients who had a complete response is unreliable because of small patient numbers\n\nThe company and ERG agreed that the analysis used to model event-free survival after transplant for patients who had a complete response in the model was uncertain because of small patient numbers. The ERG also suggested that it lacked face validity. This was because there was little difference between the 2\xa0treatment groups, unlike for overall survival after transplant. Therefore the ERG excluded these data from the model and used the overall survival analysis to inform a 2‑state model. In this model, patients were either in remission or dead. This change increased the cost effectiveness of liposomal cytarabine–daunorubicin. In response to consultation, the company adopted the ERG's approach to modelling event-free survival. The committee would have preferred the whole population to be modelled together (whether or not they had a stem cell transplant) but concluded that the company's approach was appropriate for decision making.\n\n# Mortality after transplant in the economic model\n\n## Mortality rates are higher after stem cell transplant than in the general population and should be included in the model\n\nIn its base-case economic model, the company applied general population mortality rates when the modelled mortality rates would otherwise have been lower. In a scenario analysis, the company increased mortality rates after stem cell transplant compared with the general population mortality rates by applying a standardised mortality ratio of\xa02.34. This reduced the cost effectiveness of liposomal cytarabine–daunorubicin. The ERG considered that this scenario had face validity and therefore included it in its preferred analysis. The clinical experts stated that it was generally accepted that survival would be shorter for people who had a stem cell transplant than for the general population. The committee concluded that it was appropriate to increase the mortality rate after stem cell transplant in the model to higher than that of the general population.\n\n# Utility values in the economic model\n\n## The utility values do not have a big effect on the cost-effectiveness results\n\nBecause health-related quality-of-life data were not collected in Study\xa0301, the company used a time-trade-off study to derive utility values for the economic model. The treatment-related disutilities included in the model were based on descriptions of the side effects of treatment provided by clinicians for the time-trade-off study. These described a more favourable side-effect profile for liposomal cytarabine–daunorubicin than for standard cytarabine and daunorubicin. Therefore a smaller disutility was applied to the liposomal cytarabine–daunorubicin group than the standard cytarabine and daunorubicin group. The ERG highlighted that this did not reflect the data from Study\xa0301. Therefore it estimated the mean utility value for each treatment phase and applied this to both treatment groups. The ERG also noted that the utility value used by the company for the remission after transplant health state was higher than usually reported for the general population. The company also did a scenario analysis using utility values from a study by Hensen et al. (2017). In this scenario, the utility value for the remission after transplant health state was\xa00.75, and the ERG used this value in its preferred analysis. The ERG also adjusted the utility values for age. The committee noted that these changes did not have a big effect on the cost-effectiveness results. It concluded that it was plausible to assume the disutilities were the same in both treatment groups, to use a utility value of\xa00.75 for the remission health state and to adjust the utility values for age.\n\n# Costs and resource use in the economic model\n\n## Costs and resource use in the economic model do not have a big effect on the cost-effectiveness results\n\nThe company calculated treatment doses and vial use including wastage, based on a mean body surface area of 1.79\xa0m2, calculated from a UK study of adults with cancer (Sacco et al. 2010). The ERG used a different method to calculate vial use. It accounted for the distribution of body surface area in the population, and also calculated a mean body surface area of 1.83\xa0m2 by applying the gender weighting from Study\xa0301 to the data from the Sacco study. The ERG considered that hospital length of stay was overestimated in the model compared with that seen in Study\xa0301. Therefore in its preferred analysis, it reduced the number of hospital days in the consolidation period. The ERG used a lower cost of stem cell transplant than the company, based on using the costs of transplants from sibling donors instead of from unrelated adult donors. It also increased the follow-up cost to reflect a 2‑year follow-up, instead of 6\xa0months. The clinical experts stated that, although sibling donors had been more common, it was now more likely that unrelated adult stem cells would be used for transplants. The committee noted that these changes to costs and resource use in the model had little effect on the cost-effectiveness results. It concluded that it was reasonable to use the ERG's method of calculating vial use, for the length of hospital stay in the model to match that in the trial and to include transplant follow-up costs for 2\xa0years. However, it agreed that stem cells for transplant would likely come from unrelated matched donors.\n\n# Cost-effectiveness results\n\n## The most plausible incremental cost-effectiveness ratio compared with standard cytarabine and daunorubicin is lower than £50,000 per quality-adjusted life year gained\n\nThe company updated its economic model after consultation. This included the committee's preferred assumptions, specifically:\n\ncorrecting some errors identified by the ERG\n\nbasing outcomes after transplant only on overall survival (see section\xa03.7)\n\nadjusting mortality rates after transplant (see section\xa03.8)\n\nusing some alternative utility values (see section\xa03.9)\n\nusing a different method to calculate vial use (see section\xa03.10)\n\nreducing the number of hospital days in the consolidation period (see section\xa03.10).The company used cure models after stem cell transplant (see section\xa03.6) and also increased the discount in the commercial arrangement. This resulted in an incremental cost-effectiveness ratio (ICER) for liposomal cytarabine–daunorubicin of £45,055 per quality-adjusted life year (QALY) gained. When the company used a 25% cure fraction for the standard cytarabine and daunorubicin group (see section\xa03.6), the ICER increased to £48,127 per QALY gained. When the ERG reproduced the analyses to include the confidential commercial arrangement discount for azacitidine (included in the model as a subsequent treatment), both ICERs were below £50,000 per QALY gained. The committee concluded that the most plausible ICER was lower than £50,000 per QALY gained.\n\n# Innovation\n\n## The benefits of liposomal cytarabine–daunorubicin are captured in the cost-effectiveness analysis\n\nThe company considered that liposomal cytarabine–daunorubicin was an innovative treatment because of its formulation. The drug accumulates in the bone marrow and is released inside the cells. The company also highlighted that infusion time is reduced and that people can have it as outpatients. It also noted that liposomal cytarabine–daunorubicin is the only new treatment in recent years to show a survival benefit for people with high-risk acute myeloid leukaemia. Patient and professional groups highlighted that liposomal cytarabine–daunorubicin is the first example of this type of technology in acute myeloid leukaemia, and that it is more targeted than standard chemotherapy. The committee concluded that liposomal cytarabine–daunorubicin would be beneficial for patients but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# End of life\n\n## Liposomal cytarabine–daunorubicin qualifies as a life-extending treatment for people with a short life expectancy\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that the median overall survival reported in Study\xa0301 for the comparator group was 5.95\xa0months. It also noted that the mean modelled survival was less than 24\xa0months in the company's model. Therefore the short life expectancy criterion of less than 24\xa0months was met. In Study\xa0301, overall survival in the liposomal cytarabine–daunorubicin group was higher than in the standard cytarabine and daunorubicin group by a median of 3.61\xa0months. The mean increase in overall survival predicted by the company's model was over 2\xa0years (undiscounted life years). Even when the ERG's least optimistic estimate of overall survival after transplant for liposomal cytarabine–daunorubicin was modelled, the mean increase in overall survival predicted by the model was more than 3\xa0months. Therefore liposomal cytarabine–daunorubicin met the criterion of extension to life of at least an additional 3\xa0months. The committee concluded that liposomal cytarabine–daunorubicin met NICE's criteria for being considered a life-extending treatment at the end of life.\n\n# Equalities\n\n## There are no equality issues relevant to the recommendations\n\nStakeholders highlighted that liposomal cytarabine–daunorubicin was more likely to be used for younger people than for older people. Because the recommendation for liposomal cytarabine–daunorubicin is for the whole population covered by the marketing authorisation, the committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues.\n\n# Conclusion\n\n## Liposomal cytarabine–daunorubicin is recommended for routine NHS use\n\nThe committee concluded that, with the discount agreed in the commercial arrangement, the ICERs were within the range that NICE usually considers an acceptable use of NHS resources for a life-extending treatment at the end of life. The committee recommended liposomal cytarabine–daunorubicin within its marketing authorisation for treating newly diagnosed, therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes."}
|
https://www.nice.org.uk/guidance/ta552
|
Evidence-based recommendations on liposomal cytarabine–daunorubicin (Vyxeos) for untreated acute myeloid leukaemia in adults.
|
2cd1dae749a0eb31ae9820b403f64ab5e99bb5d2
|
nice
|
Bronchiectasis (non-cystic fibrosis), acute exacerbation: antimicrobial prescribing
|
Bronchiectasis (non-cystic fibrosis), acute exacerbation: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for managing and preventing acute exacerbations of bronchiectasis (non-cystic fibrosis). It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing an acute exacerbation of bronchiectasis (non-cystic fibrosis)
Be aware that an acute exacerbation of bronchiectasis is a sustained worsening of symptoms from a person's stable state.
## Treatment
Obtain a sputum sample from people with an acute exacerbation of bronchiectasis and send for culture and susceptibility testing.
Offer an antibiotic to people with an acute exacerbation of bronchiectasis. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:
the severity of symptoms
previous exacerbation and hospital admission history, and the risk of developing complications
previous sputum culture and susceptibility results.
When results of sputum culture and susceptibility testing are available:
review the choice of antibiotic and
-nly change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving (using a narrow-spectrum antibiotic wherever possible).
With an antibiotic, give advice about:
possible adverse effects of antibiotics, particularly diarrhoea
seeking medical help if symptoms worsen rapidly or significantly at any time, or the person becomes systemically very unwell.
To find out why the committee made the recommendations, see the rationale section on treatment of an acute exacerbation .
Loading. Please wait.
## Reassessment
Reassess people with an acute exacerbation of bronchiectasis if their symptoms worsen rapidly or significantly at any time, taking account of:
-ther possible diagnoses, such as pneumonia
any symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis
previous antibiotic use, which may have led to resistant bacteria.
To find out why the committee made the recommendation, see the rationale section on reassessment .
Loading. Please wait.
## Referral and seeking specialist advice
Refer people with an acute exacerbation of bronchiectasis to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis).
Seek specialist advice for people with an acute exacerbation of bronchiectasis if they:
have symptoms that are not improving with repeated courses of antibiotic treatment or
have bacteria that are resistant to oral antibiotics or
cannot take oral medicines (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where this is appropriate).
To find out why the committee made the recommendations, see the rationale section on referral and seeking specialist advice .
Loading. Please wait.
# Choice of antibiotic for treating an acute exacerbation of bronchiectasis
When prescribing antibiotic treatment for an acute exacerbation of bronchiectasis:
follow table 1 for adults aged 18 years and over
follow table 2 for children and young people under 18 years.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotics for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Amoxicillin (preferred choice in pregnancy):
mg three times a day for 7 to 14 days
Doxycycline:
mg on first day, then 100 mg once a day for a 7‑day to 14‑day course in total
Clarithromycin:
mg twice a day for 7 to 14 days
Alternative choice oral antibiotics (if person at higher risk of treatment failure) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Co‑amoxiclav:
/125 mg three times a day for 7 to 14 days
Levofloxacin
(use is off label; with specialist advice if co‑amoxiclav cannot be used; consider safety issues):
mg once or twice a day for 7 to 14 days
First-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Co‑amoxiclav:
g three times a day
Piperacillin with tazobactam:
g three times a day, increased if necessary to 4.5 g four times a day
Levofloxacin
(use is off label; with specialist advice if co‑amoxiclav or piperacillin with tazobactam cannot be used; consider safety issues):
mg once or twice a day
When current susceptibility data available, choose antibiotics accordingly
Consult a local microbiologist as needed
See the BNF for appropriate use and dosing in specific populations, for example, in hepatic impairment, renal impairment, pregnancy and breastfeeding, and when administering intravenous antibiotics.
When a person is having antibiotic prophylaxis, treatment should be with an antibiotic from a different class.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics when possible for a total antibiotic course of 7 to 14 days.
Course length should be based on an assessment of the severity of bronchiectasis, exacerbation history, severity of exacerbation symptoms, previous culture and susceptibility results, and response to treatment.
People who may be at higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or a higher risk of developing complications.
In December 2018, the use of levofloxacin in recommendation 1.2.1 (table 1) was off label. See NICE's information on prescribing medicines.
See the Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding co‑administration with a corticosteroid (March 2019).
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotics for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Amoxicillin (preferred choice in pregnancy):
month to 11 months, 125 mg three times a day for 7 to 14 days
year to 4 years, 250 mg three times a day for 7 to 14 days
years to 17 years, 500 mg three times a day for 7 to 14 days
Clarithromycin:
month to 11 years:
Under 8 kg, 7.5 mg/kg twice a day for 7 to 14 days
kg to 11 kg, 62.5 mg twice a day for 7 to 14 days
kg to 19 kg, 125 mg twice a day for 7 to 14 days
kg to 29 kg, 187.5 mg twice a day for 7 to 14 days
kg to 40 kg, 250 mg twice a day for 7 to 14 days
years to 17 years, 250 mg to 500 mg twice a day for 7 to 14 days
Doxycycline:
years to 17 years, 200 mg on first day, then 100 mg once a day for a 7‑day to 14‑day course in total
Alternative choice oral antibiotics (if person at higher risk of treatment failure) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Co‑amoxiclav:
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 7 to 14 days
year to 5 years, 5 ml of 125/31 suspension three times a day or 0.25 ml/kg of 125/31 suspension three times a day for 7 to 14 days
years to 11 years, 5 ml of 250/62 suspension three times a day or 0.15 ml/kg of 250/62 suspension three times a day for 7 to 14 days
years to 17 years, 250/125 mg three times a day or 500/125 mg three times a day for 7 to 14 days
Ciprofloxacin (with specialist advice if co‑amoxiclav cannot be used; consider safety issues):
year to 17 years, 20 mg/kg twice a day (maximum 750 mg per dose) for 7 to 14 days
First-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)
Co‑amoxiclav:
month to 2 months, 30 mg/kg twice a day
months to 17 years, 30 mg/kg three times a day (maximum 1.2 g three times a day)
Piperacillin with tazobactam:
month to 11 years, 90 mg/kg three or four times a day (maximum per dose 4.5 g four times a day)
years to 17 years, 4.5 g three times a day, increased if necessary to 4.5 g four times a day
Ciprofloxacin (with specialist advice if co-amoxiclav or piperacillin with tazobactam cannot be used; consider safety issues):
year to 17 years, 10 mg/kg three times a day (maximum 400 mg per dose)
When current susceptibility data available, choose antibiotics accordingly
Consult a local microbiologist as needed
See the BNF for children for appropriate use and dosing in specific populations, for example, in hepatic impairment and renal impairment, and when administering intravenous antibiotics.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.
When a person is having antibiotic prophylaxis, treatment should be with an antibiotic from a different class.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible for a total antibiotic course of 7 to 14 days.
Course length should be based on an assessment of the severity of bronchiectasis, exacerbation history, severity of exacerbation symptoms, previous culture and susceptibility results, and response to treatment.
People who may be at higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or a higher risk of developing complications.
See the Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding co‑administration with a corticosteroid (March 2019).
To find out why the committee made the recommendations, see the rationale section on choice and duration of antibiotics for managing an acute exacerbation .
Loading. Please wait.
# Preventing acute exacerbations of bronchiectasis (non-cystic fibrosis)
Do not routinely offer antibiotic prophylaxis to prevent acute exacerbations of bronchiectasis. Give advice about seeking medical help if symptoms of an acute exacerbation develop.
Seek specialist advice about options for preventing exacerbations in people with repeated acute exacerbations, which may include a trial of antibiotic prophylaxis.
Only start a trial of antibiotic prophylaxis (with oral or inhaled antibiotics) in people with repeated acute exacerbations on the advice of a specialist. To ensure shared decision making, discuss the following with the person:
the potential benefits of antibiotics for reducing exacerbations (taking into account the uncertain evidence of benefit for inhaled antibiotics)
the risks of antimicrobial resistance with long-term antibiotics, which may mean fewer effective antibiotics for future exacerbations
the possible adverse effects of long-term antibiotics, such as:
diarrhoea, cardiac events, hearing loss or tinnitus with macrolide antibiotics
bronchospasm with inhaled antibiotics
the possible interactions of macrolide antibiotics with other medicines
the need to regularly review prophylaxis.
To find out why the committee made the recommendations, see the rationale section on preventing acute exacerbations of bronchiectasis .
Loading. Please wait.# Terms used in this guideline
# Acute exacerbation of bronchiectasis
An acute exacerbation of bronchiectasis is characterised by an acute deterioration of normal symptoms and signs usually over several days. It presents with worsening local symptoms (such as cough, increased sputum volume, change of sputum viscosity, or increased sputum purulence) with or without increased wheeze, breathlessness or haemoptysis. Fever or pleurisy may also be present (British Thoracic Society's 2010 guideline on non-cystic fibrosis bronchiectasis).
Bronchiectasis is defined as persistent or recurrent bronchial sepsis related to irreversibly damaged and dilated bronchi (British Thoracic Society's 2010 guideline on non-cystic fibrosis bronchiectasis).# Rationales
# Treatment
Recommendations 1.1.2 to 1.1.5
## Why the committee made the recommendations
The committee agreed, based on their experience, that people with an acute exacerbation of bronchiectasis presenting with worsening local symptoms (such as cough, increased sputum volume, change of sputum viscosity or increased sputum purulence) with or without increased wheeze, breathlessness, haemoptysis, fever or pleurisy, should receive an antibiotic. Choice should take account of the severity of their symptoms, their previous exacerbation and hospital admission history, their risk of developing complications, and previous sputum culture and susceptibility results.
The committee discussed the limited evidence base for antibiotics for treating an acute exacerbation of bronchiectasis. No evidence was found comparing antibiotics with placebo from systematic reviews or randomised controlled trials from the search, which went back to 2006. However, the committee were aware of older, heterogeneous, head-to-head studies comparing different antibiotic regimens (which may not reflect current practice).
Based on experience, the committee agreed that although in the first instance, antibiotic treatment for an acute exacerbation may be empirical, a new sputum sample should be sent for culture to confirm susceptibility of the bacteria. The committee discussed that for empirical treatment, antibiotics should be chosen initially based on the most recent sputum culture and susceptibility results. People with bronchiectasis are likely to have previous sputum samples, and because pathogenic bacteria are reasonably static in this population, antibiotics that worked previously are a good starting point to treat new exacerbations. However, pathogenic bacteria can change and a new sputum sample should be sent for culture when people present with a new exacerbation of bronchiectasis, and this new susceptibility data used to review antibiotic choice. The committee discussed the importance of all prescribers having access to microbiology results, with hospital managers ensuring that primary care teams have easy access to microbiology results.
Based on experience, the committee agreed that when results of sputum cultures are available, if they suggest the bacteria are not susceptible, the person should be contacted to assess symptoms. However, the antibiotic should only be changed according to susceptibility results if symptoms are not already improving. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible.
The committee agreed that when an antibiotic is given, people should be advised about possible adverse effects and also be given safety netting advice.
Return to recommendations
# Reassessment
Recommendation 1.1.6
## Why the committee made the recommendation
Based on experience, the committee agreed that, for safety netting, reassessment was needed if symptoms of the acute exacerbation worsen rapidly or significantly at any time.
Return to recommendation
# Referral and seeking specialist advice
Recommendations 1.1.7 and 1.1.8
## Why the committee made the recommendations
Based on experience, the committee agreed that, for safety netting, people with an acute exacerbation of bronchiectasis should be referred to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or suspected sepsis).
The committee discussed that some people who are severely ill or have resistant bacteria (particularly Pseudomonas aeruginosa) may need intravenous antibiotics, particularly if their symptoms are not responding to several courses of oral antibiotics for the same episode, or if several sputum samples show resistance to oral antibiotics. The committee discussed that specialist advice should be sought for people needing intravenous antibiotics, to discuss local options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate for the person.
Return to recommendations
# Choice of antibiotic for treating an acute exacerbation of bronchiectasis
Recommendations 1.2.1 to 1.2.3, and tables 1 and 2
## Why the committee made the recommendations
Very limited evidence was identified to guide the choice of antibiotic for treating an acute exacerbation of bronchiectasis. Based on experience, common pathogens in acute exacerbations, the susceptibility of these to various classes of antibiotics, the risks of resistance and good antimicrobial stewardship, the committee agreed the following antibiotic choices for empirical treatment in the absence of current susceptibility data. Choice should be guided by the most recent sputum culture and susceptibilities where possible. Several oral and intravenous antibiotics were recommended to enable antibiotics to be selected based on the severity of illness and previous antibiotic use.
First-choice oral antibiotics for empirical treatment are:
amoxicillin (a penicillin), which has good activity against common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae
clarithromycin (a macrolide)
doxycycline (a tetracycline; adults and young people over 12 years only).
Alternative choice oral antibiotics for empirical treatment for people who are at higher risk of treatment failure (which may include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or people at higher risk of developing complications) are:
co-amoxiclav, a broad-spectrum antibiotic which combines a penicillin with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone or
a fluoroquinolone: levofloxacin in adults or ciprofloxacin in children (only on specialist advice because fluoroquinolones are generally not recommended in children or young people who are growing), which have good activity against atypical bacteria, particularly Pseudomonas aeruginosa.
The committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system (press release October 2018). This includes a recommendation to not use them for mild or moderately severe infections unless other antibiotics cannot be used. The committee discussed that fluoroquinolones are appropriate as an alternative option for people who may be at a higher risk of treatment failure. However, the committee was keen to point out that fluoroquinolone safety concerns should be taken into account on an individual patient basis.
First-choice intravenous antibiotics for empirical treatment in people who are unable to take oral antibiotics or are severely unwell are:
co-amoxiclav (a penicillin with a beta-lactamase inhibitor)
piperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor)
levofloxacin (in adults) or ciprofloxacin (in children ), which are fluoroquinolones.
When current susceptibility data are available, antibiotics should be chosen and modified accordingly, consulting local microbiologists as needed.
The committee discussed evidence from a randomised controlled trial, which showed that adding nebulised tobramycin to oral ciprofloxacin did not improve the resolution of exacerbation symptoms, and increased wheeze.
Very limited evidence was identified to guide the duration of antibiotics for treating an acute exacerbation of bronchiectasis. The 1 randomised controlled trial identified, which compared a nebulised antibiotic plus an oral antibiotic with an oral antibiotic alone, used a 14‑day course, which is current practice.
Based on experience, the committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
The committee agreed that a course of 7 to 14 days was required to treat an acute exacerbation, based on an assessment of the person's severity of bronchiectasis, their exacerbation history, the severity of their exacerbation symptoms, previous culture and susceptibility results, and response to treatment.
Oral antibiotics should be used first line where possible, in line with the NICE guideline on antimicrobial stewardship.
The committee agreed that the use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and susceptibility results from sputum culture) and switched to oral treatment where possible. This aligns with the NICE guideline on antimicrobial stewardship and Public Health England's 'Start smart – then focus' toolkit.
Return to recommendations
# Preventing acute exacerbations of bronchiectasis (non-cystic fibrosis) and choice of antibiotic
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
The committee discussed the evidence for prophylactic antibiotics. Overall, antibiotics reduced exacerbation rates, hospitalisations and the number of people with an exacerbation. However, there was a significant increase in antibiotic resistance and adverse effects.
Most of the studies were in populations who had experienced multiple exacerbations in the previous year, and the committee thought the findings could not be generalised to everyone with bronchiectasis.
Based on evidence and experience, the committee agreed that people should not routinely be offered antibiotic prophylaxis to prevent acute exacerbations, because of the balance of risks and benefits in the overall population.
For people with repeated exacerbations, where the benefits of prophylaxis may outweigh the risks, specialist advice should be sought on various management options, which may include a trial of antibiotic prophylaxis (with oral or inhaled antibiotics).
The committee noted it was difficult to give a precise definition of 'repeated exacerbations' and clinical judgement would be needed to define this on an individualised patient basis.
The committee agreed that a trial of antibiotic prophylaxis should only be started in people with repeated acute exacerbations on the advice of a specialist, because it is important to consider antibiotic prophylaxis alongside other management options. Shared decision making is important for taking into account the risks and benefits of prophylaxis on an individualised patient basis. This includes discussing the potential benefits of antibiotics for reducing exacerbations, but also the harms of long-term antibiotics. There is an increased risk of resistance with long-term antibiotics, which impacts at both a population and an individual level, and people should be advised that this can mean fewer antibiotics may work for their exacerbations in the future. People should also be advised about possible adverse effects. With macrolides, diarrhoea is common but there are also less common cardiac events, hearing loss and tinnitus, and the potential to interact with other medicines. Bronchospasm is a possible adverse effect with inhaled antibiotics and a challenge test is needed. The committee discussed that people being considered for antibiotic prophylaxis would also need to return for regular review.
The committee discussed that most evidence for prophylactic antibiotics was for oral macrolide antibiotics in adults, where they reduced exacerbation rates and the number of people with an exacerbation. However, they also increased antibiotic resistance and adverse effects. The limited evidence in children and young people found prophylactic oral macrolide antibiotics did not significantly reduce exacerbations but increased antimicrobial resistance.
The evidence for nebulised or inhaled antibiotics was particularly limited, and not all products studied are available in the UK. As a class, prophylaxis with nebulised or inhaled antibiotics did not significantly reduce exacerbations in adults. In 1 trial of nebulised colistimethate sodium in people with chronic Pseudomonas aeruginosa infection, exacerbations were significantly reduced in an adherent population, but not in the intention-to-treat population, which was the primary end point. In another trial of nebulised tobramycin, a non-significant increase in exacerbations, and adverse events such as dyspnoea, chest pain and wheeze were seen.
The committee were unable to make specific recommendations on the choice of antibiotic for prophylaxis, because this will be an individualised decision based on the clinical needs of the person, their preferences and advice from a specialist.
Return to recommendations
See the full evidence review for a summary of the evidence and more information.
|
{'Recommendations': "# Managing an acute exacerbation of bronchiectasis (non-cystic fibrosis)\n\nBe aware that an acute exacerbation of bronchiectasis is a sustained worsening of symptoms from a person's stable state.\n\n## Treatment\n\nObtain a sputum sample from people with an acute exacerbation of bronchiectasis and send for culture and susceptibility testing.\n\nOffer an antibiotic to people with an acute exacerbation of bronchiectasis. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:\n\nthe severity of symptoms\n\nprevious exacerbation and hospital admission history, and the risk of developing complications\n\nprevious sputum culture and susceptibility results.\n\nWhen results of sputum culture and susceptibility testing are available:\n\nreview the choice of antibiotic and\n\nonly change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving (using a narrow-spectrum antibiotic wherever possible).\n\nWith an antibiotic, give advice about:\n\npossible adverse effects of antibiotics, particularly diarrhoea\n\nseeking medical help if symptoms worsen rapidly or significantly at any time, or the person becomes systemically very unwell.\n\nTo find out why the committee made the recommendations, see the rationale section on treatment of an acute exacerbation\xa0.\n\nLoading. Please wait.\n\n## Reassessment\n\nReassess people with an acute exacerbation of bronchiectasis if their symptoms worsen rapidly or significantly at any time, taking account of:\n\nother possible diagnoses, such as pneumonia\n\nany symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nTo find out why the committee made the recommendation, see the rationale section on reassessment\xa0.\n\nLoading. Please wait.\n\n## Referral and seeking specialist advice\n\nRefer people with an acute exacerbation of bronchiectasis to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis).\n\nSeek specialist advice for people with an acute exacerbation of bronchiectasis if they:\n\nhave symptoms that are not improving with repeated courses of antibiotic treatment or\n\nhave bacteria that are resistant to oral antibiotics or\n\ncannot take oral medicines (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where this is appropriate).\n\nTo find out why the committee made the recommendations, see the rationale section on referral and seeking specialist advice\xa0.\n\nLoading. Please wait.\n\n# Choice of antibiotic for treating an acute exacerbation of bronchiectasis\n\nWhen prescribing antibiotic treatment for an acute exacerbation of bronchiectasis:\n\nfollow table\xa01 for adults aged 18\xa0years and over\n\nfollow table\xa02 for children and young people under 18\xa0years.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotics for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nAmoxicillin (preferred choice in pregnancy):\n\nmg three times a day for 7\xa0to\xa014\xa0days\n\n\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for a 7‑day\xa0to\xa014‑day course in total\n\n\n\nClarithromycin:\n\nmg twice a day for 7\xa0to\xa014\xa0days\n\nAlternative choice oral antibiotics (if person at higher risk of treatment failure) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nCo‑amoxiclav:\n\n/125\xa0mg three times a day for 7\xa0to\xa014\xa0days\n\n\n\nLevofloxacin\n (use is off label; with specialist advice if co‑amoxiclav cannot be used; consider safety issues):\n\nmg once or twice a day for 7\xa0to\xa014\xa0days\n\nFirst-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nCo‑amoxiclav:\n\ng three times a day\n\n\n\nPiperacillin with tazobactam:\n\ng three times a day, increased if necessary to 4.5\xa0g four times a day\n\n\n\nLevofloxacin\n (use is off label; with specialist advice if co‑amoxiclav or piperacillin with tazobactam cannot be used; consider safety issues):\n\nmg once or twice a day\n\nWhen current susceptibility data available, choose antibiotics accordingly\n\nConsult a local microbiologist as needed\n\nSee the BNF for appropriate use and dosing in specific populations, for example, in hepatic impairment, renal impairment, pregnancy and breastfeeding, and when administering intravenous antibiotics.\n\nWhen a person is having antibiotic prophylaxis, treatment should be with an antibiotic from a different class.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics when possible for a total antibiotic course of 7\xa0to\xa014\xa0days.\n\nCourse length should be based on an assessment of the severity of bronchiectasis, exacerbation history, severity of exacerbation symptoms, previous culture and susceptibility results, and response to treatment.\n\nPeople who may be at higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or a higher risk of developing complications.\n\nIn December 2018, the use of levofloxacin in recommendation 1.2.1 (table\xa01) was off label. See NICE's information on prescribing medicines.\n\nSee the Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60\xa0years and avoiding co‑administration with a corticosteroid (March\xa02019).\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotics for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nAmoxicillin (preferred choice in pregnancy):\n\nmonth to 11\xa0months, 125\xa0mg three times a day for 7\xa0to\xa014\xa0days\n\nyear to 4\xa0years, 250\xa0mg three times a day for 7\xa0to\xa014\xa0days\n\nyears to 17\xa0years, 500\xa0mg three times a day for 7\xa0to\xa014\xa0days\n\n\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 7\xa0to\xa014\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 7\xa0to\xa014\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 7\xa0to\xa014\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 7\xa0to\xa014\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 7\xa0to\xa014\xa0days\n\n\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day for 7\xa0to\xa014\xa0days\n\n\n\nDoxycycline:\n\nyears to 17\xa0years, 200\xa0mg on first day, then 100\xa0mg once a day for a 7‑day\xa0to\xa014‑day course in total\n\nAlternative choice oral antibiotics (if person at higher risk of treatment failure) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nCo‑amoxiclav:\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31\xa0suspension three times a day for 7\xa0to\xa014\xa0days\n\nyear to 5\xa0years, 5\xa0ml of 125/31\xa0suspension three times a day or 0.25\xa0ml/kg of 125/31\xa0suspension three times a day for 7\xa0to\xa014\xa0days\n\nyears to 11\xa0years, 5\xa0ml of 250/62\xa0suspension three times a day or 0.15\xa0ml/kg of 250/62\xa0suspension three times a day for 7\xa0to\xa014\xa0days\n\nyears to 17\xa0years, 250/125\xa0mg three times a day or 500/125\xa0mg three times a day for 7\xa0to\xa014\xa0days\n\n\n\nCiprofloxacin (with specialist advice if co‑amoxiclav cannot be used; consider safety issues):\n\nyear to 17\xa0years, 20\xa0mg/kg twice a day (maximum 750\xa0mg per dose) for 7\xa0to\xa014\xa0days\n\nFirst-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell) for empirical treatment in the absence of current susceptibility data (guided by most recent sputum culture and susceptibilities where possible)\n\nCo‑amoxiclav:\n\nmonth to 2\xa0months, 30\xa0mg/kg twice a day\n\nmonths to 17\xa0years, 30\xa0mg/kg three times a day (maximum 1.2\xa0g three times a day)\n\n\n\nPiperacillin with tazobactam:\n\nmonth to 11\xa0years, 90\xa0mg/kg three or four times a day (maximum per dose 4.5\xa0g four times a day)\n\nyears to 17\xa0years, 4.5\xa0g three times a day, increased if necessary to 4.5\xa0g four times a day\n\n\n\nCiprofloxacin (with specialist advice if co-amoxiclav or piperacillin with tazobactam cannot be used; consider safety issues):\n\nyear to 17\xa0years, 10\xa0mg/kg three times a day (maximum 400\xa0mg per dose)\n\nWhen current susceptibility data available, choose antibiotics accordingly\n\nConsult a local microbiologist as needed\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, in hepatic impairment and renal impairment, and when administering intravenous antibiotics.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.\n\nWhen a person is having antibiotic prophylaxis, treatment should be with an antibiotic from a different class.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible for a total antibiotic course of 7\xa0to\xa014\xa0days.\n\nCourse length should be based on an assessment of the severity of bronchiectasis, exacerbation history, severity of exacerbation symptoms, previous culture and susceptibility results, and response to treatment.\n\nPeople who may be at higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or a higher risk of developing complications.\n\nSee the Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60\xa0years and avoiding co‑administration with a corticosteroid (March 2019).\n\nTo find out why the committee made the recommendations, see the rationale section on choice and duration of antibiotics for managing an acute exacerbation\xa0.\n\nLoading. Please wait.\n\n# Preventing acute exacerbations of bronchiectasis (non-cystic fibrosis)\n\nDo not routinely offer antibiotic prophylaxis to prevent acute exacerbations of bronchiectasis. Give advice about seeking medical help if symptoms of an acute exacerbation develop.\n\nSeek specialist advice about options for preventing exacerbations in people with repeated acute exacerbations, which may include a trial of antibiotic prophylaxis.\n\nOnly start a trial of antibiotic prophylaxis (with oral or inhaled antibiotics) in people with repeated acute exacerbations on the advice of a specialist. To ensure shared decision making, discuss the following with the person:\n\nthe potential benefits of antibiotics for reducing exacerbations (taking into account the uncertain evidence of benefit for inhaled antibiotics)\n\nthe risks of antimicrobial resistance with long-term antibiotics, which may mean fewer effective antibiotics for future exacerbations\n\nthe possible adverse effects of long-term antibiotics, such as:\n\n\n\ndiarrhoea, cardiac events, hearing loss or tinnitus with macrolide antibiotics\n\nbronchospasm with inhaled antibiotics\n\n\n\nthe possible interactions of macrolide antibiotics with other medicines\n\nthe need to regularly review prophylaxis.\n\nTo find out why the committee made the recommendations, see the rationale section on preventing acute exacerbations of bronchiectasis\xa0.\n\nLoading. Please wait.", 'Terms used in this guideline': "# Acute exacerbation of bronchiectasis\n\nAn acute exacerbation of bronchiectasis is characterised by an acute deterioration of normal symptoms and signs usually over several days. It presents with worsening local symptoms (such as cough, increased sputum volume, change of sputum viscosity, or increased sputum purulence) with or without increased wheeze, breathlessness or haemoptysis. Fever or pleurisy may also be present (British Thoracic Society's 2010 guideline on non-cystic fibrosis bronchiectasis).\n\nBronchiectasis is defined as persistent or recurrent bronchial sepsis related to irreversibly damaged and dilated bronchi (British Thoracic Society's 2010 guideline on non-cystic fibrosis bronchiectasis).", 'Rationales': "# Treatment\n\nRecommendations 1.1.2\xa0to\xa01.1.5\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their experience, that people with an acute exacerbation of bronchiectasis presenting with worsening local symptoms (such as cough, increased sputum volume, change of sputum viscosity or increased sputum purulence) with or without increased wheeze, breathlessness, haemoptysis, fever or pleurisy, should receive an antibiotic. Choice should take account of the severity of their symptoms, their previous exacerbation and hospital admission history, their risk of developing complications, and previous sputum culture and susceptibility results.\n\nThe committee discussed the limited evidence base for antibiotics for treating an acute exacerbation of bronchiectasis. No evidence was found comparing antibiotics with placebo from systematic reviews or randomised controlled trials from the search, which went back to 2006. However, the committee were aware of older, heterogeneous, head-to-head studies comparing different antibiotic regimens (which may not reflect current practice).\n\nBased on experience, the committee agreed that although in the first instance, antibiotic treatment for an acute exacerbation may be empirical, a new sputum sample should be sent for culture to confirm susceptibility of the bacteria. The committee discussed that for empirical treatment, antibiotics should be chosen initially based on the most recent sputum culture and susceptibility results. People with bronchiectasis are likely to have previous sputum samples, and because pathogenic bacteria are reasonably static in this population, antibiotics that worked previously are a good starting point to treat new exacerbations. However, pathogenic bacteria can change and a new sputum sample should be sent for culture when people present with a new exacerbation of bronchiectasis, and this new susceptibility data used to review antibiotic choice. The committee discussed the importance of all prescribers having access to microbiology results, with hospital managers ensuring that primary care teams have easy access to microbiology results.\n\nBased on experience, the committee agreed that when results of sputum cultures are available, if they suggest the bacteria are not susceptible, the person should be contacted to assess symptoms. However, the antibiotic should only be changed according to susceptibility results if symptoms are not already improving. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible.\n\nThe committee agreed that when an antibiotic is given, people should be advised about possible adverse effects and also be given safety netting advice.\n\nReturn to recommendations\n\n# Reassessment\n\nRecommendation 1.1.6\n\n## Why the committee made the recommendation\n\nBased on experience, the committee agreed that, for safety netting, reassessment was needed if symptoms of the acute exacerbation worsen rapidly or significantly at any time.\n\nReturn to recommendation\n\n# Referral and seeking specialist advice\n\nRecommendations 1.1.7\xa0and\xa01.1.8\n\n## Why the committee made the recommendations\n\nBased on experience, the committee agreed that, for safety netting, people with an acute exacerbation of bronchiectasis should be referred to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or suspected sepsis).\n\nThe committee discussed that some people who are severely ill or have resistant bacteria (particularly Pseudomonas aeruginosa) may need intravenous antibiotics, particularly if their symptoms are not responding to several courses of oral antibiotics for the same episode, or if several sputum samples show resistance to oral antibiotics. The committee discussed that specialist advice should be sought for people needing intravenous antibiotics, to discuss local options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate for the person.\n\nReturn to recommendations\n\n# Choice of antibiotic for treating an acute exacerbation of bronchiectasis\n\nRecommendations 1.2.1 to 1.2.3, and tables\xa01 and 2\n\n## Why the committee made the recommendations\n\nVery limited evidence was identified to guide the choice of antibiotic for treating an acute exacerbation of bronchiectasis. Based on experience, common pathogens in acute exacerbations, the susceptibility of these to various classes of antibiotics, the risks of resistance and good antimicrobial stewardship, the committee agreed the following antibiotic choices for empirical treatment in the absence of current susceptibility data. Choice should be guided by the most recent sputum culture and susceptibilities where possible. Several oral and intravenous antibiotics were recommended to enable antibiotics to be selected based on the severity of illness and previous antibiotic use.\n\nFirst-choice oral antibiotics for empirical treatment are:\n\namoxicillin (a penicillin), which has good activity against common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae\n\nclarithromycin (a macrolide)\n\ndoxycycline (a tetracycline; adults and young people over 12\xa0years only).\n\nAlternative choice oral antibiotics for empirical treatment for people who are at higher risk of treatment failure (which may include people who have had repeated courses of antibiotics, a previous sputum culture with resistant or atypical bacteria, or people at higher risk of developing complications) are:\n\nco-amoxiclav, a broad-spectrum antibiotic which combines a penicillin with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone or\n\na fluoroquinolone: levofloxacin in adults or ciprofloxacin in children (only on specialist advice because fluoroquinolones are generally not recommended in children or young people who are growing), which have good activity against atypical bacteria, particularly Pseudomonas aeruginosa.\n\nThe committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system (press release October 2018). This includes a recommendation to not use them for mild or moderately severe infections unless other antibiotics cannot be used. The committee discussed that fluoroquinolones are appropriate as an alternative option for people who may be at a higher risk of treatment failure. However, the committee was keen to point out that fluoroquinolone safety concerns should be taken into account on an individual patient basis.\n\nFirst-choice intravenous antibiotics for empirical treatment in people who are unable to take oral antibiotics or are severely unwell are:\n\nco-amoxiclav (a penicillin with a beta-lactamase inhibitor)\n\npiperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor)\n\nlevofloxacin (in adults) or ciprofloxacin (in children [on specialist advice only]), which are fluoroquinolones.\n\nWhen current susceptibility data are available, antibiotics should be chosen and modified accordingly, consulting local microbiologists as needed.\n\nThe committee discussed evidence from a randomised controlled trial, which showed that adding nebulised tobramycin to oral ciprofloxacin did not improve the resolution of exacerbation symptoms, and increased wheeze.\n\nVery limited evidence was identified to guide the duration of antibiotics for treating an acute exacerbation of bronchiectasis. The 1\xa0randomised controlled trial identified, which compared a nebulised antibiotic plus an oral antibiotic with an oral antibiotic alone, used a 14‑day course, which is current practice.\n\nBased on experience, the committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nThe committee agreed that a course of 7\xa0to\xa014\xa0days was required to treat an acute exacerbation, based on an assessment of the person's severity of bronchiectasis, their exacerbation history, the severity of their exacerbation symptoms, previous culture and susceptibility results, and response to treatment.\n\nOral antibiotics should be used first line where possible, in line with the NICE guideline on antimicrobial stewardship.\n\nThe committee agreed that the use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and susceptibility results from sputum culture) and switched to oral treatment where possible. This aligns with the NICE guideline on antimicrobial stewardship and Public Health England's 'Start smart – then focus' toolkit.\n\nReturn to recommendations\n\n# Preventing acute exacerbations of bronchiectasis (non-cystic fibrosis) and choice of antibiotic\n\nRecommendations 1.3.1\xa0to\xa01.3.3\n\n## Why the committee made the recommendations\n\nThe committee discussed the evidence for prophylactic antibiotics. Overall, antibiotics reduced exacerbation rates, hospitalisations and the number of people with an exacerbation. However, there was a significant increase in antibiotic resistance and adverse effects.\n\nMost of the studies were in populations who had experienced multiple exacerbations in the previous year, and the committee thought the findings could not be generalised to everyone with bronchiectasis.\n\nBased on evidence and experience, the committee agreed that people should not routinely be offered antibiotic prophylaxis to prevent acute exacerbations, because of the balance of risks and benefits in the overall population.\n\nFor people with repeated exacerbations, where the benefits of prophylaxis may outweigh the risks, specialist advice should be sought on various management options, which may include a trial of antibiotic prophylaxis (with oral or inhaled antibiotics).\n\nThe committee noted it was difficult to give a precise definition of 'repeated exacerbations' and clinical judgement would be needed to define this on an individualised patient basis.\n\nThe committee agreed that a trial of antibiotic prophylaxis should only be started in people with repeated acute exacerbations on the advice of a specialist, because it is important to consider antibiotic prophylaxis alongside other management options. Shared decision making is important for taking into account the risks and benefits of prophylaxis on an individualised patient basis. This includes discussing the potential benefits of antibiotics for reducing exacerbations, but also the harms of long-term antibiotics. There is an increased risk of resistance with long-term antibiotics, which impacts at both a population and an individual level, and people should be advised that this can mean fewer antibiotics may work for their exacerbations in the future. People should also be advised about possible adverse effects. With macrolides, diarrhoea is common but there are also less common cardiac events, hearing loss and tinnitus, and the potential to interact with other medicines. Bronchospasm is a possible adverse effect with inhaled antibiotics and a challenge test is needed. The committee discussed that people being considered for antibiotic prophylaxis would also need to return for regular review.\n\nThe committee discussed that most evidence for prophylactic antibiotics was for oral macrolide antibiotics in adults, where they reduced exacerbation rates and the number of people with an exacerbation. However, they also increased antibiotic resistance and adverse effects. The limited evidence in children and young people found prophylactic oral macrolide antibiotics did not significantly reduce exacerbations but increased antimicrobial resistance.\n\nThe evidence for nebulised or inhaled antibiotics was particularly limited, and not all products studied are available in the UK. As a class, prophylaxis with nebulised or inhaled antibiotics did not significantly reduce exacerbations in adults. In 1\xa0trial of nebulised colistimethate sodium in people with chronic Pseudomonas aeruginosa infection, exacerbations were significantly reduced in an adherent population, but not in the intention-to-treat population, which was the primary end point. In another trial of nebulised tobramycin, a non-significant increase in exacerbations, and adverse events such as dyspnoea, chest pain and wheeze were seen.\n\nThe committee were unable to make specific recommendations on the choice of antibiotic for prophylaxis, because this will be an individualised decision based on the clinical needs of the person, their preferences and advice from a specialist.\n\nReturn to recommendations\n\nSee the full evidence review for a summary of the evidence and more information."}
|
https://www.nice.org.uk/guidance/ng117
|
This guideline sets out an antimicrobial prescribing strategy for managing and preventing acute exacerbations of bronchiectasis (non-cystic fibrosis). It aims to optimise antibiotic use and reduce antibiotic resistance.
|
ffa2e658c7ce1d30d35aaa8da3771b1124675315
|
nice
|
Vandetanib for treating medullary thyroid cancer
|
Vandetanib for treating medullary thyroid cancer
Evidence-based recommendations on vandetanib (Caprelsa) for treating medullary thyroid cancer in adults.
# Recommendations
Vandetanib is not recommended, within its marketing authorisation, for treating aggressive and symptomatic medullary thyroid cancer in adults with unresectable, locally advanced or metastatic disease.
This recommendation is not intended to affect treatment with vandetanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Vandetanib and cabozantinib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. Best supportive care is the only other available option for people who cannot have vandetanib or cabozantinib.
Clinical trial evidence suggests that vandetanib may delay disease progression compared with best supportive care, but the benefit is uncertain. The evidence about whether vandetanib increases the overall length of time people live is unreliable. Clinical experts consider that vandetanib and cabozantinib are similarly effective, so more robust data from a cabozantinib trial are used because of the uncertainties in the evidence.
Cost-effectiveness estimates for vandetanib compared with either best supportive care or cabozantinib are much higher than what NICE normally considers an acceptable use of NHS resources. Vandetanib does not meet NICE's end-of-life or Cancer Drugs Fund criteria. Therefore, it cannot be recommended as a cost-effective use of NHS resources.# Information about vandetanib
# Marketing authorisation indication
Vandetanib (Caprelsa, Sanofi) is indicated for the 'treatment of aggressive and symptomatic medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease'. For patients in whom rearranged during transfection mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.
# Dosage in the marketing authorisation
300 mg taken orally once daily until disease progression or until the benefits of treatment continuation no longer outweigh its risk. Dose reductions of 200 mg or 100 mg are available if needed.
# Price
£5,000 per 30×300-mg pack, or £2,500 per 30×100-mg pack (excluding VAT; British national formulary July 2017). The company has a commercial arrangement, which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (see section 4) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# The condition and current treatment
## There is a clinical need for active treatments for unresectable, locally advanced or metastatic medullary thyroid cancer
Medullary thyroid cancer is rare and around 25% of cases are hereditary. The most common symptoms, such as diarrhoea and fatigue, can significantly impair patients' quality of life and wellbeing. The patient experts commented that because there was no cure, patients would welcome treatments that delay disease progression and control symptoms. The committee noted that vandetanib and cabozantinib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. The clinical experts explained that both treatments are associated with side effects, so not all patients will be able to tolerate them. The only alternative for these people is best supportive care. Also, the toxicity profile of vandetanib differs from that of cabozantinib, so some people who can have vandetanib may not be able to have cabozantinib. The committee agreed that the relevant comparators were therefore cabozantinib and best supportive care. It concluded that there is a clinical need for active treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer.
# Clinical trial evidence
## The clinical trial population is broader than the marketing authorisation population so the company presented subgroup analyses
Evidence for the clinical effectiveness of vandetanib was from ZETA, a double-blind, randomised controlled trial comparing vandetanib with placebo. The trial included 331 patients with unresectable, locally advanced or metastatic medullary thyroid cancer. The clinical experts advised that in practice, targeted treatment is only considered for progressive and symptomatic disease. They explained that progressive and symptomatic disease was considered to be the same as aggressive and symptomatic disease, for which vandetinib has a marketing authorisation and is available through the Cancer Drugs Fund. Because the trial's inclusion criteria were not restricted to progressive disease, the trial included patients with less severe disease than covered by the marketing authorisation. Therefore the trial included patients who would not be considered for targeted treatment in clinical practice. To address this, the company presented clinical effectiveness data for 2 subgroups from ZETA:
a marketing authorisation subgroup, comprising 186 patients with progressive and symptomatic disease (the 'MA subgroup')
a subgroup comprising patients from the MA subgroup who also had calcitonin (CTN) and carcinoembryonic antigen (CEA) doubling times of 24 months or less (the 'restricted subgroup').
## The MA subgroup best reflected the population having treatment in NHS clinical practice
The company considered the restricted subgroup to represent patients in most need of treatment, and therefore those seen in NHS clinical practice. It noted that the summary of product characteristics emphasised the importance of limiting treatment with vandetanib to patients who are in real need, and that 'rate of change in biomarker levels such as of CTN and/or CEA…might help to identify not only patients in need for treatment but also the optimal moment to commence treatment'. The clinical experts explained that CTN and CEA biomarkers are regularly monitored, can be prognostic and may contribute to a decision to carry out imaging. But the decision to start treatment is based on radiological progression and when the disease becomes symptomatic. The company acknowledged this in its response to consultation on the assessment group's report. The clinical experts considered that it was likely that patients with progressive and symptomatic disease in clinical practice would have tumour biomarker doubling times of 24 months or less. However, the committee considered it clinically inappropriate to wait for biomarker trends before starting treatment for people with progressive and symptomatic disease. The assessment group considered that the baseline characteristics of the MA subgroup reflected patients seen in clinical practice. Having heard from the clinical experts and the assessment group, the committee concluded that the MA subgroup best reflected patients having treatment in practice.
# Other subgroups
## RET mutation status is not an appropriate subgroup for consideration
The marketing authorisation for vandetanib specifies that a possible lower benefit should be taken into account for patients in whom rearranged during transfection (RET) mutation status is negative or unknown. The committee was aware that germline RET mutation testing is standard practice to identify hereditary disease, but that somatic RET mutation testing (to identify RET mutations in those with sporadic or non-hereditary disease) is not funded in the NHS. The clinical experts explained that RET mutation testing is not reliable enough to inform treatment decisions and needs further research. The committee therefore concluded that it was not appropriate to consider the clinical or cost effectiveness of vandetanib based on patients' RET mutation status alone, so its recommendations would cover the whole population regardless of RET mutation status.
# Clinical trial results
## In the MA subgroup, vandetanib improves progression-free survival but the exact benefit is uncertain and the overall survival results are confounded
The ZETA results showed that the overall survival benefit for vandetanib compared with placebo in the MA subgroup analysis was negative, but not statistically significant, with a median follow-up of 105 months (results are academic in confidence and cannot be reported here). ZETA was designed so that patients with progressed disease (at investigator‑assessed progression) in the placebo arm could switch to open-label vandetanib, and those in the vandetanib arm could continue with open‑label vandetanib. A large proportion of patients switched to open-label vandetanib after their disease progressed (80% of patients having placebo and 44% of patients having vandetanib), and neither the company nor the assessment group were able to adjust the trial results for treatment switching. This meant that the trial results were more likely to show the effect of immediate vandetanib compared with delayed vandetanib rather than vandetanib compared with placebo. The committee considered that this did not represent how the drug would be used in clinical practice and that the overall survival results presented were confounded and not reliable. For the primary outcome of centrally reviewed median progression-free survival, the results showed a statistically significant benefit for vandetanib compared with placebo, which was 28.0 months for vandetanib and 16.4 months for placebo (hazard ratio 0.47; 95% confidence interval 0.29 to 0.77), with a median trial follow-up of 24 months. The investigator-assessed median progression-free survival was 22.1 months for vandetanib and 8.3 months for placebo (HR 0.33; 95% CI 0.20 to 0.53). The committee considered that the substantial difference between the centrally reviewed and investigator-assessed results in the placebo arm (median of 16.4 months compared with 8.3 months) introduced further uncertainty into the evidence. The committee therefore concluded that vandetanib improved progression-free survival compared with placebo, but the exact benefit was difficult to establish, and the overall survival results were confounded.
## In the restricted subgroup, overall survival results adjusted for treatment switching are not robust
In additional evidence submitted after consultation, the company presented overall survival results for the restricted subgroup that were adjusted for treatment switching (crossover) in the placebo group using the rank-preserving structural failure time (RPSFT) method. The company used a covariate adjustment approach to address imbalances in the treatment arms relating to disease duration and whether patients had previous systemic treatment. The assessment group considered that the results of the crossover-adjusted analysis should be interpreted with caution because:
RPSFT is a randomisation-based crossover-adjustment method but randomisation was broken in the subgroup analysis
the common treatment effect assumption may not be plausible
covariates other than those chosen by the company may not be balanced between the treatment groups (for example RET mutation status, performance status, tumour burden)
the small number of patients results in uncertain survival estimates
the large proportion of patients in the vandetanib group having vandetanib after disease progression may exaggerate the reduction in placebo benefit generated by the crossover-adjustment method
-ther technical methods used, such as those for estimating confidence intervals, were questionable and could not be verified by the assessment group without further information.The committee noted that none of the results, with and without the covariate adjustment, were statistically significant (results are academic in confidence and cannot be reported here). Also, in the restricted subgroup the hazard ratio for overall survival in the crossover- and covariate‑adjusted analysis showed a greater benefit than the hazard ratio for progression-free survival (academic in confidence), which the committee agreed was implausible. The committee did not have confidence in the reliability of the results of the crossover-adjusted analysis. Therefore it concluded that they were not sufficiently robust for decision making.
## Evidence from ZETA is highly uncertain and not suitable for decision making
The committee considered the advice from NICE's guide to the methods of technology appraisal that when considering subgroup analyses, it should take specific note of the biological or clinical plausibility of a subgroup effect in addition to the strength of the evidence in favour of such an effect. The committee noted that subgroup analysis according to CTN and CEA doubling times was prespecified in the ZETA trial protocol, alongside a number of other subgroups. The committee noted that the very small numbers of patients included in the restricted subgroup of ZETA made any survival estimates imprecise, and any analysis subject to significant uncertainty. The committee also noted that the summary of product characteristics suggested that rate of change in biomarkers such as CTN or CEA or both might help identify patients in need of treatment. However, the company's subgroup analyses only included patients from ZETA who had both CTN and CEA doubling times of 24 months or less, meaning that patients with missing CTN or CEA data were excluded. Because clinical advice suggested that CTN was the more clinically relevant biomarker and an increase in 1 biomarker indicates an increase in the other, the assessment group re-ran the unadjusted subgroup analysis to include patients with missing CEA data. This analysis suggested a much lower treatment benefit with vandetanib than that shown in the subgroup that included only patients with CTN and CEA doubling times of 24 months or less. The committee considered that this further increased uncertainty about the treatment effect in the restricted subgroup. In addition, the company had reported that a crossover‑adjusted analysis had not been attempted in the MA subgroup because initial statistical analysis showed a negative treatment effect for vandetanib compared with placebo in this group. The committee was concerned by the plausibility of the large treatment effect shown by the crossover-adjusted results in the restricted subgroup when a negative effect had been shown in the larger MA subgroup, when the patients in both subgroups had progressive and symptomatic disease. Therefore, given the smaller size of the restricted subgroup, the extensive crossover in ZETA, the limitations with the crossover adjustments (see section 3.5 and section 3.6) including the implausibility of the results, the committee did not consider the evidence showing a differential treatment effect for the restricted subgroup to be robust. Overall, because the restricted subgroup was not considered to best reflect clinical practice in the NHS (see section 3.3) and the results of ZETA were not robust in either subgroup, the committee could not use evidence from ZETA in its decision making.
# Indirect treatment comparison
## Clinical trial evidence for cabozantinib is robust and reflects clinical practice
There was no head-to-head evidence comparing vandetanib with cabozantinib. Evidence for the clinical effectiveness of cabozantinib was from EXAM, a double-blind, randomised controlled trial comparing cabozantinib with placebo in 330 patients with unresectable, locally advanced or metastatic, progressive medullary thyroid cancer. The committee recalled the clinical experts' advice that in practice, targeted treatment is only considered for progressive and symptomatic disease (see section 3.2), and agreed that the patients in EXAM represented those who would be seen in clinical practice. The results of EXAM showed a statistically significant progression-free survival benefit for cabozantinib compared with placebo (median of 11.2 months compared with 4.0 months ; investigator-assessed results were similar) and an overall survival benefit that was not statistically significant (median of 26.6 months compared with 21.1 months ). The committee noted that EXAM did not allow for cabozantinib treatment after disease progression, which it agreed reflected clinical practice and reduced the risk of bias compared with ZETA (see section 3.5). It also noted that progression-free survival in the placebo arm was short, and indeed shorter than in the placebo arm of ZETA (both subgroups). This suggested that these patients had a worse prognosis than those in both ZETA subgroups and were in most need of treatment. It was aware, however, that patients in both arms of the trial had subsequent cancer treatments after progression that may have confounded the overall survival results, although it could not be certain to what extent. The committee concluded that the evidence for cabozantinib was robust and reflected clinical practice.
## Vandetanib and cabozantinib are likely to be similarly effective
The assessment group did an indirect treatment comparison of vandetanib with cabozantinib using a network meta-analysis, which showed that for progression-free survival the 2 treatments were broadly similar. However, the assessment group did not include overall survival in the analysis because of the significant crossover in ZETA. Because the network only contained data from EXAM and ZETA and was subject to uncertainty, the assessment group did not consider the results robust enough to use in the economic model. The committee also recalled its conclusion that the results of ZETA were not sufficiently robust to be used in decision making (see section 3.7). The clinical experts stated that in their opinion, both drugs have similar effectiveness in delaying progression and controlling symptoms, although there is no evidence to show that they prolong survival. They explained that the decision about whether to use vandetanib or cabozantinib in clinical practice was more about their different toxicity profiles than their relative effectiveness. The committee considered that an indirect comparison using data from ZETA would not be sufficiently robust to inform its decision making. It therefore concluded that because there were no robust comparative data and based on clinical advice, vandetanib and cabozantinib were likely to be similarly effective.
# Adverse events
## Adverse events are common and the decision to use vandetanib is based on consideration of the risks and benefits
Almost all patients in ZETA (99.6%) had an adverse event while having vandetanib. The committee was aware that patients with unresectable, locally advanced or metastatic medullary thyroid cancer have a substantial disease burden. This was shown by high levels of adverse events in the placebo arms of the trial and the comorbidities of patients at baseline. The patient expert described side effects such as frequent diarrhoea, rash and fatigue, but considered that the disease would have a more severe effect without treatment. The clinical experts explained that adverse events tend to occur soon after treatment starts, and for most patients the dosage is reduced after the initial treatment period. The experts explained the importance of balancing the risks and benefits when considering treatment with vandetanib, and that treatment is usually started only when the disease becomes symptomatic so that the benefits of treatment outweigh the burden of side effects.
# Economic models
## The company's economic model for vandetanib is not appropriate for decision making
Both the company's original economic model for vandetanib and its updated analysis (including crossover-adjusted results and a revised commercial arrangement) were based only on the restricted subgroup. The assessment group noted that the overall survival extrapolation across the time horizon had been done incorrectly because the parametric curves had been fitted to the crossover-adjusted data as if it were actual trial data rather than modelled data from the crossover-adjustment method. The results therefore did not fully account for the uncertainty that arises from using crossover- and covariate-adjusted data. It noted a further error about the application of costs after discontinuing vandetanib. Having previously concluded that the MA subgroup best reflected the population having treatment in clinical practice in the NHS (see section 3.3), and that the ZETA trial results (including crossover-adjusted analysis) were not appropriate for decision making (see section 3.6 and section 3.7), the committee concluded that the company's economic model for vandetanib was not appropriate for decision making.
## The assessment group's economic model is appropriate for decision making
Given the assessment group's concerns about the company's economic model, it ran its cost-effectiveness analysis in its original model, updating it to take account of the company's crossover-adjusted results from ZETA and revised commercial arrangement. The assessment group did an analysis comparing vandetanib with cabozantinib and best supportive care using EXAM data (assuming the same progression-free and overall survival benefit for both vandetanib and cabozantinib). The committee concluded that this provided a more robust cost-effectiveness estimate for vandetanib than estimates using the ZETA trial results. The committee concluded that the assessment group's model was therefore appropriate for decision making.
# Costs
## Analyses including treatment after progression do not reflect clinical practice so are not appropriate
The company's new base-case analysis did not include the costs of vandetanib after progression because the analysis had been adjusted for patients switching from placebo to vandetanib when their disease progressed. However, the assessment group considered that patients in the vandetanib arm having vandetanib after disease progression would be likely to have some benefit and so the costs should also be included. The assessment group explained that because this analysis used a partitioned survival model, after disease progression patients could only transition to the death state. This meant that treatment after disease progression continued until death. The committee noted that this resulted in an unrealistic overestimation of costs. The clinical experts stated that if imaging showed disease progression, clinicians would normally stop treatment. They explained that treatment may continue if imaging showed only 1 lesion growing and others to be stable, but emphasised that this was uncommon and treatment would only continue for another 1 or 2 months. Because treatment after disease progression does not reflect how the drugs are used in clinical practice, the committee concluded that analyses including treatment with vandetanib after disease progression were not appropriate for decision making.
## The assessment group's method of dealing with treatment discontinuation in its model is acceptable
The assessment group considered that the company's method of dealing with treatment discontinuation before disease progression in its original model underestimated costs. This was because it removed all the costs of vandetanib from the proportion of patients who stopped treatment before progression. The assessment group stated that it was unrealistic that no vandetanib costs would be incurred for patients who stopped treatment, particularly given that in clinical practice vandetanib may be stopped early because of toxicity and restarted again later. In its revised model, the company applied vandetanib costs before progression at an increasing rate in the first year, and no costs were incurred thereafter. The assessment group instead applied half the costs of vandetanib to the proportion of patients who stopped treatment before progression. The committee noted that both the company's and assessment group's methods were arbitrary, but agreed that it could not be certain that no costs would be incurred after the first year for patients who stopped treatment before the disease progressed. Because there were no data showing when patients stopped treatment, or if they restarted treatment later, the committee accepted the assessment group's method as a more acceptable approach.
# Utility values
## Utility values for medullary thyroid cancer are unknown but the assessment group's approach is the most acceptable
There are no direct estimates of health utilities for people with medullary thyroid cancer. For utility values before progression, the company mapped data from ZETA to the EQ-5D; for utility values after progression it used data from Beusterien et al. (2009), a study of melanoma. The assessment group preferred to use the same source of data for utility values both before and after progression, and so used values from Fordham et al. (2015), a study of differentiated thyroid cancer, for both. The committee noted that differentiated thyroid cancer was different to medullary thyroid cancer, but acknowledged that the only other potentially relevant study available was in melanoma, which is less generalisable. It noted that Fordham et al. had been used in a previous appraisal submission for thyroid cancer. The committee agreed that it was appropriate to use the same source of data for utility values before and after disease progression and because there were no other data relevant to medullary thyroid cancer it would therefore accept the assessment group's estimates.
# Cost-effectiveness estimates
## The most plausible scenario to assess the cost effectiveness of vandetanib uses EXAM data but some uncertainty remains
The committee had concluded that the ZETA trial results were not appropriate for decision making (see section 3.7 and section 3.11). It recalled that data from EXAM were robust (see section 3.8), but noted that the analysis using these data relied on strong assumptions about the similar effectiveness of vandetanib and cabozantinib. However, having heard clinical advice that the choice of drug is based more on adverse event profile than on effectiveness, and that clinicians generally do not prefer 1 drug over the other, the committee had concluded that vandetanib and cabozantinib were likely to be similarly effective (see section 3.9). Therefore, although the assumption of equal progression-free and overall survival benefit for vandetanib and cabozantinib was uncertain, because there was no other appropriate analysis for vandetanib, the committee concluded that the analysis using the EXAM data represented the most reliable scenario to assess the cost effectiveness of vandetanib.
## The most plausible ICERs are higher than £50,000 per QALY gained
Including the confidential commercial arrangements for vandetanib and cabozantinib and using EXAM data, the probabilistic incremental cost‑effectiveness ratio (ICER) in the incremental analysis of vandetanib compared with cabozantinib was much higher than £100,000 per quality-adjusted life year (QALY) gained (the exact ICER is commercial in confidence and cannot be reported here). The committee was aware that some people who can have vandetanib may not be able to have cabozantinib and that best supportive care was also a relevant comparator (see section 3.1). The probabilistic ICER for a pairwise comparison of vandetanib with best supportive care, using EXAM data, was higher than £50,000 per QALY gained (the exact ICER is commercial in confidence and cannot be reported here).
# Uncaptured benefits
## There are no health-related benefits that are not captured in the analyses
The committee acknowledged the company's comments that vandetanib was the first systemic therapy for medullary thyroid cancer to gain a marketing authorisation, and that the disease is rare. It considered however that although vandetanib may work well for some people, others may have substantial side effects. The committee concluded that all relevant health-related quality-of-life benefits were captured in the economic modelling and that there were no additional benefits not already captured in the QALY calculations.
# End of life
## Vandetanib meets the extension to life criterion
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The ZETA trial results were confounded and the crossover-adjusted analysis was not considered robust (see section 3.5 and section 3.6) so the committee considered the survival estimates from EXAM. EXAM showed overall survival benefit of more than 3 months for cabozantinib compared with placebo, and the model estimated a mean survival benefit of about 7 months. So the committee agreed that cabozantinib met the end-of-life criterion for extension to life (see NICE's technology appraisal guidance on cabozantinib for treating medullary thyroid cancer). Given the expected similarity in the drugs' efficacy (see section 3.9), the committee concluded that vandetanib could also be considered to meet this criterion.
## Vandetanib does not meet the short life expectancy criterion so the end-of-life criteria do not apply
For the short life expectancy criterion, the company's new analysis predicted a mean survival with best supportive care of less than 24 months in the restricted group. However, the committee had concluded that this analysis was not sufficiently robust for decision making (see section 3.6 and section 3.7), and that data on cabozantinib from EXAM were a more reliable source of survival estimates in the population that reflected clinical practice (see section 3.8). The committee was aware that the modelled mean and median overall survival estimates were 47 and 21 months respectively and that some patients with unresectable, locally advanced or metastatic medullary thyroid cancer live for a long time (see NICE's technology appraisal guidance on cabozantinib). The committee had not seen any new evidence that was robust enough to change its conclusion that vandetanib did not meet the short life expectancy criterion. It agreed, on balance, that the end-of-life criteria did not apply. The committee concluded that the most plausible ICERs for vandetanib were much higher than the range normally considered cost effective, that is £20,000 to £30,000 per QALY gained. Therefore vandetanib could not be recommended for routine use in the NHS.
# Cancer Drugs Fund
## The company proposed that vandetanib could be used in the Cancer Drugs Fund for data collection
Having concluded that vandetanib could not be recommended for routine use, the committee then considered if it could be recommended for treating medullary thyroid cancer within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company expressed an interest in vandetanib being considered for use in the Cancer Drugs Fund. It proposed that data on the baseline characteristics of patients could be collected to address uncertainty about the nature of the patient population having vandetanib in clinical practice in the NHS: specifically whether patients had progressive and symptomatic disease (the MA subgroup), or progressive and symptomatic disease and CTN or CEA doubling times of 24 months or less (the restricted subgroup).
## Vandetanib does not meet the criteria for inclusion in the Cancer Drugs Fund
The committee had previously agreed that CTN or CEA doubling times were not used to start treatment with vandetanib (see section 3.3). It considered there was limited benefit to the NHS from collecting data on patient characteristics for CTN or CEA doubling times. The key uncertainties in the clinical‑effectiveness evidence for vandetanib were about overall survival benefit, and the committee considered that not enough patients would have vandetanib for data collection to address this uncertainty. The committee also did not consider that there was plausible potential to satisfy the criteria for routine use because the most plausible ICERs were much higher than those NICE normally considers to be a cost-effective use of NHS resources. Therefore it concluded that vandetanib did not meet the criteria for inclusion in the Cancer Drugs Fund.
# Conclusions
## The disease is rare, but the cost-effectiveness estimates are too high to justify considerable deviation from NICE principles
The committee acknowledged the small patient population covered by the marketing authorisation for vandetanib. It noted the advice from NICE's social value judgements: principles for the development of NICE guidance, that NICE should evaluate drugs to treat rare conditions in the same way as any other treatment. In response to consultation, the company highlighted that the social value judgements advice specifically refers to orphan drugs, whereas medullary thyroid cancer was very rare and would be classed as 'ultra-orphan' because it affects fewer than 1 in 50,000 people. The committee was aware that despite the ultra‑orphan status of medullary thyroid cancer, vandetanib had not met the criteria for consideration through the NICE highly specialised technologies process because the disease is not chronic, does not need lifelong treatment and is not treated exclusively within a highly specialised service. When developing the social value judgements, the Citizens Council considered that rarity alone should not justify accepting high ICERs, but that the committee could take into account other factors such as disease severity in its decision making. The committee acknowledged the difficulty of appraising drugs for very rare conditions, and the severity of medullary thyroid cancer. It was aware that vandetanib was available through the Cancer Drugs Fund based on the same trial evidence reviewed by the appraisal committee, and acknowledged the importance for patients with specific characteristics to have a choice of treatment. However, it considered that the ICERs were too high to justify considerable deviation from NICE principles in terms of what is normally considered a cost‑effective use of NHS resources.
## Vandetanib cannot be considered cost effective in a subgroup; therefore it is not recommended
The committee considered whether vandetanib could be considered cost effective in a subgroup of patients covered by the marketing authorisation:
CTN and CEA doubling times of 24 months or less: the committee had concluded that patients with progressive and symptomatic disease and CTN and CEA doubling times of 24 months or less did not reflect patients in clinical practice because the decision to start treatment was not based on biomarker trends, although it accepted that some NHS patients' disease would meet this criterion. However, the committee did not consider it appropriate to wait for biomarker trends before starting treatment for people with progressive and symptomatic disease (see section 3.3). It concluded that a change in practice could not reasonably be expected when progressive and symptomatic disease remained the primary driver of treatment, notwithstanding the uncertainty of the effectiveness data in this group (see section 3.6 and section 3.7).
RET mutation status: the committee recalled its conclusion that it was not appropriate to consider the clinical or cost effectiveness of vandetanib based on patients' RET mutation status alone (see section 3.4).
Patients who cannot have cabozantinib: the committee recognised that there was an unmet need for patients who could not tolerate cabozantinib, but it had seen no evidence for the effectiveness of vandetanib in this group. Also, the ICER for vandetanib compared with best supportive care was higher than the range normally considered cost effective, that is £20,000 to £30,000 per QALY gained (see section 3.17). Therefore vandetanib could not be recommended for routine use in the NHS in this subgroup.Given the lack of robust effectiveness evidence presented for vandetanib, the committee had accepted that vandetanib was likely to be similarly effective to cabozantinib based on clinical opinion. However, it concluded that even having accepted this, the ICER for vandetanib was much too high to consider it a cost-effective use of NHS resources. Therefore the committee could not recommend it for treating medullary thyroid cancer, because the most plausible ICER was much higher than £20,000 to £30,000 per QALY gained.
|
{'Recommendations': "Vandetanib is not recommended, within its marketing authorisation, for treating aggressive and symptomatic medullary thyroid cancer in adults with unresectable, locally advanced or metastatic disease.\n\nThis recommendation is not intended to affect treatment with vandetanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nVandetanib and cabozantinib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. Best supportive care is the only other available option for people who cannot have vandetanib or cabozantinib.\n\nClinical trial evidence suggests that vandetanib may delay disease progression compared with best supportive care, but the benefit is uncertain. The evidence about whether vandetanib increases the overall length of time people live is unreliable. Clinical experts consider that vandetanib and cabozantinib are similarly effective, so more robust data from a cabozantinib trial are used because of the uncertainties in the evidence.\n\nCost-effectiveness estimates for vandetanib compared with either best supportive care or cabozantinib are much higher than what NICE normally considers an acceptable use of NHS resources. Vandetanib does not meet NICE's end-of-life or Cancer Drugs Fund criteria. Therefore, it cannot be recommended as a cost-effective use of NHS resources.", 'Information about vandetanib': "# Marketing authorisation indication\n\nVandetanib (Caprelsa, Sanofi) is indicated for the 'treatment of aggressive and symptomatic medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease'. For patients in whom rearranged during transfection mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.\n\n# Dosage in the marketing authorisation\n\n300\xa0mg taken orally once daily until disease progression or until the benefits of treatment continuation no longer outweigh its risk. Dose reductions of 200\xa0mg or 100\xa0mg are available if needed.\n\n# Price\n\n£5,000 per 30×300-mg pack, or £2,500 per 30×100-mg pack (excluding VAT; British national formulary July 2017). The company has a commercial arrangement, which would apply if the technology had been recommended.", 'Committee discussion': "The appraisal committee (see section\xa04) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## There is a clinical need for active treatments for unresectable, locally advanced or metastatic medullary thyroid cancer\n\nMedullary thyroid cancer is rare and around 25% of cases are hereditary. The most common symptoms, such as diarrhoea and fatigue, can significantly impair patients' quality of life and wellbeing. The patient experts commented that because there was no cure, patients would welcome treatments that delay disease progression and control symptoms. The committee noted that vandetanib and cabozantinib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. The clinical experts explained that both treatments are associated with side effects, so not all patients will be able to tolerate them. The only alternative for these people is best supportive care. Also, the toxicity profile of vandetanib differs from that of cabozantinib, so some people who can have vandetanib may not be able to have cabozantinib. The committee agreed that the relevant comparators were therefore cabozantinib and best supportive care. It concluded that there is a clinical need for active treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer.\n\n# Clinical trial evidence\n\n## The clinical trial population is broader than the marketing authorisation population so the company presented subgroup analyses\n\nEvidence for the clinical effectiveness of vandetanib was from ZETA, a double-blind, randomised controlled trial comparing vandetanib with placebo. The trial included 331\xa0patients with unresectable, locally advanced or metastatic medullary thyroid cancer. The clinical experts advised that in practice, targeted treatment is only considered for progressive and symptomatic disease. They explained that progressive and symptomatic disease was considered to be the same as aggressive and symptomatic disease, for which vandetinib has a marketing authorisation and is available through the Cancer Drugs Fund. Because the trial's inclusion criteria were not restricted to progressive disease, the trial included patients with less severe disease than covered by the marketing authorisation. Therefore the trial included patients who would not be considered for targeted treatment in clinical practice. To address this, the company presented clinical effectiveness data for 2\xa0subgroups from ZETA:\n\na marketing authorisation subgroup, comprising 186\xa0patients with progressive and symptomatic disease (the 'MA subgroup')\n\na subgroup comprising patients from the MA subgroup who also had calcitonin (CTN) and carcinoembryonic antigen (CEA) doubling times of 24\xa0months or less (the 'restricted subgroup').\n\n## The MA subgroup best reflected the population having treatment in NHS clinical practice\n\nThe company considered the restricted subgroup to represent patients in most need of treatment, and therefore those seen in NHS clinical practice. It noted that the summary of product characteristics emphasised the importance of limiting treatment with vandetanib to patients who are in real need, and that 'rate of change in biomarker levels such as of CTN and/or CEA…might help to identify not only patients in need for treatment but also the optimal moment to commence treatment'. The clinical experts explained that CTN and CEA biomarkers are regularly monitored, can be prognostic and may contribute to a decision to carry out imaging. But the decision to start treatment is based on radiological progression and when the disease becomes symptomatic. The company acknowledged this in its response to consultation on the assessment group's report. The clinical experts considered that it was likely that patients with progressive and symptomatic disease in clinical practice would have tumour biomarker doubling times of 24\xa0months or less. However, the committee considered it clinically inappropriate to wait for biomarker trends before starting treatment for people with progressive and symptomatic disease. The assessment group considered that the baseline characteristics of the MA subgroup reflected patients seen in clinical practice. Having heard from the clinical experts and the assessment group, the committee concluded that the MA subgroup best reflected patients having treatment in practice.\n\n# Other subgroups\n\n## RET mutation status is not an appropriate subgroup for consideration\n\nThe marketing authorisation for vandetanib specifies that a possible lower benefit should be taken into account for patients in whom rearranged during transfection (RET) mutation status is negative or unknown. The committee was aware that germline RET mutation testing is standard practice to identify hereditary disease, but that somatic RET mutation testing (to identify RET mutations in those with sporadic or non-hereditary disease) is not funded in the NHS. The clinical experts explained that RET mutation testing is not reliable enough to inform treatment decisions and needs further research. The committee therefore concluded that it was not appropriate to consider the clinical or cost effectiveness of vandetanib based on patients' RET mutation status alone, so its recommendations would cover the whole population regardless of RET mutation status.\n\n# Clinical trial results\n\n## In the MA subgroup, vandetanib improves progression-free survival but the exact benefit is uncertain and the overall survival results are confounded\n\nThe ZETA results showed that the overall survival benefit for vandetanib compared with placebo in the MA subgroup analysis was negative, but not statistically significant, with a median follow-up of 105\xa0months (results are academic in confidence and cannot be reported here). ZETA was designed so that patients with progressed disease (at investigator‑assessed progression) in the placebo arm could switch to open-label vandetanib, and those in the vandetanib arm could continue with open‑label vandetanib. A large proportion of patients switched to open-label vandetanib after their disease progressed (80% of patients having placebo and 44% of patients having vandetanib), and neither the company nor the assessment group were able to adjust the trial results for treatment switching. This meant that the trial results were more likely to show the effect of immediate vandetanib compared with delayed vandetanib rather than vandetanib compared with placebo. The committee considered that this did not represent how the drug would be used in clinical practice and that the overall survival results presented were confounded and not reliable. For the primary outcome of centrally reviewed median progression-free survival, the results showed a statistically significant benefit for vandetanib compared with placebo, which was 28.0\xa0months for vandetanib and 16.4\xa0months for placebo (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.29\xa0to\xa00.77), with a median trial follow-up of 24\xa0months. The investigator-assessed median progression-free survival was 22.1\xa0months for vandetanib and 8.3\xa0months for placebo (HR 0.33; 95% CI 0.20 to 0.53). The committee considered that the substantial difference between the centrally reviewed and investigator-assessed results in the placebo arm (median of 16.4\xa0months compared with 8.3\xa0months) introduced further uncertainty into the evidence. The committee therefore concluded that vandetanib improved progression-free survival compared with placebo, but the exact benefit was difficult to establish, and the overall survival results were confounded.\n\n## In the restricted subgroup, overall survival results adjusted for treatment switching are not robust\n\nIn additional evidence submitted after consultation, the company presented overall survival results for the restricted subgroup that were adjusted for treatment switching (crossover) in the placebo group using the rank-preserving structural failure time (RPSFT) method. The company used a covariate adjustment approach to address imbalances in the treatment arms relating to disease duration and whether patients had previous systemic treatment. The assessment group considered that the results of the crossover-adjusted analysis should be interpreted with caution because:\n\nRPSFT is a randomisation-based crossover-adjustment method but randomisation was broken in the subgroup analysis\n\nthe common treatment effect assumption may not be plausible\n\ncovariates other than those chosen by the company may not be balanced between the treatment groups (for example RET mutation status, performance status, tumour burden)\n\nthe small number of patients results in uncertain survival estimates\n\nthe large proportion of patients in the vandetanib group having vandetanib after disease progression may exaggerate the reduction in placebo benefit generated by the crossover-adjustment method\n\nother technical methods used, such as those for estimating confidence intervals, were questionable and could not be verified by the assessment group without further information.The committee noted that none of the results, with and without the covariate adjustment, were statistically significant (results are academic in confidence and cannot be reported here). Also, in the restricted subgroup the hazard ratio for overall survival in the crossover- and covariate‑adjusted analysis showed a greater benefit than the hazard ratio for progression-free survival (academic in confidence), which the committee agreed was implausible. The committee did not have confidence in the reliability of the results of the crossover-adjusted analysis. Therefore it concluded that they were not sufficiently robust for decision making.\n\n## Evidence from ZETA is highly uncertain and not suitable for decision making\n\nThe committee considered the advice from NICE's guide to the methods of technology appraisal that when considering subgroup analyses, it should take specific note of the biological or clinical plausibility of a subgroup effect in addition to the strength of the evidence in favour of such an effect. The committee noted that subgroup analysis according to CTN and CEA doubling times was prespecified in the ZETA trial protocol, alongside a number of other subgroups. The committee noted that the very small numbers of patients included in the restricted subgroup of ZETA made any survival estimates imprecise, and any analysis subject to significant uncertainty. The committee also noted that the summary of product characteristics suggested that rate of change in biomarkers such as CTN or CEA or both might help identify patients in need of treatment. However, the company's subgroup analyses only included patients from ZETA who had both CTN and CEA doubling times of 24\xa0months or less, meaning that patients with missing CTN or CEA data were excluded. Because clinical advice suggested that CTN was the more clinically relevant biomarker and an increase in 1\xa0biomarker indicates an increase in the other, the assessment group re-ran the unadjusted subgroup analysis to include patients with missing CEA data. This analysis suggested a much lower treatment benefit with vandetanib than that shown in the subgroup that included only patients with CTN and CEA doubling times of 24\xa0months or less. The committee considered that this further increased uncertainty about the treatment effect in the restricted subgroup. In addition, the company had reported that a crossover‑adjusted analysis had not been attempted in the MA subgroup because initial statistical analysis showed a negative treatment effect for vandetanib compared with placebo in this group. The committee was concerned by the plausibility of the large treatment effect shown by the crossover-adjusted results in the restricted subgroup when a negative effect had been shown in the larger MA subgroup, when the patients in both subgroups had progressive and symptomatic disease. Therefore, given the smaller size of the restricted subgroup, the extensive crossover in ZETA, the limitations with the crossover adjustments (see section\xa03.5 and\xa0section 3.6) including the implausibility of the results, the committee did not consider the evidence showing a differential treatment effect for the restricted subgroup to be robust. Overall, because the restricted subgroup was not considered to best reflect clinical practice in the NHS (see section\xa03.3) and the results of ZETA were not robust in either subgroup, the committee could not use evidence from ZETA in its decision making.\n\n# Indirect treatment comparison\n\n## Clinical trial evidence for cabozantinib is robust and reflects clinical practice\n\nThere was no head-to-head evidence comparing vandetanib with cabozantinib. Evidence for the clinical effectiveness of cabozantinib was from EXAM, a double-blind, randomised controlled trial comparing cabozantinib with placebo in 330\xa0patients with unresectable, locally advanced or metastatic, progressive medullary thyroid cancer. The committee recalled the clinical experts' advice that in practice, targeted treatment is only considered for progressive and symptomatic disease (see section\xa03.2), and agreed that the patients in EXAM represented those who would be seen in clinical practice. The results of EXAM showed a statistically significant progression-free survival benefit for cabozantinib compared with placebo (median of 11.2\xa0months compared with 4.0\xa0months [HR 0.28; 95% CI 0.19 to 0.40]; investigator-assessed results were similar) and an overall survival benefit that was not statistically significant (median of 26.6\xa0months compared with 21.1\xa0months [HR 0.85; 95% CI 0.64 to 1.12]). The committee noted that EXAM did not allow for cabozantinib treatment after disease progression, which it agreed reflected clinical practice and reduced the risk of bias compared with ZETA (see section\xa03.5). It also noted that progression-free survival in the placebo arm was short, and indeed shorter than in the placebo arm of ZETA (both subgroups). This suggested that these patients had a worse prognosis than those in both ZETA subgroups and were in most need of treatment. It was aware, however, that patients in both arms of the trial had subsequent cancer treatments after progression that may have confounded the overall survival results, although it could not be certain to what extent. The committee concluded that the evidence for cabozantinib was robust and reflected clinical practice.\n\n## Vandetanib and cabozantinib are likely to be similarly effective\n\nThe assessment group did an indirect treatment comparison of vandetanib with cabozantinib using a network meta-analysis, which showed that for progression-free survival the 2\xa0treatments were broadly similar. However, the assessment group did not include overall survival in the analysis because of the significant crossover in ZETA. Because the network only contained data from EXAM and ZETA and was subject to uncertainty, the assessment group did not consider the results robust enough to use in the economic model. The committee also recalled its conclusion that the results of ZETA were not sufficiently robust to be used in decision making (see section\xa03.7). The clinical experts stated that in their opinion, both drugs have similar effectiveness in delaying progression and controlling symptoms, although there is no evidence to show that they prolong survival. They explained that the decision about whether to use vandetanib or cabozantinib in clinical practice was more about their different toxicity profiles than their relative effectiveness. The committee considered that an indirect comparison using data from ZETA would not be sufficiently robust to inform its decision making. It therefore concluded that because there were no robust comparative data and based on clinical advice, vandetanib and cabozantinib were likely to be similarly effective.\n\n# Adverse events\n\n## Adverse events are common and the decision to use vandetanib is based on consideration of the risks and benefits\n\nAlmost all patients in ZETA (99.6%) had an adverse event while having vandetanib. The committee was aware that patients with unresectable, locally advanced or metastatic medullary thyroid cancer have a substantial disease burden. This was shown by high levels of adverse events in the placebo arms of the trial and the comorbidities of patients at baseline. The patient expert described side effects such as frequent diarrhoea, rash and fatigue, but considered that the disease would have a more severe effect without treatment. The clinical experts explained that adverse events tend to occur soon after treatment starts, and for most patients the dosage is reduced after the initial treatment period. The experts explained the importance of balancing the risks and benefits when considering treatment with vandetanib, and that treatment is usually started only when the disease becomes symptomatic so that the benefits of treatment outweigh the burden of side effects.\n\n# Economic models\n\n## The company's economic model for vandetanib is not appropriate for decision making\n\nBoth the company's original economic model for vandetanib and its updated analysis (including crossover-adjusted results and a revised commercial arrangement) were based only on the restricted subgroup. The assessment group noted that the overall survival extrapolation across the time horizon had been done incorrectly because the parametric curves had been fitted to the crossover-adjusted data as if it were actual trial data rather than modelled data from the crossover-adjustment method. The results therefore did not fully account for the uncertainty that arises from using crossover- and covariate-adjusted data. It noted a further error about the application of costs after discontinuing vandetanib. Having previously concluded that the MA subgroup best reflected the population having treatment in clinical practice in the NHS (see section\xa03.3), and that the ZETA trial results (including crossover-adjusted analysis) were not appropriate for decision making (see section\xa03.6 and\xa0section 3.7), the committee concluded that the company's economic model for vandetanib was not appropriate for decision making.\n\n## The assessment group's economic model is appropriate for decision making\n\nGiven the assessment group's concerns about the company's economic model, it ran its cost-effectiveness analysis in its original model, updating it to take account of the company's crossover-adjusted results from ZETA and revised commercial arrangement. The assessment group did an analysis comparing vandetanib with cabozantinib and best supportive care using EXAM data (assuming the same progression-free and overall survival benefit for both vandetanib and cabozantinib). The committee concluded that this provided a more robust cost-effectiveness estimate for vandetanib than estimates using the ZETA trial results. The committee concluded that the assessment group's model was therefore appropriate for decision making.\n\n# Costs\n\n## Analyses including treatment after progression do not reflect clinical practice so are not appropriate\n\nThe company's new base-case analysis did not include the costs of vandetanib after progression because the analysis had been adjusted for patients switching from placebo to vandetanib when their disease progressed. However, the assessment group considered that patients in the vandetanib arm having vandetanib after disease progression would be likely to have some benefit and so the costs should also be included. The assessment group explained that because this analysis used a partitioned survival model, after disease progression patients could only transition to the death state. This meant that treatment after disease progression continued until death. The committee noted that this resulted in an unrealistic overestimation of costs. The clinical experts stated that if imaging showed disease progression, clinicians would normally stop treatment. They explained that treatment may continue if imaging showed only 1\xa0lesion growing and others to be stable, but emphasised that this was uncommon and treatment would only continue for another 1\xa0or\xa02 months. Because treatment after disease progression does not reflect how the drugs are used in clinical practice, the committee concluded that analyses including treatment with vandetanib after disease progression were not appropriate for decision making.\n\n## The assessment group's method of dealing with treatment discontinuation in its model is acceptable\n\nThe assessment group considered that the company's method of dealing with treatment discontinuation before disease progression in its original model underestimated costs. This was because it removed all the costs of vandetanib from the proportion of patients who stopped treatment before progression. The assessment group stated that it was unrealistic that no vandetanib costs would be incurred for patients who stopped treatment, particularly given that in clinical practice vandetanib may be stopped early because of toxicity and restarted again later. In its revised model, the company applied vandetanib costs before progression at an increasing rate in the first year, and no costs were incurred thereafter. The assessment group instead applied half the costs of vandetanib to the proportion of patients who stopped treatment before progression. The committee noted that both the company's and assessment group's methods were arbitrary, but agreed that it could not be certain that no costs would be incurred after the first year for patients who stopped treatment before the disease progressed. Because there were no data showing when patients stopped treatment, or if they restarted treatment later, the committee accepted the assessment group's method as a more acceptable approach.\n\n# Utility values\n\n## Utility values for medullary thyroid cancer are unknown but the assessment group's approach is the most acceptable\n\nThere are no direct estimates of health utilities for people with medullary thyroid cancer. For utility values before progression, the company mapped data from ZETA to the EQ-5D; for utility values after progression it used data from Beusterien et al. (2009), a study of melanoma. The assessment group preferred to use the same source of data for utility values both before and after progression, and so used values from Fordham et al. (2015), a study of differentiated thyroid cancer, for both. The committee noted that differentiated thyroid cancer was different to medullary thyroid cancer, but acknowledged that the only other potentially relevant study available was in melanoma, which is less generalisable. It noted that Fordham et al. had been used in a previous appraisal submission for thyroid cancer. The committee agreed that it was appropriate to use the same source of data for utility values before and after disease progression and because there were no other data relevant to medullary thyroid cancer it would therefore accept the assessment group's estimates.\n\n# Cost-effectiveness estimates\n\n## The most plausible scenario to assess the cost effectiveness of vandetanib uses EXAM data but some uncertainty remains\n\nThe committee had concluded that the ZETA trial results were not appropriate for decision making (see section\xa03.7 and section 3.11). It recalled that data from EXAM were robust (see section\xa03.8), but noted that the analysis using these data relied on strong assumptions about the similar effectiveness of vandetanib and cabozantinib. However, having heard clinical advice that the choice of drug is based more on adverse event profile than on effectiveness, and that clinicians generally do not prefer 1\xa0drug over the other, the committee had concluded that vandetanib and cabozantinib were likely to be similarly effective (see section\xa03.9). Therefore, although the assumption of equal progression-free and overall survival benefit for vandetanib and cabozantinib was uncertain, because there was no other appropriate analysis for vandetanib, the committee concluded that the analysis using the EXAM data represented the most reliable scenario to assess the cost effectiveness of vandetanib.\n\n## The most plausible ICERs are higher than £50,000 per QALY gained\n\nIncluding the confidential commercial arrangements for vandetanib and cabozantinib and using EXAM data, the probabilistic incremental cost‑effectiveness ratio (ICER) in the incremental analysis of vandetanib compared with cabozantinib was much higher than £100,000 per quality-adjusted life year (QALY) gained (the exact ICER is commercial in confidence and cannot be reported here). The committee was aware that some people who can have vandetanib may not be able to have cabozantinib and that best supportive care was also a relevant comparator (see section\xa03.1). The probabilistic ICER for a pairwise comparison of vandetanib with best supportive care, using EXAM data, was higher than £50,000 per QALY gained (the exact ICER is commercial in confidence and cannot be reported here).\n\n# Uncaptured benefits\n\n## There are no health-related benefits that are not captured in the analyses\n\nThe committee acknowledged the company's comments that vandetanib was the first systemic therapy for medullary thyroid cancer to gain a marketing authorisation, and that the disease is rare. It considered however that although vandetanib may work well for some people, others may have substantial side effects. The committee concluded that all relevant health-related quality-of-life benefits were captured in the economic modelling and that there were no additional benefits not already captured in the QALY calculations.\n\n# End of life\n\n## Vandetanib meets the extension to life criterion\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The ZETA trial results were confounded and the crossover-adjusted analysis was not considered robust (see section 3.5 and\xa0section 3.6) so the committee considered the survival estimates from EXAM. EXAM showed overall survival benefit of more than 3\xa0months for cabozantinib compared with placebo, and the model estimated a mean survival benefit of about 7\xa0months. So the committee agreed that cabozantinib met the end-of-life criterion for extension to life (see NICE's technology appraisal guidance on cabozantinib for treating medullary thyroid cancer). Given the expected similarity in the drugs' efficacy (see section\xa03.9), the committee concluded that vandetanib could also be considered to meet this criterion.\n\n## Vandetanib does not meet the short life expectancy criterion so the end-of-life criteria do not apply\n\nFor the short life expectancy criterion, the company's new analysis predicted a mean survival with best supportive care of less than 24\xa0months in the restricted group. However, the committee had concluded that this analysis was not sufficiently robust for decision making (see section 3.6\xa0and\xa0section 3.7), and that data on cabozantinib from EXAM were a more reliable source of survival estimates in the population that reflected clinical practice (see section\xa03.8). The committee was aware that the modelled mean and median overall survival estimates were 47\xa0and 21\xa0months respectively and that some patients with unresectable, locally advanced or metastatic medullary thyroid cancer live for a long time (see NICE's technology appraisal guidance on cabozantinib). The committee had not seen any new evidence that was robust enough to change its conclusion that vandetanib did not meet the short life expectancy criterion. It agreed, on balance, that the end-of-life criteria did not apply. The committee concluded that the most plausible ICERs for vandetanib were much higher than the range normally considered cost effective, that is £20,000 to £30,000 per QALY gained. Therefore vandetanib could not be recommended for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## The company proposed that vandetanib could be used in the Cancer Drugs Fund for data collection\n\nHaving concluded that vandetanib could not be recommended for routine use, the committee then considered if it could be recommended for treating medullary thyroid cancer within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company expressed an interest in vandetanib being considered for use in the Cancer Drugs Fund. It proposed that data on the baseline characteristics of patients could be collected to address uncertainty about the nature of the patient population having vandetanib in clinical practice in the NHS: specifically whether patients had progressive and symptomatic disease (the MA subgroup), or progressive and symptomatic disease and CTN or CEA doubling times of 24\xa0months or less (the restricted subgroup).\n\n## Vandetanib does not meet the criteria for inclusion in the Cancer Drugs Fund\n\nThe committee had previously agreed that CTN or CEA doubling times were not used to start treatment with vandetanib (see section\xa03.3). It considered there was limited benefit to the NHS from collecting data on patient characteristics for CTN or CEA doubling times. The key uncertainties in the clinical‑effectiveness evidence for vandetanib were about overall survival benefit, and the committee considered that not enough patients would have vandetanib for data collection to address this uncertainty. The committee also did not consider that there was plausible potential to satisfy the criteria for routine use because the most plausible ICERs were much higher than those NICE normally considers to be a cost-effective use of NHS resources. Therefore it concluded that vandetanib did not meet the criteria for inclusion in the Cancer Drugs Fund.\n\n# Conclusions\n\n## The disease is rare, but the cost-effectiveness estimates are too high to justify considerable deviation from NICE principles\n\nThe committee acknowledged the small patient population covered by the marketing authorisation for vandetanib. It noted the advice from NICE's social value judgements: principles for the development of NICE guidance, that NICE should evaluate drugs to treat rare conditions in the same way as any other treatment. In response to consultation, the company highlighted that the social value judgements advice specifically refers to orphan drugs, whereas medullary thyroid cancer was very rare and would be classed as 'ultra-orphan' because it affects fewer than 1\xa0in\xa050,000 people. The committee was aware that despite the ultra‑orphan status of medullary thyroid cancer, vandetanib had not met the criteria for consideration through the NICE highly specialised technologies process because the disease is not chronic, does not need lifelong treatment and is not treated exclusively within a highly specialised service. When developing the social value judgements, the Citizens Council considered that rarity alone should not justify accepting high ICERs, but that the committee could take into account other factors such as disease severity in its decision making. The committee acknowledged the difficulty of appraising drugs for very rare conditions, and the severity of medullary thyroid cancer. It was aware that vandetanib was available through the Cancer Drugs Fund based on the same trial evidence reviewed by the appraisal committee, and acknowledged the importance for patients with specific characteristics to have a choice of treatment. However, it considered that the ICERs were too high to justify considerable deviation from NICE principles in terms of what is normally considered a cost‑effective use of NHS resources.\n\n## Vandetanib cannot be considered cost effective in a subgroup; therefore it is not recommended\n\nThe committee considered whether vandetanib could be considered cost effective in a subgroup of patients covered by the marketing authorisation:\n\nCTN and CEA doubling times of 24\xa0months or less: the committee had concluded that patients with progressive and symptomatic disease and CTN and CEA doubling times of 24\xa0months or less did not reflect patients in clinical practice because the decision to start treatment was not based on biomarker trends, although it accepted that some NHS patients' disease would meet this criterion. However, the committee did not consider it appropriate to wait for biomarker trends before starting treatment for people with progressive and symptomatic disease (see section\xa03.3). It concluded that a change in practice could not reasonably be expected when progressive and symptomatic disease remained the primary driver of treatment, notwithstanding the uncertainty of the effectiveness data in this group (see section\xa03.6 and\xa0section 3.7).\n\nRET mutation status: the committee recalled its conclusion that it was not appropriate to consider the clinical or cost effectiveness of vandetanib based on patients' RET mutation status alone (see section\xa03.4).\n\nPatients who cannot have cabozantinib: the committee recognised that there was an unmet need for patients who could not tolerate cabozantinib, but it had seen no evidence for the effectiveness of vandetanib in this group. Also, the ICER for vandetanib compared with best supportive care was higher than the range normally considered cost effective, that is £20,000 to £30,000 per QALY gained (see section\xa03.17). Therefore vandetanib could not be recommended for routine use in the NHS in this subgroup.Given the lack of robust effectiveness evidence presented for vandetanib, the committee had accepted that vandetanib was likely to be similarly effective to cabozantinib based on clinical opinion. However, it concluded that even having accepted this, the ICER for vandetanib was much too high to consider it a cost-effective use of NHS resources. Therefore the committee could not recommend it for treating medullary thyroid cancer, because the most plausible ICER was much higher than £20,000 to £30,000 per QALY gained."}
|
https://www.nice.org.uk/guidance/ta550
|
Evidence-based recommendations on vandetanib (Caprelsa) for treating medullary thyroid cancer in adults.
|
b2ae19b81449950b28e337fe0bb5485e008ccca1
|
nice
|
Chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing
|
Chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute exacerbations of chronic obstructive pulmonary disease (COPD). It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing an acute exacerbation of COPD with antibiotics
Be aware that:
an acute exacerbation of chronic obstructive pulmonary disease (COPD) is a sustained worsening of symptoms from a person's stable state
a range of factors (including viral infections and smoking) can trigger an exacerbation
many exacerbations (including some severe exacerbations) are not caused by bacterial infections so will not respond to antibiotics
some people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan (see the recommendations on choice of antibiotic).See the NICE guideline on COPD in over 16s.
## Treatment
Consider an antibiotic (see the recommendations on choice of antibiotic) for people with an acute exacerbation of COPD, but only after taking into account:
the severity of symptoms, particularly sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation
whether they may need to go into hospital for treatment (see the NICE guideline on COPD in over 16s)
previous exacerbation and hospital admission history, and the risk of developing complications
previous sputum culture and susceptibility results
the risk of antimicrobial resistance with repeated courses of antibiotics.
If a sputum sample has been sent for culture and susceptibility testing (in line with the NICE guideline on COPD in over 16s) and an antibiotic has been given:
review the choice of antibiotic when results are available and
-nly change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving (using a narrow-spectrum antibiotic wherever possible).
If an antibiotic is given, give advice:
about possible adverse effects of the antibiotic, particularly diarrhoea
that symptoms may not be fully resolved when the antibiotic course has been completed
about seeking medical help if:
symptoms worsen rapidly or significantly or
symptoms do not start to improve within 2–3 days (or other agreed time) or
the person becomes systemically very unwell.
If no antibiotic is given, give advice about:
an antibiotic not being needed currently
seeking medical help without delay if:
symptoms (such as sputum colour changes and increases in volume or thickness) worsen rapidly or significantly or
symptoms do not start to improve within an agreed time or
the person becomes systemically very unwell.
## Reassessment
Reassess people with an acute exacerbation of COPD if their symptoms worsen rapidly or significantly at any time, taking account of:
-ther possible diagnoses, such as pneumonia
any symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis
previous antibiotic use, which may have led to resistant bacteria.Send a sputum sample for culture and susceptibility testing if symptoms have not improved following antibiotic treatment and this has not been done already.
## Referral and seeking specialist advice
Refer people with an acute exacerbation of COPD to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis) and in line with the NICE guideline on COPD in over 16s.
Seek specialist advice for people with an acute exacerbation of COPD if they:
have symptoms that are not improving with repeated courses of antibiotics or
have bacteria that are resistant to oral antibiotics or
cannot take oral medicines (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where appropriate).
See the evidence and committee discussion on antibiotics.
# Choice of antibiotic
When prescribing an antibiotic for an acute exacerbation of COPD, follow table 1 for adults aged 18 years and over.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their exacerbation does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
## Table 1 Antibiotic treatment for adults aged 18 years and over
Antibiotic
Dosage and course length
First-choice oral antibiotics (empirical treatment or guided by most recent sputum culture and susceptibilities)
Amoxicillin
mg three times a day for 5 days (see BNF for dosage in severe infections)
Doxycycline
mg on first day, then 100 mg once a day for 5‑day course in total (see BNF for dosage in severe infections)
Clarithromycin
mg twice a day for 5 days
Second-choice oral antibiotics (no improvement in symptoms on first choice taken for at least 2 to 3 days; guided by susceptibilities when available)
Use alternative first choice (from a different class)
as above
Alternative choice oral antibiotics (if person at higher risk of treatment failure
; guided by susceptibilities when available)
Co-amoxiclav
/125 mg three times a day for 5 days
Co-trimoxazole4
mg twice a day for 5 days
Levofloxacin (with specialist advice if co-amoxiclav or co-trimoxazole cannot be used; consider safety issues5)
mg once a day for 5 days
First-choice intravenous antibiotic (if unable to take oral antibiotics or severely unwell;
guided by susceptibilities when available)
Amoxicillin
mg three times a day (see BNF for dosage in severe infections)
Co-amoxiclav
g three times a day
Clarithromycin
mg twice a day
Co-trimoxazole4
mg twice a day (see BNF for dosage in severe infections)
Piperacillin with tazobactam
g three times a day (see BNF for dosage in severe infections)
Second-choice intravenous antibiotic
Consult local microbiologist; guided by susceptibilities
See the British national formulary (BNF) for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, and administering intravenous antibiotics.
If a person is receiving antibiotic prophylaxis, treatment should be with an antibiotic from a different class.
People who may be at a higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous or current sputum culture with resistant bacteria, or people at higher risk of developing complications.
Co-trimoxazole should only be considered for use in acute exacerbations of COPD when there is bacteriological evidence of sensitivity and good reason to prefer this combination to a single antibiotic (BNF, October 2018).
See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
See the evidence and committee discussion on choice of antibiotic and antibiotic course length.# Terms used in the guideline
# Acute exacerbation of COPD
An exacerbation is a sustained worsening of the person's symptoms from their usual stable state, which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. (NICE guideline on COPD in over 16s).
# Severity of exacerbation
A general classification of the severity of an acute exacerbation (NICE guideline on COPD in over 16s; Oba Y et al. ) is:
mild exacerbation: the person has an increased need for medication, which they can manage in their own normal environment
moderate exacerbation: the person has a sustained worsening of respiratory status that requires treatment with systemic corticosteroids and/or antibiotics
severe exacerbation: the person experiences a rapid deterioration in respiratory status that requires hospitalisation.
Anthonisen et al. (1987) classified the type of an acute exacerbation based on 3 cardinal exacerbation symptoms:
increased breathlessness
increased sputum volume
sputum purulence.
The presence all 3 symptoms was defined as type 1 exacerbation; 2 of the 3 symptoms was defined as type 2 exacerbation; and 1 of the 3 symptoms with the presence of 1 or more supporting symptoms and signs was defined as type 3 exacerbation. This classification has been widely used to determine the severity of exacerbation in research studies, with more symptoms indicating a more severe exacerbation.
Supporting symptoms were:
cough
wheezing
fever without an obvious source
upper respiratory tract infection in the past 5 days
respiratory rate increase or heart rate increase 20% above baseline.# Summary of the evidence
The recommendations in this guideline are based on the evidence identified, which was for antibiotics for managing an acute exacerbation of chronic obstructive pulmonary disease (COPD) in adults. Non-antimicrobial interventions, such as bronchodilators, corticosteroids and oxygen therapy are covered in the NICE guideline on COPD in over 16s.
# Antibiotics
A number of factors are known to trigger an acute exacerbation of COPD, including a viral respiratory tract infection and environmental factors, such as smoking (see the NICE guideline on COPD in over 16s). Only about half of exacerbations are thought to be caused by a bacterial infection (Vollenweider et al. 2012).
The diagnosis of COPD or chronic bronchitis varied across included studies, and may have been confirmed by spirometry or by a clinician. It was not defined in some studies.
Similarly, the diagnosis of an acute exacerbation varied, but was mainly based on the Anthonisen classification or a clinical evaluation of worsening symptoms and signs. In some studies, it was not defined.
Studies often included people with varying severity of acute exacerbation (often based on the Anthonisen classification of type of exacerbation or not defined). Studies were conducted in various settings.
## Back-up antibiotics
No systematic reviews or randomised controlled trials (RCTs) were identified on back-up antibiotics for people with an acute exacerbation of COPD.
## Efficacy of antibiotics
The evidence review for the efficacy of antibiotics was based on a systematic review and meta-analysis of RCTs (Vollenweider et al. 2012). This systematic review conducted subgroup analyses by care setting, and a sensitivity analysis restricted to antibiotics, which the authors considered to be in current use.
With antibiotics, significantly fewer people (age range 52 to 72 years) with an acute exacerbation of COPD had symptoms that didn't resolve or improve up to 1 month after treatment starting, compared with placebo (28.4% versus 37.4%, number needed to treat 12 , very low quality evidence).
However, this was a heterogeneous population receiving treatment in the community, in hospital or in intensive care, and the result was influenced by the large positive effect observed in 1 RCT in people in intensive care. When this study was removed from the analysis, the benefit of antibiotics compared with placebo was reduced (29.4% versus 36.1%, NNT 15 , moderate quality evidence).
The diagnosis of an acute exacerbation was a worsening of previously stable COPD, with 1 or more symptoms such as increased breathlessness, increased cough, increased sputum volume or change in sputum colour. The care setting was used a marker of the severity of the acute exacerbation.
A wide range of antibiotics were included across the studies and the antibiotic course length ranged from 5 to 17 days. Corticosteroid treatment was allowed in 2 of the 16 RCTs.
Significantly fewer people who had antibiotics had symptoms that didn't resolve or improve compared with placebo. The effect of antibiotics appeared to be greater in people with increasing severity of exacerbation (based on care setting), as follows:
in people receiving treatment in the community (classified as a mild to moderate exacerbation): 19.9% versus 27.5%, NNT 14 (range 8 to 46), moderate quality evidence
in people receiving treatment in hospital (classified as a severe exacerbation): 41.8% versus 52.0%, NNT 10 (range 6 to 45), moderate quality evidence
in people receiving treatment in intensive care (classified as a very severe exacerbation): 10.6% versus 56.5%, NNT 3 (range 2 to 4), high quality evidence.
Vollenweider et al. (2012) also conducted a sensitivity analysis, which only included antibiotics that the authors considered to be in current use (including amoxicillin, co‑amoxiclav, co‑trimoxazole and doxycycline). Studies assessing oxytetracycline, tetracycline and chloramphenicol were excluded from this analysis. There remained a significant difference between antibiotics and placebo overall in this analysis (24.5% versus 34.5%; NNT 11 , low quality evidence), but there was no significant difference in a subgroup receiving treatment in the community (22.2% versus 29.1%, low quality evidence) or in people receiving treatment in hospital (excluding intensive care: 28.9% versus 45.9%, low quality evidence).
Antibiotics were not significantly more effective than placebo in reducing the length of hospital stay in 3 RCTs that reported this outcome (11 days versus 17 days, very low quality evidence). Antibiotics significantly reduced the number of days off work during follow‑up in people receiving treatment in the community in 1 RCT, although this was based on small numbers of participants (n=88) and a short follow‑up (17 days; 4.3 days versus 9.4 days, high quality evidence, Vollenweider et al. 2012).
## Safety of antibiotics
Antibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, October 2018).
Macrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, October 2018).
Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, October 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (press release October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. This includes a recommendation to not use them for mild or moderately severe infections unless other antibiotics cannot be used.
Co-trimoxazole is currently under restriction for use in the UK. It is advised that it only be considered for use in acute exacerbations of COPD when there is bacteriological evidence of sensitivity to co‑trimoxazole and good reason to prefer this combination to a single antibiotic (BNF, October 2018).
From the systematic review and meta-analysis of RCTs (Vollenweider et al. 2012), adverse events were significantly increased with antibiotics compared with placebo between 5 and 28 days after treatment (10.6% versus 7.4%, low quality evidence), although there is considerable uncertainty in this result because the frequency of adverse events was low. Significantly more people reported diarrhoea with antibiotics compared with placebo (4.4% versus 1.8%, low quality evidence), although the incidence was low in both groups.
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Committee discussion on antibiotics
Limitations of the data:
The committee discussed the evidence from a large systematic review and meta-analysis of double-blind, placebo-controlled RCTs for the use of antibiotics in people with an acute exacerbation of COPD (Vollenweider et al. 2012).
The committee noted the variations in diagnosis of COPD (or chronic bronchitis) and acute exacerbations of COPD across the included studies (particularly in older studies). The included studies covered a heterogeneous population ranging from people with mild exacerbations receiving treatment in the community to people with very severe exacerbations requiring ventilation in intensive care. There was no definition for the severity of exacerbation that was used in the studies.
The committee questioned the appropriateness of using the care setting as a proxy for the severity of exacerbation (many included studies were from the USA where hospital admission systems differ from UK practice).
Evidence that is available from RCTs in the systematic review does not help to identify people who have a bacterial infection and may be more likely to benefit from an antibiotic. The committee noted, and agreed with the authors' conclusions, that in the analysis there was a lack of power to determine clinical effectiveness by the presence or absence of particular symptoms or signs (for example, sputum colour changes). The committee also noted that the systematic review included people who presented with 1 or more exacerbation symptom, and the analysis did not stratify people by symptoms when assessing the effectiveness of antibiotics.
The committee agreed that microbiological eradication outcomes were difficult to interpret and that clinical outcome measures should be prioritised, although they recognised that the definition of treatment failure (no improvement) varied across the studies.
The committee also noted the analysis based on antibiotics in current use, and agreed that these results should be prioritised for decision-making.
Interpretation of the results
Overall, the committee noted reasonably high NNTs for antibiotics compared with placebo. In people who received treatment in the community, about 14 people would need antibiotics to prevent 1 person from having treatment failure (no improvement in symptoms). In people who received treatment in hospital, about 10 people would need antibiotics to prevent 1 person from having treatment failure.
When antibiotics not currently used in practice were excluded from the analysis, the differences between antibiotics and placebo were not statistically significant in the subgroup analyses by care setting (community and hospital). However, the committee agreed that this may be because of a lack of power when fewer studies were included in the analysis. Also not all the antibiotics considered to be in current use by the authors are in current use in the UK.
Overall, there was uncertain evidence about which groups of people may benefit most from antibiotics, although the committee noted that the NNT for symptoms that didn't resolve or improve was 3 in people receiving treatment in intensive care.
The committee agreed that the limited benefit was likely to be because many acute exacerbations are not caused by bacterial infections, but may be caused by viral infections or environmental factors, such as smoking.
Rationale for decision-making
No evidence was identified on back‑up antibiotics and the committee was not able to make a recommendation for people with an acute exacerbation of COPD.
The committee acknowledged the recommendations in the NICE guideline on COPD in over 16s, which cover managing acute exacerbations, including self-management. They recognised that some people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan. This guideline focuses on optimising the use of antibiotics for an acute exacerbation of COPD and minimising the risk of antimicrobial resistance.
Based on experience, the committee agreed that many health professionals may not be aware of the limited benefit of antibiotics, and that many exacerbations are not caused by a bacterial infection.
The committee recognised that COPD is a complex condition and people often have multiple exacerbations and receive multiple courses of antibiotics, which may not always be appropriate. They were concerned that repeated use of antibiotics means that they will not continue to be effective in the future.
The committee agreed that the evidence suggested that antibiotics had some clinical benefit in a heterogeneous population with acute exacerbations of COPD, in the context of increased harms with antibiotics and antimicrobial resistance. The committee recognised that there isn't a clear distinction between severity of exacerbation and presence of a bacterial infection.
From the evidence identified, the committee agreed that it was not possible to identify which people with an acute exacerbation are more likely to benefit from antibiotics. However, from their experience, and based on existing expert consensus, the presence of sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation appear to be important factors.
From experience, the evidence identified and the need to minimise the risk of antimicrobial resistance, the committee agreed that an antibiotic for an acute exacerbation of COPD should be considered on an individual patient basis. This should take into account the uncertain benefit of antibiotics, increased risk of harms and the risk of antimicrobial resistance with repeated courses, balanced against severity of their symptoms (particularly sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation), their need for hospital treatment, their exacerbation and hospitalisation history, their risk of complications, and previous sputum culture results.
From experience, the committee recognised that a person's condition may change rapidly during an acute exacerbation. They agreed that health professionals should give the person individualised advice about seeking medical help without delay if symptoms worsen rapidly or significantly, do not start to improve within 2 to 3 days (or other agreed time), or they become systemically very unwell.
The committee was aware of recommendations from the NICE guidelines on COPD and sepsis that cover when to refer people to hospital.
# Choice of antibiotics
## First-line antibiotics compared with second-line antibiotics
Evidence for the choice of first-line or second-line antibiotics was based on a systematic review and meta-analysis of RCTs (Dimopoulos et al. 2007).
First-line antibiotics (amoxicillin, ampicillin, pivampicillin, co‑trimoxazole and doxycycline) were significantly less effective in resolving or improving exacerbation symptoms up to 7 days after the end of treatment, compared with second-line antibiotics (co‑amoxiclav, macrolides, fluoroquinolones and cefaclor) in people (age range 49 to 71 years) with an acute exacerbation of chronic bronchitis (81.8% versus 91.3%, NNT 11 , moderate quality evidence).
Similar results were observed in a subgroup who received treatment in the community with first-line and second-line antibiotics respectively (90.3% versus 95.5%, moderate quality evidence), although most people in both groups had resolving or improving exacerbation symptoms up to 7 days after the end of treatment. In people receiving treatment in hospital, there was no significant difference between first-line and second-line antibiotics (74.0% versus 87.5%, low quality evidence), but some studies also included people receiving treatment in the community.
Dimopoulos et al. (2007) included 4 RCTs in people receiving treatment in the community and 6 RCTs in people receiving treatment in hospital (4 of these RCTs had a mixed population who received treatment in the community or in hospital).
The diagnosis of an acute exacerbation and the type of symptoms was based on the Anthonisen classification. The severity of exacerbation varied across studies and was not specified in 2 RCTs.
Dosage varied by antibiotic and the course length ranged from 5 to 14 days. Corticosteroid treatment was permitted before an acute exacerbation in 3 RCTs.
There were no significant differences between groups in antibiotic-related adverse events (14.6% versus 20.6%, very low quality evidence) or in all‑cause mortality (1.0% versus 1.6%, low quality evidence).
## Other antibiotic comparisons
There were no significant differences in clinical effectiveness between antibiotics or classes of antibiotics, including co‑amoxiclav, macrolides, fluoroquinolones, cephalosporins and trimethoprim (with or without a sulfonamide) in people with an acute exacerbation of COPD. This is based on 2 systematic reviews and meta-analyses of RCTs (Korbila et al. 2009 and Siempos et al. 2007), and 4 RCTs (Nouira et al. 2010, Petitpretz et al. 2007, Yoon et al. 2013 and Urueta-Robledo et al. 2006), which all cover different comparisons of antibiotic regimens for up to 6 months' (in 2 RCTs) follow‑up.
One large systematic review and meta-analysis of 19 RCTs (Siempos et al. 2007; n=7,045) comparing commonly used broader-spectrum antibiotics (co‑amoxiclav, macrolides and fluoroquinolones) for 3 to 10 days found no significant difference in clinical effectiveness between groups (moderate to high quality evidence). Most people included in this review received treatment in the community. The available data did not allow subgroup analyses to be carried out in people considered to be at increased risk of poorer outcomes (such as older people, people with severe COPD and people with more frequent exacerbations).
In Siempos et al. (2007), a subgroup analysis of people with moderate or severe acute exacerbations found no significant difference in the resolution or improvement in exacerbation symptoms between macrolides and fluoroquinolones (80.7% versus 80.1%, high quality of evidence).
In 1 double-blinded RCT (Nouira et al. 2010; n=170), the effectiveness of co‑trimoxazole 160/800 mg twice a day for 10 days was compared with ciprofloxacin 750 mg twice a day for 10 days in people (mean age 67 years) with a severe acute exacerbation of COPD being admitted to an intensive care unit in hospital. No significant differences between antibiotic groups were found up to 6 months after treatment (low to moderate quality evidence).
The antibiotic course length ranged from 3 to 14 days in the studies. One double-blinded RCT (Urueta-Robledo et al. 2006) found no significant difference in the resolution of exacerbation symptoms with levofloxacin for 7 days compared with moxifloxacin for 5 days (moderate quality evidence).
Overall, there were no major differences in adverse effects between antibiotics or classes of antibiotics based on the included studies (low to high quality evidence).
In the systematic review by Siempos et al. (2007), significantly more people reported adverse events with co‑amoxiclav compared with fluoroquinolones (16.6% versus 12.8%, NNH 27 , moderate quality evidence).
Committee discussion on choice of antibiotic
Although there was some evidence to suggest that second-line antibiotics were more effective than first-line antibiotics, the absolute difference between groups was small and this analysis was limited by the classification of first- and second-line antibiotics, which was not consistent with current UK practice.
Based on evidence of no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.
If an antibiotic is given, the committee agreed that this should be started empirically or based on the most recent sputum culture (if available). The committee was aware that the NICE guideline on COPD in over 16s makes recommendations about when to send sputum for culture.
The committee agreed that if a sputum sample has been sent for culture and susceptibility testing, when results are available, if they suggest the bacteria are not susceptible, the person should be contacted to assess symptoms. However, the antibiotic should only be changed according to susceptibility results if symptoms are not already improving. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible, and antibiotics switched from intravenous to oral where applicable.
Based on experience, common pathogens in acute exacerbations of COPD, the susceptibility of these to various classes of antibiotics, the risks of resistance, and good antimicrobial stewardship, the committee agreed antibiotic choices as described below. Several oral and intravenous antibiotics were recommended because people with acute exacerbations of COPD may have repeated courses of antibiotics and may be at an increased risk of resistance. It also enables antibiotics to be selected based on the severity of illness and antibiotic susceptibilities from culture results (if available).
The first-line oral antibiotics are amoxicillin (a penicillin), doxycycline (a tetracycline) and clarithromycin (a macrolide), used at the usual doses for an acute exacerbation of COPD, although the dosage may be increased in severe infections. These antibiotics have good activity against common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae. Where a person is receiving prophylactic antibiotics, antibiotic treatment for an acute exacerbation should be with an antibiotic from a different class.
The second-line oral antibiotics for people whose symptoms worsen on a first-choice antibiotic taken for at least 2 to 3 days are an alternative first-choice from a different antibiotic class (a different antibiotic may be used for a subsequent exacerbation). This allows broader-spectrum antibiotics (some of which also have additional safety warnings) to be reserved for people who may be at a higher risk of treatment failure (for example, people who have had repeated courses of antibiotics, previous or current sputum culture with resistant bacteria, or people at higher risk of developing complications).
The alternative oral antibiotics for people who may be at a higher risk of treatment failure (guided by susceptibilities when available) are:
co-amoxiclav 500/125 mg three times a day; this broad-spectrum antibiotic combines a penicillin with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone
levofloxacin 500 mg once a day; which was a fluoroquinolone used in the studies
co-trimoxazole 960 mg twice a day (trimethoprim plus a sulfonamide); which is suitable only for people with bacteriological evidence of sensitivity and good reason to prefer this combination to a single antibiotic.
The committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolones are appropriate as an alternative option for people who may be at a higher risk of treatment failure. The committee was keen to point out, however, that fluoroquinolone safety concerns should be taken into account on an individual patient basis.
First-choice intravenous antibiotics at usual doses for treating acute exacerbations in people who are unable to take oral antibiotics, or the severity of their exacerbation means than intravenous treatment is required, are:
amoxicillin
co-amoxiclav
clarithromycin
co-trimoxazole
piperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor).
Second-choice intravenous antibiotics may be needed for some people after specialist advice, based on the severity of illness, likely pathogens or antibiotic susceptibilities from culture results when available, and local resistance patterns.
The committee agreed that a sputum sample should be sent for culture and susceptibility testing if symptoms have not resolved following antibiotic treatment and this has not been done already. Specific organisms, such as Pseudomonas aeruginosa may need to be looked for if people have prolonged recurrent exacerbations. They discussed that some people with resistant bacteria may need intravenous antibiotics, particularly if their symptoms are not responding to several courses of oral antibiotics for the same episode, or if several sputum samples show resistance to oral antibiotics.
The committee discussed that specialist advice should be sought for people needing intravenous antibiotics, to discuss local options for giving intravenous antibiotics at home or in the community, rather than in hospital.
# Antibiotic course length
Short-course antibiotics (for less than 6 days) were not significantly different from long-course antibiotics (for 7 days or more of the same antibiotic) in resolution of exacerbation symptoms after completing treatment, in people with an acute exacerbation of COPD (moderate quality evidence). This was based on a systematic review and meta-analysis (Stolbrink et al. 2017). This result was consistent regardless of the length of follow‑up (within 6 days, 7 to 14 days or more than 20 days) or the care setting (3 of the 10 RCTs were in hospital).
The diagnosis of an acute exacerbation was based on clinical evaluation in all studies, except 1 RCT that used microscopically confirmed purulent sputum. The severity of exacerbation ranged from mild to severe, and 4 RCTs used the Anthonisen classification of type of exacerbation for assessing exacerbation severity.
A range of antibiotics were included in Stolbrink et al. (2017) with fluoroquinolones being the most commonly studied antibiotics. In most studies, a 3‑day or 5‑day course was compared with a 7‑day or 10‑day course of the same antibiotic.
There were significantly fewer adverse events with short-course antibiotics compared with long-course antibiotics (20.9% versus 24.9%, NNH 25 ; low quality evidence).
No systematic reviews or RCTs were identified that compared the frequency of antibiotic dosing or the route of antibiotic administration.
Committee discussion on antibiotic course length
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
Based on the evidence, if an antibiotic was prescribed, the committee agreed that a 5‑day course of all the recommended antibiotics was required to treat an acute exacerbation.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that the use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and susceptibility results from sputum culture) and switched to oral treatment where possible.
See the full evidence review for more information.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require regular dosing (for example, some antibiotics); see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are all available as generic formulations, see Drug Tariff for costs.
|
{'Recommendations': "# Managing an acute exacerbation of COPD with antibiotics\n\nBe aware that:\n\nan acute exacerbation of chronic obstructive pulmonary disease (COPD) is a sustained worsening of symptoms from a person's stable state\n\na range of factors (including viral infections and smoking) can trigger an exacerbation\n\nmany exacerbations (including some severe exacerbations) are not caused by bacterial infections so will not respond to antibiotics\n\nsome people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan (see the recommendations on choice of antibiotic).See the NICE guideline on COPD in over\xa016s.\n\n## Treatment\n\nConsider an antibiotic (see the recommendations on choice of antibiotic) for people with an acute exacerbation of COPD, but only after taking into account:\n\nthe severity of symptoms, particularly sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation\n\nwhether they may need to go into hospital for treatment (see the NICE guideline on COPD in over\xa016s)\n\nprevious exacerbation and hospital admission history, and the risk of developing complications\n\nprevious sputum culture and susceptibility results\n\nthe risk of antimicrobial resistance with repeated courses of antibiotics.\n\nIf a sputum sample has been sent for culture and susceptibility testing (in line with the NICE guideline on COPD in over\xa016s) and an antibiotic has been given:\n\nreview the choice of antibiotic when results are available and\n\nonly change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving (using a narrow-spectrum antibiotic wherever possible).\n\nIf an antibiotic is given, give advice:\n\nabout possible adverse effects of the antibiotic, particularly diarrhoea\n\nthat symptoms may not be fully resolved when the antibiotic course has been completed\n\nabout seeking medical help if:\n\n\n\nsymptoms worsen rapidly or significantly or\n\nsymptoms do not start to improve within 2–3\xa0days (or other agreed time) or\n\nthe person becomes systemically very unwell.\n\n\n\nIf no antibiotic is given, give advice about:\n\nan antibiotic not being needed currently\n\nseeking medical help without delay if:\n\n\n\nsymptoms (such as sputum colour changes and increases in volume or thickness) worsen rapidly or significantly or\n\nsymptoms do not start to improve within an agreed time or\n\nthe person becomes systemically very unwell.\n\n\n\n## Reassessment\n\nReassess people with an acute exacerbation of COPD if their symptoms worsen rapidly or significantly at any time, taking account of:\n\nother possible diagnoses, such as pneumonia\n\nany symptoms or signs suggesting a more serious illness or condition, such as cardiorespiratory failure or sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.Send a sputum sample for culture and susceptibility testing if symptoms have not improved following antibiotic treatment and this has not been done already.\n\n## Referral and seeking specialist advice\n\nRefer people with an acute exacerbation of COPD to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis) and in line with the NICE guideline on COPD in over\xa016s.\n\nSeek specialist advice for people with an acute exacerbation of COPD if they:\n\nhave symptoms that are not improving with repeated courses of antibiotics or\n\nhave bacteria that are resistant to oral antibiotics or\n\ncannot take oral medicines (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where appropriate).\n\nSee the evidence and committee discussion on antibiotics.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for an acute exacerbation of COPD, follow table\xa01 for adults aged 18\xa0years and over.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their exacerbation does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\n## Table\xa01 Antibiotic treatment for adults aged 18\xa0years and over\n\nAntibiotic\n \n 1,2\n\nDosage and course length\n\nFirst-choice oral antibiotics (empirical treatment or guided by most recent sputum culture and susceptibilities)\n\nAmoxicillin\n\nmg three times a day for 5\xa0days (see BNF for dosage in severe infections)\n\nDoxycycline\n\nmg on first day, then 100\xa0mg once a day for 5‑day course in total (see BNF for dosage in severe infections)\n\nClarithromycin\n\nmg twice a day for 5\xa0days\n\nSecond-choice oral antibiotics (no improvement in symptoms on first choice taken for at least 2\xa0to 3\xa0days; guided by susceptibilities when available)\n\nUse alternative first choice (from a different class)\n\nas above\n\nAlternative choice oral antibiotics (if person at higher risk of treatment failure\n \n 3\n \n ; guided by susceptibilities when available)\n\nCo-amoxiclav\n\n/125\xa0mg three times a day for 5\xa0days\n\nCo-trimoxazole4\n\nmg twice a day for 5\xa0days\n\nLevofloxacin (with specialist advice if co-amoxiclav or co-trimoxazole cannot be used; consider safety issues5)\n\nmg once a day for 5\xa0days\n\nFirst-choice intravenous antibiotic (if unable to take oral antibiotics or severely unwell;\n guided by susceptibilities when available)\n \n 6\n\nAmoxicillin\n\nmg three times a day (see BNF for dosage in severe infections)\n\nCo-amoxiclav\n\ng three times a day\n\nClarithromycin\n\nmg twice a day\n\nCo-trimoxazole4\n\nmg twice a day (see BNF for dosage in severe infections)\n\nPiperacillin with tazobactam\n\ng three times a day (see BNF for dosage in severe infections)\n\nSecond-choice intravenous antibiotic\n\nConsult local microbiologist; guided by susceptibilities\n\nSee the British national formulary (BNF) for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, and administering intravenous antibiotics.\n\nIf a person is receiving antibiotic prophylaxis, treatment should be with an antibiotic from a different class.\n\nPeople who may be at a higher risk of treatment failure include people who have had repeated courses of antibiotics, a previous or current sputum culture with resistant bacteria, or people at higher risk of developing complications.\n\nCo-trimoxazole should only be considered for use in acute exacerbations of COPD when there is bacteriological evidence of sensitivity and good reason to prefer this combination to a single antibiotic (BNF, October\xa02018).\n\nSee MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nSee the evidence and committee discussion on choice of antibiotic and antibiotic course length.", 'Terms used in the guideline': "# Acute exacerbation of COPD\n\nAn exacerbation is a sustained worsening of the person's symptoms from their usual stable state, which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. (NICE guideline on COPD in over\xa016s).\n\n# Severity of exacerbation\n\nA general classification of the severity of an acute exacerbation (NICE guideline on COPD in over\xa016s; Oba Y et al. ) is:\n\nmild exacerbation: the person has an increased need for medication, which they can manage in their own normal environment\n\nmoderate exacerbation: the person has a sustained worsening of respiratory status that requires treatment with systemic corticosteroids and/or antibiotics\n\nsevere exacerbation: the person experiences a rapid deterioration in respiratory status that requires hospitalisation.\n\nAnthonisen et al. (1987) classified the type of an acute exacerbation based on 3\xa0cardinal exacerbation symptoms:\n\nincreased breathlessness\n\nincreased sputum volume\n\nsputum purulence.\n\nThe presence all 3\xa0symptoms was defined as type\xa01 exacerbation; 2\xa0of the 3\xa0symptoms was defined as type\xa02 exacerbation; and 1\xa0of the 3\xa0symptoms with the presence of 1\xa0or more supporting symptoms and signs was defined as type\xa03 exacerbation. This classification has been widely used to determine the severity of exacerbation in research studies, with more symptoms indicating a more severe exacerbation.\n\nSupporting symptoms were:\n\ncough\n\nwheezing\n\nfever without an obvious source\n\nupper respiratory tract infection in the past 5\xa0days\n\nrespiratory rate increase or heart rate increase 20% above baseline.", 'Summary of the evidence': "The recommendations in this guideline are based on the evidence identified, which was for antibiotics for managing an acute exacerbation of chronic obstructive pulmonary disease (COPD) in adults. Non-antimicrobial interventions, such as bronchodilators, corticosteroids and oxygen therapy are covered in the NICE guideline on COPD in over\xa016s.\n\n# Antibiotics\n\nA number of factors are known to trigger an acute exacerbation of COPD, including a viral respiratory tract infection and environmental factors, such as smoking (see the NICE guideline on COPD in over\xa016s). Only about half of exacerbations are thought to be caused by a bacterial infection (Vollenweider et al.\xa02012).\n\nThe diagnosis of COPD or chronic bronchitis varied across included studies, and may have been confirmed by spirometry or by a clinician. It was not defined in some studies.\n\nSimilarly, the diagnosis of an acute exacerbation varied, but was mainly based on the Anthonisen classification or a clinical evaluation of worsening symptoms and signs. In some studies, it was not defined.\n\nStudies often included people with varying severity of acute exacerbation (often based on the Anthonisen classification of type of exacerbation or not defined). Studies were conducted in various settings.\n\n## Back-up antibiotics\n\nNo systematic reviews or randomised controlled trials (RCTs) were identified on back-up antibiotics for people with an acute exacerbation of COPD.\n\n## Efficacy of antibiotics\n\nThe evidence review for the efficacy of antibiotics was based on a systematic review and meta-analysis of RCTs (Vollenweider et al. 2012). This systematic review conducted subgroup analyses by care setting, and a sensitivity analysis restricted to antibiotics, which the authors considered to be in current use.\n\nWith antibiotics, significantly fewer people (age range 52\xa0to 72\xa0years) with an acute exacerbation of COPD had symptoms that didn't resolve or improve up to 1\xa0month after treatment starting, compared with placebo (28.4% versus 37.4%, number needed to treat [NNT]\xa012 [range 8\xa0to\xa023], very low quality evidence).\n\nHowever, this was a heterogeneous population receiving treatment in the community, in hospital or in intensive care, and the result was influenced by the large positive effect observed in 1\xa0RCT in people in intensive care. When this study was removed from the analysis, the benefit of antibiotics compared with placebo was reduced (29.4% versus 36.1%, NNT\xa015 [range 9\xa0to\xa050], moderate quality evidence).\n\nThe diagnosis of an acute exacerbation was a worsening of previously stable COPD, with 1\xa0or more symptoms such as increased breathlessness, increased cough, increased sputum volume or change in sputum colour. The care setting was used a marker of the severity of the acute exacerbation.\n\nA wide range of antibiotics were included across the studies and the antibiotic course length ranged from 5\xa0to 17\xa0days. Corticosteroid treatment was allowed in 2\xa0of the 16\xa0RCTs.\n\nSignificantly fewer people who had antibiotics had symptoms that didn't resolve or improve compared with placebo. The effect of antibiotics appeared to be greater in people with increasing severity of exacerbation (based on care setting), as follows:\n\n\n\nin people receiving treatment in the community (classified as a mild to moderate exacerbation): 19.9% versus 27.5%, NNT\xa014 (range 8\xa0to\xa046), moderate quality evidence\n\nin people receiving treatment in hospital (classified as a severe exacerbation): 41.8% versus 52.0%, NNT\xa010 (range 6\xa0to\xa045), moderate quality evidence\n\nin people receiving treatment in intensive care (classified as a very severe exacerbation): 10.6% versus 56.5%, NNT\xa03 (range 2\xa0to\xa04), high quality evidence.\n\n\n\nVollenweider et al. (2012) also conducted a sensitivity analysis, which only included antibiotics that the authors considered to be in current use (including amoxicillin, co‑amoxiclav, co‑trimoxazole and doxycycline). Studies assessing oxytetracycline, tetracycline and chloramphenicol were excluded from this analysis. There remained a significant difference between antibiotics and placebo overall in this analysis (24.5% versus 34.5%; NNT\xa011 [range 7\xa0to\xa021], low quality evidence), but there was no significant difference in a subgroup receiving treatment in the community (22.2% versus 29.1%, low quality evidence) or in people receiving treatment in hospital (excluding intensive care: 28.9% versus 45.9%, low quality evidence).\n\nAntibiotics were not significantly more effective than placebo in reducing the length of hospital stay in 3\xa0RCTs that reported this outcome (11\xa0days versus 17\xa0days, very low quality evidence). Antibiotics significantly reduced the number of days off work during follow‑up in people receiving treatment in the community in 1\xa0RCT, although this was based on small numbers of participants (n=88) and a short follow‑up (17\xa0days; 4.3\xa0days versus 9.4\xa0days, high quality evidence, Vollenweider et al.\xa02012).\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea is estimated to occur in 2\xa0to\xa025% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, October\xa02018).\n\nMacrolides should be used with caution in people with a predisposition to QT\xa0interval prolongation (BNF, October\xa02018).\n\nTendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, October 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (press release October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. This includes a recommendation to not use them for mild or moderately severe infections unless other antibiotics cannot be used.\n\nCo-trimoxazole is currently under restriction for use in the UK. It is advised that it only be considered for use in acute exacerbations of COPD when there is bacteriological evidence of sensitivity to co‑trimoxazole and good reason to prefer this combination to a single antibiotic (BNF, October\xa02018).\n\nFrom the systematic review and meta-analysis of RCTs (Vollenweider et al. 2012), adverse events were significantly increased with antibiotics compared with placebo between 5\xa0and 28\xa0days after treatment (10.6% versus 7.4%, low quality evidence), although there is considerable uncertainty in this result because the frequency of adverse events was low. Significantly more people reported diarrhoea with antibiotics compared with placebo (4.4% versus 1.8%, low quality evidence), although the incidence was low in both groups.\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nCommittee discussion on antibiotics\n\nLimitations of the data:\n\nThe committee discussed the evidence from a large systematic review and meta-analysis of double-blind, placebo-controlled RCTs for the use of antibiotics in people with an acute exacerbation of COPD (Vollenweider et al.\xa02012).\n\nThe committee noted the variations in diagnosis of COPD (or chronic bronchitis) and acute exacerbations of COPD across the included studies (particularly in older studies). The included studies covered a heterogeneous population ranging from people with mild exacerbations receiving treatment in the community to people with very severe exacerbations requiring ventilation in intensive care. There was no definition for the severity of exacerbation that was used in the studies.\n\nThe committee questioned the appropriateness of using the care setting as a proxy for the severity of exacerbation (many included studies were from the USA where hospital admission systems differ from UK practice).\n\nEvidence that is available from RCTs in the systematic review does not help to identify people who have a bacterial infection and may be more likely to benefit from an antibiotic. The committee noted, and agreed with the authors' conclusions, that in the analysis there was a lack of power to determine clinical effectiveness by the presence or absence of particular symptoms or signs (for example, sputum colour changes). The committee also noted that the systematic review included people who presented with 1\xa0or more exacerbation symptom, and the analysis did not stratify people by symptoms when assessing the effectiveness of antibiotics.\n\nThe committee agreed that microbiological eradication outcomes were difficult to interpret and that clinical outcome measures should be prioritised, although they recognised that the definition of treatment failure (no improvement) varied across the studies.\n\nThe committee also noted the analysis based on antibiotics in current use, and agreed that these results should be prioritised for decision-making.\n\nInterpretation of the results\n\nOverall, the committee noted reasonably high NNTs for antibiotics compared with placebo. In people who received treatment in the community, about 14\xa0people would need antibiotics to prevent 1\xa0person from having treatment failure (no improvement in symptoms). In people who received treatment in hospital, about 10\xa0people would need antibiotics to prevent 1\xa0person from having treatment failure.\n\nWhen antibiotics not currently used in practice were excluded from the analysis, the differences between antibiotics and placebo were not statistically significant in the subgroup analyses by care setting (community and hospital). However, the committee agreed that this may be because of a lack of power when fewer studies were included in the analysis. Also not all the antibiotics considered to be in current use by the authors are in current use in the UK.\n\nOverall, there was uncertain evidence about which groups of people may benefit most from antibiotics, although the committee noted that the NNT for symptoms that didn't resolve or improve was\xa03 in people receiving treatment in intensive care.\n\nThe committee agreed that the limited benefit was likely to be because many acute exacerbations are not caused by bacterial infections, but may be caused by viral infections or environmental factors, such as smoking.\n\nRationale for decision-making\n\nNo evidence was identified on back‑up antibiotics and the committee was not able to make a recommendation for people with an acute exacerbation of COPD.\n\nThe committee acknowledged the recommendations in the NICE guideline on COPD in over\xa016s, which cover managing acute exacerbations, including self-management. They recognised that some people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan. This guideline focuses on optimising the use of antibiotics for an acute exacerbation of COPD and minimising the risk of antimicrobial resistance.\n\nBased on experience, the committee agreed that many health professionals may not be aware of the limited benefit of antibiotics, and that many exacerbations are not caused by a bacterial infection.\n\nThe committee recognised that COPD is a complex condition and people often have multiple exacerbations and receive multiple courses of antibiotics, which may not always be appropriate. They were concerned that repeated use of antibiotics means that they will not continue to be effective in the future.\n\nThe committee agreed that the evidence suggested that antibiotics had some clinical benefit in a heterogeneous population with acute exacerbations of COPD, in the context of increased harms with antibiotics and antimicrobial resistance. The committee recognised that there isn't a clear distinction between severity of exacerbation and presence of a bacterial infection.\n\nFrom the evidence identified, the committee agreed that it was not possible to identify which people with an acute exacerbation are more likely to benefit from antibiotics. However, from their experience, and based on existing expert consensus, the presence of sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation appear to be important factors.\n\nFrom experience, the evidence identified and the need to minimise the risk of antimicrobial resistance, the committee agreed that an antibiotic for an acute exacerbation of COPD should be considered on an individual patient basis. This should take into account the uncertain benefit of antibiotics, increased risk of harms and the risk of antimicrobial resistance with repeated courses, balanced against severity of their symptoms (particularly sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation), their need for hospital treatment, their exacerbation and hospitalisation history, their risk of complications, and previous sputum culture results.\n\nFrom experience, the committee recognised that a person's condition may change rapidly during an acute exacerbation. They agreed that health professionals should give the person individualised advice about seeking medical help without delay if symptoms worsen rapidly or significantly, do not start to improve within 2\xa0to\xa03\xa0days (or other agreed time), or they become systemically very unwell.\n\nThe committee was aware of recommendations from the NICE guidelines on COPD and sepsis that cover when to refer people to hospital.\n\n# Choice of antibiotics\n\n## First-line antibiotics compared with second-line antibiotics\n\nEvidence for the choice of first-line or second-line antibiotics was based on a systematic review and meta-analysis of RCTs (Dimopoulos et al.\xa02007).\n\nFirst-line antibiotics (amoxicillin, ampicillin, pivampicillin, co‑trimoxazole and doxycycline) were significantly less effective in resolving or improving exacerbation symptoms up to 7\xa0days after the end of treatment, compared with second-line antibiotics (co‑amoxiclav, macrolides, fluoroquinolones and cefaclor) in people (age range 49\xa0to 71\xa0years) with an acute exacerbation of chronic bronchitis (81.8% versus 91.3%, NNT\xa011 [range 8\xa0to\xa016], moderate quality evidence).\n\nSimilar results were observed in a subgroup who received treatment in the community with first-line and second-line antibiotics respectively (90.3% versus 95.5%, moderate quality evidence), although most people in both groups had resolving or improving exacerbation symptoms up to 7\xa0days after the end of treatment. In people receiving treatment in hospital, there was no significant difference between first-line and second-line antibiotics (74.0% versus 87.5%, low quality evidence), but some studies also included people receiving treatment in the community.\n\nDimopoulos et al. (2007) included 4\xa0RCTs in people receiving treatment in the community and 6\xa0RCTs in people receiving treatment in hospital (4\xa0of these RCTs had a mixed population who received treatment in the community or in hospital).\n\nThe diagnosis of an acute exacerbation and the type of symptoms was based on the Anthonisen classification. The severity of exacerbation varied across studies and was not specified in 2\xa0RCTs.\n\nDosage varied by antibiotic and the course length ranged from 5\xa0to 14\xa0days. Corticosteroid treatment was permitted before an acute exacerbation in 3\xa0RCTs.\n\nThere were no significant differences between groups in antibiotic-related adverse events (14.6% versus 20.6%, very low quality evidence) or in all‑cause mortality (1.0% versus 1.6%, low quality evidence).\n\n## Other antibiotic comparisons\n\nThere were no significant differences in clinical effectiveness between antibiotics or classes of antibiotics, including co‑amoxiclav, macrolides, fluoroquinolones, cephalosporins and trimethoprim (with or without a sulfonamide) in people with an acute exacerbation of COPD. This is based on 2\xa0systematic reviews and meta-analyses of RCTs (Korbila et al. 2009 and Siempos et al. 2007), and 4\xa0RCTs (Nouira et al. 2010, Petitpretz et al. 2007, Yoon et al. 2013 and Urueta-Robledo et al. 2006), which all cover different comparisons of antibiotic regimens for up to 6\xa0months' (in 2\xa0RCTs) follow‑up.\n\nOne large systematic review and meta-analysis of 19\xa0RCTs (Siempos et al. 2007; n=7,045) comparing commonly used broader-spectrum antibiotics (co‑amoxiclav, macrolides and fluoroquinolones) for 3\xa0to 10\xa0days found no significant difference in clinical effectiveness between groups (moderate to high quality evidence). Most people included in this review received treatment in the community. The available data did not allow subgroup analyses to be carried out in people considered to be at increased risk of poorer outcomes (such as older people, people with severe COPD and people with more frequent exacerbations).\n\nIn Siempos et al. (2007), a subgroup analysis of people with moderate or severe acute exacerbations found no significant difference in the resolution or improvement in exacerbation symptoms between macrolides and fluoroquinolones (80.7% versus 80.1%, high quality of evidence).\n\nIn 1 double-blinded RCT (Nouira et al. 2010; n=170), the effectiveness of co‑trimoxazole 160/800\xa0mg twice a day for 10\xa0days was compared with ciprofloxacin 750\xa0mg twice a day for 10\xa0days in people (mean age 67\xa0years) with a severe acute exacerbation of COPD being admitted to an intensive care unit in hospital. No significant differences between antibiotic groups were found up to 6\xa0months after treatment (low to moderate quality evidence).\n\nThe antibiotic course length ranged from 3\xa0to 14\xa0days in the studies. One double-blinded RCT (Urueta-Robledo et al. 2006) found no significant difference in the resolution of exacerbation symptoms with levofloxacin for 7\xa0days compared with moxifloxacin for 5\xa0days (moderate quality evidence).\n\nOverall, there were no major differences in adverse effects between antibiotics or classes of antibiotics based on the included studies (low to high quality evidence).\n\nIn the systematic review by Siempos et al. (2007), significantly more people reported adverse events with co‑amoxiclav compared with fluoroquinolones (16.6% versus 12.8%, NNH\xa027 [range 13\xa0to\xa0207], moderate quality evidence).\n\nCommittee discussion on choice of antibiotic\n\nAlthough there was some evidence to suggest that second-line antibiotics were more effective than first-line antibiotics, the absolute difference between groups was small and this analysis was limited by the classification of first- and second-line antibiotics, which was not consistent with current UK practice.\n\nBased on evidence of no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.\n\nIf an antibiotic is given, the committee agreed that this should be started empirically or based on the most recent sputum culture (if available). The committee was aware that the NICE guideline on COPD in over\xa016s makes recommendations about when to send sputum for culture.\n\nThe committee agreed that if a sputum sample has been sent for culture and susceptibility testing, when results are available, if they suggest the bacteria are not susceptible, the person should be contacted to assess symptoms. However, the antibiotic should only be changed according to susceptibility results if symptoms are not already improving. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible, and antibiotics switched from intravenous to oral where applicable.\n\nBased on experience, common pathogens in acute exacerbations of COPD, the susceptibility of these to various classes of antibiotics, the risks of resistance, and good antimicrobial stewardship, the committee agreed antibiotic choices as described below. Several oral and intravenous antibiotics were recommended because people with acute exacerbations of COPD may have repeated courses of antibiotics and may be at an increased risk of resistance. It also enables antibiotics to be selected based on the severity of illness and antibiotic susceptibilities from culture results (if available).\n\nThe first-line oral antibiotics are amoxicillin (a penicillin), doxycycline (a tetracycline) and clarithromycin (a macrolide), used at the usual doses for an acute exacerbation of COPD, although the dosage may be increased in severe infections. These antibiotics have good activity against common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae. Where a person is receiving prophylactic antibiotics, antibiotic treatment for an acute exacerbation should be with an antibiotic from a different class.\n\nThe second-line oral antibiotics for people whose symptoms worsen on a first-choice antibiotic taken for at least 2\xa0to 3\xa0days are an alternative first-choice from a different antibiotic class (a different antibiotic may be used for a subsequent exacerbation). This allows broader-spectrum antibiotics (some of which also have additional safety warnings) to be reserved for people who may be at a higher risk of treatment failure (for example, people who have had repeated courses of antibiotics, previous or current sputum culture with resistant bacteria, or people at higher risk of developing complications).\n\nThe alternative oral antibiotics for people who may be at a higher risk of treatment failure (guided by susceptibilities when available) are:\n\n\n\nco-amoxiclav 500/125\xa0mg three times a day; this broad-spectrum antibiotic combines a penicillin with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone\n\nlevofloxacin 500\xa0mg once a day; which was a fluoroquinolone used in the studies\n\nco-trimoxazole 960\xa0mg twice a day (trimethoprim plus a sulfonamide); which is suitable only for people with bacteriological evidence of sensitivity and good reason to prefer this combination to a single antibiotic.\n\n\n\nThe committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolones are appropriate as an alternative option for people who may be at a higher risk of treatment failure. The committee was keen to point out, however, that fluoroquinolone safety concerns should be taken into account on an individual patient basis.\n\nFirst-choice intravenous antibiotics at usual doses for treating acute exacerbations in people who are unable to take oral antibiotics, or the severity of their exacerbation means than intravenous treatment is required, are:\n\n\n\namoxicillin\n\nco-amoxiclav\n\nclarithromycin\n\nco-trimoxazole\n\npiperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor).\n\n\n\nSecond-choice intravenous antibiotics may be needed for some people after specialist advice, based on the severity of illness, likely pathogens or antibiotic susceptibilities from culture results when available, and local resistance patterns.\n\nThe committee agreed that a sputum sample should be sent for culture and susceptibility testing if symptoms have not resolved following antibiotic treatment and this has not been done already. Specific organisms, such as Pseudomonas aeruginosa may need to be looked for if people have prolonged recurrent exacerbations. They discussed that some people with resistant bacteria may need intravenous antibiotics, particularly if their symptoms are not responding to several courses of oral antibiotics for the same episode, or if several sputum samples show resistance to oral antibiotics.\n\nThe committee discussed that specialist advice should be sought for people needing intravenous antibiotics, to discuss local options for giving intravenous antibiotics at home or in the community, rather than in hospital.\n\n# Antibiotic course length\n\nShort-course antibiotics (for less than 6\xa0days) were not significantly different from long-course antibiotics (for 7\xa0days or more of the same antibiotic) in resolution of exacerbation symptoms after completing treatment, in people with an acute exacerbation of COPD (moderate quality evidence). This was based on a systematic review and meta-analysis (Stolbrink et al. 2017). This result was consistent regardless of the length of follow‑up (within 6\xa0days, 7\xa0to 14\xa0days or more than 20\xa0days) or the care setting (3\xa0of the 10\xa0RCTs were in hospital).\n\nThe diagnosis of an acute exacerbation was based on clinical evaluation in all studies, except 1\xa0RCT that used microscopically confirmed purulent sputum. The severity of exacerbation ranged from mild to severe, and 4\xa0RCTs used the Anthonisen classification of type of exacerbation for assessing exacerbation severity.\n\nA range of antibiotics were included in Stolbrink et al. (2017) with fluoroquinolones being the most commonly studied antibiotics. In most studies, a 3‑day or 5‑day course was compared with a 7‑day or 10‑day course of the same antibiotic.\n\nThere were significantly fewer adverse events with short-course antibiotics compared with long-course antibiotics (20.9% versus 24.9%, NNH\xa025 [range 14\xa0to\xa0100]; low quality evidence).\n\nNo systematic reviews or RCTs were identified that compared the frequency of antibiotic dosing or the route of antibiotic administration.\n\nCommittee discussion on antibiotic course length\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nBased on the evidence, if an antibiotic was prescribed, the committee agreed that a 5‑day course of all the recommended antibiotics was required to treat an acute exacerbation.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that the use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and susceptibility results from sputum culture) and switched to oral treatment where possible.\n\nSee the full evidence review for more information.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require regular dosing (for example, some antibiotics); see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are all available as generic formulations, see Drug Tariff for costs.'}
|
https://www.nice.org.uk/guidance/ng114
|
This guideline sets out an antimicrobial prescribing strategy for acute exacerbations of chronic obstructive pulmonary disease (COPD). It aims to optimise antibiotic use and reduce antibiotic resistance.
|
0aea47acddfad3eb8bee383090f6178094e81d04
|
nice
|
Post-traumatic stress disorder
|
Post-traumatic stress disorder
This guideline covers recognising, assessing and treating post-traumatic stress disorder (PTSD) in children, young people and adults. It aims to improve quality of life by reducing symptoms of PTSD such as anxiety, sleep problems and difficulties with concentration. Recommendations also aim to raise awareness of the condition and improve coordination of care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Recommendations in this guideline relate to everyone who is at risk of or has post-traumatic stress disorder (PTSD). The guideline has looked at inequalities relating to gender, sexual orientation, gender reassignment, age, homelessness, refugees and asylum seekers, illegal immigrants, undocumented workers, people with neurodevelopmental disorders, people with coexisting conditions, and people who are critically ill.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Recognition of post-traumatic stress disorder
Be aware that people with post-traumatic stress disorder (PTSD), including complex PTSD, may present with a range of symptoms associated with functional impairment, including:
re-experiencing
avoidance
hyperarousal (including hypervigilance, anger and irritability)
negative alterations in mood and thinking
emotional numbing
dissociation
emotional dysregulation
interpersonal difficulties or problems in relationships
negative self-perception (including feeling diminished, defeated or worthless).
Be aware of traumatic events associated with the development of PTSD. These could be experiencing or witnessing single, repeated or multiple events and could include, for example:
serious accidents
physical and sexual assault
abuse, including childhood or domestic abuse
work-related exposure to trauma, including remote exposure
trauma related to serious health problems or childbirth experiences (for example, intensive care admission or neonatal death)
war and conflict
torture.
When assessing for PTSD, ask people specific questions about re‑experiencing, avoidance, hyperarousal, dissociation, negative alterations in mood and thinking, and associated functional impairment.
When assessing for PTSD, ask people with symptoms in recommendation 1.1.1 if they have experienced 1 or more traumatic events (which may have occurred many months or years before). Give specific examples of traumatic events as listed in recommendation 1.1.2.
For people with unexplained physical symptoms who repeatedly attend health services, think about asking whether they have experienced 1 or more traumatic events and provide specific examples of traumatic events (see recommendation 1.1.2).
## Specific recognition issues for children
Do not rely solely on the parent or carer for information when it is developmentally appropriate to directly and separately question a child or young person about the presence of PTSD symptoms.
When a child who has been involved in a traumatic event is treated in an emergency department, emergency staff should explain to their parents or carers about the normal responses to trauma and the possibility of PTSD developing. Briefly describe the possible symptoms (for example, nightmares, repetitive trauma-related play, intrusive thoughts, avoiding things related to the event, increased behavioural difficulties, problems concentrating, hypervigilance, and difficulties sleeping), and suggest they contact their GP if the symptoms persist beyond 1 month.
## Screening of people involved in a major disaster, refugees and asylum seekers
For people at high risk of developing PTSD after a major disaster, those responsible for coordinating the disaster plan should think about the routine use of a validated, brief screening instrument for PTSD at 1 month after the disaster.
For refugees and asylum seekers at high risk of PTSD, think about the routine use of a validated, brief screening instrument for PTSD as part of any comprehensive physical and mental health screen.
# Assessment and coordination of care
For people with clinically important symptoms of PTSD presenting in primary care, GPs should take responsibility for assessment and initial coordination of care. This includes determining the need for emergency physical or mental health assessment.
Assessment of people with PTSD should be comprehensive, including an assessment of physical, psychological and social needs and a risk assessment.
Where management is shared between primary and secondary care, healthcare professionals should agree who is responsible for monitoring people with PTSD. Put this agreement in writing (if appropriate, using the Care Programme Approach) and involve the person and, if appropriate, their family or carers.
## Supporting transitions between services
To support transitions when people with PTSD are moving between services:
give the person information about the service they are moving to, including the setting and who will provide their care
ensure there is effective sharing of information between all services involved
involve the person and, if appropriate, their family or carers in meetings to plan the transition
address any worries the person has, for example about changes to their routine or anxiety about meeting new people.
Provide additional support:
to children and young people with PTSD who are within the care system when they are transitioning between services or settings
during admission and discharge to people with PTSD who are admitted to hospital because of other mental or physical health problems. Follow NICE's guidelines on transition from children's to adults' services for young people using health or social care services, common mental health problems: identification and pathways to care and transition between inpatient mental health settings and community or care home settings.
During transitions between services for people with PTSD who need ongoing care, the referring team should not discharge the person before a care plan has been agreed in the new service.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on supporting transitions between services .
Full details of the evidence and the committee's discussion are in evidence review J: care pathways for adults, children and young people with PTSD.
Loading. Please wait.
# Access to care
Promote access to services for people with PTSD by:
reassuring them that PTSD is a treatable condition
providing care that places a positive emphasis on the range of interventions offered and their likely benefits
ensuring that methods of access to services take into account the needs of specific populations of people with PTSD, including migrants and asylum seekers, people who are homeless or not registered with a GP, looked-after children and young people, and preschool-aged children
minimising the need to move between different services or providers
providing multiple points of access to the service, including self-referral
establishing clear links to other care pathways, including for physical healthcare needs
-ffering flexible modes of delivery, such as text messages, email, telephone or video consultation, or care in non-clinical settings such as schools or offices
-ffering a choice of therapist that takes into account the person's trauma experience – for example they might prefer a specific gender of therapist
using proactive person-centred strategies to promote uptake and sustained engagement
assessing the need for further treatment or support for people who have not benefited fully from treatment or have relapsed.
Do not delay or withhold treatment for PTSD solely because of court proceedings or applications for compensation. Discuss with the person the implications of the timing of any treatment to help them make an informed decision about if and when to proceed, in line with Crown Prosecution Service guidance on pre-trial therapy.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on access to care .
Full details of the evidence and the committee's discussion are in evidence review J: care pathways for adults, children and young people with PTSD. Other supporting evidence and discussion is in evidence review H: principles of care, and evidence review I: organisation and delivery of care for people with PTSD.
Loading. Please wait.
# Principles of care
## Supporting people with PTSD
Provide information in both verbal and written format and in line with recommendations in the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services.
Give information and support to people with PTSD (and their family members or carers as appropriate) covering:
common reactions to traumatic events, including the symptoms of PTSD and its course
assessment, treatment and support options
where their care will take place.
## Peer support
Tell people about and help them access peer support groups if they want to and could benefit. Peer support groups should:
be facilitated by people with mental health training and supervision
be delivered in a way that reduces the risk of exacerbating symptoms
provide information and help to access services.
## Maintaining safe environments
Be aware of the risk of continued exposure to trauma-inducing environments. Avoid exposing people to triggers that could worsen their symptoms or stop them from engaging with treatment, for example, assessing or treating people in noisy or restricted environments, placing them in a noisy inpatient ward, or restraining them.
## Involving and supporting families and carers
Consider providing information and support to family members and carers of people with PTSD. This could cover:
the treatment and management of trauma-related psychological and behavioural problems, including the person's possible risk to themselves and others
discussing with family members and carers how they are being affected by the person's PTSD
how they can support the person to access treatment, including what to do if they do not engage with, or drop out of treatment.
Involve family members and carers, if appropriate, in treatment for people with PTSD as a way to:
inform and improve the care of the person with PTSD and
identify and meet their own needs as carers.
Consider providing practical and emotional support and advice to family members and carers, for example directing them to health or social services or peer support groups.
Think about the impact of the traumatic event on other family members because more than one family member might have PTSD. Consider further assessment, support and intervention for any family member suspected to have PTSD.
For members of the same family who have PTSD after experiencing the same traumatic event, think about what aspects of treatment might be usefully provided together (such as psychoeducation), alongside individual treatments.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on principles of care .
Full details of the evidence and the committee's discussion are in evidence review H: principles of care. Other supporting evidence and discussion is in evidence review G: psychological and psychosocial interventions for family members and evidence review J: care pathways for adults, children and young people with PTSD.
Loading. Please wait.
# Language and culture
Pay particular attention to identifying people with PTSD in working or living environments where there may be cultural challenges to recognising the psychological consequences of trauma (see recommendations on avoiding stigma and promoting social inclusion in the NICE guideline on service user experience in adult mental health).
Ensure that screening, assessment and interventions for PTSD are culturally and linguistically appropriate.
If language or culture differences present challenges to the use of psychological interventions in PTSD, think about using interpreters or offering a choice of therapists. See recommendations on communication in the NICE guideline on patient experience in adult NHS services.
# Management of PTSD in children, young people and adults
## Planning treatment and supporting engagement
When discussing treatment options with people with PTSD (and their family members or carers as appropriate):
give them information about any proposed interventions, including:
their aim, content, duration and mode of delivery
the likelihood of improvement and recovery
what to expect during the intervention, including that symptoms can seem to get worse temporarily
that recovery is more likely if they stay engaged with treatment
take into account the person's preferences, any previous treatment, associated functional impairment and coexisting conditions
take into account any social or personal factors that may have a role in the development or maintenance of the disorder, such as childhood maltreatment and multiple traumatic experiences.
Be aware that people with PTSD may be apprehensive, anxious, or ashamed. They may avoid treatment, believe that PTSD is untreatable, or have difficulty developing trust. Engagement strategies could include following up when people miss appointments and allowing flexibility in service attendance policies.
For people with PTSD whose assessment identifies a significant risk of harm to themselves or others, establish a risk management and safety plan (involving family members and carers if appropriate) as part of initial treatment planning.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on planning treatment and supporting engagement .
Full details of the evidence and the committee's discussion are in evidence review H: principles of care and evidence review J: care pathways for adults, children and young people with PTSD.
Loading. Please wait.
## Active monitoring
Consider active monitoring for people with subthreshold symptoms of PTSD within 1 month of a traumatic event. Arrange follow-up contact to take place within 1 month.
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on active monitoring .
Full details of the evidence and the committee's discussion are in evidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children and evidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults.
Loading. Please wait.
## Psychologically-focused debriefing
Do not offer psychologically-focused debriefing for the prevention or treatment of PTSD.
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on psychologically-focused debriefing .
Full details of the evidence and the committee's discussion are in:
evidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children
evidence review B: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in children
evidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults
evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.
Loading. Please wait.
## Psychological interventions for the prevention and treatment of PTSD in children and young people
Consider active monitoring or individual trauma-focused cognitive behavioural therapy (CBT) within 1 month of a traumatic event for children and young people aged under 18 years with a diagnosis of acute stress disorder or clinically important symptoms of PTSD.
Consider a group trauma-focused CBT intervention for children and young people aged 7 to 17 years if there has been an event within the last month leading to large‑scale shared trauma.
Group trauma-focused CBT interventions for children and young people who have been exposed to large-scale shared trauma within the last month should:
be based on a validated manual
typically be provided over 5 to 15 sessions
be delivered by trained practitioners with ongoing supervision
include psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning
involve elaboration and processing of the trauma memories
involve restructuring trauma-related meanings for the individual
provide help to overcome avoidance.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions for the prevention of PTSD in children and young people .
Full details of the evidence and the committee's discussion are in evidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children.
Loading. Please wait.
Consider an individual trauma-focused CBT intervention for children aged 5 to 6 years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 1 month after a traumatic event.
Consider an individual trauma-focused CBT intervention for children and young people aged 7 to 17 years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented between 1 and 3 months after a traumatic event.
Offer an individual trauma-focused CBT intervention to children and young people aged 7 to 17 years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a traumatic event.
Individual trauma-focused CBT interventions for children and young people should:
be based on a validated manual
typically be provided over 6 to 12 sessions, but more if clinically indicated, for example if they have experienced multiple traumas
be delivered by trained practitioners with ongoing supervision
be adapted to the child or young person's age and development
involve parents or carers as appropriate
include psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning
involve elaboration and processing of the trauma memories
involve processing trauma-related emotions, including shame, guilt, loss and anger
involve restructuring trauma-related meanings for the individual
provide help to overcome avoidance
prepare them for the end of treatment
include planning booster sessions if needed, particularly in relation to significant dates (for example trauma anniversaries).
Consider eye movement desensitisation and reprocessing (EMDR) for children and young people aged 7 to 17 years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a traumatic event only if they do not respond to or engage with trauma-focused CBT.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions for the treatment of PTSD in children and young people .
Full details of the evidence and the committee's discussion are in evidence review B: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in children.
Loading. Please wait.
## Drug treatments for children and young people
Do not offer drug treatments for the prevention or treatment of PTSD in children and young people aged under 18 years.
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on drug treatments for children and young people .
Full details of the evidence and the committee's discussion are in evidence review E: pharmacological interventions for the prevention or treatment of PTSD in children.
Loading. Please wait.
## Psychological interventions for the prevention and treatment of PTSD in adults
Offer an individual trauma-focused CBT intervention to adults who have acute stress disorder or clinically important symptoms of PTSD and have been exposed to 1 or more traumatic events within the last month. These interventions include:
cognitive processing therapy
cognitive therapy for PTSD
narrative exposure therapy
prolonged exposure therapy.
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on psychological interventions to prevent PTSD in adults .
Full details of the evidence and the committee's discussion are in evidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults.
Loading. Please wait.
Offer an individual trauma-focused CBT intervention to adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 1 month after a traumatic event. These interventions include:
cognitive processing therapy
cognitive therapy for PTSD
narrative exposure therapy
prolonged exposure therapy.
Trauma-focused CBT interventions for adults should:
be based on a validated manual
typically be provided over 8 to 12 sessions, but more if clinically indicated, for example if they have experienced multiple traumas
be delivered by trained practitioners with ongoing supervision
include psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning
involve elaboration and processing of the trauma memories
involve processing trauma-related emotions, including shame, guilt, loss and anger
involve restructuring trauma-related meanings for the individual
provide help to overcome avoidance
have a focus on re-establishing adaptive functioning, for example work and social relationships
prepare them for the end of treatment
include planning booster sessions if needed, particularly in relation to significant dates (for example trauma anniversaries).
Consider EMDR for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented between 1 and 3 months after a non-combat-related trauma if the person has a preference for EMDR.
Offer EMDR to adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a non-combat-related trauma.
EMDR for adults should:
be based on a validated manual
typically be provided over 8 to 12 sessions, but more if clinically indicated, for example if they have experienced multiple traumas
be delivered by trained practitioners with ongoing supervision
be delivered in a phased manner and include psychoeducation about reactions to trauma; managing distressing memories and situations; identifying and treating target memories (often visual images); and promoting alternative positive beliefs about the self
use repeated in-session bilateral stimulation (normally with eye movements but use other methods, including taps and tones, if preferred or more appropriate, such as for people who are visually impaired) for specific target memories until the memories are no longer distressing
include the teaching of self-calming techniques and techniques for managing flashbacks, for use within and between sessions.
Consider supported trauma-focused computerised CBT for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a traumatic event if they prefer it to face-to-face trauma-focused CBT or EMDR as long as:
they do not have severe PTSD symptoms, in particular dissociative symptoms and
they are not at risk of harm to themselves or others.
Supported trauma-focused computerised CBT interventions for adults should:
be based on a validated programme
typically be provided over 8 to 10 sessions
involve elaboration and processing of the trauma memories; processing trauma-related emotions; restructuring trauma-related meanings for the individual; helping to overcome avoidance; and re-establishing adaptive functioning (for example, work and social relationships)
include guidance and support from a trained practitioner to encourage people to complete the intervention, give feedback on homework assignments and review progress and outcomes.
Consider CBT interventions targeted at specific symptoms such as sleep disturbance or anger, for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a traumatic event only if the person:
is unable or unwilling to engage in a trauma-focused intervention or
has residual symptoms after a trauma-focused intervention.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions to treat PTSD in adults .
Full details of the evidence and the committee's discussion are in evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.
Loading. Please wait.
## Drug treatments for adults
Do not offer drug treatments, including benzodiazepines, to prevent PTSD in adults.
Consider venlafaxine or a selective serotonin reuptake inhibitor (SSRI), such as sertraline, for adults with a diagnosis of PTSD if the person has a preference for drug treatment. Review this treatment regularly. In December 2018, this was an off-label use for venlafaxine. See NICE's information on prescribing medicines.In December 2018, only sertraline and paroxetine had a UK marketing authorisation for this indication. See NICE's information on prescribing medicines. For guidance on safe prescribing of antidepressants (such as venlafaxine or SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Consider antipsychotics such as risperidone in addition to psychological therapies to manage symptoms for adults with a diagnosis of PTSD if:
they have disabling symptoms and behaviours, for example severe hyperarousal or psychotic symptoms and
their symptoms have not responded to other drug or psychological treatments.Antipsychotic treatment should be started and reviewed regularly by a specialist (see recommendations on how to use antipsychotic medication in NICE's guideline on psychosis and schizophrenia in adults). In December 2018, this was an off-label use of risperidone. See NICE's information on prescribing medicines.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on drug treatments in adults .
Full details of the evidence and the committee's discussion are in evidence review F: pharmacological interventions for the treatment of PTSD in adults.
Loading. Please wait.
# Care for people with PTSD and complex needs
For people presenting with PTSD and depression:
usually treat the PTSD first because the depression will often improve with successful PTSD treatment
treat the depression first if it is severe enough to make psychological treatment of the PTSD difficult, or there is a risk of the person harming themselves or others.
Do not exclude people with PTSD from treatment based solely on comorbid drug or alcohol misuse.
For people with additional needs, including those with complex PTSD:
build in extra time to develop trust with the person, by increasing the duration or the number of therapy sessions according to the person's needs
take into account the safety and stability of the person's personal circumstances (for example their housing situation) and how this might affect engagement with and success of treatment
help the person manage any issues that might be a barrier to engaging with trauma-focused therapies, such as substance misuse, dissociation, emotional dysregulation, interpersonal difficulties or negative self-perception
work with the person to plan any ongoing support they will need after the end of treatment, for example to manage any residual PTSD symptoms or comorbidities.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on care for people with PTSD and complex needs .
Full details of the evidence and the committee's discussion are in evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults and evidence review J: care pathways for adults, children and young people with PTSD.
Loading. Please wait.
# Disaster planning
Ensure that disaster plans provide a fully coordinated psychosocial response to the disaster. A disaster plan should include:
immediate practical help
support for the affected communities in caring for those involved in the disaster
access to specialist mental health, evidence-based assessment and treatment services
clear roles and responsibilities for all professionals involved.
# Terms used in this guideline
## Active monitoring
Also known as watchful waiting. This means regularly monitoring a person who has some symptoms but who is not currently having clinical intervention for the condition.
## Acute stress disorder
Acute stress disorder is a DSM-5 diagnosis that applies in the first month after a traumatic event. It requires the presence of 9 or more symptoms from any of the 5 categories of intrusion, negative mood, dissociation, avoidance and arousal. These can be starting or worsening after the traumatic event.
## Clinically important symptoms
People with clinically important symptoms of PTSD refer to those who are assessed as having PTSD on a validated scale, as indicated by baseline scores above clinical threshold, but who do not necessarily have a diagnosis of PTSD. They are typically referred to in studies that have not used a clinical interview to arrive at a formal diagnosis of PTSD and instead have only used self-report measures of PTSD symptoms.
## Combat-related trauma
Combat-related trauma refers to traumatic incidents associated with military combat. In many cases, the sorts of traumas that military personnel encounter are not particularly distinct from those encountered by civilians. However, they might include having to contend with challenging situations to which there is no correct answer, which may lead to shame or guilt (known as moral injuries).
## Complex PTSD
Complex PTSD develops in a subset of people with PTSD. It is a diagnosis in the ICD‑11, which defines it as arising after exposure to an event or series of events of an extremely threatening or horrific nature, most commonly prolonged or repetitive events from which escape is difficult or impossible (for example, torture, slavery, genocide campaigns, prolonged domestic violence, repeated childhood sexual or physical abuse). The disorder is characterised by the core symptoms of PTSD; that is, all diagnostic requirements for PTSD are met. In addition, complex PTSD is characterised by:
severe and pervasive problems in affect regulation
persistent beliefs about oneself as diminished, defeated or worthless, accompanied by deep and pervasive feelings of shame, guilt or failure related to the traumatic event
persistent difficulties in sustaining relationships and in feeling close to others.
DSM‑5 does not include a diagnosis of complex PTSD. It covers the complexity of presentation through a wider range of core PTSD symptoms (such as 'negative mood and cognitions') and the potential specifier of a 'dissociative subtype'.
## Disaster plan
A plan setting out the overall framework for starting, managing, coordinating and controlling staff and other resources to reduce, control or respond to an emergency.
## Practitioner
A person with mental health training, particularly in PTSD, who also has training and competence in delivering interventions for PTSD.# Recommendations for research
As part of the 2018 update, the guideline committee removed the 2005 recommendations for research and replaced them with those below.
# Key recommendations for research
## Stepped care for post-traumatic stress disorder
What is the clinical and cost effectiveness of stepped care for post-traumatic stress disorder (PTSD)?
For an explanation of why the committee made the recommendation for research on stepped care, see appendix L of evidence review I: organisation and delivery of care for people with PTSD.
## Sequencing and further line treatment
What is the clinical and cost effectiveness of sequencing and further line treatment in PTSD?
For an explanation of why the committee made the recommendation for research on sequencing and further line treatment, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.
## Trauma-informed approaches
What is the clinical and cost effectiveness of trauma-informed care or trauma-informed approaches?
For an explanation of why the committee made the recommendation for research on trauma-informed approaches, see appendix L of evidence review I: organisation and delivery of care for people with PTSD.
## Personalisation and risk markers
What prognostic and prescriptive factors are important in determining the choice of PTSD treatment?
For an explanation of why the committee made the recommendation for research on personalisation and risk markers, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.
## Complex PTSD
What is the clinical and cost effectiveness of interventions to deliver stabilisation and reintegration for people with complex PTSD?
For an explanation of why the committee made the recommendation for research on complex PTSD, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.
# Other recommendations for research
## Emotional freedom techniques
What is the clinical and cost effectiveness of emotional freedom techniques (EFT) for the treatment of PTSD in adults?
For an explanation of why the committee made the recommendation for research on EFT, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Supporting transitions between services
Recommendations 1.2.4 to 1.2.6
## Why the committee made the recommendations
There was not enough good evidence about access to care, developing care pathways and coordinating care, so the committee drew on sources from other mental health disorders describing pathways and systems that support access and engagement with care. Based on this information they used a formal consensus method to make recommendations on good practice.
The committee discussed strategies to improve care coordination and provide smooth transitions of care for people with post-traumatic stress disorder (PTSD). They agreed it was important to plan transitions in advance, involve families and carers, make sure everyone involved in the person's care is aware of their role and responsibility, and ensure that different services are communicating with each other, as well as with the person with PTSD. They noted that overall coordination and continuity of care could be achieved by having a key professional to oversee the whole period of care – they agreed that this was already covered by the recommendations on GPs taking responsibility and management shared between primary and secondary care in the section on assessment and coordination of care. The committee also identified certain groups that might need extra support during care transitions.
## How the recommendations might affect practice
These recommendations will help to improve the way in which care is provided and improve consistency between services. Any resource impact should be offset by time savings and efficiency benefits from improved care coordination and continuity.
Return to recommendations
# Access to care
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
In the absence of good evidence the committee used formal consensus to recommend some key strategies for promoting access to care. Based on their clinical experience the committee agreed that a common barrier to accessing care can be the person's belief that PTSD is untreatable. The committee agreed it was important to present a more hopeful and optimistic picture of the treatment of PTSD.
They also discussed evidence on delivering care more flexibly. Qualitative evidence showed that some people with PTSD prefer to have their treatment away from a clinical environment. There was also clinical evidence that some types of remote care (for example, computerised trauma-focused cognitive behavioural therapy and video consultation) can be as successful as face-to-face interventions. Based on this, the committee agreed that delivering care in more flexible ways, including by making it available in non-clinical locations like schools or offices, would improve access.
## How the recommendations might affect practice
These recommendations will help to improve consistency in the way services are provided. Any resource impact should be offset by time savings and efficiency benefits from improved uptake and engagement. Currently video consultation is not available everywhere so this recommendation could have a moderate impact on resources. However, it is expected to save resources in the future, in particular in remote areas where therapists need to travel further to deliver trauma-focused CBT in person.
Return to recommendations
# Principles of care
Recommendations 1.4.1 to 1.4.9
## Why the committee made the recommendations
Recommendations 1.4.1 and 1.4.2 and recommendation 1.4.4
Based on the evidence and their own clinical experience, the committee discussed how people with PTSD are often apprehensive about making contact with services and may not know what treatments and help are available. They agreed that this underlined the need for good information and support, tailored to people's needs, about interventions and services. This should cover what care and treatment people can expect and how it will be provided (for example where and by whom).
The committee discussed the importance of maintaining safe environments for people with PTSD. Based on their clinical experience, they agreed that a number of environmental triggers could worsen people's symptoms or stop them from engaging in treatment. Practitioners assessing and treating people with PTSD – including those providing treatment for other mental or physical health conditions – should be aware of the need to minimise this risk.
Recommendation 1.4.3
The evidence for peer support groups was limited but included some compelling reports from people with PTSD that sharing experiences with other people who had also experienced a traumatic event was beneficial, and this was reported for different types of traumatic experience. Findings suggested that peer support could also help people overcome their doubts and fears about having treatment by telling them about available help and support and encouraging them to engage with services.
Recommendations 1.4.6 and 1.4.9
There was evidence that involving families and carers in treatment provided extra support for the person while also giving the family or carer a greater understanding of PTSD. However, family or carer involvement was not universally reported as positive, with some people not liking the feeling of being talked about in their absence, so the committee agreed this should be discussed with the person first.
Limited evidence showed that involving families and carers in treatment had benefits for improving carer mental health and reducing parenting difficulties. However, the evidence was too uncertain to support any recommendations for specific interventions to support family members and carers. The committee recommended good practice points based on their own expert opinion.
Recommendations 1.4.5, 1.4.7 and 1.4.8
Qualitative evidence suggested that a common reason for not seeking help for PTSD is a lack of awareness about interventions and services. The committee agreed that information and support provided to family and carers could act as a facilitator for accessing services for both the carer and the person with PTSD.
The committee discussed the potential for more than one family member to have PTSD. They considered it important to raise awareness about this risk so that people are offered support promptly.
## How the recommendations might affect practice
These recommendations are good practice points that will help to improve consistency of care. Any minor resource impact should be offset by time savings and efficiency benefits from improved uptake and engagement.
Peer support groups are not routinely offered everywhere but they are in fairly widespread use. The committee noted that facilitating access to these groups should not involve major resource implications. Any costs would be offset by potential savings associated with promoting earlier access to support that will help to prevent people from developing more severe problems.
Return to recommendations
# Planning treatment and supporting engagement
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
The committee agreed it was important to use a holistic approach when planning treatment, for example by thinking about every aspect of a person's life that could be contributing to their continuing PTSD symptoms, whether they might have any other physical or mental health conditions, and whether they might be at significant risk of harm to themselves or others. It was also important to ask the person if any treatments had worked for them in the past and to take into account their preferences. In the committee's opinion these were important points of good practice, along with providing information and support to help the person to make an informed choice about treatments.
The committee agreed that any strategies for promoting engagement need to be based on an understanding that people with PTSD are often highly anxious about having treatment and frequently avoid it. This was supported by evidence that common reasons for not seeking help include worry about engaging with a therapist, fear of exacerbating symptoms and stigmatisation. People may also have difficult emotions, such as shame, linked to the trauma, which can stop them from engaging with treatment. The committee agreed that healthcare professionals need to understand these reasons so that they don't misinterpret why someone is not engaging and they know the best ways to help them – including by contacting them if they don't come for an arranged appointment.
## How the recommendations might affect practice
These recommendations are good practice points that will help to improve consistency of practice. Any minor resource impact should be offset by potential time savings and efficiency benefits from improved uptake and engagement.
Return to recommendations
# Active monitoring
Recommendation 1.6.4
## Why the committee made the recommendation
There was no consistent evidence for effective interventions to prevent PTSD in people with subthreshold PTSD symptoms within 1 month of a traumatic event. The committee drew on their clinical experience and discussed how some people do not develop PTSD symptoms after a trauma even with no, or limited, interventions. Conversely, some people develop chronic symptoms if intervention is not provided early. Based on consensus, the committee agreed that active monitoring within the first month after the trauma could help professionals to judge whether people with less severe symptoms would need further intervention.
## How the recommendation might affect practice
Any changes to practice should be minimal because active monitoring (known as watchful waiting in the 2005 version of this guideline) is already part of recommended practice.
Return to recommendation
# Psychologically-focused debriefing
Recommendation 1.6.5
## Why the committee made the recommendation
Evidence on psychologically-focused debriefing, either individually or in groups, showed no benefit for children or adults, and some suggestion of worse outcomes than having no treatment. The committee agreed that psychologically-focused debriefing should not be offered. Providing an ineffective intervention can be regarded as harmful because it means that people are being denied access to another intervention with greater evidence of benefits.
## How the recommendation might affect practice
Psychologically-focused debriefing was not part of previously recommended practice so there should be no impact on practice.
Return to recommendation
# Psychological interventions for the prevention of PTSD in children and young people
Recommendations 1.6.6 to 1.6.8
## Why the committee made the recommendations
There was no evidence for individual trauma-focused CBT for children and young people within the first month of trauma. Despite the lack of direct evidence, the committee decided to make a recommendation for this intervention in light of the strong evidence for its efficacy for children who have experienced trauma more than 1 month ago, and the evidence for benefits in adults within 1 month of trauma. There can be a lot of natural recovery in the early weeks and it can be difficult to gauge a child or young person's readiness for intervention within 1 month of trauma. Based on consensus, the committee agreed that individual trauma-focused CBT and active monitoring could both be considered as options within 1 month of trauma for children and young people with clinically important PTSD symptoms or acute stress disorder, and that this decision was best left to clinical judgement.
There was evidence that trauma-focused CBT group interventions were effective for improving PTSD symptoms and other important outcomes for children and young people who had been exposed to ongoing trauma, for example from living in a war zone. The committee agreed that these findings could also apply to other types of large-scale shared traumas. There were some gaps and uncertainties in the evidence, for example in how long the benefits might last and whether they were specific to that intervention or could be explained by other general factors such as receiving attention from a therapist. Based on this evidence and the additional considerations, the committee recommended the intervention should be considered as a possible option. The cognitive and language demands of trauma-focused group CBT mean that it would not be suitable for children under 7 so the committee used an age range that reflected the age of children in the included studies.
Although specific group trauma-focused CBT interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed to specify the structure and content.
## How the recommendations might affect practice
There is currently variation in care for children and young people with acute stress disorder or clinically important symptoms of PTSD within 1 month of a traumatic event. Recommending active monitoring or individual trauma-focused CBT as options to consider should improve consistency in practice and help to reduce the use of more resource-intensive interventions for which the effectiveness is unknown.
There is currently no guidance on interventions for children exposed to large-scale shared trauma, and current practice has involved providing a range of different interventions. Without a clear steer on what works best there has been variability in access to interventions, the type of interventions offered and the extent to which they have been evidence-based. The recommendation for group trauma-focused CBT will lead to more consistency in practice and improve clinical outcomes for children who might otherwise need more costly management for PTSD later in the care pathway.
Return to recommendations
# Psychological interventions for the treatment of PTSD in children and young people
Recommendations 1.6.9 to 1.6.13
## Why the committee made the recommendations
The evidence showed that trauma-focused CBT is effective in improving PTSD symptoms and other important outcomes, and that improvements last for at least a year. Benefits were seen for different specific trauma-focused interventions and different types of trauma. Trauma-focused CBT is more effective, as well as more cost effective, when it is provided individually than in a group so the committee agreed it should be delivered individually.
Most of the evidence for trauma-focused CBT came from children aged over 7 years. There was some evidence from 5 and 6 year olds so the committee agreed it could be an option for them, but could not be recommended with the same certainty.
There was no evidence for treatment with trauma-focused CBT between 1 and 3 months after a traumatic event compared with a non-active control, so the committee could not recommend it with the same certainty as for more than 3 months after trauma. However, by extrapolating from the broad evidence base for benefits more than 3 months after trauma and drawing on members' own clinical experience, the committee agreed that trauma-focused CBT could be an option during this period.
Although specific trauma-focused CBT interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed to specify the structure and content. This recommendation was informed by the evidence and modified by the committee's expert advice. For example, a typical number of sessions was recommended based on the evidence, but the committee agreed that more might be needed, including for those who have experienced multiple traumas.
There was limited evidence for eye movement desensitisation and reprocessing (EMDR) suggesting possible benefits on PTSD symptoms in children older than 7 years. However, EMDR was found to be less clinically effective and cost effective than all individual trauma-focused CBT interventions. On this basis, the committee decided it should be considered only if children do not respond to or engage with trauma-focused CBT.
## How the recommendations might affect practice
Offering trauma-focused CBT more than 3 months after a traumatic event is in line with previously recommended practice and the committee was not aware of wide variation in practice. Considering trauma-focused CBT between 1 and 3 months after a traumatic event and recommending EMDR as an option are both new. They are only recommended as options to consider, which should limit their impact on practice, as should the fact that EMDR should only be considered for children who do not respond to or engage with trauma-focused CBT.
NICE's previous guideline made recommendations for children with PTSD, whereas current recommendations are also relevant to children and young people with clinically important symptoms of PTSD. The structure, content and time of the assessment, as well as the benefits from treatment, are broadly the same for both populations and it was the committee's view that there should not be a significant impact on practice.
Return to recommendations
# Drug treatments for children and young people
Recommendation 1.6.14
## Why the committee made the recommendation
There was very little evidence on the use of drug treatments to prevent or treat PTSD in children and young people. This limited evidence showed no significant benefits so the committee agreed drug treatment should not be offered.
## How the recommendation might affect practice
This recommendation is in line with previously recommended practice so there should be no impact on practice.
Return to recommendation
# Psychological interventions for the prevention of PTSD in adults
Recommendation 1.6.15
## Why the committee made the recommendation
Evidence showed that individual trauma-focused CBT interventions were effective for improving PTSD symptoms in adults who had experienced a traumatic event within the last month. They also reduced the number of adults who met the criteria to be diagnosed with PTSD after 1 month. There was also limited evidence from outside the UK that trauma-focused CBT is cost effective in adults at risk of PTSD.
There was evidence for a number of specific interventions within the trauma-focused CBT class, and the committee agreed it would be helpful to give some examples of named therapies that fall under this term.
The evidence of benefits was restricted to adults with clinically important symptoms or acute stress disorder, so the committee only recommended the intervention for these groups and not for people with less significant symptoms.
## How the recommendation might affect practice
The recommendation is in line with previous recommended practice so there should not be a major change in practice.
Return to recommendation
# Psychological interventions for the treatment of PTSD in adults
Recommendations 1.6.16 to 1.6.23
## Why the committee made the recommendations
Recommendations 1.6.16 and 1.6.17
There was extensive evidence that trauma-focused CBT interventions improve PTSD symptoms as well as other important outcomes, and that these improvements can be maintained up to a year later. Benefits were seen across a wide range of types of trauma, including both single and multiple incident traumas. There was evidence for a number of specific interventions within the trauma-focused CBT class, and the committee agreed it would be helpful to give some examples of named therapies that fall under this term.
Most of the evidence for trauma-focused CBT interventions came from adults who had been exposed to 1 or more traumatic events more than 3 months ago, although there was limited evidence showing benefits between 1 and 3 months after trauma. The committee discussed this limited evidence alongside the broader evidence base that showed benefits within the first month and more than 3 months after trauma. They thought it was unlikely that effects would be different in this 2‑month time period, so recommended trauma-focused CBT for adults with a diagnosis of PTSD or clinically important symptoms of PTSD more than 1 month after a traumatic event.
There was good evidence that offering up to 12 sessions of individual trauma-focused CBT was clinically and cost effective. Group trauma-focused CBT was not seen to be clinically or cost effective based on the guideline network meta-analysis and economic analysis, although the evidence was limited. Based on the standard number of sessions outlined in most validated treatment manuals and the most common number of sessions in the evidence base, the committee recommended providing 8 to 12 sessions. However, based on their clinical experience, they recommended offering more sessions if needed, including for people who have experienced multiple traumas.
Using both the evidence and their clinical experience, the committee outlined the structure and content of individual trauma-focused CBT interventions to make sure they are delivered in a consistent way because they were concerned that this may not happen in practice.
Psychoeducation was found to be highly clinically and cost effective in comparisons with psychological interventions according to the guideline network meta-analysis and economic analysis, but its evidence base was very limited and uncertain. The committee agreed that the evidence could not support a recommendation for psychoeducation on its own but it should be delivered as part of individual trauma-focused CBT.
Recommendations 1.6.18 to 1.6.20
Less evidence was found on EMDR than on trauma-focused CBT, but the committee agreed that what was available justified recommending EMDR. Although studies that compared EMDR directly with trauma-focused CBT did not show significant differences, there was a trend towards EMDR. This trend in favour of EMDR was also present in the cost effectiveness results. The evidence suggested EMDR was not effective in people with military combat-related trauma, and this was in marked contrast to all other included trauma types for which benefits were observed. On this basis, the committee restricted their recommendation to non-combat-related trauma.
Most of the evidence for EMDR came from adults who had been exposed to 1 or more traumatic events more than 3 months ago, although there was limited evidence showing benefits between 1 and 3 months after trauma. Based on this limited evidence and by extrapolating from the stronger evidence for EMDR more than 3 months after trauma, the committee recommended considering EMDR between 1 and 3 months after a non-combat-related trauma. This recommendation was made with less certainty than treatment after 3 months because of the very limited direct evidence (a single study) and because limited evidence suggested non-statistically significant benefits of EMDR within 1 month of trauma.
Although EMDR interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed a specific structure and content based on the interventions in the evidence and modified by their expert opinion.
Recommendations 1.6.21 and 1.6.22
There was evidence that both supported and unsupported self-help, and computerised trauma-focused CBT in particular, were beneficial in terms of self-rated PTSD symptoms and other important outcomes. These benefits were maintained up to a year later. Both interventions were cost effective compared with other psychological interventions. The evidence was limited for some of the outcomes that were looked at, and it was unclear whether self-help was effective across different types of trauma. Although both supported and unsupported self-help were found to be effective, the former was more clinically and cost effective because the greater effect sizes were sufficient to offset the higher costs.
Taking the evidence for efficacy together with the gaps in the evidence, the committee agreed that supported computerised trauma-focused CBT should be considered as an option for adults with PTSD who prefer this to face-to-face trauma-focused CBT or EMDR. The committee was concerned that a lower intensity intervention might not be clinically appropriate for all adults with PTSD, so this recommendation was limited to those who do not have severe PTSD symptoms (in particular dissociative symptoms) and are not at risk of harm to themselves or others.
A number of computerised trauma-focused CBT interventions are available, and the committee felt it was important to specify their structure and content to make sure a minimum standard was set.
Recommendation 1.6.23
There was some evidence that non-trauma-focused CBT is beneficial when targeted at specific symptoms such as sleep disturbance or anger, and also leads to improvements in PTSD symptoms, but it was not clear how long these benefits would be maintained. Non-trauma-focused CBT was less cost effective than individual trauma-focused CBT, EMDR and self-help, but more cost effective than other interventions such as present-centred therapy, group trauma-focused CBT, combined individual trauma-focused CBT and SSRIs, counselling and no treatment. The committee agreed the potential benefits of non-trauma-focused CBT were important, but that symptom-specific interventions should not be seen as an alternative to a trauma-focused first-line treatment. Instead, they could be an option when people are not ready to directly confront memories of the trauma and could promote uptake and engagement with a trauma-focused intervention. They could also be used to target residual symptoms after a trauma-focused intervention.
## How the recommendations might affect practice
NICE's previous guideline made recommendations for adults with PTSD, whereas current recommendations are also relevant to adults with clinically important symptoms of PTSD. The structure, content and time of the assessment, as well as the benefits from treatment, are broadly the same for both populations and it was the committee's view that there should not be a significant impact on practice.
Both trauma-focused CBT and EMDR were already recommended and the committee did not think there was wide variation in practice. The new recommendation for non-trauma-focused CBT interventions targeted at specific symptoms represents a bigger change because previous recommendations stated that non-trauma-focused interventions should not be routinely offered to people with chronic PTSD. The impact on resources is difficult to predict because it is recommended only as an option to consider, but it might bring potential savings by improving uptake and engagement with trauma-focused therapies that should reduce missed appointments and early drop-out.
The recommendation for supported computerised trauma-focused CBT is also thought to represent a bigger change. Self-help-based interventions were not previously part of recommended practice and the committee was not aware of such interventions being in widespread use. The cost of supported computerised trauma-focused CBT includes, in addition to a therapist's time, the cost of the digital mental health programmes and computers needed for delivery. If such an intervention is delivered in a public place (like a library), or the person's home, there is no equipment cost. If the computer is used in a clinical practice setting, it can be shared by many people having computerised therapy, minimising the equipment cost. It could therefore lead to cost savings if part of routine practice is shifted from the more resource-intensive individual trauma-focused CBT and EMDR to the less resource-intensive supported computerised trauma-focused CBT.
The committee acknowledged that there would be a cost associated with providing extra trauma-focused therapy sessions if they are needed (for example, for people who have experienced multiple traumas). Previous recommended practice was to consider more than 12 sessions for people after multiple incident trauma, or who have chronic disability or significant coexisting conditions or social problems. However, in clinical practice the provision of additional sessions is variable.
Return to recommendations
# Drug treatments in adults
Recommendations 1.6.24 to 1.6.26
## Why the committee made the recommendations
Recommendation 1.6.24
There was no consistent evidence that any drug treatments are effective in preventing PTSD. Given the limited evidence of benefits and the potential harms, including side effects, the committee agreed that drug treatments should not be offered to prevent PTSD in adults. The committee specifically referred to benzodiazepines because of the lack of benefit in the evidence, concerns about harm and their clinical experience of these drugs being prescribed in practice.
Recommendations 1.6.25 and 1.6.26
There was evidence that SSRIs and venlafaxine are effective in treating PTSD. There was a large number of studies for SSRIs but the sizes of the effects were smaller than for venlafaxine. The committee decided that either an SSRI or venlafaxine could be considered if a person prefers to have drug treatment, but they should not be offered as first-line treatment for PTSD. This is based partly on the lack of follow-up data for SSRIs and venlafaxine, and because evidence showed that SSRIs are less effective than any of the psychological interventions recommended. Economic modelling also showed SSRIs are less cost effective than EMDR, brief individual trauma-focused CBT or self-help with support.
There was no evidence for significant differential efficacy of specific SSRIs (sertraline, fluoxetine and paroxetine), so the committee agreed to allow prescribers to decide which SSRI to use. However, they included sertraline as an example because it is 1 of 2 drugs licensed in the UK for this indication and the other drug, paroxetine, is more likely to be associated with discontinuation symptoms.
The committee agreed that it was important to review antidepressant treatment regularly to manage any side effects and to review clinical progress and outcomes.
There was some evidence that antipsychotics, either alone or in addition to routine medications, are effective in treating PTSD symptoms. However, it was more limited than the evidence supporting SSRIs and the psychological interventions (for example, the evidence for other important outcomes was limited and there were no follow-up data). The committee agreed that antipsychotics should not be seen as an alternative to a trauma-focused psychological intervention as first-line treatment for PTSD and should only be considered as an adjunct to psychological therapy. However, they might be beneficial for symptom management for adults with a diagnosis of PTSD if their symptoms have not responded to other drug or psychological treatments and they have disabling symptoms and behaviours that makes it difficult for them to engage with psychological treatment. Given the different side effect profiles, the committee agreed to leave the choice of antipsychotic to clinical judgement. Risperidone was included as an example because the evidence for risperidone included more participants.
The committee discussed concerns about the tolerability of antipsychotic drugs and agreed they should only be prescribed in a specialist setting, or after consultation with a specialist.
## How the recommendations might affect practice
The committee was concerned that drug treatment within the first month of trauma may be reasonably common in clinical practice. The do not offer drug treatments recommendation in the section on drug treatments for adults will therefore help to reduce the use of non-evidence-based interventions and improve consistency of practice. These recommendations represent a small change in practice because the previous guideline recommended drug treatment as an option only for adults who could not start a psychological therapy, did not want to start trauma-focused psychological therapy or who had gained little or no benefit from it.
In the UK, only paroxetine and sertraline are licensed for the treatment of PTSD so the recommendations involve off-licence use. Offering antipsychotics only in a specialist setting or after consultation with a specialist is expected to reduce variation in the way antipsychotics are used in current practice. Regular review of drug treatment is essential but might not be happening currently, so this should also improve consistency.
Return to recommendations
# Care for people with post-traumatic stress disorder and complex needs
Recommendations 1.7.1 to 1.7.3
## Why the committee made the recommendations
There was a lack of evidence on care for people with PTSD and complex needs, including people with coexisting conditions such as depression or substance misuse, so the committee used a formal consensus method to agree some overarching principles.
The evidence was limited on interventions for people who have complex PTSD, but it suggested that trauma-focused therapies could also benefit this group. Based on their clinical experience, the committee recommended modifications that may be needed to trauma-focused therapies to facilitate engagement for those with complex PTSD or other additional needs.
## How the recommendations might affect practice
The committee acknowledged that there would be a cost associated with increasing the duration or the number of therapy sessions, if this is necessary for people with PTSD and additional needs. Previous recommended practice was to consider more than 12 sessions for people after multiple incident trauma, or who have chronic disability or significant coexisting conditions or social problems. However, in clinical practice the provision of additional sessions is variable.
Return to recommendations# Context
Post-traumatic stress disorder (PTSD) develops after a stressful event or situation of an exceptionally threatening or catastrophic nature. It is a disorder that can affect people of any age. Around 25–30% of people experiencing a traumatic event go on to develop PTSD.
PTSD can present with a range of symptoms. In adults the most common of these are vivid, distressing memories of the event or flashbacks, known as intrusive symptoms. Another prominent symptom is avoidance of trauma-related reminders or general social contact. People with PTSD often try to push memories of the event out of their mind and avoid thinking or talking about it in detail. On the other hand, people may also reflect excessively on questions that prevent them from coming to terms with the event – for example, why it happened to them, how it could have been prevented, or how they could take revenge. People with PTSD often have nightmares related to the trauma that affect their sleep.
Symptoms of PTSD often develop immediately after the traumatic event but in some people (fewer than 15%) onset is delayed. People may not present for treatment for months or years despite experiencing considerable distress. PTSD is a treatable disorder, even for people who present many years later, but assessment can be challenging because many people avoid talking about their problems even when presenting with associated complaints.
Children, particularly those aged under 8 years, may not complain directly of PTSD symptoms such as re‑experiencing or avoidance. Instead, symptoms may take the form of re‑enacting the experience, repetitive play or frightening dreams with no recognisable content.
It is common for people with PTSD to have other problems such as depression. If people have had repeated or multiple traumas, or have other significant mental health problems, their presentation of PTSD may be complex and adjustments may be needed to the way in which treatment is delivered.
Effective treatment of PTSD can only take place if the disorder is recognised. Opportunities for recognition usually come during routine healthcare, for example during physical treatment after an assault or an accident, or when a person discloses domestic violence or a history of childhood sexual abuse. Many people attending for medical services in hospital have experienced traumatic events, particularly in emergency departments, and orthopaedic and plastic surgery clinics. Up to 30% of children who attend an emergency department for a traumatic injury go on to develop PTSD. Identifying PTSD in children presents particular problems, but is improved by asking children directly about their experiences.
This guideline updates NICE's 2005 guidance on PTSD. It covers children, young people and adults (aged 18 years and over) who are at risk of PTSD or have a diagnosis of PTSD, and their families and carers. It also covers people with comorbid conditions including drug and alcohol misuse and common mental health conditions.
The guideline covers all NHS and social care-commissioned services that provide care for people with PTSD.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nRecommendations in this guideline relate to everyone who is at risk of or has post-traumatic stress disorder (PTSD). The guideline has looked at inequalities relating to gender, sexual orientation, gender reassignment, age, homelessness, refugees and asylum seekers, illegal immigrants, undocumented workers, people with neurodevelopmental disorders, people with coexisting conditions, and people who are critically ill.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Recognition of post-traumatic stress disorder\n\nBe aware that people with post-traumatic stress disorder (PTSD), including complex PTSD, may present with a range of symptoms associated with functional impairment, including:\n\nre-experiencing\n\navoidance\n\nhyperarousal (including hypervigilance, anger and irritability)\n\nnegative alterations in mood and thinking\n\nemotional numbing\n\ndissociation\n\nemotional dysregulation\n\ninterpersonal difficulties or problems in relationships\n\nnegative self-perception (including feeling diminished, defeated or worthless). [2005, amended 2018]\n\nBe aware of traumatic events associated with the development of PTSD. These could be experiencing or witnessing single, repeated or multiple events and could include, for example:\n\nserious accidents\n\nphysical and sexual assault\n\nabuse, including childhood or domestic abuse\n\nwork-related exposure to trauma, including remote exposure\n\ntrauma related to serious health problems or childbirth experiences (for example, intensive care admission or neonatal death)\n\nwar and conflict\n\ntorture. [2005, amended 2018]\n\nWhen assessing for PTSD, ask people specific questions about re‑experiencing, avoidance, hyperarousal, dissociation, negative alterations in mood and thinking, and associated functional impairment. [2005, amended 2018]\n\nWhen assessing for PTSD, ask people with symptoms in recommendation 1.1.1 if they have experienced 1 or more traumatic events (which may have occurred many months or years before). Give specific examples of traumatic events as listed in recommendation 1.1.2. [2005, amended 2018]\n\nFor people with unexplained physical symptoms who repeatedly attend health services, think about asking whether they have experienced 1 or more traumatic events and provide specific examples of traumatic events (see recommendation 1.1.2). [2005, amended 2018]\n\n## Specific recognition issues for children\n\nDo not rely solely on the parent or carer for information when it is developmentally appropriate to directly and separately question a child or young person about the presence of PTSD symptoms. [2005, amended 2018]\n\nWhen a child who has been involved in a traumatic event is treated in an emergency department, emergency staff should explain to their parents or carers about the normal responses to trauma and the possibility of PTSD developing. Briefly describe the possible symptoms (for example, nightmares, repetitive trauma-related play, intrusive thoughts, avoiding things related to the event, increased behavioural difficulties, problems concentrating, hypervigilance, and difficulties sleeping), and suggest they contact their GP if the symptoms persist beyond 1\xa0month. [2005, amended 2018]\n\n## Screening of people involved in a major disaster, refugees and asylum seekers\n\nFor people at high risk of developing PTSD after a major disaster, those responsible for coordinating the disaster plan should think about the routine use of a validated, brief screening instrument for PTSD at 1\xa0month after the disaster. [2005, amended 2018]\n\nFor refugees and asylum seekers at high risk of PTSD, think about the routine use of a validated, brief screening instrument for PTSD as part of any comprehensive physical and mental health screen. [2005, amended 2018]\n\n# Assessment and coordination of care\n\nFor people with clinically important symptoms of PTSD presenting in primary care, GPs should take responsibility for assessment and initial coordination of care. This includes determining the need for emergency physical or mental health assessment. [2005, amended 2018]\n\nAssessment of people with PTSD should be comprehensive, including an assessment of physical, psychological and social needs and a risk assessment. [2005, amended 2018]\n\nWhere management is shared between primary and secondary care, healthcare professionals should agree who is responsible for monitoring people with PTSD. Put this agreement in writing (if appropriate, using the Care Programme Approach) and involve the person and, if appropriate, their family or carers. [2005, amended 2018]\n\n## Supporting transitions between services\n\nTo support transitions when people with PTSD are moving between services:\n\ngive the person information about the service they are moving to, including the setting and who will provide their care\n\nensure there is effective sharing of information between all services involved\n\ninvolve the person and, if appropriate, their family or carers in meetings to plan the transition\n\naddress any worries the person has, for example about changes to their routine or anxiety about meeting new people. \n\nProvide additional support:\n\nto children and young people with PTSD who are within the care system when they are transitioning between services or settings\n\nduring admission and discharge to people with PTSD who are admitted to hospital because of other mental or physical health problems. Follow NICE's guidelines on transition from children's to adults' services for young people using health or social care services, common mental health problems: identification and pathways to care and transition between inpatient mental health settings and community or care home settings. \n\nDuring transitions between services for people with PTSD who need ongoing care, the referring team should not discharge the person before a care plan has been agreed in the new service. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on supporting transitions between services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: care pathways for adults, children and young people with PTSD.\n\nLoading. Please wait.\n\n# Access to care\n\nPromote access to services for people with PTSD by:\n\nreassuring them that PTSD is a treatable condition\n\nproviding care that places a positive emphasis on the range of interventions offered and their likely benefits\n\nensuring that methods of access to services take into account the needs of specific populations of people with PTSD, including migrants and asylum seekers, people who are homeless or not registered with a GP, looked-after children and young people, and preschool-aged children\n\nminimising the need to move between different services or providers\n\nproviding multiple points of access to the service, including self-referral\n\nestablishing clear links to other care pathways, including for physical healthcare needs\n\noffering flexible modes of delivery, such as text messages, email, telephone or video consultation, or care in non-clinical settings such as schools or offices\n\noffering a choice of therapist that takes into account the person's trauma experience – for example they might prefer a specific gender of therapist\n\nusing proactive person-centred strategies to promote uptake and sustained engagement\n\nassessing the need for further treatment or support for people who have not benefited fully from treatment or have relapsed. \n\nDo not delay or withhold treatment for PTSD solely because of court proceedings or applications for compensation. Discuss with the person the implications of the timing of any treatment to help them make an informed decision about if and when to proceed, in line with Crown Prosecution Service guidance on pre-trial therapy. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on access to care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: care pathways for adults, children and young people with PTSD. Other supporting evidence and discussion is in evidence review H: principles of care, and evidence review I: organisation and delivery of care for people with PTSD.\n\nLoading. Please wait.\n\n# Principles of care\n\n## Supporting people with PTSD\n\nProvide information in both verbal and written format and in line with recommendations in the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services. \n\nGive information and support to people with PTSD (and their family members or carers as appropriate) covering:\n\ncommon reactions to traumatic events, including the symptoms of PTSD and its course\n\nassessment, treatment and support options\n\nwhere their care will take place. \n\n## Peer support\n\nTell people about and help them access peer support groups if they want to and could benefit. Peer support groups should:\n\nbe facilitated by people with mental health training and supervision\n\nbe delivered in a way that reduces the risk of exacerbating symptoms\n\nprovide information and help to access services. \n\n## Maintaining safe environments\n\nBe aware of the risk of continued exposure to trauma-inducing environments. Avoid exposing people to triggers that could worsen their symptoms or stop them from engaging with treatment, for example, assessing or treating people in noisy or restricted environments, placing them in a noisy inpatient ward, or restraining them. \n\n## Involving and supporting families and carers\n\nConsider providing information and support to family members and carers of people with PTSD. This could cover:\n\nthe treatment and management of trauma-related psychological and behavioural problems, including the person's possible risk to themselves and others\n\ndiscussing with family members and carers how they are being affected by the person's PTSD\n\nhow they can support the person to access treatment, including what to do if they do not engage with, or drop out of treatment. \n\nInvolve family members and carers, if appropriate, in treatment for people with PTSD as a way to:\n\ninform and improve the care of the person with PTSD and\n\nidentify and meet their own needs as carers. \n\nConsider providing practical and emotional support and advice to family members and carers, for example directing them to health or social services or peer support groups. \n\nThink about the impact of the traumatic event on other family members because more than one family member might have PTSD. Consider further assessment, support and intervention for any family member suspected to have PTSD. \n\nFor members of the same family who have PTSD after experiencing the same traumatic event, think about what aspects of treatment might be usefully provided together (such as psychoeducation), alongside individual treatments. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on principles of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: principles of care. Other supporting evidence and discussion is in evidence review G: psychological and psychosocial interventions for family members and evidence review J: care pathways for adults, children and young people with PTSD.\n\nLoading. Please wait.\n\n# Language and culture\n\nPay particular attention to identifying people with PTSD in working or living environments where there may be cultural challenges to recognising the psychological consequences of trauma (see recommendations on avoiding stigma and promoting social inclusion in the NICE guideline on service user experience in adult mental health). [2005, amended 2018]\n\nEnsure that screening, assessment and interventions for PTSD are culturally and linguistically appropriate. [2005, amended 2018]\n\nIf language or culture differences present challenges to the use of psychological interventions in PTSD, think about using interpreters or offering a choice of therapists. See recommendations on communication in the NICE guideline on patient experience in adult NHS services. [2005, amended 2018]\n\n# Management of PTSD in children, young people and adults\n\n## Planning treatment and supporting engagement\n\nWhen discussing treatment options with people with PTSD (and their family members or carers as appropriate):\n\ngive them information about any proposed interventions, including:\n\n\n\ntheir aim, content, duration and mode of delivery\n\nthe likelihood of improvement and recovery\n\nwhat to expect during the intervention, including that symptoms can seem to get worse temporarily\n\nthat recovery is more likely if they stay engaged with treatment\n\n\n\ntake into account the person's preferences, any previous treatment, associated functional impairment and coexisting conditions\n\ntake into account any social or personal factors that may have a role in the development or maintenance of the disorder, such as childhood maltreatment and multiple traumatic experiences. \n\nBe aware that people with PTSD may be apprehensive, anxious, or ashamed. They may avoid treatment, believe that PTSD is untreatable, or have difficulty developing trust. Engagement strategies could include following up when people miss appointments and allowing flexibility in service attendance policies. \n\nFor people with PTSD whose assessment identifies a significant risk of harm to themselves or others, establish a risk management and safety plan (involving family members and carers if appropriate) as part of initial treatment planning. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on planning treatment and supporting engagement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: principles of care and evidence review J: care pathways for adults, children and young people with PTSD.\n\nLoading. Please wait.\n\n## Active monitoring\n\nConsider active monitoring for people with subthreshold symptoms of PTSD within 1\xa0month of a traumatic event. Arrange follow-up contact to take place within 1\xa0month. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on active monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children and evidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults.\n\nLoading. Please wait.\n\n## Psychologically-focused debriefing\n\nDo not offer psychologically-focused debriefing for the prevention or treatment of PTSD. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on psychologically-focused debriefing\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children\n\nevidence review B: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in children\n\nevidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults\n\nevidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.\n\nLoading. Please wait.\n\n## Psychological interventions for the prevention and treatment of PTSD in children and young people\n\nConsider active monitoring or individual trauma-focused cognitive behavioural therapy (CBT) within 1\xa0month of a traumatic event for children and young people aged under 18\xa0years with a diagnosis of acute stress disorder or clinically important symptoms of PTSD. \n\nConsider a group trauma-focused CBT intervention for children and young people aged 7\xa0to 17\xa0years if there has been an event within the last month leading to large‑scale shared trauma. \n\nGroup trauma-focused CBT interventions for children and young people who have been exposed to large-scale shared trauma within the last month should:\n\nbe based on a validated manual\n\ntypically be provided over 5 to 15\xa0sessions\n\nbe delivered by trained practitioners with ongoing supervision\n\ninclude psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning\n\ninvolve elaboration and processing of the trauma memories\n\ninvolve restructuring trauma-related meanings for the individual\n\nprovide help to overcome avoidance. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions for the prevention of PTSD in children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in children.\n\nLoading. Please wait.\n\nConsider an individual trauma-focused CBT intervention for children aged 5\xa0to 6\xa0years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 1\xa0month after a traumatic event. \n\nConsider an individual trauma-focused CBT intervention for children and young people aged 7\xa0to 17\xa0years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented between 1 and 3\xa0months after a traumatic event. \n\nOffer an individual trauma-focused CBT intervention to children and young people aged 7\xa0to 17\xa0years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3\xa0months after a traumatic event. \n\nIndividual trauma-focused CBT interventions for children and young people should:\n\nbe based on a validated manual\n\ntypically be provided over 6\xa0to 12\xa0sessions, but more if clinically indicated, for example if they have experienced multiple traumas\n\nbe delivered by trained practitioners with ongoing supervision\n\nbe adapted to the child or young person's age and development\n\ninvolve parents or carers as appropriate\n\ninclude psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning\n\ninvolve elaboration and processing of the trauma memories\n\ninvolve processing trauma-related emotions, including shame, guilt, loss and anger\n\ninvolve restructuring trauma-related meanings for the individual\n\nprovide help to overcome avoidance\n\nprepare them for the end of treatment\n\ninclude planning booster sessions if needed, particularly in relation to significant dates (for example trauma anniversaries). \n\nConsider eye movement desensitisation and reprocessing (EMDR) for children and young people aged 7 to 17\xa0years with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3\xa0months after a traumatic event only if they do not respond to or engage with trauma-focused CBT. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions for the treatment of PTSD in children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in children.\n\nLoading. Please wait.\n\n## Drug treatments for children and young people\n\nDo not offer drug treatments for the prevention or treatment of PTSD in children and young people aged under 18\xa0years. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on drug treatments for children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: pharmacological interventions for the prevention or treatment of PTSD in children.\n\nLoading. Please wait.\n\n## Psychological interventions for the prevention and treatment of PTSD in adults\n\nOffer an individual trauma-focused CBT intervention to adults who have acute stress disorder or clinically important symptoms of PTSD and have been exposed to 1 or more traumatic events within the last month. These interventions include:\n\ncognitive processing therapy\n\ncognitive therapy for PTSD\n\nnarrative exposure therapy\n\nprolonged exposure therapy. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on psychological interventions to prevent PTSD in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: psychological, psychosocial and other non-pharmacological interventions for the prevention of PTSD in adults.\n\nLoading. Please wait.\n\nOffer an individual trauma-focused CBT intervention to adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 1\xa0month after a traumatic event. These interventions include:\n\ncognitive processing therapy\n\ncognitive therapy for PTSD\n\nnarrative exposure therapy\n\nprolonged exposure therapy. \n\nTrauma-focused CBT interventions for adults should:\n\nbe based on a validated manual\n\ntypically be provided over 8\xa0to 12\xa0sessions, but more if clinically indicated, for example if they have experienced multiple traumas\n\nbe delivered by trained practitioners with ongoing supervision\n\ninclude psychoeducation about reactions to trauma, strategies for managing arousal and flashbacks, and safety planning\n\ninvolve elaboration and processing of the trauma memories\n\ninvolve processing trauma-related emotions, including shame, guilt, loss and anger\n\ninvolve restructuring trauma-related meanings for the individual\n\nprovide help to overcome avoidance\n\nhave a focus on re-establishing adaptive functioning, for example work and social relationships\n\nprepare them for the end of treatment\n\ninclude planning booster sessions if needed, particularly in relation to significant dates (for example trauma anniversaries). \n\nConsider EMDR for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented between 1 and 3\xa0months after a non-combat-related trauma if the person has a preference for EMDR. \n\nOffer EMDR\xa0to adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3 months after a non-combat-related trauma. \n\nEMDR for adults should:\n\nbe based on a validated manual\n\ntypically be provided over 8\xa0to 12\xa0sessions, but more if clinically indicated, for example if they have experienced multiple traumas\n\nbe delivered by trained practitioners with ongoing supervision\n\nbe delivered in a phased manner and include psychoeducation about reactions to trauma; managing distressing memories and situations; identifying and treating target memories (often visual images); and promoting alternative positive beliefs about the self\n\nuse repeated in-session bilateral stimulation (normally with eye movements but use other methods, including taps and tones, if preferred or more appropriate, such as for people who are visually impaired) for specific target memories until the memories are no longer distressing\n\ninclude the teaching of self-calming techniques and techniques for managing flashbacks, for use within and between sessions. \n\nConsider supported trauma-focused computerised CBT for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3\xa0months after a traumatic event if they prefer it to face-to-face trauma-focused CBT or EMDR as long as:\n\nthey do not have severe PTSD symptoms, in particular dissociative symptoms and\n\nthey are not at risk of harm to themselves or others. \n\nSupported trauma-focused computerised CBT interventions for adults should:\n\nbe based on a validated programme\n\ntypically be provided over 8 to 10\xa0sessions\n\ninvolve elaboration and processing of the trauma memories; processing trauma-related emotions; restructuring trauma-related meanings for the individual; helping to overcome avoidance; and re-establishing adaptive functioning (for example, work and social relationships)\n\ninclude guidance and support from a trained practitioner to encourage people to complete the intervention, give feedback on homework assignments and review progress and outcomes. \n\nConsider CBT interventions targeted at specific symptoms such as sleep disturbance or anger, for adults with a diagnosis of PTSD or clinically important symptoms of PTSD who have presented more than 3\xa0months after a traumatic event only if the person:\n\nis unable or unwilling to engage in a trauma-focused intervention or\n\nhas residual symptoms after a trauma-focused intervention. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on psychological interventions to treat PTSD in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.\n\nLoading. Please wait.\n\n## Drug treatments for adults\n\nDo not offer drug treatments, including benzodiazepines, to prevent PTSD in adults. \n\nConsider venlafaxine or a selective serotonin reuptake inhibitor (SSRI), such as sertraline, for adults with a diagnosis of PTSD if the person has a preference for drug treatment. Review this treatment regularly. In December\xa02018, this was an off-label use for venlafaxine. See NICE's information on prescribing medicines.In December\xa02018, only sertraline and paroxetine had a UK marketing authorisation for this indication. See NICE's information on prescribing medicines. For guidance on safe prescribing of antidepressants (such as venlafaxine or SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nConsider antipsychotics such as risperidone in addition to psychological therapies to manage symptoms for adults with a diagnosis of PTSD if:\n\nthey have disabling symptoms and behaviours, for example severe hyperarousal or psychotic symptoms and\n\ntheir symptoms have not responded to other drug or psychological treatments.Antipsychotic treatment should be started and reviewed regularly by a specialist (see recommendations on how to use antipsychotic medication in NICE's guideline on psychosis and schizophrenia in adults). In December 2018, this was an off-label use of risperidone. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on drug treatments in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: pharmacological interventions for the treatment of PTSD in adults.\n\nLoading. Please wait.\n\n# Care for people with PTSD and complex needs\n\nFor people presenting with PTSD and depression:\n\nusually treat the PTSD first because the depression will often improve with successful PTSD treatment\n\ntreat the depression first if it is severe enough to make psychological treatment of the PTSD difficult, or there is a risk of the person harming themselves or others. \n\nDo not exclude people with PTSD from treatment based solely on comorbid drug or alcohol misuse. \n\nFor people with additional needs, including those with complex PTSD:\n\nbuild in extra time to develop trust with the person, by increasing the duration or the number of therapy sessions according to the person's needs\n\ntake into account the safety and stability of the person's personal circumstances (for example their housing situation) and how this might affect engagement with and success of treatment\n\nhelp the person manage any issues that might be a barrier to engaging with trauma-focused therapies, such as substance misuse, dissociation, emotional dysregulation, interpersonal difficulties or negative self-perception\n\nwork with the person to plan any ongoing support they will need after the end of treatment, for example to manage any residual PTSD symptoms or comorbidities. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on care for people with PTSD and complex needs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults and evidence review J: care pathways for adults, children and young people with PTSD.\n\nLoading. Please wait.\n\n# Disaster planning\n\nEnsure that disaster plans provide a fully coordinated psychosocial response to the disaster. A disaster plan should include:\n\nimmediate practical help\n\nsupport for the affected communities in caring for those involved in the disaster\n\naccess to specialist mental health, evidence-based assessment and treatment services\n\nclear roles and responsibilities for all professionals involved. \n\n# Terms used in this guideline\n\n## Active monitoring\n\nAlso known as watchful waiting. This means regularly monitoring a person who has some symptoms but who is not currently having clinical intervention for the condition.\n\n## Acute stress disorder\n\nAcute stress disorder is a DSM-5 diagnosis that applies in the first month after a traumatic event. It requires the presence of 9 or more symptoms from any of the 5\xa0categories of intrusion, negative mood, dissociation, avoidance and arousal. These can be starting or worsening after the traumatic event.\n\n## Clinically important symptoms\n\nPeople with clinically important symptoms of PTSD refer to those who are assessed as having PTSD on a validated scale, as indicated by baseline scores above clinical threshold, but who do not necessarily have a diagnosis of PTSD. They are typically referred to in studies that have not used a clinical interview to arrive at a formal diagnosis of PTSD and instead have only used self-report measures of PTSD symptoms.\n\n## Combat-related trauma\n\nCombat-related trauma refers to traumatic incidents associated with military combat. In many cases, the sorts of traumas that military personnel encounter are not particularly distinct from those encountered by civilians. However, they might include having to contend with challenging situations to which there is no correct answer, which may lead to shame or guilt (known as moral injuries).\n\n## Complex PTSD\n\nComplex PTSD develops in a subset of people with PTSD. It is a diagnosis in the ICD‑11, which defines it as arising after exposure to an event or series of events of an extremely threatening or horrific nature, most commonly prolonged or repetitive events from which escape is difficult or impossible (for example, torture, slavery, genocide campaigns, prolonged domestic violence, repeated childhood sexual or physical abuse). The disorder is characterised by the core symptoms of PTSD; that is, all diagnostic requirements for PTSD are met. In addition, complex PTSD is characterised by:\n\nsevere and pervasive problems in affect regulation\n\npersistent beliefs about oneself as diminished, defeated or worthless, accompanied by deep and pervasive feelings of shame, guilt or failure related to the traumatic event\n\npersistent difficulties in sustaining relationships and in feeling close to others.\n\nDSM‑5 does not include a diagnosis of complex PTSD. It covers the complexity of presentation through a wider range of core PTSD symptoms (such as 'negative mood and cognitions') and the potential specifier of a 'dissociative subtype'.\n\n## Disaster plan\n\nA plan setting out the overall framework for starting, managing, coordinating and controlling staff and other resources to reduce, control or respond to an emergency.\n\n## Practitioner\n\nA person with mental health training, particularly in PTSD, who also has training and competence in delivering interventions for PTSD.", 'Recommendations for research': 'As part of the 2018 update, the guideline committee removed the 2005 recommendations for research and replaced them with those below.\n\n# Key recommendations for research\n\n## Stepped care for post-traumatic stress disorder\n\nWhat is the clinical and cost effectiveness of stepped care for post-traumatic stress disorder (PTSD)?\n\nFor an explanation of why the committee made the recommendation for research on stepped care, see appendix L of evidence review I: organisation and delivery of care for people with PTSD.\n\n## Sequencing and further line treatment\n\nWhat is the clinical and cost effectiveness of sequencing and further line treatment in PTSD?\n\nFor an explanation of why the committee made the recommendation for research on sequencing and further line treatment, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.\n\n## Trauma-informed approaches\n\nWhat is the clinical and cost effectiveness of trauma-informed care or trauma-informed approaches?\n\nFor an explanation of why the committee made the recommendation for research on trauma-informed approaches, see appendix L of evidence review I: organisation and delivery of care for people with PTSD.\n\n## Personalisation and risk markers\n\nWhat prognostic and prescriptive factors are important in determining the choice of PTSD treatment?\n\nFor an explanation of why the committee made the recommendation for research on personalisation and risk markers, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.\n\n## Complex PTSD\n\nWhat is the clinical and cost effectiveness of interventions to deliver stabilisation and reintegration for people with complex PTSD?\n\nFor an explanation of why the committee made the recommendation for research on complex PTSD, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.\n\n# Other recommendations for research\n\n## Emotional freedom techniques\n\nWhat is the clinical and cost effectiveness of emotional freedom techniques (EFT) for the treatment of PTSD in adults?\n\nFor an explanation of why the committee made the recommendation for research on EFT, see appendix L of evidence review D: psychological, psychosocial and other non-pharmacological interventions for the treatment of PTSD in adults.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Supporting transitions between services\n\nRecommendations 1.2.4 to 1.2.6\n\n## Why the committee made the recommendations\n\nThere was not enough good evidence about access to care, developing care pathways and coordinating care, so the committee drew on sources from other mental health disorders describing pathways and systems that support access and engagement with care. Based on this information they used a formal consensus method to make recommendations on good practice.\n\nThe committee discussed strategies to improve care coordination and provide smooth transitions of care for people with post-traumatic stress disorder (PTSD). They agreed it was important to plan transitions in advance, involve families and carers, make sure everyone involved in the person's care is aware of their role and responsibility, and ensure that different services are communicating with each other, as well as with the person with PTSD. They noted that overall coordination and continuity of care could be achieved by having a key professional to oversee the whole period of care – they agreed that this was already covered by the recommendations on GPs taking responsibility and management shared between primary and secondary care in the section on assessment and coordination of care. The committee also identified certain groups that might need extra support during care transitions.\n\n## How the recommendations might affect practice\n\nThese recommendations will help to improve the way in which care is provided and improve consistency between services. Any resource impact should be offset by time savings and efficiency benefits from improved care coordination and continuity.\n\nReturn to recommendations\n\n# Access to care\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nIn the absence of good evidence the committee used formal consensus to recommend some key strategies for promoting access to care. Based on their clinical experience the committee agreed that a common barrier to accessing care can be the person's belief that PTSD is untreatable. The committee agreed it was important to present a more hopeful and optimistic picture of the treatment of PTSD.\n\nThey also discussed evidence on delivering care more flexibly. Qualitative evidence showed that some people with PTSD prefer to have their treatment away from a clinical environment. There was also clinical evidence that some types of remote care (for example, computerised trauma-focused cognitive behavioural therapy [CBT] and video consultation) can be as successful as face-to-face interventions. Based on this, the committee agreed that delivering care in more flexible ways, including by making it available in non-clinical locations like schools or offices, would improve access.\n\n## How the recommendations might affect practice\n\nThese recommendations will help to improve consistency in the way services are provided. Any resource impact should be offset by time savings and efficiency benefits from improved uptake and engagement. Currently video consultation is not available everywhere so this recommendation could have a moderate impact on resources. However, it is expected to save resources in the future, in particular in remote areas where therapists need to travel further to deliver trauma-focused CBT in person.\n\nReturn to recommendations\n\n# Principles of care\n\nRecommendations 1.4.1 to 1.4.9\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.1 and 1.4.2 and recommendation 1.4.4\n\nBased on the evidence and their own clinical experience, the committee discussed how people with PTSD are often apprehensive about making contact with services and may not know what treatments and help are available. They agreed that this underlined the need for good information and support, tailored to people's needs, about interventions and services. This should cover what care and treatment people can expect and how it will be provided (for example where and by whom).\n\nThe committee discussed the importance of maintaining safe environments for people with PTSD. Based on their clinical experience, they agreed that a number of environmental triggers could worsen people's symptoms or stop them from engaging in treatment. Practitioners assessing and treating people with PTSD – including those providing treatment for other mental or physical health conditions – should be aware of the need to minimise this risk.\n\nRecommendation 1.4.3\n\nThe evidence for peer support groups was limited but included some compelling reports from people with PTSD that sharing experiences with other people who had also experienced a traumatic event was beneficial, and this was reported for different types of traumatic experience. Findings suggested that peer support could also help people overcome their doubts and fears about having treatment by telling them about available help and support and encouraging them to engage with services.\n\nRecommendations 1.4.6 and 1.4.9\n\nThere was evidence that involving families and carers in treatment provided extra support for the person while also giving the family or carer a greater understanding of PTSD. However, family or carer involvement was not universally reported as positive, with some people not liking the feeling of being talked about in their absence, so the committee agreed this should be discussed with the person first.\n\nLimited evidence showed that involving families and carers in treatment had benefits for improving carer mental health and reducing parenting difficulties. However, the evidence was too uncertain to support any recommendations for specific interventions to support family members and carers. The committee recommended good practice points based on their own expert opinion.\n\nRecommendations 1.4.5, 1.4.7 and 1.4.8\n\nQualitative evidence suggested that a common reason for not seeking help for PTSD is a lack of awareness about interventions and services. The committee agreed that information and support provided to family and carers could act as a facilitator for accessing services for both the carer and the person with PTSD.\n\nThe committee discussed the potential for more than one family member to have PTSD. They considered it important to raise awareness about this risk so that people are offered support promptly.\n\n## How the recommendations might affect practice\n\nThese recommendations are good practice points that will help to improve consistency of care. Any minor resource impact should be offset by time savings and efficiency benefits from improved uptake and engagement.\n\nPeer support groups are not routinely offered everywhere but they are in fairly widespread use. The committee noted that facilitating access to these groups should not involve major resource implications. Any costs would be offset by potential savings associated with promoting earlier access to support that will help to prevent people from developing more severe problems.\n\nReturn to recommendations\n\n# Planning treatment and supporting engagement\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThe committee agreed it was important to use a holistic approach when planning treatment, for example by thinking about every aspect of a person's life that could be contributing to their continuing PTSD symptoms, whether they might have any other physical or mental health conditions, and whether they might be at significant risk of harm to themselves or others. It was also important to ask the person if any treatments had worked for them in the past and to take into account their preferences. In the committee's opinion these were important points of good practice, along with providing information and support to help the person to make an informed choice about treatments.\n\nThe committee agreed that any strategies for promoting engagement need to be based on an understanding that people with PTSD are often highly anxious about having treatment and frequently avoid it. This was supported by evidence that common reasons for not seeking help include worry about engaging with a therapist, fear of exacerbating symptoms and stigmatisation. People may also have difficult emotions, such as shame, linked to the trauma, which can stop them from engaging with treatment. The committee agreed that healthcare professionals need to understand these reasons so that they don't misinterpret why someone is not engaging and they know the best ways to help them – including by contacting them if they don't come for an arranged appointment.\n\n## How the recommendations might affect practice\n\nThese recommendations are good practice points that will help to improve consistency of practice. Any minor resource impact should be offset by potential time savings and efficiency benefits from improved uptake and engagement.\n\nReturn to recommendations\n\n# Active monitoring\n\nRecommendation 1.6.4\n\n## Why the committee made the recommendation\n\nThere was no consistent evidence for effective interventions to prevent PTSD in people with subthreshold PTSD symptoms within 1\xa0month of a traumatic event. The committee drew on their clinical experience and discussed how some people do not develop PTSD symptoms after a trauma even with no, or limited, interventions. Conversely, some people develop chronic symptoms if intervention is not provided early. Based on consensus, the committee agreed that active monitoring within the first month after the trauma could help professionals to judge whether people with less severe symptoms would need further intervention.\n\n## How the recommendation might affect practice\n\nAny changes to practice should be minimal because active monitoring (known as watchful waiting in the 2005 version of this guideline) is already part of recommended practice.\n\nReturn to recommendation\n\n# Psychologically-focused debriefing\n\nRecommendation 1.6.5\n\n## Why the committee made the recommendation\n\nEvidence on psychologically-focused debriefing, either individually or in groups, showed no benefit for children or adults, and some suggestion of worse outcomes than having no treatment. The committee agreed that psychologically-focused debriefing should not be offered. Providing an ineffective intervention can be regarded as harmful because it means that people are being denied access to another intervention with greater evidence of benefits.\n\n## How the recommendation might affect practice\n\nPsychologically-focused debriefing was not part of previously recommended practice so there should be no impact on practice.\n\nReturn to recommendation\n\n# Psychological interventions for the prevention of PTSD in children and young people\n\nRecommendations 1.6.6 to 1.6.8\n\n## Why the committee made the recommendations\n\nThere was no evidence for individual trauma-focused CBT for children and young people within the first month of trauma. Despite the lack of direct evidence, the committee decided to make a recommendation for this intervention in light of the strong evidence for its efficacy for children who have experienced trauma more than 1\xa0month ago, and the evidence for benefits in adults within 1\xa0month of trauma. There can be a lot of natural recovery in the early weeks and it can be difficult to gauge a child or young person's readiness for intervention within 1\xa0month of trauma. Based on consensus, the committee agreed that individual trauma-focused CBT and active monitoring could both be considered as options within 1\xa0month of trauma for children and young people with clinically important PTSD symptoms or acute stress disorder, and that this decision was best left to clinical judgement.\n\nThere was evidence that trauma-focused CBT group interventions were effective for improving PTSD symptoms and other important outcomes for children and young people who had been exposed to ongoing trauma, for example from living in a war zone. The committee agreed that these findings could also apply to other types of large-scale shared traumas. There were some gaps and uncertainties in the evidence, for example in how long the benefits might last and whether they were specific to that intervention or could be explained by other general factors such as receiving attention from a therapist. Based on this evidence and the additional considerations, the committee recommended the intervention should be considered as a possible option. The cognitive and language demands of trauma-focused group CBT mean that it would not be suitable for children under\xa07 so the committee used an age range that reflected the age of children in the included studies.\n\nAlthough specific group trauma-focused CBT interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed to specify the structure and content.\n\n## How the recommendations might affect practice\n\nThere is currently variation in care for children and young people with acute stress disorder or clinically important symptoms of PTSD within 1\xa0month of a traumatic event. Recommending active monitoring or individual trauma-focused CBT as options to consider should improve consistency in practice and help to reduce the use of more resource-intensive interventions for which the effectiveness is unknown.\n\nThere is currently no guidance on interventions for children exposed to large-scale shared trauma, and current practice has involved providing a range of different interventions. Without a clear steer on what works best there has been variability in access to interventions, the type of interventions offered and the extent to which they have been evidence-based. The recommendation for group trauma-focused CBT will lead to more consistency in practice and improve clinical outcomes for children who might otherwise need more costly management for PTSD later in the care pathway.\n\nReturn to recommendations\n\n# Psychological interventions for the treatment of PTSD in children and young people\n\nRecommendations 1.6.9 to 1.6.13\n\n## Why the committee made the recommendations\n\nThe evidence showed that trauma-focused CBT is effective in improving PTSD symptoms and other important outcomes, and that improvements last for at least a year. Benefits were seen for different specific trauma-focused interventions and different types of trauma. Trauma-focused CBT is more effective, as well as more cost effective, when it is provided individually than in a group so the committee agreed it should be delivered individually.\n\nMost of the evidence for trauma-focused CBT came from children aged over 7\xa0years. There was some evidence from 5 and 6\xa0year olds so the committee agreed it could be an option for them, but could not be recommended with the same certainty.\n\nThere was no evidence for treatment with trauma-focused CBT between 1 and 3\xa0months after a traumatic event compared with a non-active control, so the committee could not recommend it with the same certainty as for more than 3\xa0months after trauma. However, by extrapolating from the broad evidence base for benefits more than 3\xa0months after trauma and drawing on members' own clinical experience, the committee agreed that trauma-focused CBT could be an option during this period.\n\nAlthough specific trauma-focused CBT interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed to specify the structure and content. This recommendation was informed by the evidence and modified by the committee's expert advice. For example, a typical number of sessions was recommended based on the evidence, but the committee agreed that more might be needed, including for those who have experienced multiple traumas.\n\nThere was limited evidence for eye movement desensitisation and reprocessing (EMDR) suggesting possible benefits on PTSD symptoms in children older than 7\xa0years. However, EMDR was found to be less clinically effective and cost effective than all individual trauma-focused CBT interventions. On this basis, the committee decided it should be considered only if children do not respond to or engage with trauma-focused CBT.\n\n## How the recommendations might affect practice\n\nOffering trauma-focused CBT more than 3\xa0months after a traumatic event is in line with previously recommended practice and the committee was not aware of wide variation in practice. Considering trauma-focused CBT between 1 and 3\xa0months after a traumatic event and recommending EMDR as an option are both new. They are only recommended as options to consider, which should limit their impact on practice, as should the fact that EMDR should only be considered for children who do not respond to or engage with trauma-focused CBT.\n\nNICE's previous guideline made recommendations for children with PTSD, whereas current recommendations are also relevant to children and young people with clinically important symptoms of PTSD. The structure, content and time of the assessment, as well as the benefits from treatment, are broadly the same for both populations and it was the committee's view that there should not be a significant impact on practice.\n\nReturn to recommendations\n\n# Drug treatments for children and young people\n\nRecommendation 1.6.14\n\n## Why the committee made the recommendation\n\nThere was very little evidence on the use of drug treatments to prevent or treat PTSD in children and young people. This limited evidence showed no significant benefits so the committee agreed drug treatment should not be offered.\n\n## How the recommendation might affect practice\n\nThis recommendation is in line with previously recommended practice so there should be no impact on practice.\n\nReturn to recommendation\n\n# Psychological interventions for the prevention of PTSD in adults\n\nRecommendation 1.6.15\n\n## Why the committee made the recommendation\n\nEvidence showed that individual trauma-focused CBT interventions were effective for improving PTSD symptoms in adults who had experienced a traumatic event within the last month. They also reduced the number of adults who met the criteria to be diagnosed with PTSD after 1\xa0month. There was also limited evidence from outside the UK that trauma-focused CBT is cost effective in adults at risk of PTSD.\n\nThere was evidence for a number of specific interventions within the trauma-focused CBT class, and the committee agreed it would be helpful to give some examples of named therapies that fall under this term.\n\nThe evidence of benefits was restricted to adults with clinically important symptoms or acute stress disorder, so the committee only recommended the intervention for these groups and not for people with less significant symptoms.\n\n## How the recommendation might affect practice\n\nThe recommendation is in line with previous recommended practice so there should not be a major change in practice.\n\nReturn to recommendation\n\n# Psychological interventions for the treatment of PTSD in adults\n\nRecommendations 1.6.16 to 1.6.23\n\n## Why the committee made the recommendations\n\nRecommendations 1.6.16 and 1.6.17\n\nThere was extensive evidence that trauma-focused CBT interventions improve PTSD symptoms as well as other important outcomes, and that these improvements can be maintained up to a year later. Benefits were seen across a wide range of types of trauma, including both single and multiple incident traumas. There was evidence for a number of specific interventions within the trauma-focused CBT class, and the committee agreed it would be helpful to give some examples of named therapies that fall under this term.\n\nMost of the evidence for trauma-focused CBT interventions came from adults who had been exposed to 1 or more traumatic events more than 3\xa0months ago, although there was limited evidence showing benefits between 1 and 3\xa0months after trauma. The committee discussed this limited evidence alongside the broader evidence base that showed benefits within the first month and more than 3\xa0months after trauma. They thought it was unlikely that effects would be different in this 2‑month time period, so recommended trauma-focused CBT for adults with a diagnosis of PTSD or clinically important symptoms of PTSD more than 1\xa0month after a traumatic event.\n\nThere was good evidence that offering up to 12\xa0sessions of individual trauma-focused CBT was clinically and cost effective. Group trauma-focused CBT was not seen to be clinically or cost effective based on the guideline network meta-analysis and economic analysis, although the evidence was limited. Based on the standard number of sessions outlined in most validated treatment manuals and the most common number of sessions in the evidence base, the committee recommended providing 8\xa0to 12\xa0sessions. However, based on their clinical experience, they recommended offering more sessions if needed, including for people who have experienced multiple traumas.\n\nUsing both the evidence and their clinical experience, the committee outlined the structure and content of individual trauma-focused CBT interventions to make sure they are delivered in a consistent way because they were concerned that this may not happen in practice.\n\nPsychoeducation was found to be highly clinically and cost effective in comparisons with psychological interventions according to the guideline network meta-analysis and economic analysis, but its evidence base was very limited and uncertain. The committee agreed that the evidence could not support a recommendation for psychoeducation on its own but it should be delivered as part of individual trauma-focused CBT.\n\nRecommendations 1.6.18 to 1.6.20\n\nLess evidence was found on EMDR than on trauma-focused CBT, but the committee agreed that what was available justified recommending EMDR. Although studies that compared EMDR directly with trauma-focused CBT did not show significant differences, there was a trend towards EMDR. This trend in favour of EMDR was also present in the cost effectiveness results. The evidence suggested EMDR was not effective in people with military combat-related trauma, and this was in marked contrast to all other included trauma types for which benefits were observed. On this basis, the committee restricted their recommendation to non-combat-related trauma.\n\nMost of the evidence for EMDR came from adults who had been exposed to 1 or more traumatic events more than 3\xa0months ago, although there was limited evidence showing benefits between 1 and 3\xa0months after trauma. Based on this limited evidence and by extrapolating from the stronger evidence for EMDR more than 3\xa0months after trauma, the committee recommended considering EMDR between 1 and 3\xa0months after a non-combat-related trauma. This recommendation was made with less certainty than treatment after 3\xa0months because of the very limited direct evidence (a single study) and because limited evidence suggested non-statistically significant benefits of EMDR within 1\xa0month of trauma.\n\nAlthough EMDR interventions use the same broad approach, the committee was concerned that psychological interventions are not always delivered in a consistent way, so they agreed a specific structure and content based on the interventions in the evidence and modified by their expert opinion.\n\nRecommendations 1.6.21 and 1.6.22\n\nThere was evidence that both supported and unsupported self-help, and computerised trauma-focused CBT in particular, were beneficial in terms of self-rated PTSD symptoms and other important outcomes. These benefits were maintained up to a year later. Both interventions were cost effective compared with other psychological interventions. The evidence was limited for some of the outcomes that were looked at, and it was unclear whether self-help was effective across different types of trauma. Although both supported and unsupported self-help were found to be effective, the former was more clinically and cost effective because the greater effect sizes were sufficient to offset the higher costs.\n\nTaking the evidence for efficacy together with the gaps in the evidence, the committee agreed that supported computerised trauma-focused CBT should be considered as an option for adults with PTSD who prefer this to face-to-face trauma-focused CBT or EMDR. The committee was concerned that a lower intensity intervention might not be clinically appropriate for all adults with PTSD, so this recommendation was limited to those who do not have severe PTSD symptoms (in particular dissociative symptoms) and are not at risk of harm to themselves or others.\n\nA number of computerised trauma-focused CBT interventions are available, and the committee felt it was important to specify their structure and content to make sure a minimum standard was set.\n\nRecommendation 1.6.23\n\nThere was some evidence that non-trauma-focused CBT is beneficial when targeted at specific symptoms such as sleep disturbance or anger, and also leads to improvements in PTSD symptoms, but it was not clear how long these benefits would be maintained. Non-trauma-focused CBT was less cost effective than individual trauma-focused CBT, EMDR and self-help, but more cost effective than other interventions such as present-centred therapy, group trauma-focused CBT, combined individual trauma-focused CBT and SSRIs, counselling and no treatment. The committee agreed the potential benefits of non-trauma-focused CBT were important, but that symptom-specific interventions should not be seen as an alternative to a trauma-focused first-line treatment. Instead, they could be an option when people are not ready to directly confront memories of the trauma and could promote uptake and engagement with a trauma-focused intervention. They could also be used to target residual symptoms after a trauma-focused intervention.\n\n## How the recommendations might affect practice\n\nNICE's previous guideline made recommendations for adults with PTSD, whereas current recommendations are also relevant to adults with clinically important symptoms of PTSD. The structure, content and time of the assessment, as well as the benefits from treatment, are broadly the same for both populations and it was the committee's view that there should not be a significant impact on practice.\n\nBoth trauma-focused CBT and EMDR were already recommended and the committee did not think there was wide variation in practice. The new recommendation for non-trauma-focused CBT interventions targeted at specific symptoms represents a bigger change because previous recommendations stated that non-trauma-focused interventions should not be routinely offered to people with chronic PTSD. The impact on resources is difficult to predict because it is recommended only as an option to consider, but it might bring potential savings by improving uptake and engagement with trauma-focused therapies that should reduce missed appointments and early drop-out.\n\nThe recommendation for supported computerised trauma-focused CBT is also thought to represent a bigger change. Self-help-based interventions were not previously part of recommended practice and the committee was not aware of such interventions being in widespread use. The cost of supported computerised trauma-focused CBT includes, in addition to a therapist's time, the cost of the digital mental health programmes and computers needed for delivery. If such an intervention is delivered in a public place (like a library), or the person's home, there is no equipment cost. If the computer is used in a clinical practice setting, it can be shared by many people having computerised therapy, minimising the equipment cost. It could therefore lead to cost savings if part of routine practice is shifted from the more resource-intensive individual trauma-focused CBT and EMDR to the less resource-intensive supported computerised trauma-focused CBT.\n\nThe committee acknowledged that there would be a cost associated with providing extra trauma-focused therapy sessions if they are needed (for example, for people who have experienced multiple traumas). Previous recommended practice was to consider more than 12\xa0sessions for people after multiple incident trauma, or who have chronic disability or significant coexisting conditions or social problems. However, in clinical practice the provision of additional sessions is variable.\n\nReturn to recommendations\n\n# Drug treatments in adults\n\nRecommendations 1.6.24 to 1.6.26\n\n## Why the committee made the recommendations\n\nRecommendation 1.6.24\n\nThere was no consistent evidence that any drug treatments are effective in preventing PTSD. Given the limited evidence of benefits and the potential harms, including side effects, the committee agreed that drug treatments should not be offered to prevent PTSD in adults. The committee specifically referred to benzodiazepines because of the lack of benefit in the evidence, concerns about harm and their clinical experience of these drugs being prescribed in practice.\n\nRecommendations 1.6.25 and 1.6.26\n\nThere was evidence that SSRIs and venlafaxine are effective in treating PTSD. There was a large number of studies for SSRIs but the sizes of the effects were smaller than for venlafaxine. The committee decided that either an SSRI or venlafaxine could be considered if a person prefers to have drug treatment, but they should not be offered as first-line treatment for PTSD. This is based partly on the lack of follow-up data for SSRIs and venlafaxine, and because evidence showed that SSRIs are less effective than any of the psychological interventions recommended. Economic modelling also showed SSRIs are less cost effective than EMDR, brief individual trauma-focused CBT or self-help with support.\n\nThere was no evidence for significant differential efficacy of specific SSRIs (sertraline, fluoxetine and paroxetine), so the committee agreed to allow prescribers to decide which SSRI to use. However, they included sertraline as an example because it is 1 of 2\xa0drugs licensed in the UK for this indication and the other drug, paroxetine, is more likely to be associated with discontinuation symptoms.\n\nThe committee agreed that it was important to review antidepressant treatment regularly to manage any side effects and to review clinical progress and outcomes.\n\nThere was some evidence that antipsychotics, either alone or in addition to routine medications, are effective in treating PTSD symptoms. However, it was more limited than the evidence supporting SSRIs and the psychological interventions (for example, the evidence for other important outcomes was limited and there were no follow-up data). The committee agreed that antipsychotics should not be seen as an alternative to a trauma-focused psychological intervention as first-line treatment for PTSD and should only be considered as an adjunct to psychological therapy. However, they might be beneficial for symptom management for adults with a diagnosis of PTSD if their symptoms have not responded to other drug or psychological treatments and they have disabling symptoms and behaviours that makes it difficult for them to engage with psychological treatment. Given the different side effect profiles, the committee agreed to leave the choice of antipsychotic to clinical judgement. Risperidone was included as an example because the evidence for risperidone included more participants.\n\nThe committee discussed concerns about the tolerability of antipsychotic drugs and agreed they should only be prescribed in a specialist setting, or after consultation with a specialist.\n\n## How the recommendations might affect practice\n\nThe committee was concerned that drug treatment within the first month of trauma may be reasonably common in clinical practice. The do not offer drug treatments recommendation in the section on drug treatments for adults will therefore help to reduce the use of non-evidence-based interventions and improve consistency of practice. These recommendations represent a small change in practice because the previous guideline recommended drug treatment as an option only for adults who could not start a psychological therapy, did not want to start trauma-focused psychological therapy or who had gained little or no benefit from it.\n\nIn the UK, only paroxetine and sertraline are licensed for the treatment of PTSD so the recommendations involve off-licence use. Offering antipsychotics only in a specialist setting or after consultation with a specialist is expected to reduce variation in the way antipsychotics are used in current practice. Regular review of drug treatment is essential but might not be happening currently, so this should also improve consistency.\n\nReturn to recommendations\n\n# Care for people with post-traumatic stress disorder and complex needs\n\nRecommendations 1.7.1 to 1.7.3\n\n## Why the committee made the recommendations\n\nThere was a lack of evidence on care for people with PTSD and complex needs, including people with coexisting conditions such as depression or substance misuse, so the committee used a formal consensus method to agree some overarching principles.\n\nThe evidence was limited on interventions for people who have complex PTSD, but it suggested that trauma-focused therapies could also benefit this group. Based on their clinical experience, the committee recommended modifications that may be needed to trauma-focused therapies to facilitate engagement for those with complex PTSD or other additional needs.\n\n## How the recommendations might affect practice\n\nThe committee acknowledged that there would be a cost associated with increasing the duration or the number of therapy sessions, if this is necessary for people with PTSD and additional needs. Previous recommended practice was to consider more than 12\xa0sessions for people after multiple incident trauma, or who have chronic disability or significant coexisting conditions or social problems. However, in clinical practice the provision of additional sessions is variable.\n\nReturn to recommendations", 'Context': "Post-traumatic stress disorder (PTSD) develops after a stressful event or situation of an exceptionally threatening or catastrophic nature. It is a disorder that can affect people of any age. Around 25–30% of people experiencing a traumatic event go on to develop PTSD.\n\nPTSD can present with a range of symptoms. In adults the most common of these are vivid, distressing memories of the event or flashbacks, known as intrusive symptoms. Another prominent symptom is avoidance of trauma-related reminders or general social contact. People with PTSD often try to push memories of the event out of their mind and avoid thinking or talking about it in detail. On the other hand, people may also reflect excessively on questions that prevent them from coming to terms with the event – for example, why it happened to them, how it could have been prevented, or how they could take revenge. People with PTSD often have nightmares related to the trauma that affect their sleep.\n\nSymptoms of PTSD often develop immediately after the traumatic event but in some people (fewer than 15%) onset is delayed. People may not present for treatment for months or years despite experiencing considerable distress. PTSD is a treatable disorder, even for people who present many years later, but assessment can be challenging because many people avoid talking about their problems even when presenting with associated complaints.\n\nChildren, particularly those aged under 8\xa0years, may not complain directly of PTSD symptoms such as re‑experiencing or avoidance. Instead, symptoms may take the form of re‑enacting the experience, repetitive play or frightening dreams with no recognisable content.\n\nIt is common for people with PTSD to have other problems such as depression. If people have had repeated or multiple traumas, or have other significant mental health problems, their presentation of PTSD may be complex and adjustments may be needed to the way in which treatment is delivered.\n\nEffective treatment of PTSD can only take place if the disorder is recognised. Opportunities for recognition usually come during routine healthcare, for example during physical treatment after an assault or an accident, or when a person discloses domestic violence or a history of childhood sexual abuse. Many people attending for medical services in hospital have experienced traumatic events, particularly in emergency departments, and orthopaedic and plastic surgery clinics. Up to 30% of children who attend an emergency department for a traumatic injury go on to develop PTSD. Identifying PTSD in children presents particular problems, but is improved by asking children directly about their experiences.\n\nThis guideline updates NICE's 2005 guidance on PTSD. It covers children, young people and adults (aged 18\xa0years and over) who are at risk of PTSD or have a diagnosis of PTSD, and their families and carers. It also covers people with comorbid conditions including drug and alcohol misuse and common mental health conditions.\n\nThe guideline covers all NHS and social care-commissioned services that provide care for people with PTSD."}
|
https://www.nice.org.uk/guidance/ng116
|
This guideline covers recognising, assessing and treating post-traumatic stress disorder (PTSD) in children, young people and adults. It aims to improve quality of life by reducing symptoms of PTSD such as anxiety, sleep problems and difficulties with concentration. Recommendations also aim to raise awareness of the condition and improve coordination of care.
|
ab975a2fbe904afb0ff661c031011c78fc37aba2
|
nice
|
Transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain
|
Transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain
Evidence-based recommendations on transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain in adults. This involves delivering focused ultrasound to a small part of the brain (in the thalamus) responsible for transmitting pain signals to destroy it.
# Recommendations
Current evidence on the safety of transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain shows there are serious safety concerns. There is very limited evidence of efficacy. Therefore, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
Neuropathic pain results from dysfunction of sensory nerves and pathways in the nervous system. It can occur in a heterogeneous group of disorders, including painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia. People with neuropathic pain may have altered pain sensation, areas of numbness or burning, and continuous or intermittent evoked or spontaneous pain. Neuropathic pain is an unpleasant sensory and emotional experience that can have a significant effect on a person's quality of life.
# Current treatments
A range of different drugs are used to manage neuropathic pain, including antidepressants, anti-epileptic drugs, opioids, and topical treatments such as capsaicin and lidocaine (see NICE's clinical guideline on neuropathic pain in adults: pharmacological management in non-specialist settings). Neuropathic pain is often difficult to treat, because it can be refractory to many medications and because of the adverse effects associated with some drug treatments.
For neuropathic pain that is refractory to drug treatment, other options include percutaneous electrical nerve stimulation, spinal cord stimulation and deep brain stimulation.
# The procedure
Transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain is done with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low-power ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate the target tissue. Chilled water is circulated around the outside of the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3 hours and pain relief should occur within a day of the procedure.
|
{'Recommendations': 'Current evidence on the safety of transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain shows there are serious safety concerns. There is very limited evidence of efficacy. Therefore, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': "# The condition\n\nNeuropathic pain results from dysfunction of sensory nerves and pathways in the nervous system. It can occur in a heterogeneous group of disorders, including painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia. People with neuropathic pain may have altered pain sensation, areas of numbness or burning, and continuous or intermittent evoked or spontaneous pain. Neuropathic pain is an unpleasant sensory and emotional experience that can have a significant effect on a person's quality of life.\n\n# Current treatments\n\nA range of different drugs are used to manage neuropathic pain, including antidepressants, anti-epileptic drugs, opioids, and topical treatments such as capsaicin and lidocaine (see NICE's clinical guideline on neuropathic pain in adults: pharmacological management in non-specialist settings). Neuropathic pain is often difficult to treat, because it can be refractory to many medications and because of the adverse effects associated with some drug treatments.\n\nFor neuropathic pain that is refractory to drug treatment, other options include percutaneous electrical nerve stimulation, spinal cord stimulation and deep brain stimulation.\n\n# The procedure\n\nTranscranial MRI-guided focused ultrasound thalamotomy for neuropathic pain is done with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low-power ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate the target tissue. Chilled water is circulated around the outside of the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3\xa0hours and pain relief should occur within a day of the procedure."}
|
https://www.nice.org.uk/guidance/ipg632
|
Evidence-based recommendations on transcranial MRI-guided focused ultrasound thalamotomy for neuropathic pain in adults. This involves delivering focused ultrasound to a small part of the brain (in the thalamus) responsible for transmitting pain signals to destroy it.
|
27c52b7a2e07f9336613e47faa799d6b96cef0b1
|
nice
|
Percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions
|
Percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions
Evidence-based recommendations on percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions. This involves inserting temporary pump to support circulation during a heart operation.
# Recommendations
Current evidence on the safety of percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions shows there are serious, infrequent but well-recognised safety concerns. Evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support is recommended.
Details of all patients should be entered into the British Cardiovascular Intervention Society percutaneous coronary interventions database (BCIS PCI database).
Patient selection should be done by an experienced multidisciplinary team, when the urgency of the clinical situation allows.
The procedure should only be done in specialised centres by clinicians and teams with specialised training in the use of this technology and experience in complex percutaneous coronary interventions.
Further research should report details of patient selection and subsequent management.# The condition, current treatments and procedure
# The condition
Additional support for the heart is not usually needed with angioplasty or percutaneous coronary intervention. However, a subset of high-risk patients may benefit from some form of heart support during their angioplasty procedure. This includes those with extensive or complex coronary artery disease (unprotected left main disease, last remaining vessel or multi-vessel disease), poor left ventricular function, ongoing myocardial ischemia, cardiogenic shock and comorbidity, in whom revascularisation may not otherwise be possible.
# Current treatments
Temporary percutaneous mechanical haemodynamic support can be used prophylactically in some elective high-risk angioplasty procedures or in urgent procedures. The aim is to support the patient's circulatory system, provide blood flow to increase cardiac output, unload the ventricle and improve blood flow to maintain haemodynamic stability. This minimises myocardial ischemia and reduces the risk of haemodynamic collapse during the procedure. Intra-aortic balloon pumps or extra-corporeal pumps may be used for temporary percutaneous mechanical haemodynamic support. Percutaneous left ventricular-assist devices for haemodynamic support are sometimes used instead of intra-aortic balloon pumps or extra-corporeal pumps.
# The procedure
Inserting a temporary percutaneous mechanical haemodynamic support device may be done before or during percutaneous coronary intervention in selected high-risk patients, and is then taken out when the patient is stable.
The procedure is done under local anaesthesia. An introducer sheath is inserted into a large artery (usually the femoral or axillary artery) and a guidewire is passed into the left ventricle. A catheter with an integrated pump at its distal end is passed over the guidewire, into the large vessel and into the left ventricle. Fluoroscopic imaging is used during the procedure. The catheter is then attached to an automated external console, which controls the pump speed and monitors its function, allowing blood to be taken from the left ventricle and pumped into the ascending aorta.
Different miniature, catheter-based, intravascular devices are available and the precise implantation technique varies according to the device.
|
{'Recommendations': "Current evidence on the safety of percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions shows there are serious, infrequent but well-recognised safety concerns. Evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support is recommended.\n\nDetails of all patients should be entered into the British Cardiovascular Intervention Society percutaneous coronary interventions database (BCIS PCI database).\n\nPatient selection should be done by an experienced multidisciplinary team, when the urgency of the clinical situation allows.\n\nThe procedure should only be done in specialised centres by clinicians and teams with specialised training in the use of this technology and experience in complex percutaneous coronary interventions.\n\nFurther research should report details of patient selection and subsequent management.", 'The condition, current treatments and procedure': "# The condition\n\nAdditional support for the heart is not usually needed with angioplasty or percutaneous coronary intervention. However, a subset of high-risk patients may benefit from some form of heart support during their angioplasty procedure. This includes those with extensive or complex coronary artery disease (unprotected left main disease, last remaining vessel or multi-vessel disease), poor left ventricular function, ongoing myocardial ischemia, cardiogenic shock and comorbidity, in whom revascularisation may not otherwise be possible.\n\n# Current treatments\n\nTemporary percutaneous mechanical haemodynamic support can be used prophylactically in some elective high-risk angioplasty procedures or in urgent procedures. The aim is to support the patient's circulatory system, provide blood flow to increase cardiac output, unload the ventricle and improve blood flow to maintain haemodynamic stability. This minimises myocardial ischemia and reduces the risk of haemodynamic collapse during the procedure. Intra-aortic balloon pumps or extra-corporeal pumps may be used for temporary percutaneous mechanical haemodynamic support. Percutaneous left ventricular-assist devices for haemodynamic support are sometimes used instead of intra-aortic balloon pumps or extra-corporeal pumps.\n\n# The procedure\n\nInserting a temporary percutaneous mechanical haemodynamic support device may be done before or during percutaneous coronary intervention in selected high-risk patients, and is then taken out when the patient is stable.\n\nThe procedure is done under local anaesthesia. An introducer sheath is inserted into a large artery (usually the femoral or axillary artery) and a guidewire is passed into the left ventricle. A catheter with an integrated pump at its distal end is passed over the guidewire, into the large vessel and into the left ventricle. Fluoroscopic imaging is used during the procedure. The catheter is then attached to an automated external console, which controls the pump speed and monitors its function, allowing blood to be taken from the left ventricle and pumped into the ascending aorta.\n\nDifferent miniature, catheter-based, intravascular devices are available and the precise implantation technique varies according to the device."}
|
https://www.nice.org.uk/guidance/ipg633
|
Evidence-based recommendations on percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in high-risk percutaneous coronary interventions. This involves inserting temporary pump to support circulation during a heart operation.
|
fc7927d4aea0b0d66cbe7f36c2b0180a3373c0ef
|
nice
|
Tofacitinib for moderately to severely active ulcerative colitis
|
Tofacitinib for moderately to severely active ulcerative colitis
Evidence-based recommendations on tofacitinib (Xeljanz) for previously treated moderately to severely active ulcerative colitis in adults.
# Recommendations
Tofacitinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated or the disease has responded inadequately or lost response to treatment. It is recommended only if the company provides tofacitinib with the discount agreed in the commercial arrangement.
Why the committee made these recommendations
Clinical trial evidence shows that tofacitinib is more effective than placebo for treating moderately to severely active ulcerative colitis. An indirect comparison suggests that for people who have not had a TNF-alpha inhibitor, tofacitinib is more effective than adalimumab and golimumab as maintenance treatment. For people who have had a TNF-alpha inhibitor, tofacitinib is more effective than adalimumab as induction treatment. No other statistically significant differences between tofacitinib and biological therapies were identified.
Based on the health-related benefits and costs compared with conventional therapy and biologicals, tofacitinib is recommended as a cost-effective treatment for moderately to severely active ulcerative colitis in adults whose disease has responded inadequately to, or who cannot tolerate, conventional or biological therapy.# Information about tofacitinib
# Marketing authorisation
Tofacitinib (Xeljanz, Pfizer) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent'.
# Dosage in the marketing authorisation
The recommended dosage of tofacitinib for induction is 10 mg taken orally twice daily for 8 weeks, then 5 mg taken twice daily for maintenance. If adequate therapeutic benefit is not achieved by week 8 the induction dose can be taken for an additional 8 weeks (16 weeks in total). Induction therapy should be stopped if there is no evidence of therapeutic benefit by week 16.
For patients whose disease has responded inadequately to tumour necrosis factor antagonist therapy, consider continuing the 10-mg twice-daily dose for maintenance in order to maintain therapeutic benefit. If response decreases to tofacitinib 5 mg taken twice daily as maintenance therapy, consider increasing the dose to 10 mg taken twice daily.
When the disease has responded adequately to tofacitinib, corticosteroids may be reduced or stopped in accordance with standard care.
# Price
The list price of a 56‑tablet pack of 5-mg tofacitinib is £690.03; the list price of a 56‑tablet pack of 10-mg tofacitinib is £1,380.06 (excluding VAT; British national formulary online 2018). The average cost per patient for the first year is estimated at £10,350.45 and for the subsequent year is estimated at £8,970.39. The company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial-in-confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## Tofacitinib will be used in the same place in the treatment pathway as biological therapies
The clinical expert explained that current clinical management of moderate to severely active ulcerative colitis is conventional therapies (aminosalicylates, corticosteroids or thiopurines). If there is inadequate response or loss of response, patients may be offered a biological therapy (a tumour necrosis factor alpha inhibitor such as infliximab, adalimumab and golimumab or the anti-integrin agent vedolizumab). The clinical expert stated that tofacitinib could be offered instead of biological therapy. He highlighted that moderately to severely active ulcerative colitis is typically managed according to the patient's history, treatment response and tolerance of individual therapies. It is therefore important to have a range of treatment options available. The clinical expert further explained that the disease does not respond in 30% of patients having biological therapies and that, for those with a response, 20% will eventually lose this response. He explained that if there is inadequate or loss of response to the first biological therapy a second biological therapy may be offered, but there is a 30% chance that the disease will not respond. The committee concluded that tofacitinib will be used in the same place in the treatment pathway as biological therapies; that is, in second- and third-line treatment for ulcerative colitis.
## Tofacitinib offers an important new treatment option for ulcerative colitis
The patient experts explained that moderately to severely active ulcerative colitis has a major effect on people's lives and can be socially isolating. Symptoms include frequent bloody diarrhoea, abdominal pain, symptoms elsewhere in the body (such as the joints, eyes, skin and liver) and fatigue. Complications such as intestinal perforation and abscesses may need surgery. The clinical expert stated that many people who have ulcerative colitis are teenagers and younger adults. They explained that tofacitinib is a novel treatment with a different mode of action compared with biological therapies (see section 3.1). The clinical and the patient experts also highlighted that tofacitinib is taken orally, which has major benefits for patients and the NHS. The clinical expert noted that because of its molecular structure, tofacitinib has less chance of immunogenicity and loss of response over time compared with biological therapies. The committee concluded that tofacitinib offers an important new treatment option for people with ulcerative colitis.
# Clinical evidence
## The OCTAVE trials are suitable for decision-making
The clinical-effectiveness evidence for tofacitinib comes from 3 placebo-controlled, double-blinded randomised controlled trials:
Induction treatment: the OCTAVE Induction 1 and 2 trials included 598 patients and 541 patients, respectively, with moderately to severely active ulcerative colitis. They were randomised to have tofacitinib (10 mg twice daily) or placebo. The primary outcome was remission, measured using the Mayo score. Secondary outcomes included mucosal healing, Inflammatory Bowel Disease Questionnaire, SF-36 and EQ-5D. All outcomes were measured at 8‑week follow-up.
Maintenance treatment: the OCTAVE Sustain trial included 593 patients whose disease had had a clinical response to tofacitinib in OCTAVE Induction 1 or 2. Patients took either tofacitinib (5 mg or 10 mg) or placebo, twice daily. The primary outcome was remission. Secondary outcomes included sustained steroid-free remission measured at 24 weeks, mucosal healing, and clinical response and clinical remission at 52‑week follow-up.Additional clinical evidence came from a small trial and OCTAVE Open, an ongoing open-label long-term extension trial. This included patients from OCTAVE Induction 1 and 2 whose disease did not respond to tofacitinib. The committee concluded that the trials are adequate and suitable for decision-making.
## Tofacitinib is more effective than placebo for induction and maintenance treatment regardless of previous TNF-alpha inhibitor use
The committee noted that in OCTAVE Induction 1 remission at week 8 was seen in 18.5% of patients having tofacitinib 10 mg, compared with 8.2% in the placebo group (p=0.007). In OCTAVE Induction 2 remission at week 8 was 16.6% for tofacitinib and 3.6% for placebo (p<0.001). In OCTAVE Sustain, 40.6% of patients having tofacitinib 10 mg were in disease remission at week 52, compared with 11.1% in the placebo group (p<0.001). Similarly, 34.3% of patients in the tofacitinib 5 mg group were in disease remission at week 52 (p<0.001). The committee noted that the mean differences between tofacitinib and placebo in OCTAVE Induction 1 and 2 are in favour of tofacitinib and are statistically significant at the end of the induction phase (week 8). A similar effect was observed in OCTAVE Sustain for both dosages of tofacitinib (5 mg and 10 mg), with the difference in comparison with placebo being greater for tofacitinib 10 mg at the end of the maintenance phase (week 52). The subgroup results for prior TNF-alpha inhibitor exposure status, which were used by the company in their economic modelling, show a similar effect. The ERG explained that the OCTAVE trials were not powered to test the statistical significance of subgroup analyses so the results should be interpreted with caution. The committee concluded that tofacitinib is more effective than placebo for induction and maintenance treatment of moderate to severe disease, regardless of whether TNF-alpha inhibitors have been taken previously.
# Adverse events
## Tofacitinib has an acceptable safety profile
The company collected safety data from all the OCTAVE trials. Serious adverse events affected fewer than 10% of patients. There were 5 deaths, of which 1 was considered to be related to tofacitinib. Serious infections occurred only in patients having tofacitinib rather than placebo, with the exception of OCTAVE Sustain in which 2 patients taking placebo had serious infections. The clinical expert explained that the serious infections were non-specific and that they would not influence the decision to prescribe a biological instead of tofacitinib. The company highlighted that tofacitinib is also used for rheumatoid arthritis and that long-term safety data (over 9 years) are available. The committee concluded that tofacitinib's safety profile is acceptable.
# Indirect treatment comparison
## The company's indirect comparison was generally well conducted
The company presented 2 network meta-analyses according to previous TNF-alpha inhibitor use for induction and maintenance treatment with tofacitinib. Analyses were done for the outcomes of clinical response, clinical remission and mucosal healing:
The TNF-alpha inhibitor 'naive' network included people who had not taken a TNF-alpha inhibitor. It estimated the relative efficacy of tofacitinib compared with placebo, adalimumab, golimumab, infliximab, and vedolizumab.
The TNF-alpha inhibitor 'exposed' network included people who had taken TNF-alpha inhibitors. It estimated the relative efficacy of tofacitinib compared with placebo, adalimumab and vedolizumab.In the TNF-alpha inhibitor naive group all active treatments showed a statistically significant improvement for all outcomes compared with placebo. In the maintenance phase tofacitinib showed a statistically significant improvement in clinical remission and clinical response compared with adalimumab and golimumab 50 mg. No other statistically significant differences were found in the TNF-alpha inhibitor naive group. In the TNF-alpha inhibitor exposed group tofacitinib and vedolizumab showed a statistically significant improvement in all outcomes compared with placebo. In the induction phase tofacitinib showed a statistically significant improvement in clinical remission and clinical response compared with adalimumab. No other statistically significant differences were found in the TNF-alpha inhibitor exposed group. The ERG noted that the indirect comparison was generally well conducted. The ERG replicated the company's indirect treatment comparison and preferred the random-effects models, because the fixed-effects models may underestimate the uncertainty caused by heterogeneity between the studies included in the networks. It explored the impact of a random-effects model for TNF-alpha inhibitor naive and exposed groups for maintenance treatment with tofacitinib in its preferred analyses. The random-effects model showed wider credible intervals and some variation in the median estimates for adalimumab and golimumab as maintenance treatment for the TNF-alpha inhibitor naive group. This is because smaller size studies are given more weight in the random-effects model (ERG) than the fixed-effects model (company). The ERG noted that adalimumab was included in the network, but the company did not provide results for adalimumab for the TNF-alpha inhibitor exposed group and did not explain why. It considered that adalimumab is a relevant comparator and included it in its base case. The committee concluded that both the company's and the ERG's analyses should be taken into account in decision-making, and that the indirect comparison was generally well conducted.
## Indirect treatment comparisons for serious infection should be taken into account in decision-making
The company developed an indirect treatment comparison of serious infections for the induction-treatment group only. Because of the lack of events in the placebo groups (see section 3.5), credible intervals of treatment effects are very wide. This causes high uncertainty in the results for both the random and fixed models. The ERG did an alternative analysis to adjust for the lack of events in the placebo groups, using a frequentist framework (which means adding 0.5 when there is a 0 event). This resulted in a non-significant increased risk of serious infection with tofacitinib. The committee noted that no safety issues have been reported in clinical practice (see section 3.5) and concluded that both the company's and the ERG's analyses should be taken into account in decision-making.
# The company's economic model
## The model is appropriate for decision-making
The company developed a Markov model for the TNF-alpha inhibitor naive and exposed populations, comparing tofacitinib with appropriate comparators for these 2 subgroups. The model used the results from the indirect comparison networks (see section 3.6). The model for the TNF-alpha inhibitor naive group compared tofacitinib with conventional treatment (placebo), adalimumab, golimumab, infliximab, and vedolizumab. The model for the TNF-alpha inhibitor exposed group compared tofacitinib with conventional therapy (placebo) and vedolizumab. The committee noted that the company did not include adalimumab in its analysis of the TNF-alpha inhibitor exposed group (see section 3.5). The Markov model included 9 health states and considered the costs and health benefits from the perspective of the NHS, discounted by 3.5% per year over a time horizon of a lifetime. Clinical response, clinical remission and serious infections were included in the model. The ERG agreed with the company's approach. The committee concluded that the model structure is appropriate for its decision-making.
# Utility values in the economic model
## The utility values are appropriate and consistent with previous NICE technology appraisals for ulcerative colitis
The committee discussed the utility values used in the company's model. The company used published utility values (Woehl et al. 2008) for the health states of active disease (0.47), response (0.87), remission (1.00) and post-surgery (0.82). The committee noted that EQ-5D data were collected in the OCTAVE trials and it questioned the use of published utility values instead of trial-based utility values, which are generally preferred. The company explained that because 'responders' to tofacitinib from OCTAVE Induction were re-randomised to OCTAVE Sustain (see section 3.3), the EQ-5D data are difficult to interpret and not reliable for use in the model. It also highlighted that both clinical response and remission were only assessed at week 8 and week 52, and no data are available from other time points. The ERG noted that utility values from Woehl et al. 2008 were used in previous NICE technology appraisals for ulcerative colitis (that is NICE technology appraisal guidance on vedolizumab and infliximab, adalimumab and golimumab). A patient expert agreed that the utility for active disease (0.47) reflects her experience with the disease. The committee concluded that utility values from Woehl et al. are appropriate and consistent with previous NICE technology appraisals for ulcerative colitis.
# Resource use in the economic model
## The cost effectiveness of tofacitinib is unlikely to change when the induction period is extended to 16 weeks
The committee noted that the company had not modelled the effect of extending the induction period for patients with a delayed response (that is, response after 8 weeks). It noted that the summary of product characteristics indicates that when an adequate therapeutic benefit has not been achieved by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total). The company explained that it did not model this scenario because of a lack of data for the comparators. The committee acknowledged that people may also continue taking TNF-alpha inhibitors beyond the usual time for assessment of response, in the hope of a delayed response. It considered that an extra 8 weeks of the higher induction dose would not be expected to have a major effect on the relative cost effectiveness. The committee concluded that the cost effectiveness of tofacitinib is unlikely to change when the induction period is extended to 16 weeks.
# Cost-effectiveness estimates
## The company's base-case results suggest that tofacitinib is cost effective for moderate to severe ulcerative colitis
The company presented fully incremental analyses and pairwise analyses comparing all treatments with conventional therapy for people who have, or have not, taken TNF‑alpha inhibitors previously. The committee noted that the company's base case included the discount agreed in the commercial arrangement for tofacitinib and the list price for the other treatments. It was aware that the model had been corrected by the ERG for minor issues and that this did not have a significant impact on the results:
TNF-alpha inhibitor 'naive': the cost-effectiveness results showed that adalimumab, golimumab and infliximab are dominated by tofacitinib (that is, they cost more and produce fewer quality-adjusted life years ). The incremental cost-effectiveness ratio (ICER) for tofacitinib compared with conventional therapy is £8,564 per QALY gained. Tofacitinib produced fewer QALYs than vedolizumab, but at a lower cost. This resulted in an incremental saving of £615,077 per QALY lost for tofacitinib compared with vedolizumab at list price.
TNF-alpha inhibitor 'exposed': the ICER for tofacitinib compared with conventional therapy is £10,311 per QALY gained. Tofacitinib produced fewer QALYs than vedolizumab, but at a lower cost. This resulted in an incremental saving of £7,838,381 per QALY lost for tofacitinib compared with vedolizumab at list price.The committee also considered the cost-effectiveness results including the discount agreed in the commercial arrangement for vedolizumab (the ICERs are commercial-in-confidence). It concluded that this does not affect the cost effectiveness of tofacitinib.
## Tofacitinib remains a cost-effective option in the company's scenario analyses in which a 10 mg dose of tofacitinib is taken long-term
The clinical expert explained that some patients may take a 10‑mg dose long-term. This is likely to be people who have previously had TNF‑alpha inhibitors. The company explored a scenario in which a proportion of patients had a 10 mg dose long-term. The committee noted that this increased the ICER for tofacitinib compared with conventional therapy from £10,301 to £13,947 per QALY gained. It also noted that dose escalation is used for the comparator biological therapies, particularly when taken after TNF-alpha inhibitor therapy. It concluded that the company's base case should have included a proportion of patients having the higher dose long-term, but the resulting small increase in the ICER would not stop tofacitinib being cost effective.
## The ERG's base-case results confirm that tofacitinib is cost effective for moderate to severe ulcerative colitis
The ERG's base case included the following data and assumptions:
a similar average age for patients in the TNF-alpha inhibitor 'naive' and 'exposed' groups (rather than different ages, which was assumed by the company)
using efficacy results from the indirect treatment comparison, based on the random-effects model (see section 3.6)
using safety results from the indirect treatment comparison, based on the frequentist framework (see section 3.7)
including the cost of stoma care (the company did not include the cost of stoma care for the post-colectomy health states).Taking into account the commercial arrangements for tofacitinib and vedolizumab, the committee concluded that the ERG's base case shows tofacitinib is a cost-effective option for people with moderate to severe ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment.
## Tofacitinib remains a cost-effective option in the ERG's scenario analyses
The committee discussed the ERG's scenario analyses that had the most impact on the ICER, including:
using utility values from the OCTAVE trials (see section 3.9)
assuming 6.5 outpatient visits per year for all patients on maintenance therapy, which matches the treatment stopping rules for tofacitinib (4.5 outpatient visits per year were assumed by the company)
reducing the health-state resource use to match clinical practice
exploring the effect of switching within or between classes of biological therapies.In all the ERG's scenario analyses, tofacitinib remains a cost-effective option for people with moderate to severe ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment.
# Innovation
## Tofacitinib is innovative
The company stated that tofacitinib is innovative and the first therapy in its class for ulcerative colitis. The clinical experts explained that this is an oral therapy, and that it represents a step-change in the management of the disease. They also noted that tofacitinib is a small molecule. This gives it the advantage of less immunogenicity and loss of response over time compared with biological agents. The committee considered these factors to be important and concluded that tofacitinib is innovative.
# Conclusion
## Tofacitinib is a cost-effective use of NHS resources
The committee concluded that tofacitinib shows clinical benefit compared with placebo for people with moderately to severely active ulcerative colitis, irrespective of previous TNF‑alpha inhibitor exposure. It noted that when the commercial arrangements for tofacitinib and vedolizumab are included, the ICERs remain within the range normally considered a cost-effective use of NHS resources. The committee concluded that it can recommend tofacitinib as a cost-effective use of NHS resources for people with moderately to severely active ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment.
|
{'Recommendations': 'Tofacitinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated or the disease has responded inadequately or lost response to treatment. It is recommended only if the company provides tofacitinib with the discount agreed in the commercial arrangement.\n\nWhy the committee made these recommendations\n\nClinical trial evidence shows that tofacitinib is more effective than placebo for treating moderately to severely active ulcerative colitis. An indirect comparison suggests that for people who have not had a TNF-alpha inhibitor, tofacitinib is more effective than adalimumab and golimumab as maintenance treatment. For people who have had a TNF-alpha inhibitor, tofacitinib is more effective than adalimumab as induction treatment. No other statistically significant differences between tofacitinib and biological therapies were identified.\n\nBased on the health-related benefits and costs compared with conventional therapy and biologicals, tofacitinib is recommended as a cost-effective treatment for moderately to severely active ulcerative colitis in adults whose disease has responded inadequately to, or who cannot tolerate, conventional or biological therapy.', 'Information about tofacitinib': "# Marketing authorisation\n\nTofacitinib (Xeljanz, Pfizer) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent'.\n\n# Dosage in the marketing authorisation\n\nThe recommended dosage of tofacitinib for induction is 10\xa0mg taken orally twice daily for 8\xa0weeks, then 5\xa0mg taken twice daily for maintenance. If adequate therapeutic benefit is not achieved by week\xa08 the induction dose can be taken for an additional 8\xa0weeks (16\xa0weeks in total). Induction therapy should be stopped if there is no evidence of therapeutic benefit by week\xa016.\n\nFor patients whose disease has responded inadequately to tumour necrosis factor antagonist therapy, consider continuing the 10-mg twice-daily dose for maintenance in order to maintain therapeutic benefit. If response decreases to tofacitinib 5\xa0mg taken twice daily as maintenance therapy, consider increasing the dose to 10\xa0mg taken twice daily.\n\nWhen the disease has responded adequately to tofacitinib, corticosteroids may be reduced or stopped in accordance with standard care.\n\n# Price\n\nThe list price of a 56‑tablet pack of 5-mg tofacitinib is £690.03; the list price of a 56‑tablet pack of 10-mg tofacitinib is £1,380.06 (excluding VAT; British national formulary [BNF] online 2018). The average cost per patient for the first year is estimated at £10,350.45 and for the subsequent year is estimated at £8,970.39. The company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial-in-confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Tofacitinib will be used in the same place in the treatment pathway as biological therapies\n\nThe clinical expert explained that current clinical management of moderate to severely active ulcerative colitis is conventional therapies (aminosalicylates, corticosteroids or thiopurines). If there is inadequate response or loss of response, patients may be offered a biological therapy (a tumour necrosis factor [TNF] alpha inhibitor such as infliximab, adalimumab and golimumab or the anti-integrin agent vedolizumab). The clinical expert stated that tofacitinib could be offered instead of biological therapy. He highlighted that moderately to severely active ulcerative colitis is typically managed according to the patient's history, treatment response and tolerance of individual therapies. It is therefore important to have a range of treatment options available. The clinical expert further explained that the disease does not respond in 30% of patients having biological therapies and that, for those with a response, 20% will eventually lose this response. He explained that if there is inadequate or loss of response to the first biological therapy a second biological therapy may be offered, but there is a 30% chance that the disease will not respond. The committee concluded that tofacitinib will be used in the same place in the treatment pathway as biological therapies; that is, in second- and third-line treatment for ulcerative colitis.\n\n## Tofacitinib offers an important new treatment option for ulcerative colitis\n\nThe patient experts explained that moderately to severely active ulcerative colitis has a major effect on people's lives and can be socially isolating. Symptoms include frequent bloody diarrhoea, abdominal pain, symptoms elsewhere in the body (such as the joints, eyes, skin and liver) and fatigue. Complications such as intestinal perforation and abscesses may need surgery. The clinical expert stated that many people who have ulcerative colitis are teenagers and younger adults. They explained that tofacitinib is a novel treatment with a different mode of action compared with biological therapies (see section 3.1). The clinical and the patient experts also highlighted that tofacitinib is taken orally, which has major benefits for patients and the NHS. The clinical expert noted that because of its molecular structure, tofacitinib has less chance of immunogenicity and loss of response over time compared with biological therapies. The committee concluded that tofacitinib offers an important new treatment option for people with ulcerative colitis.\n\n# Clinical evidence\n\n## The OCTAVE trials are suitable for decision-making\n\nThe clinical-effectiveness evidence for tofacitinib comes from 3\xa0placebo-controlled, double-blinded randomised controlled trials:\n\nInduction treatment: the OCTAVE Induction\xa01 and\xa02 trials included 598\xa0patients and 541\xa0patients, respectively, with moderately to severely active ulcerative colitis. They were randomised to have tofacitinib (10\xa0mg twice daily) or placebo. The primary outcome was remission, measured using the Mayo score. Secondary outcomes included mucosal healing, Inflammatory Bowel Disease Questionnaire, SF-36 and EQ-5D. All outcomes were measured at 8‑week follow-up.\n\nMaintenance treatment: the OCTAVE Sustain trial included 593\xa0patients whose disease had had a clinical response to tofacitinib in OCTAVE Induction\xa01 or\xa02. Patients took either tofacitinib (5\xa0mg or 10\xa0mg) or placebo, twice daily. The primary outcome was remission. Secondary outcomes included sustained steroid-free remission measured at 24\xa0weeks, mucosal healing, and clinical response and clinical remission at 52‑week follow-up.Additional clinical evidence came from a small trial and OCTAVE Open, an ongoing open-label long-term extension trial. This included patients from OCTAVE Induction\xa01 and\xa02 whose disease did not respond to tofacitinib. The committee concluded that the trials are adequate and suitable for decision-making.\n\n## Tofacitinib is more effective than placebo for induction and maintenance treatment regardless of previous TNF-alpha inhibitor use\n\nThe committee noted that in OCTAVE Induction\xa01 remission at week\xa08 was seen in 18.5% of patients having tofacitinib 10\xa0mg, compared with 8.2% in the placebo group (p=0.007). In OCTAVE Induction\xa02 remission at week\xa08 was 16.6% for tofacitinib and 3.6% for placebo (p<0.001). In OCTAVE Sustain, 40.6% of patients having tofacitinib 10\xa0mg were in disease remission at week\xa052, compared with 11.1% in the placebo group (p<0.001). Similarly, 34.3% of patients in the tofacitinib 5\xa0mg group were in disease remission at week\xa052 (p<0.001). The committee noted that the mean differences between tofacitinib and placebo in OCTAVE Induction\xa01 and\xa02 are in favour of tofacitinib and are statistically significant at the end of the induction phase (week\xa08). A similar effect was observed in OCTAVE Sustain for both dosages of tofacitinib (5\xa0mg and 10\xa0mg), with the difference in comparison with placebo being greater for tofacitinib 10\xa0mg at the end of the maintenance phase (week\xa052). The subgroup results for prior TNF-alpha inhibitor exposure status, which were used by the company in their economic modelling, show a similar effect. The ERG explained that the OCTAVE trials were not powered to test the statistical significance of subgroup analyses so the results should be interpreted with caution. The committee concluded that tofacitinib is more effective than placebo for induction and maintenance treatment of moderate to severe disease, regardless of whether TNF-alpha inhibitors have been taken previously.\n\n# Adverse events\n\n## Tofacitinib has an acceptable safety profile\n\nThe company collected safety data from all the OCTAVE trials. Serious adverse events affected fewer than 10% of patients. There were 5\xa0deaths, of which 1 was considered to be related to tofacitinib. Serious infections occurred only in patients having tofacitinib rather than placebo, with the exception of OCTAVE Sustain in which 2\xa0patients taking placebo had serious infections. The clinical expert explained that the serious infections were non-specific and that they would not influence the decision to prescribe a biological instead of tofacitinib. The company highlighted that tofacitinib is also used for rheumatoid arthritis and that long-term safety data (over 9\xa0years) are available. The committee concluded that tofacitinib's safety profile is acceptable.\n\n# Indirect treatment comparison\n\n## The company's indirect comparison was generally well conducted\n\nThe company presented 2\xa0network meta-analyses according to previous TNF-alpha inhibitor use for induction and maintenance treatment with tofacitinib. Analyses were done for the outcomes of clinical response, clinical remission and mucosal healing:\n\nThe TNF-alpha inhibitor 'naive' network included people who had not taken a TNF-alpha inhibitor. It estimated the relative efficacy of tofacitinib compared with placebo, adalimumab, golimumab, infliximab, and vedolizumab.\n\nThe TNF-alpha inhibitor 'exposed' network included people who had taken TNF-alpha inhibitors. It estimated the relative efficacy of tofacitinib compared with placebo, adalimumab and vedolizumab.In the TNF-alpha inhibitor naive group all active treatments showed a statistically significant improvement for all outcomes compared with placebo. In the maintenance phase tofacitinib showed a statistically significant improvement in clinical remission and clinical response compared with adalimumab and golimumab 50\xa0mg. No other statistically significant differences were found in the TNF-alpha inhibitor naive group. In the TNF-alpha inhibitor exposed group tofacitinib and vedolizumab showed a statistically significant improvement in all outcomes compared with placebo. In the induction phase tofacitinib showed a statistically significant improvement in clinical remission and clinical response compared with adalimumab. No other statistically significant differences were found in the TNF-alpha inhibitor exposed group. The ERG noted that the indirect comparison was generally well conducted. The ERG replicated the company's indirect treatment comparison and preferred the random-effects models, because the fixed-effects models may underestimate the uncertainty caused by heterogeneity between the studies included in the networks. It explored the impact of a random-effects model for TNF-alpha inhibitor naive and exposed groups for maintenance treatment with tofacitinib in its preferred analyses. The random-effects model showed wider credible intervals and some variation in the median estimates for adalimumab and golimumab as maintenance treatment for the TNF-alpha inhibitor naive group. This is because smaller size studies are given more weight in the random-effects model (ERG) than the fixed-effects model (company). The ERG noted that adalimumab was included in the network, but the company did not provide results for adalimumab for the TNF-alpha inhibitor exposed group and did not explain why. It considered that adalimumab is a relevant comparator and included it in its base case. The committee concluded that both the company's and the ERG's analyses should be taken into account in decision-making, and that the indirect comparison was generally well conducted.\n\n## Indirect treatment comparisons for serious infection should be taken into account in decision-making\n\nThe company developed an indirect treatment comparison of serious infections for the induction-treatment group only. Because of the lack of events in the placebo groups (see section 3.5), credible intervals of treatment effects are very wide. This causes high uncertainty in the results for both the random and fixed models. The ERG did an alternative analysis to adjust for the lack of events in the placebo groups, using a frequentist framework (which means adding 0.5 when there is a 0 event). This resulted in a non-significant increased risk of serious infection with tofacitinib. The committee noted that no safety issues have been reported in clinical practice (see section 3.5) and concluded that both the company's and the ERG's analyses should be taken into account in decision-making.\n\n# The company's economic model\n\n## The model is appropriate for decision-making\n\nThe company developed a Markov model for the TNF-alpha inhibitor naive and exposed populations, comparing tofacitinib with appropriate comparators for these 2\xa0subgroups. The model used the results from the indirect comparison networks (see section 3.6). The model for the TNF-alpha inhibitor naive group compared tofacitinib with conventional treatment (placebo), adalimumab, golimumab, infliximab, and vedolizumab. The model for the TNF-alpha inhibitor exposed group compared tofacitinib with conventional therapy (placebo) and vedolizumab. The committee noted that the company did not include adalimumab in its analysis of the TNF-alpha inhibitor exposed group (see section 3.5). The Markov model included 9\xa0health states and considered the costs and health benefits from the perspective of the NHS, discounted by 3.5% per year over a time horizon of a lifetime. Clinical response, clinical remission and serious infections were included in the model. The ERG agreed with the company's approach. The committee concluded that the model structure is appropriate for its decision-making.\n\n# Utility values in the economic model\n\n## The utility values are appropriate and consistent with previous NICE technology appraisals for ulcerative colitis\n\nThe committee discussed the utility values used in the company's model. The company used published utility values (Woehl et al. 2008) for the health states of active disease (0.47), response (0.87), remission (1.00) and post-surgery (0.82). The committee noted that EQ-5D data were collected in the OCTAVE trials and it questioned the use of published utility values instead of trial-based utility values, which are generally preferred. The company explained that because 'responders' to tofacitinib from OCTAVE Induction were re-randomised to OCTAVE Sustain (see section 3.3), the EQ-5D data are difficult to interpret and not reliable for use in the model. It also highlighted that both clinical response and remission were only assessed at week\xa08 and week\xa052, and no data are available from other time points. The ERG noted that utility values from Woehl et al. 2008 were used in previous NICE technology appraisals for ulcerative colitis (that is NICE technology appraisal guidance on vedolizumab and infliximab, adalimumab and golimumab). A patient expert agreed that the utility for active disease (0.47) reflects her experience with the disease. The committee concluded that utility values from Woehl et al. are appropriate and consistent with previous NICE technology appraisals for ulcerative colitis.\n\n# Resource use in the economic model\n\n## The cost effectiveness of tofacitinib is unlikely to change when the induction period is extended to 16\xa0weeks\n\nThe committee noted that the company had not modelled the effect of extending the induction period for patients with a delayed response (that is, response after 8\xa0weeks). It noted that the summary of product characteristics indicates that when an adequate therapeutic benefit has not been achieved by week\xa08, the induction dose of 10\xa0mg twice daily can be extended for an additional 8\xa0weeks (16\xa0weeks total). The company explained that it did not model this scenario because of a lack of data for the comparators. The committee acknowledged that people may also continue taking TNF-alpha inhibitors beyond the usual time for assessment of response, in the hope of a delayed response. It considered that an extra 8\xa0weeks of the higher induction dose would not be expected to have a major effect on the relative cost effectiveness. The committee concluded that the cost effectiveness of tofacitinib is unlikely to change when the induction period is extended to 16\xa0weeks.\n\n# Cost-effectiveness estimates\n\n## The company's base-case results suggest that tofacitinib is cost effective for moderate to severe ulcerative colitis\n\nThe company presented fully incremental analyses and pairwise analyses comparing all treatments with conventional therapy for people who have, or have not, taken TNF‑alpha inhibitors previously. The committee noted that the company's base case included the discount agreed in the commercial arrangement for tofacitinib and the list price for the other treatments. It was aware that the model had been corrected by the ERG for minor issues and that this did not have a significant impact on the results:\n\nTNF-alpha inhibitor 'naive': the cost-effectiveness results showed that adalimumab, golimumab and infliximab are dominated by tofacitinib (that is, they cost more and produce fewer quality-adjusted life years [QALYs]). The incremental cost-effectiveness ratio (ICER) for tofacitinib compared with conventional therapy is £8,564 per QALY gained. Tofacitinib produced fewer QALYs than vedolizumab, but at a lower cost. This resulted in an incremental saving of £615,077 per QALY lost for tofacitinib compared with vedolizumab at list price.\n\nTNF-alpha inhibitor 'exposed': the ICER for tofacitinib compared with conventional therapy is £10,311 per QALY gained. Tofacitinib produced fewer QALYs than vedolizumab, but at a lower cost. This resulted in an incremental saving of £7,838,381 per QALY lost for tofacitinib compared with vedolizumab at list price.The committee also considered the cost-effectiveness results including the discount agreed in the commercial arrangement for vedolizumab (the ICERs are commercial-in-confidence). It concluded that this does not affect the cost effectiveness of tofacitinib.\n\n## Tofacitinib remains a cost-effective option in the company's scenario analyses in which a 10\xa0mg dose of tofacitinib is taken long-term\n\nThe clinical expert explained that some patients may take a 10‑mg dose long-term. This is likely to be people who have previously had TNF‑alpha inhibitors. The company explored a scenario in which a proportion of patients had a 10\xa0mg dose long-term. The committee noted that this increased the ICER for tofacitinib compared with conventional therapy from £10,301 to £13,947 per QALY gained. It also noted that dose escalation is used for the comparator biological therapies, particularly when taken after TNF-alpha inhibitor therapy. It concluded that the company's base case should have included a proportion of patients having the higher dose long-term, but the resulting small increase in the ICER would not stop tofacitinib being cost effective.\n\n## The ERG's base-case results confirm that tofacitinib is cost effective for moderate to severe ulcerative colitis\n\nThe ERG's base case included the following data and assumptions:\n\na similar average age for patients in the TNF-alpha inhibitor 'naive' and 'exposed' groups (rather than different ages, which was assumed by the company)\n\nusing efficacy results from the indirect treatment comparison, based on the random-effects model (see section 3.6)\n\nusing safety results from the indirect treatment comparison, based on the frequentist framework (see section 3.7)\n\nincluding the cost of stoma care (the company did not include the cost of stoma care for the post-colectomy health states).Taking into account the commercial arrangements for tofacitinib and vedolizumab, the committee concluded that the ERG's base case shows tofacitinib is a cost-effective option for people with moderate to severe ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment.\n\n## Tofacitinib remains a cost-effective option in the ERG's scenario analyses\n\nThe committee discussed the ERG's scenario analyses that had the most impact on the ICER, including:\n\nusing utility values from the OCTAVE trials (see section 3.9)\n\nassuming 6.5\xa0outpatient visits per year for all patients on maintenance therapy, which matches the treatment stopping rules for tofacitinib (4.5\xa0outpatient visits per year were assumed by the company)\n\nreducing the health-state resource use to match clinical practice\n\nexploring the effect of switching within or between classes of biological therapies.In all the ERG's scenario analyses, tofacitinib remains a cost-effective option for people with moderate to severe ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment.\n\n# Innovation\n\n## Tofacitinib is innovative\n\nThe company stated that tofacitinib is innovative and the first therapy in its class for ulcerative colitis. The clinical experts explained that this is an oral therapy, and that it represents a step-change in the management of the disease. They also noted that tofacitinib is a small molecule. This gives it the advantage of less immunogenicity and loss of response over time compared with biological agents. The committee considered these factors to be important and concluded that tofacitinib is innovative.\n\n# Conclusion\n\n## Tofacitinib is a cost-effective use of NHS resources\n\nThe committee concluded that tofacitinib shows clinical benefit compared with placebo for people with moderately to severely active ulcerative colitis, irrespective of previous TNF‑alpha inhibitor exposure. It noted that when the commercial arrangements for tofacitinib and vedolizumab are included, the ICERs remain within the range normally considered a cost-effective use of NHS resources. The committee concluded that it can recommend tofacitinib as a cost-effective use of NHS resources for people with moderately to severely active ulcerative colitis when conventional therapy or a biological cannot be tolerated or the disease has responded inadequately or lost response to treatment."}
|
https://www.nice.org.uk/guidance/ta547
|
Evidence-based recommendations on tofacitinib (Xeljanz) for previously treated moderately to severely active ulcerative colitis in adults.
|
224e18859a8ff2966c8fc8546a1f27000665d88d
|
nice
|
Urinary tract infection (catheter-associated): antimicrobial prescribing
|
Urinary tract infection (catheter-associated): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for catheter-associated urinary tract infection in children, young people and adults. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing catheter-associated urinary tract infection
Be aware that:
a catheter-associated urinary tract infection (UTI) is a symptomatic infection of the bladder or kidneys in a person with a urinary catheter
the longer a catheter is in place, the more likely bacteria will be found in the urine; after 1 month nearly all people have bacteriuria
antibiotic treatment is not routinely needed for asymptomatic bacteriuria in people with a catheter.
Give advice about managing symptoms with self-care (see the recommendations on self-care) to all people with catheter-associated UTI.
## Treatment
Consider removing or, if this cannot be done, changing the catheter as soon as possible in people with a catheter-associated UTI if it has been in place for more than 7 days. Do not allow catheter removal or change to delay antibiotic treatment.
Obtain a urine sample before antibiotics are taken. Take the sample from the catheter, via a sampling port if provided, and use an aseptic technique (in line with the NICE guideline on healthcare-associated infections).
If the catheter has been changed, obtain the sample from the new catheter.
If the catheter has been removed, obtain a midstream specimen of urine.
Send the urine sample for culture and susceptibility testing, noting a suspected catheter-associated infection and any antibiotic prescribed.
Offer an antibiotic (see the recommendations on choice of antibiotic) to people with catheter-associated UTI. Take account of:
the severity of symptoms
the risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract, or immunosuppression
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
When urine culture and susceptibility results are available:
review the choice of antibiotic and
change the antibiotic according to susceptibility results if the bacteria are resistant, using narrow-spectrum antibiotics wherever possible.
## Advice when an antibiotic prescription is given
When an antibiotic is given, as well as the general advice on self-care, give advice about:
possible adverse effects of antibiotics, particularly diarrhoea and nausea
seeking medical help if:
symptoms worsen at any time or
symptoms do not start to improve within 48 hours of taking the antibiotic or
the person becomes systemically very unwell.
## Reassessment
Reassess people with catheter-associated UTI if symptoms worsen at any time, or do not start to improve within 48 hours of taking the antibiotic, taking account of:
-ther possible diagnoses
any symptoms or signs suggesting a more serious illness or condition, such as sepsis
previous antibiotic use, which may have led to resistant bacteria.
## Referral and seeking specialist advice
Refer people with catheter-associated UTI to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).
Consider referring or seeking specialist advice for people with catheter-associated UTI if they:
are significantly dehydrated or unable to take oral fluids and medicines or
are pregnant or
have a higher risk of developing complications (for example, people with known or suspected structural or functional abnormality of the genitourinary tract, or underlying disease ) or
have recurrent catheter-associated UTIs or
have bacteria that are resistant to oral antibiotics.
See the evidence and committee discussion on antibiotics for managing catheter-associated UTI.
# Self-care
Advise people with catheter-associated UTI about using paracetamol for pain.
Advise people with catheter-associated UTI about drinking enough fluids to avoid dehydration.
See the evidence and committee discussion on self-care.
# Choice of antibiotic
When prescribing an antibiotic for catheter-associated UTI, take account of local antimicrobial resistance data and:
follow table 1 for non-pregnant women and men aged 16 years and over
follow table 2 for pregnant women aged 12 years and over
follow table 3 for children and young people under 16 years.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
## Table 1 Antibiotics for non-pregnant women and men aged 16 years and over
Antibiotic
Dosage and course length
First-choice
oral antibiotics if no upper UTI symptoms
Nitrofurantoin – if eGFR ≥45 ml/minute3,4
mg modified-release twice a day (or if unavailable 50 mg four times a day) for 7 days
Trimethoprim – if low risk of resistance5
mg twice a day for 7 days
Amoxicillin (only if culture results available and susceptible)
mg three times a day for 7 days
Second-choice oral antibiotic if no upper UTI symptoms (when first-choice not suitable)
Pivmecillinam (a penicillin)4
mg initial dose, then 200 mg three times a day for a total of 7 days
First-choice oral antibiotics if upper UTI symptoms
Cefalexin
mg twice or three times a day (up to 1 to 1.5 g three or four times a day for severe infections) for 7 to 10 days
Co-amoxiclav (only if culture results available and susceptible)
/125 mg three times a day for 7 to 10 days
Trimethoprim (only if culture results available and susceptible)
mg twice a day for 14 days
Ciprofloxacin (consider safety issues6)
mg twice a day for 7 days
First-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern
Co-amoxiclav (only in combination, unless culture results confirm susceptibility)
g three times a day
Cefuroxime
mg to 1.5 g three or four times a day
Ceftriaxone
to 2 g once a day
Ciprofloxacin (consider safety issues6)
mg twice or three times a day
Gentamicin
Initially 5 to 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration8
Amikacin
Initially 15 mg/kg once a day (maximum per dose 1.5 g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15 g per course)8
Second-choice intravenous antibiotics
Consult local microbiologist
See BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment and breastfeeding, and administering intravenous antibiotics.
Check any previous urine culture and susceptibility results and antibiotic prescribing, and choose antibiotics accordingly.
May be used with caution if eGFR 30–44 ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).
Nitrofurantoin and pivmecillinam are only licensed for uncomplicated lower UTIs, and are not suitable for people with upper UTI symptoms or a blocked catheter.
A lower risk of resistance is likely if not used in the past 3 months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance is likely with recent use and in older people in care homes.
See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Therapeutic drug monitoring and assessment of renal function is required (BNF, August 2018).
Abbreviations: BNF, British national formulary; eGFR, estimated glomerular filtration rate; UTI, urinary tract infection.
## Table 2 Antibiotics for pregnant women aged 12 years and over
Antibiotic
Dose and course length
First-choice oral antibiotic
Cefalexin
mg twice or three times a day (up to 1 to 1.5 g three or four times a day for severe infections) for 7 to 10 days
First-choice intravenous antibiotic (if vomiting, unable to take oral antibiotics, or severely unwell)
Cefuroxime
mg to 1.5 g three or four times a day
Second-choice antibiotics or combining antibiotics if susceptibility or sepsis a concern
Consult local microbiologist
See BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.
Check any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
## Table 3 Antibiotics for children and young people under 16 years
Antibiotic
Dosage and course length
Children under 3 months
Refer to paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under 5s.
Children aged 3 months and over
First-choice oral antibiotics
Trimethoprim – if low risk of resistance4
to 5 months, 4 mg/kg (maximum 200 mg per dose) or 25 mg twice a day for 7 to 10 days
months to 5 years, 4 mg/kg (maximum 200 mg per dose) or 50 mg twice a day for 7 to 10 days
to 11 years, 4 mg/kg (maximum 200 mg per dose) or 100 mg twice a day for 7 to 10 days
to 15 years, 200 mg twice a day for 7 to 10 days
Amoxicillin (only if culture results available and susceptible)
to 11 months, 125 mg three times a day for 7 to 10 days
to 4 years, 250 mg three times a day for 7 to 10 days
to 15 years, 500 mg three times a day for 7 to 10 days
Cefalexin
to 11 months, 12.5 mg/kg or 125 mg twice a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
to 4 years, 12.5 mg/kg twice a day or 125 mg three times a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
to 11 years, 12.5 mg/kg twice a day or 250 mg three times a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
to 15 years, 500 mg twice or three times a day (up to 1 to 1.5 g three or four times a day for severe infections) for 7 to 10 days
Co-amoxiclav (only if culture results available and susceptible)
to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
to 5 years, 0.25 ml/kg of 125/31 suspension or 5 ml of 125/31 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
to 11 years, 0.15 ml/kg of 250/62 suspension or 5 ml of 250/62 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
to 15 years, 250/125 mg or 500/125 mg three times a day for 7 to 10 days
First-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern
Co-amoxiclav (only in combination unless culture results confirm susceptibility)
months to 15 years, 30 mg/kg three times a day (maximum 1.2 g three times a day)
Cefuroxime
months to 15 years, 20 mg/kg three times a day (maximum 750 mg per dose); (50 to 60 mg/kg three or four times a day for severe infections)
Ceftriaxone
months to 11 years (up to 50 kg), 50 to 80 mg/kg once a day (maximum 4 g per day)
to 11 years (50 kg and above), 1 to 2 g once a day
to 15 years, 1 to 2 g once a day
Gentamicin
Initially 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration7
Amikacin
Initially 15 mg/kg once a day, subsequent doses adjusted according to serum amikacin concentration7
Second-choice intravenous antibiotic
Consult local microbiologist
See BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics. See table 2 if a young woman is pregnant.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
Check any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly. If a child or young person is receiving prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.
A lower risk of resistance is likely if not used in the past 3 months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance is likely with recent use.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible for a total antibiotic course of 10 days.
If intravenous treatment is not possible, consider intramuscular treatment if suitable.
Therapeutic drug monitoring and assessment of renal function is required (BNFC, August 2018).
See the evidence and committee discussion on antibiotics for managing catheter-associated UTI.
# Preventing catheter-associated urinary tract infections
Do not routinely offer antibiotic prophylaxis to prevent catheter-associated UTIs in people with a short-term or a long-term (indwelling or intermittent) catheter.
Give advice about seeking medical help if symptoms of an acute UTI develop.
See the evidence and committee discussion on antibiotic prophylaxis for preventing catheter-associated UTI and the NICE guideline on healthcare-associated infections.
See the NICE guideline on lower UTI: antimicrobial prescribing for managing asymptomatic bacteriuria in pregnant women.# Terms used in this guideline
# Asymptomatic bacteriuria
The presence of significant levels of bacteria in the urine with no symptoms of urinary tract infection (UTI).
# Catheter-associated urinary tract infection
Catheter-associated UTI is defined as the presence of symptoms or signs compatible with a UTI in people with a catheter with no other identified source of infection plus significant levels of bacteria in a catheter or a midstream urine specimen when the catheter has been removed within the previous 48 hours (adapted from Infectious Diseases Society of America's guideline on catheter-associated UTI ).# Summary of the evidence
# Self-care
One randomised controlled trial (RCT; Gunnarsson et al. 2017) in adult females (n=92) who had a hip fracture and a perioperative urinary catheter with planned removal at 48 hours, compared cranberry juice concentrate (capsules) with placebo for the prevention of postoperative urinary tract infection (UTI). There were no significant differences in positive urine cultures (>104 colony-forming units per ml) at either 5 or 14 days after surgery (low quality evidence).
No systematic reviews or RCTs of any other non-antimicrobial treatments were identified that met the inclusion criteria.
Committee discussion on self-care
There was no evidence for the use of oral analgesia in catheter-associated-UTI. However, paracetamol has a well-established efficacy and safety profile for managing pain. The committee agreed that it was reasonable to consider paracetamol for managing pain in people with a catheter-associated UTI.
Based on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.
The committee agreed that the evidence for use of cranberry in preventing catheter-associated UTI (which showed no effect) was limited to a specific population in the immediate postoperative period, and could not be extrapolated to other populations or settings. The committee was, therefore, unable to make a recommendation on its use.
# Antibiotics for managing catheter-associated UTI
In most cases, managing symptomatic catheter-associated UTI will require antibiotics.
Gram-negative bacteria, particularly Escherichia coli (E. coli), are the most common causative pathogens in UTIs. However, catheter-associated UTI can be associated with more than 1 bacterial species and is often caused by bacteria that are resistant to antibiotics (European Association of Urology guidelines on urological infections 2017).
UTI is the most common healthcare-acquired infection, accounting for 19% of all healthcare-associated infections, with around half of these infections due to an indwelling urinary catheter (Health Protection Agency 2012). In some people, catheter-associated UTI can lead to a more serious systemic infection (urosepsis).
## Efficacy of antibiotics
One RCT (Leone et al. 2007) of adults with asymptomatic bacteriuria admitted to an intensive care unit with a short-term catheter found that a short course (3 days) of antibiotics and catheter change did not significantly reduce the proportion of patients with urosepsis (p=1, low quality evidence), or bacteraemia or severe sepsis (p>0.05, low quality evidence), compared with no antibiotics and no catheter change. Short-course antibiotics and catheter change significantly reduced the proportion of positive urine cultures (>105 colony-forming units/ml) at 7 days (30% versus 70%, number needed to treat 3 , moderate quality evidence) but not at 15 days (very low quality evidence).
One RCT (Darouiche et al. 2014) of hospitalised adults with a long-term catheter for spinal cord injury and catheter-associated UTI found that a shorter course (5 days) of antibiotics plus a catheter change was not significantly different to 10 days of antibiotics and no catheter change for clinical cure at the end of therapy (p<0.001 for non-inferiority, moderate quality evidence). However, for other outcomes (microbiological response and resolution of pyuria at the end of therapy), the short course and catheter change was not as effective as the long course and no catheter change. There were also significantly more episodes of recurrent UTI in the short course plus catheter change group compared with the long course and no catheter change group (32.1% versus 11.1%, p=0.043; low quality evidence).
## Changing the catheter before antibiotics
One prospective open-label RCT (Raz et al. 2000) in older adults in a long-stay care facility with a long-term catheter and catheter-associated UTI compared catheter change before antibiotics with no catheter change before antibiotics. Antibiotic therapy was ciprofloxacin or ofloxacin, initially intravenously then orally for 14 days. There was a significant difference in cure or improvement, favouring catheter change at 72 hours (92.6% versus 40.7%, NNT 2 ; moderate quality evidence) and 28 days (88.9% versus 59.3%, NNT 4 ; low quality evidence), but not at 7 days. There was no significant difference in recurrence or treatment failure at either 7 or 28 days, but mortality was significantly lower in the catheter change group (0% versus 7.4% ; very low quality evidence).
## Safety of antibiotics
The RCT on duration of antibiotics (and catheter change) for people with spinal cord injury and catheter-associated UTI (Darouiche et al. 2014) found no significant difference in adverse events between the no catheter change and 10 days of antibiotics group, and the catheter change and 5 days of antibiotics group (40.7% versus 64.3%%; low quality evidence).
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2018).
Nitrofurantoin should be used with caution in those with renal impairment. It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should be monitored for liver function and pulmonary symptoms (BNF, August 2018).
Trimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF, August 2018). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).
Fluoroquinolones are generally not recommended in children or young people who are still growing (BNF, August 2018). The manufacturers advise to avoid in pregnancy (ciprofloxacin summary of product characteristics). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (press release October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain an option in catheter-associated UTI with upper UTI symptoms, which is a severe infection.
Aminoglycosides doses are based on weight and renal function and whenever possible treatment should not exceed 7 days (BNF, August 2018).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Committee discussion on antibiotics for managing catheter-associated UTI
Based on evidence and experience, the committee agreed that people with a symptomatic catheter-associated UTI should be offered an antibiotic.
Urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment decisions. The committee discussed and agreed that a comment should be added to the microbiology request form to alert the laboratory to a suspected catheter-associated infection and the name of any antibiotic prescribed.
The committee agreed that the evidence for antibiotic treatment for catheter-associated UTI specifically was limited, but that evidence for antibiotic treatment for acute pyelonephritis could be extrapolated. The evidence for acute pyelonephritis included some people with complicated UTI, some of whom had a catheter (see the NICE guideline on acute pyelonephritis: antimicrobial prescribing).
Limited evidence suggested that catheters should be removed or changed before antibiotics are given, but the committee discussed safety concerns with this approach and practical considerations about possible delays in primary care settings. They agreed that catheter removal or change should not delay treatment with antibiotics. The longer a catheter is in place, the more likely bacteria will be found in the urine, and the committee agreed that catheters should be removed rather than changed, where possible. Changing the catheter is based on evidence from 1 small RCT, which found higher cure or improvement rates and reduced mortality (from urosepsis) when the catheter was changed before starting antibiotics. The committee based when to remove or change the catheter (after 7 days) on their experience.
Based on evidence and experience, the committee agreed that screening and antibiotic treatment for asymptomatic bacteriuria is not routine in people with a catheter because it is not generally a risk factor for harm. Pregnant women (including those with a catheter) have routine screening and antibiotic treatment for asymptomatic bacteriuria because it is a risk factor for pyelonephritis and preterm labour.
Committee discussion on choice of antibiotic
The committee agreed, based on evidence, experience and resistance data, that several oral and intravenous antibiotics should be available for people with a catheter-associated UTI. Having a choice enables antibiotics to be selected based on the severity of illness, presence or absence of upper UTI symptoms, antibiotic susceptibilities from culture results when available, local resistance patterns, risk of resistant bacteria, setting and known patient factors. In line with antimicrobial stewardship, narrower-spectrum antibiotics should be used wherever possible.
Nationally for England, resistance of E. coli (the main causative organism of UTIs) in laboratory-processed urine specimens to the following antibiotics is:
nitrofurantoin: 2.5% (varies by area from 2.0 to 3.6%)
trimethoprim: 30.3% (varies by area from 27.1 to 33.4%)
pivmecillinam: 7.5% (varies by area from 4.1 to 15.7%)
cefalexin: 9.9% (varies by area from 8.1 to 11.4%)
ciprofloxacin: 10.6% (varies by area from 7.8 to 13.7%)
co-amoxiclav: 19.8% (varies by area from 10.8 to 30.7%).(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018)
The committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.
The committee agreed that any recent previous urine culture and susceptibility results, and antibiotic prescribing, should be reviewed before choosing an antibiotic.
Based on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, the antibiotic should be changed, using a narrow-spectrum antibiotic where possible.
Non-pregnant women and men with catheter-associated UTI
Based on evidence, their experience and resistance data, the committee agreed to recommend nitrofurantoin, trimethoprim or amoxicillin at usual doses as first-choice oral antibiotics for adults with a catheter-associated UTI but no upper UTI symptoms.
Nitrofurantoin is not recommended for people with an eGFR <45 ml/minute. It may be used with caution if eGFR is 30 to 44 ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug-resistant bacteria, and only if the potential benefit outweighs risk (BNF, August 2018). The committee noted that nitrofurantoin is only licensed for uncomplicated lower UTI. However, they agreed that for adults with a catheter-associated UTI without upper UTI symptoms, nitrofurantoin is an option (unless they have a blocked catheter, where Proteus mirabilis could be the causative organism). Based on experience, the committee felt it was important to offer 'lower UTI' antibiotics as an option for adults with catheter-associated UTI without upper UTI symptoms, otherwise all adults with a catheter-associated UTI would need to be offered a broader-spectrum 'upper UTI' antibiotic, where their symptoms may not warrant this.
The committee agreed to recommend either the modified-release preparation of nitrofurantoin or the immediate-release preparation. However, because of its twice-daily dosing and, in their experience, better tolerability the committee was keen to point out that the modified-release preparation was preferred unless it was unavailable. The committee also discussed that, in their experience, immediate-release preparations containing nitrofurantoin in a macrocrystalline form may be better tolerated than those containing nitrofurantoin in a microcrystalline form.
Trimethoprim has high resistance levels nationally and should only be prescribed if a lower risk of resistance is thought to be likely. A lower risk of resistance is likely if trimethoprim has not been used in the past 3 months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger people in areas where local epidemiology data suggest resistance is lower. There is a higher risk of trimethoprim resistance with recent use and in older people in care homes.
Amoxicillin is recommended only if culture results are available and bacteria are susceptible because resistance rates are high.
If nitrofurantoin, trimethoprim or amoxicillin are not suitable, the second-choice oral antibiotic for adults with a catheter-associated UTI but no upper UTI symptoms is pivmecillinam (a penicillin) at its usual dose. The committee acknowledged that prescribers may be less familiar with this antibiotic, but it is often used in other European countries. The committee noted that pivmecillinam is only licensed for uncomplicated lower UTI. However, as with nitrofurantoin, they agreed that for adults with a catheter-associated UTI without upper UTI symptoms, 'lower UTI' antibiotics are an option.
For adults with upper UTI symptoms, nitrofurantoin, amoxicillin and pivmecillinam are not appropriate, and cefalexin (a first-generation cephalosporin), co‑amoxiclav (a penicillin with a beta‑lactamase inhibitor), trimethoprim or ciprofloxacin (a fluoroquinolone), at usual doses, are recommended to cover a broader range of bacterial pathogens. Co‑amoxiclav and trimethoprim are only suitable if culture results are available and bacteria are susceptible, because resistance rates are high.
The committee noted that use of broad-spectrum antibiotics, such as later-generation cephalosporins, fluoroquinolones or co‑amoxiclav, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. By disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of catheter-associated UTI with upper UTI symptoms, where coverage of more resistant strains of common bacterial pathogens is required.
The committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects, mainly involving muscles, tendons and bones, and the nervous system. However, they discussed that fluoroquinolone antibiotics are a valuable option for the treatment of catheter-associated UTI with upper UTI symptoms, which is a severe infection, and it is appropriate to reserve fluoroquinolone use for such conditions. Resistant gram-negative organisms are a particular concern in catheter-associated UTI with upper UTI symptoms, and the committee agreed that ciprofloxacin should remain a first-choice option to cover what can be a complex infection. The committee was keen to point out, however, that cefalexin, co‑amoxiclav and trimethoprim are also first-choice options, and antibiotics should be chosen on an individual patient basis, taking fluoroquinolone safety concerns, as well as susceptibility and resistance, into account.
Based on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for adults who are unable to take oral antibiotics because of nausea and vomiting, or are more severely unwell. These are:
co-amoxiclav (only in combination unless culture results confirm bacteria are susceptible)
cefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)
ciprofloxacin (taking safety concerns into account)
gentamicin or amikacin (aminoglycosides); which may be appropriate for some people with catheter-associated UTI, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed by 48 hours. Gentamicin is the preferred aminoglycoside in the UK, but shortages of certain antibiotics may result in the use of alternatives; for example, amikacin in place of gentamicin.
The committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.
Pregnant women with catheter-associated UTI
Based on evidence, experience and resistance data, the committee agreed to recommend cefalexin (a first-generation cephalosporin) as the first-choice oral antibiotic for pregnant women who don't need intravenous antibiotics, and cefuroxime (a second-generation cephalosporin) as the first-choice intravenous antibiotic.
Ciprofloxacin and trimethoprim are not recommended because they should be avoided in pregnancy. Co‑amoxiclav was not recommended because of high resistance levels nationally and the risks of treatment failure in pregnancy.
The committee agreed, based on experience, that local microbiologists should be consulted for advice on second-choice antibiotics, or combining antibiotics, if susceptibility or sepsis is a concern.
Children and young people with catheter-associated UTI
Based on evidence, experience and resistance data, the committee agreed to recommend trimethoprim (if low risk of resistance), amoxicillin (only if culture results are available and bacteria are susceptible), cefalexin or co‑amoxiclav (only if culture results are available and bacteria are susceptible) at usual doses as first-choice oral antibiotics for children and young people with catheter-associated UTI.
Based on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics at usual doses for children and young people who are unable to take oral antibiotics because of nausea and vomiting, or are more severely unwell. These are:
co-amoxiclav (only in combination unless culture results confirm bacteria are susceptible); which can be given intravenously
cefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)
gentamicin or amikacin (aminoglycosides); which may be appropriate for some children and young people with upper UTI symptoms, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48 hours.
The committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of children and young people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.
Committee discussions on antibiotic course length
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that the use of intravenous antibiotics should be reviewed by 48 hours (taking into account the response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.
Course length for non-pregnant women, pregnant women, men, children and young people with catheter-associated UTI
Based on evidence, experience and resistance data, the committee agreed that, for oral treatment, at least a 7‑day course of all the recommended antibiotics was needed to treat catheter-associated UTI to ensure complete cure. This is because people with a catheter are more at risk of complications from a UTI. For adults with a catheter-associated UTI and upper UTI symptoms, pregnant women, and children and young people, course lengths are the same as those for acute pyelonephritis (see the NICE guideline on acute pyelonephritis: antimicrobial prescribing).
For intravenous treatment, antibiotics should be reviewed by 48 hours and stepped down to oral antibiotics where possible.
# Antibiotic prophylaxis for preventing catheter-associated UTI
## Antibiotic prophylaxis for people with a long-term (indwelling or intermittent) catheter
One systematic review (Niël-Weise et al. 2012) found that antibiotic prophylaxis for adults using intermittent self-catheterisation was associated with fewer episodes of either asymptomatic or symptomatic bacteriuria (incidence density rate 0.61, 95% confidence interval 0.44 to 0.87, with significant heterogeneity, using a fixed-effect model; low quality evidence) compared with antibiotics only when microbiologically indicated. Another RCT (not included in the systematic review by Niël-Weise et al. 2012) also favoured antibiotic prophylaxis for a similar population (incidence rate ratio 0.34, 95% CI 0.156 to 0.74; moderate quality evidence). However, 1 additional RCT included in the systematic review found no significant benefit of antibiotic prophylaxis compared with antibiotics when microbiologically indicated for the number of episodes of bacteriuria.
Two RCTs in the systematic review (Niël-Weise et al. 2012) showed inconsistent results for antibiotic prophylaxis for symptomatic bacteriuria in adults using intermittent catheterisation compared with antibiotics when microbiologically indicated. In 1 RCT, fewer participants had at least 1 episode of symptomatic bacteriuria with antibiotic prophylaxis compared with antibiotics when microbiologically indicated (6.1% versus 31.7%, NNT 4 ; moderate quality evidence). In the other RCT, there was no significant difference in the rate of symptomatic bacteriuria between groups.
One RCT in the systematic review (Niël-Weise et al. 2012) compared antibiotic prophylaxis with antibiotics when clinically indicated in older adults in nursing homes with indwelling urinary catheters. There were no statistically significant differences between groups for episodes of symptomatic UTI, rates of visual encrustation, or catheter obstructions (very low to low quality evidence). The prophylaxis group had a higher number of participants with improved general condition (52.2% versus 4.3%, NNT 3 ; very low quality evidence).
Evidence from 2 RCTs in the systematic review (Niël-Weise et al. 2012) included children with neurogenic bladder using intermittent catheterisation and found no significant difference between antibiotic prophylaxis and antibiotics only when clinically indicated for symptomatic UTI.
Evidence from 1 RCT in the systematic review (Niël-Weise et al. 2012) included children with spina bifida using intermittent catheterisation and found no significant difference in the risk of febrile symptomatic UTI when antibiotic prophylaxis was discontinued at 6 months compared with continued prophylaxis. However, there were significantly fewer afebrile symptomatic UTIs in the group continuing antibiotic prophylaxis (IDR 0.69, 95% CI 0.55 to 0.87; low quality evidence).
The systematic review (Niël-Weise et al. 2012) found no significant difference in adverse events between antibiotic prophylaxis and antibiotics when microbiologically indicated in adults using intermittent catheterisation. There was also no significant difference between antibiotic prophylaxis and antibiotics when clinically indicated in the rates of adverse events in older people in nursing homes (low quality evidence).
One open-label RCT (Fisher et al. 2018) in adults using clean intermittent self-catheterisation who had recurrent UTIs found antibiotic prophylaxis reduced symptomatic UTIs requiring antibiotic treatment by 48% compared with no prophylaxis at 6 months' follow‑up (IRR 0.52, 95% CI 0.44 to 0.61; moderate quality evidence). Prophylaxis also reduced the incidence of microbiologically confirmed symptomatic UTI requiring antibiotic treatment at 6 months' follow‑up compared with no prophylaxis (IRR 0.49, 95% CI 0.39 to 0.6; moderate quality evidence). Prophylaxis did not reduce the incidence of febrile UTI or asymptomatic bacteriuria.
The RCT (Fisher et al. 2018) found that antibiotic prophylaxis increased adverse events, mainly nausea, diarrhoea and Candida infection, compared with no prophylaxis (9.4% versus 2.0%, number needed to harm 16 ; low quality evidence).
The RCT (Fisher et al. 2018) found that antibiotic prophylaxis increased antibiotic resistance to nitrofurantoin, trimethoprim and co‑trimoxazole compared with no prophylaxis, but not to amoxicillin, cefalexin, ciprofloxacin, co‑amoxiclav and mecillinam. There was an increasing trend towards antibiotic resistance at 12 months compared with baseline for amoxicillin, cefalexin, co‑trimoxazole and trimethoprim, but not for ciprofloxacin, co‑amoxiclav and nitrofurantoin. There was no increase in resistance over 12 months to any antibiotic in the 'no prophylaxis' group or in perianal swabs for E. coli for either the prophylaxis or 'no prophylaxis' groups.
## Antibiotic prophylaxis before or during short-term catheterisation in hospital
One systematic review (Lusardi et al. 2013) compared antibiotic prophylaxis with no prophylaxis in hospitalised adults with a short-term catheter. A meta-analysis of 3 RCTs of surgical patients showed a significant reduction in asymptomatic bacteriuria with antibiotics (8.2% versus 31.3%, NNT 5 ; moderate quality evidence). Two further RCTs of non-surgical patients could not be pooled for the outcome of asymptomatic bacteriuria because of heterogeneity. One study showed no reduction with antibiotics (low quality evidence) and the other a significant reduction with antibiotics (10% versus 53.7%, NNT 3 , moderate quality evidence). One RCT of surgical patients found significantly fewer cases of symptomatic bacteriuria with antibiotic prophylaxis (6.3% versus 31%, NNT 4 ).
The systematic review (Lusardi et al. 2013) also found that antibiotic prophylaxis was associated with a significantly lower risk of pyuria (presence of white cells in the urine) in surgical patients (7.5% versus 32.9%, NNT 4 ; moderate quality evidence) and significantly reduced febrile (high temperature) morbidity (12.5% versus 23.2%, NNT 10 ; very low quality evidence).
Evidence from 1 additional RCT (Dieter et al. 2014) found the risk of requiring antibiotic treatment for a UTI within 3 weeks of urinary catheterisation for pelvic organ prolapse or urinary incontinence surgery was not significantly associated with prophylactic use of nitrofurantoin compared with placebo (moderate quality evidence).
The systematic review (Lusardi et al. 2013) found no significant difference between levofloxacin and ciprofloxacin (very low quality evidence) or between 2 different doses of ciprofloxacin (250 mg versus 1,000 mg daily; very low quality evidence) for asymptomatic bacteriuria at follow‑up.
Evidence from 1 RCT in the systematic review (Lusardi et al. 2013) found that a single antibiotic dose at the time of catheterisation only compared with antibiotic prophylaxis throughout the entire period of catheterisation was associated with significantly fewer cases of bacteriuria (12.5% versus 42.9%, NNT 4 ; low quality evidence).
The systematic review (Lusardi et al. 2013) included 3 RCTs that reported adverse reactions to antibiotics. One RCT reported 23 adverse reactions; none were judged to be treatment related and there were no serious adverse events. A second RCT reported no serious adverse reactions to co‑trimoxazole. The third RCT reported that 3 patients taking ciprofloxacin had moderate gastrointestinal symptoms on the second day of prophylaxis and the antibiotic was discontinued (very low quality evidence).
## Antibiotic prophylaxis at the time of short-term catheter removal in hospital
Evidence from a systematic review (Marschall et al. 2013) in hospitalised patients found that antibiotic prophylaxis at the time of short-term catheter removal was associated with a significantly lower risk of symptomatic UTI at 2 to 42 days' follow‑up compared with placebo or other control intervention (4.7% versus 10.5%, NNT 18 ).
In subgroup analyses, the effect was maintained for surgical patients (4.8% versus 10.3%, risk ratio 0.45, 95% CI 0.29 to 0.59; moderate quality evidence) but not for mixed hospital populations. Additional subgroup analysis of the surgical studies found significant benefit for people undergoing prostate surgery (3.57% versus 8.18%, RR 0.41, 95% CI 0.22 to 0.79; low quality evidence) but not for those undergoing other surgery (6.1% versus 14.1%, RR 0.45, 95% CI 0.18 to 1.14; low quality evidence).
In further subgroup analyses of surgical studies without the studies of prostate surgery, there was a significant benefit of antibiotic prophylaxis with catheter duration longer than 5 days (3.8% versus 16.7%, RR 0.25, 95% CI 0.10 to 0.59; high quality evidence) but not with catheter duration less than 5 days (3.22% versus 12.3%, RR 0.41, 95% CI 0.02 to 10.96; very low quality evidence).
## Antibiotic prophylaxis during short-term catheterisation for urodynamic procedures
A systematic review (Foon et al. 2012) in people who had short-term catheterisation during urodynamic studies found that prophylactic antibiotics did not significantly reduce episodes of symptomatic UTI (low quality evidence) but did significantly reduce bacteriuria (4.1% versus 12.5%, NNT 12 ; moderate quality evidence) compared with placebo or no treatment. In a single study of people with spinal cord injury, antibiotic prophylaxis was not significantly different to placebo or no treatment for the outcome of bacteriuria (very low quality evidence). There was a significant reduction in the number of participants with haematuria with antibiotic prophylaxis (6.3% versus 13.7%, NNT 14 ; low quality evidence) but not fever or dysuria.
The systematic review (Foon et al. 2012) found no significant difference in adverse events between antibiotics and placebo (very low quality evidence).
Committee discussion on antibiotic prophylaxis for catheter-associated UTI
The committee discussed the evidence on antibiotic prophylaxis for catheter-associated UTI in various populations.
Based on evidence, their experience and resistance data, the committee agreed that antibiotic prophylaxis should not be routinely offered to people with a long-term (indwelling or intermittent) catheter.
The benefit of antibiotic prophylaxis for symptomatic bacteriuria was mixed.
The committee noted that although there was evidence of benefit (reduced rate of UTIs per year) from 1 RCT in adults who used intermittent self-catheterisation and had recurrent UTI, there was also evidence of increasing antibiotic resistance in the microorganisms found in the group taking antibiotics for prophylaxis. The committee discussed that routine antibiotic prophylaxis would be a change in practice, which is not warranted because of increasing resistance. Decisions around prophylaxis for people who self-catheterise and have recurrent UTIs may, however, be made on an individual basis, with shared decision-making and a discussion of the risks and benefits.
The committee discussed that people should be advised to seek medical help if symptoms of a UTI develop, which would be managed as an acute UTI, rather than people receiving long-term antibiotic prophylaxis.
The committee was aware of recommendations in the NICE guideline on healthcare-associated infections that antibiotic prophylaxis should not be offered routinely when changing long-term indwelling catheters, but should be considered for people with a history of symptomatic UTI after catheter change or an experience of trauma (frank haematuria after catheterisation or 2 or more attempts of catheterisation). The committee for the healthcare-associated infections guideline agreed that for these groups, the benefits of antibiotic prophylaxis outweigh the risks of antimicrobial resistance. These groups are likely to be at high risk of a UTI and at risk of complications if a UTI develops.
Based on evidence, the committee agreed not to recommend routine antibiotic prophylaxis to prevent catheter-associated UTI in people with a short-term catheter in hospital. Prophylaxis is not recommended routinely before insertion of a short-term catheter for surgical, non-surgical or urodynamic procedures, while the catheter is in place, or at the time of removal.
Before or during short-term catheterisation, there is only limited evidence of benefit with antibiotic prophylaxis for symptomatic bacteriuria in surgical patients.
During short-term catheterisation for urodynamic studies, antibiotic prophylaxis did not reduce episodes of symptomatic UTI.
At the time of catheter removal, there is evidence of benefit for antibiotic prophylaxis for symptomatic UTI, but in subgroup analysis this was limited to surgical patients, and predominantly those who had either prostate surgery or had a catheter in place for longer than 5 days. The committee discussed that antibiotic prophylaxis for all short-term catheter removal in hospital would be a change in practice, and widespread prophylaxis is not warranted taking into account the principles of antimicrobial stewardship.
# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration. See the NICE guideline on medicines adherence.
No systematic reviews or randomised controlled trials (RCTs) were identified that addressed medicines adherence.
# Resource implications
## Antibiotic prophylaxis before or during short-term catheterisation in hospital
One RCT included in a systematic review (Lusardi et al. 2013) of hospitalised adults with a short-term catheter compared antibiotic prophylaxis (levofloxacin or ciprofloxacin) with placebo calculated hospital stay in presurgery and postsurgery phases. There was no statistically significant difference in mean presurgical or postsurgical stay between the placebo group and either the levofloxacin or ciprofloxacin groups (low quality evidence).
In a second included RCT comparing antibiotic prophylaxis with placebo, the mean hospital stay was significantly higher in the placebo group compared with the intervention group (8 days compared with 7 days , p=0.0002; low quality evidence). Febrile morbidity and urinary tract infection (UTI) prolonged hospitalisation significantly to a mean stay of 9.2 days (, p<0.05).
In a third included RCT comparing antibiotic prophylaxis with placebo, the average hospital stay was 6 days and 5.6 days for abdominal hysterectomy, and 6.1 days and 7.6 days for vaginal hysterectomy patients, in the prophylaxis group and placebo groups respectively.
Recommended antibiotics (nitrofurantoin, trimethoprim, penicillins, cephalosporins, fluoroquinolones and aminoglycosides) are available as generic formulations, see Drug Tariff for costs.
|
{'Recommendations': "# Managing catheter-associated urinary tract infection\n\nBe aware that:\n\na catheter-associated urinary tract infection (UTI) is a symptomatic infection of the bladder or kidneys in a person with a urinary catheter\n\nthe longer a catheter is in place, the more likely bacteria will be found in the urine; after 1\xa0month nearly all people have bacteriuria\n\nantibiotic treatment is not routinely needed for asymptomatic bacteriuria in people with a catheter.\n\nGive advice about managing symptoms with self-care (see the recommendations on self-care) to all people with catheter-associated UTI.\n\n## Treatment\n\nConsider removing or, if this cannot be done, changing the catheter as soon as possible in people with a catheter-associated UTI if it has been in place for more than 7\xa0days. Do not allow catheter removal or change to delay antibiotic treatment.\n\nObtain a urine sample before antibiotics are taken. Take the sample from the catheter, via a sampling port if provided, and use an aseptic technique (in line with the NICE guideline on healthcare-associated infections).\n\nIf the catheter has been changed, obtain the sample from the new catheter.\n\nIf the catheter has been removed, obtain a midstream specimen of urine.\n\nSend the urine sample for culture and susceptibility testing, noting a suspected catheter-associated infection and any antibiotic prescribed.\n\nOffer an antibiotic (see the recommendations on choice of antibiotic) to people with catheter-associated UTI. Take account of:\n\nthe severity of symptoms\n\nthe risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract, or immunosuppression\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nWhen urine culture and susceptibility results are available:\n\nreview the choice of antibiotic and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant, using narrow-spectrum antibiotics wherever possible.\n\n## Advice when an antibiotic prescription is given\n\nWhen an antibiotic is given, as well as the general advice on self-care, give advice about:\n\npossible adverse effects of antibiotics, particularly diarrhoea and nausea\n\nseeking medical help if:\n\n\n\nsymptoms worsen at any time or\n\nsymptoms do not start to improve within 48\xa0hours of taking the antibiotic or\n\nthe person becomes systemically very unwell.\n\n\n\n## Reassessment\n\nReassess people with catheter-associated UTI if symptoms worsen at any time, or do not start to improve within 48\xa0hours of taking the antibiotic, taking account of:\n\nother possible diagnoses\n\nany symptoms or signs suggesting a more serious illness or condition, such as sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\n## Referral and seeking specialist advice\n\nRefer people with catheter-associated UTI to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).\n\nConsider referring or seeking specialist advice for people with catheter-associated UTI if they:\n\nare significantly dehydrated or unable to take oral fluids and medicines or\n\nare pregnant or\n\nhave a higher risk of developing complications (for example, people with known or suspected structural or functional abnormality of the genitourinary tract, or underlying disease [such as diabetes or immunosuppression]) or\n\nhave recurrent catheter-associated UTIs or\n\nhave bacteria that are resistant to oral antibiotics.\n\nSee the evidence and committee discussion on antibiotics for managing catheter-associated UTI.\n\n# Self-care\n\nAdvise people with catheter-associated UTI about using paracetamol for pain.\n\nAdvise people with catheter-associated UTI about drinking enough fluids to avoid dehydration.\n\nSee the evidence and committee discussion on self-care.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for catheter-associated UTI, take account of local antimicrobial resistance data and:\n\nfollow table\xa01 for non-pregnant women and men aged 16\xa0years and over\n\nfollow table\xa02 for pregnant women aged 12\xa0years and over\n\nfollow table\xa03 for children and young people under 16\xa0years.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\n## Table\xa01 Antibiotics for non-pregnant women and men aged 16\xa0years and over\n\nAntibiotic\n \n 1\n\nDosage and course length\n\nFirst-choice\n oral antibiotics if no upper UTI symptoms\n \n 2\n\nNitrofurantoin – if eGFR ≥45\xa0ml/minute3,4\n\nmg modified-release twice a day (or if unavailable 50\xa0mg four times a day) for 7\xa0days\n\nTrimethoprim – if low risk of resistance5\n\nmg twice a day for 7\xa0days\n\nAmoxicillin (only if culture results available and susceptible)\n\nmg three times a day for 7\xa0days\n\nSecond-choice oral antibiotic if no upper UTI symptoms (when first-choice not suitable)\n \n 2\n\nPivmecillinam (a penicillin)4\n\nmg initial dose, then 200\xa0mg three times a day for a total of 7\xa0days\n\nFirst-choice oral antibiotics if upper UTI symptoms\n \n 2\n\nCefalexin\n\nmg twice or three times a day (up to 1\xa0to 1.5\xa0g three or four times a day for severe infections) for 7\xa0to 10\xa0days\n\nCo-amoxiclav (only if culture results available and susceptible)\n\n/125\xa0mg three times a day for 7\xa0to 10\xa0days\n\nTrimethoprim (only if culture results available and susceptible)\n\nmg twice a day for 14\xa0days\n\nCiprofloxacin (consider safety issues6)\n\nmg twice a day for 7\xa0days\n\nFirst-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern\n \n 2,7\n\nCo-amoxiclav (only in combination, unless culture results confirm susceptibility)\n\ng three times a day\n\nCefuroxime\n\nmg to 1.5\xa0g three or four times a day\n\nCeftriaxone\n\nto 2\xa0g once a day\n\nCiprofloxacin (consider safety issues6)\n\nmg twice or three times a day\n\nGentamicin\n\nInitially 5\xa0to 7\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration8\n\nAmikacin\n\nInitially 15\xa0mg/kg once a day (maximum per dose 1.5\xa0g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15\xa0g per course)8\n\nSecond-choice intravenous antibiotics\n\nConsult local microbiologist\n\nSee BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment and breastfeeding, and administering intravenous antibiotics.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing, and choose antibiotics accordingly.\n\nMay be used with caution if eGFR 30–44\xa0ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August\xa02018).\n\nNitrofurantoin and pivmecillinam are only licensed for uncomplicated lower UTIs, and are not suitable for people with upper UTI symptoms or a blocked catheter.\n\nA lower risk of resistance is likely if not used in the past 3\xa0months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance is likely with recent use and in older people in care homes.\n\nSee MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF, August\xa02018).\n\nAbbreviations: BNF, British national formulary; eGFR, estimated glomerular filtration rate; UTI, urinary tract infection.\n\n## Table\xa02 Antibiotics for pregnant women aged 12\xa0years and over\n\nAntibiotic\n \n 1\n\nDose and course length\n\nFirst-choice oral antibiotic\n \n 2\n\nCefalexin\n\nmg twice or three times a day (up to 1\xa0to 1.5\xa0g three or four times a day for severe infections) for 7\xa0to 10\xa0days\n\nFirst-choice intravenous antibiotic (if vomiting, unable to take oral antibiotics, or severely unwell)\n \n 2,3\n\nCefuroxime\n\nmg to 1.5\xa0g three or four times a day\n\nSecond-choice antibiotics or combining antibiotics if susceptibility or sepsis a concern\n\nConsult local microbiologist\n\nSee BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\n## Table\xa03 Antibiotics for children and young people under 16\xa0years\n\nAntibiotic\n \n 1\n\nDosage and course length\n \n 2\n\nChildren under 3\xa0months\n\nRefer to paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under\xa05s.\n\nChildren aged 3\xa0months and over\n\nFirst-choice oral antibiotics\n \n 3\n\nTrimethoprim – if low risk of resistance4\n\nto 5\xa0months, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 25\xa0mg twice a day for 7\xa0to 10\xa0days\n\nmonths to 5\xa0years, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 50\xa0mg twice a day for 7\xa0to 10\xa0days\n\nto 11\xa0years, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 100\xa0mg twice a day for 7\xa0to 10\xa0days\n\nto 15\xa0years, 200\xa0mg twice a day for 7\xa0to 10\xa0days\n\nAmoxicillin (only if culture results available and susceptible)\n\nto 11\xa0months, 125\xa0mg three times a day for 7\xa0to 10\xa0days\n\nto 4\xa0years, 250\xa0mg three times a day for 7\xa0to 10\xa0days\n\nto 15\xa0years, 500\xa0mg three times a day for 7\xa0to 10\xa0days\n\nCefalexin\n\nto 11\xa0months, 12.5\xa0mg/kg or 125\xa0mg twice a day for 7\xa0to 10\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nto 4\xa0years, 12.5\xa0mg/kg twice a day or 125\xa0mg three times a day for 7\xa0to 10\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nto 11\xa0years, 12.5\xa0mg/kg twice a day or 250\xa0mg three times a day for 7\xa0to 10\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nto 15\xa0years, 500\xa0mg twice or three times a day (up to 1\xa0to 1.5\xa0g three or four times a day for severe infections) for 7\xa0to 10\xa0days\n\nCo-amoxiclav (only if culture results available and susceptible)\n\nto 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day for 7\xa0to 10\xa0days (dose doubled in severe infection)\n\nto 5\xa0years, 0.25\xa0ml/kg of 125/31 suspension or 5\xa0ml of 125/31 suspension three times a day for 7\xa0to 10\xa0days (dose doubled in severe infection)\n\nto 11\xa0years, 0.15\xa0ml/kg of 250/62 suspension or 5\xa0ml of 250/62 suspension three times a day for 7\xa0to 10\xa0days (dose doubled in severe infection)\n\nto 15\xa0years, 250/125\xa0mg or 500/125\xa0mg three times a day for 7\xa0to 10\xa0days\n\nFirst-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern\n \n 3,5,6\n\nCo-amoxiclav (only in combination unless culture results confirm susceptibility)\n\nmonths to 15\xa0years, 30\xa0mg/kg three times a day (maximum 1.2\xa0g three times a day)\n\nCefuroxime\n\nmonths to 15\xa0years, 20\xa0mg/kg three times a day (maximum 750\xa0mg per dose); (50\xa0to 60\xa0mg/kg three or four times a day [maximum 1.5\xa0g per dose] for severe infections)\n\nCeftriaxone\n\nmonths to 11\xa0years (up to 50\xa0kg), 50\xa0to 80\xa0mg/kg once a day (maximum 4\xa0g per day)\n\nto 11\xa0years (50\xa0kg and above), 1\xa0to 2\xa0g once a day\n\nto 15\xa0years, 1\xa0to 2\xa0g once a day\n\nGentamicin\n\nInitially 7\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration7\n\nAmikacin\n\nInitially 15\xa0mg/kg once a day, subsequent doses adjusted according to serum amikacin concentration7\n\nSecond-choice intravenous antibiotic\n\nConsult local microbiologist\n\nSee BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics. See table\xa02 if a young woman is pregnant.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly. If a child or young person is receiving prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.\n\nA lower risk of resistance is likely if not used in the past 3\xa0months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance is likely with recent use.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible for a total antibiotic course of 10\xa0days.\n\nIf intravenous treatment is not possible, consider intramuscular treatment if suitable.\n\nTherapeutic drug monitoring and assessment of renal function is required (BNFC, August\xa02018).\n\nSee the evidence and committee discussion on antibiotics for managing catheter-associated UTI.\n\n# Preventing catheter-associated urinary tract infections\n\nDo not routinely offer antibiotic prophylaxis to prevent catheter-associated UTIs in people with a short-term or a long-term (indwelling or intermittent) catheter.\n\nGive advice about seeking medical help if symptoms of an acute UTI develop.\n\nSee the evidence and committee discussion on antibiotic prophylaxis for preventing catheter-associated UTI and the NICE guideline on healthcare-associated infections.\n\n See the NICE guideline on lower UTI: antimicrobial prescribing for managing asymptomatic bacteriuria in pregnant women.", 'Terms used in this guideline': "# Asymptomatic bacteriuria\n\nThe presence of significant levels of bacteria in the urine with no symptoms of urinary tract infection (UTI).\n\n# Catheter-associated urinary tract infection\n\nCatheter-associated UTI is defined as the presence of symptoms or signs compatible with a UTI in people with a catheter with no other identified source of infection plus significant levels of bacteria in a catheter or a midstream urine specimen when the catheter has been removed within the previous 48\xa0hours (adapted from Infectious Diseases Society of America's guideline on catheter-associated UTI ).", 'Summary of the evidence': "# Self-care\n\nOne randomised controlled trial (RCT; Gunnarsson et al. 2017) in adult females (n=92) who had a hip fracture and a perioperative urinary catheter with planned removal at 48\xa0hours, compared cranberry juice concentrate (capsules) with placebo for the prevention of postoperative urinary tract infection (UTI). There were no significant differences in positive urine cultures (>104 colony-forming units per ml) at either 5\xa0or 14\xa0days after surgery (low quality evidence).\n\nNo systematic reviews or RCTs of any other non-antimicrobial treatments were identified that met the inclusion criteria.\n\nCommittee discussion on self-care\n\nThere was no evidence for the use of oral analgesia in catheter-associated-UTI. However, paracetamol has a well-established efficacy and safety profile for managing pain. The committee agreed that it was reasonable to consider paracetamol for managing pain in people with a catheter-associated UTI.\n\nBased on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.\n\nThe committee agreed that the evidence for use of cranberry in preventing catheter-associated UTI (which showed no effect) was limited to a specific population in the immediate postoperative period, and could not be extrapolated to other populations or settings. The committee was, therefore, unable to make a recommendation on its use.\n\n# Antibiotics for managing catheter-associated UTI\n\nIn most cases, managing symptomatic catheter-associated UTI will require antibiotics.\n\nGram-negative bacteria, particularly Escherichia coli (E.\xa0coli), are the most common causative pathogens in UTIs. However, catheter-associated UTI can be associated with more than 1\xa0bacterial species and is often caused by bacteria that are resistant to antibiotics (European Association of Urology guidelines on urological infections\xa02017).\n\nUTI is the most common healthcare-acquired infection, accounting for 19% of all healthcare-associated infections, with around half of these infections due to an indwelling urinary catheter (Health Protection Agency\xa02012). In some people, catheter-associated UTI can lead to a more serious systemic infection (urosepsis).\n\n## Efficacy of antibiotics\n\nOne RCT (Leone et al. 2007) of adults with asymptomatic bacteriuria admitted to an intensive care unit with a short-term catheter found that a short course (3\xa0days) of antibiotics and catheter change did not significantly reduce the proportion of patients with urosepsis (p=1, low quality evidence), or bacteraemia or severe sepsis (p>0.05, low quality evidence), compared with no antibiotics and no catheter change. Short-course antibiotics and catheter change significantly reduced the proportion of positive urine cultures (>105 colony-forming units/ml) at 7\xa0days (30% versus 70%, number needed to treat [NNT]\xa03 [range 2\xa0to\xa06], moderate quality evidence) but not at 15\xa0days (very low quality evidence).\n\nOne RCT (Darouiche et al. 2014) of hospitalised adults with a long-term catheter for spinal cord injury and catheter-associated UTI found that a shorter course (5\xa0days) of antibiotics plus a catheter change was not significantly different to 10\xa0days of antibiotics and no catheter change for clinical cure at the end of therapy (p<0.001 for non-inferiority, moderate quality evidence). However, for other outcomes (microbiological response and resolution of pyuria at the end of therapy), the short course and catheter change was not as effective as the long course and no catheter change. There were also significantly more episodes of recurrent UTI in the short course plus catheter change group compared with the long course and no catheter change group (32.1% versus 11.1%, p=0.043; low quality evidence).\n\n## Changing the catheter before antibiotics\n\nOne prospective open-label RCT (Raz et al. 2000) in older adults in a long-stay care facility with a long-term catheter and catheter-associated UTI compared catheter change before antibiotics with no catheter change before antibiotics. Antibiotic therapy was ciprofloxacin or ofloxacin, initially intravenously then orally for 14\xa0days. There was a significant difference in cure or improvement, favouring catheter change at 72\xa0hours (92.6% versus 40.7%, NNT\xa02 [range 2\xa0to\xa04]; moderate quality evidence) and 28\xa0days (88.9% versus 59.3%, NNT\xa04 [range 2\xa0to\xa014]; low quality evidence), but not at 7\xa0days. There was no significant difference in recurrence or treatment failure at either 7\xa0or 28\xa0days, but mortality was significantly lower in the catheter change group (0% versus 7.4% [urosepsis in 1\xa0person on day\xa02 and 1\xa0person on day\xa03]; very low quality evidence).\n\n## Safety of antibiotics\n\nThe RCT on duration of antibiotics (and catheter change) for people with spinal cord injury and catheter-associated UTI (Darouiche et al. 2014) found no significant difference in adverse events between the no catheter change and 10\xa0days of antibiotics group, and the catheter change and 5\xa0days of antibiotics group (40.7% versus 64.3%%; low quality evidence).\n\nAntibiotic-associated diarrhoea occurs in 2\xa0to\xa025% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August\xa02018).\n\nNitrofurantoin should be used with caution in those with renal impairment. It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should be monitored for liver function and pulmonary symptoms (BNF, August\xa02018).\n\nTrimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF, August 2018). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).\n\nFluoroquinolones are generally not recommended in children or young people who are still growing (BNF, August 2018). The manufacturers advise to avoid in pregnancy (ciprofloxacin summary of product characteristics). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (press release October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain an option in catheter-associated UTI with upper UTI symptoms, which is a severe infection.\n\nAminoglycosides doses are based on weight and renal function and whenever possible treatment should not exceed 7\xa0days (BNF, August\xa02018).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nCommittee discussion on antibiotics for managing catheter-associated UTI\n\nBased on evidence and experience, the committee agreed that people with a symptomatic catheter-associated UTI should be offered an antibiotic.\n\nUrine should be sent for culture to confirm susceptibility of the bacteria and inform treatment decisions. The committee discussed and agreed that a comment should be added to the microbiology request form to alert the laboratory to a suspected catheter-associated infection and the name of any antibiotic prescribed.\n\nThe committee agreed that the evidence for antibiotic treatment for catheter-associated UTI specifically was limited, but that evidence for antibiotic treatment for acute pyelonephritis could be extrapolated. The evidence for acute pyelonephritis included some people with complicated UTI, some of whom had a catheter (see the NICE guideline on acute pyelonephritis: antimicrobial prescribing).\n\nLimited evidence suggested that catheters should be removed or changed before antibiotics are given, but the committee discussed safety concerns with this approach and practical considerations about possible delays in primary care settings. They agreed that catheter removal or change should not delay treatment with antibiotics. The longer a catheter is in place, the more likely bacteria will be found in the urine, and the committee agreed that catheters should be removed rather than changed, where possible. Changing the catheter is based on evidence from 1\xa0small RCT, which found higher cure or improvement rates and reduced mortality (from urosepsis) when the catheter was changed before starting antibiotics. The committee based when to remove or change the catheter (after 7\xa0days) on their experience.\n\nBased on evidence and experience, the committee agreed that screening and antibiotic treatment for asymptomatic bacteriuria is not routine in people with a catheter because it is not generally a risk factor for harm. Pregnant women (including those with a catheter) have routine screening and antibiotic treatment for asymptomatic bacteriuria because it is a risk factor for pyelonephritis and preterm labour.\n\nCommittee discussion on choice of antibiotic\n\nThe committee agreed, based on evidence, experience and resistance data, that several oral and intravenous antibiotics should be available for people with a catheter-associated UTI. Having a choice enables antibiotics to be selected based on the severity of illness, presence or absence of upper UTI symptoms, antibiotic susceptibilities from culture results when available, local resistance patterns, risk of resistant bacteria, setting and known patient factors. In line with antimicrobial stewardship, narrower-spectrum antibiotics should be used wherever possible.\n\nNationally for England, resistance of E. coli (the main causative organism of UTIs) in laboratory-processed urine specimens to the following antibiotics is:\n\n\n\nnitrofurantoin: 2.5% (varies by area from 2.0 to 3.6%)\n\ntrimethoprim: 30.3% (varies by area from 27.1 to 33.4%)\n\npivmecillinam: 7.5% (varies by area from 4.1 to 15.7%)\n\ncefalexin: 9.9% (varies by area from 8.1 to 11.4%)\n\nciprofloxacin: 10.6% (varies by area from 7.8 to 13.7%)\n\nco-amoxiclav: 19.8% (varies by area from 10.8 to 30.7%).(Public Health England. Antimicrobial resistance quarterly surveillance: March\xa02018)\n\n\n\nThe committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.\n\nThe committee agreed that any recent previous urine culture and susceptibility results, and antibiotic prescribing, should be reviewed before choosing an antibiotic.\n\nBased on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, the antibiotic should be changed, using a narrow-spectrum antibiotic where possible.\n\nNon-pregnant women and men with catheter-associated UTI\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend nitrofurantoin, trimethoprim or amoxicillin at usual doses as first-choice oral antibiotics for adults with a catheter-associated UTI but no upper UTI symptoms.\n\n\n\nNitrofurantoin is not recommended for people with an eGFR <45\xa0ml/minute. It may be used with caution if eGFR is 30\xa0to 44\xa0ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug-resistant bacteria, and only if the potential benefit outweighs risk (BNF, August 2018). The committee noted that nitrofurantoin is only licensed for uncomplicated lower UTI. However, they agreed that for adults with a catheter-associated UTI without upper UTI symptoms, nitrofurantoin is an option (unless they have a blocked catheter, where Proteus mirabilis could be the causative organism). Based on experience, the committee felt it was important to offer 'lower UTI' antibiotics as an option for adults with catheter-associated UTI without upper UTI symptoms, otherwise all adults with a catheter-associated UTI would need to be offered a broader-spectrum 'upper UTI' antibiotic, where their symptoms may not warrant this.\n\nThe committee agreed to recommend either the modified-release preparation of nitrofurantoin or the immediate-release preparation. However, because of its twice-daily dosing and, in their experience, better tolerability the committee was keen to point out that the modified-release preparation was preferred unless it was unavailable. The committee also discussed that, in their experience, immediate-release preparations containing nitrofurantoin in a macrocrystalline form may be better tolerated than those containing nitrofurantoin in a microcrystalline form.\n\nTrimethoprim has high resistance levels nationally and should only be prescribed if a lower risk of resistance is thought to be likely. A lower risk of resistance is likely if trimethoprim has not been used in the past 3\xa0months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger people in areas where local epidemiology data suggest resistance is lower. There is a higher risk of trimethoprim resistance with recent use and in older people in care homes.\n\nAmoxicillin is recommended only if culture results are available and bacteria are susceptible because resistance rates are high.\n\n\n\nIf nitrofurantoin, trimethoprim or amoxicillin are not suitable, the second-choice oral antibiotic for adults with a catheter-associated UTI but no upper UTI symptoms is pivmecillinam (a penicillin) at its usual dose. The committee acknowledged that prescribers may be less familiar with this antibiotic, but it is often used in other European countries. The committee noted that pivmecillinam is only licensed for uncomplicated lower UTI. However, as with nitrofurantoin, they agreed that for adults with a catheter-associated UTI without upper UTI symptoms, 'lower UTI' antibiotics are an option.\n\nFor adults with upper UTI symptoms, nitrofurantoin, amoxicillin and pivmecillinam are not appropriate, and cefalexin (a first-generation cephalosporin), co‑amoxiclav (a penicillin with a beta‑lactamase inhibitor), trimethoprim or ciprofloxacin (a fluoroquinolone), at usual doses, are recommended to cover a broader range of bacterial pathogens. Co‑amoxiclav and trimethoprim are only suitable if culture results are available and bacteria are susceptible, because resistance rates are high.\n\nThe committee noted that use of broad-spectrum antibiotics, such as later-generation cephalosporins, fluoroquinolones or co‑amoxiclav, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. By disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of catheter-associated UTI with upper UTI symptoms, where coverage of more resistant strains of common bacterial pathogens is required.\n\nThe committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects, mainly involving muscles, tendons and bones, and the nervous system. However, they discussed that fluoroquinolone antibiotics are a valuable option for the treatment of catheter-associated UTI with upper UTI symptoms, which is a severe infection, and it is appropriate to reserve fluoroquinolone use for such conditions. Resistant gram-negative organisms are a particular concern in catheter-associated UTI with upper UTI symptoms, and the committee agreed that ciprofloxacin should remain a first-choice option to cover what can be a complex infection. The committee was keen to point out, however, that cefalexin, co‑amoxiclav and trimethoprim are also first-choice options, and antibiotics should be chosen on an individual patient basis, taking fluoroquinolone safety concerns, as well as susceptibility and resistance, into account.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for adults who are unable to take oral antibiotics because of nausea and vomiting, or are more severely unwell. These are:\n\n\n\nco-amoxiclav (only in combination unless culture results confirm bacteria are susceptible)\n\ncefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)\n\nciprofloxacin (taking safety concerns into account)\n\ngentamicin or amikacin (aminoglycosides); which may be appropriate for some people with catheter-associated UTI, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed by 48\xa0hours. Gentamicin is the preferred aminoglycoside in the UK, but shortages of certain antibiotics may result in the use of alternatives; for example, amikacin in place of gentamicin.\n\n\n\nThe committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.\n\nPregnant women with catheter-associated UTI\n\nBased on evidence, experience and resistance data, the committee agreed to recommend cefalexin (a first-generation cephalosporin) as the first-choice oral antibiotic for pregnant women who don't need intravenous antibiotics, and cefuroxime (a second-generation cephalosporin) as the first-choice intravenous antibiotic.\n\nCiprofloxacin and trimethoprim are not recommended because they should be avoided in pregnancy. Co‑amoxiclav was not recommended because of high resistance levels nationally and the risks of treatment failure in pregnancy.\n\nThe committee agreed, based on experience, that local microbiologists should be consulted for advice on second-choice antibiotics, or combining antibiotics, if susceptibility or sepsis is a concern.\n\nChildren and young people with catheter-associated UTI\n\nBased on evidence, experience and resistance data, the committee agreed to recommend trimethoprim (if low risk of resistance), amoxicillin (only if culture results are available and bacteria are susceptible), cefalexin or co‑amoxiclav (only if culture results are available and bacteria are susceptible) at usual doses as first-choice oral antibiotics for children and young people with catheter-associated UTI.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics at usual doses for children and young people who are unable to take oral antibiotics because of nausea and vomiting, or are more severely unwell. These are:\n\n\n\nco-amoxiclav (only in combination unless culture results confirm bacteria are susceptible); which can be given intravenously\n\ncefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)\n\ngentamicin or amikacin (aminoglycosides); which may be appropriate for some children and young people with upper UTI symptoms, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48\xa0hours.\n\n\n\nThe committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of children and young people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.\n\nCommittee discussions on antibiotic course length\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that the use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.\n\nCourse length for non-pregnant women, pregnant women, men, children and young people with catheter-associated UTI\n\nBased on evidence, experience and resistance data, the committee agreed that, for oral treatment, at least a 7‑day course of all the recommended antibiotics was needed to treat catheter-associated UTI to ensure complete cure. This is because people with a catheter are more at risk of complications from a UTI. For adults with a catheter-associated UTI and upper UTI symptoms, pregnant women, and children and young people, course lengths are the same as those for acute pyelonephritis (see the NICE guideline on acute pyelonephritis: antimicrobial prescribing).\n\nFor intravenous treatment, antibiotics should be reviewed by 48\xa0hours and stepped down to oral antibiotics where possible.\n\n# Antibiotic prophylaxis for preventing catheter-associated UTI\n\n## Antibiotic prophylaxis for people with a long-term (indwelling or intermittent) catheter\n\nOne systematic review (Niël-Weise et al. 2012) found that antibiotic prophylaxis for adults using intermittent self-catheterisation was associated with fewer episodes of either asymptomatic or symptomatic bacteriuria (incidence density rate [IDR] 0.61, 95% confidence interval [CI] 0.44 to 0.87, with significant heterogeneity, using a fixed-effect model; low quality evidence) compared with antibiotics only when microbiologically indicated. Another RCT (not included in the systematic review by Niël-Weise et al. 2012) also favoured antibiotic prophylaxis for a similar population (incidence rate ratio [IRR] 0.34, 95% CI 0.156 to 0.74; moderate quality evidence). However, 1\xa0additional RCT included in the systematic review found no significant benefit of antibiotic prophylaxis compared with antibiotics when microbiologically indicated for the number of episodes of bacteriuria.\n\nTwo RCTs in the systematic review (Niël-Weise et al. 2012) showed inconsistent results for antibiotic prophylaxis for symptomatic bacteriuria in adults using intermittent catheterisation compared with antibiotics when microbiologically indicated. In 1\xa0RCT, fewer participants had at least 1\xa0episode of symptomatic bacteriuria with antibiotic prophylaxis compared with antibiotics when microbiologically indicated (6.1% versus 31.7%, NNT\xa04 [range 3\xa0to\xa08]; moderate quality evidence). In the other RCT, there was no significant difference in the rate of symptomatic bacteriuria between groups.\n\nOne RCT in the systematic review (Niël-Weise et al. 2012) compared antibiotic prophylaxis with antibiotics when clinically indicated in older adults in nursing homes with indwelling urinary catheters. There were no statistically significant differences between groups for episodes of symptomatic UTI, rates of visual encrustation, or catheter obstructions (very low to low quality evidence). The prophylaxis group had a higher number of participants with improved general condition (52.2% versus 4.3%, NNT\xa03 [range 2\xa0to\xa04]; very low quality evidence).\n\nEvidence from 2\xa0RCTs in the systematic review (Niël-Weise et al. 2012) included children with neurogenic bladder using intermittent catheterisation and found no significant difference between antibiotic prophylaxis and antibiotics only when clinically indicated for symptomatic UTI.\n\nEvidence from 1\xa0RCT in the systematic review (Niël-Weise et al. 2012) included children with spina bifida using intermittent catheterisation and found no significant difference in the risk of febrile symptomatic UTI when antibiotic prophylaxis was discontinued at 6\xa0months compared with continued prophylaxis. However, there were significantly fewer afebrile symptomatic UTIs in the group continuing antibiotic prophylaxis (IDR 0.69, 95% CI 0.55 to 0.87; low quality evidence).\n\nThe systematic review (Niël-Weise et al. 2012) found no significant difference in adverse events between antibiotic prophylaxis and antibiotics when microbiologically indicated in adults using intermittent catheterisation. There was also no significant difference between antibiotic prophylaxis and antibiotics when clinically indicated in the rates of adverse events in older people in nursing homes (low quality evidence).\n\nOne open-label RCT (Fisher et al. 2018) in adults using clean intermittent self-catheterisation who had recurrent UTIs found antibiotic prophylaxis reduced symptomatic UTIs requiring antibiotic treatment by 48% compared with no prophylaxis at 6\xa0months' follow‑up (IRR 0.52, 95% CI 0.44 to 0.61; moderate quality evidence). Prophylaxis also reduced the incidence of microbiologically confirmed symptomatic UTI requiring antibiotic treatment at 6\xa0months' follow‑up compared with no prophylaxis (IRR 0.49, 95% CI 0.39 to 0.6; moderate quality evidence). Prophylaxis did not reduce the incidence of febrile UTI or asymptomatic bacteriuria.\n\nThe RCT (Fisher et al. 2018) found that antibiotic prophylaxis increased adverse events, mainly nausea, diarrhoea and Candida infection, compared with no prophylaxis (9.4% versus 2.0%, number needed to harm\xa016 [95% CI 9 to 40]; low quality evidence).\n\nThe RCT (Fisher et al. 2018) found that antibiotic prophylaxis increased antibiotic resistance to nitrofurantoin, trimethoprim and co‑trimoxazole compared with no prophylaxis, but not to amoxicillin, cefalexin, ciprofloxacin, co‑amoxiclav and mecillinam. There was an increasing trend towards antibiotic resistance at 12\xa0months compared with baseline for amoxicillin, cefalexin, co‑trimoxazole and trimethoprim, but not for ciprofloxacin, co‑amoxiclav and nitrofurantoin. There was no increase in resistance over 12\xa0months to any antibiotic in the 'no prophylaxis' group or in perianal swabs for E. coli for either the prophylaxis or 'no prophylaxis' groups.\n\n## Antibiotic prophylaxis before or during short-term catheterisation in hospital\n\nOne systematic review (Lusardi et al. 2013) compared antibiotic prophylaxis with no prophylaxis in hospitalised adults with a short-term catheter. A meta-analysis of 3\xa0RCTs of surgical patients showed a significant reduction in asymptomatic bacteriuria with antibiotics (8.2% versus 31.3%, NNT\xa05 [range 4\xa0to\xa07]; moderate quality evidence). Two further RCTs of non-surgical patients could not be pooled for the outcome of asymptomatic bacteriuria because of heterogeneity. One study showed no reduction with antibiotics (low quality evidence) and the other a significant reduction with antibiotics (10% versus 53.7%, NNT\xa03 [range 2\xa0to\xa04], moderate quality evidence). One RCT of surgical patients found significantly fewer cases of symptomatic bacteriuria with antibiotic prophylaxis (6.3% versus 31%, NNT\xa04 [range 3\xa0to\xa011]).\n\nThe systematic review (Lusardi et al. 2013) also found that antibiotic prophylaxis was associated with a significantly lower risk of pyuria (presence of white cells in the urine) in surgical patients (7.5% versus 32.9%, NNT\xa04 [range 3\xa0to\xa07]; moderate quality evidence) and significantly reduced febrile (high temperature) morbidity (12.5% versus 23.2%, NNT\xa010 [range 6\xa0to\xa052]; very low quality evidence).\n\nEvidence from 1\xa0additional RCT (Dieter et al. 2014) found the risk of requiring antibiotic treatment for a UTI within 3\xa0weeks of urinary catheterisation for pelvic organ prolapse or urinary incontinence surgery was not significantly associated with prophylactic use of nitrofurantoin compared with placebo (moderate quality evidence).\n\nThe systematic review (Lusardi et al. 2013) found no significant difference between levofloxacin and ciprofloxacin (very low quality evidence) or between 2\xa0different doses of ciprofloxacin (250\xa0mg versus 1,000\xa0mg daily; very low quality evidence) for asymptomatic bacteriuria at follow‑up.\n\nEvidence from 1\xa0RCT in the systematic review (Lusardi et al. 2013) found that a single antibiotic dose at the time of catheterisation only compared with antibiotic prophylaxis throughout the entire period of catheterisation was associated with significantly fewer cases of bacteriuria (12.5% versus 42.9%, NNT\xa04 [range 2\xa0to\xa013]; low quality evidence).\n\nThe systematic review (Lusardi et al. 2013) included 3\xa0RCTs that reported adverse reactions to antibiotics. One RCT reported 23\xa0adverse reactions; none were judged to be treatment related and there were no serious adverse events. A second RCT reported no serious adverse reactions to co‑trimoxazole. The third RCT reported that 3\xa0patients taking ciprofloxacin had moderate gastrointestinal symptoms on the second day of prophylaxis and the antibiotic was discontinued (very low quality evidence).\n\n## Antibiotic prophylaxis at the time of short-term catheter removal in hospital\n\nEvidence from a systematic review (Marschall et al. 2013) in hospitalised patients found that antibiotic prophylaxis at the time of short-term catheter removal was associated with a significantly lower risk of symptomatic UTI at 2\xa0to\xa042\xa0days' follow‑up compared with placebo or other control intervention (4.7% versus 10.5%, NNT\xa018 [range 12\xa0to\xa031]).\n\nIn subgroup analyses, the effect was maintained for surgical patients (4.8% versus 10.3%, risk ratio [RR] 0.45, 95% CI 0.29 to 0.59; moderate quality evidence) but not for mixed hospital populations. Additional subgroup analysis of the surgical studies found significant benefit for people undergoing prostate surgery (3.57% versus 8.18%, RR 0.41, 95% CI 0.22 to 0.79; low quality evidence) but not for those undergoing other surgery (6.1% versus 14.1%, RR 0.45, 95% CI 0.18 to 1.14; low quality evidence).\n\nIn further subgroup analyses of surgical studies without the studies of prostate surgery, there was a significant benefit of antibiotic prophylaxis with catheter duration longer than 5\xa0days (3.8% versus 16.7%, RR 0.25, 95% CI 0.10 to 0.59; high quality evidence) but not with catheter duration less than 5\xa0days (3.22% versus 12.3%, RR 0.41, 95% CI 0.02 to 10.96; very low quality evidence).\n\n## Antibiotic prophylaxis during short-term catheterisation for urodynamic procedures\n\nA systematic review (Foon et al. 2012) in people who had short-term catheterisation during urodynamic studies found that prophylactic antibiotics did not significantly reduce episodes of symptomatic UTI (low quality evidence) but did significantly reduce bacteriuria (4.1% versus 12.5%, NNT\xa012 [range 9\xa0to\xa021]; moderate quality evidence) compared with placebo or no treatment. In a single study of people with spinal cord injury, antibiotic prophylaxis was not significantly different to placebo or no treatment for the outcome of bacteriuria (very low quality evidence). There was a significant reduction in the number of participants with haematuria with antibiotic prophylaxis (6.3% versus 13.7%, NNT\xa014 [range 8\xa0to\xa089]; low quality evidence) but not fever or dysuria.\n\nThe systematic review (Foon et al. 2012) found no significant difference in adverse events between antibiotics and placebo (very low quality evidence).\n\nCommittee discussion on antibiotic prophylaxis for catheter-associated UTI\n\nThe committee discussed the evidence on antibiotic prophylaxis for catheter-associated UTI in various populations.\n\nBased on evidence, their experience and resistance data, the committee agreed that antibiotic prophylaxis should not be routinely offered to people with a long-term (indwelling or intermittent) catheter.\n\n\n\nThe benefit of antibiotic prophylaxis for symptomatic bacteriuria was mixed.\n\nThe committee noted that although there was evidence of benefit (reduced rate of UTIs per year) from 1\xa0RCT in adults who used intermittent self-catheterisation and had recurrent UTI, there was also evidence of increasing antibiotic resistance in the microorganisms found in the group taking antibiotics for prophylaxis. The committee discussed that routine antibiotic prophylaxis would be a change in practice, which is not warranted because of increasing resistance. Decisions around prophylaxis for people who self-catheterise and have recurrent UTIs may, however, be made on an individual basis, with shared decision-making and a discussion of the risks and benefits.\n\nThe committee discussed that people should be advised to seek medical help if symptoms of a UTI develop, which would be managed as an acute UTI, rather than people receiving long-term antibiotic prophylaxis.\n\nThe committee was aware of recommendations in the NICE guideline on healthcare-associated infections that antibiotic prophylaxis should not be offered routinely when changing long-term indwelling catheters, but should be considered for people with a history of symptomatic UTI after catheter change or an experience of trauma (frank haematuria after catheterisation or 2\xa0or more attempts of catheterisation). The committee for the healthcare-associated infections guideline agreed that for these groups, the benefits of antibiotic prophylaxis outweigh the risks of antimicrobial resistance. These groups are likely to be at high risk of a UTI and at risk of complications if a UTI develops.\n\n\n\nBased on evidence, the committee agreed not to recommend routine antibiotic prophylaxis to prevent catheter-associated UTI in people with a short-term catheter in hospital. Prophylaxis is not recommended routinely before insertion of a short-term catheter for surgical, non-surgical or urodynamic procedures, while the catheter is in place, or at the time of removal.\n\n\n\nBefore or during short-term catheterisation, there is only limited evidence of benefit with antibiotic prophylaxis for symptomatic bacteriuria in surgical patients.\n\nDuring short-term catheterisation for urodynamic studies, antibiotic prophylaxis did not reduce episodes of symptomatic UTI.\n\nAt the time of catheter removal, there is evidence of benefit for antibiotic prophylaxis for symptomatic UTI, but in subgroup analysis this was limited to surgical patients, and predominantly those who had either prostate surgery or had a catheter in place for longer than 5\xa0days. The committee discussed that antibiotic prophylaxis for all short-term catheter removal in hospital would be a change in practice, and widespread prophylaxis is not warranted taking into account the principles of antimicrobial stewardship.\n\n", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration. See the NICE guideline on medicines adherence.\n\nNo systematic reviews or randomised controlled trials (RCTs) were identified that addressed medicines adherence.\n\n# Resource implications\n\n## Antibiotic prophylaxis before or during short-term catheterisation in hospital\n\nOne RCT included in a systematic review (Lusardi et al. 2013) of hospitalised adults with a short-term catheter compared antibiotic prophylaxis (levofloxacin or ciprofloxacin) with placebo calculated hospital stay in presurgery and postsurgery phases. There was no statistically significant difference in mean presurgical or postsurgical stay between the placebo group and either the levofloxacin or ciprofloxacin groups (low quality evidence).\n\nIn a second included RCT comparing antibiotic prophylaxis with placebo, the mean hospital stay was significantly higher in the placebo group compared with the intervention group (8\xa0days [±1.4\xa0days] compared with 7\xa0days [±1.2\xa0days], p=0.0002; low quality evidence). Febrile morbidity and urinary tract infection (UTI) prolonged hospitalisation significantly to a mean stay of 9.2\xa0days ([±1.6\xa0days], p<0.05).\n\nIn a third included RCT comparing antibiotic prophylaxis with placebo, the average hospital stay was 6\xa0days and 5.6\xa0days for abdominal hysterectomy, and 6.1\xa0days and 7.6\xa0days for vaginal hysterectomy patients, in the prophylaxis group and placebo groups respectively.\n\nRecommended antibiotics (nitrofurantoin, trimethoprim, penicillins, cephalosporins, fluoroquinolones and aminoglycosides) are available as generic formulations, see Drug Tariff for costs.'}
|
https://www.nice.org.uk/guidance/ng113
|
This guideline sets out an antimicrobial prescribing strategy for catheter-associated urinary tract infection in children, young people and adults. It aims to optimise antibiotic use and reduce antibiotic resistance.
|
cd5da777cdc96d2bbab8c51d5385d9ac56a91d2d
|
nice
|
Padeliporfin for untreated localised prostate cancer
|
Padeliporfin for untreated localised prostate cancer
Evidence-based recommendations on padeliporfin (Tookad) for untreated, unilateral, low-risk prostate cancer in adults.
# Recommendations
Padeliporfin is not recommended, within its marketing authorisation, for untreated, unilateral, low-risk prostate cancer in adults.
This recommendation is not intended to affect treatment with padeliporfin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatments for low-risk prostate cancer include active surveillance and, for people whose disease has progressed (usually beyond low-risk disease), radical therapies such as surgery and radiotherapy. Focal therapies such as cryotherapy and high-intensity focused ultrasound can also be used, but are not routinely available.
Professional organisations and NHS England say that there is a growing trend for people with low-risk disease to have active surveillance rather than radical therapy. This is because long-term studies show that people with low-risk disease live as long whichever they have, but radical therapies are associated with long-term, severe side effects. Also, improvements in diagnostic tests mean that low-risk disease can be more accurately identified.
The company proposes padeliporfin as an option for people with low-risk disease who choose not to have active surveillance and so would otherwise have radical therapies. There is no clinical evidence on how effective padeliporfin is at slowing the disease compared with radical therapies. Also, there is no evidence to support the company's assumption that the length of time people live with padeliporfin is the same as with radical therapies.
Clinical trial evidence comparing padeliporfin with active surveillance does show that, at 2 years, it is more effective at slowing prostate cancer. However, it is unclear whether the benefit seen at 2 years leads to people living longer. Also, it is unclear whether some of the people in the trial would have had intermediate-risk prostate cancer.
Professional organisations and NHS England do not support using padeliporfin for low-risk prostate cancer because, like radical therapies, it is associated with long-term side effects, without supporting evidence of long-term clinical benefit.
The company's cost-effectiveness analyses compare padeliporfin with radical therapies. However, because there is no clinical-effectiveness evidence comparing padeliporfin and radical therapies, it is not possible to consider these analyses. Therefore, padeliporfin cannot be recommended for untreated, unilateral, low-risk prostate cancer.# Information about padeliporfin
# Marketing authorisation indication
Padeliporfin (Tookad, Steba Biotech) is indicated as monotherapy for 'adults with previously untreated, unilateral, low-risk, adenocarcinoma of the prostate with a life expectancy of at least 10 years and:
clinical stage T1c or T2a
Gleason score no more than 6, based on high-resolution biopsy strategies
prostate-specific antigen (PSA) no more than 10 ng/ml
positive cancer cores with a maximum cancer core length of 5 mm in any 1 core or 1 to 2 positive cancer cores with at least 50% cancer involvement in any 1 core or a PSA density of at least 0.15 ng/ml/cm3'.
# Dosage in the marketing authorisation
The recommended dose, given intravenously is a single dose of 3.66 mg/kg of padeliporfin, given using a vascular-targeted photodynamic therapy procedure.
# Price
The list price of padeliporfin is £3,761 per 183 mg vial (excluding VAT; company submission). The average cost of treatment is £12,111 per patient (including consumables and leasing the laser; excluding VAT; company submission). The company has a commercial arrangement, which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Steba Biotech and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Diagnosing prostate cancer and risk stratification
## New diagnostic techniques for prostate cancer are more accurate at identifying low-risk disease
NICE's guideline on prostate cancer considers tumours to be low risk if the following criteria are met: serum prostate-specific antigen (PSA) no more than 10 ng/ml, a Gleason score no more than 6, and a clinical stage of T1 to T2a. (The Gleason Score is a grading system that rates the aggressiveness of the 2 largest areas of prostate cancer cells in a tumour. Each area is scored on how healthy it looks, so healthy tissue scores 1 or 2 and abnormal tissue scores 3). The clinical experts explained that the techniques used to diagnose prostate cancer in the NHS are changing, for example, transrectal ultrasound (TRUS) guided biopsy is being replaced by multiparametric MRI. MRI techniques are more accurate at differentiating low-risk disease that does not need treatment, from disease that is likely to progress. In response to consultation, professional organisations confirmed that, over the past 5 years, in line with guidance issued by NHS England, everyone with an elevated PSA level should be offered prebiopsy multiparametric MRI as the first diagnostic test, followed by MRI-targeted biopsy. They confirmed that misclassification of low-risk disease is much lower because multiparametric MRI can identify 90% of significant cancers compared with about 50% identified by TRUS-guided biopsy alone. The committee was aware that the NICE prostate cancer guideline is currently updating the diagnostic criteria. It agreed that the main technique used to initially diagnose low-risk prostate cancer in the NHS is multiparametric MRI.
# Treatment pathway for localised prostate cancer
## Low-risk disease is usually managed with active surveillance to prevent over-treatment with radical or focal therapies
The clinical experts explained that, in practice, active surveillance (that is, monitoring for disease progression without an active treatment) is usually offered to people with low-risk disease in line with recommendations in NICE's guideline on prostate cancer. The committee understood that active surveillance in the NHS includes multiparametric MRI (if not already done), regular serum PSA testing and kinetics, digital rectal examinations and rebiopsy. The aim of encouraging active surveillance is to avoid over-treatment of disease that is unlikely to progress or shorten people's lives (given the long-term, severe adverse events associated with treatment). Clinicians generally only offer patients radical therapies including prostatectomy (surgery), external beam radiotherapy and brachytherapy if the disease progresses to intermediate risk. One clinical expert explained that there are 4 ways to move from active surveillance to radical therapies: patients no longer wish to stay on active surveillance (surveillance fatigue); increasing PSA levels (biochemical progression); increase in risk of disease progression; or increase in clinical stage (such as from T2a to T2b). If patients have radical therapy, surveillance continues with less intensive monitoring specific to the type of radical therapy. Professional organisations and NHS England have confirmed that current practice manages low-risk disease with active surveillance. Low-risk disease is unlikely to progress and clinical trial evidence has shown no difference in cancer-specific or overall survival whether people have radical therapies or active surveillance. Also, large prospective cohort studies have shown that in the medium to long term, people on active surveillance have low mortality rates. Therefore, people with low-risk disease are now choosing to be monitored rather than have active treatment with radical or focal therapies that have unwanted side effects. The NHS England Cancer Drug Fund clinical lead explained that the main reason for this trend is the growing confidence that the diagnostic techniques accurately identify low-risk disease (see section 3.1). The committee concluded that low-risk disease is usually managed with active surveillance in the NHS.
## There is variation in access to current focal therapies in the NHS
The clinical experts explained that padeliporfin is a type of focal therapy that targets the main lesion, rather than the whole prostate. The committee was aware that NICE's interventional procedures guidance recommend cryotherapy and high-intensity focused ultrasound for localised prostate cancer only under special arrangements. NICE's guideline on prostate cancer recommends these options only in a clinical trial setting. The committee was aware that NICE made these recommendations in 2012 and 2008 and that the evidence for these focal therapies may have progressed. The clinical experts explained that focal therapy is used as an alternative to radical therapy for clinically significant disease or for patients with low-risk disease who choose not to have active surveillance. It is not used when there are no clinical indications suggesting disease progression because of concerns about long-term side effects and a lack of evidence about long-term survival benefits. In response to consultation, NHS England stated that focal therapies are usually used to treat intermediate- or high-risk prostate cancer in the UK. It also highlighted that the UK Focal Therapy Users Group had issued guidance that focal therapy should be used only in intermediate-risk disease. It should not be used as an alternative to active surveillance in disease that is unlikely to progress. The committee concluded that focal therapies are not routinely available in the NHS, but when they are used, it is to treat intermediate- or high-risk disease, which is not included in the marketing authorisation for padeliporfin (see section 2).
# Positioning of padeliporfin in the treatment pathway
## There is little unmet need for a new treatment such as padeliporfin for people with low-risk disease
The company explained that padeliporfin is not an alternative to active surveillance for clinically insignificant disease (that is, disease that has little to no chance of progression in a person's expected lifetime and which is unlikely to benefit from active treatments; see section 3.1 and section 3.2). It suggested that padeliporfin might be an option for people with low-risk disease who choose not to have active surveillance either at diagnosis or after a period of active surveillance (surveillance fatigue), but before radical therapies. It highlighted that studies suggest about 30% to 65% of people with low-risk disease choose to have radical therapy. However, the committee noted that more recent data from the 2015 to 2016 National Prostate Cancer Audit showed that only 8% of people had radical therapy for low-risk disease, likely related to improved diagnostic techniques (see sections 3.1 and 3.2). It also noted that clinicians are unlikely to offer active treatment to people with low-risk disease without disease progression (see section 3.2). The committee considered that padeliporfin would not be appropriate for people with surveillance fatigue because the company had confirmed that surveillance continues after padeliporfin. In response to consultation, the company explained that active surveillance after padeliporfin is different to active surveillance without treatment. Professional organisations agreed with the company that treatment of low-risk disease may address patients' anxiety about not having any treatment for their cancer. However, they highlighted that survival rates with active surveillance are high (98.8% at 10 years in the ProtecT trial). The committee concluded that there is little unmet need for a new treatment such as padeliporfin for people with low-risk disease.
# Comparators
## Relevant comparators are radical therapies
The company considered that, given the proposed position of padeliporfin in the treatment pathway, the most appropriate comparators are radical therapies (including prostatectomy, external beam radiotherapy and brachytherapy). The committee noted that other focal therapies are not routinely available in the NHS but, where available, are normally used to manage intermediate- or high-risk disease (see section 3.3). Therefore, it agreed that focal therapies could not be considered comparators. It concluded that although there is little unmet need for additional treatments at this stage of the treatment pathway, the relevant comparators are radical therapies.
# Clinical evidence
## The key clinical evidence comes from a subgroup of 1 trial comparing padeliporfin plus active surveillance with active surveillance alone
The evidence for padeliporfin came from a subgroup of the PCM301 trial: a phase 3, multicentre, randomised, open-label, parallel-group study. It compared padeliporfin plus active surveillance with active surveillance alone in 413 adults with untreated, low-risk prostate cancer. The subgroup had 158 patients with unilateral, low-risk but not very-low-risk prostate cancer. The co-primary outcomes at 24 months were absence of definitive cancer and treatment failure, defined as histological cancer progression from low- to intermediate- or high-risk or prostate cancer-related death.
## The patients in the PCM301 subgroup are likely to be different to those seen in the NHS
The committee noted that the diagnostic techniques used in PCM301 (TRUS-guided biopsy) were different to those currently used in the NHS (multiparametric MRI; see section 3.1). In response to consultation, professional organisations highlighted that these differences in diagnostic techniques meant that some patients in PCM301 were likely to have been misclassified as having low-risk disease when they would have been identified as having higher-risk disease in the NHS. The committee agreed that the patients in the PCM301 subgroup may not reflect patients with low-risk disease likely to be seen in the NHS. It is therefore unlikely that the trial results are generalisable to NHS patients.
## The treatment-failure end point used in PCM301 has no proven relationship to longer-term survival outcomes
The committee noted that, in patients randomised to padeliporfin plus active surveillance, there were higher rates of absence of definitive cancer and absence of disease progression compared with active surveillance alone (see table 1, below). The ERG noted that disease progression was higher in the active surveillance group in PCM301 (58%) compared with other trials. For example, ProtecT, a UK-based, randomised controlled trial on prostatectomy and external beam radiotherapy that mainly recruited people with low- and intermediate-risk disease from 1999 to 2009 (77% of people had a Gleason score of 6). This study reported that 30% of patients in the active surveillance group had disease progression. The company explained that patients in PCM301 had rebiopsies at 12 months and 24 months, while ProtecT did not have any planned rebiopsies. It suggested that these planned biopsies in PCM301 led to earlier detection of disease progression. In response to consultation, professional organisations highlighted that, because of the misclassification errors associated with TRUS-guided biopsies, higher-risk disease missed at the baseline screening in PCM301 (see section 3.7) may have been correctly identified at the rebiopsies. As such, some people meeting PCM301's disease-progression end point may not have done so because of biological progression. While this misclassification bias would apply to both arms of PCM301, the committee agreed that it was likely that the trial overestimated the absolute difference in treatment effect for low-risk disease. Also, the professional organisations explained that the absence of the disease-progression end point used in PCM301 had no proven relationship to longer-term survival outcomes. The committee concluded that although padeliporfin plus active surveillance is more likely to achieve the trial end point compared with active surveillance alone in the short term, any benefit and long-term effectiveness with respect to length and quality of life are uncertain. Also, it is unclear that there would be lower rates of disease progression with padeliporfin than with active surveillance in NHS clinical practice because fewer patients are likely to have their cancer misclassified as low risk under current diagnostic techniques (see section 3.1).
Outcomes
Padeliporfin plus active surveillance
(n=80, unless otherwise stated)
Active surveillance alone (n=78, unless otherwise stated)
Risk ratio
(95% confidence intervals)
Absence of definitive cancer at 24 months: lobe diagnosed at baseline
(2.7 to 7.9)
Absence of definitive cancer at 24 months: whole gland
(2.2 to 8.3)
Absence of disease progression at 27 months: lobe diagnosed at baseline (no prostate cancer-related deaths in study)
% of 71 patients
% of 67 patients
(1.6 to 2.9; calculated by evidence review group)
Absence of disease progression at 27 months: whole gland (no prostate cancer-related deaths in study)
% of 76 patients
% of 71 patients
not available
## There is no clinical evidence from the company comparing padeliporfin with radical therapies
The company explained in its submission that it could not indirectly compare padeliporfin and radical therapies. This was because of the different outcomes reported in the trials and those used in its economic model, such as time to radical therapy. The ERG agreed with the company that a network meta-analysis was not possible given the available evidence. The committee noted that the company had not presented any evidence compared with focal therapies (see section 3.3), that might have allowed an indirect comparison with radical therapies. In response to consultation, the company stated that biochemical recurrence studies (increase in serum PSA levels) have shown that, at 3 years, 87% of people having prostatectomy and 95% of people having radiotherapy had biochemical disease-free survival. But, in PCM301, 90% of people having padeliporfin had no disease progression, based on increasing Gleason score, tumour volume or PSA levels, or advanced disease at 2 years. The company did not provide any analyses comparing the clinical effectiveness of padeliporfin with radical therapies. The committee agreed that it had not seen any evidence of the effectiveness of padeliporfin compared with radical therapies, the only relevant comparator (see section 3.5). It also recognised that radical therapies are rarely offered to people with low-risk disease in the NHS, the only population for which padeliporfin is licensed for use. During consultation, professional organisations highlighted that padeliporfin 'should not be recommended for use in the UK for this indication', and that they did not consider padeliporfin would advance patient care. The committee agreed that it could not conclude whether padeliporfin offered any clinical benefit compared with radical therapies.
# Adverse events
## Adverse events such as sexual and bowel dysfunction may be lower with padeliporfin than with radical therapies
The committee noted that the rates of sexual and bowel dysfunction were much higher in the padeliporfin plus active surveillance group than in patients having active surveillance alone. The clinical experts explained that radical therapies are associated with higher rates of bowel, urinary and sexual dysfunction than those seen in patients having padeliporfin in PCM301. The committee was aware that no long-term evidence on the adverse effects of padeliporfin was available. The committee concluded that a likely clinical benefit of padeliporfin is a lower risk of having these adverse events than with radical therapies, but agreed that it had not seen any supporting evidence (see section 3.9).
# Company's economic model
## It is not appropriate to consider padeliporfin's cost effectiveness compared with radical therapies because the relative clinical effectiveness is unknown
The committee recalled that the company did not present any clinical evidence comparing padeliporfin with radical therapies (see section 3.9). It noted that the clinical benefit of padeliporfin in terms of oncological or survival outcomes and quality of life compared with radical therapies was unknown. Survival with padeliporfin was assumed to be the same as with radical therapies. However, given that there was no relative clinical-effectiveness evidence and the short duration of the padeliporfin trial (2 years), the committee could not assess whether this was a reasonable assumption. The committee acknowledged that the company had revised its economic model to consider some of the committee's preferences in the appraisal consultation document. However, the committee agreed that, because it had seen no evidence of the relative clinical effectiveness of padeliporfin compared with radical therapies, it could not consider the cost-effectiveness analyses.
# Conclusion
## Padeliporfin is not recommended for use in the NHS for untreated, unilateral, localised, low-risk prostate cancer
The committee recalled the comments from NHS England and the professional organisations that padeliporfin should not be recommended for use in the NHS for this indication, and that over-treatment of low-risk prostate cancer should be discouraged because it is unlikely to progress (see section 3.2). It concluded that it could not recommend padeliporfin for use in the NHS for untreated, unilateral, localised, low-risk prostate cancer because:
it had not seen any clinical-effectiveness evidence comparing padeliporfin with the relevant comparators (see section 3.9)
people who currently have the relevant comparators (radical therapies) are unlikely to have low-risk disease (the only population specified in the marketing authorisation for padeliporfin, see section 2).
# Other factors
## The recommendations apply to all people with prostate cancer
The committee noted that, as with previous appraisals of technologies for treating prostate cancer, its recommendations should apply to everyone with prostate cancer (that is, both transgender people and people with a prostate who do not identify as being male).
## Padeliporfin is a new method of applying focal therapy
The committee heard differing views about whether padeliporfin was innovative in its potential to have a substantial effect on health-related benefits in low-risk disease. One clinical expert explained that adverse events resulting in sexual dysfunction do not capture important toxicities associated with prostatectomy such as loss of penile function and incontinence during sexual intercourse. These specific toxicities may be minimised with padeliporfin, but the company did not provide any supporting clinical evidence. The committee agreed that padeliporfin used a new method of applying focal therapy but, in the absence of data on clinical effectiveness compared with radical therapies, could not consider it a step change in treatment.
|
{'Recommendations': "Padeliporfin is not recommended, within its marketing authorisation, for untreated, unilateral, low-risk prostate cancer in adults.\n\nThis recommendation is not intended to affect treatment with padeliporfin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatments for low-risk prostate cancer include active surveillance and, for people whose disease has progressed (usually beyond low-risk disease), radical therapies such as surgery and radiotherapy. Focal therapies such as cryotherapy and high-intensity focused ultrasound can also be used, but are not routinely available.\n\nProfessional organisations and NHS England say that there is a growing trend for people with low-risk disease to have active surveillance rather than radical therapy. This is because long-term studies show that people with low-risk disease live as long whichever they have, but radical therapies are associated with long-term, severe side effects. Also, improvements in diagnostic tests mean that low-risk disease can be more accurately identified.\n\nThe company proposes padeliporfin as an option for people with low-risk disease who choose not to have active surveillance and so would otherwise have radical therapies. There is no clinical evidence on how effective padeliporfin is at slowing the disease compared with radical therapies. Also, there is no evidence to support the company's assumption that the length of time people live with padeliporfin is the same as with radical therapies.\n\nClinical trial evidence comparing padeliporfin with active surveillance does show that, at 2\xa0years, it is more effective at slowing prostate cancer. However, it is unclear whether the benefit seen at 2\xa0years leads to people living longer. Also, it is unclear whether some of the people in the trial would have had intermediate-risk prostate cancer.\n\nProfessional organisations and NHS England do not support using padeliporfin for low-risk prostate cancer because, like radical therapies, it is associated with long-term side effects, without supporting evidence of long-term clinical benefit.\n\nThe company's cost-effectiveness analyses compare padeliporfin with radical therapies. However, because there is no clinical-effectiveness evidence comparing padeliporfin and radical therapies, it is not possible to consider these analyses. Therefore, padeliporfin cannot be recommended for untreated, unilateral, low-risk prostate cancer.", 'Information about padeliporfin': "# Marketing authorisation indication\n\nPadeliporfin (Tookad, Steba Biotech) is indicated as monotherapy for 'adults with previously untreated, unilateral, low-risk, adenocarcinoma of the prostate with a life expectancy of at least 10\xa0years and:\n\nclinical stage T1c or T2a\n\nGleason score no more than\xa06, based on high-resolution biopsy strategies\n\nprostate-specific antigen (PSA) no more than 10\xa0ng/ml\n\npositive cancer cores with a maximum cancer core length of 5\xa0mm in any 1 core or 1\xa0to 2\xa0positive cancer cores with at least 50% cancer involvement in any 1\xa0core or a PSA density of at least 0.15\xa0ng/ml/cm3'.\n\n# Dosage in the marketing authorisation\n\nThe recommended dose, given intravenously is a single dose of 3.66\xa0mg/kg of padeliporfin, given using a vascular-targeted photodynamic therapy procedure.\n\n# Price\n\nThe list price of padeliporfin is £3,761 per 183\xa0mg vial (excluding VAT; company submission). The average cost of treatment is £12,111 per patient (including consumables and leasing the laser; excluding VAT; company submission). The company has a commercial arrangement, which would apply if the technology had been recommended.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Steba Biotech and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Diagnosing prostate cancer and risk stratification\n\n## New diagnostic techniques for prostate cancer are more accurate at identifying low-risk disease\n\nNICE's guideline on prostate cancer considers tumours to be low risk if the following criteria are met: serum prostate-specific antigen (PSA) no more than 10\xa0ng/ml, a Gleason score no more than\xa06, and a clinical stage of T1 to T2a. (The Gleason Score is a grading system that rates the aggressiveness of the 2\xa0largest areas of prostate cancer cells in a tumour. Each area is scored on how healthy it looks, so healthy tissue scores\xa01 or\xa02 and abnormal tissue scores\xa03). The clinical experts explained that the techniques used to diagnose prostate cancer in the NHS are changing, for example, transrectal ultrasound (TRUS) guided biopsy is being replaced by multiparametric MRI. MRI techniques are more accurate at differentiating low-risk disease that does not need treatment, from disease that is likely to progress. In response to consultation, professional organisations confirmed that, over the past 5\xa0years, in line with guidance issued by NHS England, everyone with an elevated PSA level should be offered prebiopsy multiparametric MRI as the first diagnostic test, followed by MRI-targeted biopsy. They confirmed that misclassification of low-risk disease is much lower because multiparametric MRI can identify 90% of significant cancers compared with about 50% identified by TRUS-guided biopsy alone. The committee was aware that the NICE prostate cancer guideline is currently updating the diagnostic criteria. It agreed that the main technique used to initially diagnose low-risk prostate cancer in the NHS is multiparametric MRI.\n\n# Treatment pathway for localised prostate cancer\n\n## Low-risk disease is usually managed with active surveillance to prevent over-treatment with radical or focal therapies\n\nThe clinical experts explained that, in practice, active surveillance (that is, monitoring for disease progression without an active treatment) is usually offered to people with low-risk disease in line with recommendations in NICE's guideline on prostate cancer. The committee understood that active surveillance in the NHS includes multiparametric MRI (if not already done), regular serum PSA testing and kinetics, digital rectal examinations and rebiopsy. The aim of encouraging active surveillance is to avoid over-treatment of disease that is unlikely to progress or shorten people's lives (given the long-term, severe adverse events associated with treatment). Clinicians generally only offer patients radical therapies including prostatectomy (surgery), external beam radiotherapy and brachytherapy if the disease progresses to intermediate risk. One clinical expert explained that there are 4\xa0ways to move from active surveillance to radical therapies: patients no longer wish to stay on active surveillance (surveillance fatigue); increasing PSA levels (biochemical progression); increase in risk of disease progression; or increase in clinical stage (such as from T2a to T2b). If patients have radical therapy, surveillance continues with less intensive monitoring specific to the type of radical therapy. Professional organisations and NHS England have confirmed that current practice manages low-risk disease with active surveillance. Low-risk disease is unlikely to progress and clinical trial evidence has shown no difference in cancer-specific or overall survival whether people have radical therapies or active surveillance. Also, large prospective cohort studies have shown that in the medium to long term, people on active surveillance have low mortality rates. Therefore, people with low-risk disease are now choosing to be monitored rather than have active treatment with radical or focal therapies that have unwanted side effects. The NHS England Cancer Drug Fund clinical lead explained that the main reason for this trend is the growing confidence that the diagnostic techniques accurately identify low-risk disease (see section\xa03.1). The committee concluded that low-risk disease is usually managed with active surveillance in the NHS.\n\n## There is variation in access to current focal therapies in the NHS\n\nThe clinical experts explained that padeliporfin is a type of focal therapy that targets the main lesion, rather than the whole prostate. The committee was aware that NICE's interventional procedures guidance recommend cryotherapy and high-intensity focused ultrasound for localised prostate cancer only under special arrangements. NICE's guideline on prostate cancer recommends these options only in a clinical trial setting. The committee was aware that NICE made these recommendations in 2012 and 2008 and that the evidence for these focal therapies may have progressed. The clinical experts explained that focal therapy is used as an alternative to radical therapy for clinically significant disease or for patients with low-risk disease who choose not to have active surveillance. It is not used when there are no clinical indications suggesting disease progression because of concerns about long-term side effects and a lack of evidence about long-term survival benefits. In response to consultation, NHS England stated that focal therapies are usually used to treat intermediate- or high-risk prostate cancer in the UK. It also highlighted that the UK Focal Therapy Users Group had issued guidance that focal therapy should be used only in intermediate-risk disease. It should not be used as an alternative to active surveillance in disease that is unlikely to progress. The committee concluded that focal therapies are not routinely available in the NHS, but when they are used, it is to treat intermediate- or high-risk disease, which is not included in the marketing authorisation for padeliporfin (see section\xa02).\n\n# Positioning of padeliporfin in the treatment pathway\n\n## There is little unmet need for a new treatment such as padeliporfin for people with low-risk disease\n\nThe company explained that padeliporfin is not an alternative to active surveillance for clinically insignificant disease (that is, disease that has little to no chance of progression in a person's expected lifetime and which is unlikely to benefit from active treatments; see section\xa03.1 and\xa0section 3.2). It suggested that padeliporfin might be an option for people with low-risk disease who choose not to have active surveillance either at diagnosis or after a period of active surveillance (surveillance fatigue), but before radical therapies. It highlighted that studies suggest about 30% to 65% of people with low-risk disease choose to have radical therapy. However, the committee noted that more recent data from the 2015 to 2016 National Prostate Cancer Audit showed that only 8% of people had radical therapy for low-risk disease, likely related to improved diagnostic techniques (see sections\xa03.1 and\xa03.2). It also noted that clinicians are unlikely to offer active treatment to people with low-risk disease without disease progression (see section\xa03.2). The committee considered that padeliporfin would not be appropriate for people with surveillance fatigue because the company had confirmed that surveillance continues after padeliporfin. In response to consultation, the company explained that active surveillance after padeliporfin is different to active surveillance without treatment. Professional organisations agreed with the company that treatment of low-risk disease may address patients' anxiety about not having any treatment for their cancer. However, they highlighted that survival rates with active surveillance are high (98.8% at 10\xa0years in the ProtecT trial). The committee concluded that there is little unmet need for a new treatment such as padeliporfin for people with low-risk disease.\n\n# Comparators\n\n## Relevant comparators are radical therapies\n\nThe company considered that, given the proposed position of padeliporfin in the treatment pathway, the most appropriate comparators are radical therapies (including prostatectomy, external beam radiotherapy and brachytherapy). The committee noted that other focal therapies are not routinely available in the NHS but, where available, are normally used to manage intermediate- or high-risk disease (see section\xa03.3). Therefore, it agreed that focal therapies could not be considered comparators. It concluded that although there is little unmet need for additional treatments at this stage of the treatment pathway, the relevant comparators are radical therapies.\n\n# Clinical evidence\n\n## The key clinical evidence comes from a subgroup of 1\xa0trial comparing padeliporfin plus active surveillance with active surveillance alone\n\nThe evidence for padeliporfin came from a subgroup of the PCM301\xa0trial: a phase\xa03, multicentre, randomised, open-label, parallel-group study. It compared padeliporfin plus active surveillance with active surveillance alone in 413\xa0adults with untreated, low-risk prostate cancer. The subgroup had 158\xa0patients with unilateral, low-risk but not very-low-risk prostate cancer. The co-primary outcomes at 24\xa0months were absence of definitive cancer and treatment failure, defined as histological cancer progression from low- to intermediate- or high-risk or prostate cancer-related death.\n\n## The patients in the PCM301 subgroup are likely to be different to those seen in the NHS\n\nThe committee noted that the diagnostic techniques used in PCM301 (TRUS-guided biopsy) were different to those currently used in the NHS (multiparametric MRI; see section\xa03.1). In response to consultation, professional organisations highlighted that these differences in diagnostic techniques meant that some patients in PCM301 were likely to have been misclassified as having low-risk disease when they would have been identified as having higher-risk disease in the NHS. The committee agreed that the patients in the PCM301 subgroup may not reflect patients with low-risk disease likely to be seen in the NHS. It is therefore unlikely that the trial results are generalisable to NHS patients.\n\n## The treatment-failure end point used in PCM301 has no proven relationship to longer-term survival outcomes\n\nThe committee noted that, in patients randomised to padeliporfin plus active surveillance, there were higher rates of absence of definitive cancer and absence of disease progression compared with active surveillance alone (see table\xa01, below). The ERG noted that disease progression was higher in the active surveillance group in PCM301 (58%) compared with other trials. For example, ProtecT, a UK-based, randomised controlled trial on prostatectomy and external beam radiotherapy that mainly recruited people with low- and intermediate-risk disease from 1999 to 2009 (77% of people had a Gleason score of\xa06). This study reported that 30% of patients in the active surveillance group had disease progression. The company explained that patients in PCM301 had rebiopsies at 12\xa0months and 24\xa0months, while ProtecT did not have any planned rebiopsies. It suggested that these planned biopsies in PCM301 led to earlier detection of disease progression. In response to consultation, professional organisations highlighted that, because of the misclassification errors associated with TRUS-guided biopsies, higher-risk disease missed at the baseline screening in PCM301 (see section\xa03.7) may have been correctly identified at the rebiopsies. As such, some people meeting PCM301's disease-progression end point may not have done so because of biological progression. While this misclassification bias would apply to both arms of PCM301, the committee agreed that it was likely that the trial overestimated the absolute difference in treatment effect for low-risk disease. Also, the professional organisations explained that the absence of the disease-progression end point used in PCM301 had no proven relationship to longer-term survival outcomes. The committee concluded that although padeliporfin plus active surveillance is more likely to achieve the trial end point compared with active surveillance alone in the short term, any benefit and long-term effectiveness with respect to length and quality of life are uncertain. Also, it is unclear that there would be lower rates of disease progression with padeliporfin than with active surveillance in NHS clinical practice because fewer patients are likely to have their cancer misclassified as low risk under current diagnostic techniques (see section\xa03.1).\n\nOutcomes\n\nPadeliporfin plus active surveillance\n\n(n=80, unless otherwise stated)\n\nActive surveillance alone (n=78, unless otherwise stated)\n\nRisk ratio\n\n(95% confidence intervals)\n\nAbsence of definitive cancer at 24 months: lobe diagnosed at baseline\n\n%\n\n%\n\n(2.7 to 7.9)\n\nAbsence of definitive cancer at 24 months: whole gland\n\n%\n\n%\n\n(2.2 to 8.3)\n\nAbsence of disease progression at 27 months: lobe diagnosed at baseline (no prostate cancer-related deaths in study)\n\n% of 71 patients\n\n% of 67 patients\n\n(1.6 to 2.9; calculated by evidence review group)\n\nAbsence of disease progression at 27 months: whole gland (no prostate cancer-related deaths in study)\n\n% of 76 patients\n\n% of 71 patients\n\nnot available\n\n## There is no clinical evidence from the company comparing padeliporfin with radical therapies\n\nThe company explained in its submission that it could not indirectly compare padeliporfin and radical therapies. This was because of the different outcomes reported in the trials and those used in its economic model, such as time to radical therapy. The ERG agreed with the company that a network meta-analysis was not possible given the available evidence. The committee noted that the company had not presented any evidence compared with focal therapies (see section\xa03.3), that might have allowed an indirect comparison with radical therapies. In response to consultation, the company stated that biochemical recurrence studies (increase in serum PSA levels) have shown that, at 3\xa0years, 87% of people having prostatectomy and 95% of people having radiotherapy had biochemical disease-free survival. But, in PCM301, 90% of people having padeliporfin had no disease progression, based on increasing Gleason score, tumour volume or PSA levels, or advanced disease at 2\xa0years. The company did not provide any analyses comparing the clinical effectiveness of padeliporfin with radical therapies. The committee agreed that it had not seen any evidence of the effectiveness of padeliporfin compared with radical therapies, the only relevant comparator (see section\xa03.5). It also recognised that radical therapies are rarely offered to people with low-risk disease in the NHS, the only population for which padeliporfin is licensed for use. During consultation, professional organisations highlighted that padeliporfin 'should not be recommended for use in the UK for this indication', and that they did not consider padeliporfin would advance patient care. The committee agreed that it could not conclude whether padeliporfin offered any clinical benefit compared with radical therapies.\n\n# Adverse events\n\n## Adverse events such as sexual and bowel dysfunction may be lower with padeliporfin than with radical therapies\n\nThe committee noted that the rates of sexual and bowel dysfunction were much higher in the padeliporfin plus active surveillance group than in patients having active surveillance alone. The clinical experts explained that radical therapies are associated with higher rates of bowel, urinary and sexual dysfunction than those seen in patients having padeliporfin in PCM301. The committee was aware that no long-term evidence on the adverse effects of padeliporfin was available. The committee concluded that a likely clinical benefit of padeliporfin is a lower risk of having these adverse events than with radical therapies, but agreed that it had not seen any supporting evidence (see section\xa03.9).\n\n# Company's economic model\n\n## It is not appropriate to consider padeliporfin's cost effectiveness compared with radical therapies because the relative clinical effectiveness is unknown\n\nThe committee recalled that the company did not present any clinical evidence comparing padeliporfin with radical therapies (see section\xa03.9). It noted that the clinical benefit of padeliporfin in terms of oncological or survival outcomes and quality of life compared with radical therapies was unknown. Survival with padeliporfin was assumed to be the same as with radical therapies. However, given that there was no relative clinical-effectiveness evidence and the short duration of the padeliporfin trial (2\xa0years), the committee could not assess whether this was a reasonable assumption. The committee acknowledged that the company had revised its economic model to consider some of the committee's preferences in the appraisal consultation document. However, the committee agreed that, because it had seen no evidence of the relative clinical effectiveness of padeliporfin compared with radical therapies, it could not consider the cost-effectiveness analyses.\n\n# Conclusion\n\n## Padeliporfin is not recommended for use in the NHS for untreated, unilateral, localised, low-risk prostate cancer\n\nThe committee recalled the comments from NHS England and the professional organisations that padeliporfin should not be recommended for use in the NHS for this indication, and that over-treatment of low-risk prostate cancer should be discouraged because it is unlikely to progress (see section\xa03.2). It concluded that it could not recommend padeliporfin for use in the NHS for untreated, unilateral, localised, low-risk prostate cancer because:\n\nit had not seen any clinical-effectiveness evidence comparing padeliporfin with the relevant comparators (see section\xa03.9)\n\npeople who currently have the relevant comparators (radical therapies) are unlikely to have low-risk disease (the only population specified in the marketing authorisation for padeliporfin, see section\xa02).\n\n# Other factors\n\n## The recommendations apply to all people with prostate cancer\n\nThe committee noted that, as with previous appraisals of technologies for treating prostate cancer, its recommendations should apply to everyone with prostate cancer (that is, both transgender people and people with a prostate who do not identify as being male).\n\n## Padeliporfin is a new method of applying focal therapy\n\nThe committee heard differing views about whether padeliporfin was innovative in its potential to have a substantial effect on health-related benefits in low-risk disease. One clinical expert explained that adverse events resulting in sexual dysfunction do not capture important toxicities associated with prostatectomy such as loss of penile function and incontinence during sexual intercourse. These specific toxicities may be minimised with padeliporfin, but the company did not provide any supporting clinical evidence. The committee agreed that padeliporfin used a new method of applying focal therapy but, in the absence of data on clinical effectiveness compared with radical therapies, could not consider it a step change in treatment."}
|
https://www.nice.org.uk/guidance/ta546
|
Evidence-based recommendations on padeliporfin (Tookad) for untreated, unilateral, low-risk prostate cancer in adults.
|
2a27c53eb1ca5aad639fbffd11fdac1548b796b2
|
nice
|
Subcutaneous automated low-flow pump implantation for refractory ascites caused by cirrhosis
|
Subcutaneous automated low-flow pump implantation for refractory ascites caused by cirrhosis
Evidence-based recommendations on subcutaneous automated low-flow pump implantation for refractory ascites in adults. This involves inserting a pump under the skin to move excess fluid from the abdomen to the bladder, where it is passed in the urine.
# Recommendations
Current evidence on the safety of subcutaneous automated low-flow pump implantation for refractory ascites shows there are serious but well-recognised safety concerns, including device failure and acute kidney injury. Evidence on efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do subcutaneous automated low-flow pump implantation for refractory ascites should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on subcutaneous automated low-flow pump implantation for refractory ascites is recommended.
Audit and review clinical outcomes of all patients having subcutaneous automated low-flow pump implantation for refractory ascites. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
All device failures should be reported to the Medicines and Healthcare products Regulatory Agency.
Patient selection should be done in specialist centres, by clinicians experienced in managing liver disease and in the various options available for managing ascites.
Further research should report details of patient selection, the frequency of pump-related complications, and the need for regular albumin infusions.# The condition, current treatments and procedure
# The condition
Ascites is a common complication of cirrhosis of the liver. Build-up of fluid causes the abdomen to swell and may lead to discomfort, difficulty breathing, fatigue, nausea and poor appetite.
# Current treatments
Treatment is usually diuretics and advice about dietary sodium restriction. For refractory ascites, treatment options include large-volume paracentesis, albumin infusion and insertion of a transjugular intrahepatic portosystemic shunt. These procedures may be used to support a patient who is waiting for a liver transplant.
# The procedure
Subcutaneous automated low-flow pump implantation for refractory ascites is usually done under general anaesthesia, typically through 3 small incisions in the abdominal wall. A battery-powered pump with internal pressure sensors is implanted on the right side above the belt line. One catheter connects the pump to the peritoneal cavity, and another connects it to the urinary bladder. The pump and both catheters are secured with sutures to prevent migration. The pump removes fluid from the peritoneal cavity through the first catheter, and puts it into the bladder through the second catheter. The fluid is eliminated through normal micturition. The pump is programmed to remove pre-set daily volumes of fluid, and the pressure sensors prevent it from over-distending the bladder.
A clinician programs the pump wirelessly using an external hand-held charging device, according to the needs of the patient (based on previous large-volume paracentesis requirements, observed accumulation of ascites and body weight). The hand-held device is also used by the patient to charge the pump wirelessly, by holding it above the pump for about 30 minutes each day. The hand-held device collects data sent by the pump, which are downloaded to a computer for review by the clinician. Anonymised data are sent to the manufacturer, which sends a report to the clinician with a detailed analysis of the data and any recommendations.
The aim of the procedure is to avoid the accumulation of fluid, abdominal swelling and accompanying complications.
|
{'Recommendations': "Current evidence on the safety of subcutaneous automated low-flow pump implantation for refractory ascites shows there are serious but well-recognised safety concerns, including device failure and acute kidney injury. Evidence on efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do subcutaneous automated low-flow pump implantation for refractory ascites should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on subcutaneous automated low-flow pump implantation for refractory ascites is recommended.\n\nAudit and review clinical outcomes of all patients having subcutaneous automated low-flow pump implantation for refractory ascites. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nAll device failures should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nPatient selection should be done in specialist centres, by clinicians experienced in managing liver disease and in the various options available for managing ascites.\n\nFurther research should report details of patient selection, the frequency of pump-related complications, and the need for regular albumin infusions.", 'The condition, current treatments and procedure': '# The condition\n\nAscites is a common complication of cirrhosis of the liver. Build-up of fluid causes the abdomen to swell and may lead to discomfort, difficulty breathing, fatigue, nausea and poor appetite.\n\n# Current treatments\n\nTreatment is usually diuretics and advice about dietary sodium restriction. For refractory ascites, treatment options include large-volume paracentesis, albumin infusion and insertion of a transjugular intrahepatic portosystemic shunt. These procedures may be used to support a patient who is waiting for a liver transplant.\n\n# The procedure\n\nSubcutaneous automated low-flow pump implantation for refractory ascites is usually done under general anaesthesia, typically through 3\xa0small incisions in the abdominal wall. A battery-powered pump with internal pressure sensors is implanted on the right side above the belt line. One catheter connects the pump to the peritoneal cavity, and another connects it to the urinary bladder. The pump and both catheters are secured with sutures to prevent migration. The pump removes fluid from the peritoneal cavity through the first catheter, and puts it into the bladder through the second catheter. The fluid is eliminated through normal micturition. The pump is programmed to remove pre-set daily volumes of fluid, and the pressure sensors prevent it from over-distending the bladder.\n\nA clinician programs the pump wirelessly using an external hand-held charging device, according to the needs of the patient (based on previous large-volume paracentesis requirements, observed accumulation of ascites and body weight). The hand-held device is also used by the patient to charge the pump wirelessly, by holding it above the pump for about 30\xa0minutes each day. The hand-held device collects data sent by the pump, which are downloaded to a computer for review by the clinician. Anonymised data are sent to the manufacturer, which sends a report to the clinician with a detailed analysis of the data and any recommendations.\n\nThe aim of the procedure is to avoid the accumulation of fluid, abdominal swelling and accompanying complications.'}
|
https://www.nice.org.uk/guidance/ipg631
|
Evidence-based recommendations on subcutaneous automated low-flow pump implantation for refractory ascites in adults. This involves inserting a pump under the skin to move excess fluid from the abdomen to the bladder, where it is passed in the urine.
|
00286dce4f318501ef860e1e618a3fa36418f21c
|
nice
|
Gemtuzumab ozogamicin for untreated acute myeloid leukaemia
|
Gemtuzumab ozogamicin for untreated acute myeloid leukaemia
Evidence-based recommendations on gemtuzumab oxogamicin (Mylotarg) for untreated acute myeloid leukaemia in people aged 15 years and over.
# Recommendations
Gemtuzumab ozogamicin, with daunorubicin and cytarabine, is recommended as an option for untreated de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia, in people 15 years and over, only if:
they start induction therapy when either the cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (that is, because the test was unsuccessful) or when their cytogenetic test results are not yet available and
they start consolidation therapy when their cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (because the test was unsuccessful) and
the company provides gemtuzumab ozogamicin according to the commercial arrangement.
These recommendations are not intended to affect treatment with gemtuzumab ozogamicin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people aged 15 to 17, this decision should be made jointly by the young person and their parents or carers and the clinician.
Why the committee made these recommendations
AML is currently treated with daunorubicin plus cytarabine. Cytogenetic testing is used to look for specific gene mutations in certain types of leukaemia, which might predict how a person's disease responds to treatment and affect treatment options. People whose disease has favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics in terms of treatment response, risk of relapse and survival. However, for some patients the cytogenetic test results are not available at the start of induction treatment.
Evidence from a randomised clinical trial shows that, for people whose disease has favourable or intermediate cytogenetics, gemtuzumab ozogamicin with daunorubicin and cytarabine is more clinically effective than daunorubicin and cytarabine. People are more likely to live longer without the disease relapsing or symptoms returning.
Because no clinical- or cost-effectiveness analysis is presented for people whose disease has unfavourable cytogenetics, gemtuzumab ozogamicin cannot be recommended for this group.
The most plausible cost-effectiveness estimates (including the stopping rule for consolidation therapy in people who have unfavourable cytogenetics) for gemtuzumab ozogamicin compared with daunorubicin and cytarabine in people whose disease has favourable, intermediate or unknown cytogenetics (because the cytogenetic test is unsuccessful) are within the range that NICE normally considers an acceptable use of NHS resources. Therefore gemtuzumab ozogamicin can be recommended for these groups of people.# Information about gemtuzumab ozogamicin
# Marketing authorisation indication
Gemtuzumab ozogamicin (Mylotarg, Pfizer) is indicated 'for the treatment of previously untreated, de novo CD33-positive acute myeloid leukaemia, except acute promyelocytic leukaemia for patients age 15 years and above, in combination with daunorubicin and cytarabine.'
# Dosage in the marketing authorisation
The gemtuzumab ozogamicin dose is 3 mg/m2/dose (up to a maximum of 1×5-mg vial) infused over a 2-hour period. Induction: gemtuzumab ozogamicin 3 mg/m2/dose (up to a maximum of 5 mg/dose) given on days 1, 4 and 7. Consolidation courses 1 and 2: gemtuzumab ozogamicin 3 mg/m2/dose (up to a maximum of 5 mg/dose) given on day 1 of each course.
# Price
£6,300 per 5-mg vial (excluding VAT; British national formulary online ). The company has a commercial arrangement. This makes gemtuzumab ozogamicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with acute myeloid leukaemia would welcome a new treatment option
Acute myeloid leukaemia (AML) is a rapidly progressing form of leukaemia. People with the disease have fatigue, weakness or breathlessness, memory loss, bruising, bleeding and frequent infections. There is a poor prognosis for patients whose disease does not respond to treatment, or whose disease responds then relapses. The committee agreed that new treatments, which could improve the chance of successfully inducing first remission would be welcomed.
# Clinical management
## Current treatment for AML is daunorubicin plus cytarabine and this is the appropriate comparator
The aim of intensive chemotherapy is to induce complete remission. After this people would have either consolidation chemotherapy or a stem cell transplant. Most patients with AML in the UK are entered into the National Cancer Research Institute AML trials; AML 19 for younger patients and AML 18 for patients over 60 years. Both trials currently include gemtuzumab ozogamicin as an induction therapy for patients without a known adverse karyotype at diagnosis. Outside of clinical trials, most patients for whom intensive chemotherapy is considered suitable currently have standard combination chemotherapy (daunorubicin plus cytarabine) without the addition of gemtuzumab ozogamicin. Intensive treatment for AML is essentially unchanged in 40 years. Although survival has gradually improved this has been largely a result of improvements in supportive care and decision-making about when to have allogeneic stem cell transplant. The committee concluded that established clinical management is daunorubicin plus cytarabine and this is the relevant comparator for this appraisal.
## Cytogenetic testing is standard clinical practice in England
Everyone with newly diagnosed AML has cytogenetic testing because this provides important information about prognosis and how the disease might respond to different treatments. People who have AML with favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics. The committee understood that larger centres have placed great emphasis on obtaining the cytogenetic results as quickly as possible, usually within days. However in smaller centres, it may take between 1 and 3 weeks to obtain the results. The clinical experts confirmed that cytogenetic testing takes between 7 to 10 days and it would be challenging to reduce this to less than 7 days. The committee acknowledged that cytogenetic testing is standard clinical practice and confirmed its importance in the clinical management of untreated AML.
## Cytogenetic test results are not always available at the start of the induction treatment
Some patients need to start treatment urgently before cytogenetic results have been received. The clinical experts at the first committee meeting explained that around 15% to 20% of patients have a very high or rapidly increasing white blood cell count, evidence of tumour lysis or disseminated intravascular coagulation, or life-threatening bleeding or infection when they are diagnosed. They also explained that for this group of patients there is no evidence to suggest that starting treatment before cytogenetic results are available is harmful. Treatment would be stopped if the tests revealed that the patient had AML with unfavourable cytogenetics. In response to consultation, consultees emphasised the importance of patients with AML having treatment within a week of their diagnosis. One of the consultees highlighted that 32% of patients with AML start treatment on the day of diagnosis and a further 47% start treatment within a week of their diagnosis. The committee accepted that the proportion of patients who have to start treatment urgently before cytogenetic results have been received (approximately 80%) was much higher than the 15% to 20% initially considered at the first committee meeting. The committee acknowledged the importance of being able to start treatment for these people before cytogenetic test results are available. It agreed to explore the effect of including the costs that would be incurred in patients who need urgent treatment while waiting for cytogenetic results and who were later found to have unfavourable cytogenetics (see section 3.5) and to take this into account in its decision-making (see section 3.16).
# Population
## The population specified in the company's decision problem is appropriate
The committee considered the population relevant to this appraisal and noted that the marketing authorisation does not define the population by cytogenetic status. But the company's base case focused on patients whose disease was not known to have unfavourable cytogenetics. This included people whose disease had favourable, intermediate or unknown cytogenetics. The committee was aware from responses to consultation that approximately 20% of patients have favourable cytogenetics, 60% have intermediate cytogenetics and 20% have unfavourable cytogenetics. The clinical experts supported the company's rationale for excluding patients whose disease had unfavourable cytogenetics because these patients have a worse prognosis (see section 3.3). The committee recalled that patients who have AML with favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics (see section 3.3). It was also aware that there was a subgroup of patients with unknown cytogenetics in the company's base case. This subgroup could include those for whom treatment was started before the test results had become available (see section 3.4) and those for whom the testing was unsuccessful in determining cytogenetic status. The clinical experts explained that if the testing was unsuccessful, it was not routine clinical practice to re-test. The committee understood that an element of clinical judgement was needed when offering treatment to these patients but they would generally have the same treatment as those with favourable or intermediate cytogenetics. The committee concluded that the population specified in the company's decision problem was appropriate.
# Clinical evidence
## The results from ALFA-0701 are generalisable to clinical practice in England
ALFA-0701 (n=271) was an open-label, phase III, randomised controlled trial, done across 26 haematology centres in France. It included patients aged 50 to 70 years with previously untreated de novo (that is, it excluded secondary leukaemia) AML. The trial compared gemtuzumab ozogamicin plus daunorubicin and cytarabine with daunorubicin and cytarabine alone. The data presented were from the 30 April 2013 data cut and the committee stated that a more recent data cut from ALFA-0701 trial would be informative. The population covered by the marketing authorisation was extended to include people aged 15 to 17 years and restricted to de novo CD33-positive AML. Most patients diagnosed with AML are over 50 years. Therefore, the population included in the trial is likely to reflect most patients for whom gemtuzumab ozogamicin would be suitable in clinical practice. The trial did include a small number of patients whose disease was not CD33-positive, who would not have gemtuzumab ozogamicin according to the marketing authorisation. The committee agreed that it can only appraise gemtuzumab ozogamicin within its marketing authorisation. It concluded that ALFA-0701 trial is generalisable to the population who would have gemtuzumab ozogamicin plus daunorubicin and cytarabine in clinical practice in England.
## The dosing schedule in ALFA-0701 differs from the dose in ongoing trials in the UK
The dosage for gemtuzumab ozogamicin in ALFA-0701 is in line with the marketing authorisation. However, the 2 ongoing UK trials (AML 18 and AML 19) use a different dosage. Therefore, the granting of the marketing authorisation may have implications for practice, because UK clinicians are currently using the dosage used in AML 18 and AML 19, rather than the licensed dosage. The committee agreed that it could only recommend gemtuzumab ozogamicin in line with the dosage specified in the marketing authorisation.
## The individual patient data meta-analysis may not be generalisable to clinical practice in England
The main clinical evidence was supported by an individual patient data meta-analysis. However, the meta-analysis included patients aged 15 years or over with newly diagnosed de novo or secondary AML or high-risk myelodysplastic syndrome. This is a broader population than the marketing authorisation. The committee concluded that the results may not be generalisable to people who would have gemtuzumab ozogamicin in clinical practice in England.
# Clinical-effectiveness results
## Gemtuzumab ozogamicin increases event-free survival and relapse-free survival compared with chemotherapy
The company reported outcomes assessed by investigator and by independent review committee. The analysis by independent review committee was considered to be academic-in-confidence by the company and cannot be reported here. Because the analyses by investigator assessment are reported in the summary of product characteristics, those results are reported here. The primary outcome measure in ALFA-0701 was event-free survival. An event was defined as induction failure, relapse or death. Treatment with gemtuzumab ozogamicin plus daunorubicin and cytarabine increased median event-free survival compared with daunorubicin and cytarabine alone. The analysis by investigator assessment shows increased median event-free survival from 9.5 months to 17.3 months (hazard ratio 0.56; 95% confidence intervals 0.42 to 0.76, p=0.0002). Relapse-free survival and overall survival were secondary end points. Median relapse-free survival increased from 11.4 months to 28 months (HR 0.53; 95% CI 0.36 to 0.76, p=0.0006) in patients who had gemtuzumab ozogamicin plus daunorubicin and cytarabine. Median overall survival increased from 21.8 months to 27.5 months (HR 0.81; 95% Cl 0.60 to 1.09, p=0.165). However, the difference between treatment groups did not reach statistical significance. The committee concluded that gemtuzumab ozogamicin plus daunorubicin and cytarabine was clinically effective compared with chemotherapy.
## Gemtuzumab ozogamicin increases event-free survival and relapse-free survival in the combined favourable and intermediate cytogenetic group but not in the unfavourable group compared with chemotherapy
The company reported outcomes assessed by investigators and by independent review committee, categorised by cytogenetic profile. The analysis by independent review committee was considered to be academic-in-confidence by the company and cannot be reported here. Because analyses by investigator assessment are reported in the summary of product characteristics, those results are reported here. Gemtuzumab ozogamicin plus daunorubicin and cytarabine increased median event-free survival from 12.2 months to 22.5 months (HR 0.49; 95% CI 0.33 to 0.72, p=0.0003) in those whose disease had favourable or intermediate cytogenetics. There was no statistically significant difference in median event-free survival in patients whose disease had unfavourable cytogenetics (from 2.8 months to 4.5 months ). For patients whose disease had favourable or intermediate cytogenetics, overall survival increased from 26.0 months to 38.6 months (HR 0.747; 95% CI 0.511 to 1.091, p=0.1288). For patients whose disease had unfavourable cytogenetics, overall survival decreased from 13.5 months to 12.0 months (HR 1.553; CI 0.878 to 2.748, p=0.1267). The committee concluded that gemtuzumab ozogamicin plus daunorubicin and cytarabine compared with chemotherapy was clinically effective for patients whose disease had favourable and intermediate cytogenetics. Also, results from those subgroups were better than for the overall population, but only when results from patients with unfavourable cytogenetics were excluded.
## There is heterogeneity in the clinical outcomes in the intermediate cytogenetic subgroup
The company provided additional analyses for the intermediate cytogenetic group by cytogenetic and molecular risk profile (that is, for intermediate-1 and intermediate-2 subgroups). The company reported outcomes by independent review committee only. The analysis was considered to be academic-in-confidence by the company and cannot be reported here. The ERG highlighted the differences in the clinical benefit seen in patients whose disease had an intermediate-1 or intermediate-2 cytogenetic and molecular risk profile. The committee acknowledged that results for the intermediate-2 group were based on small numbers of patients. The committee concluded that the results highlighted heterogeneity in the clinical outcomes in the intermediate group. Therefore it agreed to account for this in its decision-making (see section 3.24).
## The intermediate-1 and -2 cytogenetic subgroup classification system is outdated
The clinical experts explained that the classification of intermediate-1 and intermediate-2 by cytogenetics only is outdated, and a new classification is being used in clinical practice. This updated classification takes account of more genetic abnormalities such as abnormalities in FLT3, NPM1, CEBPA and other genes. In response to consultation, the company highlighted that although clinicians may consider the intermediate-1 and ‑2 classification outdated, the intermediate-1 subgroup accounts for two-thirds of the total patients expected to have treatment in clinical practice. The committee concluded that, although the clinical results are different between intermediate-1 and -2, it would prefer not to split the intermediate group using an outdated classification system.
## Gemtuzumab ozogamicin is generally well tolerated
There was an increase in veno-occlusive disease in patients taking gemtuzumab ozogamicin plus daunorubicin and cytarabine compared with those taking daunorubicin and cytarabine alone. However, the numbers of patients who had other adverse effects were similar between the 2 groups. The committee concluded that gemtuzumab ozogamicin was generally well tolerated.
## The risk of developing veno-occlusive disease is low
The patient organisation stated that the risk of veno-occlusive disease appeared to be relatively low when gemtuzumab ozogamicin doses of 3 mg/m2 or less are used with standard therapy as part of initial therapy for AML. This is in line with the dosage in the marketing authorisation and in ALFA-0701. The clinical experts confirmed that it was a rare side effect but clinicians are experienced in managing it. The committee concluded that the risk of developing veno-occlusive disease because of gemtuzumab ozogamicin was low.
# Company's economic model
## The model is complex and appropriate for decision-making
In its original submission, the company presented a semi-Markov cohort state-transition model with 12 health states. The main effectiveness data came from ALFA-0701. It was used to estimate overall survival and relapse-free survival, using mixture cure models fit to Kaplan–Meier data. The committee was aware that there was no explicit structural link between a number of key model parameters, including between relapse and haematopoietic stem cell transplant; the model structure was complex and challenging to critique. However, the committee concluded that model was appropriate for decision-making.
## The company updated its model and cost-effectiveness analyses after the second appraisal committee meeting
After the second appraisal committee meeting, the company updated its economic model to address the committee's concerns about the following scenarios:
The potential effect of including the costs that would be incurred for patients who need urgent treatment while waiting for cytogenetic results and who were later found to have disease with unfavourable cytogenetics (see section 3.22).
The cost effectiveness of treatment for patients whose disease has an intermediate cytogenetic profile.For each scenario, the results incorporated a confidential simple discount patient access scheme and were presented using 2 alternative sets of input parameters, based on:
The ERG's proposed inputs for its alternative base-case analysis considered at the first appraisal committee meeting. These were:
corrections for minor errors in the company's base case
using initial treatment costs of induction and consolidation therapy based on investigators' assessed data
using individual rates of response based on unpooled ALFA-0701 data
amending haematopoietic stem cell transplant treatment costs to match NHS reference costs
including hospital costs (26.8 days) for treating veno-occlusive disease
excluding specific costs of graft versus host disease
excluding veno-occlusive disease events from the standard care arm
changing assumptions to ensure that patients who are functionally cured have lower health-related quality of life than the general population
adjusting the mortality rate, so that it is equal to the general population mortality rate when the observed mortality rate is reported to be lower than that for the general population.
The company added 2 adjustments to the ERG's base case:
utility value of 0.77 for functionally cured patients (see section 3.20) and
an update to the mixture cure model parameters (see section 3.19).
# Survival modelling
## People who have not relapsed after 5 years are considered to be cured
In its original submission, the company assumed that patients who were alive after 5 years from the start of the gemtuzumab ozogamicin treatment were considered to be functionally cured. The clinical experts confirmed that if patients have not had a haematopoietic stem cell transplant and have not relapsed within 5 years, they would be considered cured. The clinical experts also estimated that relapses between 3 and 5 years are rare; they happen in less than 5% of AML patients. The committee concluded that using 5 years as a cure point was appropriate.
## Survival curves for people considered to be cured are appropriately modelled
In its original submission, the company explored various alternative approaches for extrapolating survival data. It explored a range of mixture cure model survival functions and concluded that the log-normal and Weibull models showed the best statistical and visual fit. The difference in the cure fraction between treatment groups was broadly similar for both the mixture cure model log-normal and Weibull functions for both event-free survival and overall survival. The ERG noted that this was important because the difference between the groups is the main driver of differences in the quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) estimates. The committee concluded that the company's approach to curve fitting and the rationale for selecting the log-normal function in its base case was appropriately justified.
## A mortality risk higher than that for the general population is appropriate for patients who are considered to be cured
In its original submission, the company calculated an increased mortality risk for functionally cured patients compared with the general population. The company considered the increased mortality risk to be academic-in-confidence and therefore it cannot be reported here. The ERG noted that in some years the probability of death was still higher for the general population than for the functionally cured patients. The ERG adjusted the mortality calculations so that the mortality risk for functionally cured patients was always higher than for the general population. This increased the hazard ratio. The committee agreed that the ERG's hazard ratio was more plausible. In response to consultation and in the analyses provided after the second appraisal committee meeting (see section 3.16), the company re-estimated its base-case mixture cure curves with background mortality based on the lifetables (Office of National Statistics, 2017). The committee considered this amendment to be reasonable and noted that it had little effect on the ICER.
# Utility values in the model
## Patients considered to be cured would have a lower quality of life than that of the general population
The company used utility values from literature sources, because information on health-related quality of life was not collected as part of ALFA-0701. In the economic model, the company assumed that functionally cured patients have the same health-related quality of life as the general population. The ERG used lower utility values for functionally cured patients. The committee considered the ERG's approach to be reasonable and that this was consistent with the assumption that functionally cured patients have a higher mortality risk than the general population (see section 3.19). The committee concluded that the ERG's alternative utility values were the most plausible. After the second appraisal committee meeting, the company presented a scenario analysis with an alternative utility value of 0.77 (from NICE's technology appraisal guidance on azacitidine for treating acute myeloid leukaemia with more than 30% bone marrow blasts) compared with that used by the ERG (0.74) and 0.74 for the complete remission health state. The committee considered that the company's alternative utility value was reasonable and noted that it had little effect on the ICER.
# A stopping rule for people who have treatment before cytogenetic test results are available
## A stopping rule is appropriate for people who need gemtuzumab ozogamicin induction therapy before their cytogenetic test results are available
The committee recalled that some patients might need urgent treatment, which would involve starting gemtuzumab ozogamicin without their cytogenetic test results being available (see section 3.4). It also recalled that urgent therapy was needed if the patient had a very high white blood cell count, a rapidly increasing white blood cell count, evidence of tumour lysis with or without disseminated intravascular coagulation or had life-threatening bleeding or infection (see section 3.4). The committee was aware that the treatment costs for patients who need urgent treatment while waiting for their cytogenetic test results and who were later found to have unfavourable cytogenetics were not included in the company's original economic model. Including them may result in an increase in the ICER. The committee agreed that in clinical practice, patients would have gemtuzumab ozogamicin with the first course of chemotherapy while waiting for their cytogenetic results. Treatment with gemtuzumab ozogamicin should only be continued after induction therapy (that is consolidation therapy) for patients whose disease did not have unfavourable cytogenetics. The committee concluded that it was appropriate to include a stopping rule in the cost-effectiveness analyses for people who need urgent treatment with gemtuzumab ozogamicin before cytogenetic test results are available.
## The company's approach to modelling the stopping rule is appropriate for decision-making
To address the committee's concerns about the potential effect of including the costs that would be incurred in patients who need urgent treatment while waiting for cytogenetic test results and who were later found to have disease with unfavourable cytogenetics, the company did a revised analysis after the second appraisal committee meeting (see section 3.16). In this analysis, 100% of patients were assumed to have disease of unknown cytogenetic status and were given 1 cycle of induction therapy with gemtuzumab ozogamicin. The analysis further assumed that, at the time a decision is made to proceed (or not) with consolidation therapy, cytogenetic status would be known and only patients with disease of favourable and intermediate cytogenetics would continue gemtuzumab ozogamicin consolidation therapy. To support the above assumption, the company noted that the time lag between induction and consolidation therapies is approximately 3 months. In the revised analysis, it was assumed that 21% of patients would have disease with unfavourable cytogenetics, based on the distribution observed in ALFA-0701. The cost of providing gemtuzumab ozogamicin consolidation therapy was adjusted accordingly by excluding the costs of consolidation therapy for this proportion of patients. The clinical-effectiveness data for gemtuzumab ozogamicin for this analysis was based on the 'all patient' survival analysis. It was assumed that gemtuzumab ozogamicin would not provide any clinical benefit for patients whose disease had unfavourable cytogenetics. Therefore removing the consolidation courses would not be expected to change incremental QALYs. The committee noted the ERG's critique of the company's implementation of the stopping rule. It was aware of the ERG's concerns about the company's comment that only patients who had disease with known favourable and intermediate cytogenetics would continue with gemtuzumab ozogamicin consolidation therapy, and that this appeared to exclude consolidation treatment for patients with disease with unknown cytogenetics because the cytogenetic test was unsuccessful (see section 3.5). The committee also noted the ERG's comment that the company's revised analysis actually assumed that patients would continue with consolidation therapy only if they were known not to have unfavourable cytogenetics (that is, including people who had disease with favourable, intermediate or unknown cytogenetics because the cytogenetic test was unsuccessful). The committee agreed that the company's interpretation was consistent with the committee's preferred stopping rule and that the company's approach to modelling the stopping rule was appropriate for its decision-making.
# Cost-effectiveness results
## The most plausible ICER for the company's base-case population (including the stopping rule) is below £20,000 per QALY gained
At the first committee meeting, the committee noted that the company's and ERG's original deterministic base-case ICERs for gemtuzumab ozogamicin compared with standard care for patients whose disease did not have unfavourable cytogenetics (that is, the disease had favourable, intermediate or unknown cytogenetics) were £12,251 per QALY gained and £16,910 per QALY gained respectively (see section 3.16 for the ERG's inputs into its alternative base case). The committee was aware that neither of these analyses incorporated its preferred stopping rule for people who need urgent treatment with gemtuzumab ozogamicin before cytogenetic test results are available. It therefore considered the company's revised analyses provided after the second appraisal committee meeting, which incorporated its preferred stopping rule (see sections 3.16, 3.21 and 3.22). The committee noted that the probabilistic ICERs based on the list price for gemtuzumab ozogamicin were:
£20,787 per QALY gained based on the ERG's original parameter inputs only (see section 3.16) or
£19,556 per QALY gained based on the company's 2 additional amendments to the ERG's original analysis (see section 3.16).The committee noted that the 2 scenarios using the 2 alternative sets of input parameters (see section 3.16) were similar and that both approaches were reasonable. It was aware that the company had provided probabilistic ICERs for these analyses incorporating a simple discount patient access scheme (the ICERs incorporating the patient access scheme for gemtuzumab ozogamicin are confidential and cannot be reported here). The committee noted that the ICERs decreased when the gemtuzumab ozogamicin patient access scheme was taken into account. The committee recalled that it considered the company to have modelled the stopping rule appropriately. It therefore concluded that the most plausible ICER (including the stopping rule) for gemtuzumab ozogamicin compared with chemotherapy for a group of people whose disease had favourable, intermediate or unknown (because their test results were unsuccessful) cytogenetics was below £20,000 per QALY gained.
## The ICER for people whose disease has intermediate cytogenetics is below £30,000 per QALY gained
The committee was aware of the ERG's concerns about heterogeneity in the clinical outcomes in the subgroup whose disease had intermediate cytogenetics (see section 3.11). This subgroup was included in the company's original base-case analysis. At the first appraisal committee meeting the committee considered the ERG's original exploratory analyses, which explored the effect of the heterogeneity on the ICERs. The committee noted that the deterministic ICER for the subgroup of patients whose disease had intermediate cytogenetics only was £31,709 per QALY gained, but that it was lower for the subgroup of patients whose disease had intermediate-1 molecular status (£16,343 per QALY gained). It agreed that it was reasonable to assume that the heterogeneity in the clinical outcomes was leading to the higher ICER for the intermediate cytogenetic group. The committee recalled that the clinical experts explained that such classification of the intermediate group was not being used in clinical practice and that it had concluded not to split the intermediate cytogenetic group using an outdated classification system (see section 3.12). The committee therefore agreed that the most relevant ICER for its decision-making was the ICER for the intermediate group, which was £31,709 per QALY gained. The committee considered the company's additional cost-effectiveness analysis for the intermediate cytogenetic group provided after the second appraisal committee meeting (see section 3.16). The committee noted that the probabilistic list price ICERs were £33,683 per QALY gained or £32,991 per QALY gained, depending on whether they were based on the ERG's original proposed parameter inputs only or with the company's 2 additional amendments (see section 3.16). The committee was aware that the company had provided probabilistic ICERs for these analyses incorporating a simple discount patient access scheme (the ICERs incorporating the patient access scheme are confidential and cannot be reported here). The committee noted the ICERs decreased when the gemtuzumab ozogamicin patient access scheme was taken into account. It concluded that the most plausible ICER for the intermediate group was below £30,000 per QALY gained.
## It is not appropriate to consider the subgroup of patients with unfavourable cytogenetic status
The committee was aware that neither the company nor the ERG had presented clinical- or cost-effectiveness evidence for the subgroup of patients whose disease had unfavourable cytogenetic status. The committee recalled that the clinical experts' comments and the consultation comments supported the company's rationale for excluding patients whose disease had unfavourable cytogenetics (see sections 3.3 and 3.5). In the response to consultation, a consultee highlighted that a meta-analysis by Hills et al., which was based on ALFA 0701, AML 15 and 16, showed that gemtuzumab ozogamicin should not be given to patients whose disease is known to have unfavourable cytogenetics. The committee agreed that it was not appropriate to consider the subgroup of patients whose disease had unfavourable cytogenetics in its recommendations.
# Innovation
## There are no additional benefits that are not captured in the QALY calculations
The company considered gemtuzumab ozogamicin to be an innovative treatment because when used with daunorubicin and cytarabine it extends the duration of remission. It works in a novel way to directly target CD33-positive AML blasts and induce leukaemia cell death. The committee concluded that gemtuzumab ozogamicin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# End of life
## Gemtuzumab ozogamicin does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a 'life-extending treatment at the end of life' if it is indicated for patients with a short life expectancy, normally less than 24 months, and it offers an extension to life, normally of a mean value of at least an additional 3 months compared with current NHS treatment. The committee noted that the results of ALFA-0701 showed that gemtuzumab ozogamicin could increase life expectancy compared with standard care by more than 3 months. However, the short life expectancy criterion was not met (company model: standard care life years gained was 6.02).
# Conclusion
## Gemtuzumab ozogamicin is recommended for routine use for disease with cytogenetics that are favourable, intermediate or unknown (because the test was unsuccessful)
The committee concluded that gemtuzumab ozogamicin, plus daunorubicin and cytarabine, was clinically effective compared with chemotherapy (see sections 3.10 and 3.11). The committee was aware that some patients need gemtuzumab ozogamicin before cytogenetic test results are available (see section 3.21). The committee concluded that patients should have gemtuzumab ozogamicin induction therapy while waiting for their cytogenetic results. Gemtuzumab ozogamicin should only be continued after induction therapy (that is consolidation therapy) for patients whose disease has favourable or intermediate cytogenetics, confirmed by cytogenetic testing, or unknown cytogenetics (because the cytogenetic test was unsuccessful; see section 3.21). The most plausible cost-effectiveness estimates for gemtuzumab ozogamicin for people whose disease has favourable, intermediate or unknown cytogenetics (because the cytogenetic test was unsuccessful) are within the range that NICE normally considers an acceptable use of NHS resources (see sections 3.23 and 3.24). Therefore, gemtuzumab ozogamicin can be recommended for these groups of people. Because no clinical- or cost-effectiveness analysis was presented for people whose disease has unfavourable cytogenetics, gemtuzumab ozogamicin cannot be recommended for this group (see section 3.25).
|
{'Recommendations': "Gemtuzumab ozogamicin, with daunorubicin and cytarabine, is recommended as an option for untreated de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia, in people 15\xa0years and over, only if:\n\nthey start induction therapy when either the cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (that is, because the test was unsuccessful) or when their cytogenetic test results are not yet available and\n\nthey start consolidation therapy when their cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (because the test was unsuccessful) and\n\nthe company provides gemtuzumab ozogamicin according to the commercial arrangement.\n\nThese recommendations are not intended to affect treatment with gemtuzumab ozogamicin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people aged 15 to 17, this decision should be made jointly by the young person and their parents or carers and the clinician.\n\nWhy the committee made these recommendations\n\nAML is currently treated with daunorubicin plus cytarabine. Cytogenetic testing is used to look for specific gene mutations in certain types of leukaemia, which might predict how a person's disease responds to treatment and affect treatment options. People whose disease has favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics in terms of treatment response, risk of relapse and survival. However, for some patients the cytogenetic test results are not available at the start of induction treatment.\n\nEvidence from a randomised clinical trial shows that, for people whose disease has favourable or intermediate cytogenetics, gemtuzumab ozogamicin with daunorubicin and cytarabine is more clinically effective than daunorubicin and cytarabine. People are more likely to live longer without the disease relapsing or symptoms returning.\n\nBecause no clinical- or cost-effectiveness analysis is presented for people whose disease has unfavourable cytogenetics, gemtuzumab ozogamicin cannot be recommended for this group.\n\nThe most plausible cost-effectiveness estimates (including the stopping rule for consolidation therapy in people who have unfavourable cytogenetics) for gemtuzumab ozogamicin compared with daunorubicin and cytarabine in people whose disease has favourable, intermediate or unknown cytogenetics (because the cytogenetic test is unsuccessful) are within the range that NICE normally considers an acceptable use of NHS resources. Therefore gemtuzumab ozogamicin can be recommended for these groups of people.", 'Information about gemtuzumab ozogamicin': "# Marketing authorisation indication\n\nGemtuzumab ozogamicin (Mylotarg, Pfizer) is indicated 'for the treatment of previously untreated, de novo CD33-positive acute myeloid leukaemia, except acute promyelocytic leukaemia for patients age 15\xa0years and above, in combination with daunorubicin and cytarabine.'\n\n# Dosage in the marketing authorisation\n\nThe gemtuzumab ozogamicin dose is 3\xa0mg/m2/dose (up to a maximum of 1×5-mg vial) infused over a 2-hour period. Induction: gemtuzumab ozogamicin 3\xa0mg/m2/dose (up to a maximum of 5\xa0mg/dose) given on days 1, 4 and 7. Consolidation courses 1 and 2: gemtuzumab ozogamicin 3\xa0mg/m2/dose (up to a maximum of 5\xa0mg/dose) given on day\xa01 of each course.\n\n# Price\n\n£6,300 per 5-mg vial (excluding VAT; British national formulary [BNF] online [accessed August 2018]). The company has a commercial arrangement. This makes gemtuzumab ozogamicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with acute myeloid leukaemia would welcome a new treatment option\n\nAcute myeloid leukaemia (AML) is a rapidly progressing form of leukaemia. People with the disease have fatigue, weakness or breathlessness, memory loss, bruising, bleeding and frequent infections. There is a poor prognosis for patients whose disease does not respond to treatment, or whose disease responds then relapses. The committee agreed that new treatments, which could improve the chance of successfully inducing first remission would be welcomed.\n\n# Clinical management\n\n## Current treatment for AML is daunorubicin plus cytarabine and this is the appropriate comparator\n\nThe aim of intensive chemotherapy is to induce complete remission. After this people would have either consolidation chemotherapy or a stem cell transplant. Most patients with AML in the UK are entered into the National Cancer Research Institute AML trials; AML\xa019 for younger patients and AML\xa018 for patients over 60\xa0years. Both trials currently include gemtuzumab ozogamicin as an induction therapy for patients without a known adverse karyotype at diagnosis. Outside of clinical trials, most patients for whom intensive chemotherapy is considered suitable currently have standard combination chemotherapy (daunorubicin plus cytarabine) without the addition of gemtuzumab ozogamicin. Intensive treatment for AML is essentially unchanged in 40\xa0years. Although survival has gradually improved this has been largely a result of improvements in supportive care and decision-making about when to have allogeneic stem cell transplant. The committee concluded that established clinical management is daunorubicin plus cytarabine and this is the relevant comparator for this appraisal.\n\n## Cytogenetic testing is standard clinical practice in England\n\nEveryone with newly diagnosed AML has cytogenetic testing because this provides important information about prognosis and how the disease might respond to different treatments. People who have AML with favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics. The committee understood that larger centres have placed great emphasis on obtaining the cytogenetic results as quickly as possible, usually within days. However in smaller centres, it may take between 1 and 3\xa0weeks to obtain the results. The clinical experts confirmed that cytogenetic testing takes between 7\xa0to\xa010\xa0days and it would be challenging to reduce this to less than 7\xa0days. The committee acknowledged that cytogenetic testing is standard clinical practice and confirmed its importance in the clinical management of untreated AML.\n\n## Cytogenetic test results are not always available at the start of the induction treatment\n\nSome patients need to start treatment urgently before cytogenetic results have been received. The clinical experts at the first committee meeting explained that around 15% to 20% of patients have a very high or rapidly increasing white blood cell count, evidence of tumour lysis or disseminated intravascular coagulation, or life-threatening bleeding or infection when they are diagnosed. They also explained that for this group of patients there is no evidence to suggest that starting treatment before cytogenetic results are available is harmful. Treatment would be stopped if the tests revealed that the patient had AML with unfavourable cytogenetics. In response to consultation, consultees emphasised the importance of patients with AML having treatment within a week of their diagnosis. One of the consultees highlighted that 32% of patients with AML start treatment on the day of diagnosis and a further 47% start treatment within a week of their diagnosis. The committee accepted that the proportion of patients who have to start treatment urgently before cytogenetic results have been received (approximately 80%) was much higher than the 15% to 20% initially considered at the first committee meeting. The committee acknowledged the importance of being able to start treatment for these people before cytogenetic test results are available. It agreed to explore the effect of including the costs that would be incurred in patients who need urgent treatment while waiting for cytogenetic results and who were later found to have unfavourable cytogenetics (see section\xa03.5) and to take this into account in its decision-making (see section\xa03.16).\n\n# Population\n\n## The population specified in the company's decision problem is appropriate\n\nThe committee considered the population relevant to this appraisal and noted that the marketing authorisation does not define the population by cytogenetic status. But the company's base case focused on patients whose disease was not known to have unfavourable cytogenetics. This included people whose disease had favourable, intermediate or unknown cytogenetics. The committee was aware from responses to consultation that approximately 20% of patients have favourable cytogenetics, 60% have intermediate cytogenetics and 20% have unfavourable cytogenetics. The clinical experts supported the company's rationale for excluding patients whose disease had unfavourable cytogenetics because these patients have a worse prognosis (see section\xa03.3). The committee recalled that patients who have AML with favourable or intermediate cytogenetics have a better prognosis than those whose disease has unfavourable cytogenetics (see section\xa03.3). It was also aware that there was a subgroup of patients with unknown cytogenetics in the company's base case. This subgroup could include those for whom treatment was started before the test results had become available (see section\xa03.4) and those for whom the testing was unsuccessful in determining cytogenetic status. The clinical experts explained that if the testing was unsuccessful, it was not routine clinical practice to re-test. The committee understood that an element of clinical judgement was needed when offering treatment to these patients but they would generally have the same treatment as those with favourable or intermediate cytogenetics. The committee concluded that the population specified in the company's decision problem was appropriate.\n\n# Clinical evidence\n\n## The results from ALFA-0701 are generalisable to clinical practice in England\n\nALFA-0701 (n=271) was an open-label, phase\xa0III, randomised controlled trial, done across 26\xa0haematology centres in France. It included patients aged 50 to 70\xa0years with previously untreated de novo (that is, it excluded secondary leukaemia) AML. The trial compared gemtuzumab ozogamicin plus daunorubicin and cytarabine with daunorubicin and cytarabine alone. The data presented were from the 30\xa0April\xa02013 data cut and the committee stated that a more recent data cut from ALFA-0701 trial would be informative. The population covered by the marketing authorisation was extended to include people aged 15 to 17\xa0years and restricted to de novo CD33-positive AML. Most patients diagnosed with AML are over 50\xa0years. Therefore, the population included in the trial is likely to reflect most patients for whom gemtuzumab ozogamicin would be suitable in clinical practice. The trial did include a small number of patients whose disease was not CD33-positive, who would not have gemtuzumab ozogamicin according to the marketing authorisation. The committee agreed that it can only appraise gemtuzumab ozogamicin within its marketing authorisation. It concluded that ALFA-0701 trial is generalisable to the population who would have gemtuzumab ozogamicin plus daunorubicin and cytarabine in clinical practice in England.\n\n## The dosing schedule in ALFA-0701 differs from the dose in ongoing trials in the UK\n\nThe dosage for gemtuzumab ozogamicin in ALFA-0701 is in line with the marketing authorisation. However, the 2\xa0ongoing UK trials (AML\xa018 and AML\xa019) use a different dosage. Therefore, the granting of the marketing authorisation may have implications for practice, because UK clinicians are currently using the dosage used in AML\xa018 and AML\xa019, rather than the licensed dosage. The committee agreed that it could only recommend gemtuzumab ozogamicin in line with the dosage specified in the marketing authorisation.\n\n## The individual patient data meta-analysis may not be generalisable to clinical practice in England\n\nThe main clinical evidence was supported by an individual patient data meta-analysis. However, the meta-analysis included patients aged 15\xa0years or over with newly diagnosed de novo or secondary AML or high-risk myelodysplastic syndrome. This is a broader population than the marketing authorisation. The committee concluded that the results may not be generalisable to people who would have gemtuzumab ozogamicin in clinical practice in England.\n\n# Clinical-effectiveness results\n\n## Gemtuzumab ozogamicin increases event-free survival and relapse-free survival compared with chemotherapy\n\nThe company reported outcomes assessed by investigator and by independent review committee. The analysis by independent review committee was considered to be academic-in-confidence by the company and cannot be reported here. Because the analyses by investigator assessment are reported in the summary of product characteristics, those results are reported here. The primary outcome measure in ALFA-0701 was event-free survival. An event was defined as induction failure, relapse or death. Treatment with gemtuzumab ozogamicin plus daunorubicin and cytarabine increased median event-free survival compared with daunorubicin and cytarabine alone. The analysis by investigator assessment shows increased median event-free survival from 9.5\xa0months to 17.3\xa0months (hazard ratio [HR] 0.56; 95% confidence intervals [CI] 0.42 to 0.76, p=0.0002). Relapse-free survival and overall survival were secondary end points. Median relapse-free survival increased from 11.4\xa0months to 28\xa0months (HR 0.53; 95% CI 0.36 to 0.76, p=0.0006) in patients who had gemtuzumab ozogamicin plus daunorubicin and cytarabine. Median overall survival increased from 21.8\xa0months to 27.5\xa0months (HR 0.81; 95% Cl 0.60 to 1.09, p=0.165). However, the difference between treatment groups did not reach statistical significance. The committee concluded that gemtuzumab ozogamicin plus daunorubicin and cytarabine was clinically effective compared with chemotherapy.\n\n## Gemtuzumab ozogamicin increases event-free survival and relapse-free survival in the combined favourable and intermediate cytogenetic group but not in the unfavourable group compared with chemotherapy\n\nThe company reported outcomes assessed by investigators and by independent review committee, categorised by cytogenetic profile. The analysis by independent review committee was considered to be academic-in-confidence by the company and cannot be reported here. Because analyses by investigator assessment are reported in the summary of product characteristics, those results are reported here. Gemtuzumab ozogamicin plus daunorubicin and cytarabine increased median event-free survival from 12.2\xa0months to 22.5\xa0months (HR 0.49; 95% CI 0.33 to 0.72, p=0.0003) in those whose disease had favourable or intermediate cytogenetics. There was no statistically significant difference in median event-free survival in patients whose disease had unfavourable cytogenetics (from 2.8\xa0months to 4.5\xa0months [HR 1.111; 95% CI 0.63 to 1.95, p=0.72]). For patients whose disease had favourable or intermediate cytogenetics, overall survival increased from 26.0\xa0months to 38.6\xa0months (HR 0.747; 95% CI 0.511 to 1.091, p=0.1288). For patients whose disease had unfavourable cytogenetics, overall survival decreased from 13.5\xa0months to 12.0\xa0months (HR 1.553; CI 0.878 to 2.748, p=0.1267). The committee concluded that gemtuzumab ozogamicin plus daunorubicin and cytarabine compared with chemotherapy was clinically effective for patients whose disease had favourable and intermediate cytogenetics. Also, results from those subgroups were better than for the overall population, but only when results from patients with unfavourable cytogenetics were excluded.\n\n## There is heterogeneity in the clinical outcomes in the intermediate cytogenetic subgroup\n\nThe company provided additional analyses for the intermediate cytogenetic group by cytogenetic and molecular risk profile (that is, for intermediate-1 and intermediate-2 subgroups). The company reported outcomes by independent review committee only. The analysis was considered to be academic-in-confidence by the company and cannot be reported here. The ERG highlighted the differences in the clinical benefit seen in patients whose disease had an intermediate-1 or intermediate-2 cytogenetic and molecular risk profile. The committee acknowledged that results for the intermediate-2 group were based on small numbers of patients. The committee concluded that the results highlighted heterogeneity in the clinical outcomes in the intermediate group. Therefore it agreed to account for this in its decision-making (see section\xa03.24).\n\n## The intermediate-1 and -2 cytogenetic subgroup classification system is outdated\n\nThe clinical experts explained that the classification of intermediate-1 and intermediate-2 by cytogenetics only is outdated, and a new classification is being used in clinical practice. This updated classification takes account of more genetic abnormalities such as abnormalities in FLT3, NPM1, CEBPA and other genes. In response to consultation, the company highlighted that although clinicians may consider the intermediate-1 and ‑2 classification outdated, the intermediate-1 subgroup accounts for two-thirds of the total patients expected to have treatment in clinical practice. The committee concluded that, although the clinical results are different between intermediate-1 and -2, it would prefer not to split the intermediate group using an outdated classification system.\n\n## Gemtuzumab ozogamicin is generally well tolerated\n\nThere was an increase in veno-occlusive disease in patients taking gemtuzumab ozogamicin plus daunorubicin and cytarabine compared with those taking daunorubicin and cytarabine alone. However, the numbers of patients who had other adverse effects were similar between the 2\xa0groups. The committee concluded that gemtuzumab ozogamicin was generally well tolerated.\n\n## The risk of developing veno-occlusive disease is low\n\nThe patient organisation stated that the risk of veno-occlusive disease appeared to be relatively low when gemtuzumab ozogamicin doses of 3\xa0mg/m2 or less are used with standard therapy as part of initial therapy for AML. This is in line with the dosage in the marketing authorisation and in ALFA-0701. The clinical experts confirmed that it was a rare side effect but clinicians are experienced in managing it. The committee concluded that the risk of developing veno-occlusive disease because of gemtuzumab ozogamicin was low.\n\n# Company's economic model\n\n## The model is complex and appropriate for decision-making\n\nIn its original submission, the company presented a semi-Markov cohort state-transition model with 12\xa0health states. The main effectiveness data came from ALFA-0701. It was used to estimate overall survival and relapse-free survival, using mixture cure models fit to Kaplan–Meier data. The committee was aware that there was no explicit structural link between a number of key model parameters, including between relapse and haematopoietic stem cell transplant; the model structure was complex and challenging to critique. However, the committee concluded that model was appropriate for decision-making.\n\n## The company updated its model and cost-effectiveness analyses after the second appraisal committee meeting\n\nAfter the second appraisal committee meeting, the company updated its economic model to address the committee's concerns about the following scenarios:\n\n\n\nThe potential effect of including the costs that would be incurred for patients who need urgent treatment while waiting for cytogenetic results and who were later found to have disease with unfavourable cytogenetics (see section\xa03.22).\n\nThe cost effectiveness of treatment for patients whose disease has an intermediate cytogenetic profile.For each scenario, the results incorporated a confidential simple discount patient access scheme and were presented using 2\xa0alternative sets of input parameters, based on:\n\nThe ERG's proposed inputs for its alternative base-case analysis considered at the first appraisal committee meeting. These were:\n\n\n\ncorrections for minor errors in the company's base case\n\nusing initial treatment costs of induction and consolidation therapy based on investigators' assessed data\n\nusing individual rates of response based on unpooled ALFA-0701 data\n\namending haematopoietic stem cell transplant treatment costs to match NHS reference costs\n\nincluding hospital costs (26.8\xa0days) for treating veno-occlusive disease\n\nexcluding specific costs of graft versus host disease\n\nexcluding veno-occlusive disease events from the standard care arm\n\nchanging assumptions to ensure that patients who are functionally cured have lower health-related quality of life than the general population\n\nadjusting the mortality rate, so that it is equal to the general population mortality rate when the observed mortality rate is reported to be lower than that for the general population.\n\n\n\nThe company added 2\xa0adjustments to the ERG's base case:\n\n\n\nutility value of 0.77\xa0for functionally cured patients (see section\xa03.20) and\n\nan update to the mixture cure model parameters (see section\xa03.19).\n\n\n\n\n\n# Survival modelling\n\n## People who have not relapsed after 5\xa0years are considered to be cured\n\nIn its original submission, the company assumed that patients who were alive after 5\xa0years from the start of the gemtuzumab ozogamicin treatment were considered to be functionally cured. The clinical experts confirmed that if patients have not had a haematopoietic stem cell transplant and have not relapsed within 5\xa0years, they would be considered cured. The clinical experts also estimated that relapses between 3 and 5\xa0years are rare; they happen in less than 5% of AML patients. The committee concluded that using 5\xa0years as a cure point was appropriate.\n\n## Survival curves for people considered to be cured are appropriately modelled\n\nIn its original submission, the company explored various alternative approaches for extrapolating survival data. It explored a range of mixture cure model survival functions and concluded that the log-normal and Weibull models showed the best statistical and visual fit. The difference in the cure fraction between treatment groups was broadly similar for both the mixture cure model log-normal and Weibull functions for both event-free survival and overall survival. The ERG noted that this was important because the difference between the groups is the main driver of differences in the quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) estimates. The committee concluded that the company's approach to curve fitting and the rationale for selecting the log-normal function in its base case was appropriately justified.\n\n## A mortality risk higher than that for the general population is appropriate for patients who are considered to be cured\n\nIn its original submission, the company calculated an increased mortality risk for functionally cured patients compared with the general population. The company considered the increased mortality risk to be academic-in-confidence and therefore it cannot be reported here. The ERG noted that in some years the probability of death was still higher for the general population than for the functionally cured patients. The ERG adjusted the mortality calculations so that the mortality risk for functionally cured patients was always higher than for the general population. This increased the hazard ratio. The committee agreed that the ERG's hazard ratio was more plausible. In response to consultation and in the analyses provided after the second appraisal committee meeting (see section\xa03.16), the company re-estimated its base-case mixture cure curves with background mortality based on the lifetables (Office of National Statistics, 2017). The committee considered this amendment to be reasonable and noted that it had little effect on the ICER.\n\n# Utility values in the model\n\n## Patients considered to be cured would have a lower quality of life than that of the general population\n\nThe company used utility values from literature sources, because information on health-related quality of life was not collected as part of ALFA-0701. In the economic model, the company assumed that functionally cured patients have the same health-related quality of life as the general population. The ERG used lower utility values for functionally cured patients. The committee considered the ERG's approach to be reasonable and that this was consistent with the assumption that functionally cured patients have a higher mortality risk than the general population (see section\xa03.19). The committee concluded that the ERG's alternative utility values were the most plausible. After the second appraisal committee meeting, the company presented a scenario analysis with an alternative utility value of 0.77 (from NICE's technology appraisal guidance on azacitidine for treating acute myeloid leukaemia with more than 30% bone marrow blasts) compared with that used by the ERG (0.74) and 0.74 for the complete remission health state. The committee considered that the company's alternative utility value was reasonable and noted that it had little effect on the ICER.\n\n# A stopping rule for people who have treatment before cytogenetic test results are available\n\n## A stopping rule is appropriate for people who need gemtuzumab ozogamicin induction therapy before their cytogenetic test results are available\n\nThe committee recalled that some patients might need urgent treatment, which would involve starting gemtuzumab ozogamicin without their cytogenetic test results being available (see section\xa03.4). It also recalled that urgent therapy was needed if the patient had a very high white blood cell count, a rapidly increasing white blood cell count, evidence of tumour lysis with or without disseminated intravascular coagulation or had life-threatening bleeding or infection (see section 3.4). The committee was aware that the treatment costs for patients who need urgent treatment while waiting for their cytogenetic test results and who were later found to have unfavourable cytogenetics were not included in the company's original economic model. Including them may result in an increase in the ICER. The committee agreed that in clinical practice, patients would have gemtuzumab ozogamicin with the first course of chemotherapy while waiting for their cytogenetic results. Treatment with gemtuzumab ozogamicin should only be continued after induction therapy (that is consolidation therapy) for patients whose disease did not have unfavourable cytogenetics. The committee concluded that it was appropriate to include a stopping rule in the cost-effectiveness analyses for people who need urgent treatment with gemtuzumab ozogamicin before cytogenetic test results are available.\n\n## The company's approach to modelling the stopping rule is appropriate for decision-making\n\nTo address the committee's concerns about the potential effect of including the costs that would be incurred in patients who need urgent treatment while waiting for cytogenetic test results and who were later found to have disease with unfavourable cytogenetics, the company did a revised analysis after the second appraisal committee meeting (see section\xa03.16). In this analysis, 100% of patients were assumed to have disease of unknown cytogenetic status and were given 1\xa0cycle of induction therapy with gemtuzumab ozogamicin. The analysis further assumed that, at the time a decision is made to proceed (or not) with consolidation therapy, cytogenetic status would be known and only patients with disease of favourable and intermediate cytogenetics would continue gemtuzumab ozogamicin consolidation therapy. To support the above assumption, the company noted that the time lag between induction and consolidation therapies is approximately 3\xa0months. In the revised analysis, it was assumed that 21% of patients would have disease with unfavourable cytogenetics, based on the distribution observed in ALFA-0701. The cost of providing gemtuzumab ozogamicin consolidation therapy was adjusted accordingly by excluding the costs of consolidation therapy for this proportion of patients. The clinical-effectiveness data for gemtuzumab ozogamicin for this analysis was based on the 'all patient' survival analysis. It was assumed that gemtuzumab ozogamicin would not provide any clinical benefit for patients whose disease had unfavourable cytogenetics. Therefore removing the consolidation courses would not be expected to change incremental QALYs. The committee noted the ERG's critique of the company's implementation of the stopping rule. It was aware of the ERG's concerns about the company's comment that only patients who had disease with known favourable and intermediate cytogenetics would continue with gemtuzumab ozogamicin consolidation therapy, and that this appeared to exclude consolidation treatment for patients with disease with unknown cytogenetics because the cytogenetic test was unsuccessful (see section\xa03.5). The committee also noted the ERG's comment that the company's revised analysis actually assumed that patients would continue with consolidation therapy only if they were known not to have unfavourable cytogenetics (that is, including people who had disease with favourable, intermediate or unknown cytogenetics because the cytogenetic test was unsuccessful). The committee agreed that the company's interpretation was consistent with the committee's preferred stopping rule and that the company's approach to modelling the stopping rule was appropriate for its decision-making.\n\n# Cost-effectiveness results\n\n## The most plausible ICER for the company's base-case population (including the stopping rule) is below £20,000 per QALY gained\n\nAt the first committee meeting, the committee noted that the company's and ERG's original deterministic base-case ICERs for gemtuzumab ozogamicin compared with standard care for patients whose disease did not have unfavourable cytogenetics (that is, the disease had favourable, intermediate or unknown cytogenetics) were £12,251\xa0per QALY gained and £16,910 per QALY gained respectively (see section\xa03.16 for the ERG's inputs into its alternative base case). The committee was aware that neither of these analyses incorporated its preferred stopping rule for people who need urgent treatment with gemtuzumab ozogamicin before cytogenetic test results are available. It therefore considered the company's revised analyses provided after the second appraisal committee meeting, which incorporated its preferred stopping rule (see sections\xa03.16, 3.21 and 3.22). The committee noted that the probabilistic ICERs based on the list price for gemtuzumab ozogamicin were:\n\n\n\n\n\n£20,787 per QALY gained based on the ERG's original parameter inputs only (see section\xa03.16) or\n\n£19,556 per QALY gained based on the company's 2\xa0additional amendments to the ERG's original analysis (see section\xa03.16).The committee noted that the 2\xa0scenarios using the 2\xa0alternative sets of input parameters (see section\xa03.16) were similar and that both approaches were reasonable. It was aware that the company had provided probabilistic ICERs for these analyses incorporating a simple discount patient access scheme (the ICERs incorporating the patient access scheme for gemtuzumab ozogamicin are confidential and cannot be reported here). The committee noted that the ICERs decreased when the gemtuzumab ozogamicin patient access scheme was taken into account. The committee recalled that it considered the company to have modelled the stopping rule appropriately. It therefore concluded that the most plausible ICER (including the stopping rule) for gemtuzumab ozogamicin compared with chemotherapy for a group of people whose disease had favourable, intermediate or unknown (because their test results were unsuccessful) cytogenetics was below £20,000 per QALY gained.\n\n\n\n\n\n## The ICER for people whose disease has intermediate cytogenetics is below £30,000\xa0per QALY gained\n\nThe committee was aware of the ERG's concerns about heterogeneity in the clinical outcomes in the subgroup whose disease had intermediate cytogenetics (see section\xa03.11). This subgroup was included in the company's original base-case analysis. At the first appraisal committee meeting the committee considered the ERG's original exploratory analyses, which explored the effect of the heterogeneity on the ICERs. The committee noted that the deterministic ICER for the subgroup of patients whose disease had intermediate cytogenetics only was £31,709 per QALY gained, but that it was lower for the subgroup of patients whose disease had intermediate-1 molecular status (£16,343 per QALY gained). It agreed that it was reasonable to assume that the heterogeneity in the clinical outcomes was leading to the higher ICER for the intermediate cytogenetic group. The committee recalled that the clinical experts explained that such classification of the intermediate group was not being used in clinical practice and that it had concluded not to split the intermediate cytogenetic group using an outdated classification system (see section\xa03.12). The committee therefore agreed that the most relevant ICER for its decision-making was the ICER for the intermediate group, which was £31,709 per QALY gained. The committee considered the company's additional cost-effectiveness analysis for the intermediate cytogenetic group provided after the second appraisal committee meeting (see section\xa03.16). The committee noted that the probabilistic list price ICERs were £33,683 per QALY gained or £32,991 per QALY gained, depending on whether they were based on the ERG's original proposed parameter inputs only or with the company's 2\xa0additional amendments (see section\xa03.16). The committee was aware that the company had provided probabilistic ICERs for these analyses incorporating a simple discount patient access scheme (the ICERs incorporating the patient access scheme are confidential and cannot be reported here). The committee noted the ICERs decreased when the gemtuzumab ozogamicin patient access scheme was taken into account. It concluded that the most plausible ICER for the intermediate group was below £30,000 per QALY gained.\n\n## It is not appropriate to consider the subgroup of patients with unfavourable cytogenetic status\n\nThe committee was aware that neither the company nor the ERG had presented clinical- or cost-effectiveness evidence for the subgroup of patients whose disease had unfavourable cytogenetic status. The committee recalled that the clinical experts' comments and the consultation comments supported the company's rationale for excluding patients whose disease had unfavourable cytogenetics (see sections\xa03.3 and 3.5). In the response to consultation, a consultee highlighted that a meta-analysis by Hills et al., which was based on ALFA 0701, AML 15 and 16, showed that gemtuzumab ozogamicin should not be given to patients whose disease is known to have unfavourable cytogenetics. The committee agreed that it was not appropriate to consider the subgroup of patients whose disease had unfavourable cytogenetics in its recommendations.\n\n# Innovation\n\n## There are no additional benefits that are not captured in the QALY calculations\n\nThe company considered gemtuzumab ozogamicin to be an innovative treatment because when used with daunorubicin and cytarabine it extends the duration of remission. It works in a novel way to directly target CD33-positive AML blasts and induce leukaemia cell death. The committee concluded that gemtuzumab ozogamicin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# End of life\n\n## Gemtuzumab ozogamicin does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a 'life-extending treatment at the end of life' if it is indicated for patients with a short life expectancy, normally less than 24\xa0months, and it offers an extension to life, normally of a mean value of at least an additional 3\xa0months compared with current NHS treatment. The committee noted that the results of ALFA-0701 showed that gemtuzumab ozogamicin could increase life expectancy compared with standard care by more than 3\xa0months. However, the short life expectancy criterion was not met (company model: standard care life years gained was 6.02).\n\n# Conclusion\n\n## Gemtuzumab ozogamicin is recommended for routine use for disease with cytogenetics that are favourable, intermediate or unknown (because the test was unsuccessful)\n\nThe committee concluded that gemtuzumab ozogamicin, plus daunorubicin and cytarabine, was clinically effective compared with chemotherapy (see sections\xa03.10 and 3.11). The committee was aware that some patients need gemtuzumab ozogamicin before cytogenetic test results are available (see section\xa03.21). The committee concluded that patients should have gemtuzumab ozogamicin induction therapy while waiting for their cytogenetic results. Gemtuzumab ozogamicin should only be continued after induction therapy (that is consolidation therapy) for patients whose disease has favourable or intermediate cytogenetics, confirmed by cytogenetic testing, or unknown cytogenetics (because the cytogenetic test was unsuccessful; see section\xa03.21). The most plausible cost-effectiveness estimates for gemtuzumab ozogamicin for people whose disease has favourable, intermediate or unknown cytogenetics (because the cytogenetic test was unsuccessful) are within the range that NICE normally considers an acceptable use of NHS resources (see sections\xa03.23 and 3.24). Therefore, gemtuzumab ozogamicin can be recommended for these groups of people. Because no clinical- or cost-effectiveness analysis was presented for people whose disease has unfavourable cytogenetics, gemtuzumab ozogamicin cannot be recommended for this group (see section\xa03.25)."}
|
https://www.nice.org.uk/guidance/ta545
|
Evidence-based recommendations on gemtuzumab oxogamicin (Mylotarg) for untreated acute myeloid leukaemia in people aged 15 years and over.
|
f8e4c11e51d10138fc2a0b8c94f5034601aacf53
|
nice
|
Selective internal radiation therapy for unresectable primary intrahepatic cholangiocarcinoma
|
Selective internal radiation therapy for unresectable primary intrahepatic cholangiocarcinoma
Evidence-based recommendations on selective internal radiation therapy for unresectable primary intrahepatic cholangiocarcinoma in adults. This involves injecting tiny radioactive ‘beads’ into blood vessels that supply the liver, where they become trapped and release radiation directly into the cancer cells.
# Recommendations
Current evidence on the safety of selective internal radiation therapy (SIRT) for unresectable primary intrahepatic cholangiocarcinoma shows that there are well-recognised, serious but rare safety concerns. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research in the form of prospective studies, including randomised controlled trials, should address patient selection, quality-of-life outcomes and overall survival. Patient selection for the research studies should be done by a multidisciplinary team. The procedure should only be done in specialist centres by clinicians trained and experienced in managing cholangiocarcinoma.
Clinicians should enter details about all patients having SIRT for unresectable primary intrahepatic cholangiocarcinoma onto a suitable registry.# The condition, current treatments and procedure
# The condition
Intrahepatic cholangiocarcinoma is a rare type of primary liver cancer originating in the bile ducts within the liver parenchyma. It accounts for about 10% of all cholangiocarcinomas (bile duct cancers).
# Current treatments
Intrahepatic cholangiocarcinoma is not usually diagnosed before the symptoms of biliary obstruction occur, by which time the cancer may be too advanced for curative surgical resection. However, surgical removal with curative intent may occasionally be possible by downstaging the tumour using other types of treatment first. The standard options for palliative treatment include chemotherapy, surgical bypass of the bile duct, or inserting a stent using surgical, endoscopic or percutaneous techniques.
Selective internal radiation therapy (SIRT; also known as radio-embolisation) can be used as palliative treatment for unresectable primary liver cancer. It may also be used as a neoadjuvant treatment before surgery in patients being considered for curative treatments such as resection or liver transplantation. It aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to surrounding healthy tissue.
# The procedure
SIRT involves delivering microspheres containing radionuclides that emit beta radiation directly into the tumour via the hepatic artery. Under local anaesthesia with fluoroscopic guidance, the radioactive microspheres, which are made of glass, resin or poly(L‑lactic) acid, are injected into branches of the hepatic artery supplying the tumour. Usually, the percutaneous femoral or radial approach is used. The microspheres are designed to lodge in the small arteries surrounding the tumour and release high doses of localised radiation directly into the tumour. The procedure may be repeated depending on the response.
|
{'Recommendations': 'Current evidence on the safety of selective internal radiation therapy (SIRT) for unresectable primary intrahepatic cholangiocarcinoma shows that there are well-recognised, serious but rare safety concerns. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research in the form of prospective studies, including randomised controlled trials, should address patient selection, quality-of-life outcomes and overall survival. Patient selection for the research studies should be done by a multidisciplinary team. The procedure should only be done in specialist centres by clinicians trained and experienced in managing cholangiocarcinoma.\n\nClinicians should enter details about all patients having SIRT for unresectable primary intrahepatic cholangiocarcinoma onto a suitable registry.', 'The condition, current treatments and procedure': '# The condition\n\nIntrahepatic cholangiocarcinoma is a rare type of primary liver cancer originating in the bile ducts within the liver parenchyma. It accounts for about 10% of all cholangiocarcinomas (bile duct cancers).\n\n# Current treatments\n\nIntrahepatic cholangiocarcinoma is not usually diagnosed before the symptoms of biliary obstruction occur, by which time the cancer may be too advanced for curative surgical resection. However, surgical removal with curative intent may occasionally be possible by downstaging the tumour using other types of treatment first. The standard options for palliative treatment include chemotherapy, surgical bypass of the bile duct, or inserting a stent using surgical, endoscopic or percutaneous techniques.\n\nSelective internal radiation therapy (SIRT; also known as radio-embolisation) can be used as palliative treatment for unresectable primary liver cancer. It may also be used as a neoadjuvant treatment before surgery in patients being considered for curative treatments such as resection or liver transplantation. It aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to surrounding healthy tissue.\n\n# The procedure\n\nSIRT involves delivering microspheres containing radionuclides that emit beta radiation directly into the tumour via the hepatic artery. Under local anaesthesia with fluoroscopic guidance, the radioactive microspheres, which are made of glass, resin or poly(L‑lactic) acid, are injected into branches of the hepatic artery supplying the tumour. Usually, the percutaneous femoral or radial approach is used. The microspheres are designed to lodge in the small arteries surrounding the tumour and release high doses of localised radiation directly into the tumour. The procedure may be repeated depending on the response.'}
|
https://www.nice.org.uk/guidance/ipg630
|
Evidence-based recommendations on selective internal radiation therapy for unresectable primary intrahepatic cholangiocarcinoma in adults. This involves injecting tiny radioactive ‘beads’ into blood vessels that supply the liver, where they become trapped and release radiation directly into the cancer cells.
|
6ec8bd835f7c54666596d4bb51a2fa641c1b3781
|
nice
|
Urinary tract infection (lower): antimicrobial prescribing
|
Urinary tract infection (lower): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for lower urinary tract infection (also called cystitis) in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing lower urinary tract infection
Be aware that lower urinary tract infection (UTI) is an infection of the bladder usually caused by bacteria from the gastrointestinal tract entering the urethra and travelling up to the bladder.
Give advice about managing symptoms with self-care (see the recommendations on self-care) to all people with lower UTI.
## Treatment for women with lower UTI who are not pregnant
Consider a back-up antibiotic prescription (to use if symptoms do not start to improve within 48 hours or worsen at any time) or an immediate antibiotic prescription (see the recommendations on choice of antibiotic) for women with lower UTI who are not pregnant. Take account of:
the severity of symptoms
the risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract or immunosuppression
the evidence for back-up antibiotic prescriptions, which was only in non-pregnant women with lower UTI where immediate antibiotic treatment was not considered necessary
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria
preferences of the woman for antibiotic use.
If a urine sample has been sent for culture and susceptibility testing and an antibiotic prescription has been given:
review the choice of antibiotic when microbiological results are available, and
change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.
## Treatment for pregnant women and men with lower UTI
Offer an immediate antibiotic prescription (see the recommendations on choice of antibiotic) to pregnant women and men with lower UTI. Take account of:
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
Obtain a midstream urine sample from pregnant women and men before antibiotics are taken, and send for culture and susceptibility testing.
For pregnant women with lower UTI:
review the choice of antibiotic when microbiological results are available, and
change the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow-spectrum antibiotic wherever possible.
For men with lower UTI:
review the choice of antibiotic when microbiological results are available, and
change the antibiotic according to susceptibility results if the bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.
## Treatment for children and young people under 16 years with lower UTI
Obtain a urine sample from children and young people with lower UTI before antibiotics are taken, and dipstick test or send for culture and susceptibility testing in line with the NICE guideline on urinary tract infection in under 16s.
Assess and manage children under 5 with lower UTI who present with fever as outlined in the NICE guideline on fever in under 5s.
Offer an immediate antibiotic prescription (see the recommendations on choice of antibiotic) for children and young people under 16 years with lower UTI. Take account of:
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
If a urine sample has been sent for culture and sensitivity testing when an antibiotic prescription has been given:
review the choice of antibiotic when microbiological results are available, and
change the antibiotic according to susceptibility results if the bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.
## Advice for all people with lower UTI when an antibiotic prescription is given
When a back-up antibiotic prescription is given, as well as the general advice on self-care, give advice about:
an antibiotic not being needed immediately
using the back-up prescription if symptoms do not start to improve within 48 hours or if they worsen at any time
possible adverse effects of antibiotics, particularly diarrhoea and nausea
seeking medical help if antibiotics are taken and:
symptoms worsen rapidly or significantly at any time or
symptoms do not start to improve within 48 hours of taking the antibiotic or
the person becomes systemically very unwell.
When an immediate antibiotic prescription is given, as well as the general advice on self-care, give advice about:
possible adverse effects of the antibiotic, particularly diarrhoea and nausea
seeking medical help if symptoms worsen rapidly or significantly at any time, do not start to improve within 48 hours of taking the antibiotic, or the person becomes systemically very unwell.
## Reassessment
Reassess if symptoms worsen rapidly or significantly at any time, or do not start to improve within 48 hours of taking the antibiotic, taking account of:
-ther possible diagnoses
any symptoms or signs suggesting a more serious illness or condition, such as pyelonephritis
previous antibiotic use, which may have led to resistant bacteria.Send a urine sample for culture and susceptibility testing if this has not already been done and review treatment when results are available (see recommendations 1.1.4, 1.1.7, 1.1.8 and 1.1.12).
## Referral
Refer people aged 16 years and over with lower UTI to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).
Refer children or young people with lower UTI to hospital in line with the NICE guideline on urinary tract infection in under 16s.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.
Full details of the evidence and the committee's discussion are in the evidence review.
# Managing asymptomatic bacteriuria
Be aware that asymptomatic bacteriuria:
is significant levels of bacteria (greater than 105 colony forming units/ml) in the urine with no symptoms of UTI
is not routinely screened for, or treated, in women who are not pregnant, men, young people and children
is treated with antibiotics in pregnant women because it is a risk factor for pyelonephritis and premature delivery (see the recommendations on choice of antibiotic).
Offer an immediate antibiotic prescription to pregnant women with asymptomatic bacteriuria, taking account of:
recent urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.
Full details of the evidence and the committee's discussion are in the evidence review.
# Self-care
Advise people with lower UTI about using paracetamol for pain, or if preferred and suitable ibuprofen.
Advise people with lower UTI about drinking enough fluids to avoid dehydration.
Be aware that no evidence was found on cranberry products or urine alkalinising agents to treat lower UTI.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.
Full details of the evidence and the committee's discussion are in the evidence review.
# Choice of antibiotic
When prescribing antibiotic treatment for lower UTI, take account of local antimicrobial resistance data and follow:
table 1 for non-pregnant women aged 16 years and over
table 2 for pregnant women aged 12 years and over
table 3 for men aged 16 years and over
table 4 for children and young people under 16 years.
Treatment
Antibiotic, dosage and course length
First choices
If there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.
Nitrofurantoin (if estimated glomerular filtration rate is 45 ml/minute or more):
mg modified-release twice a day (or, if unavailable, 50 mg four times a day) for 3 days
Trimethoprim (if there is a low risk of resistance):
mg twice a day for 3 days
Second choices (if no improvement in lower UTI symptoms on first choice taken for at least 48 hours, or when first choice is not suitable)
If there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.
Nitrofurantoin (if eGFR is 45 ml/minute or more, and it was not used as first-choice):
mg modified-release twice a day (or, if unavailable, 50 mg four times a day) for 3 days
Pivmecillinam (a penicillin):
mg initial dose, then 200 mg three times a day for a total of 3 days
Fosfomycin:
g single dose sachet
See the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment, and breastfeeding.
Check any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.
Nitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).
A lower risk of resistance may be more likely if trimethoprim has not been used in the past 3 months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance may be more likely with recent use and in older people in residential facilities.
Treatment
Antibiotic, dosage and course length
First choice
If there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.
Nitrofurantoin (if estimated glomerular filtration rate is 45 ml/minute or more):
mg modified-release twice a day (or, if unavailable, 50 mg four times a day) for 7 days
Avoid at term because it may produce neonatal haemolysis (BNF, August 2018)
Second choices (if no improvement in lower UTI symptoms on first choice taken for at least 48 hours, or when first choice is not suitable)
If there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.
Amoxicillin (only if culture results are available and susceptible):
mg three times a day for 7 days
Cefalexin:
mg twice a day for 7 days
Alternative second choices
Consult local microbiologist, and choose antibiotics based on culture and susceptibility results
Treatment of asymptomatic bacteriuria
Choose from nitrofurantoin, amoxicillin or cefalexin based on recent culture and susceptibility results
See the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment.
Check any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.
Nitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).
Treatment
Antibiotic, dosage and course length
First choices
If there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.
Trimethoprim:
mg twice a day for 7 days
Nitrofurantoin (if estimated glomerular filtration rate is 45 ml/minute or more):
mg modified-release twice a day (or, if unavailable, 50 mg four times a day) for 7 days
Nitrofurantoin is not recommended for men with suspected prostate involvement because it is unlikely to reach therapeutic levels in the prostate.
Second choices (if no improvement in lower UTI symptoms on first choice taken for at least 48 hours, or when first choice is not suitable)
If there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.
Consider alternative diagnoses and follow recommendations in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing or the NICE guideline on prostatitis (acute): antimicrobial prescribing, basing antibiotic choice on recent culture and susceptibility results.
See the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment.
Check any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.
Nitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).
Treatment
Antibiotic, dosage and course length
Children under 3 months
Refer to a paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under 5s
First choices for children aged 3 months and over
If there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.
If 2 or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost. Some children may also be able to take a tablet or part-tablet, rather than a liquid formulation, if the dose is appropriate.
Trimethoprim (if there is a low risk of resistance):
months to 5 months, 4 mg/kg (maximum 200 mg per dose) or 25 mg twice a day for 3 days
months to 5 years, 4 mg/kg (maximum 200 mg per dose) or 50 mg twice a day for 3 days
years to 11 years, 4 mg/kg (maximum 200 mg per dose) or 100 mg twice a day for 3 days
years to 15 years, 200 mg twice a day for 3 days
Nitrofurantoin (if estimated glomerular filtration rate (eGFR) is 45 ml/minute or more):
months to 11 years, 750 micrograms/kg four times a day for 3 days
years to 15 years, 50 mg four times a day or 100 mg modified-release twice a day for 3 days
Second choices for children aged 3 months and over (if no improvement in lower UTI symptoms on first choice taken for at least 48 hours, or when first choice is not suitable)
If there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.
If 2 or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost. Some children may also be able to take a tablet or part-tablet, rather than a liquid formulation, if the dose is appropriate.
Nitrofurantoin (if eGFR is 45 ml/minute or more and it was not used as first-choice):
months to 11 years, 750 micrograms/kg four times a day for 3 days
years to 15 years, 50 mg four times a day or 100 mg modified-release twice a day for 3 days
Amoxicillin (only if culture results available and susceptible):
month to 11 months, 125 mg three times a day for 3 days
year to 4 years, 250 mg three times a day for 3 days
years to 15 years, 500 mg three times a day for 3 days
Cefalexin:
months to 11 months, 12.5 mg/kg or 125 mg twice a day for 3 days
year to 4 years, 12.5 mg/kg twice a day or 125 mg three times a day for 3 days
years to 11 years, 12.5 mg/kg twice a day or 250 mg three times a day for 3 days
years to 15 years, 500 mg twice a day for 3 days
See the BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment. See table 2 if a young woman is pregnant.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
Check any previous urine culture and susceptibility results, and antibiotic prescribing. and choose antibiotics accordingly. When a child or young person is having prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.
Nitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNFC, August 2018).
A lower risk of resistance may be more likely if trimethoprim has not been used in the past 3 months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance may be more likely with recent use and in older people in residential facilities.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic and antibiotic course length.
Full details of the evidence and the committee's discussion are in the evidence review.# Summary of the evidence
# Self-care
Recommendations 1.3.1 to 1.3.3
## Oral analgesia (ibuprofen)
Two randomised controlled trials (RCTs) (Bleidorn et al. 2010 and Gagyor et al. 2015) in non-pregnant women found conflicting evidence regarding the effectiveness of ibuprofen compared with antibiotics. One small RCT, Bleidorn et al. 2010, found no significant differences between ibuprofen and ciprofloxacin in reducing symptoms and symptom duration (very low to low quality evidence). However, a more recent larger RCT, Gagyor et al. 2015, found that women using ibuprofen were more likely to report a higher burden of symptoms over the first 7 days after the start of their treatment, compared with women using fosfomycin (moderate quality evidence).
Subgroup analyses, based on the results of urine culture prior to treatment, showed that women who received ibuprofen had significantly fewer antibiotic courses per patient compared with women who received fosfomycin (Gagyor et al. 2015; moderate quality evidence). However, this effect was driven mostly by the randomisation process, rather than the effect of the treatment itself.
Women who received ibuprofen (irrespective of urine culture) were significantly more likely to receive an additional antibiotic prescription to treat a urinary tract infection (UTI) during 12 months of follow-up (31.1% versus 12.3%; high quality evidence), but were less likely to experience a recurrent UTI between days 15 to 28 of follow-up (5.8% versus 11.1%; moderate quality evidence). The authors noted that this result could be because the baseline risk of having recurrent UTI was greater in the fosfomycin group, as more women had experienced a UTI in the past year.
Bleidorn et al. (2010) did not report any safety or tolerability outcomes. However, Gagyor et al. (2015) found no significant difference between ibuprofen and fosfomycin in the incidence of pyelonephritis, febrile UTIs, patient-reported adverse events, or serious drug-related adverse effects (low to moderate quality evidence).
## Cranberry products
Two RCTs (Wing et al. 2008 and Wing et al. 2015) assessed the clinical effectiveness and safety of cranberry products for preventing asymptomatic bacteriuria in healthy pregnant women.
Wing et al. (2008) found that cranberry juice was not effective in preventing episodes of asymptomatic bacteriuria or UTI. However, a significant reduction in adherence was seen in women receiving cranberry juice compared with placebo (very low quality evidence).
Wing et al. (2015) assessed the safety and tolerability of cranberry capsules and found no significant difference in the number of babies born with a 1-minute Apgar score <7 in women who received cranberry capsules compared with placebo (21.4% versus 0%; very low quality evidence).
## Other non-pharmacological or non-antimicrobial interventions
No systematic reviews or RCTs of any non-pharmacological or non-antimicrobial interventions were identified in men, older people or children.
No systematic reviews or RCTs of paracetamol were identified.
No systematic reviews or RCTs of hydration were identified.
Based on experience, the committee agreed that it was reasonable to advise people with lower UTI about using paracetamol for self-management of pain as this medicine has a well-established efficacy and safety profile.
The committee agreed, based on evidence and experience, that it was also reasonable to advise people with lower UTI about using ibuprofen for self-management of pain if this was preferred and suitable, taking account of safety concerns with NSAIDs, for example, renal impairment.
Based on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.
No evidence was found for using cranberry products or alkalinising agents to treat lower UTI or asymptomatic bacteriuria. There was only evidence assessing the efficacy and safety of cranberry products for preventing asymptomatic bacteriuria in healthy pregnant women.
Return to recommendations
# Antibiotics
Recommendations 1.1.1 to 1.1.17
Recommendations 1.2.1 to 1.2.2
In most cases, managing lower UTI will require antibiotic treatment. However, acute, uncomplicated lower UTI in non-pregnant women can be self-limiting and for some women delaying antibiotic treatment with a back-up prescription to see if symptoms will resolve without antibiotic treatment may be an option.
The most common causative pathogen in uncomplicated UTIs is Escherichia coli (in 70 to 95% of cases). Staphylococcus saprophyticus accounts for 5 to 10% of cases and occasionally other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella species are isolated (European Association of Urology guidelines on urological infections 2017).
The main complication of lower UTI is ascending infection leading to upper UTI (acute pyelonephritis). Most episodes of acute pyelonephritis are uncomplicated and result in no residual kidney damage. However, complications can include impaired renal function or renal failure, septicaemia and preterm labour in pregnancy (NICE clinical knowledge summary on pyelonephritis).
In men, prostate involvement is common, which may lead to acute prostatitis, chronic bacterial prostatitis or a prostatic abscess; urinary stones are also a possibility (NICE clinical knowledge summary on UTI (lower) - men).
In children, UTIs can lead to renal scarring, but more often this is preceded by acute pyelonephritis rather than lower UTI, and it is more common in children with vesicoureteral reflux (NICE clinical knowledge summary on UTI - children).
Asymptomatic bacteriuria, where there is significant bacteriuria but no symptoms or signs of infection, is not routinely screened for or treated, except if it is considered a risk factor, such as in pregnant women (European Association of Urology guidelines on urological infections 2017).
In pregnancy, asymptomatic bacteriuria can lead to pyelonephritis and preterm labour (NICE clinical knowledge summary on UTI (lower) - women and pyelonephritis).
## Efficacy of antibiotics
One systematic review of RCTs (Falagas et al. 2009) in non-pregnant women found that women who were treated with antibiotics were more likely to have complete symptom resolution (61.8% versus 25.7%; NNT 3 ; high quality evidence) and microbiological success (defined as negative urine culture) (90% versus 33.3%; NNT 2 ; moderate quality evidence), and less likely to experience relapse after the end of treatment (15.8% versus 41.6%; NNT 3 ; moderate quality evidence), compared with placebo. There was no significant difference between groups in the incidence of pyelonephritis (0.14% versus 0.75%; low quality evidence), although due to the very low incidence of pyelonephritis, it is likely the studies lacked statistical power to detect a clinically important difference.
One systematic review (Smaill et al. 2015) and 1 RCT (Kazemier et al. 2015) assessed antibiotics compared with placebo or no treatment for managing asymptomatic bacteriuria in pregnant women. Smaill et al. (2015) found that pregnant women who received antibiotics for asymptomatic bacteriuria had a reduced incidence of persistent bacteriuria (20.3% versus 66.3%; NNT 2 ; low quality evidence); were less likely to develop pyelonephritis (5.6% versus 20.8%; NNT 7 ; moderate quality evidence) or deliver a preterm baby (<37 weeks) (5.8% versus 22.1%; NNT 7 ; moderate quality evidence), compared with those who received no treatment.
Smaill et al. (2015) found no significant difference between antibiotics and placebo in serious adverse neonatal outcomes (very low quality evidence).
Kazemier et al. (2015) found no significant difference between nitrofurantoin and placebo in reducing the incidence of symptomatic UTI, pyelonephritis or preterm birth (<34 weeks; very low quality evidence). Significantly more women had non-spontaneous onset of labour with nitrofurantoin compared with placebo, but there is considerable uncertainty with these results (very low quality evidence).
Zalmanovici-Trestioreanu et al. (2015) found that there was a greater incidence of bacteriological cure in older people who received antibiotics for treating asymptomatic bacteriuria compared with those who received placebo or no treatment (61% versus 17%; NNT 3 ; high quality evidence). However, there was no significant benefit in reducing symptomatic UTI (very low quality evidence) and people who received antibiotics were more likely to report adverse events (high quality evidence).
## Safety of antibiotics
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2018).
Nitrofurantoin should be used with caution in those with renal impairment (MHRA Drug Safety Update, September 2014). It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should have monitoring for liver function and pulmonary symptoms (BNF, August 2018).
Trimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF, August 2018). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).
A systematic review (Falagas et al. 2009) in non-pregnant women found a significant increase in the total number of adverse events with antibiotics compared with placebo (19.2% versus 12.9%; NNH 15 ; moderate quality evidence). However there was no significant difference between antibiotics and placebo in the number of withdrawals due to adverse events.
Zalmanovici-Trestioreanu et al. (2015) assessed the safety of antibiotics in the management of asymptomatic bacteriuria in older people. There was a significant increase in the incidence of adverse events in those treated with antibiotics compared with placebo or no treatment (4.2% versus 1.0%; NNH 31 ; high quality evidence).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
## Back‑up antibiotics
One RCT (Little et al. 2010) assessed various antibiotic prescribing strategies in non-pregnant women with acute uncomplicated lower UTI, where immediate antibiotic treatment was not necessary. The women included in the study had a mean age of 39 to 45 years and had moderate symptoms (mean score of 1.7 to 1.8, on a scale of 0=no problem, 1=mild problem, 2=moderately bad problem, 3=severe problem) at baseline. Although bacterial confirmation was not essential for inclusion into the study, the proportion of women who had urine culture ranged from 23 to 89% (p2, a positive dipstick test, or a midstream urine culture result. Only two-thirds of women randomised to receive antibiotics based on a midstream urine result had a positive urine culture.
There was no difference between the different prescribing strategies (immediate empirical antibiotics; back-up empirical antibiotics; immediate antibiotics based on symptom severity score >2, positive dipstick test or midstream urine culture result) in the severity or duration of symptoms during follow-up, or in the time to reconsultation (low to very low quality evidence). However, significantly more women who were prescribed immediate antibiotics used them, compared with all other prescribing strategy groups, except immediate antibiotics based on symptom severity scoring (very low quality evidence). There were also significantly fewer women waiting 48 hours before taking their antibiotics in the immediate antibiotics group, compared with all other prescribing strategy groups, except immediate antibiotics based on symptom severity score (low to very low quality evidence).
Little et al. (2010) found that despite randomisation, all groups delayed starting their antibiotic course by at least 24 hours (very low quality evidence). However, a delay of more than 48 hours was associated with a longer duration of moderately bad symptoms (very low quality evidence).
No systematic reviews or RCTs of back‑up antibiotic prescribing strategies were identified in men, pregnant women, older people or children.
The committee recognised the equality considerations for managing a lower UTI in transgender people, due to anatomical differences between women and men.
Based on evidence and experience, the committee agreed that either a back-up antibiotic prescription or an immediate antibiotic prescription could be prescribed for non-pregnant women with a lower UTI. The committee discussed that sending a urine sample for culture and susceptibility testing is not usual practice in most young, non-pregnant women with a first lower UTI. Lower UTI is generally confirmed by symptoms and signs of infection together with dipstick testing of urine for some people. If urine culture has been taken, delaying the antibiotic until microbiological results are available could also be considered, depending on the severity of symptoms. Decisions around prescribing strategies should be individualised, taking account of the severity of symptoms, the risk of developing complications or having treatment failure, and preference for back-up or immediate antibiotics, or awaiting the results of urine culture.
The committee discussed that the evidence for back-up prescribing was only in non-pregnant women aged 18 to 70 years (mean age of 39 to 45 years) with, on average, moderate symptoms of an acute uncomplicated lower UTI, where immediate antibiotic treatment was not necessary. In this population, back-up empirical antibiotics were as effective as immediate empirical antibiotics for the severity or duration of UTI symptoms and the time to reconsultation. Back-up antibiotics (particularly a forward dated prescription) also reduced antibiotic use.
The committee agreed that a back-up antibiotic prescription could be used if symptoms do not start to improve within 48 hours (by which point most UTIs should be starting to improve) or if they worsen at any time.
Based on evidence, the committee agreed that antibiotics were effective in curing lower UTI symptoms and reducing relapse in non-pregnant women, but increased adverse events. There was no significant difference between antibiotics and placebo for the development of pyelonephritis (a complication of lower UTI). However, due to the very low incidence of pyelonephritis, it is likely the studies lacked statistical power to detect a clinically important difference.
Based on experience, the committee agreed that if a urine culture has been taken, and results suggest the bacteria are resistant to the antibiotic given, the woman should be contacted and the antibiotic changed if symptoms are not already improving. The committee agreed that for non-pregnant women where 3-day courses of antibiotics are given, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back before short courses are nearly completed, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.
The committee discussed that no evidence was identified on antibiotic treatment for pregnant women with a symptomatic lower UTI. However, evidence in pregnant women with asymptomatic bacteriuria showed that antibiotics were effective in reducing persistent bacteriuria, pyelonephritis and the delivery of a preterm baby.
Based on limited evidence and experience, the committee agreed that pregnant women with a lower UTI should be offered an immediate antibiotic, and urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.
Based on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, pregnant woman should be contacted and the antibiotic changed regardless of whether symptoms are improving or not. The committee agreed there was a greater risk from UTIs in pregnant women and antibiotics should be changed to ensure cure.
The committee discussed that no evidence was identified on antibiotic treatment for men with a lower UTI, apart from 1 systematic review where about 10% of the study population were men.
Based on experience, the committee agreed that men with a lower UTI should be offered an immediate antibiotic, and urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.
Based on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, men should be contacted and, if symptoms are not already improving, the antibiotic should be changed. The committee agreed that for men, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back for some days, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.
The committee was aware that the NICE guideline on urinary tract infection in under 16s makes recommendations on diagnosing lower UTIs (including the use of dipsticks and urine culture).
Based on experience, the committee agreed that if a urine culture has been taken, and results suggest the bacteria are resistant to the antibiotic given, the child or young person should be contacted and, if symptoms are not already improving, the antibiotic changed. The committee agreed that for children and young people where 3-day courses of antibiotics are given, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back before short courses are nearly completed, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.
Based on evidence and experience, the committee agreed that asymptomatic bacteriuria is not routinely screened for, or treated with antibiotics, in non-pregnant women, men, young people or children because it is not a risk factor for harm in these groups. It is routinely screened for, and treated with antibiotics, in pregnant women because it is a risk factor for harm.
Based on evidence, the committee agreed that antibiotics reduce persistent bacteriuria, pyelonephritis and the delivery of a preterm baby in pregnant women with asymptomatic bacteriuria.
Return to recommendations
# Choice of antibiotic
Recommendation 1.4.1
Three systematic reviews (Falagas et al. 2010, Rafalsky et al. 2006 and Zalmanovici-Trestioreanu et al. 2010) assessed the appropriate choice of antibiotics when treating UTIs in non-pregnant women.
In Zalmanovici-Trestioreanu et al. (2010) there were no major differences in treatment outcomes among various antibiotics and antibiotic classes: nitrofurantoin, trimethoprim, co-trimoxazole, beta-lactams, and quinolones (very low to high quality evidence).
Falagas et al. (2010) showed that fosfomycin did not offer any additional benefit over other antibiotics, despite it having a single-dose regimen (very low to moderate quality evidence). Fosfomycin did not reduce the rate of adverse events or withdrawal from treatment compared with other antibiotics (very low to low quality evidence).
Rafalsky et al. (2006) reviewed the efficacy and safety of quinolones for the treatment of acute uncomplicated lower UTI. No quinolone showed additional benefit over another (very low to high quality evidence).
One systematic review (Guinto et al. 2010) assessed the effectiveness of different antibiotics for the treatment of asymptomatic bacteriuria in pregnant women. There was no significant difference between fosfomycin and cefuroxime in reducing the incidence of persistent infection, or in the number of women who required a change of antibiotic (very low quality evidence). Similarly, there was no significant difference between pivmecillinam and ampicillin in the number of women with persistent infection after treatment or in the incidence of recurrent infection (very low quality evidence).
One systematic review (Fitzgerald et al. 2012) assessed choice of antibiotic in children with uncomplicated lower UTI. Overall, there were no significant differences between antibiotics of any class or course length (very low quality evidence).
Zalmonovici-Trestioreanu et al. (2010) compared the safety of different antibiotic classes in non-pregnant women with uncomplicated lower UTI. There was no significant difference in the number of adverse events reported, or in the number of women who discontinued treatment due to an adverse event, for quinolones compared with co-trimoxazole; beta-lactams compared with co-trimoxazole; nitrofurantoin compared with beta-lactams; quinolones compared with beta-lactams; or nitrofurantoin compared with co-trimoxazole (very low to high quality evidence).
Rafalsky et al. (2006) compared the safety of different quinolone antibiotics in non-pregnant women with uncomplicated lower UTI and found no significant difference in the number of adverse events reported, or withdrawals from treatment due to adverse events, for ciprofloxacin compared with ofloxacin; levofloxacin compared with ofloxacin; or standard-release ciprofloxacin compared with extended-release ciprofloxacin (very low to moderate quality evidence).
Falagas et al. (2010) compared the safety of fosfomycin to other antibiotics in the treatment of UTI in non-pregnant women. There was no significant difference in the number of adverse events reported or in the number of women withdrawing from treatment due to an adverse event in the fosfomycin group compared with those who received other antibiotics (very low to low quality evidence).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
## Committee discussion on choice of antibiotic
Based on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance. Resistant bacteria are a particular concern in UTIs and, where possible, any previous urine culture and susceptibility results, and antibiotic prescribing, should be checked and antibiotics chosen accordingly.
The committee discussed that, if an antibiotic is needed to treat an infection that is not life threatening, a narrow-spectrum antibiotic should generally be first-choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.
Nationally for England, resistance of E. coli (the main causative organism of lower UTIs) in laboratory-processed urine specimens to the following antibiotics is:
nitrofurantoin: 2.5% (varies by area from 2.0 to 3.6%)
trimethoprim: 30.3% (varies by area from 27.1 to 33.4%)
pivmecillinam: 7.5% (varies by area from 4.1 to 15.7%)
cefalexin: 9.9% (varies by area from 8.1 to 11.4%).(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018)
The committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.
Based on evidence, experience and resistance data, the committee agreed to recommend nitrofurantoin or trimethoprim at usual doses as first-choice antibiotics.
Nitrofurantoin is not recommended for people with an eGFR <45 ml/minute. It may be used with caution if eGFR is 30–44 ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).
The committee agreed to recommend either the modified-release preparation of nitrofurantoin or the immediate-release preparation. However, because of its twice daily dosing and, in their experience, better tolerability, the committee was keen to point out that the modified-release preparation was preferred unless it was unavailable. The committee also discussed that, in their experience, immediate-release preparations containing nitrofurantoin in a macrocrystalline form may be better tolerated than those containing nitrofurantoin in a microcrystalline form.
Trimethoprim should only be prescribed if a lower risk of resistance is likely because of high resistance levels nationally. Based on experience, the committee agreed that a lower risk of resistance may be more likely if trimethoprim has not been used in the past 3 months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of trimethoprim resistance may be more likely with recent use (the committee was aware of evidence that trimethoprim is significantly associated with resistant E. coli infections treated in the previous 2 to 3 months), and in older people in residential facilities.
Based on evidence, their experience and resistance data, the committee agreed to recommend nitrofurantoin (if not used as first-choice), pivmecillinam (a penicillin) or fosfomycin at usual doses as second-choice antibiotics for use if lower UTI symptoms do not improve on a first-choice antibiotic taken for at least 48 hours or first-choice antibiotics are not suitable. The committee acknowledged that prescribers may be less familiar with pivmecillinam or fosfomycin, but these antibiotics are often used in other European countries.
If there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.
Based on evidence, experience and resistance data, the committee agreed to recommend usual dose nitrofurantoin as the first-choice antibiotic (with the cautions outlined above):
Nitrofurantoin is not recommended at term in pregnancy because it may produce neonatal haemolysis (BNF, August 2018).
Trimethoprim was not recommended because it is contraindicated in pregnancy. Trimethoprim is a folate antagonist and there is a teratogenic risk in the first trimester (BNF, August 2018). However, the committee acknowledged that trimethoprim is sometimes used in pregnancy when given with folic acid 5 mg daily in the first trimester (NICE clinical knowledge summary on UTI (lower) – women).
Based on evidence, experience and resistance data, the committee agreed to recommend amoxicillin, cefalexin or other antibiotics recommended by local microbiologists (based on culture and susceptibility results) at usual doses as second-choice antibiotics for use if lower UTI symptoms do not improve on a first-choice antibiotic taken for at least 48 hours or first-choice antibiotics are not suitable.
Amoxicillin is recommended only if culture results are available and bacteria are susceptible because resistance rates are high.
If there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.
Based on evidence, experience and resistance data, the committee agreed to recommend a course of nitrofurantoin, amoxicillin or cefalexin, (with the cautions outlined above) for the treatment of asymptomatic bacteriuria in pregnant women. Choice should be based on recent culture and susceptibility results.
Based on experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin at usual doses as first-choice antibiotics (with the cautions outlined above).
Trimethoprim generally has a lower risk of resistance in men, and can reach therapeutic prostate levels. However, if acute prostatitis is suspected, quinolones are the first-choice antibiotic (see the NICE guideline on prostatitis (acute): antimicrobial prescribing).
Nitrofurantoin is not recommended for men with suspected prostate involvement because it is unlikely to reach therapeutic levels in the prostate.
Based on experience, the committee agreed that alternative diagnoses (such as acute pyelonephritis or acute prostatitis) should be considered in men whose symptoms have not responded to a first-choice antibiotic, and second-choice antibiotics should be based on recent culture and susceptibility results.
Based on evidence, experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin at usual doses as first-choice antibiotics (with the cautions outlined above).
The committee was aware that nitrofurantoin suspension is currently substantially more expensive than trimethoprim suspension and, if both antibiotics are appropriate, the one with the lowest acquisition cost should be chosen.
Based on evidence, experience and resistance data, the committee agreed to recommend nitrofurantoin (if not used as first-choice), amoxicillin or cefalexin at usual doses as second-choice antibiotics for use if lower UTI symptoms get worse on a first-choice antibiotic taken for at least 48 hours or first-choice antibiotics are not suitable.
Amoxicillin is recommended only if culture results are available and bacteria are susceptible, because resistance rates are high.
If there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.
Return to recommendation
# Antibiotic course length
Recommendation 1.4.1
One systematic review (Milo et al. 2005) assessed the effectiveness of 3‑day courses compared with 5- to 10-day courses of antibiotics in the treatment of lower UTI in mainly non-pregnant women (some data from men were included). Three-day courses of any antibiotic were not significantly different to longer courses (5 to 10 days) of any antibiotic in preventing short-term or long-term symptomatic failure, short-term bacteriological failure, or the development of pyelonephritis (very low to high quality evidence). However, long‑term bacteriological failure (at 4 to 10 weeks) was significantly higher with 3‑day courses of any antibiotic compared with longer courses of any antibiotic (low quality evidence).
Subgroup analysis showed a significant increase in the number of women reporting short-term bacteriological failure with a 3-day course of a quinolone compared with a 5- to 10-day course of a quinolone (7.6% versus 5.1%; low quality evidence). However, there was no significant difference in long-term bacteriological failure (moderate quality evidence).
Milo et al. (2005) found a significant reduction in the number of women reporting adverse events (16.3% versus 20.6%; NNH 23 ; very low quality evidence), withdrawing due to adverse events (1.5% versus 3.2%; very low quality evidence), or reporting gastrointestinal adverse effects (6.7% versus 8.5%; very low quality evidence) with a 3-day course compared with a 5- to 10-day course of antibiotics.
Three systematic reviews (Guinto et al. 2010, Smaill et al. 2015 and Widmer et al. 2015) assessed the effectiveness of different antibiotic course lengths for treating asymptomatic bacteriuria in pregnant women. Smaill et al. (2015) conducted a subgroup analysis which found that women who received a short course of antibiotics (3 to 7 days) or continuous treatment were less likely to deliver preterm babies (before 37 weeks) compared with no treatment (low to moderate quality evidence). Continuous courses of antibiotics reduced the number of babies born with a birthweight below 2,500 g compared with no treatment (low quality evidence). Single-dose, an intermediate course of 3 to 6 weeks and continuous antibiotics also significantly reduced the incidence of pyelonephritis compared with no treatment (low to moderate quality data). There was no significant difference between a short course of antibiotics and no treatment in the incidence of pyelonephritis (low quality evidence).
Guinto et al. (2010) assessed the effectiveness of single-dose antibiotics compared with short courses of 7 days. Women who received a 1-day course of nitrofurantoin were more likely to have a persistent infection compared with women who received a 7-day course of nitrofurantoin (high quality evidence). There was no significant difference in nausea or preterm delivery between treatment groups (moderate quality evidence).
Widmer et al. (2015) found that women who received a single dose of antibiotics were more likely to deliver a baby with a low birthweight compared with those who received a short course (4 to 7 days) of antibiotics (moderate quality evidence). However, they found no significant difference between a single dose and a short course (4 to 7 days) for the number of women who reported no cure at the end of follow-up, experienced recurrent asymptomatic bacteriuria, developed pyelonephritis, or had a preterm delivery (very low to moderate quality evidence).
One systematic review in older women with lower UTI (Lutters et al. 2008) found that single-dose antibiotics were associated with higher rates of persistent UTI compared with short courses (3 to 6 days) or long courses (7 to 14 days) of antibiotics in the short‑term, but this was no longer significant in the long‑term (very low to low quality evidence). Long courses did not offer any clinical benefit over short courses, and there was no significant difference between 3- or 5-day courses in reducing the incidence of persistent UTIs or clinical failure (very low to low quality evidence). Antibiotic course length, such as single-dose, short-course, or long-course, had no effect on adverse events, or on the number of withdrawals due to adverse events (very low to moderate quality evidence).
Two systematic reviews (Michael et al. 2003 and Fitzgerald et al. 2012) assessed the clinical effectiveness of varying antibiotic course lengths in children with uncomplicated lower UTI. Fitzgerald et al. (2012) found no significant difference between short-course (3 to 7 days) and long-course (10 to 14 days) antibiotics in the number of children with persistent bacteriuria; and course length did not affect the rate of reinfection or recurrence (very low quality evidence). Michael et al. (2003) found no significant difference between antibiotics given as either a short course (2 to 4 days) or a longer course (7 to 14 days) on the number of children with UTIs at the end of treatment, or the rate of recurrence of UTI (very low quality evidence).
## Committee discussions on antibiotic course length
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
Based on evidence, the committee agreed that a 3-day course of antibiotics was as effective as a 5- to 10-day course of antibiotics in non-pregnant women with lower UTI, and resulted in significantly fewer adverse events. The committee agreed that a longer course may increase the likelihood of complete bacteriological eradication, which may be important for some women (for example, women who experience repeated lower UTIs). However, it was not possible to analyse data separately for people with repeated lower UTIs.
Based on evidence, the committee agreed that a 7- to 10-day course of antibiotics did not offer any clinical advantage over a 3- to 6-day course in older women with lower UTI.
Based on evidence, experience and resistance data, the committee agreed that a 3-day course of all the recommended antibiotics (apart from fosfomycin where a single dose is given) was sufficient to treat lower UTI in non-pregnant women of any age, with no longer duration of treatment required for older women. If women have a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.
Based on evidence and their experience, the committee agreed that a 7-day course of all the recommended antibiotics was required to treat bacteriuria in pregnant women with either symptomatic lower UTI or asymptomatic bacteriuria.
A 7-day course is required to ensure complete cure because the risk of harm from a UTI is higher in pregnant women than in non-pregnant women.
Based on their experience, the committee agreed that a 7‑day course of all the recommended antibiotics was required to treat lower UTI in men.
A 7-day course is required to ensure complete cure because men are more at risk of complications from UTIs than women due to anatomical differences and possible outflow obstruction.
Based on evidence, the committee agreed that a 3- to 7-day course of antibiotics was as effective as a 7- to 14-day course of antibiotics in children and young people with lower UTI.
Based on evidence, experience and resistance data, the committee agreed that a 3-day course of all the recommended antibiotics was sufficient to treat lower UTI in children and young people. If children and young people have a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.
Return to recommendation
See the full evidence review for more information.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing or longer treatment duration (for example, some antibiotics). See the NICE guideline on medicines adherence.
# Resource implications
There is a potential resource saving if a back-up antibiotic prescription strategy is used in non-pregnant women with lower urinary tract infection (UTI).
Recommended antibiotics (nitrofurantoin, trimethoprim, amoxicillin, cefalexin and fosfomycin) are available as generic formulations, but there is currently no generic formulation of pivmecillinam, although the cost is comparable to other generic antibiotics, see Drug Tariff for costs.
Nitrofurantoin 25 mg/5 ml oral suspension is more expensive than other oral suspensions, such as trimethoprim 50 mg/5 ml. The cost of a 300-ml bottle of nitrofurantoin is £446.95 compared with £4.87 for a 100-ml bottle of trimethoprim (Drug Tariff, September 2018).
|
{'Recommendations': "# Managing lower urinary tract infection\n\nBe aware that lower urinary tract infection (UTI) is an infection of the bladder usually caused by bacteria from the gastrointestinal tract entering the urethra and travelling up to the bladder.\n\nGive advice about managing symptoms with self-care (see the recommendations on self-care) to all people with lower UTI.\n\n## Treatment for women with lower UTI who are not pregnant\n\nConsider a back-up antibiotic prescription (to use if symptoms do not start to improve within 48 hours or worsen at any time) or an immediate antibiotic prescription (see the recommendations on choice of antibiotic) for women with lower UTI who are not pregnant. Take account of:\n\nthe severity of symptoms\n\nthe risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract or immunosuppression\n\nthe evidence for back-up antibiotic prescriptions, which was only in non-pregnant women with lower UTI where immediate antibiotic treatment was not considered necessary\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria\n\npreferences of the woman for antibiotic use.\n\nIf a urine sample has been sent for culture and susceptibility testing and an antibiotic prescription has been given:\n\nreview the choice of antibiotic when microbiological results are available, and\n\nchange the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.\n\n## Treatment for pregnant women and men with lower UTI\n\nOffer an immediate antibiotic prescription (see the recommendations on choice of antibiotic) to pregnant women and men with lower UTI. Take account of:\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nObtain a midstream urine sample from pregnant women and men before antibiotics are taken, and send for culture and susceptibility testing.\n\nFor pregnant women with lower UTI:\n\nreview the choice of antibiotic when microbiological results are available, and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow-spectrum antibiotic wherever possible.\n\nFor men with lower UTI:\n\nreview the choice of antibiotic when microbiological results are available, and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.\n\n## Treatment for children and young people under 16\xa0years with lower UTI\n\nObtain a urine sample from children and young people with lower UTI before antibiotics are taken, and dipstick test or send for culture and susceptibility testing in line with the NICE guideline on urinary tract infection in under 16s.\n\nAssess and manage children under 5 with lower UTI who present with fever as outlined in the NICE guideline on fever in under 5s.\n\nOffer an immediate antibiotic prescription (see the recommendations on choice of antibiotic) for children and young people under 16\xa0years with lower UTI. Take account of:\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nIf a urine sample has been sent for culture and sensitivity testing when an antibiotic prescription has been given:\n\nreview the choice of antibiotic when microbiological results are available, and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant and symptoms are not already improving, using a narrow-spectrum antibiotic wherever possible.\n\n## Advice for all people with lower UTI when an antibiotic prescription is given\n\nWhen a back-up antibiotic prescription is given, as well as the general advice on self-care, give advice about:\n\nan antibiotic not being needed immediately\n\nusing the back-up prescription if symptoms do not start to improve within 48\xa0hours or if they worsen at any time\n\npossible adverse effects of antibiotics, particularly diarrhoea and nausea\n\nseeking medical help if antibiotics are taken and:\n\n\n\nsymptoms worsen rapidly or significantly at any time or\n\nsymptoms do not start to improve within 48\xa0hours of taking the antibiotic or\n\nthe person becomes systemically very unwell.\n\n\n\nWhen an immediate antibiotic prescription is given, as well as the general advice on self-care, give advice about:\n\npossible adverse effects of the antibiotic, particularly diarrhoea and nausea\n\nseeking medical help if symptoms worsen rapidly or significantly at any time, do not start to improve within 48\xa0hours of taking the antibiotic, or the person becomes systemically very unwell.\n\n## Reassessment\n\nReassess if symptoms worsen rapidly or significantly at any time, or do not start to improve within 48\xa0hours of taking the antibiotic, taking account of:\n\nother possible diagnoses\n\nany symptoms or signs suggesting a more serious illness or condition, such as pyelonephritis\n\nprevious antibiotic use, which may have led to resistant bacteria.Send a urine sample for culture and susceptibility testing if this has not already been done and review treatment when results are available (see recommendations 1.1.4, 1.1.7, 1.1.8 and 1.1.12).\n\n## Referral\n\nRefer people aged 16\xa0years and over with lower UTI to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).\n\nRefer children or young people with lower UTI to hospital in line with the NICE guideline on urinary tract infection in under 16s.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Managing asymptomatic bacteriuria\n\nBe aware that asymptomatic bacteriuria:\n\nis significant levels of bacteria (greater than 105\xa0colony forming units/ml) in the urine with no symptoms of UTI\n\nis not routinely screened for, or treated, in women who are not pregnant, men, young people and children\n\nis treated with antibiotics in pregnant women because it is a risk factor for pyelonephritis and premature delivery (see the recommendations on choice of antibiotic).\n\nOffer an immediate antibiotic prescription to pregnant women with asymptomatic bacteriuria, taking account of:\n\nrecent urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Self-care\n\nAdvise people with lower UTI about using paracetamol for pain, or if preferred and suitable ibuprofen.\n\nAdvise people with lower UTI about drinking enough fluids to avoid dehydration.\n\nBe aware that no evidence was found on cranberry products or urine alkalinising agents to treat lower UTI.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Choice of antibiotic\n\nWhen prescribing antibiotic treatment for lower UTI, take account of local antimicrobial resistance data and follow:\n\ntable\xa01 for non-pregnant women aged 16\xa0years and over\n\ntable\xa02 for pregnant women aged 12\xa0years and over\n\ntable\xa03 for men aged 16\xa0years and over\n\ntable\xa04 for children and young people under 16\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst choices\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nNitrofurantoin (if estimated glomerular filtration rate [eGFR] is 45\xa0ml/minute or more):\n\nmg modified-release twice a day (or, if unavailable, 50\xa0mg four times a day) for 3\xa0days\n\nTrimethoprim (if there is a low risk of resistance):\n\nmg twice a day for 3\xa0days\n\nSecond choices (if no improvement in lower UTI symptoms on first choice taken for at least 48\xa0hours, or when first choice is not suitable)\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nNitrofurantoin (if eGFR is 45\xa0ml/minute or more, and it was not used as first-choice):\n\nmg modified-release twice a day (or, if unavailable, 50\xa0mg four times a day) for 3\xa0days\n\nPivmecillinam (a penicillin):\n\nmg initial dose, then 200\xa0mg three times a day for a total of 3\xa0days\n\nFosfomycin:\n\ng single dose sachet\n\nSee the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment, and breastfeeding.\n\nCheck any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.\n\nNitrofurantoin may be used with caution if eGFR is 30\xa0ml/minute to 44\xa0ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).\n\nA lower risk of resistance may be more likely if trimethoprim has not been used in the past 3\xa0months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance may be more likely with recent use and in older people in residential facilities.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst choice\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nNitrofurantoin (if estimated glomerular filtration rate [eGFR] is 45\xa0ml/minute or more):\n\nmg modified-release twice a day (or, if unavailable, 50\xa0mg four times a day) for 7\xa0days\n\nAvoid at term because it may produce neonatal haemolysis (BNF, August 2018)\n\nSecond choices (if no improvement in lower UTI symptoms on first choice taken for at least 48\xa0hours, or when first choice is not suitable)\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nAmoxicillin (only if culture results are available and susceptible):\n\nmg three times a day for 7\xa0days\n\nCefalexin:\n\nmg twice a day for 7\xa0days\n\nAlternative second choices\n\nConsult local microbiologist, and choose antibiotics based on culture and susceptibility results\n\nTreatment of asymptomatic bacteriuria\n\nChoose from nitrofurantoin, amoxicillin or cefalexin based on recent culture and susceptibility results\n\nSee the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment.\n\nCheck any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.\n\nNitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst choices\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated urinary tract infection (UTI), see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nTrimethoprim:\n\nmg twice a day for 7\xa0days\n\nNitrofurantoin (if estimated glomerular filtration rate [eGFR] is 45\xa0ml/minute or more):\n\nmg modified-release twice a day (or, if unavailable, 50\xa0mg four times a day) for 7\xa0days\n\nNitrofurantoin is not recommended for men with suspected prostate involvement because it is unlikely to reach therapeutic levels in the prostate.\n\nSecond choices (if no improvement in lower UTI symptoms on first choice taken for at least 48\xa0hours, or when first choice is not suitable)\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nConsider alternative diagnoses and follow recommendations in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing or the NICE guideline on prostatitis (acute): antimicrobial prescribing, basing antibiotic choice on recent culture and susceptibility results.\n\nSee the BNF for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment.\n\nCheck any previous urine culture and susceptibility results, and antibiotic prescribing, and choose antibiotics accordingly.\n\nNitrofurantoin may be used with caution if eGFR is 30 ml/minute to 44 ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).\n\nTreatment\n\nAntibiotic, dosage and course length\n\nChildren under 3\xa0months\n\nRefer to a paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under 5s\n\nFirst choices for children aged 3\xa0months and over\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nIf 2\xa0or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost. Some children may also be able to take a tablet or part-tablet, rather than a liquid formulation, if the dose is appropriate.\n\nTrimethoprim (if there is a low risk of resistance):\n\nmonths to 5\xa0months, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 25\xa0mg twice a day for 3\xa0days\n\nmonths to 5\xa0years, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 50\xa0mg twice a day for 3\xa0days\n\nyears to 11\xa0years, 4\xa0mg/kg (maximum 200\xa0mg per dose) or 100\xa0mg twice a day for 3\xa0days\n\nyears to 15\xa0years, 200\xa0mg twice a day for 3\xa0days\n\nNitrofurantoin (if estimated glomerular filtration rate (eGFR) is 45\xa0ml/minute or more):\n\nmonths to 11\xa0years, 750\xa0micrograms/kg four times a day for 3\xa0days\n\nyears to 15\xa0years, 50\xa0mg four times a day or 100\xa0mg modified-release twice a day for 3\xa0days\n\nSecond choices for children aged 3\xa0months and over (if no improvement in lower UTI symptoms on first choice taken for at least 48\xa0hours, or when first choice is not suitable)\n\nIf there are symptoms of pyelonephritis (such as fever) or a complicated UTI, see the NICE guideline on acute pyelonephritis for antibiotic choices.\n\nIf 2\xa0or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost. Some children may also be able to take a tablet or part-tablet, rather than a liquid formulation, if the dose is appropriate.\n\nNitrofurantoin (if eGFR is 45\xa0ml/minute or more and it was not used as first-choice):\n\nmonths to 11\xa0years, 750\xa0micrograms/kg four times a day for 3\xa0days\n\nyears to 15\xa0years, 50\xa0mg four times a day or 100\xa0mg modified-release twice a day for 3\xa0days\n\nAmoxicillin (only if culture results available and susceptible):\n\nmonth to 11\xa0months, 125\xa0mg three times a day for 3\xa0days\n\nyear to 4\xa0years, 250\xa0mg three times a day for 3\xa0days\n\nyears to 15\xa0years, 500\xa0mg three times a day for 3\xa0days\n\nCefalexin:\n\nmonths to 11\xa0months, 12.5\xa0mg/kg or 125\xa0mg twice a day for 3\xa0days\n\nyear to 4\xa0years, 12.5\xa0mg/kg twice a day or 125\xa0mg three times a day for 3\xa0days\n\nyears to 11\xa0years, 12.5\xa0mg/kg twice a day or 250\xa0mg three times a day for 3\xa0days\n\nyears to 15\xa0years, 500\xa0mg twice a day for 3\xa0days\n\nSee the BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, in hepatic or renal impairment. See table\xa02 if a young woman is pregnant.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nCheck any previous urine culture and susceptibility results, and antibiotic prescribing. and choose antibiotics accordingly. When a child or young person is having prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.\n\nNitrofurantoin may be used with caution if eGFR is 30\xa0ml/minute to 44\xa0ml/minute to treat uncomplicated lower UTIs caused by suspected or proven multidrug-resistant bacteria and only if potential benefit outweighs risk (BNFC, August 2018).\n\nA lower risk of resistance may be more likely if trimethoprim has not been used in the past 3\xa0months, previous urine culture suggests susceptibility (but this was not used), and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of resistance may be more likely with recent use and in older people in residential facilities.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic and antibiotic course length.\n\nFull details of the evidence and the committee's discussion are in the evidence review.", 'Summary of the evidence': "# Self-care\n\nRecommendations 1.3.1 to 1.3.3\n\n## Oral analgesia (ibuprofen)\n\nTwo randomised controlled trials (RCTs) (Bleidorn et al. 2010 and Gagyor et al. 2015) in non-pregnant women found conflicting evidence regarding the effectiveness of ibuprofen compared with antibiotics. One small RCT, Bleidorn et al. 2010, found no significant differences between ibuprofen and ciprofloxacin in reducing symptoms and symptom duration (very low to low quality evidence). However, a more recent larger RCT, Gagyor et al. 2015, found that women using ibuprofen were more likely to report a higher burden of symptoms over the first 7\xa0days after the start of their treatment, compared with women using fosfomycin (moderate quality evidence).\n\nSubgroup analyses, based on the results of urine culture prior to treatment, showed that women who received ibuprofen had significantly fewer antibiotic courses per patient compared with women who received fosfomycin (Gagyor et al. 2015; moderate quality evidence). However, this effect was driven mostly by the randomisation process, rather than the effect of the treatment itself.\n\nWomen who received ibuprofen (irrespective of urine culture) were significantly more likely to receive an additional antibiotic prescription to treat a urinary tract infection (UTI) during 12\xa0months of follow-up (31.1% versus 12.3%; high quality evidence), but were less likely to experience a recurrent UTI between days 15 to 28 of follow-up (5.8% versus 11.1%; moderate quality evidence). The authors noted that this result could be because the baseline risk of having recurrent UTI was greater in the fosfomycin group, as more women had experienced a UTI in the past year.\n\nBleidorn et al. (2010) did not report any safety or tolerability outcomes. However, Gagyor et al. (2015) found no significant difference between ibuprofen and fosfomycin in the incidence of pyelonephritis, febrile UTIs, patient-reported adverse events, or serious drug-related adverse effects (low to moderate quality evidence).\n\n## Cranberry products\n\nTwo RCTs (Wing et al. 2008 and Wing et al. 2015) assessed the clinical effectiveness and safety of cranberry products for preventing asymptomatic bacteriuria in healthy pregnant women.\n\nWing et al. (2008) found that cranberry juice was not effective in preventing episodes of asymptomatic bacteriuria or UTI. However, a significant reduction in adherence was seen in women receiving cranberry juice compared with placebo (very low quality evidence).\n\nWing et al. (2015) assessed the safety and tolerability of cranberry capsules and found no significant difference in the number of babies born with a 1-minute Apgar score <7 in women who received cranberry capsules compared with placebo (21.4% versus 0%; very low quality evidence).\n\n## Other non-pharmacological or non-antimicrobial interventions\n\nNo systematic reviews or RCTs of any non-pharmacological or non-antimicrobial interventions were identified in men, older people or children.\n\nNo systematic reviews or RCTs of paracetamol were identified.\n\nNo systematic reviews or RCTs of hydration were identified.\n\nBased on experience, the committee agreed that it was reasonable to advise people with lower UTI about using paracetamol for self-management of pain as this medicine has a well-established efficacy and safety profile.\n\nThe committee agreed, based on evidence and experience, that it was also reasonable to advise people with lower UTI about using ibuprofen for self-management of pain if this was preferred and suitable, taking account of safety concerns with NSAIDs, for example, renal impairment.\n\nBased on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.\n\nNo evidence was found for using cranberry products or alkalinising agents to treat lower UTI or asymptomatic bacteriuria. There was only evidence assessing the efficacy and safety of cranberry products for preventing asymptomatic bacteriuria in healthy pregnant women.\n\nReturn to recommendations\n\n# Antibiotics\n\nRecommendations 1.1.1 to 1.1.17\n\nRecommendations 1.2.1 to 1.2.2\n\nIn most cases, managing lower UTI will require antibiotic treatment. However, acute, uncomplicated lower UTI in non-pregnant women can be self-limiting and for some women delaying antibiotic treatment with a back-up prescription to see if symptoms will resolve without antibiotic treatment may be an option.\n\nThe most common causative pathogen in uncomplicated UTIs is Escherichia coli (in 70 to 95% of cases). Staphylococcus saprophyticus accounts for 5 to 10% of cases and occasionally other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella species are isolated (European Association of Urology guidelines on urological infections 2017).\n\nThe main complication of lower UTI is ascending infection leading to upper UTI (acute pyelonephritis). Most episodes of acute pyelonephritis are uncomplicated and result in no residual kidney damage. However, complications can include impaired renal function or renal failure, septicaemia and preterm labour in pregnancy (NICE clinical knowledge summary on pyelonephritis).\n\n\n\nIn men, prostate involvement is common, which may lead to acute prostatitis, chronic bacterial prostatitis or a prostatic abscess; urinary stones are also a possibility (NICE clinical knowledge summary on UTI (lower) - men).\n\nIn children, UTIs can lead to renal scarring, but more often this is preceded by acute pyelonephritis rather than lower UTI, and it is more common in children with vesicoureteral reflux (NICE clinical knowledge summary on UTI - children).\n\n\n\nAsymptomatic bacteriuria, where there is significant bacteriuria but no symptoms or signs of infection, is not routinely screened for or treated, except if it is considered a risk factor, such as in pregnant women (European Association of Urology guidelines on urological infections 2017).\n\n\n\nIn pregnancy, asymptomatic bacteriuria can lead to pyelonephritis and preterm labour (NICE clinical knowledge summary on UTI (lower) - women and pyelonephritis).\n\n\n\n## Efficacy of antibiotics\n\nOne systematic review of RCTs (Falagas et al. 2009) in non-pregnant women found that women who were treated with antibiotics were more likely to have complete symptom resolution (61.8% versus 25.7%; NNT 3 [range 3 to 4]; high quality evidence) and microbiological success (defined as negative urine culture) (90% versus 33.3%; NNT 2 [range 2 to 2]; moderate quality evidence), and less likely to experience relapse after the end of treatment (15.8% versus 41.6%; NNT 3 [range 3 to 5]; moderate quality evidence), compared with placebo. There was no significant difference between groups in the incidence of pyelonephritis (0.14% versus 0.75%; low quality evidence), although due to the very low incidence of pyelonephritis, it is likely the studies lacked statistical power to detect a clinically important difference.\n\nOne systematic review (Smaill et al. 2015) and 1 RCT (Kazemier et al. 2015) assessed antibiotics compared with placebo or no treatment for managing asymptomatic bacteriuria in pregnant women. Smaill et al. (2015) found that pregnant women who received antibiotics for asymptomatic bacteriuria had a reduced incidence of persistent bacteriuria (20.3% versus 66.3%; NNT 2 [range 2 to 3]; low quality evidence); were less likely to develop pyelonephritis (5.6% versus 20.8%; NNT 7 [range 6 to 9]; moderate quality evidence) or deliver a preterm baby (<37\xa0weeks) (5.8% versus 22.1%; NNT 7 [range 4 to 13]; moderate quality evidence), compared with those who received no treatment.\n\nSmaill et al. (2015) found no significant difference between antibiotics and placebo in serious adverse neonatal outcomes (very low quality evidence).\n\nKazemier et al. (2015) found no significant difference between nitrofurantoin and placebo in reducing the incidence of symptomatic UTI, pyelonephritis or preterm birth (<34\xa0weeks; very low quality evidence). Significantly more women had non-spontaneous onset of labour with nitrofurantoin compared with placebo, but there is considerable uncertainty with these results (very low quality evidence).\n\nZalmanovici-Trestioreanu et al. (2015) found that there was a greater incidence of bacteriological cure in older people who received antibiotics for treating asymptomatic bacteriuria compared with those who received placebo or no treatment (61% versus 17%; NNT 3 [range 2 to 3]; high quality evidence). However, there was no significant benefit in reducing symptomatic UTI (very low quality evidence) and people who received antibiotics were more likely to report adverse events (high quality evidence).\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2018).\n\nNitrofurantoin should be used with caution in those with renal impairment (MHRA Drug Safety Update, September 2014). It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should have monitoring for liver function and pulmonary symptoms (BNF, August 2018).\n\nTrimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF, August 2018). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).\n\nA systematic review (Falagas et al. 2009) in non-pregnant women found a significant increase in the total number of adverse events with antibiotics compared with placebo (19.2% versus 12.9%; NNH 15 [range 9 to 16]; moderate quality evidence). However there was no significant difference between antibiotics and placebo in the number of withdrawals due to adverse events.\n\nZalmanovici-Trestioreanu et al. (2015) assessed the safety of antibiotics in the management of asymptomatic bacteriuria in older people. There was a significant increase in the incidence of adverse events in those treated with antibiotics compared with placebo or no treatment (4.2% versus 1.0%; NNH 31 [range 19 to 82]; high quality evidence).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\n## Back‑up antibiotics\n\nOne RCT (Little et al. 2010) assessed various antibiotic prescribing strategies in non-pregnant women with acute uncomplicated lower UTI, where immediate antibiotic treatment was not necessary. The women included in the study had a mean age of 39 to 45\xa0years and had moderate symptoms (mean score of 1.7 to 1.8, on a scale of 0=no problem, 1=mild problem, 2=moderately bad problem, 3=severe problem) at baseline. Although bacterial confirmation was not essential for inclusion into the study, the proportion of women who had urine culture ranged from 23 to 89% (p<0.001), across 5 treatment groups. Immediate empirical antibiotics were compared with back‑up (delayed by 48\xa0hours) empirical antibiotics, and immediate antibiotics based on either a symptom severity score >2, a positive dipstick test, or a midstream urine culture result. Only two-thirds of women randomised to receive antibiotics based on a midstream urine result had a positive urine culture.\n\nThere was no difference between the different prescribing strategies (immediate empirical antibiotics; back-up empirical antibiotics; immediate antibiotics based on symptom severity score >2, positive dipstick test or midstream urine culture result) in the severity or duration of symptoms during follow-up, or in the time to reconsultation (low to very low quality evidence). However, significantly more women who were prescribed immediate antibiotics used them, compared with all other prescribing strategy groups, except immediate antibiotics based on symptom severity scoring (very low quality evidence). There were also significantly fewer women waiting 48\xa0hours before taking their antibiotics in the immediate antibiotics group, compared with all other prescribing strategy groups, except immediate antibiotics based on symptom severity score (low to very low quality evidence).\n\nLittle et al. (2010) found that despite randomisation, all groups delayed starting their antibiotic course by at least 24\xa0hours (very low quality evidence). However, a delay of more than 48\xa0hours was associated with a longer duration of moderately bad symptoms (very low quality evidence).\n\nNo systematic reviews or RCTs of back‑up antibiotic prescribing strategies were identified in men, pregnant women, older people or children.\n\nThe committee recognised the equality considerations for managing a lower UTI in transgender people, due to anatomical differences between women and men.\n\nBased on evidence and experience, the committee agreed that either a back-up antibiotic prescription or an immediate antibiotic prescription could be prescribed for non-pregnant women with a lower UTI. The committee discussed that sending a urine sample for culture and susceptibility testing is not usual practice in most young, non-pregnant women with a first lower UTI. Lower UTI is generally confirmed by symptoms and signs of infection together with dipstick testing of urine for some people. If urine culture has been taken, delaying the antibiotic until microbiological results are available could also be considered, depending on the severity of symptoms. Decisions around prescribing strategies should be individualised, taking account of the severity of symptoms, the risk of developing complications or having treatment failure, and preference for back-up or immediate antibiotics, or awaiting the results of urine culture.\n\nThe committee discussed that the evidence for back-up prescribing was only in non-pregnant women aged 18 to 70\xa0years (mean age of 39 to 45\xa0years) with, on average, moderate symptoms of an acute uncomplicated lower UTI, where immediate antibiotic treatment was not necessary. In this population, back-up empirical antibiotics were as effective as immediate empirical antibiotics for the severity or duration of UTI symptoms and the time to reconsultation. Back-up antibiotics (particularly a forward dated prescription) also reduced antibiotic use.\n\nThe committee agreed that a back-up antibiotic prescription could be used if symptoms do not start to improve within 48\xa0hours (by which point most UTIs should be starting to improve) or if they worsen at any time.\n\nBased on evidence, the committee agreed that antibiotics were effective in curing lower UTI symptoms and reducing relapse in non-pregnant women, but increased adverse events. There was no significant difference between antibiotics and placebo for the development of pyelonephritis (a complication of lower UTI). However, due to the very low incidence of pyelonephritis, it is likely the studies lacked statistical power to detect a clinically important difference.\n\nBased on experience, the committee agreed that if a urine culture has been taken, and results suggest the bacteria are resistant to the antibiotic given, the woman should be contacted and the antibiotic changed if symptoms are not already improving. The committee agreed that for non-pregnant women where 3-day courses of antibiotics are given, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back before short courses are nearly completed, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.\n\nThe committee discussed that no evidence was identified on antibiotic treatment for pregnant women with a symptomatic lower UTI. However, evidence in pregnant women with asymptomatic bacteriuria showed that antibiotics were effective in reducing persistent bacteriuria, pyelonephritis and the delivery of a preterm baby.\n\nBased on limited evidence and experience, the committee agreed that pregnant women with a lower UTI should be offered an immediate antibiotic, and urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.\n\nBased on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, pregnant woman should be contacted and the antibiotic changed regardless of whether symptoms are improving or not. The committee agreed there was a greater risk from UTIs in pregnant women and antibiotics should be changed to ensure cure.\n\nThe committee discussed that no evidence was identified on antibiotic treatment for men with a lower UTI, apart from 1 systematic review where about 10% of the study population were men.\n\nBased on experience, the committee agreed that men with a lower UTI should be offered an immediate antibiotic, and urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.\n\nBased on experience, the committee agreed that when results of urine cultures are available, if the results suggest the bacteria are resistant to the antibiotic given, men should be contacted and, if symptoms are not already improving, the antibiotic should be changed. The committee agreed that for men, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back for some days, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.\n\nThe committee was aware that the NICE guideline on urinary tract infection in under 16s makes recommendations on diagnosing lower UTIs (including the use of dipsticks and urine culture).\n\nBased on experience, the committee agreed that if a urine culture has been taken, and results suggest the bacteria are resistant to the antibiotic given, the child or young person should be contacted and, if symptoms are not already improving, the antibiotic changed. The committee agreed that for children and young people where 3-day courses of antibiotics are given, only changing antibiotics according to susceptibility results if symptoms are not already improving is appropriate. Often, susceptibility results may not be back before short courses are nearly completed, and because of differences between the in vitro and in vivo effectiveness of antibiotics, susceptibility results may not always be accurate. For some populations, where symptoms of the UTI are already improving, an additional course of antibiotics may be unnecessary treatment.\n\nBased on evidence and experience, the committee agreed that asymptomatic bacteriuria is not routinely screened for, or treated with antibiotics, in non-pregnant women, men, young people or children because it is not a risk factor for harm in these groups. It is routinely screened for, and treated with antibiotics, in pregnant women because it is a risk factor for harm. [In May 2022, we removed the reference to routine screening in pregnancy from recommendation 1.2.1, in line with amended recommendations from the UK National Screening Committee.]\n\nBased on evidence, the committee agreed that antibiotics reduce persistent bacteriuria, pyelonephritis and the delivery of a preterm baby in pregnant women with asymptomatic bacteriuria.\n\nReturn to recommendations\n\n# Choice of antibiotic\n\nRecommendation 1.4.1\n\nThree systematic reviews (Falagas et al. 2010, Rafalsky et al. 2006 and Zalmanovici-Trestioreanu et al. 2010) assessed the appropriate choice of antibiotics when treating UTIs in non-pregnant women.\n\nIn Zalmanovici-Trestioreanu et al. (2010) there were no major differences in treatment outcomes among various antibiotics and antibiotic classes: nitrofurantoin, trimethoprim, co-trimoxazole, beta-lactams, and quinolones (very low to high quality evidence).\n\nFalagas et al. (2010) showed that fosfomycin did not offer any additional benefit over other antibiotics, despite it having a single-dose regimen (very low to moderate quality evidence). Fosfomycin did not reduce the rate of adverse events or withdrawal from treatment compared with other antibiotics (very low to low quality evidence).\n\nRafalsky et al. (2006) reviewed the efficacy and safety of quinolones for the treatment of acute uncomplicated lower UTI. No quinolone showed additional benefit over another (very low to high quality evidence).\n\nOne systematic review (Guinto et al. 2010) assessed the effectiveness of different antibiotics for the treatment of asymptomatic bacteriuria in pregnant women. There was no significant difference between fosfomycin and cefuroxime in reducing the incidence of persistent infection, or in the number of women who required a change of antibiotic (very low quality evidence). Similarly, there was no significant difference between pivmecillinam and ampicillin in the number of women with persistent infection after treatment or in the incidence of recurrent infection (very low quality evidence).\n\nOne systematic review (Fitzgerald et al. 2012) assessed choice of antibiotic in children with uncomplicated lower UTI. Overall, there were no significant differences between antibiotics of any class or course length (very low quality evidence).\n\nZalmonovici-Trestioreanu et al. (2010) compared the safety of different antibiotic classes in non-pregnant women with uncomplicated lower UTI. There was no significant difference in the number of adverse events reported, or in the number of women who discontinued treatment due to an adverse event, for quinolones compared with co-trimoxazole; beta-lactams compared with co-trimoxazole; nitrofurantoin compared with beta-lactams; quinolones compared with beta-lactams; or nitrofurantoin compared with co-trimoxazole (very low to high quality evidence).\n\nRafalsky et al. (2006) compared the safety of different quinolone antibiotics in non-pregnant women with uncomplicated lower UTI and found no significant difference in the number of adverse events reported, or withdrawals from treatment due to adverse events, for ciprofloxacin compared with ofloxacin; levofloxacin compared with ofloxacin; or standard-release ciprofloxacin compared with extended-release ciprofloxacin (very low to moderate quality evidence).\n\nFalagas et al. (2010) compared the safety of fosfomycin to other antibiotics in the treatment of UTI in non-pregnant women. There was no significant difference in the number of adverse events reported or in the number of women withdrawing from treatment due to an adverse event in the fosfomycin group compared with those who received other antibiotics (very low to low quality evidence).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\n## Committee discussion on choice of antibiotic\n\nBased on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance. Resistant bacteria are a particular concern in UTIs and, where possible, any previous urine culture and susceptibility results, and antibiotic prescribing, should be checked and antibiotics chosen accordingly.\n\nThe committee discussed that, if an antibiotic is needed to treat an infection that is not life threatening, a narrow-spectrum antibiotic should generally be first-choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.\n\nNationally for England, resistance of E. coli (the main causative organism of lower UTIs) in laboratory-processed urine specimens to the following antibiotics is:\n\n\n\nnitrofurantoin: 2.5% (varies by area from 2.0 to 3.6%)\n\ntrimethoprim: 30.3% (varies by area from 27.1 to 33.4%)\n\npivmecillinam: 7.5% (varies by area from 4.1 to 15.7%)\n\ncefalexin: 9.9% (varies by area from 8.1 to 11.4%).(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018)\n\n\n\nThe committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend nitrofurantoin or trimethoprim at usual doses as first-choice antibiotics.\n\n\n\nNitrofurantoin is not recommended for people with an eGFR <45\xa0ml/minute. It may be used with caution if eGFR is 30–44\xa0ml/minute to treat uncomplicated lower UTI caused by suspected or proven multidrug resistant bacteria and only if potential benefit outweighs risk (BNF, August 2018).\n\nThe committee agreed to recommend either the modified-release preparation of nitrofurantoin or the immediate-release preparation. However, because of its twice daily dosing and, in their experience, better tolerability, the committee was keen to point out that the modified-release preparation was preferred unless it was unavailable. The committee also discussed that, in their experience, immediate-release preparations containing nitrofurantoin in a macrocrystalline form may be better tolerated than those containing nitrofurantoin in a microcrystalline form.\n\nTrimethoprim should only be prescribed if a lower risk of resistance is likely because of high resistance levels nationally. Based on experience, the committee agreed that a lower risk of resistance may be more likely if trimethoprim has not been used in the past 3\xa0months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger people in areas where local epidemiology data suggest resistance is low. A higher risk of trimethoprim resistance may be more likely with recent use (the committee was aware of evidence that trimethoprim is significantly associated with resistant E. coli infections treated in the previous 2 to\xa03 months), and in older people in residential facilities.\n\n\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend nitrofurantoin (if not used as first-choice), pivmecillinam (a penicillin) or fosfomycin at usual doses as second-choice antibiotics for use if lower UTI symptoms do not improve on a first-choice antibiotic taken for at least 48\xa0hours or first-choice antibiotics are not suitable. The committee acknowledged that prescribers may be less familiar with pivmecillinam or fosfomycin, but these antibiotics are often used in other European countries.\n\nIf there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend usual dose nitrofurantoin as the first-choice antibiotic (with the cautions outlined above):\n\n\n\nNitrofurantoin is not recommended at term in pregnancy because it may produce neonatal haemolysis (BNF, August 2018).\n\nTrimethoprim was not recommended because it is contraindicated in pregnancy. Trimethoprim is a folate antagonist and there is a teratogenic risk in the first trimester (BNF, August 2018). However, the committee acknowledged that trimethoprim is sometimes used in pregnancy when given with folic acid 5\xa0mg daily in the first trimester (NICE clinical knowledge summary on UTI (lower) – women).\n\n\n\nBased on evidence, experience and resistance data, the committee agreed to recommend amoxicillin, cefalexin or other antibiotics recommended by local microbiologists (based on culture and susceptibility results) at usual doses as second-choice antibiotics for use if lower UTI symptoms do not improve on a first-choice antibiotic taken for at least 48\xa0hours or first-choice antibiotics are not suitable.\n\n\n\nAmoxicillin is recommended only if culture results are available and bacteria are susceptible because resistance rates are high.\n\nIf there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.\n\n\n\nBased on evidence, experience and resistance data, the committee agreed to recommend a course of nitrofurantoin, amoxicillin or cefalexin, (with the cautions outlined above) for the treatment of asymptomatic bacteriuria in pregnant women. Choice should be based on recent culture and susceptibility results.\n\nBased on experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin at usual doses as first-choice antibiotics (with the cautions outlined above).\n\n\n\nTrimethoprim generally has a lower risk of resistance in men, and can reach therapeutic prostate levels. However, if acute prostatitis is suspected, quinolones are the first-choice antibiotic (see the NICE guideline on prostatitis (acute): antimicrobial prescribing).\n\nNitrofurantoin is not recommended for men with suspected prostate involvement because it is unlikely to reach therapeutic levels in the prostate.\n\n\n\nBased on experience, the committee agreed that alternative diagnoses (such as acute pyelonephritis or acute prostatitis) should be considered in men whose symptoms have not responded to a first-choice antibiotic, and second-choice antibiotics should be based on recent culture and susceptibility results.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin at usual doses as first-choice antibiotics (with the cautions outlined above).\n\n\n\nThe committee was aware that nitrofurantoin suspension is currently substantially more expensive than trimethoprim suspension and, if both antibiotics are appropriate, the one with the lowest acquisition cost should be chosen.\n\n\n\nBased on evidence, experience and resistance data, the committee agreed to recommend nitrofurantoin (if not used as first-choice), amoxicillin or cefalexin at usual doses as second-choice antibiotics for use if lower UTI symptoms get worse on a first-choice antibiotic taken for at least 48\xa0hours or first-choice antibiotics are not suitable.\n\n\n\nAmoxicillin is recommended only if culture results are available and bacteria are susceptible, because resistance rates are high.\n\nIf there are symptoms of upper UTI (acute pyelonephritis) or the person has a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.\n\n\n\nReturn to recommendation\n\n# Antibiotic course length\n\nRecommendation 1.4.1\n\nOne systematic review (Milo et al. 2005) assessed the effectiveness of 3‑day courses compared with 5- to 10-day courses of antibiotics in the treatment of lower UTI in mainly non-pregnant women (some data [less than 10%] from men were included). Three-day courses of any antibiotic were not significantly different to longer courses (5 to 10\xa0days) of any antibiotic in preventing short-term or long-term symptomatic failure, short-term bacteriological failure, or the development of pyelonephritis (very low to high quality evidence). However, long‑term bacteriological failure (at 4 to 10\xa0weeks) was significantly higher with 3‑day courses of any antibiotic compared with longer courses of any antibiotic (low quality evidence).\n\nSubgroup analysis showed a significant increase in the number of women reporting short-term bacteriological failure with a 3-day course of a quinolone compared with a 5- to 10-day course of a quinolone (7.6% versus 5.1%; low quality evidence). However, there was no significant difference in long-term bacteriological failure (moderate quality evidence).\n\nMilo et al. (2005) found a significant reduction in the number of women reporting adverse events (16.3% versus 20.6%; NNH 23 [range 16 to 39]; very low quality evidence), withdrawing due to adverse events (1.5% versus 3.2%; very low quality evidence), or reporting gastrointestinal adverse effects (6.7% versus 8.5%; very low quality evidence) with a 3-day course compared with a 5- to 10-day course of antibiotics.\n\nThree systematic reviews (Guinto et al. 2010, Smaill et al. 2015 and Widmer et al. 2015) assessed the effectiveness of different antibiotic course lengths for treating asymptomatic bacteriuria in pregnant women. Smaill et al. (2015) conducted a subgroup analysis which found that women who received a short course of antibiotics (3 to 7\xa0days) or continuous treatment were less likely to deliver preterm babies (before 37\xa0weeks) compared with no treatment (low to moderate quality evidence). Continuous courses of antibiotics reduced the number of babies born with a birthweight below 2,500\xa0g compared with no treatment (low quality evidence). Single-dose, an intermediate course of 3 to 6\xa0weeks and continuous antibiotics also significantly reduced the incidence of pyelonephritis compared with no treatment (low to moderate quality data). There was no significant difference between a short course of antibiotics and no treatment in the incidence of pyelonephritis (low quality evidence).\n\nGuinto et al. (2010) assessed the effectiveness of single-dose antibiotics compared with short courses of 7\xa0days. Women who received a 1-day course of nitrofurantoin were more likely to have a persistent infection compared with women who received a 7-day course of nitrofurantoin (high quality evidence). There was no significant difference in nausea or preterm delivery between treatment groups (moderate quality evidence).\n\nWidmer et al. (2015) found that women who received a single dose of antibiotics were more likely to deliver a baby with a low birthweight compared with those who received a short course (4 to 7\xa0days) of antibiotics (moderate quality evidence). However, they found no significant difference between a single dose and a short course (4 to 7\xa0days) for the number of women who reported no cure at the end of follow-up, experienced recurrent asymptomatic bacteriuria, developed pyelonephritis, or had a preterm delivery (very low to moderate quality evidence).\n\nOne systematic review in older women with lower UTI (Lutters et al. 2008) found that single-dose antibiotics were associated with higher rates of persistent UTI compared with short courses (3 to 6 days) or long courses (7 to 14 days) of antibiotics in the short‑term, but this was no longer significant in the long‑term (very low to low quality evidence). Long courses did not offer any clinical benefit over short courses, and there was no significant difference between 3- or 5-day courses in reducing the incidence of persistent UTIs or clinical failure (very low to low quality evidence). Antibiotic course length, such as single-dose, short-course, or long-course, had no effect on adverse events, or on the number of withdrawals due to adverse events (very low to moderate quality evidence).\n\nTwo systematic reviews (Michael et al. 2003 and Fitzgerald et al. 2012) assessed the clinical effectiveness of varying antibiotic course lengths in children with uncomplicated lower UTI. Fitzgerald et al. (2012) found no significant difference between short-course (3 to 7\xa0days) and long-course (10 to 14\xa0days) antibiotics in the number of children with persistent bacteriuria; and course length did not affect the rate of reinfection or recurrence (very low quality evidence). Michael et al. (2003) found no significant difference between antibiotics given as either a short course (2 to 4\xa0days) or a longer course (7 to 14\xa0days) on the number of children with UTIs at the end of treatment, or the rate of recurrence of UTI (very low quality evidence).\n\n## Committee discussions on antibiotic course length\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nBased on evidence, the committee agreed that a 3-day course of antibiotics was as effective as a 5- to 10-day course of antibiotics in non-pregnant women with lower UTI, and resulted in significantly fewer adverse events. The committee agreed that a longer course may increase the likelihood of complete bacteriological eradication, which may be important for some women (for example, women who experience repeated lower UTIs). However, it was not possible to analyse data separately for people with repeated lower UTIs.\n\nBased on evidence, the committee agreed that a 7- to 10-day course of antibiotics did not offer any clinical advantage over a 3- to 6-day course in older women with lower UTI.\n\nBased on evidence, experience and resistance data, the committee agreed that a 3-day course of all the recommended antibiotics (apart from fosfomycin where a single dose is given) was sufficient to treat lower UTI in non-pregnant women of any age, with no longer duration of treatment required for older women. If women have a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.\n\nBased on evidence and their experience, the committee agreed that a 7-day course of all the recommended antibiotics was required to treat bacteriuria in pregnant women with either symptomatic lower UTI or asymptomatic bacteriuria.\n\nA 7-day course is required to ensure complete cure because the risk of harm from a UTI is higher in pregnant women than in non-pregnant women.\n\nBased on their experience, the committee agreed that a 7‑day course of all the recommended antibiotics was required to treat lower UTI in men.\n\nA 7-day course is required to ensure complete cure because men are more at risk of complications from UTIs than women due to anatomical differences and possible outflow obstruction.\n\nBased on evidence, the committee agreed that a 3- to 7-day course of antibiotics was as effective as a 7- to 14-day course of antibiotics in children and young people with lower UTI.\n\nBased on evidence, experience and resistance data, the committee agreed that a 3-day course of all the recommended antibiotics was sufficient to treat lower UTI in children and young people. If children and young people have a complicated UTI (associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure), antibiotics recommended in the NICE guideline on pyelonephritis (acute): antimicrobial prescribing should be prescribed.\n\nReturn to recommendation\n\nSee the full evidence review for more information.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing or longer treatment duration (for example, some antibiotics). See the NICE guideline on medicines adherence.\n\n# Resource implications\n\nThere is a potential resource saving if a back-up antibiotic prescription strategy is used in non-pregnant women with lower urinary tract infection (UTI).\n\nRecommended antibiotics (nitrofurantoin, trimethoprim, amoxicillin, cefalexin and fosfomycin) are available as generic formulations, but there is currently no generic formulation of pivmecillinam, although the cost is comparable to other generic antibiotics, see Drug Tariff for costs.\n\nNitrofurantoin 25\xa0mg/5\xa0ml oral suspension is more expensive than other oral suspensions, such as trimethoprim 50\xa0mg/5\xa0ml. The cost of a 300-ml bottle of nitrofurantoin is £446.95 compared with £4.87 for a 100-ml bottle of trimethoprim (Drug Tariff, September 2018).'}
|
https://www.nice.org.uk/guidance/ng109
|
This guideline sets out an antimicrobial prescribing strategy for lower urinary tract infection (also called cystitis) in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
|
cb0258f4ba6a08d15dd3f36c177067f628b3e902
|
nice
|
Prostatitis (acute): antimicrobial prescribing
|
Prostatitis (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute prostatitis. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing acute prostatitis
Be aware that acute prostatitis:
is a bacterial infection of the prostate needing treatment with antibiotics
is usually caused by bacteria entering the prostate from the urinary tract
can occur spontaneously or after medical procedures such as prostate biopsy
can last several weeks
can cause complications such as acute urinary retention and prostatic abscess.
## Treatment
Offer an antibiotic (see the recommendations on choice of antibiotic) to people with acute prostatitis. Take account of:
the severity of symptoms
the risk of developing complications or having treatment failure, particularly after medical procedures such as prostate biopsy
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
Obtain a midstream urine sample before antibiotics are taken and send for culture and susceptibility testing.
When results of urine cultures are available:
review the choice of antibiotic, and
change the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow spectrum antibiotic wherever possible.
## Advice when an antibiotic prescription is given
When an antibiotic is given, give advice about:
the usual course of acute prostatitis (several weeks)
possible adverse effects of the antibiotic, particularly diarrhoea and nausea
seeking medical help if:
symptoms worsen at any time, or
symptoms do not start to improve within 48 hours of taking the antibiotic, or
the person becomes systemically very unwell.
## Reassessment
Reassess if symptoms worsen at any time, taking account of:
-ther possible diagnoses
any symptoms or signs suggesting a more serious illness or condition, such as acute urinary retention, prostatic abscess or sepsis
previous antibiotic use, which may have led to resistant bacteria.
## Referral
Refer people with acute prostatitis to hospital if:
they have any symptoms or signs suggesting a more serious illness or condition (for example sepsis, acute urinary retention or prostatic abscess), or
their symptoms are not improving 48 hours after starting the antibiotic.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.
Full details of the evidence and the committee's discussion are in the evidence review.
# Self-care
Advise people with acute prostatitis about using paracetamol (with or without a low‑dose weak opioid, such as codeine) for pain, or ibuprofen if this is preferred and suitable.
Advise people with acute prostatitis about drinking enough fluids to avoid dehydration.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.
Full details of the evidence and the committee's discussion are in the evidence review.
# Choice of antibiotic
When prescribing an antibiotic for acute prostatitis, take account of local antimicrobial resistance (AMR) data from Public Health England and follow table 1 for adults aged 18 years and over.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Review antibiotic treatment after 14 days and either stop the antibiotic or continue for a further 14 days if needed, based on an assessment of the person's history, symptoms, clinical examination, urine and blood tests.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotics (guided by susceptibilities when available)
Ciprofloxacin (consider safety issues):
mg twice a day for 14 days then review
Ofloxacin (consider safety issues):
mg twice a day for 14 days then review
Alternative first-choice oral antibiotic if a fluoroquinolone antibiotic is not appropriate (seek specialist advice; guided by susceptibilities when available)
Trimethoprim:
mg twice a day for 14 days then review
Second-choice oral antibiotics (after discussion with specialist)
Levofloxacin (consider safety issues):
mg once a day for 14 days then review
Co‑trimoxazole:
mg twice day for 14 days then review
Co-trimoxazole should only be considered when there is bacteriological evidence of sensitivity and good reasons to prefer this combination to a single antibiotic (BNF information on co-trimoxazole).
First-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell; guided by susceptibilities when available). Antibiotics may be combined if sepsis a concern
Ciprofloxacin (consider safety issues):
mg twice or three times a day
Levofloxacin (consider safety issues):
mg once a day
Cefuroxime:
g three or four times a day
Ceftriaxone:
g once a day
Gentamicin:
Initially 5 mg/kg to 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration.
Therapeutic drug monitoring and assessment of renal function is required (BNF information on gentamicin).
Amikacin:
Initially 15 mg/kg once a day (maximum per dose 1.5 g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15 g per course).
Therapeutic drug monitoring and assessment of renal function is required (BNF information on amikacin).
Second-choice intravenous antibiotics
Consult a local microbiologist
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.
Check any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.
See Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Review treatment after 14 days and either stop the antibiotic or continue for a further 14 days if needed based on clinical assessment.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible for a total of 14 days then review.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.# Summary of the evidence
# Self-care
No systematic reviews, randomised controlled trials (RCTs) or observational studies of the efficacy of non-antimicrobial treatments for acute prostatitis were identified.
## Committee discussion on self-care
Based on experience, the committee agreed that it was reasonable to advise adults with acute prostatitis about paracetamol (with or without a low‑dose weak opioid, such as codeine) for self‑care management of pain. These medicines have a well-established efficacy and safety profile for managing pain.
If preferred and suitable, ibuprofen could be considered. However, the safety profile of non‑steroidal anti-inflammatory drugs (NSAIDs) and drug interactions (potential increased risk of seizures with fluoroquinolones) should be taken into account when selecting pain relief.
Based on experience that dehydration is often cited as a cause of urinary tract infections, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.
# Antibiotics
Acute prostatitis is a bacterial infection needing prompt treatment with antibiotics.
Gram-negative bacteria are the most common causative pathogens in acute prostatitis, most commonly Escherichia coli, Proteus species, Klebsiella species and Pseudomonas species.
Complications of acute prostatitis include acute urinary retention secondary to prostatic oedema, chronic prostatitis, prostatic abscess, bacteraemia, epididymitis and pyelonephritis.
## Efficacy of antibiotics
No systematic reviews, RCTs or observational studies of the efficacy of antibiotics for treating acute prostatitis were identified.
## Safety of antibiotics
Fluoroquinolones can interact with NSAIDs, potentially increasing the risk of seizures (BNF information on ciprofloxacin). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee in a press release (October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain appropriate in acute prostatitis, which is a severe infection.
Antibiotic-associated diarrhoea occurs in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).
Aminoglycoside doses are based on weight and renal function and whenever possible treatment should not exceed 7 days (BNF information on gentamicin).
There are restrictions on the use of co-trimoxazole in the UK. It should only be used in urinary tract infections where there is bacteriological evidence of sensitivity and good reasons to prefer this antibiotic (BNF information on co-trimoxazole).
See the summaries of product characteristics and BNF for information on contraindications, cautions and adverse effects of individual medicines.
The committee agreed that acute prostatitis is a bacterial infection needing prompt treatment with antibiotics, but no evidence was identified to support this.
The committee was aware of several guidelines, which reflect current practice, that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.
Based on experience, the committee agreed that adults with acute prostatitis should be offered an antibiotic. Urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.
The committee agreed that if the results of urine culture suggest the bacteria are resistant to the antibiotic given, adults with acute prostatitis should be contacted and the antibiotic should be changed. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible, and antibiotics switched from intravenous to oral where applicable.
The committee agreed that if symptoms do not start to improve within 48 hours of taking an antibiotic, people should be referred to hospital because of concerns around complications, such as acute urinary retention or prostatic abscess, and treatment failure because of resistant bacteria.
# Choice of antibiotic
Many antibiotics penetrate the prostate gland poorly, but fluoroquinolones reach therapeutic levels in the prostate. Where fluoroquinolone resistance is a concern, other antibiotics that can reach therapeutic prostate levels include third-generation cephalosporins (such as ceftriaxone), carbapenems (such as imipenem or ertapenem), some aminoglycosides, aztreonam, piperacillin, minocycline, doxycycline, erythromycin, clindamycin and trimethoprim (Lipsky et al. 2010). In acute prostatitis, where there is intense inflammation of the prostate gland, antibiotic penetration can be better than in chronic prostatitis (National guidelines for the management of prostatitis, British Association for Sexual Health and HIV , 2001).
Several guidelines make recommendations on antibiotic choice based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns. These include:
European Association of Urology guidelines on urological infections (2018)
RCGP/BASHH Sexually transmitted infections in primary care guidelines (2013)
BASHH national guidelines for the management of prostatitis (2001).
## Committee discussion on choice of antibiotic
No evidence was identified to guide the choice of antibiotics for treating acute prostatitis. The committee was aware of several guidelines, which reflect current practice, that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.
Based on experience, the committee agreed that treating acute prostatitis requires high doses of fluoroquinolones, second- or third-generation cephalosporins or broad-spectrum penicillins (possibly combined with an aminoglycoside), with intravenous or oral use based on the severity of symptoms and the ability to take oral medicines. These antibiotics reach therapeutic levels in the prostate, and are in line with current guidelines and practice.
Nationally for England, resistance of E. coli (the main causative organism of acute prostatitis) in laboratory processed urine specimens to the following antibiotics is:
ciprofloxacin: 10.6% (varies by area from 7.8% to 13.7%)
trimethoprim: 30.3% (varies by area from 27.1% to 33.4%)(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018).
The committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.
Based on experience and resistance data, the committee agreed that the choice of first- and second-line oral antibiotics for managing acute prostatitis are:
First-choice: ciprofloxacin or ofloxacin (fluoroquinolones), or trimethoprim (for adults unable to take a fluoroquinolone). Fluoroquinolones are more effective against a wider range of urinary pathogens than trimethoprim. But for adults unable to take a fluoroquinolone, trimethoprim is recommended. Trimethoprim generally has a lower risk of resistance in men, and can reach therapeutic prostate levels.
Second-choice: levofloxacin (a fluoroquinolone) or co-trimoxazole
The committee agreed that second-choice oral antibiotics should be reserved for use after discussion with a specialist. This is to preserve the use of the broader spectrum fluoroquinolone, levofloxacin, for people with a more severe infection, and because of restrictions on the use of co‑trimoxazole in the UK.
The committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolone antibiotics are the mainstay of treatment in acute prostatitis, which is a severe infection. The committee was keen to point out, however, that fluoroquinolone safety concerns should be taken into account on an individual patient basis.
The committee agreed that the choice of intravenous antibiotics for managing acute prostatitis in people who are severely unwell or unable to take oral antibiotics (with combined use if sepsis is a concern) are:
ciprofloxacin or levofloxacin (fluoroquinolones)
cefuroxime or ceftriaxone (second- or third-generation cephalosporins)
gentamicin or amikacin (aminoglycosides).
This choice allows intravenous antibiotics to be selected based on the severity of illness and likely pathogens, antibiotic susceptibilities from culture results when available, and local resistance data.
The committee noted that use of broad-spectrum antibiotics, such as fluoroquinolones or later-generation cephalosporins, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. And, by disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of acute prostatitis, where coverage of more resistant strains of common bacterial pathogens is required.
# Antibiotic course length
Several guidelines make recommendations on antibiotic course length based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns. These include:
European Association of Urology guidelines on urological infections (2018)
RCGP/BASHH Sexually transmitted infections in primary care guidelines (2013)
BASHH national guidelines for the management of prostatitis (2001).
In line with Department of Health and Social Care 'Start smart – then focus' toolkit, the NICE guideline on antimicrobial stewardship recommends considering a review of intravenous antibiotic prescriptions at 48 to 72 hours, documenting response to treatment and any available culture and susceptibility results to determine if the antibiotic should be continued or switched to a narrower spectrum or an oral antibiotic.
## Committee discussion on antibiotic course length
No evidence was identified to guide antibiotic course length for treating acute prostatitis. The committee was aware of several guidelines that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.
Based on experience, the committee agreed that treating acute prostatitis requires oral antibiotics for between 2 and 4 weeks, with initial intravenous antibiotics if adults are unable to take oral antibiotics or are severely unwell. This is in line with current guidelines and practice.
However, in line with good antimicrobial stewardship, the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects. First-line antibiotics for acute prostatitis are fluoroquinolones, which are broad-spectrum antibiotics. These antibiotics, in particular, should be used for the shortest effective time because they can create a selective advantage for bacteria resistant to these 'last-line' broad-spectrum agents, and can leave people susceptible to Clostridium difficile.
Use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.
The committee agreed that a minimum of a 14-day course of all the recommended antibiotics was required for acute prostatitis. At 14 days, treatment should be reviewed, and either stopped or continued for a further 14 days as needed based on clinical assessment. From experience, the committee discussed that whether to continue treatment or not would be based on the person's history or risk of developing chronic prostatitis, their current symptoms and any recent examination, urine and blood test results. Continued symptoms, such as fever or lower urinary tract symptoms (dysuria, frequency, urgency, or acute urinary retention) require ongoing treatment.
# Antibiotic prophylaxis for preventing infective complications, including acute prostatitis, after biopsy
One double blind RCT from Iran (Dadashpour et al. 2016) and 4 observational studies from Taiwan, Turkey or Korea (Lee et al. 2015, Chiang et al. 2007, Ryu et al. 2016 and Bulut et al. 2015) compared the effectiveness of various short-term antibiotic regimens in preventing complications, including acute prostatitis, after prostate biopsy. All the observational studies were retrospective analyses of medical records, often with non-concurrent controls. The prophylactic antibiotics varied, but most studies used a fluoroquinolone. The definition of post-biopsy complications, including acute prostatitis, varied between clinical symptoms (fever more than 38 degrees Celsius or more than 39 degrees Celsius, chills, dysuria, frequent urination and pelvic pain), abnormal digital rectal examination or urinalysis.
## Committee discussion on preventing acute prostatitis and other complications after prostate biopsy
The committee reviewed the available evidence and agreed that it was limited by its design (mostly observational studies) and its relevance to UK practice (studies were undertaken in Iran, Taiwan, Turkey and Korea where the choice of antibiotics may be very different).
The committee agreed that the limitations with the evidence base, and the wide range of antibiotics included at varying dosage regimens, makes interpretation of study findings difficult.
The committee agreed that the available evidence on antibiotic prophylaxis was insufficient to make recommendations and local microbiologists should be consulted.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are all available as generic formulations, see the Drug Tariff for costs.
|
{'Recommendations': "# Managing acute prostatitis\n\nBe aware that acute prostatitis:\n\nis a bacterial infection of the prostate needing treatment with antibiotics\n\nis usually caused by bacteria entering the prostate from the urinary tract\n\ncan occur spontaneously or after medical procedures such as prostate biopsy\n\ncan last several weeks\n\ncan cause complications such as acute urinary retention and prostatic abscess.\n\n## Treatment\n\nOffer an antibiotic (see the recommendations on choice of antibiotic) to people with acute prostatitis. Take account of:\n\nthe severity of symptoms\n\nthe risk of developing complications or having treatment failure, particularly after medical procedures such as prostate biopsy\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nObtain a midstream urine sample before antibiotics are taken and send for culture and susceptibility testing.\n\nWhen results of urine cultures are available:\n\nreview the choice of antibiotic, and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow spectrum antibiotic wherever possible.\n\n## Advice when an antibiotic prescription is given\n\nWhen an antibiotic is given, give advice about:\n\nthe usual course of acute prostatitis (several weeks)\n\npossible adverse effects of the antibiotic, particularly diarrhoea and nausea\n\nseeking medical help if:\n\n\n\nsymptoms worsen at any time, or\n\nsymptoms do not start to improve within 48\xa0hours of taking the antibiotic, or\n\nthe person becomes systemically very unwell.\n\n\n\n## Reassessment\n\nReassess if symptoms worsen at any time, taking account of:\n\nother possible diagnoses\n\nany symptoms or signs suggesting a more serious illness or condition, such as acute urinary retention, prostatic abscess or sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\n## Referral\n\nRefer people with acute prostatitis to hospital if:\n\nthey have any symptoms or signs suggesting a more serious illness or condition (for example sepsis, acute urinary retention or prostatic abscess), or\n\ntheir symptoms are not improving 48\xa0hours after starting the antibiotic.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotics.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Self-care\n\nAdvise people with acute prostatitis about using paracetamol (with or without a low‑dose weak opioid, such as codeine) for pain, or ibuprofen if this is preferred and suitable.\n\nAdvise people with acute prostatitis about drinking enough fluids to avoid dehydration.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for acute prostatitis, take account of local antimicrobial resistance (AMR) data from Public Health England and follow table\xa01 for adults aged 18\xa0years and over.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nReview antibiotic treatment after 14\xa0days and either stop the antibiotic or continue for a further 14\xa0days if needed, based on an assessment of the person's history, symptoms, clinical examination, urine and blood tests.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotics (guided by susceptibilities when available)\n\nCiprofloxacin (consider safety issues):\n\nmg twice a day for 14\xa0days then review\n\n\n\nOfloxacin (consider safety issues):\n\nmg twice a day for 14\xa0days then review\n\nAlternative first-choice oral antibiotic if a fluoroquinolone antibiotic is not appropriate (seek specialist advice; guided by susceptibilities when available)\n\nTrimethoprim:\n\nmg twice a day for 14\xa0days then review\n\nSecond-choice oral antibiotics (after discussion with specialist)\n\nLevofloxacin (consider safety issues):\n\nmg once a day for 14\xa0days then review\n\n\n\nCo‑trimoxazole:\n\nmg twice day for 14\xa0days then review\n\nCo-trimoxazole should only be considered when there is bacteriological evidence of sensitivity and good reasons to prefer this combination to a single antibiotic (BNF information on co-trimoxazole).\n\nFirst-choice intravenous antibiotics (if unable to take oral antibiotics or severely unwell; guided by susceptibilities when available). Antibiotics may be combined if sepsis a concern\n\nCiprofloxacin (consider safety issues):\n\nmg twice or three times a day\n\n\n\nLevofloxacin (consider safety issues):\n\nmg once a day\n\n\n\nCefuroxime:\n\ng three or four times a day\n\n\n\nCeftriaxone:\n\ng once a day\n\n\n\nGentamicin:\n\nInitially 5\xa0mg/kg to 7\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration.\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF information on gentamicin).\n\n\n\nAmikacin:\n\nInitially 15\xa0mg/kg once a day (maximum per dose 1.5\xa0g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15\xa0g per course).\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF information on amikacin).\n\nSecond-choice intravenous antibiotics\n\nConsult a local microbiologist\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.\n\nSee Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60\xa0years and avoiding coadministration with a corticosteroid (March 2019).\n\nReview treatment after 14\xa0days and either stop the antibiotic or continue for a further 14\xa0days if needed based on clinical assessment.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible for a total of 14\xa0days then review.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.", 'Summary of the evidence': "# Self-care\n\nNo systematic reviews, randomised controlled trials (RCTs) or observational studies of the efficacy of non-antimicrobial treatments for acute prostatitis were identified.\n\n## Committee discussion on self-care\n\nBased on experience, the committee agreed that it was reasonable to advise adults with acute prostatitis about paracetamol (with or without a low‑dose weak opioid, such as codeine) for self‑care management of pain. These medicines have a well-established efficacy and safety profile for managing pain.\n\nIf preferred and suitable, ibuprofen could be considered. However, the safety profile of non‑steroidal anti-inflammatory drugs (NSAIDs) and drug interactions (potential increased risk of seizures with fluoroquinolones) should be taken into account when selecting pain relief.\n\nBased on experience that dehydration is often cited as a cause of urinary tract infections, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.\n\n# Antibiotics\n\nAcute prostatitis is a bacterial infection needing prompt treatment with antibiotics.\n\nGram-negative bacteria are the most common causative pathogens in acute prostatitis, most commonly Escherichia coli, Proteus species, Klebsiella species and Pseudomonas species.\n\nComplications of acute prostatitis include acute urinary retention secondary to prostatic oedema, chronic prostatitis, prostatic abscess, bacteraemia, epididymitis and pyelonephritis.\n\n## Efficacy of antibiotics\n\nNo systematic reviews, RCTs or observational studies of the efficacy of antibiotics for treating acute prostatitis were identified.\n\n## Safety of antibiotics\n\nFluoroquinolones can interact with NSAIDs, potentially increasing the risk of seizures (BNF information on ciprofloxacin). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee in a press release (October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain appropriate in acute prostatitis, which is a severe infection.\n\nAntibiotic-associated diarrhoea occurs in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).\n\nAminoglycoside doses are based on weight and renal function and whenever possible treatment should not exceed 7\xa0days (BNF information on gentamicin).\n\nThere are restrictions on the use of co-trimoxazole in the UK. It should only be used in urinary tract infections where there is bacteriological evidence of sensitivity and good reasons to prefer this antibiotic (BNF information on co-trimoxazole).\n\nSee the summaries of product characteristics and BNF for information on contraindications, cautions and adverse effects of individual medicines.\n\nThe committee agreed that acute prostatitis is a bacterial infection needing prompt treatment with antibiotics, but no evidence was identified to support this.\n\nThe committee was aware of several guidelines, which reflect current practice, that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.\n\nBased on experience, the committee agreed that adults with acute prostatitis should be offered an antibiotic. Urine should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.\n\nThe committee agreed that if the results of urine culture suggest the bacteria are resistant to the antibiotic given, adults with acute prostatitis should be contacted and the antibiotic should be changed. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible, and antibiotics switched from intravenous to oral where applicable.\n\nThe committee agreed that if symptoms do not start to improve within 48\xa0hours of taking an antibiotic, people should be referred to hospital because of concerns around complications, such as acute urinary retention or prostatic abscess, and treatment failure because of resistant bacteria.\n\n# Choice of antibiotic\n\nMany antibiotics penetrate the prostate gland poorly, but fluoroquinolones reach therapeutic levels in the prostate. Where fluoroquinolone resistance is a concern, other antibiotics that can reach therapeutic prostate levels include third-generation cephalosporins (such as ceftriaxone), carbapenems (such as imipenem or ertapenem), some aminoglycosides, aztreonam, piperacillin, minocycline, doxycycline, erythromycin, clindamycin and trimethoprim (Lipsky et al. 2010). In acute prostatitis, where there is intense inflammation of the prostate gland, antibiotic penetration can be better than in chronic prostatitis (National guidelines for the management of prostatitis, British Association for Sexual Health and HIV [BASHH], 2001).\n\nSeveral guidelines make recommendations on antibiotic choice based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns. These include:\n\n\n\nEuropean Association of Urology guidelines on urological infections (2018)\n\nRCGP/BASHH Sexually transmitted infections in primary care guidelines (2013)\n\nBASHH national guidelines for the management of prostatitis (2001).\n\n\n\n## Committee discussion on choice of antibiotic\n\nNo evidence was identified to guide the choice of antibiotics for treating acute prostatitis. The committee was aware of several guidelines, which reflect current practice, that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.\n\nBased on experience, the committee agreed that treating acute prostatitis requires high doses of fluoroquinolones, second- or third-generation cephalosporins or broad-spectrum penicillins (possibly combined with an aminoglycoside), with intravenous or oral use based on the severity of symptoms and the ability to take oral medicines. These antibiotics reach therapeutic levels in the prostate, and are in line with current guidelines and practice.\n\nNationally for England, resistance of E. coli (the main causative organism of acute prostatitis) in laboratory processed urine specimens to the following antibiotics is:\n\n\n\nciprofloxacin: 10.6% (varies by area from 7.8% to 13.7%)\n\ntrimethoprim: 30.3% (varies by area from 27.1% to 33.4%)(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018).\n\n\n\nThe committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.\n\nBased on experience and resistance data, the committee agreed that the choice of first- and second-line oral antibiotics for managing acute prostatitis are:\n\n\n\nFirst-choice: ciprofloxacin or ofloxacin (fluoroquinolones), or trimethoprim (for adults unable to take a fluoroquinolone). Fluoroquinolones are more effective against a wider range of urinary pathogens than trimethoprim. But for adults unable to take a fluoroquinolone, trimethoprim is recommended. Trimethoprim generally has a lower risk of resistance in men, and can reach therapeutic prostate levels.\n\nSecond-choice: levofloxacin (a fluoroquinolone) or co-trimoxazole\n\n\n\nThe committee agreed that second-choice oral antibiotics should be reserved for use after discussion with a specialist. This is to preserve the use of the broader spectrum fluoroquinolone, levofloxacin, for people with a more severe infection, and because of restrictions on the use of co‑trimoxazole in the UK.\n\nThe committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolone antibiotics are the mainstay of treatment in acute prostatitis, which is a severe infection. The committee was keen to point out, however, that fluoroquinolone safety concerns should be taken into account on an individual patient basis.\n\nThe committee agreed that the choice of intravenous antibiotics for managing acute prostatitis in people who are severely unwell or unable to take oral antibiotics (with combined use if sepsis is a concern) are:\n\n\n\nciprofloxacin or levofloxacin (fluoroquinolones)\n\ncefuroxime or ceftriaxone (second- or third-generation cephalosporins)\n\ngentamicin or amikacin (aminoglycosides).\n\n\n\nThis choice allows intravenous antibiotics to be selected based on the severity of illness and likely pathogens, antibiotic susceptibilities from culture results when available, and local resistance data.\n\nThe committee noted that use of broad-spectrum antibiotics, such as fluoroquinolones or later-generation cephalosporins, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. And, by disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of acute prostatitis, where coverage of more resistant strains of common bacterial pathogens is required.\n\n# Antibiotic course length\n\nSeveral guidelines make recommendations on antibiotic course length based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns. These include:\n\n\n\nEuropean Association of Urology guidelines on urological infections (2018)\n\nRCGP/BASHH Sexually transmitted infections in primary care guidelines (2013)\n\nBASHH national guidelines for the management of prostatitis (2001).\n\n\n\nIn line with Department of Health and Social Care 'Start smart – then focus' toolkit, the NICE guideline on antimicrobial stewardship recommends considering a review of intravenous antibiotic prescriptions at 48 to 72\xa0hours, documenting response to treatment and any available culture and susceptibility results to determine if the antibiotic should be continued or switched to a narrower spectrum or an oral antibiotic.\n\n## Committee discussion on antibiotic course length\n\nNo evidence was identified to guide antibiotic course length for treating acute prostatitis. The committee was aware of several guidelines that make recommendations based on expert consensus and overviews of the literature on pharmacokinetics and antimicrobial resistance patterns.\n\nBased on experience, the committee agreed that treating acute prostatitis requires oral antibiotics for between 2 and 4\xa0weeks, with initial intravenous antibiotics if adults are unable to take oral antibiotics or are severely unwell. This is in line with current guidelines and practice.\n\nHowever, in line with good antimicrobial stewardship, the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects. First-line antibiotics for acute prostatitis are fluoroquinolones, which are broad-spectrum antibiotics. These antibiotics, in particular, should be used for the shortest effective time because they can create a selective advantage for bacteria resistant to these 'last-line' broad-spectrum agents, and can leave people susceptible to Clostridium difficile.\n\nUse of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.\n\nThe committee agreed that a minimum of a 14-day course of all the recommended antibiotics was required for acute prostatitis. At 14\xa0days, treatment should be reviewed, and either stopped or continued for a further 14\xa0days as needed based on clinical assessment. From experience, the committee discussed that whether to continue treatment or not would be based on the person's history or risk of developing chronic prostatitis, their current symptoms and any recent examination, urine and blood test results. Continued symptoms, such as fever or lower urinary tract symptoms (dysuria, frequency, urgency, or acute urinary retention) require ongoing treatment.\n\n# Antibiotic prophylaxis for preventing infective complications, including acute prostatitis, after biopsy\n\nOne double blind RCT from Iran (Dadashpour et al. 2016) and 4\xa0observational studies from Taiwan, Turkey or Korea (Lee et al. 2015, Chiang et al. 2007, Ryu et al. 2016 and Bulut et al. 2015) compared the effectiveness of various short-term antibiotic regimens in preventing complications, including acute prostatitis, after prostate biopsy. All the observational studies were retrospective analyses of medical records, often with non-concurrent controls. The prophylactic antibiotics varied, but most studies used a fluoroquinolone. The definition of post-biopsy complications, including acute prostatitis, varied between clinical symptoms (fever more than 38\xa0degrees Celsius or more than 39\xa0degrees Celsius, chills, dysuria, frequent urination and pelvic pain), abnormal digital rectal examination or urinalysis.\n\n## Committee discussion on preventing acute prostatitis and other complications after prostate biopsy\n\nThe committee reviewed the available evidence and agreed that it was limited by its design (mostly observational studies) and its relevance to UK practice (studies were undertaken in Iran, Taiwan, Turkey and Korea where the choice of antibiotics may be very different).\n\nThe committee agreed that the limitations with the evidence base, and the wide range of antibiotics included at varying dosage regimens, makes interpretation of study findings difficult.\n\nThe committee agreed that the available evidence on antibiotic prophylaxis was insufficient to make recommendations and local microbiologists should be consulted.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are all available as generic formulations, see the Drug Tariff for costs.'}
|
https://www.nice.org.uk/guidance/ng110
|
This guideline sets out an antimicrobial prescribing strategy for acute prostatitis. It aims to optimise antibiotic use and reduce antibiotic resistance.
|
3ca6e04aec398485c082a7f3c10e4625883b90fc
|
nice
|
Pyelonephritis (acute): antimicrobial prescribing
|
Pyelonephritis (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute pyelonephritis (upper urinary tract infection) in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing acute pyelonephritis
Be aware that acute pyelonephritis is an infection of one or both kidneys usually caused by bacteria travelling up from the bladder.
## Treatment
In people aged 16 years and over with acute pyelonephritis, obtain a midstream urine sample before antibiotics are taken and send for culture and susceptibility testing.
In children and young people under 16 years with acute pyelonephritis, obtain a urine sample before antibiotics are taken and send for culture and susceptibility testing in line with the NICE guideline on urinary tract infection in under 16s.
Assess and manage children under 5 with acute pyelonephritis who present with fever as outlined in the NICE guideline on fever in under 5s.
Offer an antibiotic (see the recommendations on choice of antibiotic) to people with acute pyelonephritis. Take account of:
the severity of symptoms
the risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract or immunosuppression
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria.
When results of urine cultures are available:
review the choice of antibiotic and
change the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow spectrum antibiotic wherever possible.
## Advice when an antibiotic prescription is given
When an antibiotic is given, as well as the general advice on self-care, give advice about:
possible adverse effects of the antibiotic, particularly diarrhoea and nausea
nausea with vomiting also being a possible indication of worsening pyelonephritis
seeking medical help if:
symptoms worsen at any time or
symptoms do not start to improve within 48 hours of taking the antibiotic or
the person becomes systemically very unwell.
## Reassessment
Reassess if symptoms worsen at any time, or do not start to improve within 48 hours of taking the antibiotic, taking account of:
-ther possible diagnoses
any symptoms or signs suggesting a more serious illness or condition, such as sepsis
previous antibiotic use, which may have led to resistant bacteria.
## Referral and seeking specialist advice
Refer people aged 16 years and over with acute pyelonephritis to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).
Consider referring or seeking specialist advice for people aged 16 years and over with acute pyelonephritis if they:
are significantly dehydrated or unable to take oral fluids and medicines or
are pregnant or
have a higher risk of developing complications (for example, people with known or suspected structural or functional abnormality of the genitourinary tract or underlying disease ).
Refer children and young people with acute pyelonephritis to hospital in line with the NICE guideline on urinary tract infection in under 16s.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.
Full details of the evidence and the committee's discussion are available in the evidence review.
# Self-care
Advise people with acute pyelonephritis about using paracetamol for pain, with the possible addition of a low-dose weak opioid such as codeine for people over 12 years.
Advise people with acute pyelonephritis about drinking enough fluids to avoid dehydration.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.
Full details of the evidence and the committee's discussion are available in the evidence review.
# Choice of antibiotic
When prescribing an antibiotic for acute pyelonephritis, take account of local antimicrobial resistance (AMR) data from Public Health England and follow:
table 1 for non-pregnant women and men aged 16 years and over
table 2 for pregnant women aged 12 years and over
table 3 for children and young people under 16 years.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotics
Cefalexin:
mg twice or three times a day (up to 1 to 1.5 g three or four times a day for severe infections) for 7 to 10 days
Co‑amoxiclav (only if culture results available and susceptible):
/125 mg three times a day for 7 to 10 days
Trimethoprim (only if culture results available and susceptible):
mg twice a day for 14 days
Ciprofloxacin (consider safety issues):
mg twice a day for 7 days
First-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics, or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern.
Co‑amoxiclav (only in combination or if culture results available and susceptible):
g three times a day
Cefuroxime:
mg to 1.5 g three or four times a day
Ceftriaxone:
g to 2 g once a day
Ciprofloxacin (consider safety issues):
mg twice or three times a day
Gentamicin:
Initially 5 mg/kg to 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration
Therapeutic drug monitoring and assessment of renal function is required (BNF information on gentamicin)
Amikacin:
Initially 15 mg/kg once a day (maximum per dose 1.5 g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15 g per course)
Therapeutic drug monitoring and assessment of renal function is required (BNF information on amikacin)
Second-choice intravenous antibiotics
Consult a local microbiologist
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment and breastfeeding, and administering intravenous antibiotics.
Check any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.
See Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Cefalexin:
mg twice or three times a day (up to 1 g to 1.5 g three or four times a day for severe infections) for 7 to 10 days
First-choice intravenous antibiotic (if vomiting, unable to take oral antibiotics, or severely unwell)
Cefuroxime:
mg to 1.5 g three or four times a day
Second-choice antibiotics or when combining antibiotics if susceptibility or sepsis a concern
Consult local microbiologist
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.
Check any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible.
Treatment
Antibiotic, dosage and course length
Choice for children under 3 months
Refer to paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under 5s
First-choice oral antibiotic for children aged 3 months and over
Cefalexin:
months to 11 months, 12.5 mg/kg or 125 mg twice a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
year to 4 years, 12.5 mg/kg twice a day or 125 mg three times a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
years to 11 years, 12.5 mg/kg twice a day or 250 mg three times a day for 7 to 10 days (25 mg/kg two to four times a day for severe infections)
years to 15 years, 500 mg twice or three times a day (up to 1 g to 1.5 g three or four times a day for severe infections) for 7 to 10 days
Co‑amoxiclav (only if culture results available and susceptible):
months to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
years to 5 years, 0.25 ml/kg of 125/31 suspension or 5 ml of 125/31 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
years to 11 years, 0.15 ml/kg of 250/62 suspension or 5 ml of 250/62 suspension three times a day for 7 to 10 days (dose doubled in severe infection)
years to 15 years, 250/125 mg or 500/125 mg three times a day for 7 to 10 days
First-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell) for children aged 3 months and over. Antibiotics may be combined if susceptibility or sepsis a concern
Co‑amoxiclav (only in combination or if culture results available and susceptible):
months to 15 years, 30 mg/kg three times a day (maximum 1.2 g three times a day)
Cefuroxime:
months to 15 years, 20 mg/kg three times a day (maximum 750 mg per dose), increased to 50 mg/kg to 60 mg/kg three or four times a day (maximum 1.5 g per dose) for severe infections
Ceftriaxone:
months to 11 years (up to 50 kg), 50 mg/kg to 80 mg/kg once a day (maximum 4 g per day)
years to 11 years (50 kg and above), 1 g to 2 g once a day
years to 15 years, 1 g to 2 g once a day
Gentamicin:
Initially 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration
Therapeutic drug monitoring and assessment of renal function is required (BNFC information on gentamicin)
Amikacin:
Initially 15 mg/kg once a day, subsequent doses adjusted according to serum amikacin concentration
Therapeutic drug monitoring and assessment of renal function is required (BNFC information on amikacin)
Second-choice intravenous antibiotics for children aged 3 months and over
Consult a local microbiologist
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic and renal impairment, and administering intravenous antibiotics. See table 2 if a young woman is pregnant.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
Check any previous urine culture and susceptibility results and antibiotic prescribing, and choose antibiotics accordingly. Where a child or young person is receiving prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.
Review intravenous antibiotics by 48 hours and consider stepping down to oral antibiotics where possible for a total of 10 days. If intravenous treatment is not possible, consider intramuscular treatment if suitable.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic, antibiotic course length and antibiotic route of administration.
Full details of the evidence and the committee's discussion are available in the evidence review.# Summary of the evidence
The recommendations in this guideline are based on the evidence identified, which was mainly for people with acute pyelonephritis. Some studies also included people with a complicated urinary tract infection (UTI; associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure) or urosepsis (a systemic response to a UTI).
# Self-care
No systematic reviews or randomised controlled trials (RCTs) of any non‑antimicrobial treatments were identified that met the inclusion criteria.
## Committee discussion on self-care
There was no evidence for the use of oral analgesia in acute pyelonephritis. However, paracetamol has a well-established efficacy and safety profile for managing pain. The committee agreed that it was reasonable to advise people about paracetamol for self-management of pain. A low-dose weak opioid, such as codeine, could be taken with paracetamol by adults and young people over 12 years for more severe pain.
Non-steroidal anti-inflammatory drugs, such as ibuprofen, are generally not recommended for people with acute pyelonephritis because of concerns about renal safety.
The committee discussed the need for an adequate intake of fluids to ensure a high urine output, which is believed to help resolve acute pyelonephritis through a mechanical flushing of bacteria from the kidney. No evidence was found for this and there was no evidence of what constitutes adequate hydration. However, based on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.
# Antibiotics
Acute pyelonephritis is a bacterial infection needing treatment with an antibiotic that reaches therapeutic concentrations in the kidney.
Gram-negative bacteria are the most common causative pathogens in acute pyelonephritis, with Escherichia coli (E. coli) causing 60 to 80% of uncomplicated infections. Other gram-negative pathogens include Proteus mirabilis (responsible for about 15% of infections) as well as Klebsiella (approximately 20%), Enterobacter and Pseudomonas species. Less commonly, gram-positive bacteria such as Enterococcus faecalis, Staphylococcus saprophyticus and Staphylococcus aureus may be seen.
Complications of acute pyelonephritis include impaired renal function or renal failure, sepsis and preterm labour in pregnancy.
# Choice of antibiotic
## Efficacy of antibiotics
An intravenous cephalosporin (ceftolozane/tazobactam or ceftazidime) was compared with an intravenous fluoroquinolone (levofloxacin or ciprofloxacin) in 2 RCTs (Wagenlehner et al. 2015 and Pasiechnikov et al. 2015) in adults with acute pyelonephritis, acute obstructive pyelonephritis or complicated UTI. Moderate quality evidence found that ceftolozane/tazobactam was significantly more effective than levofloxacin for improving composite cure (clinical cure and microbiological eradication and microbiological cure; 76.9% versus 68.4%, number needed to treat 12 ) but there was no significant difference between antibiotics for clinical cure. Ceftazidime had a significantly higher rate of clinical cure compared with ciprofloxacin (88.9% versus 73.8%; NNT 7 ; very low quality evidence).
An intravenous cephalosporin (ceftriaxone or ceftazidime/avibactam) was compared with an intravenous carbapenem (ertapenem or imipenem/cilastatin) in 2 RCTs (Park et al. 2012 and Vazquez et al. 2012) in adults with acute pyelonephritis or complicated UTI. Very low to high quality evidence found that these cephalosporins and carbapenems were equally effective.
Very low quality evidence from a small single RCT (Moramezi et al. 2008) in pregnant women with acute pyelonephritis found no significant difference between intravenous cephalothin and intravenous ampicillin plus gentamicin in the duration of lower UTI symptoms or costovertebral angle pain. The mean time to end of fever was reduced with ampicillin plus gentamicin compared with cephalothin (mean 11 hours lower, p=0.01; very low quality evidence).
One RCT (Peterson et al. 2008) compared different fluoroquinolones (levofloxacin and ciprofloxacin: intravenous or oral) for acute pyelonephritis and complicated UTI in adults and found no significant differences in clinical or microbiological outcomes at follow‑up (high quality evidence).
One RCT (Talan et al. 2000) compared oral ciprofloxacin with oral co‑trimoxazole for acute pyelonephritis in adult women. Low to moderate quality evidence found that ciprofloxacin was significantly more effective for clinical cure (96.5% versus 82.9%; NNT 8 ) and microbiological cure (99.1% versus 89.1%; NNT 10 ) than co‑trimoxazole.
Low quality evidence from 2 RCTs (Wagenlehner et al. 2015 and Park et al. 2012) found no difference between antibiotics (ceftolozane/tazobactam versus levofloxacin, and ertapenem versus ceftriaxone) for treating bacteraemia secondary to complicated UTI or acute pyelonephritis in adults.
The evidence for children is based on 1 systematic review (Strohmeier et al. 2014) in acute pyelonephritis. No evidence from systematic reviews or RCTs was identified for children with complicated UTI. This systematic review did not find major differences in clinical effectiveness between different antibiotics compared in the studies (third- and fourth-generation cephalosporins, aminoglycosides, co‑amoxiclav and co‑trimoxazole; very low to moderate quality evidence).
## Safety of antibiotics
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).
Trimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF information on trimethoprim). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).
Fluoroquinolones are generally not recommended in children or young people who are still growing (BNF information on ciprofloxacin). The manufacturers advise to avoid in pregnancy (ciprofloxacin summary of product characteristics). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF information on ciprofloxacin), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee in a press release (October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long‑lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain an option in acute pyelonephritis, which is a severe infection.
Aminoglycoside doses are based on weight and renal function, and whenever possible treatment should not exceed 7 days (BNF information on aminoglycosides).
Overall there did not appear to be major differences in adverse effects between antibiotics based on the included studies, although these were not well reported (very low to low quality evidence).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Based on evidence and experience, the committee agreed that acute pyelonephritis is a bacterial infection needing treatment with antibiotics that reach therapeutic concentrations in the kidney. Antibiotics that don't achieve adequate levels in renal tissue, such as nitrofurantoin, fosfomycin and pivmecillinam, are to be avoided.
A urine sample should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.
The committee reviewed the available evidence comparing different antibiotics in adults and children and agreed that it was limited by its setting (most studies in adults were undertaken in a hospital, and in children the setting of the studies was not reported). The studies included various different antibiotics, which may not reflect those chosen in UK practice. The committee discussed the evidence for a benefit of the intravenous third-generation cephalosporins, ceftolozane/tazobactam or ceftazidime, over an intravenous fluoroquinolone, but this was mainly limited to a benefit for composite cure (which included clinical cure, microbiological eradication and microbiological cure) and the absolute benefits were small.
The committee agreed, based on experience, that several oral and intravenous antibiotics should be available for people with acute pyelonephritis. This enables antibiotics to be selected based on the severity of illness, antibiotic susceptibilities from culture results when available, local resistance patterns, risk of resistant bacteria, the setting, and known patient factors (such as whether the person has a higher risk of developing complications). In line with antimicrobial stewardship, narrower-spectrum antibiotics should be used wherever possible.
Nationally for England, resistance of E. coli (the main causative organism of acute pyelonephritis) in laboratory-processed urine specimens to the following antibiotics is:
cefalexin: 9.9% (varies by area from 8.1 to 11.4%)
ciprofloxacin: 10.6% (varies by area from 7.8 to 13.7%)
co-amoxiclav: 19.8% (varies by area from 10.8 to 30.7%)
trimethoprim: 30.3% (varies by area from 27.1 to 33.4%).(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018)
The committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.
The committee agreed that any recent previous urine culture and susceptibility results, and antibiotic prescribing, should be reviewed before choosing an antibiotic.
Based on experience, the committee agreed that if the results of urine culture suggest the bacteria are resistant to the antibiotic given, people with acute pyelonephritis should be contacted and the antibiotic changed regardless of whether symptoms are improving or not. The committee agreed that acute pyelonephritis is a serious infection and antibiotics should be changed to ensure cure.
Non-pregnant women and men with acute pyelonephritis
Based on evidence, their experience and resistance data, the committee agreed to recommend a choice of first-line oral antibiotics, at usual doses for acute pyelonephritis. These are:
cefalexin (a first-generation cephalosporin); based on its broad spectrum of activity and acceptable levels of resistance
co-amoxiclav (a penicillin with a beta-lactamase inhibitor); which is only suitable if culture results are available and bacteria are susceptible, because resistance rates are high
trimethoprim; which is only suitable if culture results are available and bacteria are susceptible, because resistance rates are high
ciprofloxacin (a fluoroquinolone); based on its broad spectrum of activity and acceptable levels of resistance (particularly for people who have had previous treatment with penicillins, or cannot tolerate or are allergic to penicillins).
The committee noted that use of broad-spectrum antibiotics, such as later-generation cephalosporins, fluoroquinolones or co‑amoxiclav, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. And, by disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of acute pyelonephritis, where coverage of more resistant strains of common bacterial pathogens is required.
The committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolone antibiotics are a valuable option for the treatment of acute pyelonephritis, which is a severe infection, and it is appropriate to reserve fluoroquinolone use for such conditions. Resistant gram-negative organisms are a particular concern in acute pyelonephritis, and the committee agreed that ciprofloxacin should remain a first-choice option to cover what can be a complex infection. The committee was keen to point out, however, that cefalexin, co‑amoxiclav and trimethoprim are also first-choice options, and antibiotics should be chosen on an individual patient basis, taking fluoroquinolone safety concerns, as well as susceptibility and resistance, into account.
Based on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for people with acute pyelonephritis who are unable to take oral antibiotics due to vomiting, or are more severely unwell. These are:
co‑amoxiclav (only in combination or if culture results are available and bacteria are susceptible)
cefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)
ciprofloxacin (taking safety concerns into account)
gentamicin or amikacin (aminoglycosides); which may be appropriate for some people with acute pyelonephritis, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48 hours. Gentamicin is the preferred aminoglycoside in the UK, but shortages of certain antibiotics may result in the use of alternatives; for example, amikacin in place of gentamicin.
The committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.
Pregnant women with acute pyelonephritis
Based on experience and resistance data, the committee agreed to recommend cefalexin (a first-generation cephalosporin) as the first-choice oral antibiotic for pregnant women who don't require intravenous antibiotics, and cefuroxime (a second-generation cephalosporin) as the first-choice intravenous antibiotic.
Ciprofloxacin and trimethoprim are not recommended because they should be avoided in pregnancy. Co‑amoxiclav was not recommended because of high resistance levels nationally and the risks of treatment failure in pregnancy.
The committee agreed, based on experience, that local microbiologists should be consulted for advice on second-choice antibiotics, or combining antibiotics if susceptibility or sepsis is a concern.
Children and young people with acute pyelonephritis
The committee was aware that the NICE guideline on urinary tract infection in under 16s makes recommendations on diagnosing acute pyelonephritis and considering referral to a paediatric specialist.
Based on evidence, their experience and resistance data, the committee agreed to recommend cefalexin or co‑amoxiclav (only if culture results are available and bacteria are susceptible) at usual doses for acute pyelonephritis, as first-choice oral antibiotics.
Based on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for children and young people who are unable to take oral antibiotics due to vomiting, or are more severely unwell. These are:
co-amoxiclav (only in combination or if culture results are available and bacteria are susceptible); which can be given intravenously
cefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin); which would be suitable alternatives to co‑amoxiclav
gentamicin or amikacin (aminoglycosides); which may be appropriate for some children and young people with acute pyelonephritis, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48 hours.
The committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of children and young people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.
# Antibiotic course length
The evidence for antibiotic course length in the treatment of acute pyelonephritis in adults comes from 2 systematic reviews (Eliakim-Raz et al. 2013 and Kyriakidou et al. 2008) and 1 RCT (Ren et al. 2017). No significant differences were found for clinical, microbiological or safety and tolerability outcomes between short courses and longer courses of antibiotics (7 days or fewer compared with 10 days to 6 weeks in 1 systematic review, and 7 to 14 days compared with 14 to 42 days in the other systematic review ). There were no significant differences between a short course (5 days) of intravenous levofloxacin (750 mg once daily) and a longer course (7 to 14 days) of intravenous and then oral levofloxacin (500 mg once daily; moderate quality evidence).
There were some significant differences in clinical effectiveness between different antibiotic course lengths in 1 systematic review in children with acute pyelonephritis (Strohmeier et al. 2014). However, this was limited to 1 RCT comparing 10 days of oral sulfafurazole with 42 days (moderate quality evidence), with other studies in the review finding no differences in outcomes (very low quality evidence). Safety and tolerability outcomes were not reported.
## Committee discussions on antibiotic course length
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
Based on evidence, the committee agreed that a short course of antibiotics was generally as effective as a long course of antibiotics for acute pyelonephritis, but the definition of short and long course differed depending on the clinical trial definition and the antibiotic used.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's 'Start smart – then focus' toolkit, the committee agreed that the use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.
Non-pregnant women and men with acute pyelonephritis
Based on evidence, experience and resistance data, the committee agreed that, for oral treatment, a 7‑day course of ciprofloxacin was sufficient to treat acute pyelonephritis in non‑pregnant women and men. However, because there was no evidence for 7‑day courses of cefalexin or co‑amoxiclav, a range of 7 to 10 days was recommended for these antibiotics. For trimethoprim, a 14‑day course was recommended because there was no evidence for course lengths shorter than 14 days.
For intravenous treatment, antibiotics should be reviewed by 48 hours and stepped down to oral antibiotics where possible, for a total of 7 days.
Pregnant women with acute pyelonephritis
Based on evidence, experience and resistance data, the committee agreed that, for oral treatment, a 7- to 10‑day course of cefalexin was required to treat acute pyelonephritis in pregnant women. For intravenous treatment, antibiotics should be reviewed by 48 hours and stepped down to oral antibiotics where possible, for a total of 7 days.
Children and young people with acute pyelonephritis
Based on evidence, experience and resistance data, the committee agreed that a 7- to 10‑day course of oral antibiotics was required to treat acute pyelonephritis in children and young people. For intravenous treatment, antibiotics should be reviewed by 48 hours and stepped down to oral antibiotics where possible, for a total of 10 days.
# Antibiotic dose frequency
No systematic reviews or RCTs that compared the frequency of antibiotic dosing in adults were identified that met the inclusion criteria.
Evidence from 1 systematic review in children with acute pyelonephritis (Strohmeier et al. 2014) found no significant difference in the clinical effectiveness of aminoglycosides with once-daily administration compared with 8‑hourly administration (moderate quality evidence). There were no significant differences in the number of children with hearing impairment or kidney dysfunction (very low quality evidence).
# Antibiotic route of administration
The evidence for route of antibiotic administration in acute pyelonephritis is based on 1 systematic review of 15 RCTs in adults and children (Pohl 2007). This review addressed different modes of administration of antibiotics, which cover:
sequential intravenous then oral treatment compared with intravenous or intramuscular treatment
sequential intravenous then oral treatment compared with oral treatment
-ral treatment compared with intravenous or intramuscular treatment
single-dose intravenous or intramuscular treatment then oral treatment compared with sequential intravenous then oral treatment.
Overall, this review found that oral antibiotics were as effective as other routes of administration in treating symptomatic severe UTI (including pyelonephritis) in both adults and children. Intravenous or intramuscular antibiotics were significantly better for bacteriological cure than oral antibiotics at the end of treatment, but this is based on 1 small RCT (NNT 4 ; low quality evidence).
There were no significant differences in adverse effects between different routes of administration of antibiotics (very low quality evidence).
Further evidence is available from 1 systematic review in children with acute pyelonephritis (Strohmeier et al. 2014), which compared different routes of administration, which cover:
-ral treatment compared with sequential intravenous then oral treatment
sequential intravenous then oral treatment (short course of 3 to 4 days) compared with intravenous treatment (longer course of 7 to 14 days)
single-dose intramuscular then oral treatment compared with oral treatment
-ral treatment compared with rectal treatment.
Overall, this review found no significant differences in the clinical effectiveness of oral antibiotics (cephalosporins or co‑amoxiclav) in children with acute pyelonephritis compared with other routes of administration (very low to moderate quality evidence).
Safety and tolerability outcomes were poorly reported in the RCTs included in Strohmeier et al. 2014, but there did not appear to be any significant differences between different routes of administration of antibiotics (very low quality evidence).
## Committee discussions on antibiotic route of administration
Based on evidence, the committee agreed that, overall, oral antibiotics were as effective as other routes of administration for treating acute pyelonephritis in adults and children.
The committee agreed, based on evidence and experience, that oral antibiotics should be given first line when people can take oral medicines and the severity of their condition does not require intravenous antibiotics.
The committee agreed, based on evidence and experience, that intravenous antibiotics can be used for people who are unable to take oral antibiotics due to vomiting, or are more severely unwell, in line with Public Health England's 'Start smart – then focus' toolkit.
See the full evidence review for more information.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
One small randomised controlled trial (RCT; Moramezi et al. 2008) in pregnant women with acute pyelonephritis found no significant difference in length of hospital stay in women taking a cephalosporin compared with ampicillin plus gentamicin (p=0.22; very low quality evidence).
One RCT (Talan et al. 2000), which compared ciprofloxacin with co‑trimoxazole in adult women with acute pyelonephritis, found that resource use (hospital stay, visits and telephone contacts, laboratory tests and prescription costs) was higher in the co‑trimoxazole group (no analysis reported). The only exception was for radiological procedures, which was slightly higher in the ciprofloxacin group (no analysis reported). One systematic review (Eliakim-Raz et al. 2013), which compared antibiotic course lengths in adults with acute pyelonephritis and included the Talan et al. (2000) study, noted a shorter duration of hospital stay with a short course of antibiotics (7 days or fewer) compared with a longer course (10 days to 6 weeks).
One RCT in the systematic review by Strohmeier et al. (2014) in children with acute pyelonephritis found that giving sequential intravenous then oral antibiotics reduced the duration of hospital stay compared with a longer duration of intravenous antibiotics (4.9 days compared with 9.8 days).
Recommended antibiotics are available as generic formulations, see the Drug Tariff for costs.
|
{'Recommendations': "# Managing acute pyelonephritis\n\nBe aware that acute pyelonephritis is an infection of one or both kidneys usually caused by bacteria travelling up from the bladder.\n\n## Treatment\n\nIn people aged 16\xa0years and over with acute pyelonephritis, obtain a midstream urine sample before antibiotics are taken and send for culture and susceptibility testing.\n\nIn children and young people under 16\xa0years with acute pyelonephritis, obtain a urine sample before antibiotics are taken and send for culture and susceptibility testing in line with the NICE guideline on urinary tract infection in under\xa016s.\n\nAssess and manage children under\xa05 with acute pyelonephritis who present with fever as outlined in the NICE guideline on fever in under 5s.\n\nOffer an antibiotic (see the recommendations on choice of antibiotic) to people with acute pyelonephritis. Take account of:\n\nthe severity of symptoms\n\nthe risk of developing complications, which is higher in people with known or suspected structural or functional abnormality of the genitourinary tract or immunosuppression\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nWhen results of urine cultures are available:\n\nreview the choice of antibiotic and\n\nchange the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow spectrum antibiotic wherever possible.\n\n## Advice when an antibiotic prescription is given\n\nWhen an antibiotic is given, as well as the general advice on self-care, give advice about:\n\npossible adverse effects of the antibiotic, particularly diarrhoea and nausea\n\nnausea with vomiting also being a possible indication of worsening pyelonephritis\n\nseeking medical help if:\n\n\n\nsymptoms worsen at any time or\n\nsymptoms do not start to improve within 48\xa0hours of taking the antibiotic or\n\nthe person becomes systemically very unwell.\n\n\n\n## Reassessment\n\nReassess if symptoms worsen at any time, or do not start to improve within 48\xa0hours of taking the antibiotic, taking account of:\n\nother possible diagnoses\n\nany symptoms or signs suggesting a more serious illness or condition, such as sepsis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\n## Referral and seeking specialist advice\n\nRefer people aged 16\xa0years and over with acute pyelonephritis to hospital if they have any symptoms or signs suggesting a more serious illness or condition (for example, sepsis).\n\nConsider referring or seeking specialist advice for people aged 16\xa0years and over with acute pyelonephritis if they:\n\nare significantly dehydrated or unable to take oral fluids and medicines or\n\nare pregnant or\n\nhave a higher risk of developing complications (for example, people with known or suspected structural or functional abnormality of the genitourinary tract or underlying disease [such as diabetes or immunosuppression]).\n\nRefer children and young people with acute pyelonephritis to hospital in line with the NICE guideline on urinary tract infection in under\xa016s.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are available in the evidence review.\n\n# Self-care\n\nAdvise people with acute pyelonephritis about using paracetamol for pain, with the possible addition of a low-dose weak opioid such as codeine for people over 12\xa0years.\n\nAdvise people with acute pyelonephritis about drinking enough fluids to avoid dehydration.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.\n\nFull details of the evidence and the committee's discussion are available in the evidence review.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for acute pyelonephritis, take account of local antimicrobial resistance (AMR) data from Public Health England and follow:\n\ntable\xa01 for non-pregnant women and men aged 16\xa0years and over\n\ntable\xa02 for pregnant women aged 12\xa0years and over\n\ntable\xa03 for children and young people under 16\xa0years.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotics\n\nCefalexin:\n\nmg twice or three times a day (up to 1\xa0to\xa01.5\xa0g three or four times a day for severe infections) for 7\xa0to\xa010\xa0days\n\n\n\nCo‑amoxiclav (only if culture results available and susceptible):\n\n/125\xa0mg three times a day for 7\xa0to\xa010\xa0days\n\n\n\nTrimethoprim (only if culture results available and susceptible):\n\nmg twice a day for 14\xa0days\n\n\n\nCiprofloxacin (consider safety issues):\n\nmg twice a day for 7\xa0days\n\nFirst-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics, or severely unwell). Antibiotics may be combined if susceptibility or sepsis a concern.\n\nCo‑amoxiclav (only in combination or if culture results available and susceptible):\n\ng three times a day\n\n\n\nCefuroxime:\n\nmg to 1.5\xa0g three or four times a day\n\n\n\nCeftriaxone:\n\ng to 2\xa0g once a day\n\n\n\nCiprofloxacin (consider safety issues):\n\nmg twice or three times a day\n\n\n\nGentamicin:\n\nInitially 5\xa0mg/kg to\xa07\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF information on gentamicin)\n\n\n\nAmikacin:\n\nInitially 15\xa0mg/kg once a day (maximum per dose 1.5\xa0g once a day), subsequent doses adjusted according to serum amikacin concentration (maximum 15\xa0g per course)\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF information on amikacin)\n\nSecond-choice intravenous antibiotics\n\nConsult a local microbiologist\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment and breastfeeding, and administering intravenous antibiotics.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.\n\nSee Medicines and Healthcare products Regulatory Agency advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60\xa0years and avoiding coadministration with a corticosteroid (March 2019).\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nCefalexin:\n\nmg twice or three times a day (up to 1\xa0g to\xa01.5\xa0g three or four times a day for severe infections) for 7\xa0to\xa010\xa0days\n\nFirst-choice intravenous antibiotic (if vomiting, unable to take oral antibiotics, or severely unwell)\n\nCefuroxime:\n\nmg to 1.5\xa0g three or four times a day\n\nSecond-choice antibiotics or when combining antibiotics if susceptibility or sepsis a concern\n\nConsult local microbiologist\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment, and administering intravenous antibiotics.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing and choose antibiotics accordingly.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nChoice for children under 3\xa0months\n\nRefer to paediatric specialist and treat with intravenous antibiotics in line with the NICE guideline on fever in under\xa05s\n\nFirst-choice oral antibiotic for children aged 3\xa0months and over\n\nCefalexin:\n\nmonths to 11\xa0months, 12.5\xa0mg/kg or 125\xa0mg twice a day for 7\xa0to\xa010\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nyear to 4\xa0years, 12.5\xa0mg/kg twice a day or 125\xa0mg three times a day for 7\xa0to\xa010\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nyears to 11\xa0years, 12.5\xa0mg/kg twice a day or 250\xa0mg three times a day for 7\xa0to\xa010\xa0days (25\xa0mg/kg two to four times a day [maximum 1\xa0g per dose four times a day] for severe infections)\n\nyears to 15\xa0years, 500\xa0mg twice or three times a day (up to 1\xa0g to\xa01.5\xa0g three or four times a day for severe infections) for 7\xa0to\xa010\xa0days\n\n\n\nCo‑amoxiclav (only if culture results available and susceptible):\n\nmonths to 11\xa0months, 0.25\xa0ml/kg of 125/31\xa0suspension three times a day for 7\xa0to\xa010\xa0days (dose doubled in severe infection)\n\nyears to 5\xa0years, 0.25\xa0ml/kg of 125/31\xa0suspension or 5\xa0ml of 125/31\xa0suspension three times a day for 7\xa0to\xa010\xa0days (dose doubled in severe infection)\n\nyears to 11\xa0years, 0.15\xa0ml/kg of 250/62\xa0suspension or 5\xa0ml of 250/62\xa0suspension three times a day for 7\xa0to\xa010\xa0days (dose doubled in severe infection)\n\nyears to 15\xa0years, 250/125\xa0mg or 500/125\xa0mg three times a day for 7\xa0to\xa010\xa0days\n\nFirst-choice intravenous antibiotics (if vomiting, unable to take oral antibiotics or severely unwell) for children aged 3\xa0months and over. Antibiotics may be combined if susceptibility or sepsis a concern\n\nCo‑amoxiclav (only in combination or if culture results available and susceptible):\n\nmonths to 15\xa0years, 30\xa0mg/kg three times a day (maximum 1.2\xa0g three times a day)\n\n\n\nCefuroxime:\n\nmonths to 15\xa0years, 20\xa0mg/kg three times a day (maximum 750\xa0mg per dose), increased to 50\xa0mg/kg to\xa060\xa0mg/kg three or four times a day (maximum 1.5\xa0g per dose) for severe infections\n\n\n\nCeftriaxone:\n\nmonths to 11\xa0years (up to 50\xa0kg), 50\xa0mg/kg to\xa080\xa0mg/kg once a day (maximum 4\xa0g per day)\n\nyears to 11\xa0years (50\xa0kg and above), 1\xa0g to\xa02\xa0g once a day\n\nyears to 15\xa0years, 1\xa0g to\xa02\xa0g once a day\n\n\n\nGentamicin:\n\nInitially 7\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration\n\nTherapeutic drug monitoring and assessment of renal function is required (BNFC information on gentamicin)\n\n\n\nAmikacin:\n\nInitially 15\xa0mg/kg once a day, subsequent doses adjusted according to serum amikacin concentration\n\nTherapeutic drug monitoring and assessment of renal function is required (BNFC information on amikacin)\n\nSecond-choice intravenous antibiotics for children aged 3\xa0months and over\n\nConsult a local microbiologist\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic and renal impairment, and administering intravenous antibiotics. See table\xa02 if a young woman is pregnant.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nCheck any previous urine culture and susceptibility results and antibiotic prescribing, and choose antibiotics accordingly. Where a child or young person is receiving prophylactic antibiotics, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.\n\nReview intravenous antibiotics by 48\xa0hours and consider stepping down to oral antibiotics where possible for a total of 10\xa0days. If intravenous treatment is not possible, consider intramuscular treatment if suitable.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic, antibiotic course length and antibiotic route of administration.\n\nFull details of the evidence and the committee's discussion are available in the evidence review.", 'Summary of the evidence': "The recommendations in this guideline are based on the evidence identified, which was mainly for people with acute pyelonephritis. Some studies also included people with a complicated urinary tract infection (UTI; associated with a structural or functional abnormality, or underlying disease, which increases the risk of a more serious outcome or treatment failure) or urosepsis (a systemic response to a UTI).\n\n# Self-care\n\nNo systematic reviews or randomised controlled trials (RCTs) of any non‑antimicrobial treatments were identified that met the inclusion criteria.\n\n## Committee discussion on self-care\n\nThere was no evidence for the use of oral analgesia in acute pyelonephritis. However, paracetamol has a well-established efficacy and safety profile for managing pain. The committee agreed that it was reasonable to advise people about paracetamol for self-management of pain. A low-dose weak opioid, such as codeine, could be taken with paracetamol by adults and young people over 12\xa0years for more severe pain.\n\nNon-steroidal anti-inflammatory drugs, such as ibuprofen, are generally not recommended for people with acute pyelonephritis because of concerns about renal safety.\n\nThe committee discussed the need for an adequate intake of fluids to ensure a high urine output, which is believed to help resolve acute pyelonephritis through a mechanical flushing of bacteria from the kidney. No evidence was found for this and there was no evidence of what constitutes adequate hydration. However, based on committee experience that dehydration is often cited as a cause of UTIs, the committee agreed that people should be advised about drinking enough fluids to avoid dehydration.\n\n# Antibiotics\n\nAcute pyelonephritis is a bacterial infection needing treatment with an antibiotic that reaches therapeutic concentrations in the kidney.\n\nGram-negative bacteria are the most common causative pathogens in acute pyelonephritis, with Escherichia coli (E.\xa0coli) causing 60 to 80% of uncomplicated infections. Other gram-negative pathogens include Proteus mirabilis (responsible for about 15% of infections) as well as Klebsiella (approximately 20%), Enterobacter and Pseudomonas species. Less commonly, gram-positive bacteria such as Enterococcus faecalis, Staphylococcus saprophyticus and Staphylococcus aureus may be seen.\n\nComplications of acute pyelonephritis include impaired renal function or renal failure, sepsis and preterm labour in pregnancy.\n\n# Choice of antibiotic\n\n## Efficacy of antibiotics\n\nAn intravenous cephalosporin (ceftolozane/tazobactam or ceftazidime) was compared with an intravenous fluoroquinolone (levofloxacin or ciprofloxacin) in 2\xa0RCTs (Wagenlehner et al. 2015 and Pasiechnikov et al. 2015) in adults with acute pyelonephritis, acute obstructive pyelonephritis or complicated UTI. Moderate quality evidence found that ceftolozane/tazobactam was significantly more effective than levofloxacin for improving composite cure (clinical cure and microbiological eradication and microbiological cure; 76.9% versus 68.4%, number needed to treat [NNT]\xa012 [range 7 to 43]) but there was no significant difference between antibiotics for clinical cure. Ceftazidime had a significantly higher rate of clinical cure compared with ciprofloxacin (88.9% versus 73.8%; NNT\xa07 [range 4 to 62]; very low quality evidence).\n\nAn intravenous cephalosporin (ceftriaxone or ceftazidime/avibactam) was compared with an intravenous carbapenem (ertapenem or imipenem/cilastatin) in 2\xa0RCTs (Park et al. 2012 and Vazquez et al. 2012) in adults with acute pyelonephritis or complicated UTI. Very low to high quality evidence found that these cephalosporins and carbapenems were equally effective.\n\nVery low quality evidence from a small single RCT (Moramezi et al. 2008) in pregnant women with acute pyelonephritis found no significant difference between intravenous cephalothin and intravenous ampicillin plus gentamicin in the duration of lower UTI symptoms or costovertebral angle pain. The mean time to end of fever was reduced with ampicillin plus gentamicin compared with cephalothin (mean 11\xa0hours lower, p=0.01; very low quality evidence).\n\nOne RCT (Peterson et al. 2008) compared different fluoroquinolones (levofloxacin and ciprofloxacin: intravenous or oral) for acute pyelonephritis and complicated UTI in adults and found no significant differences in clinical or microbiological outcomes at follow‑up (high quality evidence).\n\nOne RCT (Talan et al. 2000) compared oral ciprofloxacin with oral co‑trimoxazole for acute pyelonephritis in adult women. Low to moderate quality evidence found that ciprofloxacin was significantly more effective for clinical cure (96.5% versus 82.9%; NNT\xa08 [range 5 to 18]) and microbiological cure (99.1% versus 89.1%; NNT 10 [range 7 to 28]) than co‑trimoxazole.\n\nLow quality evidence from 2\xa0RCTs (Wagenlehner et al. 2015 and Park et al. 2012) found no difference between antibiotics (ceftolozane/tazobactam versus levofloxacin, and ertapenem versus ceftriaxone) for treating bacteraemia secondary to complicated UTI or acute pyelonephritis in adults.\n\nThe evidence for children is based on 1\xa0systematic review (Strohmeier et al. 2014) in acute pyelonephritis. No evidence from systematic reviews or RCTs was identified for children with complicated UTI. This systematic review did not find major differences in clinical effectiveness between different antibiotics compared in the studies (third- and fourth-generation cephalosporins, aminoglycosides, co‑amoxiclav and co‑trimoxazole; very low to moderate quality evidence).\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea occurs in 2\xa0to\xa025% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).\n\nTrimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF information on trimethoprim). The manufacturers advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics).\n\nFluoroquinolones are generally not recommended in children or young people who are still growing (BNF information on ciprofloxacin). The manufacturers advise to avoid in pregnancy (ciprofloxacin summary of product characteristics). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF information on ciprofloxacin), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee in a press release (October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long‑lasting side effects mainly involving muscles, tendons and bones and the nervous system. Fluoroquinolones remain an option in acute pyelonephritis, which is a severe infection.\n\nAminoglycoside doses are based on weight and renal function, and whenever possible treatment should not exceed 7\xa0days (BNF information on aminoglycosides).\n\nOverall there did not appear to be major differences in adverse effects between antibiotics based on the included studies, although these were not well reported (very low to low quality evidence).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nBased on evidence and experience, the committee agreed that acute pyelonephritis is a bacterial infection needing treatment with antibiotics that reach therapeutic concentrations in the kidney. Antibiotics that don't achieve adequate levels in renal tissue, such as nitrofurantoin, fosfomycin and pivmecillinam, are to be avoided.\n\nA urine sample should be sent for culture to confirm susceptibility of the bacteria and inform treatment choice.\n\nThe committee reviewed the available evidence comparing different antibiotics in adults and children and agreed that it was limited by its setting (most studies in adults were undertaken in a hospital, and in children the setting of the studies was not reported). The studies included various different antibiotics, which may not reflect those chosen in UK practice. The committee discussed the evidence for a benefit of the intravenous third-generation cephalosporins, ceftolozane/tazobactam or ceftazidime, over an intravenous fluoroquinolone, but this was mainly limited to a benefit for composite cure (which included clinical cure, microbiological eradication and microbiological cure) and the absolute benefits were small.\n\nThe committee agreed, based on experience, that several oral and intravenous antibiotics should be available for people with acute pyelonephritis. This enables antibiotics to be selected based on the severity of illness, antibiotic susceptibilities from culture results when available, local resistance patterns, risk of resistant bacteria, the setting, and known patient factors (such as whether the person has a higher risk of developing complications). In line with antimicrobial stewardship, narrower-spectrum antibiotics should be used wherever possible.\n\nNationally for England, resistance of E. coli (the main causative organism of acute pyelonephritis) in laboratory-processed urine specimens to the following antibiotics is:\n\n\n\ncefalexin: 9.9% (varies by area from 8.1 to 11.4%)\n\nciprofloxacin: 10.6% (varies by area from 7.8 to 13.7%)\n\nco-amoxiclav: 19.8% (varies by area from 10.8 to 30.7%)\n\ntrimethoprim: 30.3% (varies by area from 27.1 to 33.4%).(Public Health England. Antimicrobial resistance quarterly surveillance: March 2018)\n\n\n\nThe committee also discussed that prescribers should be aware of their local antimicrobial prescribing data, because resistance rates do vary by area.\n\nThe committee agreed that any recent previous urine culture and susceptibility results, and antibiotic prescribing, should be reviewed before choosing an antibiotic.\n\nBased on experience, the committee agreed that if the results of urine culture suggest the bacteria are resistant to the antibiotic given, people with acute pyelonephritis should be contacted and the antibiotic changed regardless of whether symptoms are improving or not. The committee agreed that acute pyelonephritis is a serious infection and antibiotics should be changed to ensure cure.\n\nNon-pregnant women and men with acute pyelonephritis\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend a choice of first-line oral antibiotics, at usual doses for acute pyelonephritis. These are:\n\n\n\ncefalexin (a first-generation cephalosporin); based on its broad spectrum of activity and acceptable levels of resistance\n\nco-amoxiclav (a penicillin with a beta-lactamase inhibitor); which is only suitable if culture results are available and bacteria are susceptible, because resistance rates are high\n\ntrimethoprim; which is only suitable if culture results are available and bacteria are susceptible, because resistance rates are high\n\nciprofloxacin (a fluoroquinolone); based on its broad spectrum of activity and acceptable levels of resistance (particularly for people who have had previous treatment with penicillins, or cannot tolerate or are allergic to penicillins).\n\n\n\nThe committee noted that use of broad-spectrum antibiotics, such as later-generation cephalosporins, fluoroquinolones or co‑amoxiclav, can create a selective advantage for bacteria resistant to these second-line broad-spectrum agents, allowing such strains to proliferate and spread. And, by disrupting normal flora, broad-spectrum antibiotics can leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. However, these antibiotics are appropriate for the empirical treatment of acute pyelonephritis, where coverage of more resistant strains of common bacterial pathogens is required.\n\nThe committee was aware of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolone antibiotics are a valuable option for the treatment of acute pyelonephritis, which is a severe infection, and it is appropriate to reserve fluoroquinolone use for such conditions. Resistant gram-negative organisms are a particular concern in acute pyelonephritis, and the committee agreed that ciprofloxacin should remain a first-choice option to cover what can be a complex infection. The committee was keen to point out, however, that cefalexin, co‑amoxiclav and trimethoprim are also first-choice options, and antibiotics should be chosen on an individual patient basis, taking fluoroquinolone safety concerns, as well as susceptibility and resistance, into account.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for people with acute pyelonephritis who are unable to take oral antibiotics due to vomiting, or are more severely unwell. These are:\n\n\n\nco‑amoxiclav (only in combination or if culture results are available and bacteria are susceptible)\n\ncefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin)\n\nciprofloxacin (taking safety concerns into account)\n\ngentamicin or amikacin (aminoglycosides); which may be appropriate for some people with acute pyelonephritis, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48\xa0hours. Gentamicin is the preferred aminoglycoside in the UK, but shortages of certain antibiotics may result in the use of alternatives; for example, amikacin in place of gentamicin.\n\n\n\nThe committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.\n\nPregnant women with acute pyelonephritis\n\nBased on experience and resistance data, the committee agreed to recommend cefalexin (a first-generation cephalosporin) as the first-choice oral antibiotic for pregnant women who don't require intravenous antibiotics, and cefuroxime (a second-generation cephalosporin) as the first-choice intravenous antibiotic.\n\nCiprofloxacin and trimethoprim are not recommended because they should be avoided in pregnancy. Co‑amoxiclav was not recommended because of high resistance levels nationally and the risks of treatment failure in pregnancy.\n\nThe committee agreed, based on experience, that local microbiologists should be consulted for advice on second-choice antibiotics, or combining antibiotics if susceptibility or sepsis is a concern.\n\nChildren and young people with acute pyelonephritis\n\nThe committee was aware that the NICE guideline on urinary tract infection in under 16s makes recommendations on diagnosing acute pyelonephritis and considering referral to a paediatric specialist.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend cefalexin or co‑amoxiclav (only if culture results are available and bacteria are susceptible) at usual doses for acute pyelonephritis, as first-choice oral antibiotics.\n\nBased on evidence, experience and resistance data, the committee agreed to recommend a choice of first-line intravenous antibiotics, at usual doses, for children and young people who are unable to take oral antibiotics due to vomiting, or are more severely unwell. These are:\n\n\n\nco-amoxiclav (only in combination or if culture results are available and bacteria are susceptible); which can be given intravenously\n\ncefuroxime (a second-generation cephalosporin) or ceftriaxone (a third-generation cephalosporin); which would be suitable alternatives to co‑amoxiclav\n\ngentamicin or amikacin (aminoglycosides); which may be appropriate for some children and young people with acute pyelonephritis, particularly those with severe infection or sepsis, but that efforts should be made to identify the causal bacteria and use reviewed at 48\xa0hours.\n\n\n\nThe committee agreed, based on experience, that it may be necessary to combine antibiotics in the care of children and young people with suspected sepsis. This should be done according to local policy or on the advice of a microbiologist, taking into account local antimicrobial resistance data.\n\n# Antibiotic course length\n\nThe evidence for antibiotic course length in the treatment of acute pyelonephritis in adults comes from 2\xa0systematic reviews (Eliakim-Raz et al. 2013 and Kyriakidou et al. 2008) and 1\xa0RCT (Ren et al. 2017). No significant differences were found for clinical, microbiological or safety and tolerability outcomes between short courses and longer courses of antibiotics (7\xa0days or fewer compared with 10\xa0days to 6\xa0weeks in 1\xa0systematic review, and 7\xa0to\xa014\xa0days compared with 14\xa0to\xa042\xa0days in the other systematic review [very low to moderate quality evidence]). There were no significant differences between a short course (5\xa0days) of intravenous levofloxacin (750\xa0mg once daily) and a longer course (7\xa0to\xa014\xa0days) of intravenous and then oral levofloxacin (500\xa0mg once daily; moderate quality evidence).\n\nThere were some significant differences in clinical effectiveness between different antibiotic course lengths in 1\xa0systematic review in children with acute pyelonephritis (Strohmeier et al. 2014). However, this was limited to 1\xa0RCT comparing 10\xa0days of oral sulfafurazole with 42\xa0days (moderate quality evidence), with other studies in the review finding no differences in outcomes (very low quality evidence). Safety and tolerability outcomes were not reported.\n\n## Committee discussions on antibiotic course length\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nBased on evidence, the committee agreed that a short course of antibiotics was generally as effective as a long course of antibiotics for acute pyelonephritis, but the definition of short and long course differed depending on the clinical trial definition and the antibiotic used.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's 'Start smart – then focus' toolkit, the committee agreed that the use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and susceptibility results from urine culture) and switched to oral treatment where possible.\n\nNon-pregnant women and men with acute pyelonephritis\n\nBased on evidence, experience and resistance data, the committee agreed that, for oral treatment, a 7‑day course of ciprofloxacin was sufficient to treat acute pyelonephritis in non‑pregnant women and men. However, because there was no evidence for 7‑day courses of cefalexin or co‑amoxiclav, a range of 7\xa0to\xa010\xa0days was recommended for these antibiotics. For trimethoprim, a 14‑day course was recommended because there was no evidence for course lengths shorter than 14\xa0days.\n\nFor intravenous treatment, antibiotics should be reviewed by 48\xa0hours and stepped down to oral antibiotics where possible, for a total of 7\xa0days.\n\nPregnant women with acute pyelonephritis\n\nBased on evidence, experience and resistance data, the committee agreed that, for oral treatment, a 7- to 10‑day course of cefalexin was required to treat acute pyelonephritis in pregnant women. For intravenous treatment, antibiotics should be reviewed by 48\xa0hours and stepped down to oral antibiotics where possible, for a total of 7\xa0days.\n\nChildren and young people with acute pyelonephritis\n\nBased on evidence, experience and resistance data, the committee agreed that a 7- to 10‑day course of oral antibiotics was required to treat acute pyelonephritis in children and young people. For intravenous treatment, antibiotics should be reviewed by 48\xa0hours and stepped down to oral antibiotics where possible, for a total of 10\xa0days.\n\n# Antibiotic dose frequency\n\nNo systematic reviews or RCTs that compared the frequency of antibiotic dosing in adults were identified that met the inclusion criteria.\n\nEvidence from 1\xa0systematic review in children with acute pyelonephritis (Strohmeier et al. 2014) found no significant difference in the clinical effectiveness of aminoglycosides with once-daily administration compared with 8‑hourly administration (moderate quality evidence). There were no significant differences in the number of children with hearing impairment or kidney dysfunction (very low quality evidence).\n\n# Antibiotic route of administration\n\nThe evidence for route of antibiotic administration in acute pyelonephritis is based on 1\xa0systematic review of 15\xa0RCTs in adults and children (Pohl 2007). This review addressed different modes of administration of antibiotics, which cover:\n\n\n\nsequential intravenous then oral treatment compared with intravenous or intramuscular treatment\n\nsequential intravenous then oral treatment compared with oral treatment\n\noral treatment compared with intravenous or intramuscular treatment\n\nsingle-dose intravenous or intramuscular treatment then oral treatment compared with sequential intravenous then oral treatment.\n\n\n\nOverall, this review found that oral antibiotics were as effective as other routes of administration in treating symptomatic severe UTI (including pyelonephritis) in both adults and children. Intravenous or intramuscular antibiotics were significantly better for bacteriological cure than oral antibiotics at the end of treatment, but this is based on 1\xa0small RCT (NNT\xa04 [range 3 to 15]; low quality evidence).\n\nThere were no significant differences in adverse effects between different routes of administration of antibiotics (very low quality evidence).\n\nFurther evidence is available from 1\xa0systematic review in children with acute pyelonephritis (Strohmeier et al. 2014), which compared different routes of administration, which cover:\n\n\n\noral treatment compared with sequential intravenous then oral treatment\n\nsequential intravenous then oral treatment (short course of 3\xa0to\xa04\xa0days) compared with intravenous treatment (longer course of 7\xa0to\xa014\xa0days)\n\nsingle-dose intramuscular then oral treatment compared with oral treatment\n\noral treatment compared with rectal treatment.\n\n\n\nOverall, this review found no significant differences in the clinical effectiveness of oral antibiotics (cephalosporins or co‑amoxiclav) in children with acute pyelonephritis compared with other routes of administration (very low to moderate quality evidence).\n\nSafety and tolerability outcomes were poorly reported in the RCTs included in Strohmeier et al. 2014, but there did not appear to be any significant differences between different routes of administration of antibiotics (very low quality evidence).\n\n## Committee discussions on antibiotic route of administration\n\nBased on evidence, the committee agreed that, overall, oral antibiotics were as effective as other routes of administration for treating acute pyelonephritis in adults and children.\n\nThe committee agreed, based on evidence and experience, that oral antibiotics should be given first line when people can take oral medicines and the severity of their condition does not require intravenous antibiotics.\n\nThe committee agreed, based on evidence and experience, that intravenous antibiotics can be used for people who are unable to take oral antibiotics due to vomiting, or are more severely unwell, in line with Public Health England's 'Start smart – then focus' toolkit.\n\nSee the full evidence review for more information.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nOne small randomised controlled trial (RCT; Moramezi et al. 2008) in pregnant women with acute pyelonephritis found no significant difference in length of hospital stay in women taking a cephalosporin compared with ampicillin plus gentamicin (p=0.22; very low quality evidence).\n\nOne RCT (Talan et al. 2000), which compared ciprofloxacin with co‑trimoxazole in adult women with acute pyelonephritis, found that resource use (hospital stay, visits and telephone contacts, laboratory tests and prescription costs) was higher in the co‑trimoxazole group (no analysis reported). The only exception was for radiological procedures, which was slightly higher in the ciprofloxacin group (no analysis reported). One systematic review (Eliakim-Raz et al. 2013), which compared antibiotic course lengths in adults with acute pyelonephritis and included the Talan et al. (2000) study, noted a shorter duration of hospital stay with a short course of antibiotics (7\xa0days or fewer) compared with a longer course (10\xa0days to 6\xa0weeks).\n\nOne RCT in the systematic review by Strohmeier et al. (2014) in children with acute pyelonephritis found that giving sequential intravenous then oral antibiotics reduced the duration of hospital stay compared with a longer duration of intravenous antibiotics (4.9\xa0days compared with 9.8\xa0days).\n\nRecommended antibiotics are available as generic formulations, see the Drug Tariff for costs.'}
|
https://www.nice.org.uk/guidance/ng111
|
This guideline sets out an antimicrobial prescribing strategy for acute pyelonephritis (upper urinary tract infection) in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
|
2a786a4140b04ba7edbba559cd5323dfc39a7a9c
|
nice
|
Urinary tract infection (recurrent): antimicrobial prescribing
|
Urinary tract infection (recurrent): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for preventing recurrent urinary tract infections in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Preventing recurrent urinary tract infections
Manage an acute UTI as outlined in the NICE guidelines on urinary tract infection (lower): antimicrobial prescribing or pyelonephritis (acute): antimicrobial prescribing.
Be aware that recurrent UTI:
includes lower UTI and upper UTI (acute pyelonephritis)
may be due to relapse (with the same strain of organism) or reinfection (with a different strain or species of organism)
is particularly common in women.
Give advice to people with recurrent UTI about behavioural and personal hygiene measures and self‑care treatments (see the recommendations on self-care) that may help to reduce the risk of UTI.
## Referral and seeking specialist advice
Refer or seek specialist advice on further investigation and management for:
men aged 16 years and over
people with recurrent upper UTI
people with recurrent lower UTI when the underlying cause is unknown
pregnant women
children and young people under 16 years in line with the NICE guideline on urinary tract infection in under 16s
people with suspected cancer in line with the NICE guideline on suspected cancer: recognition and referral.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.
Full details of the evidence and committee's discussion are available in the evidence review.
## Treatment for women with recurrent UTI who are not pregnant
Consider the lowest effective dose of vaginal oestrogen (for example, estriol cream) for postmenopausal women with recurrent UTI if behavioural and personal hygiene measures alone are not effective or not appropriate. Discuss the following with the woman to ensure shared decision-making:
the severity and frequency of previous symptoms
the risk of developing complications from recurrent UTIs
the possible benefits of treatment, including for other related symptoms, such as vaginal dryness
the possible adverse effects such as breast tenderness and vaginal bleeding (which should be reported because it may require investigation)
the uncertainty of endometrial safety with long-term or repeated use
preferences of the woman for treatment with vaginal oestrogen.Review treatment within 12 months, or earlier if agreed with the woman. In October 2018, this was an off-label use of vaginal oestrogen products. See NICE's information on prescribing medicines.
Do not offer oral oestrogens (hormone replacement therapy) specifically to reduce the risk of recurrent UTI in postmenopausal women.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on oestrogens.
Full details of the evidence and committee's discussion are available in the evidence review.
For women with recurrent UTI who are not pregnant, consider a trial of antibiotic prophylaxis only if behavioural and personal hygiene measures, and vaginal oestrogen (in postmenopausal women) are not effective or not appropriate.
For women with recurrent UTI who are not pregnant, ensure that any current UTI has been adequately treated then consider single-dose antibiotic prophylaxis for use when exposed to an identifiable trigger (see the recommendations on choice of antibiotic prophylaxis). Take account of:
the severity and frequency of previous symptoms
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria
the woman's preferences for antibiotic use.
When single-dose antibiotic prophylaxis is given, give advice about:
how to use the antibiotic
possible adverse effects of antibiotics, particularly diarrhoea and nausea
returning for review within 6 months
seeking medical help if there are symptoms of an acute UTI.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis and antibiotic dosing and course length.
Full details of the evidence and committee's discussion are available in the evidence review.
For women with recurrent UTI who are not pregnant and have had no improvement after single‑dose antibiotic prophylaxis or have no identifiable triggers, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis). Take account of:
any further investigations (for example, ultrasound) that may be needed to identify an underlying cause
the severity and frequency of previous symptoms
the risks of long‑term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria
the woman's preferences for antibiotic use.
When a trial of daily antibiotic prophylaxis is given, give advice about:
the risk of resistance with long-term antibiotics, which means they may be less effective in the future
possible adverse effects of long-term antibiotics
returning for review within 6 months
seeking medical help if there are symptoms of an acute UTI.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.
Full details of the evidence and committee's discussion are available in the evidence review.
## Treatment for men and pregnant women with recurrent UTI
For men and pregnant women with recurrent UTI, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis) if behavioural and personal hygiene measures alone are not effective or not appropriate, with specialist advice. Take account of:
any further investigations (for example, ultrasound) that may be needed to identify an underlying cause
the severity and frequency of previous symptoms
the risks of long‑term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria
the person's preferences for antibiotic use.
When a trial of daily antibiotic prophylaxis is given, give advice as in recommendation 1.1.11.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.
Full details of the evidence and committee's discussion are available in the evidence review.
## Treatment for children and young people under 16 years with recurrent UTI
For children and young people under 16 years with recurrent UTI, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis) if behavioural and personal hygiene measures alone are not effective or not appropriate, with specialist advice. Take account of:
underlying causes following specialist assessment and investigations
the uncertain evidence of benefit of antibiotic prophylaxis for reducing the risk of recurrent UTI and the rate of deterioration of renal scars
the severity and frequency of previous symptoms
the risks of long‑term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use, which may have led to resistant bacteria
preferences for antibiotic use.
When a trial of daily antibiotic prophylaxis is given, give advice as in recommendation 1.1.11.
## Reassessment
Review antibiotic prophylaxis for recurrent UTI at least every 6 months, with the review to include:
assessing the success of prophylaxis
discussion of continuing, stopping or changing prophylaxis (taking into account the person's preferences for antibiotic use and the risk of antimicrobial resistance)
a reminder about behavioural and personal hygiene measures and self-care treatments (see the recommendations on self-care).If antibiotic prophylaxis is stopped, ensure that people have rapid access to treatment if they have an acute UTI.
# Self-care
Be aware that:
Some women with recurrent UTI may wish to try D‑mannose if they are not pregnant (the evidence for D‑mannose was based on a study in which it was taken as 200 ml of 1% solution once daily in the evening). D‑mannose is a sugar that is available to buy as powder or tablets; it is not a medicine.
Some women with recurrent UTI may wish to try cranberry products if they are not pregnant (evidence of benefit is uncertain and there is no evidence of benefit for older women).
Some children and young people under 16 years with recurrent UTI may wish to try cranberry products with the advice of a paediatric specialist (evidence of benefit is uncertain).
Advise people taking cranberry products or D‑mannose about the sugar content of these products, which should be considered as part of the person's daily sugar intake.
Be aware that evidence is inconclusive about whether probiotics (lactobacillus) reduce the risk of UTI in people with recurrent UTI.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.
Full details of the evidence and committee's discussion are available in the evidence review.
# Choice of antibiotic prophylaxis
When prescribing antibiotic prophylaxis for recurrent UTI, take account of local antimicrobial resistance (AMR) data from Public Health England and:
follow the recommendations in table 1 for people aged 16 years and over
follow the recommendations in table 2 for children and young people under 16 years.
Treatment
Antibiotic prophylaxis and dosage
First-choice oral antibiotics
Trimethoprim:
mg as a single dose when exposed to a trigger, or 100 mg at night
There is a teratogenic risk in first trimester of pregnancy (folate antagonist; BNF information on trimpethoprim). The companies advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics)
Nitrofurantoin (if estimated glomerular filtration rate is 45 ml/minute or more):
mg as a single dose when exposed to a trigger, or 50 mg to 100 mg at night
Avoid at term in pregnancy; may produce neonatal haemolysis (BNF information on nitrofurantoin)
Second-choice oral antibiotics
Amoxicillin (off-label use):
mg as a single dose when exposed to a trigger, or 250 mg at night
Cefalexin:
mg as a single dose when exposed to a trigger, or 125 mg at night
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding.
Choose antibiotics according to recent culture and susceptibility results where possible, with rotational use based on local policies. Select a different antibiotic for prophylaxis if treating an acute UTI.
For off-label use, see NICE's information on prescribing medicines.
Treatment
Antibiotic prophylaxis and dosage
Choice for children under 3 months
Refer to paediatric specialist
First-choice oral antibiotics for children aged 3 months and over (specialist advice only)
Trimethoprim:
months to 5 months, 2 mg/kg at night (maximum 100 mg per dose) or 12.5 mg at night
months to 5 years, 2 mg/kg at night (maximum 100 mg per dose) or 25 mg at night
years to 11 years, 2 mg/kg at night (maximum 100 mg per dose) or 50 mg at night
years to 15 years, 100 mg at night
There is a teratogenic risk in first trimester of pregnancy (folate antagonist; BNFC information on trimpethoprim). The companies advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics)
Nitrofurantoin (if estimated glomerular filtration rate is 45 ml/minute or more):
months to 11 years, 1 mg/kg at night
years to 15 years, 50 mg to 100 mg at night
Avoid at term in pregnancy; may produce neonatal haemolysis (BNFC information on nitrofurantoin)
Second-choice oral antibiotics for children aged 3 months and over
Cefalexin:
months to 15 years, 12.5 mg/kg at night (maximum 125 mg per dose)
Amoxicillin (off-label use):
months to 11 months, 62.5 mg at night
year to 4 years, 125 mg at night
years to 15 years, 250 mg at night
See the BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, hepatic and renal impairment.
Choose antibiotics according to recent culture and susceptibility results where possible, with rotational use based on local policies. Select a different antibiotic for prophylaxis if treating an acute UTI. If 2 or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.
For off-label use, see NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic prophylaxis and antibiotic dosing and course length.
Full details of the evidence and committee's discussions are available in the evidence review.# Terms used in the guideline
# Recurrent urinary tract infection
Recurrent urinary tract infection (UTI) in adults is defined as repeated UTI with a frequency of 2 or more UTIs in the last 6 months or 3 or more UTIs in the last 12 months (European Association of Urology guidelines on urological infections ).
Recurrent UTI is diagnosed in children and young people under 16 years if they have:
-r more episodes of UTI with acute pyelonephritis/upper UTI or
episode of UTI with acute pyelonephritis plus 1 or more episode of UTI with cystitis/lower UTI or
-r more episodes of UTI with cystitis/lower UTI.
See the NICE guideline on urinary tract infection in under 16s.
# Trigger
Some people (mainly women) may be able to identify 1 or more triggers (for example, sexual intercourse) that often brings on a UTI. These triggers may vary for different people.# Summary of the evidence
# Self-care
## Probiotics (lactobacillus)
Lactobacillus did not significantly reduce the risk of recurrent infection in premenopausal women with a history of previous urinary tract infection (UTI; 1 or more episode in the past 12 months) compared with placebo (low quality evidence). This was based on a systematic review and meta‑analysis of randomised controlled trials (RCTs; Grin et al. 2013). When the analysis was restricted to 2 RCTs with 'effective strains' of lactobacillus, there was a statistically significant difference (16.1% versus 32.3%: number needed to treat 7 ; moderate quality evidence).
In most studies lactobacillus was used following a UTI treated with antibiotics until the infection resolved. Lactobacillus pessaries were used in 4 RCTs and a drink preparation was used in 1 RCT.
Evidence for lactobacillus compared with antibiotic prophylaxis (co‑trimoxazole) in postmenopausal women with 1 or more previous UTI found, overall, no significant differences between treatment options (low quality evidence). This was based on 1 RCT included in a systematic review (Schwenger et al. 2015).
No safety data were reported for lactobacillus compared with placebo. Data for lactobacillus compared with antibiotic were reported narratively, and the reason for not pooling data was unclear. One systematic review reported no significant difference in the number of people experiencing at least 1 adverse event with lactobacillus compared with antibiotics (Schwenger et al. 2015; low quality evidence).
No systematic reviews or RCTs were identified that included data on lactobacillus in men or children.
## Cranberry products
A range of cranberry products are available; a liquid preparation (juice or syrup), tablets or capsules were used in the included studies.
Evidence for these products was identified in different populations (non‑pregnant women, pregnant women, elderly men and women, and children), with some conflicting results.
In women (unclear whether pregnant women were included) with a previous history of UTI, cranberry products used for up to 12 months did not significantly reduce the risk of recurrent infection (19.9% versus 22.8%) compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Jepson et al. 2012).
However, a more recent systematic review and meta‑analysis of RCTs (Fu et al. 2017) was identified following stakeholder consultation, which included additional data to Jepson et al. (2012). Cranberry products used for 6 to 12 months did significantly reduce the incidence of UTI in non‑pregnant women with a previous history of UTI compared with placebo or no treatment (20.7% versus 26.5%; NNT 17 ; very low quality evidence). This significant reduction was not seen when UTIs were confirmed by urine culture (19.8% versus 24.0%; very low quality evidence).
Subgroup analysis in Fu et al. (2017) found that cranberry juice used for 6 to 12 months did not reduce the incidence of UTI diagnosed by symptom presence or culture confirmation compared with placebo or no treatment (22.0% versus 26.6%; very low quality evidence); whereas cranberry tablets taken for 6 to 12 months did show a significant reduction in the incidence of UTI (13.5% versus 28.0%; NNT 7 ; low quality evidence). However, the analysis for cranberry tablets was based on much smaller numbers of participants.
In elderly adults (men and women) with a previous history of UTI, cranberry products used for up to 12 months did not significantly reduce the risk of recurrent infection (9.7% versus 12.6%; moderate quality evidence) compared with placebo or no treatment (Jepson et al. 2012).
In pregnant women with a previous history of UTI, cranberry products did not show a significant benefit in reducing recurrent UTI (56.6% versus 55.6%; moderate quality evidence) when compared with placebo or no treatment (Jepson et al. 2012).
In children with a previous history of 1 or more UTIs or 'repeated symptomatic UTI', cranberry products used for up to 12 months did not significantly reduce the risk of recurrent infection compared with placebo or no treatment (16.3% versus 29.5%; low quality evidence; Jepson et al. 2012).
However, a more recent systematic review and meta‑analysis of RCTs (Roshdibonab et al. 2017) was identified following stakeholder consultation, which included additional data to Jepson et al. (2012). Cranberry products used for up to 12 months did significantly reduce the incidence of UTI in children with recurrent UTI compared with placebo (odds ratio 0.31, 95% confidence interval 0.21 to 0.46; no absolute figures stated; very low quality evidence).
When cranberry products were compared with antibiotics (trimethoprim or co‑trimoxazole), there was no significant difference between groups in reducing the risk of recurrent infection in women (51.1% versus 40.4%; moderate quality evidence; Jepson et al. 2012). There was also no significant difference between cranberry products and antibiotics (trimethoprim) in reducing the risk of recurrent infection in children (10.7% versus 15.4%; low quality evidence; Jepson et al. 2012).
Evidence for cranberry products reducing the risk of antimicrobial resistance compared with antibiotics was conflicting. Cranberry products reduced the risk in premenopausal women compared with antibiotic prophylaxis (co‑trimoxazole) during a 12‑month treatment period (Beerepoot et al. 2011; moderate quality evidence). However, the risk was not reduced in children during a 12‑month treatment period (including children with vesicoureteral reflux ; Uberos et al. 2012; moderate quality evidence).
There were no significant differences in gastrointestinal adverse events in adults treated with cranberry products compared with no treatment or antibiotics (Jepson et al. 2012; low quality evidence). Two further studies showed higher numbers of adverse events in adults given placebo compared with cranberry products and 1 further study showed similar numbers of adverse events between groups.
No data were identified for adverse effects of cranberry products in children.
## D-mannose
D-mannose (200 ml of 1% solution once daily in the evening) used for up to 6 months significantly reduced the risk of recurrent infection in non‑pregnant women compared with no treatment (14.6% versus 60.8%, NNT 3 ; high quality evidence). This was based on 1 RCT in non-pregnant women presenting with a current UTI and a history of recurrent UTI (Kranjcec et al. 2014). All women were treated with ciprofloxacin 500 mg twice a day for 7 days for their current infection.
There was no significant reduction in recurrent infection when D‑mannose was compared with antibiotic prophylaxis (nitrofurantoin 50 mg a day) over the 6‑month study period (Kranjcec et al. 2014; low quality evidence).
There were significantly fewer adverse events (such as diarrhoea, nausea and vaginal burning) with D‑mannose compared with antibiotics in non‑pregnant women (7.8% versus 28.2%, number needed to harm 5 ; Kranjcec et al. 2014; high quality evidence).
No systematic reviews or RCTs were identified that included data on D‑mannose in pregnant women, men or children.
Based on their experience, and the need to minimise inappropriate use of antibiotics, the committee agreed that people should be given advice about behavioural and personal hygiene measures to reduce the risk of UTI, such as:
drinking enough fluids to avoid dehydration
not delaying habitual and post-coital urination
wiping from front to back after defaecation
not douching or wearing occlusive underwear.
The committee discussed the evidence for the probiotic lactobacillus. While there was some evidence to support the use of 'effective strains', there was no information on which lactobacillus products were included in this analysis. They also noted the high drop-out rate in the study.
Based on evidence, the committee agreed that people should be told that there is inconclusive evidence to recommend the use of lactobacillus to prevent recurrent UTIs.
The committee recognised that cranberry products are used widely and discussed the very low quality evidence showing some benefit for reducing the risk of UTIs, specifically in non-pregnant women, and children and young people. They were also aware that there was no evidence to suggest benefit in older women. The committee also noted the conflicting evidence for cranberry products in reducing the risk of antimicrobial resistance.
Taking account of the limitations of the evidence, and the need to minimise antimicrobial resistance, the committee agreed that some women who are not pregnant and some children and young people under 16 may wish to try cranberry products as a self-care treatment. However, due to safety concerns with delayed treatment, particularly in children and young people, the committee agreed that cranberry products should only be considered in this population following advice from a paediatric specialist.
The committee recognised that there was some evidence to suggest that cranberry juice was not significantly better than placebo in non‑pregnant women, while cranberry capsules showed a significant benefit. However, due to significant limitations in the evidence the committee was not able to recommend a specific cranberry product.
The committee discussed the sugar content of cranberry products, and based on their experience, agreed that people should be advised to take account of their daily sugar intake if using cranberry products.
The committee was aware of the mechanism of action of D‑mannose, which is also in cranberry products.
The committee noted evidence suggesting that D‑mannose was effective in reducing the risk of recurrent UTI in non pregnant women, and noted the low NNT of 3 (range 2 to 3) over 6 months, compared with no treatment. However, this was based on 1 small RCT. The committee agreed to make a recommendation that some women who are not pregnant may wish to try D‑mannose, as a self care treatment, noting the sugar content of this product which should be considered.
# Oestrogens
Oral oestrogens (with or without progestogens) taken for up to 4 years did not significantly reduce the risk of recurrent infection in postmenopausal women with recurrent UTI compared with placebo (moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Perrotta et al. 2008). Recurrent UTI was defined as 3 or more episodes in the past 12 months or 2 or more episodes in the past 6 months.
Vaginal oestrogen cream (estriol cream 0.5 mg applied topically at night for 2 weeks then twice weekly) for 8 months significantly reduced the risk of recurrent infection in postmenopausal women compared with placebo (16.0% versus 62.8%, NNT 3 ; high quality evidence). This was based on 1 RCT in the Perrotta et al. (2008) systematic review.
Vaginal oestrogen cream was also significantly more effective than oral antibiotics (ofloxacin 600 mg a day) in reducing the risk of recurrent infection over a 3‑month study period (7.4% versus 80.0%, NNT 2 ; low quality evidence). However, no difference was seen 2 months after treatment was stopped (very low quality evidence). This was based on 1 RCT included in the Perrotta et al. (2008) systematic review.
Vaginal oestrogen administered via a vaginal ring in 12‑week cycles, for a total of 36 weeks significantly reduced the risk of recurrent infection in postmenopausal women compared with placebo (50.9% versus 80.0%, NNT 4 ; Perrotta et al. 2008, moderate quality evidence).
However, vaginal oestrogen administered via a pessary (used daily for 2 weeks then once every 2 weeks) significantly increased the risk of recurrent infection in postmenopausal women compared with an oral antibiotic (nitrofurantoin 100 mg a day) over a 9‑month study period (67.4% versus 51.8%; Perrotta et al. 2008; low quality evidence).
Oral oestrogens increased adverse events (such as breast tenderness and vaginal bleeding) in postmenopausal women compared with placebo (NNH 5 ; Perrotta et al. 2008; high quality evidence).
Vaginal oestrogens did not significantly increase adverse events (such as breast tenderness and vaginal bleeding) in postmenopausal women compared with placebo or no treatment, but there was a significant increase in burning, itching or vaginal bleeding when compared with oral antibiotics (Perrotta et al. 2008; low to moderate quality evidence).
Oestrogens (hormone replacement therapy ) increase the risk of venous thromboembolism (when taken orally), stroke, endometrial cancer (reduced by a progestogen), breast cancer and ovarian cancer; there is an increased risk of coronary heart disease in women who start combined HRT more than 10 years after menopause (Medicines and Healthcare products Regulatory Agency Drug Safety Update on HRT, September 2007 and BNF information on sex hormones). Before prescribing HRT, health professionals should consider carefully the potential benefits and risks for every woman. See the NICE guideline on menopause for more information on using vaginal oestrogen for urogenital atrophy.
Vaginal oestrogens should be used in the smallest effective amount, for the shortest duration to minimise systemic effects. The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain; treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma (MHRA Drug Safety Update on HRT, September 2007 and BNF information on sex hormones). The NICE guideline on menopause recommends that women using vaginal oestrogen should report unscheduled vaginal bleeding to their GP.
## Committee discussion on oestrogens
Based on evidence of a lack of effectiveness and taking account of MHRA safety advice, the committee agreed to not recommend oral oestrogens (HRT) specifically to prevent recurrent UTI in postmenopausal women.
Based on evidence, the committee agreed that vaginal oestrogens were effective in reducing the risk of recurrent UTI in postmenopausal women, although this was based on small numbers of women and appears to diminish when the treatment is stopped. They noted the low NNTs for recurrent infection compared with placebo (NNT 3 for topical cream; NNT 4 for vaginal ring), and also when a topical cream was compared with antibiotics (NNT 2 ). However, oestrogen administered via a pessary was less effective than antibiotics.
Based on evidence and their experience, the committee recognised the adverse effects of vaginal oestrogens (such as breast tenderness and vaginal bleeding), which may require additional investigations.
The committee was aware of MHRA safety advice on the use of HRT; they agreed this was important for women and prescribers to discuss the possible harms of vaginal oestrogens, but that it should not prevent the safe use of an effective treatment for recurrent UTI.
Vaginal oestrogens are not licensed for preventing recurrent UTI, although oestrogen deficiency is a known risk factor. The committee noted that there do not appear to be any effective, licensed, non‑antimicrobial alternatives for preventing recurrent UTI in postmenopausal women.
Based on evidence, their experience and data on antimicrobial resistance, the committee agreed that vaginal oestrogens could be considered for postmenopausal women with recurrent UTI, with review within 12 months, or earlier if agreed with the woman. The committee recognised that this was a preference-sensitive decision and the benefits and harms of vaginal oestrogens need to be discussed with the woman, taking account of other symptoms the woman may want to address, such as vaginal dryness. The committee agreed that, before vaginal oestrogen is given, women should be asked about their preferences and given advice about the possible risks and benefits, returning for review and reporting unscheduled vaginal bleeding.
The committee could not make any firm conclusions from the evidence or their experience about different vaginal oestrogen products. They agreed that this will need to be considered with the woman on an individual basis.
# Antibiotic prophylaxis
The main complication of lower UTIs, including recurrent infections, is ascending infection leading to pyelonephritis. Most episodes of pyelonephritis are uncomplicated and result in no residual kidney damage. However, complications can include impaired renal function or renal failure, septicaemia and preterm labour in pregnancy (NICE clinical knowledge summary on pyelonephritis).
In pregnancy, asymptomatic bacteriuria can lead to pyelonephritis; and symptomatic UTI has been associated with developmental delay or cerebral palsy in the infant, and fetal death (NICE clinical knowledge summary on UTI – women).
In men with UTIs, prostate involvement is common, which may lead to complications such as prostatic abscess or chronic bacterial prostatitis, and urinary stones are a possibility (NICE clinical knowledge summary on UTI – men).
In children, UTIs can lead to renal scarring, but more often this is preceded by acute pyelonephritis rather than cystitis. Renal scarring is more common in children with vesicoureteral reflux, where recurrent UTIs are more likely (NICE clinical knowledge summary on UTI – children).
## Efficacy of antibiotic prophylaxis
Antibiotic prophylaxis for 6 to 12 months significantly reduced the risk of recurrent infection (using microbiological criteria) in non‑pregnant women with recurrent UTI (2 or more 'uncomplicated' episodes in the past 12 months) compared with placebo (12.3% versus 65.5%, NNT 2 ; high quality evidence). This was based on a systematic review and meta-analysis (Albert et al. 2004). However, there was no significant difference when recurrent infections were reported after the period of prophylaxis (very low quality evidence).
Antibiotic prophylaxis with nitrofurantoin for 5 weeks to 24 months significantly reduced the risk of recurrent infection in a mixed population of adults (including non-pregnant women and men) and children (mainly females) with recurrent UTI when compared with placebo or no treatment (22.5% versus 59.0%, NNT 3 ; low quality evidence). This was based on a systematic review and meta-analysis of RCTs (Muller et al. 2017).
Antibiotic prophylaxis with nitrofurantoin 50 mg three times a day for the duration of pregnancy significantly reduced the risk of recurrent asymptomatic bacteriuria in pregnant women who were admitted to hospital with acute pyelonephritis (32.6% versus 59.3%, NNT 4 ) compared with no treatment (monitoring alone; moderate quality evidence). This was based on 1 RCT (n=102) included in a systematic review (Schneeberger et al. 2015). However, antibiotic prophylaxis did not significantly reduce the risk of recurrent UTI (including pyelonephritis) in pregnant women, or birth outcomes such as pre‑term birth, low birthweight and miscarriage (Schneeberger et al. 2015; very low to low quality evidence).
Antibiotic prophylaxis with nitrofurantoin or co‑trimoxazole for at least 6 months (duration not reported in all studies) did not significantly reduce the risk of recurrent infection in children under 18 with recurrent UTI compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Williams and Craig 2011). Not all studies had clearly defined inclusion and exclusion criteria, and some had a small proportion of children with VUR. However, the result did not change when the analysis was restricted to studies that included children without VUR (very low quality evidence).
Antibiotic prophylaxis for at least 2 months (co‑trimoxazole in most studies) did not significantly reduce the rate of deteriorated renal scars in children under 18 years (with or without VUR) compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Dai et al. 2010).
There was no significant difference in the rate of antimicrobial resistance antibiotic prophylaxis compared with placebo in children under 18 years (Williams and Craig 2011, very low quality evidence).
## Safety of antibiotic prophylaxis
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
Nitrofurantoin should be used with caution in those with renal impairment (MHRA Drug Safety Update on nitrofurantoin, September 2014). It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should be monitored for liver function and pulmonary symptoms (BNF information on nitrofurantoin).
Trimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF information on trimethoprim). Manufacturers advise that trimethoprim is contraindicated in pregnancy (trimethoprim summary of product characteristics).
In non‑pregnant women, there was no significant difference in serious adverse effects with antibiotic prophylaxis compared with placebo, but there was a significant increase in the number of 'other adverse effects' (low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (NNH 13 ; Albert et al. 2004).
In children, there was no significant difference in the incidence of adverse effects reported or the number of withdrawals due to adverse events with antibiotic prophylaxis compared with placebo or no treatment (Williams and Craig 2011; very low quality evidence).
No systematic reviews or RCTs were identified that assessed the adverse effects of antibiotic prophylaxis in pregnant women.
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Based on evidence and their experience, the committee agreed that antibiotic prophylaxis was effective in reducing the risk of recurrent UTI in non‑pregnant women, although this benefit was not seen after the treatment is stopped. They noted the low NNTs for recurrent infection compared with placebo (NNT 2 ). However, they also recognised the increased risk of harms with antibiotic prophylaxis compared with placebo.
Based on evidence, the committee agreed that antibiotic prophylaxis was also effective in a mixed population of people with recurrent UTI, including pre‑ and postmenopausal women, men and children (NNT 3 ). However, interpretation of the evidence was more difficult due to variations in the populations studied and antibiotic choice, dosage and duration.
The committee discussed the evidence specifically in pregnant women, which found that antibiotic prophylaxis was effective in reducing the risk of recurrent asymptomatic bacteriuria in pregnant women (NNT 4 ). However, they recognised that the study had a number of limitations. The study was small and not powered to show any benefit in preterm births. The population was pregnant women who were admitted to hospital with acute pyelonephritis. The committee noted that nitrofurantoin is not an appropriate choice of antibiotic to show benefit in this population. They were also aware that UTI has been associated with developmental delay or cerebral palsy in the infant, and fetal death.
Taking account of the benefits and harms of antibiotic prophylaxis and the need to minimise antimicrobial resistance, the committee agreed that antibiotic prophylaxis could be considered in people aged 16 years and over with recurrent UTI, but only after other management options had been unsuccessful (behavioural and personal hygiene measures, managing any triggers and using non‑antimicrobial treatments), if appropriate.
The committee recognised the importance of reviewing antibiotic prophylaxis, and considered that up to every 6 months was reasonable based on possible adverse effects of antibiotics, the risk of resistance with long-term antibiotics, the possible need for any further investigations if recurrence of UTIs continues, and to allow time to assess treatment success. People should also know to seek medical help if they experience symptoms of an acute infection despite taking prophylaxis.
The committee discussed the importance of the review and were aware of other conditions where a specific date is included on the prescription to prompt review within 6 months.
To reduce the risk of antimicrobial resistance, the committee agreed that at each review women should be reminded about self-care, and consideration should be given to either stopping, continuing or changing antibiotic prophylaxis (for example, from single‑dose to daily prophylaxis). However the committee was not able to make specific recommendations about when to stop, continue or change antibiotic prophylaxis as it will depend on the circumstances of an individual person.
Based on evidence that suggests antibiotic prophylaxis does not continue to be effective after stopping treatment, the committee agreed that if antibiotic prophylaxis was stopped, women should be able to access treatment rapidly if they have symptoms of an acute UTI.
The committee recognised the limitations of the evidence on antibiotic prophylaxis in pregnant women and men, and the lack of evidence to support the use of non‑antimicrobial treatments. Therefore, the committee agreed that it was appropriate to refer all pregnant women to an obstetrician if recurrent UTI is diagnosed during pregnancy. They also agreed that most men with recurrent UTI should be referred for further specialist urology investigation and management, taking an individualised approach that takes account of multimorbidity. The committee agreed that any decision to prescribe antibiotic prophylaxis in pregnant women or men should be under specialist advice.
The committee also recognised the higher risks associated with recurrent upper UTIs (pyelonephritis), and agreed that it was appropriate to refer these people for further specialist investigation and management.
The committee agreed that further consideration should be made for women with recurrent lower UTI if the underlying cause of recurrence was unknown or required further investigation. However, due to resource implications and the lower risk of complications for this population, the committee agreed that specialist advice should be sought, rather than specialist referral.
The committee was aware of the recommendation in the NICE guideline on suspected cancer: recognition and referral, which states that a non-urgent referral for bladder cancer should be considered for people over 60 with recurrent unexplained UTI.
The committee also recognised the equality considerations for managing recurrent UTI in transgender people, due to anatomical differences between women and men.
The committee was aware that the NICE guideline on urinary tract infection in under 16s makes recommendations on referring children and young people with recurrent UTI to a paediatric specialist for assessment and investigations.
Based on evidence, the committee noted that antibiotic prophylaxis does not appear to be effective in reducing the risk of recurrent UTI in children. However, there was considerable uncertainty in the evidence (all very low quality).
Based on their experience, the committee agreed that most cases of recurrent UTI in children and young people are due to a functional or structural abnormality of the urinary tract.
Taking account of the uncertainty in the evidence and the need to minimise antimicrobial resistance from long-term antibiotic use, the committee agreed that antibiotic prophylaxis could be considered in children and young people under 16 years, but only under specialist advice when other management options have been unsuccessful. This would be an individualised decision following an assessment of underlying causes, taking into account the severity and frequency of previous symptoms and the risk of developing complications.
The committee recognised the importance of reviewing antibiotic prophylaxis, and considered that every 6 months was reasonable. They agreed that the same principles for the review in adults apply to children and young people.
# Choice of antibiotic prophylaxis
Antibiotic prophylaxis with nitrofurantoin (various doses: 100 mg a day, 75 mg a day, 50 mg a day or 50 mg twice a day) for at least 3 months significantly reduced the risk of recurrent infection in a mixed population of adults (including non-pregnant women and men) and children (mainly females) compared with methenamine hippurate (NNT 7 ; low quality evidence). However, there was no significant difference between nitrofurantoin and either trimethoprim, beta-lactams or quinolones (very low to low quality evidence). This was based on a systematic review and meta‑analyses of RCTs (Muller et al. 2017).
Antibiotic prophylaxis with nitrofurantoin (1 to 1.5 mg/kg daily) for 6 months significantly reduced the risk of having a positive urine culture at the end of the study period in children with recurrent UTI compared with trimethoprim (2 to 3 mg/kg daily; NNT 3 ) and reduced the risk of having a recurrent symptomatic UTI compared with co‑trimoxazole (2 mg/kg daily; NNT 6 ; very low to moderate quality evidence). However, there was no difference with nitrofurantoin compared with cefixime (2 mg/kg daily; 6 to 12 months; moderate quality evidence). This was based on a systematic review of single RCTs (Williams and Craig 2011).
Overall, antibiotic prophylaxis with nitrofurantoin (for at least 3 months) increased the risk of mild (not defined) adverse effects compared with other antibiotics in a mixed population of adults and children (30.6% versus 11.7%; NNH 5 ; Muller et al. 2017; low quality evidence). When specific antibiotics were compared, there were significantly more mild adverse effects with nitrofurantoin compared with beta‑lactams (NNH 7 ), trimethoprim (NNH 3 ) and methenamine (NNH 3 ), but no difference between nitrofurantoin and quinolones or co‑trimoxazole (Muller et al. 2017; very low to moderate quality evidence).
In children, there were significantly fewer adverse events with nitrofurantoin compared with trimethoprim (NNH 2 ), but significantly more adverse events with nitrofurantoin compared with cefixime (NNH 3 ; moderate quality evidence). This was based on a systematic review of single RCTs (Williams and Craig 2011).
No systematic reviews or RCTs were identified that included data on the choice of antibiotic in pregnant women.
## Committee discussion on choice of antibiotic prophylaxis
Based on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic prophylaxis should largely be driven by minimising the risk of resistance. Resistant bacteria are a particular concern in UTIs and, where possible, any previous urine culture and susceptibility results, and antibiotic prescribing for UTI, should be checked and antibiotics chosen accordingly.
Based on their experience and resistance data, the committee agreed that a different antibiotic should be selected for antibiotic prophylaxis if an acute UTI is being treated. They also recognised that rotational use of antibiotics may be needed, based on local policies.
The committee discussed that, if antibiotic prophylaxis is needed to prevent an infection that is not life threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last‑line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. Broad-spectrum antibiotics need to be reserved for second-choice treatment of non-life-threatening infections when narrow-spectrum antibiotics are ineffective.
Based on evidence, their experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin (based on culture and susceptibility results) as first choice antibiotics for prophylaxis. These antibiotics have less effect on the normal intestinal microflora in gastrointestinal tract, which is particularly important when continuous antibiotic prophylaxis is used.
Trimethoprim should only be prescribed if a lower risk of resistance is likely, for example, if trimethoprim has not been used in the past 3 months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger women in areas where local epidemiology data suggest resistance is low. There is a higher risk of trimethoprim resistance with recent use and in older people in residential facilities. Trimethoprim is contraindicated in pregnant women.
Nitrofurantoin is not recommended for people with an estimated glomerular filtration rate (eGFR) of less than 45 ml/minute. With long-term use, there is a lower risk of resistance of nitrofurantoin compared with trimethoprim, but this needs to be balanced against the increased harms, such as pulmonary fibrosis.
The committee was aware that nitrofurantoin suspension is currently substantially more expensive than trimethoprim suspension and, if both antibiotics are appropriate, the one with the lowest acquisition cost should be chosen.
Based on evidence, their experience and resistance data, the committee agreed to recommend cefalexin or amoxicillin (based on culture and susceptibility results) as second-choice antibiotics for prophylaxis.
Amoxicillin and cefalexin are broad spectrum antibiotics that have a similar spectrum of activity and can be used if bacteria are susceptible.
Based on evidence that methenamine hippurate was less effective than antibiotic prophylaxis with nitrofurantoin, the committee was not able to make a recommendation on its use. They were also aware that methenamine hippurate is a medicine that is considered less suitable for prescribing (BNF information on methenamine hippurate).
# Antibiotic dosing and course length
Single-dose antibiotic prophylaxis (used when exposed to conditions that may trigger a UTI) was not significantly different to daily antibiotic prophylaxis in the number of women with at least 1 recurrent infection over a 12‑month study period in postmenopausal women with recurrent UTI (3 or more episodes in the past 12 months; 80.6% versus 70.3%; moderate quality evidence). This was based on 1 RCT (Zhong et al. 2011).
The conditions for using the single-dose antibiotic were determined by the woman's experience, such as walking for a long time or sexual intercourse. The choice of antibiotic (nitrofurantoin, amoxicillin, co‑trimoxazole, quinolones or cephalosporins) varied and was determined on a case by case basis, depending on the woman's previous antibiotic use and following an antibiotic susceptibility test.
In 1 RCT (reported in a systematic review by Albert et al. 2004) single-dose ciprofloxacin (250 mg) taken immediately after sexual intercourse was as effective as a daily dose in non-pregnant women in reducing the risk of recurrent UTI during the period of prophylaxis (Albert et al. 2004; low quality evidence).
There were significantly fewer adverse events with single-dose antibiotic prophylaxis compared with daily antibiotic prophylaxis (NNH 3 ; Zhong et al. 2011; moderate quality evidence).
There was no significant difference in the number of non-serious adverse effects between those who took a single dose of ciprofloxacin (250 mg) immediately after sexual intercourse, or daily at night (Albert et al. 2004; low quality evidence).
## Committee discussions on antibiotic dosing and course length
Based on evidence, the committee was aware that a range of doses and course lengths were used for daily antibiotic prophylaxis. The committee agreed that usual BNF doses for daily prophylaxis should be used. The duration of treatment needs to be determined on an individual basis with a review of treatment success within 6 months, to include discussion of a trial of stopping antibiotic prophylaxis as appropriate.
The committee discussed the evidence for using single‑dose antibiotic prophylaxis (including post-coital single‑dose antibiotics) in non‑pregnant women. The committee agreed that the single dose used when exposed to an identifiable trigger would be the same as a single treatment dose for a UTI.
Based on evidence, their experience and antimicrobial resistance data, the committee agreed that single-dose prophylaxis was as effective as continuous prophylaxis, with fewer adverse effects in non‑pregnant women with an identifiable trigger, and should be considered as the first option for antibiotic prophylaxis in this group of women. Prophylaxis needs to be tailored to an individual woman's personal triggers, and advice given about how to use the antibiotic. Antibiotics for single-dose prophylaxis would be kept at home to avoid unnecessary GP and pharmacy visits.
No evidence from systematic reviews and RCTs was identified for using a course of antibiotics to keep at home for treating an acute UTI in people with recurrent UTIs (also known as stand‑by antibiotics). The use of stand‑by antibiotics could potentially lead to inappropriate antibiotic overuse in the absence of medical supervision, which would not reflect the principles of antimicrobial stewardship. Therefore, while the committee recognised that they may have a role in some specialist cases, they were not able to make a recommendation on their use.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require regular dosing or longer treatment duration (for example, continuous antibiotic prophylaxis). See the NICE guideline on medicines adherence.
# Resource implications
Recommended antibiotics are available as generic formulations, see the Drug Tariff for costs.
Nitrofurantoin 25 mg/5 ml oral suspension is more expensive than other oral suspensions, such as trimethoprim 50 mg/5 ml. The cost of a 300‑ml bottle of nitrofurantoin is £446.95 compared with £4.87 for a 100‑ml bottle of trimethoprim (Drug Tariff, September 2018).
|
{'Recommendations': "# Preventing recurrent urinary tract infections\n\nManage an acute UTI as outlined in the NICE guidelines on urinary tract infection (lower): antimicrobial prescribing or pyelonephritis (acute): antimicrobial prescribing.\n\nBe aware that recurrent UTI:\n\nincludes lower UTI and upper UTI (acute pyelonephritis)\n\nmay be due to relapse (with the same strain of organism) or reinfection (with a different strain or species of organism)\n\nis particularly common in women.\n\nGive advice to people with recurrent UTI about behavioural and personal hygiene measures and self‑care treatments (see the recommendations on self-care) that may help to reduce the risk of UTI.\n\n## Referral and seeking specialist advice\n\nRefer or seek specialist advice on further investigation and management for:\n\nmen aged 16\xa0years and over\n\npeople with recurrent upper UTI\n\npeople with recurrent lower UTI when the underlying cause is unknown\n\npregnant women\n\nchildren and young people under 16\xa0years in line with the NICE guideline on urinary tract infection in under\xa016s\n\npeople with suspected cancer in line with the NICE guideline on suspected cancer: recognition and referral.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\n## Treatment for women with recurrent UTI who are not pregnant\n\nConsider the lowest effective dose of vaginal oestrogen (for example, estriol cream) for postmenopausal women with recurrent UTI if behavioural and personal hygiene measures alone are not effective or not appropriate. Discuss the following with the woman to ensure shared decision-making:\n\nthe severity and frequency of previous symptoms\n\nthe risk of developing complications from recurrent UTIs\n\nthe possible benefits of treatment, including for other related symptoms, such as vaginal dryness\n\nthe possible adverse effects such as breast tenderness and vaginal bleeding (which should be reported because it may require investigation)\n\nthe uncertainty of endometrial safety with long-term or repeated use\n\npreferences of the woman for treatment with vaginal oestrogen.Review treatment within 12\xa0months, or earlier if agreed with the woman. In October 2018, this was an off-label use of vaginal oestrogen products. See NICE's information on prescribing medicines.\n\nDo not offer oral oestrogens (hormone replacement therapy) specifically to reduce the risk of recurrent UTI in postmenopausal women.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on oestrogens.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\nFor women with recurrent UTI who are not pregnant, consider a trial of antibiotic prophylaxis only if behavioural and personal hygiene measures, and vaginal oestrogen (in postmenopausal women) are not effective or not appropriate.\n\nFor women with recurrent UTI who are not pregnant, ensure that any current UTI has been adequately treated then consider single-dose antibiotic prophylaxis for use when exposed to an identifiable trigger (see the recommendations on choice of antibiotic prophylaxis). Take account of:\n\nthe severity and frequency of previous symptoms\n\nthe risk of developing complications\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria\n\nthe woman's preferences for antibiotic use.\n\nWhen single-dose antibiotic prophylaxis is given, give advice about:\n\nhow to use the antibiotic\n\npossible adverse effects of antibiotics, particularly diarrhoea and nausea\n\nreturning for review within 6\xa0months\n\nseeking medical help if there are symptoms of an acute UTI.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis and antibiotic dosing and course length.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\nFor women with recurrent UTI who are not pregnant and have had no improvement after single‑dose antibiotic prophylaxis or have no identifiable triggers, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis). Take account of:\n\nany further investigations (for example, ultrasound) that may be needed to identify an underlying cause\n\nthe severity and frequency of previous symptoms\n\nthe risks of long‑term antibiotic use\n\nthe risk of developing complications\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria\n\nthe woman's preferences for antibiotic use.\n\nWhen a trial of daily antibiotic prophylaxis is given, give advice about:\n\nthe risk of resistance with long-term antibiotics, which means they may be less effective in the future\n\npossible adverse effects of long-term antibiotics\n\nreturning for review within 6\xa0months\n\nseeking medical help if there are symptoms of an acute UTI.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\n## Treatment for men and pregnant women with recurrent UTI\n\nFor men and pregnant women with recurrent UTI, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis) if behavioural and personal hygiene measures alone are not effective or not appropriate, with specialist advice. Take account of:\n\nany further investigations (for example, ultrasound) that may be needed to identify an underlying cause\n\nthe severity and frequency of previous symptoms\n\nthe risks of long‑term antibiotic use\n\nthe risk of developing complications\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria\n\nthe person's preferences for antibiotic use.\n\nWhen a trial of daily antibiotic prophylaxis is given, give advice as in recommendation\xa01.1.11.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic prophylaxis.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\n## Treatment for children and young people under 16\xa0years with recurrent UTI\n\nFor children and young people under 16\xa0years with recurrent UTI, ensure that any current UTI has been adequately treated then consider a trial of daily antibiotic prophylaxis (see the recommendations on choice of antibiotic prophylaxis) if behavioural and personal hygiene measures alone are not effective or not appropriate, with specialist advice. Take account of:\n\nunderlying causes following specialist assessment and investigations\n\nthe uncertain evidence of benefit of antibiotic prophylaxis for reducing the risk of recurrent UTI and the rate of deterioration of renal scars\n\nthe severity and frequency of previous symptoms\n\nthe risks of long‑term antibiotic use\n\nthe risk of developing complications\n\nprevious urine culture and susceptibility results\n\nprevious antibiotic use, which may have led to resistant bacteria\n\npreferences for antibiotic use.\n\nWhen a trial of daily antibiotic prophylaxis is given, give advice as in recommendation\xa01.1.11.\n\n## Reassessment\n\nReview antibiotic prophylaxis for recurrent UTI at least every 6\xa0months, with the review to include:\n\nassessing the success of prophylaxis\n\ndiscussion of continuing, stopping or changing prophylaxis (taking into account the person's preferences for antibiotic use and the risk of antimicrobial resistance)\n\na reminder about behavioural and personal hygiene measures and self-care treatments (see the recommendations on self-care).If antibiotic prophylaxis is stopped, ensure that people have rapid access to treatment if they have an acute UTI.\n\n# Self-care\n\nBe aware that:\n\nSome women with recurrent UTI may wish to try D‑mannose if they are not pregnant (the evidence for D‑mannose was based on a study in which it was taken as 200\xa0ml of 1%\xa0solution once daily in the evening). D‑mannose is a sugar that is available to buy as powder or tablets; it is not a medicine.\n\nSome women with recurrent UTI may wish to try cranberry products if they are not pregnant (evidence of benefit is uncertain and there is no evidence of benefit for older women).\n\nSome children and young people under 16\xa0years with recurrent UTI may wish to try cranberry products with the advice of a paediatric specialist (evidence of benefit is uncertain).\n\nAdvise people taking cranberry products or D‑mannose about the sugar content of these products, which should be considered as part of the person's daily sugar intake.\n\nBe aware that evidence is inconclusive about whether probiotics (lactobacillus) reduce the risk of UTI in people with recurrent UTI.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.\n\nFull details of the evidence and committee's discussion are available in the evidence review.\n\n# Choice of antibiotic prophylaxis\n\nWhen prescribing antibiotic prophylaxis for recurrent UTI, take account of local antimicrobial resistance (AMR) data from Public Health England and:\n\nfollow the recommendations in table\xa01 for people aged 16\xa0years and over\n\nfollow the recommendations in table\xa02 for children and young people under 16\xa0years.\n\nTreatment\n\nAntibiotic prophylaxis and dosage\n\nFirst-choice oral antibiotics\n\nTrimethoprim:\n\nmg as a single dose when exposed to a trigger, or 100\xa0mg at night\n\nThere is a teratogenic risk in first trimester of pregnancy (folate antagonist; BNF information on trimpethoprim). The companies advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics)\n\n\n\nNitrofurantoin (if estimated glomerular filtration rate is 45\xa0ml/minute or more):\n\nmg as a single dose when exposed to a trigger, or 50\xa0mg to\xa0100\xa0mg at night\n\nAvoid at term in pregnancy; may produce neonatal haemolysis (BNF information on nitrofurantoin)\n\nSecond-choice oral antibiotics\n\nAmoxicillin (off-label use):\n\nmg as a single dose when exposed to a trigger, or 250\xa0mg at night\n\n\n\nCefalexin:\n\nmg as a single dose when exposed to a trigger, or 125\xa0mg at night\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding.\n\nChoose antibiotics according to recent culture and susceptibility results where possible, with rotational use based on local policies. Select a different antibiotic for prophylaxis if treating an acute UTI.\n\nFor off-label use, see NICE's information on prescribing medicines.\n\nTreatment\n\nAntibiotic prophylaxis and dosage\n\nChoice for children under 3\xa0months\n\nRefer to paediatric specialist\n\nFirst-choice oral antibiotics for children aged 3\xa0months and over (specialist advice only)\n\nTrimethoprim:\n\nmonths to 5\xa0months, 2\xa0mg/kg at night (maximum 100\xa0mg per dose) or 12.5\xa0mg at night\n\nmonths to 5\xa0years, 2\xa0mg/kg at night (maximum 100\xa0mg per dose) or 25\xa0mg at night\n\nyears to 11\xa0years, 2\xa0mg/kg at night (maximum 100\xa0mg per dose) or 50\xa0mg at night\n\nyears to 15\xa0years, 100\xa0mg at night\n\nThere is a teratogenic risk in first trimester of pregnancy (folate antagonist; BNFC information on trimpethoprim). The companies advise that it is contraindicated in pregnancy (trimethoprim summary of product characteristics)\n\n\n\nNitrofurantoin (if estimated glomerular filtration rate is 45\xa0ml/minute or more):\n\nmonths to 11\xa0years, 1\xa0mg/kg at night\n\nyears to\xa015\xa0years, 50\xa0mg to\xa0100\xa0mg at night\n\n\n\nAvoid at term in pregnancy; may produce neonatal haemolysis (BNFC information on nitrofurantoin)\n\nSecond-choice oral antibiotics for children aged 3\xa0months and over\n\nCefalexin:\n\nmonths to 15\xa0years, 12.5\xa0mg/kg at night (maximum 125\xa0mg per dose)\n\n\n\nAmoxicillin (off-label use):\n\nmonths to 11\xa0months, 62.5\xa0mg at night\n\nyear to 4\xa0years, 125\xa0mg at night\n\nyears to 15\xa0years, 250\xa0mg at night\n\nSee the BNF for children (BNFC) for appropriate use and dosing in specific populations, for example, hepatic and renal impairment.\n\nChoose antibiotics according to recent culture and susceptibility results where possible, with rotational use based on local policies. Select a different antibiotic for prophylaxis if treating an acute UTI. If 2\xa0or more antibiotics are appropriate, choose the antibiotic with the lowest acquisition cost.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.\n\nFor off-label use, see NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic prophylaxis and antibiotic dosing and course length.\n\nFull details of the evidence and committee's discussions are available in the evidence review.", 'Terms used in the guideline': '# Recurrent urinary tract infection\n\nRecurrent urinary tract infection (UTI) in adults is defined as repeated UTI with a frequency of 2\xa0or more UTIs in the last 6\xa0months or 3\xa0or more UTIs in the last 12\xa0months (European Association of Urology [EAU] guidelines on urological infections ).\n\nRecurrent UTI is diagnosed in children and young people under 16\xa0years if they have:\n\nor more episodes of UTI with acute pyelonephritis/upper UTI or\n\nepisode of UTI with acute pyelonephritis plus 1\xa0or more episode of UTI with cystitis/lower UTI or\n\nor more episodes of UTI with cystitis/lower UTI.\n\nSee the NICE guideline on urinary tract infection in under\xa016s.\n\n# Trigger\n\nSome people (mainly women) may be able to identify 1\xa0or more triggers (for example, sexual intercourse) that often brings on a UTI. These triggers may vary for different people.', 'Summary of the evidence': "# Self-care\n\n## Probiotics (lactobacillus)\n\nLactobacillus did not significantly reduce the risk of recurrent infection in premenopausal women with a history of previous urinary tract infection (UTI; 1\xa0or more episode in the past 12\xa0months) compared with placebo (low quality evidence). This was based on a systematic review and meta‑analysis of randomised controlled trials (RCTs; Grin et al. 2013). When the analysis was restricted to 2\xa0RCTs with 'effective strains' of lactobacillus, there was a statistically significant difference (16.1% versus 32.3%: number needed to treat [NNT] 7 [range 4 to 64]; moderate quality evidence).\n\nIn most studies lactobacillus was used following a UTI treated with antibiotics until the infection resolved. Lactobacillus pessaries were used in 4\xa0RCTs and a drink preparation was used in 1\xa0RCT.\n\nEvidence for lactobacillus compared with antibiotic prophylaxis (co‑trimoxazole) in postmenopausal women with 1\xa0or more previous UTI found, overall, no significant differences between treatment options (low quality evidence). This was based on 1\xa0RCT included in a systematic review (Schwenger et al.\xa02015).\n\nNo safety data were reported for lactobacillus compared with placebo. Data for lactobacillus compared with antibiotic were reported narratively, and the reason for not pooling data was unclear. One systematic review reported no significant difference in the number of people experiencing at least 1\xa0adverse event with lactobacillus compared with antibiotics (Schwenger et al. 2015; low quality evidence).\n\nNo systematic reviews or RCTs were identified that included data on lactobacillus in men or children.\n\n## Cranberry products\n\nA range of cranberry products are available; a liquid preparation (juice or syrup), tablets or capsules were used in the included studies.\n\nEvidence for these products was identified in different populations (non‑pregnant women, pregnant women, elderly men and women, and children), with some conflicting results.\n\nIn women (unclear whether pregnant women were included) with a previous history of UTI, cranberry products used for up to 12\xa0months did not significantly reduce the risk of recurrent infection (19.9% versus 22.8%) compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Jepson et al.\xa02012).\n\nHowever, a more recent systematic review and meta‑analysis of RCTs (Fu et al. 2017) was identified following stakeholder consultation, which included additional data to Jepson et al. (2012). Cranberry products used for 6\xa0to\xa012\xa0months did significantly reduce the incidence of UTI in non‑pregnant women with a previous history of UTI compared with placebo or no treatment (20.7% versus 26.5%; NNT\xa017 [range 9 to 68]; very low quality evidence). This significant reduction was not seen when UTIs were confirmed by urine culture (19.8% versus 24.0%; very low quality evidence).\n\nSubgroup analysis in Fu et al. (2017) found that cranberry juice used for 6\xa0to\xa012\xa0months did not reduce the incidence of UTI diagnosed by symptom presence or culture confirmation compared with placebo or no treatment (22.0% versus 26.6%; very low quality evidence); whereas cranberry tablets taken for 6\xa0to\xa012\xa0months did show a significant reduction in the incidence of UTI (13.5% versus 28.0%; NNT\xa07 [range 5 to 20]; low quality evidence). However, the analysis for cranberry tablets was based on much smaller numbers of participants.\n\nIn elderly adults (men and women) with a previous history of UTI, cranberry products used for up to 12\xa0months did not significantly reduce the risk of recurrent infection (9.7% versus 12.6%; moderate quality evidence) compared with placebo or no treatment (Jepson et al.\xa02012).\n\nIn pregnant women with a previous history of UTI, cranberry products did not show a significant benefit in reducing recurrent UTI (56.6% versus 55.6%; moderate quality evidence) when compared with placebo or no treatment (Jepson et al.\xa02012).\n\nIn children with a previous history of 1\xa0or more UTIs or 'repeated symptomatic UTI', cranberry products used for up to 12\xa0months did not significantly reduce the risk of recurrent infection compared with placebo or no treatment (16.3% versus 29.5%; low quality evidence; Jepson et al.\xa02012).\n\nHowever, a more recent systematic review and meta‑analysis of RCTs (Roshdibonab et al. 2017) was identified following stakeholder consultation, which included additional data to Jepson et al. (2012). Cranberry products used for up to 12\xa0months did significantly reduce the incidence of UTI in children with recurrent UTI compared with placebo (odds ratio 0.31, 95% confidence interval 0.21 to 0.46; no absolute figures stated; very low quality evidence).\n\nWhen cranberry products were compared with antibiotics (trimethoprim or co‑trimoxazole), there was no significant difference between groups in reducing the risk of recurrent infection in women (51.1% versus 40.4%; moderate quality evidence; Jepson et al. 2012). There was also no significant difference between cranberry products and antibiotics (trimethoprim) in reducing the risk of recurrent infection in children (10.7% versus 15.4%; low quality evidence; Jepson et al. 2012).\n\nEvidence for cranberry products reducing the risk of antimicrobial resistance compared with antibiotics was conflicting. Cranberry products reduced the risk in premenopausal women compared with antibiotic prophylaxis (co‑trimoxazole) during a 12‑month treatment period (Beerepoot et al. 2011; moderate quality evidence). However, the risk was not reduced in children during a 12‑month treatment period (including children with vesicoureteral reflux [VUR]; Uberos et al. 2012; moderate quality evidence).\n\nThere were no significant differences in gastrointestinal adverse events in adults treated with cranberry products compared with no treatment or antibiotics (Jepson et al. 2012; low quality evidence). Two further studies showed higher numbers of adverse events in adults given placebo compared with cranberry products and 1\xa0further study showed similar numbers of adverse events between groups.\n\nNo data were identified for adverse effects of cranberry products in children.\n\n## D-mannose\n\nD-mannose (200\xa0ml of 1% solution once daily in the evening) used for up to 6\xa0months significantly reduced the risk of recurrent infection in non‑pregnant women compared with no treatment (14.6% versus 60.8%, NNT\xa03 [range 2 to 3]; high quality evidence). This was based on 1\xa0RCT in non-pregnant women presenting with a current UTI and a history of recurrent UTI (Kranjcec et al. 2014). All women were treated with ciprofloxacin 500\xa0mg twice a day for 7\xa0days for their current infection.\n\nThere was no significant reduction in recurrent infection when D‑mannose was compared with antibiotic prophylaxis (nitrofurantoin 50\xa0mg a day) over the 6‑month study period (Kranjcec et al. 2014; low quality evidence).\n\nThere were significantly fewer adverse events (such as diarrhoea, nausea and vaginal burning) with D‑mannose compared with antibiotics in non‑pregnant women (7.8% versus 28.2%, number needed to harm [NNH] 5\xa0[range 4 to 10]; Kranjcec et al. 2014; high quality evidence).\n\nNo systematic reviews or RCTs were identified that included data on D‑mannose in pregnant women, men or children.\n\nBased on their experience, and the need to minimise inappropriate use of antibiotics, the committee agreed that people should be given advice about behavioural and personal hygiene measures to reduce the risk of UTI, such as:\n\n\n\ndrinking enough fluids to avoid dehydration\n\nnot delaying habitual and post-coital urination\n\nwiping from front to back after defaecation\n\nnot douching or wearing occlusive underwear.\n\n\n\nThe committee discussed the evidence for the probiotic lactobacillus. While there was some evidence to support the use of 'effective strains', there was no information on which lactobacillus products were included in this analysis. They also noted the high drop-out rate in the study.\n\nBased on evidence, the committee agreed that people should be told that there is inconclusive evidence to recommend the use of lactobacillus to prevent recurrent UTIs.\n\nThe committee recognised that cranberry products are used widely and discussed the very low quality evidence showing some benefit for reducing the risk of UTIs, specifically in non-pregnant women, and children and young people. They were also aware that there was no evidence to suggest benefit in older women. The committee also noted the conflicting evidence for cranberry products in reducing the risk of antimicrobial resistance.\n\nTaking account of the limitations of the evidence, and the need to minimise antimicrobial resistance, the committee agreed that some women who are not pregnant and some children and young people under\xa016 may wish to try cranberry products as a self-care treatment. However, due to safety concerns with delayed treatment, particularly in children and young people, the committee agreed that cranberry products should only be considered in this population following advice from a paediatric specialist.\n\nThe committee recognised that there was some evidence to suggest that cranberry juice was not significantly better than placebo in non‑pregnant women, while cranberry capsules showed a significant benefit. However, due to significant limitations in the evidence the committee was not able to recommend a specific cranberry product.\n\nThe committee discussed the sugar content of cranberry products, and based on their experience, agreed that people should be advised to take account of their daily sugar intake if using cranberry products.\n\nThe committee was aware of the mechanism of action of D‑mannose, which is also in cranberry products.\n\nThe committee noted evidence suggesting that D‑mannose was effective in reducing the risk of recurrent UTI in non pregnant women, and noted the low NNT of 3 (range 2 to 3) over 6 months, compared with no treatment. However, this was based on 1 small RCT. The committee agreed to make a recommendation that some women who are not pregnant may wish to try D‑mannose, as a self care treatment, noting the sugar content of this product which should be considered.\n\n# Oestrogens\n\nOral oestrogens (with or without progestogens) taken for up to 4\xa0years did not significantly reduce the risk of recurrent infection in postmenopausal women with recurrent UTI compared with placebo (moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Perrotta et al. 2008). Recurrent UTI was defined as 3\xa0or more episodes in the past 12\xa0months or 2\xa0or more episodes in the past 6\xa0months.\n\nVaginal oestrogen cream (estriol cream 0.5\xa0mg applied topically at night for 2\xa0weeks then twice weekly) for 8\xa0months significantly reduced the risk of recurrent infection in postmenopausal women compared with placebo (16.0% versus 62.8%, NNT\xa03 [range 2 to 4]; high quality evidence). This was based on 1\xa0RCT in the Perrotta et al. (2008) systematic review.\n\nVaginal oestrogen cream was also significantly more effective than oral antibiotics (ofloxacin 600\xa0mg a day) in reducing the risk of recurrent infection over a 3‑month study period (7.4% versus 80.0%, NNT\xa02 [range 2 to 2]; low quality evidence). However, no difference was seen 2\xa0months after treatment was stopped (very low quality evidence). This was based on 1\xa0RCT included in the Perrotta et al. (2008) systematic review.\n\nVaginal oestrogen administered via a vaginal ring in 12‑week cycles, for a total of 36\xa0weeks significantly reduced the risk of recurrent infection in postmenopausal women compared with placebo (50.9% versus 80.0%, NNT 4 [range 3 to 9]; Perrotta et al. 2008, moderate quality evidence).\n\nHowever, vaginal oestrogen administered via a pessary (used daily for 2\xa0weeks then once every 2\xa0weeks) significantly increased the risk of recurrent infection in postmenopausal women compared with an oral antibiotic (nitrofurantoin 100\xa0mg a day) over a 9‑month study period (67.4% versus 51.8%; Perrotta et al. 2008; low quality evidence).\n\nOral oestrogens increased adverse events (such as breast tenderness and vaginal bleeding) in postmenopausal women compared with placebo (NNH\xa05 [range 3 to 14]; Perrotta et al. 2008; high quality evidence).\n\nVaginal oestrogens did not significantly increase adverse events (such as breast tenderness and vaginal bleeding) in postmenopausal women compared with placebo or no treatment, but there was a significant increase in burning, itching or vaginal bleeding when compared with oral antibiotics (Perrotta et al. 2008; low to moderate quality evidence).\n\nOestrogens (hormone replacement therapy [HRT]) increase the risk of venous thromboembolism (when taken orally), stroke, endometrial cancer (reduced by a progestogen), breast cancer and ovarian cancer; there is an increased risk of coronary heart disease in women who start combined HRT more than 10\xa0years after menopause (Medicines and Healthcare products Regulatory Agency [MHRA] Drug Safety Update on HRT, September 2007 and BNF information on sex hormones). Before prescribing HRT, health professionals should consider carefully the potential benefits and risks for every woman. See the NICE guideline on menopause for more information on using vaginal oestrogen for urogenital atrophy.\n\nVaginal oestrogens should be used in the smallest effective amount, for the shortest duration to minimise systemic effects. The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain; treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma (MHRA Drug Safety Update on HRT, September 2007 and BNF information on sex hormones). The NICE guideline on menopause recommends that women using vaginal oestrogen should report unscheduled vaginal bleeding to their GP.\n\n## Committee discussion on oestrogens\n\nBased on evidence of a lack of effectiveness and taking account of MHRA safety advice, the committee agreed to not recommend oral oestrogens (HRT) specifically to prevent recurrent UTI in postmenopausal women.\n\nBased on evidence, the committee agreed that vaginal oestrogens were effective in reducing the risk of recurrent UTI in postmenopausal women, although this was based on small numbers of women and appears to diminish when the treatment is stopped. They noted the low NNTs for recurrent infection compared with placebo (NNT\xa03 [range 2 to 4] for topical cream; NNT\xa04 [range 3 to 9] for vaginal ring), and also when a topical cream was compared with antibiotics (NNT\xa02 [range 2 to 2]). However, oestrogen administered via a pessary was less effective than antibiotics.\n\nBased on evidence and their experience, the committee recognised the adverse effects of vaginal oestrogens (such as breast tenderness and vaginal bleeding), which may require additional investigations.\n\nThe committee was aware of MHRA safety advice on the use of HRT; they agreed this was important for women and prescribers to discuss the possible harms of vaginal oestrogens, but that it should not prevent the safe use of an effective treatment for recurrent UTI.\n\nVaginal oestrogens are not licensed for preventing recurrent UTI, although oestrogen deficiency is a known risk factor. The committee noted that there do not appear to be any effective, licensed, non‑antimicrobial alternatives for preventing recurrent UTI in postmenopausal women.\n\nBased on evidence, their experience and data on antimicrobial resistance, the committee agreed that vaginal oestrogens could be considered for postmenopausal women with recurrent UTI, with review within 12\xa0months, or earlier if agreed with the woman. The committee recognised that this was a preference-sensitive decision and the benefits and harms of vaginal oestrogens need to be discussed with the woman, taking account of other symptoms the woman may want to address, such as vaginal dryness. The committee agreed that, before vaginal oestrogen is given, women should be asked about their preferences and given advice about the possible risks and benefits, returning for review and reporting unscheduled vaginal bleeding.\n\nThe committee could not make any firm conclusions from the evidence or their experience about different vaginal oestrogen products. They agreed that this will need to be considered with the woman on an individual basis.\n\n# Antibiotic prophylaxis\n\nThe main complication of lower UTIs, including recurrent infections, is ascending infection leading to pyelonephritis. Most episodes of pyelonephritis are uncomplicated and result in no residual kidney damage. However, complications can include impaired renal function or renal failure, septicaemia and preterm labour in pregnancy (NICE clinical knowledge summary on pyelonephritis).\n\nIn pregnancy, asymptomatic bacteriuria can lead to pyelonephritis; and symptomatic UTI has been associated with developmental delay or cerebral palsy in the infant, and fetal death (NICE clinical knowledge summary on UTI [lower] – women).\n\nIn men with UTIs, prostate involvement is common, which may lead to complications such as prostatic abscess or chronic bacterial prostatitis, and urinary stones are a possibility (NICE clinical knowledge summary on UTI [lower] – men).\n\nIn children, UTIs can lead to renal scarring, but more often this is preceded by acute pyelonephritis rather than cystitis. Renal scarring is more common in children with vesicoureteral reflux, where recurrent UTIs are more likely (NICE clinical knowledge summary on UTI – children).\n\n## Efficacy of antibiotic prophylaxis\n\nAntibiotic prophylaxis for 6\xa0to\xa012\xa0months significantly reduced the risk of recurrent infection (using microbiological criteria) in non‑pregnant women with recurrent UTI (2 or more 'uncomplicated' episodes in the past 12\xa0months) compared with placebo (12.3% versus 65.5%, NNT 2 [range 2 to 3]; high quality evidence). This was based on a systematic review and meta-analysis (Albert et al. 2004). However, there was no significant difference when recurrent infections were reported after the period of prophylaxis (very low quality evidence).\n\nAntibiotic prophylaxis with nitrofurantoin for 5\xa0weeks to 24\xa0months significantly reduced the risk of recurrent infection in a mixed population of adults (including non-pregnant women and men) and children (mainly females) with recurrent UTI when compared with placebo or no treatment (22.5% versus 59.0%, NNT 3 [range 3 to 4]; low quality evidence). This was based on a systematic review and meta-analysis of RCTs (Muller et al.\xa02017).\n\nAntibiotic prophylaxis with nitrofurantoin 50\xa0mg three times a day for the duration of pregnancy significantly reduced the risk of recurrent asymptomatic bacteriuria in pregnant women who were admitted to hospital with acute pyelonephritis (32.6% versus 59.3%, NNT 4 [range 3 to 13]) compared with no treatment (monitoring alone; moderate quality evidence). This was based on 1\xa0RCT (n=102) included in a systematic review (Schneeberger et al. 2015). However, antibiotic prophylaxis did not significantly reduce the risk of recurrent UTI (including pyelonephritis) in pregnant women, or birth outcomes such as pre‑term birth, low birthweight and miscarriage (Schneeberger et al. 2015; very low to low quality evidence).\n\nAntibiotic prophylaxis with nitrofurantoin or co‑trimoxazole for at least 6\xa0months (duration not reported in all studies) did not significantly reduce the risk of recurrent infection in children under\xa018 with recurrent UTI compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Williams and Craig 2011). Not all studies had clearly defined inclusion and exclusion criteria, and some had a small proportion of children with VUR. However, the result did not change when the analysis was restricted to studies that included children without VUR (very low quality evidence).\n\nAntibiotic prophylaxis for at least 2\xa0months (co‑trimoxazole in most studies) did not significantly reduce the rate of deteriorated renal scars in children under 18\xa0years (with or without VUR) compared with placebo or no treatment (very low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Dai et al.\xa02010).\n\nThere was no significant difference in the rate of antimicrobial resistance antibiotic prophylaxis compared with placebo in children under 18\xa0years (Williams and Craig 2011, very low quality evidence).\n\n## Safety of antibiotic prophylaxis\n\nAntibiotic-associated diarrhoea occurs in 2\xa0to\xa025% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this has often been because of a skin rash that occurred during a course of penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nNitrofurantoin should be used with caution in those with renal impairment (MHRA Drug Safety Update on nitrofurantoin, September 2014). It should be avoided at term in pregnancy because it may produce neonatal haemolysis. Adults (especially older adults) and children on long-term therapy should be monitored for liver function and pulmonary symptoms (BNF information on nitrofurantoin).\n\nTrimethoprim has a teratogenic risk in the first trimester of pregnancy (folate antagonist; BNF information on trimethoprim). Manufacturers advise that trimethoprim is contraindicated in pregnancy (trimethoprim summary of product characteristics).\n\nIn non‑pregnant women, there was no significant difference in serious adverse effects with antibiotic prophylaxis compared with placebo, but there was a significant increase in the number of 'other adverse effects' (low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (NNH\xa013 [range 7 to 70]; Albert et al.\xa02004).\n\nIn children, there was no significant difference in the incidence of adverse effects reported or the number of withdrawals due to adverse events with antibiotic prophylaxis compared with placebo or no treatment (Williams and Craig 2011; very low quality evidence).\n\nNo systematic reviews or RCTs were identified that assessed the adverse effects of antibiotic prophylaxis in pregnant women.\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nBased on evidence and their experience, the committee agreed that antibiotic prophylaxis was effective in reducing the risk of recurrent UTI in non‑pregnant women, although this benefit was not seen after the treatment is stopped. They noted the low NNTs for recurrent infection compared with placebo (NNT 2 [range 2 to 3]). However, they also recognised the increased risk of harms with antibiotic prophylaxis compared with placebo.\n\nBased on evidence, the committee agreed that antibiotic prophylaxis was also effective in a mixed population of people with recurrent UTI, including pre‑ and postmenopausal women, men and children (NNT\xa03 [3 to 4]). However, interpretation of the evidence was more difficult due to variations in the populations studied and antibiotic choice, dosage and duration.\n\nThe committee discussed the evidence specifically in pregnant women, which found that antibiotic prophylaxis was effective in reducing the risk of recurrent asymptomatic bacteriuria in pregnant women (NNT\xa04 [range 3 to 13]). However, they recognised that the study had a number of limitations. The study was small and not powered to show any benefit in preterm births. The population was pregnant women who were admitted to hospital with acute pyelonephritis. The committee noted that nitrofurantoin is not an appropriate choice of antibiotic to show benefit in this population. They were also aware that UTI has been associated with developmental delay or cerebral palsy in the infant, and fetal death.\n\nTaking account of the benefits and harms of antibiotic prophylaxis and the need to minimise antimicrobial resistance, the committee agreed that antibiotic prophylaxis could be considered in people aged 16\xa0years and over with recurrent UTI, but only after other management options had been unsuccessful (behavioural and personal hygiene measures, managing any triggers and using non‑antimicrobial treatments), if appropriate.\n\nThe committee recognised the importance of reviewing antibiotic prophylaxis, and considered that up to every 6\xa0months was reasonable based on possible adverse effects of antibiotics, the risk of resistance with long-term antibiotics, the possible need for any further investigations if recurrence of UTIs continues, and to allow time to assess treatment success. People should also know to seek medical help if they experience symptoms of an acute infection despite taking prophylaxis.\n\nThe committee discussed the importance of the review and were aware of other conditions where a specific date is included on the prescription to prompt review within 6\xa0months.\n\nTo reduce the risk of antimicrobial resistance, the committee agreed that at each review women should be reminded about self-care, and consideration should be given to either stopping, continuing or changing antibiotic prophylaxis (for example, from single‑dose to daily prophylaxis). However the committee was not able to make specific recommendations about when to stop, continue or change antibiotic prophylaxis as it will depend on the circumstances of an individual person.\n\nBased on evidence that suggests antibiotic prophylaxis does not continue to be effective after stopping treatment, the committee agreed that if antibiotic prophylaxis was stopped, women should be able to access treatment rapidly if they have symptoms of an acute UTI.\n\nThe committee recognised the limitations of the evidence on antibiotic prophylaxis in pregnant women and men, and the lack of evidence to support the use of non‑antimicrobial treatments. Therefore, the committee agreed that it was appropriate to refer all pregnant women to an obstetrician if recurrent UTI is diagnosed during pregnancy. They also agreed that most men with recurrent UTI should be referred for further specialist urology investigation and management, taking an individualised approach that takes account of multimorbidity. The committee agreed that any decision to prescribe antibiotic prophylaxis in pregnant women or men should be under specialist advice.\n\nThe committee also recognised the higher risks associated with recurrent upper UTIs (pyelonephritis), and agreed that it was appropriate to refer these people for further specialist investigation and management.\n\nThe committee agreed that further consideration should be made for women with recurrent lower UTI if the underlying cause of recurrence was unknown or required further investigation. However, due to resource implications and the lower risk of complications for this population, the committee agreed that specialist advice should be sought, rather than specialist referral.\n\nThe committee was aware of the recommendation in the NICE guideline on suspected cancer: recognition and referral, which states that a non-urgent referral for bladder cancer should be considered for people over\xa060 with recurrent unexplained UTI.\n\nThe committee also recognised the equality considerations for managing recurrent UTI in transgender people, due to anatomical differences between women and men.\n\nThe committee was aware that the NICE guideline on urinary tract infection in under\xa016s makes recommendations on referring children and young people with recurrent UTI to a paediatric specialist for assessment and investigations.\n\nBased on evidence, the committee noted that antibiotic prophylaxis does not appear to be effective in reducing the risk of recurrent UTI in children. However, there was considerable uncertainty in the evidence (all very low quality).\n\nBased on their experience, the committee agreed that most cases of recurrent UTI in children and young people are due to a functional or structural abnormality of the urinary tract.\n\nTaking account of the uncertainty in the evidence and the need to minimise antimicrobial resistance from long-term antibiotic use, the committee agreed that antibiotic prophylaxis could be considered in children and young people under 16\xa0years, but only under specialist advice when other management options have been unsuccessful. This would be an individualised decision following an assessment of underlying causes, taking into account the severity and frequency of previous symptoms and the risk of developing complications.\n\nThe committee recognised the importance of reviewing antibiotic prophylaxis, and considered that every 6\xa0months was reasonable. They agreed that the same principles for the review in adults apply to children and young people.\n\n# Choice of antibiotic prophylaxis\n\nAntibiotic prophylaxis with nitrofurantoin (various doses: 100\xa0mg a day, 75\xa0mg a day, 50\xa0mg a day or 50\xa0mg twice a day) for at least 3\xa0months significantly reduced the risk of recurrent infection in a mixed population of adults (including non-pregnant women and men) and children (mainly females) compared with methenamine hippurate (NNT\xa07 [range 4 to 102]; low quality evidence). However, there was no significant difference between nitrofurantoin and either trimethoprim, beta-lactams or quinolones (very low to low quality evidence). This was based on a systematic review and meta‑analyses of RCTs (Muller et al.\xa02017).\n\nAntibiotic prophylaxis with nitrofurantoin (1 to 1.5\xa0mg/kg daily) for 6\xa0months significantly reduced the risk of having a positive urine culture at the end of the study period in children with recurrent UTI compared with trimethoprim (2 to 3\xa0mg/kg daily; NNT\xa03 [range 2 to 8]) and reduced the risk of having a recurrent symptomatic UTI compared with co‑trimoxazole (2\xa0mg/kg daily; NNT\xa06 [range 3 to 27]; very low to moderate quality evidence). However, there was no difference with nitrofurantoin compared with cefixime (2\xa0mg/kg daily; 6\xa0to\xa012\xa0months; moderate quality evidence). This was based on a systematic review of single RCTs (Williams and Craig\xa02011).\n\nOverall, antibiotic prophylaxis with nitrofurantoin (for at least 3\xa0months) increased the risk of mild (not defined) adverse effects compared with other antibiotics in a mixed population of adults and children (30.6% versus 11.7%; NNH\xa05 [range 4 to 6]; Muller et al. 2017; low quality evidence). When specific antibiotics were compared, there were significantly more mild adverse effects with nitrofurantoin compared with beta‑lactams (NNH 7\xa0[range 4 to 28]), trimethoprim (NNH 3 [range 2 to 4]) and methenamine (NNH 3 [range 2 to 6]), but no difference between nitrofurantoin and quinolones or co‑trimoxazole (Muller et al. 2017; very low to moderate quality evidence).\n\nIn children, there were significantly fewer adverse events with nitrofurantoin compared with trimethoprim (NNH 2 [range 1 to 8]), but significantly more adverse events with nitrofurantoin compared with cefixime (NNH 3 [range 2 to 6]; moderate quality evidence). This was based on a systematic review of single RCTs (Williams and Craig\xa02011).\n\nNo systematic reviews or RCTs were identified that included data on the choice of antibiotic in pregnant women.\n\n## Committee discussion on choice of antibiotic prophylaxis\n\nBased on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic prophylaxis should largely be driven by minimising the risk of resistance. Resistant bacteria are a particular concern in UTIs and, where possible, any previous urine culture and susceptibility results, and antibiotic prescribing for UTI, should be checked and antibiotics chosen accordingly.\n\nBased on their experience and resistance data, the committee agreed that a different antibiotic should be selected for antibiotic prophylaxis if an acute UTI is being treated. They also recognised that rotational use of antibiotics may be needed, based on local policies.\n\nThe committee discussed that, if antibiotic prophylaxis is needed to prevent an infection that is not life threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last‑line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. Broad-spectrum antibiotics need to be reserved for second-choice treatment of non-life-threatening infections when narrow-spectrum antibiotics are ineffective.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend trimethoprim or nitrofurantoin (based on culture and susceptibility results) as first choice antibiotics for prophylaxis. These antibiotics have less effect on the normal intestinal microflora in gastrointestinal tract, which is particularly important when continuous antibiotic prophylaxis is used.\n\n\n\nTrimethoprim should only be prescribed if a lower risk of resistance is likely, for example, if trimethoprim has not been used in the past 3\xa0months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment) and in younger women in areas where local epidemiology data suggest resistance is low. There is a higher risk of trimethoprim resistance with recent use and in older people in residential facilities. Trimethoprim is contraindicated in pregnant women.\n\nNitrofurantoin is not recommended for people with an estimated glomerular filtration rate (eGFR) of less than 45\xa0ml/minute. With long-term use, there is a lower risk of resistance of nitrofurantoin compared with trimethoprim, but this needs to be balanced against the increased harms, such as pulmonary fibrosis.\n\nThe committee was aware that nitrofurantoin suspension is currently substantially more expensive than trimethoprim suspension and, if both antibiotics are appropriate, the one with the lowest acquisition cost should be chosen.\n\n\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend cefalexin or amoxicillin (based on culture and susceptibility results) as second-choice antibiotics for prophylaxis.\n\n\n\nAmoxicillin and cefalexin are broad spectrum antibiotics that have a similar spectrum of activity and can be used if bacteria are susceptible.\n\n\n\nBased on evidence that methenamine hippurate was less effective than antibiotic prophylaxis with nitrofurantoin, the committee was not able to make a recommendation on its use. They were also aware that methenamine hippurate is a medicine that is considered less suitable for prescribing (BNF information on methenamine hippurate).\n\n# Antibiotic dosing and course length\n\nSingle-dose antibiotic prophylaxis (used when exposed to conditions that may trigger a UTI) was not significantly different to daily antibiotic prophylaxis in the number of women with at least 1\xa0recurrent infection over a 12‑month study period in postmenopausal women with recurrent UTI (3\xa0or more episodes in the past 12\xa0months; 80.6% versus 70.3%; moderate quality evidence). This was based on 1\xa0RCT (Zhong et al.\xa02011).\n\nThe conditions for using the single-dose antibiotic were determined by the woman's experience, such as walking for a long time or sexual intercourse. The choice of antibiotic (nitrofurantoin, amoxicillin, co‑trimoxazole, quinolones or cephalosporins) varied and was determined on a case by case basis, depending on the woman's previous antibiotic use and following an antibiotic susceptibility test.\n\nIn 1\xa0RCT (reported in a systematic review by Albert et al. 2004) single-dose ciprofloxacin (250\xa0mg) taken immediately after sexual intercourse was as effective as a daily dose in non-pregnant women in reducing the risk of recurrent UTI during the period of prophylaxis (Albert et al. 2004; low quality evidence).\n\nThere were significantly fewer adverse events with single-dose antibiotic prophylaxis compared with daily antibiotic prophylaxis (NNH\xa03 [range 2 to\xa09]; Zhong et al. 2011; moderate quality evidence).\n\nThere was no significant difference in the number of non-serious adverse effects between those who took a single dose of ciprofloxacin (250\xa0mg) immediately after sexual intercourse, or daily at night (Albert et al. 2004; low quality evidence).\n\n## Committee discussions on antibiotic dosing and course length\n\nBased on evidence, the committee was aware that a range of doses and course lengths were used for daily antibiotic prophylaxis. The committee agreed that usual BNF doses for daily prophylaxis should be used. The duration of treatment needs to be determined on an individual basis with a review of treatment success within 6\xa0months, to include discussion of a trial of stopping antibiotic prophylaxis as appropriate.\n\nThe committee discussed the evidence for using single‑dose antibiotic prophylaxis (including post-coital single‑dose antibiotics) in non‑pregnant women. The committee agreed that the single dose used when exposed to an identifiable trigger would be the same as a single treatment dose for a UTI.\n\nBased on evidence, their experience and antimicrobial resistance data, the committee agreed that single-dose prophylaxis was as effective as continuous prophylaxis, with fewer adverse effects in non‑pregnant women with an identifiable trigger, and should be considered as the first option for antibiotic prophylaxis in this group of women. Prophylaxis needs to be tailored to an individual woman's personal triggers, and advice given about how to use the antibiotic. Antibiotics for single-dose prophylaxis would be kept at home to avoid unnecessary GP and pharmacy visits.\n\nNo evidence from systematic reviews and RCTs was identified for using a course of antibiotics to keep at home for treating an acute UTI in people with recurrent UTIs (also known as stand‑by antibiotics). The use of stand‑by antibiotics could potentially lead to inappropriate antibiotic overuse in the absence of medical supervision, which would not reflect the principles of antimicrobial stewardship. Therefore, while the committee recognised that they may have a role in some specialist cases, they were not able to make a recommendation on their use.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require regular dosing or longer treatment duration (for example, continuous antibiotic prophylaxis). See the NICE guideline on medicines adherence.\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations, see the Drug Tariff for costs.\n\nNitrofurantoin 25\xa0mg/5\xa0ml oral suspension is more expensive than other oral suspensions, such as trimethoprim 50\xa0mg/5\xa0ml. The cost of a 300‑ml bottle of nitrofurantoin is £446.95 compared with £4.87 for a 100‑ml bottle of trimethoprim (Drug Tariff, September\xa02018).'}
|
https://www.nice.org.uk/guidance/ng112
|
This guideline sets out an antimicrobial prescribing strategy for preventing recurrent urinary tract infections in children, young people and adults who do not have a catheter. It aims to optimise antibiotic use and reduce antibiotic resistance.
|
4a5a1f28593886e1b06e22881f875153823f6076
|
nice
|
Romiplostim for the treatment of chronic immune thrombocytopenia
|
Romiplostim for the treatment of chronic immune thrombocytopenia
Evidence-based recommendations on romiplostim (Nplate) for treating chronic immune thrombocytopenia in adults.
# Guidance
Romiplostim is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:
their condition is refractory to standard active treatments and rescue therapies or
they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies. Romiplostim is recommended only if the company makes it available with the discount agreed in the patient access scheme.
These recommendations are not intended to affect treatment with romiplostim that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Romiplostim (Nplate, Amgen) is a protein that mimics the action of thrombopoietin by acting as an agonist at thrombopoietin receptors. It stimulates the differentiation and proliferation of bone marrow cells responsible for producing platelets (megakaryocytes), thereby increasing platelet production and platelet counts (concentrations). Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterised by increased platelet destruction and, in some cases, inadequate platelet production. The disorder can result in low platelet counts and bleeding. Chronic ITP is defined as that which lasts longer than 12 months. Clinicians in the UK treat people with ITP as needed with 'rescue therapies' (corticosteroids, intravenous immunoglobulins and platelet infusions) and thereafter, as needed, with 'active treatments' (rituximab, immunosuppressive agents including azathioprine, mycophenolate mofetil and ciclosporin, danazol, dapsone, and cytotoxic agents including cyclophosphamide and vinca alkaloids). Romiplostim has a marketing authorisation 'for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients 1 year of age and older who are refractory to other treatments (e.g. corticosteroids, immunoglobulins)'.
The summary of product characteristics (SPC) states that the recommended initial dose of romiplostim is 1 microgram/kg of actual body weight, administered once weekly as a subcutaneous injection. The dose may be increased by increments of 1 microgram/kg until a platelet count equal to or above 50 × 109 platelets per litre of blood is reached. A maximum dose of 10 micrograms/kg once weekly should not be exceeded. Platelet counts should be measured weekly until a stable count equal to or above 50 × 109 platelets per litre is observed for at least 4 weeks without adjusting the dose. Thereafter, platelet counts should be measured monthly. Treatment with romiplostim should be stopped if the platelet count does not increase sufficiently to avoid clinically significant bleeding after 4 weeks of romiplostim therapy at the highest weekly dose of 10 micrograms/kg. Romiplostim should also be stopped if a peripheral blood smear indicates increased bone marrow reticulin as well as if a loss of efficacy is observed. For full details of dose and administration, see the SPC.
The SPC lists special warnings and precautions for the use of romiplostim, including: recurrence of thrombocytopenia and bleeding after stopping treatment; increased bone marrow reticulin; thrombotic and/or thromboembolic complications (described by the SPC as a 'theoretical risk' from platelet counts above the reference range); and loss of response (which could result from immunogenicity or increased bone marrow reticulin). The SPC lists headache as a 'very common' undesirable effect. For full details of side effects and contraindications, see the SPC.
The SPC states that romiplostim is supplied in both 500 microgram and 250 microgram vials. However, only 250 microgram vials are available in the UK. Romiplostim costs £1.93 per microgram, so a 250 microgram vial costs £482 (excluding VAT; 'British national formulary' edition 60). The cost of treatment varies depending on the patient's weight and the dosing regimen. The cost will also be affected by any waste that results from discarding any unused drug from the single use of a 250 microgram vial. The SPC states that romiplostim is a sterile but unpreserved product and therefore is intended for single use only. The annual cost of romiplostim treatment for a person weighing 80 kg would be £8020 at a dose of 1 microgram/kg weekly and £80,204 at a dose of 10 micrograms/kg weekly (assuming no waste). The manufacturer of romiplostim (Amgen) has agreed a patient access scheme with the Department of Health which makes romiplostim available with a discount on the 250 microgram vial. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of romiplostim and a review of this submission by the Evidence Review Group (ERG; appendix B).
# Clinical effectiveness
The manufacturer's submission compared romiplostim in addition to standard care with standard care alone for patients with ITP who had undergone splenectomy and, separately, for patients with ITP who had not undergone splenectomy. Evidence was obtained from two double-blind placebo-controlled randomised controlled trials (RCTs) of romiplostim in addition to standard care (defined as prednisone, azathioprine and danazol) compared with standard care alone. One RCT enrolled patients with ITP who had undergone splenectomy (42 patients were assigned to romiplostim and 21 to placebo). The other RCT enrolled patients with ITP who had not undergone splenectomy, but who did not necessarily have a contraindication to splenectomy (41 patients were assigned to romiplostim and 21 to placebo).
In both RCTs, patients with ITP (defined as the mean of three platelet counts being below or equal to 30 × 109 per litre, with none of the three counts being above 35 × 109 per litre) whose condition was refractory to at least one previous treatment were randomised to romiplostim plus standard care or to standard care alone (placebo) for 24 weeks. The mean platelet count at baseline in the trials was 18 × 109 per litre in the non-splenectomised group and 15 × 109 per litre in the splenectomised group. Romiplostim was given weekly. Platelet counts were monitored and the dose of romiplostim was adjusted to achieve and maintain a platelet count of between 50 × 109 and 200 × 109 per litre. Investigators could increase the dose by 2 micrograms/kg each week (for platelet counts of 10 × 109 per litre or below) or every 2 weeks (after 2 consecutive weeks of platelet counts between 10 × 109 and 50 × 109 per litre). The dose remained stable for platelet counts above 50 × 109 per litre. If a patient's platelet count reached 50 × 109 per litre or more and subsequently fell, the maintenance dose could be increased by 1 microgram/kg each week (if the platelet count fell to 10 × 109 per litre or below) or by 1 microgram/kg every 2 weeks (if the platelet count fell to between 10 × 109 and 50 × 109 per litre for 2 consecutive weeks). The maximum dose permitted in the trial was 15 micrograms/kg, which exceeds the maximum dose of 10 micrograms/kg recommended in the SPC.
No studies were found that compared romiplostim with a specified sequence of active treatments or rescue therapies for the treatment of ITP. Concurrent active treatments or rescue therapies for ITP in trials were given at the investigators' discretion. Six non-RCTs investigating the safety of romiplostim and one open-label extension study of the phase III RCTs were reported in the manufacturer's submission. In the latter, patients treated with romiplostim or placebo who had completed the phase III study and other clinical studies, and whose platelet counts had fallen below 50 x 109 per litre after stopping romiplostim or placebo, were eligible to enrol in the study and to receive open-label romiplostim. Data from patients going into this extension study were used to calculate time to failure for romiplostim, as this could not be calculated from the phase III studies alone because the interventions ended after 24 weeks.
The primary endpoint for the two RCTs was the incidence of a durable platelet response, defined as a platelet count of at least 50 × 109 per litre in at least six weekly assessments in the last 8 weeks of treatment without the use of rescue therapies. Rescue therapies included corticosteroids (oral or intravenous), intravenous immunoglobulin (IVIg) and intravenous anti-D immunoglobulin. Other outcomes were: incidence of an overall platelet response (either a durable or a transient platelet response, where a transient response is defined as a platelet count of at least 50 × 109 per litre in at least four weekly assessments during weeks 2 to 25 of treatment, with no weekly response eligible within 8 weeks of the use of rescue therapies, and in the absence of a durable response); time to platelet response (Kaplan–Meier estimated time to first platelet response); duration of platelet response; use of rescue therapies; mortality; adverse events; and health-related quality of life. The primary and secondary outcomes were analysed prospectively. Time to failure (that is, time to stopping romiplostim) and bleeding events were analysed retrospectively.
In the RCT of splenectomised patients, 16 of 42 patients (38.1%) in the romiplostim group and none of 21 patients in the placebo group had a durable platelet response. Thirty-three patients (78.6%) in the romiplostim group had an overall platelet response. The median time to the first platelet response was 3 weeks. No patients in the placebo group had an overall platelet response. The mean number of weeks with a platelet count equal to or above 50 x 109 per litre (in a study period of 24 weeks) was 12.3 weeks for the romiplostim group and 0.2 weeks for the placebo group (p < 0.0001). Eleven patients (26.2%) in the romiplostim group and twelve patients (57.1%) in the placebo group received rescue therapies during the treatment period (odds ratio 0.3; 95% confidence interval 0.1 to 0.8; p = 0.02). There were no deaths in the romiplostim group. Three patients in the placebo group died; the causes of death were pneumonia (after the end of the study), pulmonary embolism and cerebral haemorrhage.
The manufacturer's submission stated that in the RCT of non-splenectomised patients, 25 of 41 patients (61.0%) in the romiplostim group and one of 21 patients (4.8%) in the placebo group had a durable platelet response (odds ratio 24.5; 95% CI 3.3 to 179.2; p < 0.0001). Thirty-six patients (87.8%) in the romiplostim group and three patients (14.3%) in the placebo group had an overall platelet response (odds ratio 34.7; 95% CI 7.8 to 155.4; p < 0.0001). The median time to the first platelet response was 2 weeks. The mean number of weeks with a platelet count equal to or above 50 x 109 per litre (in a study period of 24 weeks) was 15.2 weeks for the romiplostim group and 1.3 weeks for the placebo group (p < 0.0001). Seven patients (17.1%) in the romiplostim group and 13 patients (61.9%) in the placebo group received rescue therapies during the treatment period. One patient in the romiplostim group and no patients in the placebo group died. The cause of death was intracranial haemorrhage 2 weeks after stopping romiplostim. All patients included in both RCTs received at least one dose of either romiplostim or placebo. One non-splenectomised patient randomly assigned to placebo received three doses of romiplostim in error and was included in the safety analysis as a patient given romiplostim and in the efficacy analysis as a patient randomised to placebo.
The manufacturer's submission reported results for bleeding events, adverse events and health-related quality-of-life outcomes pooled from the two RCTs. These showed that 45 of 84 patients (54%) in the combined romiplostim groups (a revised figure of 48 of 84 was given in the Evidence Review Group report using data provided by the manufacturer following a request for clarification) and 25 of 41 patients (61%) in the combined placebo groups experienced at least one bleeding event of any severity. A serious bleeding event, as defined by the regulatory protocol (which includes, but may not be limited to, any event that: is fatal, is life threatening , needs in-patient hospitalisation or prolongation of existing hospitalisation, or is a persistent or significant disability or incapacity), was reported for 5 of 84 patients (6%) in the combined romiplostim groups and 4 of 41 patients (10%) in the combined placebo groups. Bleeding of grade 3 or above (rated as severe, life threatening or fatal) occurred in 6 of 84 patients (7%) in the combined romiplostim groups and 5 of 41 patients (12%) in the combined placebo groups. Bleeding events of grade 2 or above (rated as moderate, severe, life threatening or fatal) occurred in 13 of 84 patients (15%) in the combined romiplostim groups and 14 of 41 patients (34%) in the combined placebo groups.
Data on safety were derived from combined results from the two RCTs and seven case series, which included dose-finding studies, an open-label extension study (that included patients from other romiplostim studies), a study of patients with severe refractory ITP and a bone marrow morphology substudy. Both the incidence and event rates adjusted for study duration for all adverse events that occurred during treatment were calculated. Safety data were submitted as academic-in-confidence information by the manufacturer.
Data on health-related quality of life from the two phase III RCTs included data from EuroQol 5-D (EQ-5D) and from the ITP Patient Assessment Questionnaire, which is a disease-specific instrument comprising 10 scales. Statistically significant differences between health-related quality of life were not reported in the manufacturer's original submission. In a revised submission, the manufacturer provided a linear regression analysis of combined EQ-5D data from both RCTs, which showed statistically significant differences favouring romiplostim compared with placebo in the mean change in EQ-5D score. Combined data from both RCTs for the change from baseline using the ITP Patient Assessment Questionnaire indicated a statistically significantly greater (p < 0.05) improvement in the 'Symptoms', 'Bother', 'Social Activity' and 'Women's Reproductive Health' scales in the romiplostim group than the placebo group for splenectomised patients. For non-splenectomised patients, those in the romiplostim group had a statistically significantly greater improvement in the 'Activity' scale than those in the placebo group.
The manufacturer did not identify any RCTs on the effectiveness of comparator treatments used in standard care for ITP compared with romiplostim, as defined in the scope of this appraisal. These included corticosteroids, IVIg, rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil and ciclosporin), anti-D immunoglobulin and splenectomy for non-splenectomised patients, and corticosteroids, IVIg, rituximab and immunosuppressive agents for splenectomised patients. The manufacturer assessed clinical guidelines, systematic reviews, trials and observational studies for evidence on the effectiveness of comparator treatments and found mostly case series. The manufacturer combined data on efficacy from different studies that examined the same treatment by a method described in the manufacturer's submission as 'taking a weighted average, weighting by sample size'. The number of studies combined in this way varied by treatment.
# Cost effectiveness
## Original economic model
The manufacturer submitted an original economic model and, after consultation on the first appraisal consultation document (ACD), a revised model. The manufacturer's original cohort-type economic model used a lifetime horizon and assessed the impact of romiplostim separately for patients with ITP who had undergone splenectomy and those who had not. The model assumed that all patients started with a platelet count below 50 × 109 per litre. Romiplostim was compared with standard care in a model structure in which patients initially either enter 'watch and rescue' (treated as necessary with intravenous immunoglobulin, anti-D immunoglobulin or intravenous corticosteroids) or are treated with romiplostim followed by 'watch and rescue'. In the model, patients move through a care pathway consisting of active treatments and 'watch and rescue'. When a patient becomes refractory to an active treatment they receive 'watch and rescue'. The active treatments modelled in the remainder of the care pathway were rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone and cytotoxic agents (such as cyclophosphamide and vinca alkaloids).
The manufacturer built seven health states into the model. The manufacturer conducted a utility survey with the primary objective of directly measuring health utility values for these ITP health states as perceived by members of the public in the UK. Respondents were presented with descriptions of each ITP health state, and utility values for five of the seven health states were derived using the time trade-off method. The utility values for these five health states were: 0.863 for platelet count above 50 × 109 per litre and no bleed; 0.734 for platelet count above 50 × 109 per litre and outpatient bleed; 0.841 for platelet count below 50 × 109 per litre and no bleed; 0.732 for platelet count below 50 × 109 per litre and outpatient bleed; 0.038 for platelet count below 50 × 109 per litre and intracranial haemorrhage. For the remaining two health states included in the model (low platelet count with gastrointestinal bleed and low platelet count with other bleeding events requiring hospitalisation) the manufacturer used a utility value of 0.54 taken from the literature.
The manufacturer divided use of resources and costs into 4-week cycles. Costs of treatment included those of the romiplostim vials, laboratory testing to check blood counts every cycle (four tests), physician appointments (two sessions), and other drugs. Costs of management of bleeds included those for minor bleeds treated in an outpatient setting, intracranial haemorrhage, gastrointestinal bleeds and other bleeds requiring hospitalisation.
Other costs for drugs used in treatment and in managing bleeds were taken from the BNF (edition 55) and NHS reference costs.
The manufacturer's base-case analyses using the original economic model gave incremental cost-effectiveness ratios (ICERs) of £14,633 per quality-adjusted life year (QALY) gained for non-splenectomised patients and £15,595 per QALY gained for splenectomised patients, when using romiplostim as a first-option treatment compared with 'watch and rescue' standard care and with a target platelet count of 50 × 109 per litre. These ICERs reflected new inputs added to the model at the request of the ERG during the clarification step.
Sensitivity analyses performed by the manufacturer using the original economic model, in response to a request for clarification from the ERG, included the effects of: changes in drug costs to account for vial wastage in practice; the use of EQ-5D data available from the RCTs for serious adverse events; the cost of a bone marrow assessment needed when the condition no longer responds to romiplostim; and the cost of blood film tests (which are needed before treatment with romiplostim can begin).
The manufacturer, in response to a request for clarification from the ERG, also performed a sensitivity analysis in which it assumed a target platelet count of 30 × 109 per litre (instead of 50 × 109 per litre). This gave ICERs of £14,840 per QALY gained for non-splenectomised patients and £14,655 per QALY gained for splenectomised patients using romiplostim as a first-option treatment compared with 'watch and rescue'.
The manufacturer estimated that the probability that romiplostim would be cost effective using a target platelet count of 50 × 109 per litre at different acceptability threshold levels of £10,000, £20,000 and £30,000 per QALY gained was 10%, 60% and 81% respectively for non-splenectomised patients (mean ICER £14,633 per QALY gained), and 25%, 55% and 77% respectively for splenectomised patients (mean ICER £15,595 per QALY gained).
The ERG noted that limited evidence was available for romiplostim and potential comparators for the treatment of patients with chronic ITP, and particularly for long-term outcomes. The ERG also considered that the evidence for comparators did not distinguish between patients who had not undergone splenectomy and splenectomised patients. The ERG was particularly concerned about the methods the manufacturer had used to estimate the efficacy of romiplostim and the comparators, while acknowledging that using formal methods may also have been inappropriate. The ERG was not presented with further evidence that would have significantly altered the results presented in the manufacturer's original submission.
The ERG performed explorative sensitivity analyses using the manufacturer's original economic model. The one-way sensitivity analysis that had the most effect on the ICER was that in which the cost of romiplostim was adjusted to account for wastage from single-use vials that would occur in practice. On changing the number of vials from 0.93 to 1 for non-splenectomised patients, the ICER increased from £14,633 to £21,214 per QALY gained. For splenectomised patients, a change in the number of vials from 1.4 to 2 increased the ICER from £15,595 to £91,406 per QALY gained. The ERG carried out multivariate analyses which combined sensitivity analyses conducted by the ERG with those provided by the manufacturer. When patients entered the model on active treatment (rituximab) in the comparator arm (rather than 'watch and rescue') the ERG reported ICERs that increased from £14,633 to £21,674 per QALY gained for non-splenectomised patients and from £15,595 to £29,771 per QALY gained for splenectomised patients. When patients entered the model on active treatment (with rituximab) and the cost of romiplostim was adjusted to account for wastage, the ICER increased from £16,633 to £28,556 per QALY gained for non-splenectomised patients and from £15,595 to £109,802 per QALY gained for splenectomised patients. In a multivariate analysis that incorporated EQ-5D data from the RCTs rather than the utility values originally provided by the manufacturer, the cost of romiplostim adjusted to account for wastage, a 50% reduction in serious adverse events and the cost of bone marrow tests and blood film assessments, the ICERs increased from £14,633 to £37,290 per QALY gained for non-splenectomised patients and from £15,595 to £131,017 per QALY gained for splenectomised patients.
## Revised economic model
After consultation on the first ACD, the manufacturer provided revised analyses of the cost effectiveness of romiplostim that addressed a number of the key issues that were raised by the Committee in the first ACD.
In the manufacturer's revised base-case analysis, it was assumed that 59% of patients in the comparator group start on rituximab and the remaining 41% start on another active treatment in the pathway (that is, immunosuppressive agents, dapsone, danazol and cytotoxic agents). Once an active treatment fails, and before the next active treatment is used, the model assumes that a patient enters a period of 'watch and rescue'.
The manufacturer took into account potential vial wastage of romiplostim and the fact that patients in the trials received doses that were higher than the maximum dose recommended in the SPC of 10 micrograms/kg. The manufacturer stated that six of the 42 patients in the trial of splenectomised patients were given more than 10 micrograms/kg romiplostim, and one of these showed a response to treatment. In the trial of non-splenectomised patients, two of the 41 patients received more than 10 micrograms/kg romiplostim, one of whom showed a response to treatment. In the cost-effectiveness analyses, the manufacturer provided two base-case scenario analyses: a 'conservative' scenario and a 'realistic' scenario. In both scenarios, all patients who received more than 10 micrograms/kg romiplostim were modelled as 'non-responders'. In the conservative scenario, the costs of continuing treatment at doses above 10 micrograms/kg were included in the model. In the realistic scenario, romiplostim costs were capped at 10 micrograms/kg.
The manufacturer pooled two sources of utility data: the individual patient level EQ-5D utility values from the two RCTs, and individual person level utility values from the time trade-off study (see section 3.12). The two resulting utility values that differed from the manufacturer's original utility values (based on the time trade-off study) were 0.835 for patients with a platelet count above 50 × 109 per litre and no bleed, and 0.800 for patients with a platelet count below 50 × 109 per litre and no bleed.
The manufacturer included the costs of bone marrow tests and blood film assessments associated with treatment with romiplostim in the revised analyses. The manufacturer also accounted for reductions in the number of blood counts and patient visits to clinicians.
The manufacturer submitted a patient access scheme, which is a discount on the 250 microgram vial of romiplostim, and provided four cost-effectiveness analyses: for the use of the 250 microgram vial with and without the patient access scheme, and for the use of a 100 microgram vial with and without the patient access scheme. This document only details the results for the use of the 250 microgram vial with the patient access scheme.
The manufacturer's revised base-case ICERs for the non-splenectomised group, incorporating all of the above assumptions and the patient access scheme, were £24,795 and £28,278 per QALY gained for the realistic scenario and the conservative scenario respectively. The ICERs for the splenectomised group were £4615 and £16,530 per QALY gained for the realistic scenario and the conservative scenario respectively.
The ERG reviewed the manufacturer's revised base-case analysis, and noted that uncertainty remained about which active treatment best reflects UK clinical practice. The ERG highlighted that the manufacturer's model describes a defined sequence of treatments, and questioned whether it was reasonable to exclude some treatments in the comparator arm. The ERG performed analyses using the manufacturer's revised base-case model and noted that a patient who enters the comparator arm of the model spends most time on 'watch and rescue' rather than on any other treatment. The ERG noted that any change in the model structure that reduces the amount of time a patient spends in 'watch and rescue' would increase the ICERs for romiplostim.
The ERG expressed concerns about the methods by which the manufacturer calculated the utility values in its revised base-case analysis. The ERG noted that the manufacturer simply aggregated the two utility measures, without considering whether it was appropriate to combine data from two different tools and two different samples. The ERG questioned whether the EQ-5D data derived directly from the trials might provide the best estimates of utility values.
The ERG reviewed the approach taken by the manufacturer to account for patients who received doses of romiplostim above the maximum dose stated in the SPC. The ERG noted that patients lost to follow-up in the trials may not have had the same outcomes as patients not lost to follow-up, which could affect the calculation of time to failure. Censored patients were defined as 'lost to follow-up' in the evaluation of time to failure for romiplostim, and were those who had a last observed visit that was not recorded as a withdrawal in the open-label extension study. The ERG expressed further concerns about the assumption that romiplostim extends life, and about the generalisability and applicability of the trial results to a typical NHS population of patients with ITP. The ERG identified no additional evidence that would reduce this uncertainty.
The ERG conducted an exploratory analysis using the manufacturer's 'realistic' scenario, to test the impact of a 10% increase in the average number of 250 microgram vials of romiplostim used. For splenectomised patients the ICER rose from £4615 to £20,340 per QALY gained, and for non-splenectomised patients the ICER rose from £24,795 to £34,410 per QALY gained. The ERG also noted that if there was lower usage of romiplostim in NHS clinical practice than is reflected in the values included in the manufacturer's model the ICERs for romiplostim would decrease.
The ERG explored the impact of reducing the duration of the response to romiplostim in the model by 10%, 20% and 30%. When this was reduced by 30%, the ICER rose from £4615 to £6138 per QALY gained for splenectomised patients, and from £24,795 to £25,363 per QALY gained for non-splenectomised patients.
The ERG conducted one-way sensitivity analyses by varying individual parameters in the revised base-case model to check the impact on the ICERs. These changes included increasing the use of comparator treatments by 25%; increasing the response time for comparators by 50%; increasing response rates for comparators by 25%; reducing the use of rescue therapies to 80% of the base case in both the comparator and romiplostim arms; using alternative utility values; and assuming a 'worst case scenario' in which all patients who were censored in the open-label extension study were assumed to have no longer responded to romiplostim and were treated as withdrawals. The change in the use of rescue therapies had the greatest impact, increasing the ICERs from £24,795 to £35,248 per QALY gained for non-splenectomised patients and from £4615 to £32,190 per QALY gained for splenectomised patients. The ERG noted that when all patients who were censored in the open-label extension study were assumed to have no longer responded to romiplostim and were treated as withdrawals, the ICERs rose from £24,795 to £31,601 per QALY gained for non-splenectomised patients and from £4615 to £18,647 per QALY gained for splenectomised patients.
The ERG performed a multi-way sensitivity analysis to show the impact on the ICERs of the cumulative effects of varying all individual parameters explored in the one-way sensitivity analyses (see section 3.33). The ICER for splenectomised patients rose from £4615 to £64,646 per QALY gained, and that for non-splenectomised patients rose from £24,795 to £55,470 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of romiplostim, having considered evidence on the nature of chronic ITP and the value placed on the benefits of romiplostim by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the clinical signs and symptoms associated with chronic ITP. The Committee heard that the signs and symptoms associated with low platelet counts vary, and that bleeding and bruising can have a considerable impact on the daily activities of people with chronic ITP, may attract a social stigma associated with the appearance of bruises, and can limit lifestyle choices. The Committee heard that many people with ITP experience fatigue, but that there is no clear relationship between fatigue and platelet count or haemoglobin concentration. The Committee understood that anxiety about the risk of bleeding can affect a person's quality of life and the ability to work, travel and/or undertake leisure activities. The Committee understood from patient experts that a bleed could result in a person seeking medical care to receive rescue therapies, and if the bleeding was severe the person could need hospitalisation.
The Committee discussed the clinical management of chronic ITP. It noted that the pathway of care for chronic ITP varies depending on the person's circumstances, and that no single standard treatment pathway is used in routine practice. The Committee heard from the clinical specialists that, in the UK, first-line treatment for chronic ITP is considered to be corticosteroids (or intravenous immunoglobulin for people for whom corticosteroids are contraindicated), also referred to as rescue therapy. The clinical specialists estimated that approximately 30% of people would enter remission after such first-line treatment. The Committee heard from the clinical specialists that, for chronic ITP that does not respond to rescue therapy, active treatments are considered as second-line treatment including rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone, and cytotoxic agents (cyclophosphamide, vinca alkaloids). The clinical specialists explained that clinicians increasingly prescribe rituximab as the first choice of active treatment (for approximately 50–60% of patients who need active treatment), and this leads to remission in approximately 50% of people treated. However, the clinical specialists noted that these people will, in general, eventually relapse and need further treatment. The clinical specialists also stated that azathioprine would be used for people whose condition is refractory to rituximab or who are intolerant of rituximab, but that cyclophosphamide and ciclosporin were considered too toxic, and that people do not tolerate vinca alkaloids and danazol well and were considered unlikely to benefit from them. The Committee understood that people receiving active treatments for ITP would need monitoring and would still be likely to need rescue therapies from time to time.
The Committee understood that people who have certain treatments (intravenous immunoglobulin, corticosteroids and immunosuppressive agents) over long periods of time will experience adverse effects that can lead to chronic conditions, including infections, diabetes mellitus, an increased risk of gastrointestinal bleeds, and hypertension. The Committee heard that some people may need knee or hip replacements as a result of the side effects of long-term use of corticosteroids. The Committee understood from comments made by consultees and commentators in response to the first ACD that the consequences of treatment with alkylating agents (such as cyclophosphamide and vinca alkaloids) can include malignancies and fertility problems.
The Committee discussed when a person with chronic ITP would receive treatment and heard from the clinical specialists that a person's platelet count alone does not determine whether or not he or she receives treatment, and that clinicians take into account the person's symptoms (such as fatigue) and risk of bleeding. Overall, the Committee understood from the clinical specialists that the lower a person's platelet count, the more likely a clinician is to offer treatment, but that treatment is not usually offered unless absolutely necessary because of the side effects of many of the current treatments. Active treatments are more likely to be considered for people with severe symptoms or who are at high risk of bleeding, and in particular when rescue therapies are failing to produce satisfactory platelet counts or relief of symptoms. The Committee heard that people with a platelet count of between 20 × 109 and 30 × 109 per litre would rarely be offered an active treatment in the UK unless they had a significant bleed. The clinical specialists and patient experts informed the Committee that in clinical practice a platelet count of between 10 × 109 and 20 × 109 per litre would be the level at which clinicians would be likely to begin active treatment. A separate group of people who may be considered for active treatments at higher platelet counts would be those, for example, who needed aspirin therapy for cardiovascular disease. For people without severe symptoms and who are not perceived to be at high risk of bleeding, the preferred approach would be a strategy of 'watch and rescue' (with 'rescue' intervention dictated by the frequency of bleeding episodes) rather than an active treatment. The Committee heard from the clinical specialists that only people who are classed as having severe ITP would receive an active treatment, and this accounts for approximately 5–10% of people with chronic ITP. The Committee concluded that, in UK clinical practice, treatment for people with chronic ITP is dictated by the severity of symptoms, in particular bleeding.
The Committee discussed the place of romiplostim in the pathway of care for people with chronic ITP, and considered the appropriate comparators. It noted that the licensed indication for romiplostim for people who have undergone splenectomy is restricted to people who are refractory to other treatments such as corticosteroids and immunoglobulin, and also that romiplostim may be considered as a second-line treatment for people with a contraindication to splenectomy. The Committee understood that there are few treatments licensed for the treatment of chronic ITP. The Committee heard from the clinical specialists that the place of romiplostim in clinical practice would be for people whose condition is refractory to rituximab, or who are intolerant of rituximab.
The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of romiplostim compared with placebo and standard care. It was mindful that the evidence was mainly derived from two small placebo-controlled RCTs. The Committee noted that romiplostim significantly improved platelet count (the response measure used in the trials) and reduced the frequency of bleeding – particularly the occurrence of moderate and severe bleeding episodes. However, the Committee was mindful that these two RCTs did not provide clear evidence about the relative effectiveness of romiplostim compared with the active comparator treatments listed in the scope for the appraisal. The Committee noted that the manufacturer took a pragmatic rather than a systematic approach when collecting evidence for comparator treatments because of heterogeneity among studies of the comparators and because many of the comparators do not have a marketing authorisation for the treatment of ITP. The Committee also noted that data related to certain outcomes, such as the time to failure and the mean response time for romiplostim, had been generated by the manufacturer from a non-comparative open-label study. The Committee acknowledged comments received from consultees and commentators in response to consultation on the first ACD that highlighted the difficulty of conducting comparative trials with romiplostim, mainly because ITP is a rare and heterogeneous disease. The Committee heard from the clinical specialists that the population in the trials had the most severe ITP, which is estimated as representing 1–4% of people with chronic ITP, and were at high risk of bleeding and therefore needed high levels of rescue therapies throughout the trial. The Committee was aware of the limitations of the evidence on clinical effectiveness provided by the small RCTs, but considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP who are at high risk of bleeding and need repeated and frequent courses of rescue therapies.
The Committee then discussed the adverse effects associated with romiplostim. It noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee heard from the clinical specialists that romiplostim may have benefits over other active treatments because it produces a sustained platelet response during treatment, it can be continued for a longer time than other active treatments, it can be used in a wider population, and because adverse effects limit both the use and duration of other active treatments. The Committee noted from comments received from consultees and commentators in response to consultation on the first ACD that romiplostim has a different mode of action from current treatments for chronic ITP. The clinical specialists stated that romiplostim represents a 'step-change' for the treatment of ITP, in that it does not have immunosuppressive properties. The Committee also considered comments from consultees and commentators in response to consultation on the second ACD about setting a stopping rule for romiplostim, but noted that the modelling of the cost effectiveness for romiplostim did not include analyses addressing stopping. The Committee was also aware that the SPC specifies conditions under which to stop treatment with romiplostim. The Committee concluded that romiplostim has a novel mechanism of action (as a thrombopoietin receptor agonist) and a good adverse-effect profile, particularly in comparison with currently available treatments.
The Committee next considered the revised economic model submitted by the manufacturer that included the patient access scheme. The Committee agreed with the new approach taken by the manufacturer, wherein the comparator arm of the model started with active treatments instead of 'watch and rescue' and the costs of bone marrow tests and blood film assessment were included in the cost of treatment with romiplostim. The Committee noted that it would have been preferable to see romiplostim modelled after rituximab, which is where the clinical specialists currently position romiplostim in the treatment pathway for ITP, but recognised that this was not the case at the time of the consultation on the first ACD. The Committee considered the ERG's comments on the manufacturer's revised base-case analysis that included the patient access scheme, and noted that the ERG considered the approaches taken by the manufacturer in the revised analyses to being generally reasonable.
The Committee considered the ICERs in the manufacturer's revised base-case analysis that included the patient access scheme. For non-splenectomised patients the ICERs were £24,800 and £28,300 per QALY gained for the realistic and conservative scenarios respectively. For splenectomised patients the ICERs were £4620 and £16,500 per QALY gained for the realistic and conservative scenarios respectively.
The Committee noted that the median dose of romiplostim used in the RCTs was 3 micrograms/kg for splenectomised patients and 2 micrograms/kg for non-splenectomised patients, and heard from the clinical specialists that these doses reflect clinical practice. The Committee discussed the number of vials used in the realistic and conservative scenarios presented by the manufacturer. It heard from the clinical specialists that although they would not use doses as high as those given in the trials, there may be some instances where the entire contents of a vial of romiplostim would be used, rather than wasting some, and so the dose may occasionally exceed the maximum dose specified in the SPC. Therefore the Committee concluded that the most plausible scenario would be somewhere between the realistic and conservative scenarios modelled by the manufacturer.
The Committee noted that in clinical practice it would be rare for clinicians to use doses of romiplostim that were aimed at obtaining a platelet count above 50 × 109 per litre (as was the case in the trials). Therefore, in practice, aiming for a lower target platelet count would mean less frequent use of romiplostim, and lower doses of romiplostim when it is used. The Committee noted that, in the ERG's exploratory analyses, the ICERs were sensitive to a change in the number of vials used, and concluded that romiplostim would be more cost effective if less romiplostim was used in clinical practice than was assumed in the model.
The Committee considered the estimates of the effectiveness of the comparators assumed in the model, and heard from the clinical specialists that these estimates seemed reasonable and reflected clinical practice. The Committee noted that the model did not sufficiently account for long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs of romiplostim would have been lower.
The Committee noted that the submitted model assumed that treatment with romiplostim extended the life of people with chronic ITP by 2.92 and 2.03 years for the non-splenectomised and splenectomised groups respectively. The Committee noted that the survival advantage associated with romiplostim resulted from avoiding severe life-threatening bleeds. The Committee understood from the comments of consultees and commentators that observational evidence supported the association between low platelet counts and an increased risk of dying. The Committee heard from the clinical specialists that this assumption was plausible, and that an additional mortality benefit could result from reducing the number of deaths associated with the long-term adverse effects of the comparator treatments. The Committee concluded that although there were no robust data supporting the ability of romiplostim to reduce the risk of dying compared with standard care in people with chronic ITP, this possibility was plausible.
The Committee noted the ERG's concern that if it was assumed that romiplostim was no longer effective in the patients who were lost to follow-up during the trial period, the ICERs increased markedly. The Committee heard from the manufacturer that of the 31 patients who withdrew during the open-label extension study, only two patients (6%) withdrew because they did not respond to romiplostim. The Committee concluded that the patients who were lost to follow-up were neither more nor less likely to have stopped responding to romiplostim than patients who were not lost to follow-up.
The Committee noted that the use of intravenous immunoglobulin in 'watch and rescue' care was a major driver of costs in the comparator arm. The Committee noted that the manufacturer had used data from the clinical trials to model the costs and use of resources by assuming that a certain proportion of patients would need rescue therapies during each monthly cycle in the model. The Committee noted that in the ERG's one-way sensitivity analyses, the use of rescue therapies had the greatest impact on the ICER. When the use of rescue therapies was reduced to 80% of the base case in both the comparator and romiplostim arms, the ICER for romiplostim for the realistic scenario increased from £4620 to £32,200 per QALY gained for the splenectomised patients, and from £24,800 to £35,200 per QALY gained for the non-splenectomised patients. The Committee heard from the clinical specialists that the use of rescue therapies was higher in the RCTs than in UK clinical practice on average. This reflected the disease severity of the patients in the RCTs and was consistent with 'severe refractory ITP'. The clinical specialists agreed with the ERG's estimates of time spent on each treatment in the model and stated that people with severe refractory ITP could potentially be on 'watch and rescue' for 18 out of 20 years, and receive rescue treatment as frequently as in the romiplostim RCTs (that is, on 'watch' for 4 months and on rescue treatment for 8 months in each year). The Committee concluded that the majority of people with chronic ITP would not receive rescue therapies as frequently as this, and that the manufacturer's revised base-case ICERs would be relevant only for the treatment of patients at the very severe end of the spectrum of ITP. However, the Committee noted that there remained some uncertainty over the manufacturer's revised base-case ICERs, because even a small reduction of the amount of rescue treatments would increase the ICERs.
The Committee considered the comments received from consultees and commentators in response to consultation on the second ACD. The consultees and commentators requested that the Committee clarify the terms 'specialist in haematology' and 'standard active treatments', and define the dosages of unlicensed treatments. In response to the first point, the Committee recommended that the wording be changed to 'haematologist'. The Committee believed that a haematologist would have a good understanding of what is meant by standard active treatments for chronic ITP, and of dosages. The Committee did not agree that recommending an arrangement of shared care with general practitioners, as proposed by one commentator, was appropriate at this time. Consultees and commentators also requested that a registry is set up to collect data on the use of romiplostim, in order to monitor adverse events, and to audit the implementation of this guidance on romiplostim. The Committee was aware of the UK ITP registry and supported the collection of data on treatment with romiplostim. The Committee furthermore concluded that these data would be useful for any future appraisal of romiplostim for the treatment of chronic ITP.
The Committee agreed that a starting point for the most plausible ICERs would lie between the ICERs for the manufacturer's realistic and conservative scenarios, and may be slightly higher to account for any small reduction in the amount of rescue therapy seen in clinical practice compared with the romiplostim RCTs. Therefore the Committee concluded that the ICERs would be under £20,000 per QALY gained for the treatment of splenectomised patients, and around £30,000 per QALY gained for the treatment of non-splenectomised patients. In addition, the Committee concluded that two factors would reduce these ICERs: the potentially lower use of romiplostim in clinical practice when clinicians aim for target platelet counts lower than those in the romiplostim RCTs, and the fact that the model excluded the long-term adverse effects of the comparator treatments. The Committee was also aware that since the publication of the second ACD, the marketing authorisation of romiplostim had changed such that the platelet count at which the dose of romiplostim can be reduced had been lowered. The Committee appreciated that this would be likely to reduce the ICERs for romiplostim. Therefore the Committee concluded that romiplostim is recommended as a cost-effective use of NHS resources for the treatment of adults with chronic ITP whose condition is refractory to standard active treatments and rescue therapies, or who have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and if the manufacturer makes romiplostim available with the discount agreed as part of the patient access scheme. The Committee heard from clinical specialists that approximately 1–4% of the UK population with chronic ITP would be eligible for treatment with romiplostim using these criteria. Because these people have severe ITP, the Committee concluded that only a haematologist should start and supervise treatment with romiplostim.
The Committee considered whether its recommendations raised any equality issues for people with chronic ITP. The Committee was aware that certain religious groups would not consent to the use of blood products, and also that ITP might affect pre-menopausal women more than men. It also understood that romiplostim might reduce the burden of hospital admission for long hours to receive intravenous immunoglobulin, especially for people for whom it is difficult to travel to a hospital. The Committee noted that no specific representations had been made for these groups of people. The Committee concluded that its recommendations do account for the individual needs of people to receive romiplostim, and do not make it more difficult for any particular group to access treatment with romiplostim compared with any other group.
# Summary of the Appraisal Committee's key conclusions
TA221
Appraisal title: Romiplostim for the treatment of chronic immune thrombocytopenia
Section
Key conclusion
Romiplostim is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:
their condition is refractory to standard active treatments and rescue therapies or
they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies.
Romiplostim is recommended only if the company makes it available with the discount agreed in the patient access scheme.
This is because treatment with romiplostim has been shown to be cost effective only for patients with severe refractory ITP.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted that the pathway of care for ITP varies depending on the person's circumstances, and that no single standard treatment pathway is used in routine practice. The clinical specialists stated that clinicians increasingly prescribe rituximab as the first choice of active treatment; that azathioprine would be used for people whose condition is refractory to rituximab or who are intolerant of rituximab; that cyclophosphamide and ciclosporin were considered too toxic; and that people do not tolerate vinca alkaloids and danazol well and were considered unlikely to benefit from them.
The Committee heard from the clinical specialists that only people who are classed as having severe ITP would receive an active treatment, and this accounts for approximately 5–10% of people with chronic ITP.
The Committee heard from the clinical specialists that, in the UK, first-line treatment for chronic ITP is considered to be corticosteroids (or intravenous immunoglobulin for people for whom corticosteroids are contraindicated), also referred to as rescue therapy.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee heard from the clinical specialists that romiplostim may have benefits over other active treatments because it produces a sustained platelet response during treatment, it can be continued for a longer time than other active treatments, it can be used in a wider population, and adverse effects limit both the use and duration of other active treatments.
The clinical specialists stated that romiplostim represents a 'step-change' for the treatment of ITP, in that it does not have immunosuppressive properties.
What is the position of the treatment in the pathway of care for the condition?
Clinical specialists stated that the place of romiplostim in clinical practice would be for people whose condition is refractory to rituximab, or who are intolerant of rituximab.
Adverse events
The Committee noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee concluded that romiplostim has a novel mechanism of action (as a thrombopoietin receptor agonist) and a good adverse-effect profile, particularly in comparison with currently available treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee was mindful that the evidence was mainly derived from two small placebo-controlled RCTs and a non-comparative open-label study.
Relevance to general clinical practice in the NHS
The Committee considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP who are at high risk of bleeding and need repeated and frequent courses of rescue therapies.
Uncertainties generated by the evidence
The Committee was mindful that the two RCTs did not provide clear evidence about the relative effectiveness of romiplostim compared with the active comparator treatments listed in the scope for the appraisal. The Committee noted that the manufacturer took a pragmatic rather than a systematic approach when collecting evidence for comparator treatments because of heterogeneity among studies of the comparators.
The Committee also noted that data related to certain outcomes, such as the time to treatment failure and the mean response time for romiplostim, had been generated by the manufacturer from a non-comparative open-label study.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups based on differential effectiveness were identified.
N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee was aware of the limitations of the evidence on clinical effectiveness provided by the small RCTs, but considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP at high risk of bleeding who need repeated and frequent courses of rescue therapies.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer's economic model assumed that all patients started with a platelet count below 50 × 109 per litre. Romiplostim was compared with standard care in a model structure in which patients in the romiplostim group start treatment with romiplostim, while 59% of patients in the comparator group start on rituximab and the remaining 41% start on another active treatment in the pathway: immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone and cytotoxic agents (such as cyclophosphamide and vinca alkaloids). Once an active treatment fails, and before the next active treatment is used, patients enter a period of 'watch and rescue' (treated as necessary with intravenous immunoglobulin, anti-D immunoglobulin or intravenous corticosteroids). Modelled patients then move through a care pathway consisting of active treatments and 'watch and rescue'.
Uncertainties and plausibility of assumptions and inputs in the economic model
The Committee agreed with the new approach taken by the manufacturer, wherein the comparator arm of the model started with active treatments instead of 'watch and rescue'. The Committee noted that it would have been preferable to see romiplostim modelled after rituximab, which is where the clinical specialists currently position romiplostim in the treatment pathway for ITP, but recognised that this was not the case at the time of the consultation on the first ACD.
The Committee noted that in clinical practice it would be rare for clinicians to use doses of romiplostim that were aimed at obtaining a platelet count above 50 × 109 per litre (as was the case in the trials). Therefore, in practice, aiming for a lower target platelet count would mean less frequent use of romiplostim, and lower doses of romiplostim when it is used. The Committee noted that, in the ERG's exploratory analyses, the ICERs were sensitive to a change in the number of vials used, and concluded that romiplostim would be more cost effective if less romiplostim was used in clinical practice than was assumed in the model.
The Committee heard from the clinical specialists that the estimates of the effectiveness of the comparators assumed in the model seemed reasonable and reflected clinical practice.
The Committee noted that the model did not sufficiently account for the long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs for romiplostim would be lower.
The Committee noted that the submitted model assumed that treatment with romiplostim extended the life of people with chronic ITP by 2–3 years, and that this survival advantage resulted from avoiding severe life-threatening bleeds. The Committee heard from the clinical specialists that this assumption was plausible, and that an additional mortality benefit could result from reducing the number of deaths associated with the long-term adverse effects of the comparator treatments.
Incorporation of health-related quality-of-life benefits and utility values
The manufacturer pooled two sources of utility data: the individual patient level EQ-5D utility values from the two RCTs, and individual person level utility values from the time trade-off study.
The ERG expressed concerns about the methods by which the manufacturer calculated the utility values in its revised base-case analysis. The ERG noted that the manufacturer simply aggregated the two utility measures, without considering whether it was appropriate to combine data from two different tools and two different samples. The ERG questioned whether the EQ-5D data derived directly from the trials might provide the best estimates of utility values.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the model did not sufficiently account for long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs for romiplostim would be lower.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that the manufacturer's revised base-case ICERs would be relevant only for the treatment of patients at the very severe end of the spectrum of ITP.
What are the key drivers of cost effectiveness?
The Committee noted that the use of rescue therapies, in particular intravenous immunoglobulin in 'watch and rescue', had the greatest impact on the ICER.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee agreed that a starting point for the most plausible ICERs would lie between the ICERs for the manufacturer's realistic and conservative scenarios, and may be slightly higher to account for any small reduction in the amount of rescue therapy seen in clinical practice compared with the romiplostim RCTs. Therefore the Committee concluded that the ICERs would be under £20,000 per QALY gained for the treatment of splenectomised patients, and around £30,000 per QALY gained for the treatment of non-splenectomised patients. In addition, the Committee concluded that two factors would reduce these ICERs: the potentially lower use of romiplostim in clinical practice when clinicians aim for target platelet counts lower than those in the romiplostim RCTs, and the fact that the model excluded the long-term adverse effects of the comparator treatments.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer submitted a patient access scheme. The scheme is a discount on the 250 microgram vial of romiplostim. The size of the discount is commercial in confidence.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The Committee considered whether its recommendations raised any equality issues for people with chronic ITP. The Committee was aware that certain religious groups would not consent to the use of blood products, and also that ITP might affect pre-menopausal women more than men. It also understood that romiplostim might reduce the burden of hospital admission for long hours to receive intravenous immunoglobulin, especially for people for whom it is difficult to travel to a hospital. The Committee noted that no specific representations had been made for these groups of people. The Committee concluded that its recommendations do account for the individual needs of people to receive romiplostim, and do not make it more difficult for any particular group to access treatment with romiplostim compared with any other group.
|
{'Guidance': 'Romiplostim is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:\n\ntheir condition is refractory to standard active treatments and rescue therapies or\n\nthey have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies. Romiplostim is recommended only if the company makes it available with the discount agreed in the patient access scheme.\n\nThese recommendations are not intended to affect treatment with romiplostim that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Romiplostim (Nplate, Amgen) is a protein that mimics the action of thrombopoietin by acting as an agonist at thrombopoietin receptors. It stimulates the differentiation and proliferation of bone marrow cells responsible for producing platelets (megakaryocytes), thereby increasing platelet production and platelet counts (concentrations). Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterised by increased platelet destruction and, in some cases, inadequate platelet production. The disorder can result in low platelet counts and bleeding. Chronic ITP is defined as that which lasts longer than 12\xa0months. Clinicians in the UK treat people with ITP as needed with 'rescue therapies' (corticosteroids, intravenous immunoglobulins and platelet infusions) and thereafter, as needed, with 'active treatments' (rituximab, immunosuppressive agents including azathioprine, mycophenolate mofetil and ciclosporin, danazol, dapsone, and cytotoxic agents including cyclophosphamide and vinca alkaloids). Romiplostim has a marketing authorisation 'for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients 1\xa0year of age and older who are refractory to other treatments (e.g. corticosteroids, immunoglobulins)'.\n\nThe summary of product characteristics (SPC) states that the recommended initial dose of romiplostim is 1\xa0microgram/kg of actual body weight, administered once weekly as a subcutaneous injection. The dose may be increased by increments of 1\xa0microgram/kg until a platelet count equal to or above 50\xa0×\xa0109\xa0platelets per litre of blood is reached. A maximum dose of\xa010\xa0micrograms/kg once weekly should not be exceeded. Platelet counts should be measured weekly until a stable count equal to or above 50\xa0×\xa0109 platelets per litre is observed for at least 4\xa0weeks without adjusting the dose. Thereafter, platelet counts should be measured monthly. Treatment with romiplostim should be stopped if the platelet count does not increase sufficiently to avoid clinically significant bleeding after 4\xa0weeks of romiplostim therapy at the highest weekly dose of 10\xa0micrograms/kg. Romiplostim should also be stopped if a peripheral blood smear indicates increased bone marrow reticulin as well as if a loss of efficacy is observed. For full details of dose and administration, see the SPC.\n\nThe SPC lists special warnings and precautions for the use of romiplostim, including: recurrence of thrombocytopenia and bleeding after stopping treatment; increased bone marrow reticulin; thrombotic and/or thromboembolic complications (described by the SPC as a 'theoretical risk' from platelet counts above the reference range); and loss of response (which could result from immunogenicity or increased bone marrow reticulin). The SPC lists headache as a 'very common' undesirable effect. For full details of side effects and contraindications, see the SPC.\n\nThe SPC states that romiplostim is supplied in both 500 microgram and 250 microgram vials. However, only 250 microgram vials are available in the UK. Romiplostim costs £1.93 per microgram, so a 250\xa0microgram vial costs £482 (excluding VAT; 'British national formulary' [BNF] edition 60). The cost of treatment varies depending on the patient's weight and the dosing regimen. The cost will also be affected by any waste that results from discarding any unused drug from the single use of a 250\xa0microgram vial. The SPC states that romiplostim is a sterile but unpreserved product and therefore is intended for single use only. The annual cost of romiplostim treatment for a person weighing 80\xa0kg would be £8020 at a dose of 1\xa0microgram/kg weekly and £80,204 at a dose of 10\xa0micrograms/kg weekly (assuming no waste). The manufacturer of romiplostim (Amgen) has agreed a patient access scheme with the Department of Health which makes romiplostim available with a discount on the 250 microgram vial. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of romiplostim and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\nThe manufacturer's submission compared romiplostim in addition to standard care with standard care alone for patients with ITP who had undergone splenectomy and, separately, for patients with ITP who had not undergone splenectomy. Evidence was obtained from two double-blind placebo-controlled randomised controlled trials (RCTs) of romiplostim in addition to standard care (defined as prednisone, azathioprine and danazol) compared with standard care alone. One RCT enrolled patients with ITP who had undergone splenectomy (42\xa0patients were assigned to romiplostim and 21 to placebo). The other RCT enrolled patients with ITP who had not undergone splenectomy, but who did not necessarily have a contraindication to splenectomy (41 patients were assigned to romiplostim and 21 to placebo).\n\nIn both RCTs, patients with ITP (defined as the mean of three platelet counts being below or equal to 30\xa0×\xa0109 per litre, with none of the three counts being above 35\xa0×\xa0109 per litre) whose condition was refractory to at least one previous treatment were randomised to romiplostim plus standard care or to standard care alone (placebo) for 24\xa0weeks. The mean platelet count at baseline in the trials was 18\xa0×\xa0109 per litre in the non-splenectomised group and 15\xa0×\xa0109 per litre in the splenectomised group. Romiplostim was given weekly. Platelet counts were monitored and the dose of romiplostim was adjusted to achieve and maintain a platelet count of between 50\xa0×\xa0109 and 200\xa0×\xa0109 per litre. Investigators could increase the dose by 2\xa0micrograms/kg each week (for platelet counts of 10\xa0×\xa0109 per litre or below) or every 2\xa0weeks (after 2\xa0consecutive weeks of platelet counts between 10\xa0×\xa0109 and 50\xa0×\xa0109 per litre). The dose remained stable for platelet counts above 50\xa0×\xa0109 per litre. If a patient's platelet count reached 50\xa0×\xa0109 per litre or more and subsequently fell, the maintenance dose could be increased by 1\xa0microgram/kg each week (if the platelet count fell to 10\xa0×\xa0109 per litre or below) or by 1\xa0microgram/kg every 2\xa0weeks (if the platelet count fell to between 10\xa0×\xa0109 and 50\xa0×\xa0109 per litre for 2\xa0consecutive weeks). The maximum dose permitted in the trial was 15\xa0micrograms/kg, which exceeds the maximum dose of\xa010\xa0micrograms/kg recommended in the SPC.\n\nNo studies were found that compared romiplostim with a specified sequence of active treatments or rescue therapies for the treatment of ITP. Concurrent active treatments or rescue therapies for ITP in trials were given at the investigators' discretion. Six non-RCTs investigating the safety of romiplostim and one open-label extension study of the phase\xa0III RCTs were reported in the manufacturer's submission. In the latter, patients treated with romiplostim or placebo who had completed the phase III study and other clinical studies, and whose platelet counts had fallen below 50\xa0x 109 per litre after stopping romiplostim or placebo, were eligible to enrol in the study and to receive open-label romiplostim. Data from patients going into this extension study were used to calculate time to failure for romiplostim, as this could not be calculated from the phase III studies alone because the interventions ended after 24\xa0weeks.\n\nThe primary endpoint for the two RCTs was the incidence of a durable platelet response, defined as a platelet count of at least 50\xa0×\xa0109 per litre in at least six weekly assessments in the last 8\xa0weeks of treatment without the use of rescue therapies. Rescue therapies included corticosteroids (oral or intravenous), intravenous immunoglobulin (IVIg) and intravenous anti-D immunoglobulin. Other outcomes were: incidence of an overall platelet response (either a durable or a transient platelet response, where a transient response is defined as a platelet count of at least 50\xa0×\xa0109 per litre in at least four weekly assessments during weeks 2 to 25 of treatment, with no weekly response eligible within 8\xa0weeks of the use of rescue therapies, and in the absence of a durable response); time to platelet response (Kaplan–Meier estimated time to first platelet response); duration of platelet response; use of rescue therapies; mortality; adverse events; and health-related quality of life. The primary and secondary outcomes were analysed prospectively. Time to failure (that is, time to stopping romiplostim) and bleeding events were analysed retrospectively.\n\nIn the RCT of splenectomised patients, 16\xa0of\xa042 patients (38.1%) in the romiplostim group and none of 21 patients in the placebo group had a durable platelet response. Thirty-three patients (78.6%) in the romiplostim group had an overall platelet response. The median time to the first platelet response was 3\xa0weeks. No patients in the placebo group had an overall platelet response. The mean number of weeks with a platelet count equal to or above 50\xa0x\xa0109 per litre (in a study period of 24 weeks) was 12.3\xa0weeks for the romiplostim group and 0.2\xa0weeks for the placebo group (p\xa0<\xa00.0001). Eleven\xa0patients (26.2%) in the romiplostim group and twelve\xa0patients (57.1%) in the placebo group received rescue therapies during the treatment period (odds ratio 0.3; 95% confidence interval [CI] 0.1 to 0.8; p\xa0=\xa00.02). There were no deaths in the romiplostim group. Three patients in the placebo group died; the causes of death were pneumonia (after the end of the study), pulmonary embolism and cerebral haemorrhage.\n\nThe manufacturer's submission stated that in the RCT of non-splenectomised patients, 25 of 41 patients (61.0%) in the romiplostim group and one of 21 patients (4.8%) in the placebo group had a durable platelet response (odds ratio 24.5; 95% CI 3.3 to 179.2; p\xa0<\xa00.0001). Thirty-six\xa0patients (87.8%) in the romiplostim group and three patients (14.3%) in the placebo group had an overall platelet response (odds ratio 34.7; 95% CI 7.8 to 155.4; p\xa0<\xa00.0001). The median time to the first platelet response was 2\xa0weeks. The mean number of weeks with a platelet count equal to or above 50\xa0x\xa0109 per litre (in a study period of 24 weeks) was 15.2\xa0weeks for the romiplostim group and 1.3\xa0weeks for the placebo group (p\xa0<\xa00.0001). Seven patients (17.1%) in the romiplostim group and 13\xa0patients (61.9%) in the placebo group received rescue therapies during the treatment period. One patient in the romiplostim group and no patients in the placebo group died. The cause of death was intracranial haemorrhage 2\xa0weeks after stopping romiplostim. All patients included in both RCTs received at least one dose of either romiplostim or placebo. One non-splenectomised patient randomly assigned to placebo received three doses of romiplostim in error and was included in the safety analysis as a patient given romiplostim and in the efficacy analysis as a patient randomised to placebo.\n\nThe manufacturer's submission reported results for bleeding events, adverse events and health-related quality-of-life outcomes pooled from the two RCTs. These showed that 45 of 84 patients (54%) in the combined romiplostim groups (a revised figure of 48 of 84 [57%] was given in the Evidence Review Group [ERG] report using data provided by the manufacturer following a request for clarification) and 25 of 41 patients (61%) in the combined placebo groups experienced at least one bleeding event of any severity. A serious bleeding event, as defined by the regulatory protocol (which includes, but may not be limited to, any event that: is fatal, is life threatening [puts the person at immediate risk of death], needs in-patient hospitalisation or prolongation of existing hospitalisation, or is a persistent or significant disability or incapacity), was reported for 5 of 84 patients (6%) in the combined romiplostim groups and 4 of 41 patients (10%) in the combined placebo groups. Bleeding of grade 3 or above (rated as severe, life threatening or fatal) occurred in 6 of 84 patients (7%) in the combined romiplostim groups and 5 of 41 patients (12%) in the combined placebo groups. Bleeding events of grade 2 or above (rated as moderate, severe, life threatening or fatal) occurred in 13 of 84 patients (15%) in the combined romiplostim groups and 14 of 41 patients (34%) in the combined placebo groups.\n\nData on safety were derived from combined results from the two RCTs and seven case series, which included dose-finding studies, an open-label extension study (that included patients from other romiplostim studies), a study of patients with severe refractory ITP and a bone marrow morphology substudy. Both the incidence and event rates adjusted for study duration for all adverse events that occurred during treatment were calculated. Safety data were submitted as academic-in-confidence information by the manufacturer.\n\nData on health-related quality of life from the two phase III RCTs included data from EuroQol 5-D (EQ-5D) and from the ITP Patient Assessment Questionnaire, which is a disease-specific instrument comprising 10 scales. Statistically significant differences between health-related quality of life were not reported in the manufacturer's original submission. In a revised submission, the manufacturer provided a linear regression analysis of combined EQ-5D data from both RCTs, which showed statistically significant differences favouring romiplostim compared with placebo in the mean change in EQ-5D score. Combined data from both RCTs for the change from baseline using the ITP Patient Assessment Questionnaire indicated a statistically significantly greater (p\xa0<\xa00.05) improvement in the 'Symptoms', 'Bother', 'Social Activity' and 'Women's Reproductive Health' scales in the romiplostim group than the placebo group for splenectomised patients. For non-splenectomised patients, those in the romiplostim group had a statistically significantly greater improvement in the 'Activity' scale than those in the placebo group.\n\nThe manufacturer did not identify any RCTs on the effectiveness of comparator treatments used in standard care for ITP compared with romiplostim, as defined in the scope of this appraisal. These included corticosteroids, IVIg, rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil and ciclosporin), anti-D immunoglobulin and splenectomy for non-splenectomised patients, and corticosteroids, IVIg, rituximab and immunosuppressive agents for splenectomised patients. The manufacturer assessed clinical guidelines, systematic reviews, trials and observational studies for evidence on the effectiveness of comparator treatments and found mostly case series. The manufacturer combined data on efficacy from different studies that examined the same treatment by a method described in the manufacturer's submission as 'taking a weighted average, weighting by sample size'. The number of studies combined in this way varied by treatment.\n\n# Cost effectiveness\n\n## Original economic model\n\nThe manufacturer submitted an original economic model and, after consultation on the first appraisal consultation document (ACD), a revised model. The manufacturer's original cohort-type economic model used a lifetime horizon and assessed the impact of romiplostim separately for patients with ITP who had undergone splenectomy and those who had not. The model assumed that all patients started with a platelet count below 50\xa0×\xa0109 per litre. Romiplostim was compared with standard care in a model structure in which patients initially either enter 'watch and rescue' (treated as necessary with intravenous immunoglobulin, anti-D immunoglobulin [non-splenectomised patients] or intravenous corticosteroids) or are treated with romiplostim followed by 'watch and rescue'. In the model, patients move through a care pathway consisting of active treatments and 'watch and rescue'. When a patient becomes refractory to an active treatment they receive 'watch and rescue'. The active treatments modelled in the remainder of the care pathway were rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone and cytotoxic agents (such as cyclophosphamide and vinca alkaloids).\n\nThe manufacturer built seven health states into the model. The manufacturer conducted a utility survey with the primary objective of directly measuring health utility values for these ITP health states as perceived by members of the public in the UK. Respondents were presented with descriptions of each ITP health state, and utility values for five of the seven health states were derived using the time trade-off method. The utility values for these five health states were: 0.863 for platelet count above 50\xa0×\xa0109 per litre and no bleed; 0.734 for platelet count above 50\xa0×\xa0109 per litre and outpatient bleed; 0.841 for platelet count below 50\xa0×\xa0109 per litre and no bleed; 0.732 for platelet count below 50\xa0×\xa0109 per litre and outpatient bleed; 0.038 for platelet count below 50\xa0×\xa0109 per litre and intracranial haemorrhage. For the remaining two health states included in the model (low platelet count with gastrointestinal bleed and low platelet count with other bleeding events requiring hospitalisation) the manufacturer used a utility value of 0.54 taken from the literature.\n\nThe manufacturer divided use of resources and costs into 4-week cycles. Costs of treatment included those of the romiplostim vials, laboratory testing to check blood counts every cycle (four tests), physician appointments (two sessions), and other drugs. Costs of management of bleeds included those for minor bleeds treated in an outpatient setting, intracranial haemorrhage, gastrointestinal bleeds and other bleeds requiring hospitalisation.\n\nOther costs for drugs used in treatment and in managing bleeds were taken from the BNF (edition 55) and NHS reference costs.\n\nThe manufacturer's base-case analyses using the original economic model gave incremental cost-effectiveness ratios (ICERs) of £14,633 per quality-adjusted life year (QALY) gained for non-splenectomised patients and £15,595 per QALY gained for splenectomised patients, when using romiplostim as a first-option treatment compared with 'watch and rescue' standard care and with a target platelet count of 50\xa0×\xa0109 per litre. These ICERs reflected new inputs added to the model at the request of the ERG during the clarification step.\n\nSensitivity analyses performed by the manufacturer using the original economic model, in response to a request for clarification from the ERG, included the effects of: changes in drug costs to account for vial wastage in practice; the use of EQ-5D data available from the RCTs for serious adverse events; the cost of a bone marrow assessment needed when the condition no longer responds to romiplostim; and the cost of blood film tests (which are needed before treatment with romiplostim can begin).\n\nThe manufacturer, in response to a request for clarification from the ERG, also performed a sensitivity analysis in which it assumed a target platelet count of 30\xa0×\xa0109 per\xa0litre (instead of 50\xa0×\xa0109 per litre). This gave ICERs of £14,840 per QALY gained for non-splenectomised patients and £14,655 per QALY gained for splenectomised patients using romiplostim as a first-option treatment compared with 'watch and rescue'.\n\nThe manufacturer estimated that the probability that romiplostim would be cost effective using a target platelet count of 50\xa0×\xa0109 per litre at different acceptability threshold levels of £10,000, £20,000 and £30,000 per QALY gained was 10%, 60% and 81% respectively for non-splenectomised patients (mean ICER £14,633 per QALY gained), and 25%, 55% and 77% respectively for splenectomised patients (mean ICER £15,595 per QALY gained).\n\nThe ERG noted that limited evidence was available for romiplostim and potential comparators for the treatment of patients with chronic ITP, and particularly for long-term outcomes. The ERG also considered that the evidence for comparators did not distinguish between patients who had not undergone splenectomy and splenectomised patients. The ERG was particularly concerned about the methods the manufacturer had used to estimate the efficacy of romiplostim and the comparators, while acknowledging that using formal methods may also have been inappropriate. The ERG was not presented with further evidence that would have significantly altered the results presented in the manufacturer's original submission.\n\nThe ERG performed explorative sensitivity analyses using the manufacturer's original economic model. The one-way sensitivity analysis that had the most effect on the ICER was that in which the cost of romiplostim was adjusted to account for wastage from single-use vials that would occur in practice. On changing the number of vials from 0.93 to 1 for non-splenectomised patients, the ICER increased from £14,633 to £21,214 per QALY gained. For splenectomised patients, a change in the number of vials from 1.4 to 2 increased the ICER from £15,595 to £91,406 per QALY gained. The ERG carried out multivariate analyses which combined sensitivity analyses conducted by the ERG with those provided by the manufacturer. When patients entered the model on active treatment (rituximab) in the comparator arm (rather than 'watch and rescue') the ERG reported ICERs that increased from £14,633 to £21,674 per QALY gained for non-splenectomised patients and from £15,595 to £29,771 per QALY gained for splenectomised patients. When patients entered the model on active treatment (with rituximab) and the cost of romiplostim was adjusted to account for wastage, the ICER increased from £16,633 to £28,556 per QALY gained for non-splenectomised patients and from £15,595 to £109,802 per QALY gained for splenectomised patients. In a multivariate analysis that incorporated EQ-5D data from the RCTs rather than the utility values originally provided by the manufacturer, the cost of romiplostim adjusted to account for wastage, a 50% reduction in serious adverse events and the cost of bone marrow tests and blood film assessments, the ICERs increased from £14,633 to £37,290 per QALY gained for non-splenectomised patients and from £15,595 to £131,017 per QALY gained for splenectomised patients.\n\n## Revised economic model\n\nAfter consultation on the first ACD, the manufacturer provided revised analyses of the cost effectiveness of romiplostim that addressed a number of the key issues that were raised by the Committee in the first ACD.\n\nIn the manufacturer's revised base-case analysis, it was assumed that 59% of patients in the comparator group start on rituximab and the remaining 41% start on another active treatment in the pathway (that is, immunosuppressive agents, dapsone, danazol and cytotoxic agents). Once an active treatment fails, and before the next active treatment is used, the model assumes that a patient enters a period of 'watch and rescue'.\n\nThe manufacturer took into account potential vial wastage of romiplostim and the fact that patients in the trials received doses that were higher than the maximum dose recommended in the SPC of 10\xa0micrograms/kg. The manufacturer stated that six of the 42 patients in the trial of splenectomised patients were given more than 10\xa0micrograms/kg romiplostim, and one of these showed a response to treatment. In the trial of non-splenectomised patients, two of the 41 patients received more than 10\xa0micrograms/kg romiplostim, one of whom showed a response to treatment. In the cost-effectiveness analyses, the manufacturer provided two base-case scenario analyses: a 'conservative' scenario and a 'realistic' scenario. In both scenarios, all patients who received more than 10\xa0micrograms/kg romiplostim were modelled as 'non-responders'. In the conservative scenario, the costs of continuing treatment at doses above 10 micrograms/kg were included in the model. In the realistic scenario, romiplostim costs were capped at 10 micrograms/kg.\n\nThe manufacturer pooled two sources of utility data: the individual patient level EQ-5D utility values from the two RCTs, and individual person level utility values from the time trade-off study (see section 3.12). The two resulting utility values that differed from the manufacturer's original utility values (based on the time trade-off study) were 0.835 for patients with a platelet count above 50\xa0×\xa0109 per litre and no bleed, and 0.800 for patients with a platelet count below 50\xa0×\xa0109 per litre and no bleed.\n\nThe manufacturer included the costs of bone marrow tests and blood film assessments associated with treatment with romiplostim in the revised analyses. The manufacturer also accounted for reductions in the number of blood counts and patient visits to clinicians.\n\nThe manufacturer submitted a patient access scheme, which is a discount on the 250 microgram vial of romiplostim, and provided four cost-effectiveness analyses: for the use of the 250 microgram vial with and without the patient access scheme, and for the use of a 100 microgram vial with and without the patient access scheme. This document only details the results for the use of the 250 microgram vial with the patient access scheme.\n\nThe manufacturer's revised base-case ICERs for the non-splenectomised group, incorporating all of the above assumptions and the patient access scheme, were £24,795 and £28,278 per QALY gained for the realistic scenario and the conservative scenario respectively. The ICERs for the splenectomised group were £4615 and £16,530 per QALY gained for the realistic scenario and the conservative scenario respectively.\n\nThe ERG reviewed the manufacturer's revised base-case analysis, and noted that uncertainty remained about which active treatment best reflects UK clinical practice. The ERG highlighted that the manufacturer's model describes a defined sequence of treatments, and questioned whether it was reasonable to exclude some treatments in the comparator arm. The ERG performed analyses using the manufacturer's revised base-case model and noted that a patient who enters the comparator arm of the model spends most time on 'watch and rescue' rather than on any other treatment. The ERG noted that any change in the model structure that reduces the amount of time a patient spends in 'watch and rescue' would increase the ICERs for romiplostim.\n\nThe ERG expressed concerns about the methods by which the manufacturer calculated the utility values in its revised base-case analysis. The ERG noted that the manufacturer simply aggregated the two utility measures, without considering whether it was appropriate to combine data from two different tools and two different samples. The ERG questioned whether the EQ-5D data derived directly from the trials might provide the best estimates of utility values.\n\nThe ERG reviewed the approach taken by the manufacturer to account for patients who received doses of romiplostim above the maximum dose stated in the SPC. The ERG noted that patients lost to follow-up in the trials may not have had the same outcomes as patients not lost to follow-up, which could affect the calculation of time to failure. Censored patients were defined as 'lost to follow-up' in the evaluation of time to failure for romiplostim, and were those who had a last observed visit that was not recorded as a withdrawal in the open-label extension study. The ERG expressed further concerns about the assumption that romiplostim extends life, and about the generalisability and applicability of the trial results to a typical NHS population of patients with ITP. The ERG identified no additional evidence that would reduce this uncertainty.\n\nThe ERG conducted an exploratory analysis using the manufacturer's 'realistic' scenario, to test the impact of a 10% increase in the average number of 250\xa0microgram vials of romiplostim used. For splenectomised patients the ICER rose from £4615 to £20,340 per QALY gained, and for non-splenectomised patients the ICER rose from £24,795 to £34,410 per QALY gained. The ERG also noted that if there was lower usage of romiplostim in NHS clinical practice than is reflected in the values included in the manufacturer's model the ICERs for romiplostim would decrease.\n\nThe ERG explored the impact of reducing the duration of the response to romiplostim in the model by 10%, 20% and 30%. When this was reduced by 30%, the ICER rose from £4615 to £6138 per QALY gained for splenectomised patients, and from £24,795 to £25,363 per QALY gained for non-splenectomised patients.\n\nThe ERG conducted one-way sensitivity analyses by varying individual parameters in the revised base-case model to check the impact on the ICERs. These changes included increasing the use of comparator treatments by 25%; increasing the response time for comparators by 50%; increasing response rates for comparators by 25%; reducing the use of rescue therapies to 80% of the base case in both the comparator and romiplostim arms; using alternative utility values; and assuming a 'worst case scenario' in which all patients who were censored in the open-label extension study were assumed to have no longer responded to romiplostim and were treated as withdrawals. The change in the use of rescue therapies had the greatest impact, increasing the ICERs from £24,795 to £35,248 per QALY gained for non-splenectomised patients and from £4615 to £32,190 per QALY gained for splenectomised patients. The ERG noted that when all patients who were censored in the open-label extension study were assumed to have no longer responded to romiplostim and were treated as withdrawals, the ICERs rose from £24,795 to £31,601 per QALY gained for non-splenectomised patients and from £4615 to £18,647 per QALY gained for splenectomised patients.\n\nThe ERG performed a multi-way sensitivity analysis to show the impact on the ICERs of the cumulative effects of varying all individual parameters explored in the one-way sensitivity analyses (see section 3.33). The ICER for splenectomised patients rose from £4615 to £64,646 per QALY gained, and that for non-splenectomised patients rose from £24,795 to £55,470 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of romiplostim, having considered evidence on the nature of chronic ITP and the value placed on the benefits of romiplostim by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the clinical signs and symptoms associated with chronic ITP. The Committee heard that the signs and symptoms associated with low platelet counts vary, and that bleeding and bruising can have a considerable impact on the daily activities of people with chronic ITP, may attract a social stigma associated with the appearance of bruises, and can limit lifestyle choices. The Committee heard that many people with ITP experience fatigue, but that there is no clear relationship between fatigue and platelet count or haemoglobin concentration. The Committee understood that anxiety about the risk of bleeding can affect a person's quality of life and the ability to work, travel and/or undertake leisure activities. The Committee understood from patient experts that a bleed could result in a person seeking medical care to receive rescue therapies, and if the bleeding was severe the person could need hospitalisation.\n\nThe Committee discussed the clinical management of chronic ITP. It noted that the pathway of care for chronic ITP varies depending on the person's circumstances, and that no single standard treatment pathway is used in routine practice. The Committee heard from the clinical specialists that, in the UK, first-line treatment for chronic ITP is considered to be corticosteroids (or intravenous immunoglobulin for people for whom corticosteroids are contraindicated), also referred to as rescue therapy. The clinical specialists estimated that approximately 30% of people would enter remission after such first-line treatment. The Committee heard from the clinical specialists that, for chronic ITP that does not respond to rescue therapy, active treatments are considered as second-line treatment including rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone, and cytotoxic agents (cyclophosphamide, vinca alkaloids). The clinical specialists explained that clinicians increasingly prescribe rituximab as the first choice of active treatment (for approximately 50–60% of patients who need active treatment), and this leads to remission in approximately 50% of people treated. However, the clinical specialists noted that these people will, in general, eventually relapse and need further treatment. The clinical specialists also stated that azathioprine would be used for people whose condition is refractory to rituximab or who are intolerant of rituximab, but that cyclophosphamide and ciclosporin were considered too toxic, and that people do not tolerate vinca alkaloids and danazol well and were considered unlikely to benefit from them. The Committee understood that people receiving active treatments for ITP would need monitoring and would still be likely to need rescue therapies from time to time.\n\nThe Committee understood that people who have certain treatments (intravenous immunoglobulin, corticosteroids and immunosuppressive agents) over long periods of time will experience adverse effects that can lead to chronic conditions, including infections, diabetes mellitus, an increased risk of gastrointestinal bleeds, and hypertension. The Committee heard that some people may need knee or hip replacements as a result of the side effects of long-term use of corticosteroids. The Committee understood from comments made by consultees and commentators in response to the first ACD that the consequences of treatment with alkylating agents (such as cyclophosphamide and vinca alkaloids) can include malignancies and fertility problems.\n\nThe Committee discussed when a person with chronic ITP would receive treatment and heard from the clinical specialists that a person's platelet count alone does not determine whether or not he or she receives treatment, and that clinicians take into account the person's symptoms (such as fatigue) and risk of bleeding. Overall, the Committee understood from the clinical specialists that the lower a person's platelet count, the more likely a clinician is to offer treatment, but that treatment is not usually offered unless absolutely necessary because of the side effects of many of the current treatments. Active treatments are more likely to be considered for people with severe symptoms or who are at high risk of bleeding, and in particular when rescue therapies are failing to produce satisfactory platelet counts or relief of symptoms. The Committee heard that people with a platelet count of between 20\xa0×\xa0109 and 30\xa0×\xa0109 per litre would rarely be offered an active treatment in the UK unless they had a significant bleed. The clinical specialists and patient experts informed the Committee that in clinical practice a platelet count of between 10\xa0×\xa0109 and 20\xa0×\xa0109 per litre would be the level at which clinicians would be likely to begin active treatment. A separate group of people who may be considered for active treatments at higher platelet counts would be those, for example, who needed aspirin therapy for cardiovascular disease. For people without severe symptoms and who are not perceived to be at high risk of bleeding, the preferred approach would be a strategy of 'watch and rescue' (with 'rescue' intervention dictated by the frequency of bleeding episodes) rather than an active treatment. The Committee heard from the clinical specialists that only people who are classed as having severe ITP would receive an active treatment, and this accounts for approximately 5–10% of people with chronic ITP. The Committee concluded that, in UK clinical practice, treatment for people with chronic ITP is dictated by the severity of symptoms, in particular bleeding.\n\nThe Committee discussed the place of romiplostim in the pathway of care for people with chronic ITP, and considered the appropriate comparators. It noted that the licensed indication for romiplostim for people who have undergone splenectomy is restricted to people who are refractory to other treatments such as corticosteroids and immunoglobulin, and also that romiplostim may be considered as a second-line treatment for people with a contraindication to splenectomy. The Committee understood that there are few treatments licensed for the treatment of chronic ITP. The Committee heard from the clinical specialists that the place of romiplostim in clinical practice would be for people whose condition is refractory to rituximab, or who are intolerant of rituximab.\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of romiplostim compared with placebo and standard care. It was mindful that the evidence was mainly derived from two small placebo-controlled RCTs. The Committee noted that romiplostim significantly improved platelet count (the response measure used in the trials) and reduced the frequency of bleeding – particularly the occurrence of moderate and severe bleeding episodes. However, the Committee was mindful that these two RCTs did not provide clear evidence about the relative effectiveness of romiplostim compared with the active comparator treatments listed in the scope for the appraisal. The Committee noted that the manufacturer took a pragmatic rather than a systematic approach when collecting evidence for comparator treatments because of heterogeneity among studies of the comparators and because many of the comparators do not have a marketing authorisation for the treatment of ITP. The Committee also noted that data related to certain outcomes, such as the time to failure and the mean response time for romiplostim, had been generated by the manufacturer from a non-comparative open-label study. The Committee acknowledged comments received from consultees and commentators in response to consultation on the first ACD that highlighted the difficulty of conducting comparative trials with romiplostim, mainly because ITP is a rare and heterogeneous disease. The Committee heard from the clinical specialists that the population in the trials had the most severe ITP, which is estimated as representing 1–4% of people with chronic ITP, and were at high risk of bleeding and therefore needed high levels of rescue therapies throughout the trial. The Committee was aware of the limitations of the evidence on clinical effectiveness provided by the small RCTs, but considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP who are at high risk of bleeding and need repeated and frequent courses of rescue therapies.\n\nThe Committee then discussed the adverse effects associated with romiplostim. It noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee heard from the clinical specialists that romiplostim may have benefits over other active treatments because it produces a sustained platelet response during treatment, it can be continued for a longer time than other active treatments, it can be used in a wider population, and because adverse effects limit both the use and duration of other active treatments. The Committee noted from comments received from consultees and commentators in response to consultation on the first ACD that romiplostim has a different mode of action from current treatments for chronic ITP. The clinical specialists stated that romiplostim represents a 'step-change' for the treatment of ITP, in that it does not have immunosuppressive properties. The Committee also considered comments from consultees and commentators in response to consultation on the second ACD about setting a stopping rule for romiplostim, but noted that the modelling of the cost effectiveness for romiplostim did not include analyses addressing stopping. The Committee was also aware that the SPC specifies conditions under which to stop treatment with romiplostim. The Committee concluded that romiplostim has a novel mechanism of action (as a thrombopoietin receptor agonist) and a good adverse-effect profile, particularly in comparison with currently available treatments.\n\nThe Committee next considered the revised economic model submitted by the manufacturer that included the patient access scheme. The Committee agreed with the new approach taken by the manufacturer, wherein the comparator arm of the model started with active treatments instead of 'watch and rescue' and the costs of bone marrow tests and blood film assessment were included in the cost of treatment with romiplostim. The Committee noted that it would have been preferable to see romiplostim modelled after rituximab, which is where the clinical specialists currently position romiplostim in the treatment pathway for ITP, but recognised that this was not the case at the time of the consultation on the first ACD. The Committee considered the ERG's comments on the manufacturer's revised base-case analysis that included the patient access scheme, and noted that the ERG considered the approaches taken by the manufacturer in the revised analyses to being generally reasonable.\n\nThe Committee considered the ICERs in the manufacturer's revised base-case analysis that included the patient access scheme. For non-splenectomised patients the ICERs were £24,800 and £28,300 per QALY gained for the realistic and conservative scenarios respectively. For splenectomised patients the ICERs were £4620 and £16,500 per QALY gained for the realistic and conservative scenarios respectively.\n\nThe Committee noted that the median dose of romiplostim used in the RCTs was 3\xa0micrograms/kg for splenectomised patients and 2\xa0micrograms/kg for non-splenectomised patients, and heard from the clinical specialists that these doses reflect clinical practice. The Committee discussed the number of vials used in the realistic and conservative scenarios presented by the manufacturer. It heard from the clinical specialists that although they would not use doses as high as those given in the trials, there may be some instances where the entire contents of a vial of romiplostim would be used, rather than wasting some, and so the dose may occasionally exceed the maximum dose specified in the SPC. Therefore the Committee concluded that the most plausible scenario would be somewhere between the realistic and conservative scenarios modelled by the manufacturer.\n\nThe Committee noted that in clinical practice it would be rare for clinicians to use doses of romiplostim that were aimed at obtaining a platelet count above 50\xa0×\xa0109 per litre (as was the case in the trials). Therefore, in practice, aiming for a lower target platelet count would mean less frequent use of romiplostim, and lower doses of romiplostim when it is used. The Committee noted that, in the ERG's exploratory analyses, the ICERs were sensitive to a change in the number of vials used, and concluded that romiplostim would be more cost effective if less romiplostim was used in clinical practice than was assumed in the model.\n\nThe Committee considered the estimates of the effectiveness of the comparators assumed in the model, and heard from the clinical specialists that these estimates seemed reasonable and reflected clinical practice. The Committee noted that the model did not sufficiently account for long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs of romiplostim would have been lower.\n\nThe Committee noted that the submitted model assumed that treatment with romiplostim extended the life of people with chronic ITP by 2.92\xa0and 2.03 years for the non-splenectomised and splenectomised groups respectively. The Committee noted that the survival advantage associated with romiplostim resulted from avoiding severe life-threatening bleeds. The Committee understood from the comments of consultees and commentators that observational evidence supported the association between low platelet counts and an increased risk of dying. The Committee heard from the clinical specialists that this assumption was plausible, and that an additional mortality benefit could result from reducing the number of deaths associated with the long-term adverse effects of the comparator treatments. The Committee concluded that although there were no robust data supporting the ability of romiplostim to reduce the risk of dying compared with standard care in people with chronic ITP, this possibility was plausible.\n\nThe Committee noted the ERG's concern that if it was assumed that romiplostim was no longer effective in the patients who were lost to follow-up during the trial period, the ICERs increased markedly. The Committee heard from the manufacturer that of the 31 patients who withdrew during the open-label extension study, only two patients (6%) withdrew because they did not respond to romiplostim. The Committee concluded that the patients who were lost to follow-up were neither more nor less likely to have stopped responding to romiplostim than patients who were not lost to follow-up.\n\nThe Committee noted that the use of intravenous immunoglobulin in 'watch and rescue' care was a major driver of costs in the comparator arm. The Committee noted that the manufacturer had used data from the clinical trials to model the costs and use of resources by assuming that a certain proportion of patients would need rescue therapies during each monthly cycle in the model. The Committee noted that in the ERG's one-way sensitivity analyses, the use of rescue therapies had the greatest impact on the ICER. When the use of rescue therapies was reduced to 80% of the base case in both the comparator and romiplostim arms, the ICER for romiplostim for the realistic scenario increased from £4620 to £32,200 per QALY gained for the splenectomised patients, and from £24,800 to £35,200 per QALY gained for the non-splenectomised patients. The Committee heard from the clinical specialists that the use of rescue therapies was higher in the RCTs than in UK clinical practice on average. This reflected the disease severity of the patients in the RCTs and was consistent with 'severe refractory ITP'. The clinical specialists agreed with the ERG's estimates of time spent on each treatment in the model and stated that people with severe refractory ITP could potentially be on 'watch and rescue' for 18 out of 20 years, and receive rescue treatment as frequently as in the romiplostim RCTs (that is, on 'watch' for 4 months and on rescue treatment for 8 months in each year). The Committee concluded that the majority of people with chronic ITP would not receive rescue therapies as frequently as this, and that the manufacturer's revised base-case ICERs would be relevant only for the treatment of patients at the very severe end of the spectrum of ITP. However, the Committee noted that there remained some uncertainty over the manufacturer's revised base-case ICERs, because even a small reduction of the amount of rescue treatments would increase the ICERs.\n\nThe Committee considered the comments received from consultees and commentators in response to consultation on the second ACD. The consultees and commentators requested that the Committee clarify the terms 'specialist in haematology' and 'standard active treatments', and define the dosages of unlicensed treatments. In response to the first point, the Committee recommended that the wording be changed to 'haematologist'. The Committee believed that a haematologist would have a good understanding of what is meant by standard active treatments for chronic ITP, and of dosages. The Committee did not agree that recommending an arrangement of shared care with general practitioners, as proposed by one commentator, was appropriate at this time. Consultees and commentators also requested that a registry is set up to collect data on the use of romiplostim, in order to monitor adverse events, and to audit the implementation of this guidance on romiplostim. The Committee was aware of the UK ITP registry and supported the collection of data on treatment with romiplostim. The Committee furthermore concluded that these data would be useful for any future appraisal of romiplostim for the treatment of chronic ITP.\n\nThe Committee agreed that a starting point for the most plausible ICERs would lie between the ICERs for the manufacturer's realistic and conservative scenarios, and may be slightly higher to account for any small reduction in the amount of rescue therapy seen in clinical practice compared with the romiplostim RCTs. Therefore the Committee concluded that the ICERs would be under £20,000 per QALY gained for the treatment of splenectomised patients, and around £30,000 per QALY gained for the treatment of non-splenectomised patients. In addition, the Committee concluded that two factors would reduce these ICERs: the potentially lower use of romiplostim in clinical practice when clinicians aim for target platelet counts lower than those in the romiplostim RCTs, and the fact that the model excluded the long-term adverse effects of the comparator treatments. The Committee was also aware that since the publication of the second ACD, the marketing authorisation of romiplostim had changed such that the platelet count at which the dose of romiplostim can be reduced had been lowered. The Committee appreciated that this would be likely to reduce the ICERs for romiplostim. Therefore the Committee concluded that romiplostim is recommended as a cost-effective use of NHS resources for the treatment of adults with chronic ITP whose condition is refractory to standard active treatments and rescue therapies, or who have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and if the manufacturer makes romiplostim available with the discount agreed as part of the patient access scheme. The Committee heard from clinical specialists that approximately 1–4% of the UK population with chronic ITP would be eligible for treatment with romiplostim using these criteria. Because these people have severe ITP, the Committee concluded that only a haematologist should start and supervise treatment with romiplostim.\n\nThe Committee considered whether its recommendations raised any equality issues for people with chronic ITP. The Committee was aware that certain religious groups would not consent to the use of blood products, and also that ITP might affect pre-menopausal women more than men. It also understood that romiplostim might reduce the burden of hospital admission for long hours to receive intravenous immunoglobulin, especially for people for whom it is difficult to travel to a hospital. The Committee noted that no specific representations had been made for these groups of people. The Committee concluded that its recommendations do account for the individual needs of people to receive romiplostim, and do not make it more difficult for any particular group to access treatment with romiplostim compared with any other group.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA221\n\n\n\nAppraisal title: Romiplostim for the treatment of chronic immune thrombocytopenia\n\nSection\n\nKey conclusion\n\nRomiplostim is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:\n\ntheir condition is refractory to standard active treatments and rescue therapies or\n\nthey have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies.\n\nRomiplostim is recommended only if the company makes it available with the discount agreed in the patient access scheme.\n\nThis is because treatment with romiplostim has been shown to be cost effective only for patients with severe refractory ITP.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted that the pathway of care for ITP varies depending on the person's circumstances, and that no single standard treatment pathway is used in routine practice. The clinical specialists stated that clinicians increasingly prescribe rituximab as the first choice of active treatment; that azathioprine would be used for people whose condition is refractory to rituximab or who are intolerant of rituximab; that cyclophosphamide and ciclosporin were considered too toxic; and that people do not tolerate vinca alkaloids and danazol well and were considered unlikely to benefit from them.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard from the clinical specialists that only people who are classed as having severe ITP would receive an active treatment, and this accounts for approximately 5–10% of people with chronic ITP.\n\n\n\n\n\nThe Committee heard from the clinical specialists that, in the UK, first-line treatment for chronic ITP is considered to be corticosteroids (or intravenous immunoglobulin for people for whom corticosteroids are contraindicated), also referred to as rescue therapy.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee heard from the clinical specialists that romiplostim may have benefits over other active treatments because it produces a sustained platelet response during treatment, it can be continued for a longer time than other active treatments, it can be used in a wider population, and adverse effects limit both the use and duration of other active treatments.\n\nThe clinical specialists stated that romiplostim represents a 'step-change' for the treatment of ITP, in that it does not have immunosuppressive properties.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nClinical specialists stated that the place of romiplostim in clinical practice would be for people whose condition is refractory to rituximab, or who are intolerant of rituximab.\n\n\n\n\n\n\n\n\n\n\n\nAdverse events\n\n\n\nThe Committee noted that very few patients treated with romiplostim in the trials experienced adverse effects, including bleeding. The Committee concluded that romiplostim has a novel mechanism of action (as a thrombopoietin receptor agonist) and a good adverse-effect profile, particularly in comparison with currently available treatments.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee was mindful that the evidence was mainly derived from two small placebo-controlled RCTs and a non-comparative open-label study.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP who are at high risk of bleeding and need repeated and frequent courses of rescue therapies.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was mindful that the two RCTs did not provide clear evidence about the relative effectiveness of romiplostim compared with the active comparator treatments listed in the scope for the appraisal. The Committee noted that the manufacturer took a pragmatic rather than a systematic approach when collecting evidence for comparator treatments because of heterogeneity among studies of the comparators.\n\nThe Committee also noted that data related to certain outcomes, such as the time to treatment failure and the mean response time for romiplostim, had been generated by the manufacturer from a non-comparative open-label study.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups based on differential effectiveness were identified.\n\n\n\nN/A\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee was aware of the limitations of the evidence on clinical effectiveness provided by the small RCTs, but considered that the available data demonstrated that romiplostim was clinically effective in people with severe ITP at high risk of bleeding who need repeated and frequent courses of rescue therapies.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe manufacturer's economic model assumed that all patients started with a platelet count below 50\xa0×\xa0109 per litre. Romiplostim was compared with standard care in a model structure in which patients in the romiplostim group start treatment with romiplostim, while 59% of patients in the comparator group start on rituximab and the remaining 41% start on another active treatment in the pathway: immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone and cytotoxic agents (such as cyclophosphamide and vinca alkaloids). Once an active treatment fails, and before the next active treatment is used, patients enter a period of 'watch and rescue' (treated as necessary with intravenous immunoglobulin, anti-D immunoglobulin [non-splenectomised patients] or intravenous corticosteroids). Modelled patients then move through a care pathway consisting of active treatments and 'watch and rescue'.\n\n, 3.22\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nUncertainties and plausibility of assumptions and inputs in the economic model\n\nThe Committee agreed with the new approach taken by the manufacturer, wherein the comparator arm of the model started with active treatments instead of 'watch and rescue'. The Committee noted that it would have been preferable to see romiplostim modelled after rituximab, which is where the clinical specialists currently position romiplostim in the treatment pathway for ITP, but recognised that this was not the case at the time of the consultation on the first ACD.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that in clinical practice it would be rare for clinicians to use doses of romiplostim that were aimed at obtaining a platelet count above 50\xa0×\xa0109 per litre (as was the case in the trials). Therefore, in practice, aiming for a lower target platelet count would mean less frequent use of romiplostim, and lower doses of romiplostim when it is used. The Committee noted that, in the ERG's exploratory analyses, the ICERs were sensitive to a change in the number of vials used, and concluded that romiplostim would be more cost effective if less romiplostim was used in clinical practice than was assumed in the model.\n\n\n\nThe Committee heard from the clinical specialists that the estimates of the effectiveness of the comparators assumed in the model seemed reasonable and reflected clinical practice.\n\n\n\nThe Committee noted that the model did not sufficiently account for the long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs for romiplostim would be lower.\n\n\n\nThe Committee noted that the submitted model assumed that treatment with romiplostim extended the life of people with chronic ITP by 2–3 years, and that this survival advantage resulted from avoiding severe life-threatening bleeds. The Committee heard from the clinical specialists that this assumption was plausible, and that an additional mortality benefit could result from reducing the number of deaths associated with the long-term adverse effects of the comparator treatments.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nThe manufacturer pooled two sources of utility data: the individual patient level EQ-5D utility values from the two RCTs, and individual person level utility values from the time trade-off study.\n\n\n\n\n\n\n\nThe ERG expressed concerns about the methods by which the manufacturer calculated the utility values in its revised base-case analysis. The ERG noted that the manufacturer simply aggregated the two utility measures, without considering whether it was appropriate to combine data from two different tools and two different samples. The ERG questioned whether the EQ-5D data derived directly from the trials might provide the best estimates of utility values.\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the model did not sufficiently account for long-term adverse effects of some of the comparators. The Committee concluded that had the model incorporated these adverse effects, the ICERs for romiplostim would be lower.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that the manufacturer's revised base-case ICERs would be relevant only for the treatment of patients at the very severe end of the spectrum of ITP.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that the use of rescue therapies, in particular intravenous immunoglobulin in 'watch and rescue', had the greatest impact on the ICER.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee agreed that a starting point for the most plausible ICERs would lie between the ICERs for the manufacturer's realistic and conservative scenarios, and may be slightly higher to account for any small reduction in the amount of rescue therapy seen in clinical practice compared with the romiplostim RCTs. Therefore the Committee concluded that the ICERs would be under £20,000 per QALY gained for the treatment of splenectomised patients, and around £30,000 per QALY gained for the treatment of non-splenectomised patients. In addition, the Committee concluded that two factors would reduce these ICERs: the potentially lower use of romiplostim in clinical practice when clinicians aim for target platelet counts lower than those in the romiplostim RCTs, and the fact that the model excluded the long-term adverse effects of the comparator treatments.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer submitted a patient access scheme. The scheme is a discount on the 250\xa0microgram vial of romiplostim. The size of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether its recommendations raised any equality issues for people with chronic ITP. The Committee was aware that certain religious groups would not consent to the use of blood products, and also that ITP might affect pre-menopausal women more than men. It also understood that romiplostim might reduce the burden of hospital admission for long hours to receive intravenous immunoglobulin, especially for people for whom it is difficult to travel to a hospital. The Committee noted that no specific representations had been made for these groups of people. The Committee concluded that its recommendations do account for the individual needs of people to receive romiplostim, and do not make it more difficult for any particular group to access treatment with romiplostim compared with any other group.\n\n"}
|
https://www.nice.org.uk/guidance/ta221
|
Evidence-based recommendations on romiplostim (Nplate) for treating chronic immune thrombocytopenia in adults.
|
597fdce32e2a6932f2046c99adbe8ba79cb49af0
|
nice
|
Eltrombopag for treating chronic immune thrombocytopenia
|
Eltrombopag for treating chronic immune thrombocytopenia
Evidence-based recommendations on eltrombopag (Revolade) for treating chronic immune thrombocytopenia in adults.
# Guidance
Eltrombopag is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:
their condition is refractory to standard active treatments and rescue therapies or
they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies. Eltrombopag is recommended only if the company provides it with the discount agreed in the patient access scheme.
These recommendations are not intended to affect treatment with eltrombopag that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Eltrombopag (Revolade, GlaxoSmithKline) increases platelet production by activating the thrombopoietin receptor, thereby stimulating platelet production and reducing bleeding. Eltrombopag has a UK marketing authorisation for the treatment of 'chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins)'.
Eltrombopag is taken orally. The summary of product characteristics states that the recommended starting dose is 50 mg once daily but that patients of East Asian ancestry should start eltrombopag at a reduced dose of 25 mg once daily. It recommends that patients should take eltrombopag at least 4 hours before or after antacids, dairy products (or other calcium-containing food products) or mineral supplements containing polyvalent cations (for example, iron, calcium, magnesium, aluminium, selenium and zinc). If, after initial therapy, platelet counts are below the target level (50×109 per litre), the dosage may be increased to a maximum of 75 mg once daily. Treatment should be stopped if the platelet count does not increase sufficiently to avoid clinically significant bleeding after 4 weeks of therapy at a dosage of 75 mg once daily. The summary of product characteristics stipulates that eltrombopag treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases. For full details of dosage and administration, see the summary of product characteristics.
The summary of product characteristics lists the following adverse reactions for eltrombopag as being common (1 or more patient in every 100 and fewer than 1 patient in every 10) or very common (1 or more patient in every 10): psychiatric disorders (insomnia), nervous system disorders (headache and paraesthesia), eye disorders (cataract and dry eye), gastrointestinal disorders (nausea, diarrhoea, constipation and upper abdominal pain), hepatobiliary disorders (increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin and hyperbilirubinaemia, and abnormal hepatic function), skin and subcutaneous tissue disorders (rash, pruritus and alopecia), musculoskeletal and connective tissue disorders (arthralgia, myalgia, muscle spasm and bone pain), and general disorders (fatigue and peripheral oedema). For full details of adverse reactions and contraindications, see the summary of product characteristics.
The 'British national formulary' (BNF; edition 64) states that the net price of a 28‑tablet pack of 25 mg eltrombopag is £770 (a single 25 mg dose costs £27.50). The net price of a 28‑tablet pack of 50 mg eltrombopag is £1540 (a single 50 mg dose costs £55). The cost per patient will vary with dose adjustment and treatment duration. The manufacturer indicated that the average daily cost of eltrombopag (based on the mean dose of eltrombopag in the EXTEND study of 51.3 mg per day) is £56.43. The manufacturer of eltrombopag (GlaxoSmithKline) has agreed a patient access scheme with the Department of Health that makes eltrombopag available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of eltrombopag and a review of this submission by the Evidence Review Group (ERG; section 10).
The manufacturer compared eltrombopag within a standard care pathway with the standard care pathway alone, and separately with romiplostim plus standard care. Standard care was defined as a pathway of care without eltrombopag or romiplostim, that is, without thrombopoietin receptor agonists (non-thrombopoietin receptor agonist pathway). It consisted of a sequence of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine. The manufacturer evaluated the clinical and cost effectiveness of eltrombopag for 2 groups: patients who had had a splenectomy and patients who had not had a splenectomy.
# Clinical effectiveness
The manufacturer presented clinical evidence from 3 randomised controlled trials (RCTs), TRA 100773A, TRA 100773B and RAISE, all of which were placebo-controlled, and from an extension study (EXTEND) that followed patients who had previously participated in the RCTs. The key clinical evidence was obtained from RAISE. The manufacturer also presented a meta-analysis of the results of the 3 eltrombopag RCTs (TRA 100773A, and TRA 100773B and RAISE), and 2 indirect comparisons, 1 between eltrombopag and romiplostim, and the other between eltrombopag and standard care.
RAISE was a phase IIl multicentre RCT (including 9 UK centres) that evaluated the efficacy and safety of eltrombopag plus standard care compared with placebo plus standard care in adults with a platelet count of less than 30×109 per litre. RAISE was a 6‑month study that followed patients for up to 4 weeks after treatment had been stopped, then at 3 and 6 months. Investigators randomised 197 patients to eltrombopag (n=135) or placebo (n=62), and stratified randomisation by baseline platelet counts (15×109 per litre or less, and more than 15×109 per litre), whether or not a patient had had a splenectomy, and whether or not patients were taking medication for immune thrombocytopenia (ITP) at baseline. Approximately 30% of patients had ITP that was refractory to, or had relapsed after, splenectomy. Patients randomised to either treatment group received standard care (that is, treatment with corticosteroids, non-selective immunosuppressants and rescue medication) as needed, plus either 50 mg eltrombopag or placebo, and investigators adjusted the dose of eltrombopag based on individual platelet counts. Over the 6‑month study period, the mean dose of eltrombopag was 54.7 mg per person per day. At the end of the study, 69% of patients randomised to the placebo group and 55% of those randomised to the eltrombopag group had received concomitant ITP medication.
The primary outcome in the RAISE trial was the odds of achieving a platelet count of 50–400×109 per litre at any point during the 6‑month study period. Secondary outcomes included use of rescue treatment (defined as a composite of a newly prescribed ITP medication, an increased dose of a concomitant ITP medication, a platelet transfusion or a splenectomy), incidence and severity of bleeding, and health-related quality of life.
In RAISE, the odds ratio reflecting a response during the 6‑month study period (primary outcome) was 8.2 (99% confidence interval 3.59 to 18.73; p<0.001). At the end of the study, 52% of patients receiving eltrombopag and 17% of those receiving placebo had platelet counts of 50–400×109 per litre. Once treatment was stopped, the proportions of patients with target platelet counts in the eltrombopag and placebo groups converged, reaching 20% for eltrombopag and 14% for placebo after 4 weeks. The manufacturer reported that the response to eltrombopag did not depend on whether or not the patient had had a splenectomy (p value for interaction was 0.562).
The manufacturer carried out a post hoc analysis of platelet response in RAISE, that is, an analysis of how long during the study patients maintained platelet counts of 50–400×109 per litre. The manufacturer categorised platelet response into 'sustained' platelet response, when a patient had a platelet count of 50–400×109 per litre for at least 6 of the last 8 weeks of treatment; 'transient' platelet response, when a patient had a platelet response for 4 or more consecutive weeks during the treatment period; and 'overall' platelet response, when a patient had either a sustained or a transient response. The manufacturer performed the analysis on the intention-to-treat population and on the subset of patients treated with study medication for 6 months or more (that is, including patients who continued taking eltrombopag after the study ended). In both groups, a higher proportion of patients receiving eltrombopag had 'sustained' and 'overall' platelet responses than patients receiving placebo, irrespective of whether or not they had had a splenectomy.
The manufacturer reported results for secondary outcomes in the RAISE trial. Fewer patients randomised to eltrombopag needed protocol-defined rescue treatments than those randomised to placebo (18% and 40% respectively). Among the safety population, the odds of experiencing bleeding (World Health Organization grades 1–4) during the study period were 76% lower among patients who took at least 1 dose of eltrombopag than in those who took at least 1 dose of placebo (odds ratio 0.24; p0.001; CI not given). However, a grade 2‑4 WHO bleed (clinically significant bleeding) did not differ between treatment groups (13% and 10% in the placebo and eltrombopag groups respectively). The manufacturer also performed an analysis of the risk of bleeding at least once at any point during the study, and stratified this analysis by whether or not the patient had had a splenectomy. It found that patients randomised to eltrombopag were statistically significantly less likely to have clinically significant bleeding than those randomised to placebo (33% for eltrombopag and 53% for placebo; OR 0.30; p>0.001); the results of the analysis were also statistically significantly different in favour of eltrombopag for patients who had or had not had a splenectomy.
The manufacturer reported treatment-related adverse reactions for 48 patients (36%) in the eltrombopag group and 18 patients (30%) in the placebo group. The most common adverse reactions experienced by patients receiving eltrombopag were headache (30%), diarrhoea (13%), nausea (12%), nasopharyngitis (10%), upper respiratory tract infection (10%) and fatigue (10%). The manufacturer also reported 2 thromboembolic events in the eltrombopag group and none in the placebo group. A post hoc analysis of patients treated with concomitant medication showed a reduction in corticosteroid-related adverse reactions (including dyspepsia, peripheral oedema and hyperglycaemia) in the eltrombopag group.
The RAISE trial assessed health-related quality of life at baseline, and at 6, 14 and 26 weeks using the SF‑36 instrument, which consists of 8 subdomains and 2 component summary scores (representing physical and mental health). In addition, investigators used subscales of the Functional Assessment of Chronic Illness Therapy for Patients with Thrombocytopenia (FACIT‑Th) and Functional Assessment of Chronic Illness Therapy (FACIT) instruments. The manufacturer reported that patients receiving eltrombopag improved more from baseline to week 26 across most of the SF‑36 domains for health and wellbeing than those receiving placebo. There were statistically significant differences between treatment groups in the change from baseline in the component summaries for physical role, vitality, emotional role and mental health.
The manufacturer did a meta-analysis of TRA 100773A, TRA 100773B and RAISE to establish whether treatment with eltrombopag improved platelet counts compared with placebo. It reported the odds ratios for attaining a platelet count of 50×109 per litre or more 6 weeks after the beginning of the study. In this analysis, eltrombopag was associated with higher odds of responding to treatment compared with placebo, with an odds ratio from a fixed effects model of 8.23 (95% CI 4.68 to 14.48) and an odds ratio from a random effects model of 8.16 (95% CI 4.63 to 14.37); there was little evidence of statistical heterogeneity.
Because there were no head-to-head trials comparing eltrombopag with romiplostim, the manufacturer performed an indirect comparison between the 2 treatments. A systematic review by the manufacturer identified 2 RCTs comparing romiplostim with placebo (both reported in Kuter et al. 2008), which the manufacturer used to compare eltrombopag with romiplostim for efficacy and rates of clinically significant bleeding. Both RCTs evaluated the safety and efficacy of romiplostim in patients with ITP; 1 enrolled 63 patients who had had a splenectomy, and the other enrolled 62 patients who had not. In both studies, patients had platelet counts of 30×109 per litre or less and ITP that was refractory to at least 1 previous treatment. Patients were randomised to either romiplostim plus standard care, or standard care alone, and they received treatment for 6 months. The primary outcome in both studies was the proportion of patients with a durable platelet response (defined as a platelet count of 50×109 per litre or more in 6 or more weekly assessments in the last 8 weeks of treatment), and who did not need rescue medication. The manufacturer combined the results of the 2 studies using standard meta-analytic techniques and then treated them as a single trial to do the indirect comparison.
The manufacturer used the Bucher method in its indirect comparison between eltrombopag (data from RAISE) and romiplostim (data from the 2 Kuter et al. 2008 trials), using placebo as a common comparator. It performed the comparison for the whole population, and separately for patients who had or had not had a splenectomy. The manufacturer considered 2 main outcome measures: platelet response and clinically significant bleeding. The end points for platelet response differed between the eltrombopag and romiplostim trials. In Kuter et al., the primary outcome was the proportion of patients with platelet counts of 50×109 per litre or more in 6 or more weekly assessments during the last 8 weeks of treatment without using rescue medication (durable platelet response), which the manufacturer equated to 'sustained response' as defined in the post hoc analyses of RAISE (section 3.6). The manufacturer further defined an 'overall response' as having either a durable response or a transient response. There were also differences in the definitions of bleeding between the eltrombopag and romiplostim trials: in RAISE, data on bleeding were collected using the WHO bleeding scale and the Common Terminology Criteria for Adverse Events (CTCAE) scale, whereas in Kuter et al., they were collected using an unnamed scale.
The manufacturer performed separate analyses for durable response and overall response. The results of the indirect comparison were framed so that odds ratios of more than 1.00 favoured eltrombopag. When eltrombopag was compared with romiplostim, the odds ratio for attaining a durable response was 0.32 (95% CI 0.03 to 3.14) and that for attaining an overall response was 0.22 (95% CI 0.05 to 1.02). For people who had had a splenectomy, the odds ratios were 0.50 (95% CI 0.01 to 17.3) for durable response and 0.09 (95% CI 0.00 to 2.52) for overall response; for people who had not had a splenectomy, the odds ratios were 0.41 (95% CI 0.04 to 4.80) and 0.34 (95% CI 0.06 to 2.14) for durable response and overall response respectively.
The indirect comparison of rates of bleeding showed that the point estimates favoured eltrombopag in some analyses and romiplostim in others, with no statistically significant differences between the 2 treatments. When eltrombopag was compared with romiplostim, the odds ratio of a clinically significant bleed was 0.60 (95% CI 0.08 to 4.29), and that of a moderate or clinically significant bleed was 1.63 (95% CI 0.4.6 to 5.80).
The manufacturer highlighted that the indirect comparison showed no statistically significant differences between eltrombopag and romiplostim, and suggested that the differences between individual studies should be acknowledged when interpreting the results. The manufacturer indicated that patients differed between RAISE and the 2 Kuter et al. (2008) trials in terms of duration of ITP, previous use of ITP medications, use of concomitant medication, and whether or not patients had had a splenectomy. It also indicated that the design of the trials was different for timing of platelet count assessments, timeframes in which patients were allowed to reduce concomitant ITP medications, definitions of response and definitions of 'period of rescue medication'. The manufacturer pointed out that 2 published clinical guidelines, the 'International consensus report on the investigation and management of primary immune thrombocytopenia' (Provan et al. 2010) and 'The American Society of Haematology 2011 evidence-based practice guideline for immune thrombocytopenia' (Neunert et al. 2011), do not favour 1 treatment over the other. The manufacturer concluded that its indirect comparison between eltrombopag and romiplostim did not provide evidence of clinical superiority for 1 treatment over the other. In absence of evidence to the contrary, the manufacturer concluded that eltrombopag and romiplostim have 'equal efficacy' and applied this assumption to the cost-effectiveness analysis.
The manufacturer presented an indirect comparison between eltrombopag and standard care alone (excluding eltrombopag and romiplostim). In this, the manufacturer restricted the treatments used in standard care to those included in the international consensus report (that is, intravenous immunoglobulin G, anti‑D, rituximab, corticosteroids, vinca alkaloids, mycophenolate mofetil, ciclosporin, cyclophosphamide, danazol and dapsone). The manufacturer's systematic review of treatments used in standard care identified 113 studies (including 20 RCTs). However, the manufacturer altered its inclusion criteria after performing the search, which resulted in the exclusion of most of the identified studies. The manufacturer combined results from 37 studies, including 6 RCTs, to calculate weighted averages of response rate, time to response and duration of response for each drug used within the standard care pathway. The manufacturer pooled data regardless of the definition of response, and calculated the efficacy of each intervention using a simple average. The manufacturer highlighted that the results of the weighted averages for each of the included treatments were obtained mainly from non-randomised, highly heterogeneous, older trials; however, it acknowledged that the results largely reflected the response rates outlined in the international consensus report (Provan et al. 2010) and in Romiplostim for the treatment of chronic immune thrombocytopenia (NICE technology appraisal guidance 221).
# Cost effectiveness
The manufacturer developed a de novo economic model to assess the cost effectiveness of eltrombopag in 2 populations of chronic ITP:
adults who have not had a splenectomy
adults who have had a splenectomy, but whose condition is refractory to previous treatments. The manufacturer assumed that patients who have not had a splenectomy reflect those for whom splenectomy is contraindicated.
The cost-effectiveness model developed by the manufacturer is a state-transition Markov cohort model with a 4‑week cycle length. The model simulates patients with chronic ITP receiving eltrombopag plus standard care, romiplostim plus standard care, or standard care alone. The manufacturer assumed that all patients entering the model have ITP that is refractory to first-line treatment with corticosteroids or immunoglobulins and, if rituximab is considered an appropriate treatment option, patients will have already received it. For patients starting a treatment, the model permits their platelet count to reach 50×109 per litre or more (equal to a response) in the first, second, third or fourth cycle, depending on the time to response associated with each treatment. When the platelet count reaches 50×109 per litre, patients have a treatment-specific probability of losing the response in each cycle, and of receiving rescue therapy when bleeding occurs or a patient is deemed at high risk of bleeding. If the platelet count does not reach 50×109 per litre or patients lose their response, they stop treatment but may receive rescue therapy (intravenous immunoglobulin, anti‑D and corticosteroids), which may result in a temporary platelet response lasting for 1 cycle. During each cycle, a proportion of patients who experience a bleed or whose platelet count does not respond 'exit' the 'non-responder' state and move on to other treatments further down the treatment sequence. Rates of rescue treatment, rates of non-severe bleeds treated in the outpatient setting, and rates of severe bleeds treated in the inpatient setting were lower in patients whose condition responds than in those whose condition does not. Patients in the model who are less likely to bleed are less likely to die.
The economic evaluation compared 3 treatment sequences: a pathway reflecting standard care without a thrombopoietin agonist (sequence 'a': azathioprine, mycophenolate mofetil, ciclosporin, danazol, dapsone, cyclophosphamide, vinblastine and vincristine), a pathway of eltrombopag with standard care (eltrombopag followed by sequence 'a'), and a pathway of romiplostim with standard care (romiplostim followed by sequence 'a'). The sequence of treatments used as standard care reflects that used by the manufacturer of romiplostim in NICE technology appraisal guidance 221, except that rituximab is removed from the sequence for the base-case analysis in the current submission. This is because, as the manufacturer explained, UK local guidance suggests that clinicians offer rituximab to patients before eltrombopag or romiplostim. The manufacturer discounted costs and benefits at an annual 3.5% rate.
The manufacturer submitted 3 separate economic evaluations: a base case, an 'alternative' evaluation and a scenario analysis. In the base case, the manufacturer applied a set of assumptions it deemed most relevant to the decision problem, using NICE technology appraisal guidance 221 as its main source of data and assumptions. The only parameters in the base-case model that the manufacturer sourced from the RAISE and EXTEND trials were the thrombopoietin receptor agonist response rates and the thrombopoietin receptor agonist time on treatment. The alternative evaluation applied data from RAISE and EXTEND, along with clinical evidence retrieved from the manufacturer's systematic review for this appraisal. In the scenario analysis, the manufacturer applied all the assumptions and model inputs used in the economic evaluation for romiplostim in NICE technology appraisal guidance 221 (including those that were not used in the base case) to try to replicate as closely as possible the analysis in that technology appraisal.
In the base case and alternative evaluation, the manufacturer assumed that the response rate (attaining a platelet count of 50–400×109 per litre at any time during the 6‑month study period) for eltrombopag was the same as that observed in the RAISE trial. It also assumed that, if a patient had a platelet response at any time during the 6‑month period, the patient maintained the platelet response while on treatment and had a probability of bleeding and death as if the platelet count had remained elevated. Both the base case and alternative evaluation assumed complete clinical equivalence between eltrombopag and romiplostim, and so a patient in the model taking eltrombopag had the same rate of platelet response as a patient taking romiplostim. The manufacturer assumed that the effectiveness of the 2 treatments was the same because its indirect comparison had not shown that the treatments were different (section 3.15). However, the manufacturer performed sensitivity analyses to test the possibility that romiplostim was more effective than eltrombopag by applying the odds ratio for overall response from its indirect comparison between eltrombopag and romiplostim (0.22).
For treatments considered to be standard care, the manufacturer took response rates for the base case from NICE technology appraisal guidance 221, in which the response rates were calculated from a systematic review that the manufacturer of romiplostim had done. In the alternative evaluation, the manufacturer estimated a response rate for each treatment from its indirect comparison between eltrombopag and treatments comprising standard care (section 3.16).
In the base case and alternative evaluation, time to platelet response for eltrombopag was 15 days (standard error 3.75 days), as observed in RAISE. For romiplostim, the time to response was assumed to be 28 days (standard error 7 days), based on the Kuter et al. (2008) trials. For treatments comprising standard care, time to response from NICE technology appraisal guidance 221 was used in the base case and, for the alternative evaluation, it was obtained from the manufacturer's indirect comparison between eltrombopag and standard care (section 3.16).
Because the manufacturer assumed that eltrombopag and romiplostim were equally effective, it also assumed that time on treatment was the same for eltrombopag and romiplostim. To extrapolate time on treatment over a lifetime horizon, the manufacturer modelled time on treatment as a survival variable using patient-level data on treatment discontinuation from RAISE and EXTEND, and carried out a parametric analysis. The manufacturer found that, among patients whose condition responded to treatment, those who had had a splenectomy spent less time on eltrombopag than those who had not.
For the time on treatment for therapies included in standard care, the manufacturer took values from NICE technology appraisal guidance 221 for its base case, and from the indirect comparison between eltrombopag and standard care (section 3.16) for its alternative evaluation. The manufacturer assumed that time on treatment for standard therapy followed an exponential distribution.
The manufacturer assumed that the risk of bleeding in the model is a function of platelet response irrespective of treatment, so patients with platelet counts of 50×109 per litre or more were at risk of non-severe bleeds (treated as an outpatient), and patients with platelet counts of less than 50×109 per litre had a risk of severe (needing inpatient care) or non-severe bleeds. For its base case, the manufacturer applied the rates of bleeding previously used in NICE technology appraisal guidance 221 for romiplostim. For patients who did not have a platelet response, the rate of severe bleeds applied in the base-case model was 4.3% per month. For its alternative evaluation, the manufacturer used the rate of severe bleeds from RAISE and EXTEND (0.8% per month). The manufacturer assumed that patients whose condition is refractory to all previous treatments are twice as likely to bleed as patients whose condition does not respond to treatment but who are between treatments. The manufacturer took this assumption from NICE technology appraisal guidance 221.
The manufacturer modelled mortality from chronic ITP as a function of severe bleeds in the base case and alternative evaluation. For each bleed for which a patient needed to be hospitalised, the manufacturer applied a mortality rate from Danese et al. (2009), and assumed that this rate doubles for patients whose condition is refractory to all previous treatments. The manufacturer considered that patients would need to be hospitalised for the following categories of bleeds: gastrointestinal haemorrhage, intracranial haemorrhage and haemorrhage resulting from a 'coagulation disorder'.
For the base case, the modelling assumed that only patients with platelet counts of less than 50×109 per litre receive rescue medication, the types and rates of which were used in NICE technology appraisal guidance 221. The rate of rescue therapy for patients who had had a splenectomy was 68% and, for patients who had not had splenectomy, it was 33%. Rescue medications included intravenous immunoglobulin, anti‑D and corticosteroids, and the proportions in which patients received these medications in the model were based on a survey of 169 UK haematologists that the manufacturer of romiplostim did for NICE technology appraisal guidance 221. To estimate the rate of rescue for patients with platelet counts above and below 50×109 per litre for its alternative evaluation, the manufacturer used data from RAISE and EXTEND limited to countries with healthcare resources comparable to the UK.
Adverse events in the model were considered as either severe or 'other'. In the base case and alternative evaluation, the manufacturer assumed that the rates of adverse events for eltrombopag and romiplostim were equivalent and used the rates from NICE technology appraisal guidance 221. The manufacturer estimated adverse event rates for treatments included in standard care from the same technology appraisal.
Although RAISE and EXTEND collected health-related quality-of-life data, the manufacturer chose to use utility data for the base case and alternative evaluation from a study it had identified (Szende et al. 2010). This study developed 6 ITP-related health states that investigators had evaluated using the time trade-off method in 359 members of the UK general public.
The manufacturer did not identify any resource-use studies relevant to the UK from its systematic review of the literature. Therefore, it used unpublished data to estimate costs including the costs of acquisition and administration of the intervention and comparators, and the costs of the rescue medication, as well as the costs of monitoring. The manufacturer took the list prices of the different drugs from the 'British national formulary' (BNF) edition 63 and applied the patient access schemes for eltrombopag and romiplostim. It calculated the average doses of eltrombopag from RAISE and, after the 6‑month study period, it estimated a stable dose from the EXTEND study. For romiplostim, the manufacturer calculated the average doses from Kuter et al. (2008) and assumed that the dose on which a patient is likely to remain (the stable dose) equals the last dose used in the trials (last dose carried forward). Dosages of drugs other than romiplostim and eltrombopag were taken from Provan et al. (2010), the international consensus report, or NICE technology appraisal guidance 221. Eltrombopag and other oral treatments did not have administration costs. Because romiplostim is injected subcutaneously, it can be administered at home or in hospital; the manufacturer assumed that costs were incurred only when the drug was administered in hospital. The cost of bleeds covered drug costs, hospitalisation and follow-up. The manufacturer assumed that all patients, regardless of treatment, needed monitoring by a haematologist and 2 laboratory tests every 4 weeks.
In the manufacturer's base-case analysis, eltrombopag dominated romiplostim (that is, was more effective and less costly) for patients who had or had not had a splenectomy. For the comparison of eltrombopag with standard care, eltrombopag dominated standard care for patients who had had a splenectomy, and its incremental cost-effectiveness ratio (ICER) for patients who had not had a splenectomy was £15,105 per quality-adjusted life year (QALY) gained.
The manufacturer carried out a wide range of sensitivity analyses on the base case, varying 1 parameter at a time. It did not perform one‑way sensitivity analyses on the results of the alternative evaluation or the scenario analysis.
For patients who had had a splenectomy, eltrombopag dominated the standard care pathway in all analyses explored. In comparison with romiplostim, eltrombopag dominated in all analyses except when the model incorporated the odds ratio for overall response between eltrombopag and romiplostim from the manufacturer's indirect comparison (0.22, section 3.13). In this scenario, romiplostim gave 0.56 additional QALYs compared with eltrombopag, but at an additional cost of £95,649; the resulting ICER for eltrombopag compared with romiplostim was £171,156 saved per QALY lost (that is, eltrombopag was less effective but also less expensive than romiplostim).
For patients who had not had a splenectomy, the ICER for eltrombopag compared with standard care remained below £33,000 per QALY gained in all scenarios except when a 6‑month time horizon was used, in which case the ICER for eltrombopag compared with standard care was £74,250 per QALY gained. For the comparison of eltrombopag with romiplostim, eltrombopag dominated romiplostim in all sensitivity analyses, except when the odds ratio for overall response from the indirect comparison was used to estimate the relative efficacy of eltrombopag and romiplostim (OR 0.22, section 3.13). In this scenario, romiplostim offered 0.46 additional QALYs compared with eltrombopag, but at an additional cost of £51,416. This gave an ICER for eltrombopag compared with romiplostim of £110,983 saved per QALY lost.
The manufacturer carried out probabilistic sensitivity analyses to summarise the uncertainty in the base-case ICER. This showed that, for patients who had had a splenectomy, there was a 65% probability of eltrombopag being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and a 70% probability of it being cost effective if the maximum acceptable ICER was £30,000 per QALY gained. For patients who had not had a splenectomy, there was a 54% probability of eltrombopag being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and a 63% probability of it being cost effective if the maximum acceptable ICER was £30,000 per QALY gained.
In the manufacturer's alternative evaluation, eltrombopag dominated romiplostim in the analyses for patients who had or had not had a splenectomy. When eltrombopag was compared with standard care, the ICER for eltrombopag was £61,337 per QALY gained for patients who had had a splenectomy and £95,536 per QALY gained for patients who had not had a splenectomy.
The manufacturer presented a scenario analysis to replicate the analysis for NICE technology appraisal guidance 221. In this, the manufacturer:
assumed that eltrombopag and romiplostim are administered before rituximab in the treatment pathway
assumed that time on treatment followed an exponential distribution (instead of a log‑normal distribution for the base case)
remodelled the response rates for eltrombopag and romiplostim to exclude patients whose condition responded to unlicensed doses
calibrated rescue rates to produce rates when the treatment pathway is set to exclude maintenance treatments
based utility values on pooled EQ‑5D and vignette utility data as per NICE technology appraisal guidance 221
estimated the number of vials of romiplostim needed from NICE technology appraisal guidance 221
set administration costs to £262 per cycle for all treatments and assumed that romiplostim did not incur further costs of administration.
In the scenario analysis, eltrombopag dominated both romiplostim and standard care for all patients.
# Evidence Review Group critique and exploratory analyses
The ERG stated that the manufacturer identified all relevant studies comparing eltrombopag with placebo and presented a suitable meta-analysis. It also considered that the literature review carried out by the manufacturer to estimate the efficacy of standard care was reasonable.
For the indirect comparison of eltrombopag with romiplostim, the manufacturer used a Mantel‑Haenszel fixed-effect approach to combine the results of the 2 Kuter et al. (2008) trials and then used the Bucher method. The ERG expressed the following concerns about this methodology:
Heterogeneity exists between the 2 Kuter et al. trials, and pooling their results may have introduced bias.
Although differences exist between RAISE and the 2 Kuter et al. trials (section 3.15), the ERG felt that it was reasonable that the manufacturer had proceeded with the indirect comparison, but advised caution with respect to the results.
Because the manufacturer had presented the indirect comparison stratified by splenectomy status, the analyses did not preserve randomisation in RAISE, and the ERG considered them to be observational analyses.
The ERG performed an exploratory indirect comparison between eltrombopag and romiplostim for the outcomes of durable and overall response, and for clinically significant and moderate bleeds using a Bayesian network meta-analysis to account for the heterogeneity between the 2 Kuter et al. (2008) studies. For durable response and bleeding, the ERG found similar results to those of the manufacturer. For overall response, the manufacturer had found no statistically significant difference between treatments (OR 0.22; 95% CI 0.05 to 1.02), but the ERG found a statistically significant difference in favour of romiplostim (OR 0.15; 95% credible interval 0.02 to 0.84).
For the indirect comparison of eltrombopag with standard care, the ERG expressed concerns about the methodological rigor of the manufacturer's approach. Because the manufacturer excluded studies from the systematic review after the review had been performed, and had pooled response estimates using a simple weighted average regardless of the definition of response, the ERG considered that bias may exist. The ERG recommended caution when considering the results of this indirect comparison.
The ERG noted that a major weakness in the base-case analysis was that the manufacturer chose not to use data from the eltrombopag RCTs or from its systematic review of the literature, and instead opted to populate the base-case model with estimates from NICE technology appraisal guidance 221 for romiplostim. Because of this, the ERG considered the alternative evaluation to be more appropriate.
The ERG had concerns about the manufacturer's assumption that eltrombopag and romiplostim are equally effective, given the uncertainty around the results of the indirect comparison between eltrombopag and romiplostim (section 3.15).
The ERG noted that the manufacturer did not address the optimal positioning of eltrombopag and romiplostim within the treatment sequence in the model. The manufacturer assumed that eltrombopag and romiplostim followed after rituximab, but preceded other drugs used in standard care. In addition, the ERG pointed out that there is uncertainty about the optimal place of eltrombopag and romiplostim if one is assumed to be more effective than the other. The ERG stated that the manufacturer should have explored additional sequences of treatment.
The ERG had concerns about the manufacturer's assumption that 'response' and 'platelet response' are the same. The ERG noted that, in RAISE, only 60–80% of patients whose condition responded to eltrombopag had a sustained platelet response of more than 50×109 per litre. Because platelet counts drive bleeding rates and mortality in the model, the ERG stated that the manufacturer's assumption would improve the ICERs for eltrombopag and romiplostim.
The manufacturer averaged eltrombopag and romiplostim doses from the relevant trials across patients whose condition had responded and those whose condition had not. The ERG noted that, in the Kuter et al. (2008) trials, the median dose of romiplostim in patients whose condition had responded was 40–60% lower than that across the trial as a whole. The ERG stated that eltrombopag and romiplostim doses should be response-specific.
To model utility, the ERG considered that the manufacturer, in its cost-effectiveness analysis, should have used the SF‑6D health-related quality-of-life data collected from the RAISE and EXTEND trials, which are derived from a validated generic instrument.
The ERG questioned the manufacturer's assumption that the rate of severe bleeding doubles for patients whose ITP is refractory to all previous treatments, noting that these rates were high.
The ERG undertook exploratory sensitivity analyses, varying 1 parameter at a time, on both the base case and alternative evaluation; these included the following:
Applying the overall response rates from the manufacturer's indirect comparison (60% for eltrombopag and 94% for romiplostim for people who had had a splenectomy , and 72% for eltrombopag and 88% for romiplostim for people who had not had a splenectomy ).
In the comparison of eltrombopag with romiplostim, eltrombopag was associated with both fewer QALYs and lower costs than romiplostim. For the base-case analysis, the ICERs suggested savings of £174,503 per QALY lost for people who had had a splenectomy when using eltrombopag instead of romiplostim. The ERG did not explicitly report ICERs for people who had not had a splenectomy from its analyses on the base case, nor did it report the ICERs for any of the subpopulations from its analyses on the alternative evaluation.
In the comparison of eltrombopag with standard care, the ERG reported costs and QALYs for the base-case analysis only for people who had not had a splenectomy, and for the alternative evaluation both for people who had or had not had a splenectomy. In the base-case analysis, eltrombopag dominated standard care for people who had had a splenectomy. For those who had not had a splenectomy, the ICER for eltrombopag compared with standard care was £15,843 per QALY gained. In the alternative evaluation, the ICERs for eltrombopag compared with standard care were £73,335 and £108,336 per QALY gained for people who had and had not had a splenectomy respectively.
Applying the SF‑6D utility data collected from RAISE and EXTEND.
In the comparison of eltrombopag with romiplostim, the ERG found that eltrombopag dominated romiplostim for both the base case and alternative evaluation, irrespective of whether or not the person had had a splenectomy.
For the comparison of eltrombopag with standard care in the base-case analysis, eltrombopag was dominant for people who had had a splenectomy, and gave an ICER of £18,489 per QALY gained for people who had not had a splenectomy. When the ERG applied the utility values to the alternative evaluation, eltrombopag was associated with ICERs of £90,753 and £133,508 per QALY gained for people who had and had not had a splenectomy respectively.
Reducing modelled doses of romiplostim by 40% for people who had had a splenectomy and 60% for people who had not had a splenectomy.
In the comparison of eltrombopag with romiplostim, the ERG found that, despite the lower cost of romiplostim, eltrombopag dominated romiplostim in both the base case and alternative evaluation, irrespective of whether or not people had had a splenectomy.
In response to comments received during consultation on the first appraisal consultation document, the ERG carried out additional exploratory sensitivity analyses on the alternative evaluation, varying 1 parameter at a time, and then varying multiple parameters simultaneously. The ERG stated that, in its opinion, the alternative parameter inputs used in these analyses did not necessarily reflect the most reasonable assumptions. For the following parameters, the ERG:
a. applied the odds ratio of 0.22 for overall response from the manufacturer's indirect comparison between eltrombopag and romiplostim (section 3.13). The resulting overall response rates were 60% for eltrombopag and 87% for romiplostim for patients who had had a splenectomy, and 72% for eltrombopag and 92% for romiplostim for patients who had not had a splenectomy
b. applied the SF‑6D utility data collected from RAISE
c. removed anti‑D treatment from the rescue therapies for patients who had not had a splenectomy
d. applied the odds ratio of 0.15 for overall response from the ERG's indirect comparison between eltrombopag and romiplostim, for which the ERG had used a Bayesian approach (section 3.40). The resulting overall response rates were 60% for eltrombopag and 91% for romiplostim for patients who had had a splenectomy, and 72% for eltrombopag and 94% for romiplostim for patients who had not had a splenectomy
e. applied a dose of romiplostim of 1.54 vials for patients who had had a splenectomy and 1.10 vials for patients who had not had a splenectomy, as calculated by the manufacturer of romiplostim
f. applied a cost per administration of romiplostim equal to £11.50, as suggested by the manufacturer of romiplostim
g. applied the above-listed sensitivity analyses b and c simultaneously
h. applied the above-listed sensitivity analyses b, c and d simultaneously
i. applied the above-listed sensitivity analyses b, c, d and e simultaneously
j. applied the above-listed sensitivity analyses b, c, d, e and f simultaneously.The ERG found that, when varying 1 parameter at a time, eltrombopag dominated romiplostim (that is, gave the same QALYs as romiplostim but at a lower cost) for patients who had or had not had a splenectomy in all analyses, except when the odds ratio of 0.22 or 0.15 was applied for overall response. In these instances, eltrombopag was associated with fewer QALYs and lower costs compared with romiplostim; when the ERG applied the odds ratio of 0.22, the corresponding ICERs suggested savings of £689,084 and £372,782 per QALY lost for patients who had and had not had a splenectomy respectively; when the odds ratio of 0.15 was applied, the ICERs were savings of £638,042 and £350,685 per QALY lost for patients who had and had not had a splenectomy respectively. The ERG estimated from the analyses in which it varied multiple parameters simultaneously that eltrombopag compared with romiplostim was associated with savings per QALY lost greater than £250,000 in all analyses, irrespective of whether or not the patient had had a splenectomy. The ICER from the sensitivity analysis in which all parameters were varied simultaneously (sensitivity analysis j) was £388,799 saved per QALY lost for patients who had had a splenectomy and £270,694 saved per QALY lost for patients who had not had a splenectomy.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of eltrombopag, having considered evidence on the nature of chronic immune thrombocytopenia (ITP) and the value placed on the benefits of eltrombopag by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the nature of the condition with patient experts and clinical specialists, and heard that chronic ITP impacts on quality of life by affecting both the physical and emotional wellbeing of people with the condition. The Committee heard from clinical specialists that the signs and symptoms associated with chronic ITP vary; some people may not have any signs or symptoms, while others may have fatigue and bruise easily. It also heard from patient experts that chronic ITP may cause a patient to worry about the risk of bleeding because significant bleeding would normally cause a person to seek medical care, receive rescue treatment and possibly be hospitalised. The Committee recognised that anxiety related to bleeding may affect work or leisure activities, and, in extreme situations, causes people to become housebound. The Committee heard that family members may also worry on behalf of their relatives about the complications that may result from low platelet counts. The Committee noted that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the calculation of the quality-adjusted life year (QALY).
The Committee discussed the clinical management of chronic ITP. The clinical specialists explained that managing ITP depends on individual circumstances, and the specialists could not define a single treatment pathway as routine practice. The Committee understood that, although clinicians tend to offer active treatment to patients with low platelet counts or before surgery, treatment would not normally be determined solely on the platelet count. The Committee heard that splenectomy would be considered as first-line, second-line or subsequent-line treatment, and that approximately two‑thirds of patients can expect remission after splenectomy. The Committee was aware that splenectomy might be contraindicated in patients at greater risk of bleeding, but that laparoscopic procedures for splenectomy have lowered the risk of bleeding.
The Committee heard from patient experts about the perceived benefits of eltrombopag for patients with chronic ITP. It understood that the adverse reactions of most standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that thrombopoietin receptor agonists (eltrombopag and romiplostim) had a different mode of action and a better adverse reaction profile than these standard treatments. It also understood that eltrombopag, as a daily oral treatment, would represent significant value for some patients with chronic ITP, while other patients would prefer romiplostim administered weekly by subcutaneous injections. The Committee heard from patient experts that some patients take a tablet of eltrombopag only once every 3 days rather than daily. The Committee noted that the summary of product characteristics states potential interactions of eltrombopag with dairy or calcium-containing products. The patient experts felt that, given the severity of ITP and the alternative treatment options available, few patients would have difficulties adhering to eltrombopag's dosage regimen because most would take it before bedtime to minimise the impact of dairy or calcium-containing foods on absorption. The Committee recognised that an oral treatment would add value for patients who have an aversion to needles.
The Committee considered the place of eltrombopag in the treatment pathway for people with chronic ITP and discussed the appropriate comparators, noting the licensed indications for eltrombopag. The Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP, and the specialists' view was that eltrombopag represents an effective approach. The Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab, although rituximab is not licensed for the treatment of chronic ITP.
The Committee discussed the manufacturer's decision problem, noting that the manufacturer compared a pathway of eltrombopag plus standard care with a pathway of standard care alone, and separately with a pathway of romiplostim plus standard care. In all 3 pathways, the manufacturer defined standard care as sequential use of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine. The Committee considered the relevance of the 2 comparator pathways (that is, the pathway of standard care alone, and the pathway of romiplostim plus standard care) in relation to the population in the RAISE trial. The Committee was aware that, since the publication of NICE technology appraisal guidance 221, romiplostim had been introduced into standard care in the NHS in England and Wales, and it was aware that the clinical specialists had indicated that eltrombopag was likely to be used in the same position as romiplostim in the treatment pathway. The Committee noted that the RAISE trial had included all patients with chronic ITP with a low platelet count for whom other treatments had failed, and not only those with severe chronic ITP who are at high risk of bleeding and need frequent courses of rescue therapy (that is, the population for which romiplostim is recommended in NICE technology appraisal guidance 221). The Committee agreed that comparing eltrombopag with the pathway including romiplostim plus standard care would be appropriate only for the same population for which romiplostim is recommended in NICE technology appraisal guidance 221. It also agreed that, for the population in the RAISE trial for which romiplostim is not recommended in NICE technology appraisal guidance 221 (that is, patients who did not have severe disease and a high risk of bleeding), comparing eltrombopag with the pathway of standard care alone would be appropriate. The Committee therefore concluded that both comparator pathways described in the manufacturer's decision problem were appropriate, but for 2 different populations.
# Clinical effectiveness
The Committee considered the evidence on the clinical effectiveness of eltrombopag, noting that the evidence was derived mainly from the RAISE trial. It noted that the available evidence showed that, for people with chronic ITP for whom other treatments had failed, eltrombopag was clinically effective when compared with placebo in attaining the target platelet count and reducing the need for rescue therapy.
The Committee discussed the safety and tolerability of eltrombopag and noted that the adverse reactions other than bleeding were similar between people who took eltrombopag or placebo in the RAISE trial. The Committee noted the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had better safety profiles than most standard treatments for chronic ITP.
The Committee discussed whether the manufacturer's indirect comparison between eltrombopag and romiplostim was appropriate. The Committee was aware that both the manufacturer and the Evidence Review Group (ERG) had advised caution when interpreting the results of the indirect comparison because of differences in baseline patient characteristics between RAISE and the 2 Kuter et al. (2008) trials for: duration of ITP, the proportion of patients who had received more than 3 prior ITP therapies, and the proportion of patients receiving concomitant ITP medication at baseline. The Committee discussed the sources of heterogeneity between the trials, and heard from the clinical specialists that the romiplostim trials were conducted before the eltrombopag trials; the Committee recognised that this may have caused more patients with severe chronic ITP to be enrolled into the earlier romiplostim trials. The Committee agreed that the differences between the RAISE trial and the 2 Kuter et al. trials may have introduced bias in the indirect comparison, but it concluded that it would be appropriate to perform an indirect comparison between the 2 treatments.
The Committee considered the manufacturer's indirect comparison and the ERG's exploratory analysis between eltrombopag and romiplostim, noting the different statistical approaches used to estimate the results. The Committee noted that, for the outcomes durable response and overall response, the manufacturer's indirect comparison gave odds ratios lower than 1 (favouring romiplostim), but the confidence intervals around those odds ratios suggested that the differences between eltrombopag and romiplostim were not statistically significant; for example, the odds ratio for overall response was 0.22 (in favour of romiplostim) with an upper limit of the 95% confidence interval of 1.02. The Committee understood that the statistical approach used by the manufacturer did not account for the heterogeneity between the 2 Kuter et al. (2008) trials, whereas the ERG's exploratory indirect comparison, which used a Bayesian approach, treated the Kuter et al. trials separately. The Committee noted that, for overall response, the ERG's indirect comparison suggested a statistically significant difference in favour of romiplostim (odds ratio 0.15). For durable response, the Committee noted that the ERG found non-significant differences similar to those found by the manufacturer. The Committee was aware that the ERG's results depended on the degree of heterogeneity it assumed. The Committee agreed that the point estimates in both the manufacturer's and the ERG's analyses were associated with considerable uncertainty.
The Committee considered the relative effectiveness of eltrombopag and romiplostim in light of the manufacturer's indirect comparison and the ERG's exploratory analysis. It noted that the manufacturer interpreted the effectiveness of the 2 drugs as the same (that is, not different) on the basis that its indirect comparison did not show a statistically significant difference between them. The Committee heard from the clinical specialists that, while it is difficult to know whether 1 treatment is superior to the other, the use of eltrombopag and romiplostim in clinical practice is broadly interchangeable. The Committee accepted that the manufacturer's indirect comparison may have underestimated the clinical effectiveness of romiplostim given that the romiplostim trials preceded those for eltrombopag, and so the clinical trials for romiplostim may have enrolled patients whose condition was relatively more severe. The Committee noted that more patients in the romiplostim trials had received multiple previous therapies, which suggests that they better reflected patients whose condition had not responded than those in the eltrombopag trials. The Committee agreed that the available evidence suggested that romiplostim was likely to be more effective than eltrombopag rather than equally effective, and so it did not agree with the manufacturer's assumption used for the modelling that the treatments were equally effective. The Committee concluded that the most plausible odds ratio for overall response for eltrombopag compared with romiplostim would be less than 1.00 but, given the uncertainty around the point estimates obtained from the indirect comparison, it could not determine the likely value of this ratio.
The Committee considered the clinical effectiveness of eltrombopag compared with the pathway of standard care alone. The Committee understood that there was no direct evidence comparing eltrombopag with standard care, and so discussed the manufacturer's indirect comparison (section 3.16). The Committee noted that the evidence for treatments used in standard care was derived mainly from non-randomised, highly heterogeneous trials. It also noted that the manufacturer had altered its inclusion criteria after performing the literature review, and pooled response estimates using a simple weighted average of treatment groups. The Committee agreed that the indirect comparison lacked methodological rigor, and concluded that the results of the indirect comparison were not sufficiently robust to compare eltrombopag with the pathway of standard care alone.
# Cost effectiveness
The Committee considered the manufacturer's cost-effectiveness analyses, and the ERG's critique of the analyses. The Committee agreed that, of the 3 economic evaluations (the base case, the alternative evaluation and the scenario analysis), the alternative evaluation represented the most valid analysis because the modelling applied data derived directly from the pivotal trials of eltrombopag and the manufacturer's own systematic review.
The Committee considered the cost effectiveness of eltrombopag compared with the pathway of standard care alone in the alternative evaluation, that is, for people with ITP for whom romiplostim is not recommended. It noted that the manufacturer had estimated response rates and time on treatment for drugs used in standard care from its indirect comparison of treatments used in standard care (section 3.22), and used the estimates in the alternative evaluation. The Committee, however, agreed that the indirect comparison lacked methodological rigor (section 4.12), and that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone. The Committee concluded that it could not recommend eltrombopag for patients who do not have severe disease and a high risk of bleeding.
The Committee then considered the cost effectiveness of eltrombopag compared with the pathway of standard care plus romiplostim in the alternative evaluation. It noted that the results of this comparison would apply only to people with severe chronic ITP and a persistent high risk of bleeding (that is, people for whom romiplostim is recommended in NICE technology appraisal guidance 221 for romiplostim). The Committee considered the sensitivity analyses in which romiplostim was more effective than eltrombopag, and noted that neither the manufacturer nor the ERG had provided incremental cost-effectiveness ratios (ICERs) for eltrombopag compared with romiplostim. However, from the costs and QALYs presented by the ERG from its exploratory sensitivity analyses on the alternative evaluation (section 3.49), the Committee initially estimated that the ICERs would be more than £400,000 saved per QALY lost for patients who had or had not had a splenectomy. The Committee noted that a comment received during consultation on the first appraisal consultation document indicated that it would be more appropriate to include in the sensitivity analyses the odds ratio for overall response of 0.15 estimated from the ERG's indirect comparison (section 3.40). The Committee heard from the ERG that, in response to this comment, it had carried out sensitivity analyses within the alternative evaluation, varying the parameter for overall response rate in the model (section 3.50). The Committee noted that, when the ERG applied an odds ratio of 0.22 to derive overall response rates, the ICERs for eltrombopag compared with romiplostim were savings of £689,000 and £373,000 per QALY lost for patients who had and had not had a splenectomy respectively; when the ERG applied an odds ratio of 0.15, these ICERs decreased to £638,000 and £351,000 per QALY lost respectively. The Committee was aware that the clinical specialists felt that eltrombopag and romiplostim were broadly interchangeable (section 4.11), and it concluded that, if the odds ratio for overall response moved towards 1.0 (as implied by the clinical specialists' willingness to substitute 1 treatment for another), the ICERs would further increase leading to further savings per QALY lost.
The Committee noted that the ERG questioned the source of the data on health-related quality of life used in the manufacturer's model because the manufacturer did not use the SF‑36 health-related quality-of-life data collected from RAISE and EXTEND that it had mapped on to the SF‑6D. The Committee noted that the manufacturer applied the SF‑6D utility data in a sensitivity analysis within the base case, but not within the alternative evaluation favoured by the Committee. The Committee noted comments received during consultation on the second appraisal consultation document suggesting that it would be more appropriate to use, in sensitivity analyses within the alternative evaluation, EQ‑5D utility data obtained either from mapping SF‑36 data on to the EQ‑5D or from other studies from the literature identified by the manufacturer (such as Szende et al. 2010). The Committee heard that mathematical algorithms exist to map from SF‑36 (used in RAISE and EXTEND) on to EQ‑5D, and that, because no single algorithm is considered more valid than others, the EQ‑5D data obtained from using a particular algorithm would be associated with further uncertainty. It also heard from the ERG that the Szende et al. study used by the manufacturer in its base-case analysis did not report EQ‑5D utility values. The Committee was aware that the reference case outlined in NICE's Guide to the methods of technology appraisal states that EQ‑5D is the preferred measure of health-related quality of life in adults. However, in the absence of EQ‑5D data, the Committee concluded that, of the utility data available, the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.
The Committee discussed the ERG's concern about the dosing of romiplostim in the analyses (section 3.46). It noted that the doses of romiplostim used in the manufacturer's model did not depend on whether or not the patient's condition had responded, whereas in the Kuter et al. (2008) trials, the median dose of romiplostim in patients whose condition had responded was 40–60% lower than that across the trial as a whole. The Committee noted a comment received during consultation on the second appraisal consultation document suggesting to set the dose of eltrombopag after 24 weeks of treatment equal to the average dose from week 12 to week 23 in the RAISE trial (which was 7–12% higher than the originally modelled doses) to link the doses of eltrombopag with the modelled response rates from RAISE. The Committee discussed the impact of this suggestion on the cost effectiveness of eltrombopag compared with romiplostim, and heard from the ERG that the proposed dosing for eltrombopag would only minimally affect the relative cost effectiveness of the 2 treatments. In addition, the Committee was aware that patient experts indicated that some patients take a tablet of eltrombopag only once every 3 days rather than daily (section 4.4), which implies that the dose of eltrombopag in clinical practice might in fact be lower than that observed in the RAISE trial. The Committee concluded that it was appropriate to use a median dose of romiplostim that is 40–60% lower than that used in the Kuter et al. trials and that the dose of eltrombopag used in the model was appropriate.
The Committee noted that comments received during consultation on the first appraisal consultation document raised concerns about some of the parameters used in the model, namely that the duration of treatment for romiplostim is longer than that for eltrombopag; that doses of romiplostim should be calculated in line with the approach used for NICE technology appraisal guidance 221 (that is, 1.54 vials for patients who had had a splenectomy and 1.10 vials for patients who had not had a splenectomy); that time to response for eltrombopag should be equal to that for romiplostim; that an in-hospital cost of £11.75 per administration for romiplostim should be used; and that anti‑D should be excluded as a rescue therapy for patients who had not had a splenectomy.
The Committee considered these comments as follows:
With regard to duration of treatment, the Committee heard from the ERG that the curves used to determine time on treatment within the model are specific to patients whose condition responded to eltrombopag; and, even if response rates differ between eltrombopag and romiplostim, it may still be reasonable to assume that duration of treatment is similar for both drugs. The ERG explained that the assumption of equal duration of treatment does not rely on the assumption of equal response rates and that, in the absence of other robust evidence, it was acceptable to assume equal time on treatment. The Committee concluded that no sensitivity analyses varying the duration of treatment parameter were needed.
With regard to time to response, the Committee heard from the ERG that, in the model, for both eltrombopag and romiplostim, all patients receive 1 full 4‑week cycle of treatment, at the end of which patients whose condition does not respond stop treatment. The ERG indicated that the assumption about time to response does not affect the relative costs and QALYs associated with eltrombopag and romiplostim in the model. The Committee accepted that the ICERs were not sensitive to the assumptions underlying time to response, and concluded that it did not need to consider those assumptions further.
With regard to the cost of administering romiplostim, the Committee noted that the model included an average in-hospital cost of £204.81 per administration. The Committee was aware that the manufacturer of eltrombopag assumed that patients receive romiplostim in hospital for the first 4 weeks, and that 72% self-administer thereafter. Although the Committee agreed that the cost of administering romiplostim used in the model was likely to be an overestimate, it considered the alternative cost of £11.75, as suggested in the comments received during consultation on the first appraisal consultation document, to be too low.
With regard to the use of anti‑D as a rescue therapy, the Committee agreed that it would be appropriate to exclude it from the model.
The Committee noted the comment received during consultation on the second appraisal consultation document, which suggested that it would be more appropriate to model higher rates of bleed and rescue therapy from the Kuter et al. (2008) trial to reflect the severely affected population for which romiplostim is recommended. The Committee recognised that rates of bleeding and use of rescue therapies are important parameters in the model. It noted that both rates were higher in the romiplostim trials (Kuter et al.) than in the eltrombopag trials (RAISE and EXTEND). It heard from the ERG that the SF‑6D utility data (favoured by the Committee, section 4.16) for bleeding events were aligned with the definition of bleeds in RAISE, but not with the definition in the Kuter et al. trials. The Committee was aware that neither the manufacturer nor the ERG applied the bleed and rescue rates from Kuter et al. in sensitivity analyses within the alternative evaluation favoured by the Committee. The Committee noted that there was no information available on bleeding and rescue rates in clinical practice, but it heard from the ERG that including the higher rates from Kuter et al. would not lower the cost effectiveness of eltrombopag compared with romiplostim below £30,000 saved per QALY lost. It accepted that, if the higher rates of bleeds and rescue therapy from Kuter et al. were more pertinent to the population with severe ITP for which romiplostim is recommended and for which eltrombopag was being considered, this would have an impact on the ICERs in favour of romiplostim, but it would be extremely unlikely to affect the relative cost effectiveness of eltrombopag and romiplostim to a degree where the Committee would change its recommendations. The Committee concluded that it did not need to consider further sensitivity analyses incorporating the higher bleed and rescue rates from the Kuter et al. trials.
The Committee discussed the most plausible ICERs for eltrombopag compared with romiplostim. The Committee noted that the ERG did not initially report ICERs for eltrombopag compared with romiplostim from its exploratory sensitivity analyses within the alternative evaluation. It was also aware that no ICERs were available that incorporated all the parameter inputs favoured by the Committee within a single analysis. Therefore, the Committee considered the additional sensitivity analyses carried out by the ERG in response to comments on the first appraisal consultation document (section 4.18). The Committee agreed that romiplostim is likely to be more clinically effective than eltrombopag; that it was appropriate to use the SF‑6D utility data collected from RAISE and EXTEND, a lower romiplostim dose and a lower administration cost for romiplostim, and to exclude anti‑D. The Committee considered the analysis that mirrored this, and noted that the resulting ICERs for eltrombopag compared with romiplostim were £389,000 saved per QALY lost for patients who had had a splenectomy and £271,000 saved per QALY lost for patients who had not had a splenectomy. The Committee acknowledged that these ICERs are associated with considerable uncertainty. It accepted that the ICERs would be higher (in favour of eltrombopag) when accounting for a romiplostim administration cost in hospital of more than £11.50, or if romiplostim relative to eltrombopag was less effective (that is, if the odds ratio for overall response was greater than the 0.15 used in the ERG's analyses). The Committee also accepted that the ICER would be lower (in favour of romiplostim) if the rates of bleeding and rescue therapy in clinical practice were higher than those applied in the cost-effectiveness analysis. The Committee accepted that there was a degree of uncertainty surrounding the ICER for eltrombopag compared with romiplostim. However, it was satisfied that, based on the evidence it had seen and the comments received during consultation on 2 appraisal consultation documents, eltrombopag can be considered a cost-effective use of NHS resources. The Committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The Committee concluded that eltrombopag should be recommended as specified in its marketing authorisation (that is, in adults who have had a splenectomy and whose condition is refractory to other treatments, or as a second-line treatment in adults who have not had a splenectomy because surgery is contraindicated) as an option for treating adults with chronic ITP, but only if their condition is refractory to standard active treatments and rescue therapies, or they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and the manufacturer provides eltrombopag with the discount agreed in the patient access scheme.
The Committee noted that comments received in response to consultation on the appraisal consultation documents suggested that a specialist haematologist should supervise treatment with eltrombopag. The Committee agreed that, because the summary of product characteristics stipulates that eltrombopag treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases (section 2.2), it did not need to repeat this in its recommendations.
The Committee was aware of comments received in response to the consultation on the appraisal consultation documents expressing concerns about the wording of the preliminary recommendation for eltrombopag, which, unlike the recommendation for romiplostim in NICE technology appraisal guidance 221, included reference to whether a person had or had not had a splenectomy. While the Committee appreciated the concerns raised, it was aware that the wording of the marketing authorisations for eltrombopag and romiplostim stipulates that both of these treatments should only be used if a person has had a splenectomy or has not had a splenectomy because such surgery is contraindicated. The Committee acknowledged that NICE cannot recommend a treatment outside its marketing authorisation, and agreed that the wording of the recommendation in section 1 should reflect the wording of the marketing authorisation for eltrombopag.
The Committee discussed the limited published data on the long-term safety and effectiveness for both eltrombopag and romiplostim (sections 4.8 and 4.11), and on observed rates of bleeding and rescue therapy in clinical practice (section 4.20). The Committee considered that the collection of more data on the clinical effectiveness of both eltrombopag and romiplostim would be useful for future appraisals of treatments for chronic ITP because it would enable a more robust estimate of the clinical and cost effectiveness of the treatments. Given the difficulties of conducting randomised controlled trials and in generalising their results to clinical practice, the Committee supported generating and analysing observational data including, but not limited to, the existing UK ITP Registry, which collects data on the long-term outcomes of patients treated with eltrombopag and romiplostim.
The Committee discussed the differences in the wording of the guidance developed in this appraisal and the wording in the recommendations for romiplostim in NICE technology appraisal guidance 221, the latter of which were developed some time ago. The Committee concluded that it is necessary to ensure clarity around the fact that the recommendations for eltrombopag and romiplostim are for exactly the same patient population.
# Summary of Appraisal Committee's key conclusions
TA293
Appraisal title: Eltrombopag for treating chronic immune thrombocytopenia (review of technology appraisal 205)
Section
Key conclusion
Eltrombopag is recommended as an option for treating adults with chronic immune thrombocytopenia, only if:
their condition is refractory to standard active treatments and rescue therapies or
they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies.
Eltrombopag is recommended only if the company provides it with the discount agreed in the patient access scheme.
For people with severe chronic ITP who are at high risk of bleeding and need frequent courses of rescue therapy (that is, the population for which romiplostim is recommended in NICE technology appraisal guidance 221), the Committee agreed that eltrombopag was less effective and less costly than romiplostim. The analysis that mirrored the Committee's preferred assumptions gave ICERs of more than £250,000 saved per QALY lost. The Committee noted that, in this situation, the higher the ICER, the more cost effective a treatment becomes. The Committee therefore concluded that eltrombopag can be considered a cost-effective use of NHS resources in this population.
The Committee agreed that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone. Therefore, it concluded that it could not recommend eltrombopag for patients who do not have severe disease and a high risk of bleeding (that is, the population for which romiplostim is not recommended in NICE technology appraisal guidance 221).
Current practice
Clinical need of patients, including the availability of alternative treatments
The clinical specialists indicated that the signs and symptoms associated with chronic ITP vary. Chronic ITP may cause a patient to worry about the risk of bleeding, which may affect the ability of patients with chronic ITP to lead a normal life. The Committee recognised that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives.
The Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee understood that eltrombopag had a better adverse reaction profile than most standard treatments.
The Committee understood that a daily oral treatment would represent significant value for some patients with chronic ITP.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab.
Adverse reactions
The Committee understood that the adverse reactions of most standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that eltrombopag had a better adverse reaction profile than those standard treatments.
The Committee noted the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had better safety profiles than most standard treatments for chronic ITP.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The evidence on the clinical effectiveness of eltrombopag was derived mainly from the RAISE trial.
In the manufacturer's indirect comparison between eltrombopag and romiplostim, the Committee agreed that heterogeneity exists between RAISE and the 2 Kuter et al. (2008) trials, which may have introduced bias in the indirect comparison. However, the Committee concluded that it would be appropriate to perform an indirect comparison between both treatments.
Relevance to general clinical practice in the NHS
No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated by the evidence
The Committee heard from the clinical specialists that the romiplostim trials were conducted before the eltrombopag trials; the Committee recognised that this may have caused more patients with severe chronic ITP to be enrolled into the earlier romiplostim trials. The Committee also heard that the use of eltrombopag and romiplostim in clinical practice is broadly interchangeable.
The Committee noted that the different statistical approaches used to perform an indirect comparison between eltrombopag and romiplostim gave an odds ratio for overall response that was statistically significantly in favour of romiplostim in the ERG's analysis but not in the manufacturer's. The Committee understood that the statistical approach used by the manufacturer did not account for heterogeneity between the 2 Kuter et al. (2008) trials, and that the ERG's results depended on the degree of heterogeneity it assumed. The Committee agreed that the point estimates in both the manufacturer's and the ERG's analyses were associated with considerable uncertainty.
The Committee agreed that the manufacturer's indirect comparison between eltrombopag and the pathway of standard care alone was not sufficiently robust to compare eltrombopag with the pathway of standard care alone.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The available evidence showed that eltrombopag was clinically effective when compared with placebo.
The odds ratio for overall response from the manufacturer's indirect comparison between eltrombopag and romiplostim was 0.22, and that from the ERG's indirect comparison was 0.15. Only the latter was statistically significant.
The Committee concluded that the most plausible odds ratio for overall response for eltrombopag compared with romiplostim would be less than 1.00 but, given the uncertainty around the point estimates obtained from the indirect comparison, it could not determine the likely value of this ratio.
For the comparison of eltrombopag with the pathway of standard care alone, the Committee concluded that the results of the indirect comparison between the 2 pathways of care were not sufficiently robust to estimate a relative effect size.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer presented 3 economic analyses: a base case, an alternative evaluation and a scenario analysis. In all 3 analyses, the manufacturer compared eltrombopag with a pathway of standard care alone, and separately with a pathway of romiplostim plus standard care.
The Committee agreed that the alternative evaluation represented the most valid analysis because the modelling applied data derived directly from the pivotal trials of eltrombopag and the manufacturer's own systematic review.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone because the model incorporated data based on the manufacturer's indirect comparison of treatments used in standard care that, in the Committee's opinion, lacked methodological rigor.
The Committee agreed that romiplostim is likely to be more clinically effective than eltrombopag, that it was appropriate to use the SF‑6D utility data collected from RAISE and EXTEND, a lower romiplostim dose and a lower administration cost for romiplostim, and to exclude anti‑D. The Committee acknowledged that the ICERs, even those reflecting its favoured parameters and assumptions, are associated with considerable uncertainty.
The Committee noted that there was no information available on bleeding and rescue rates observed in clinical practice. It accepted that, if these rates are higher than those applied in the model, this would have an impact on the ICERs in favour of romiplostim, but it would be extremely unlikely to affect the relative cost effectiveness of eltrombopag and romiplostim to a degree where the Committee would change its recommendations.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the manufacturer did not use the health-related quality-of-life data collected from RAISE and EXTEND. The Committee concluded that, of the utility data available, the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.
The Committee considered that the EQ‑5D data obtained from using a particular mapping algorithm would be associated with further uncertainty and, in the absence of other EQ‑5D data, the Committee concluded that the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.
The Committee noted that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the calculation of the QALY.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee considered the cost effectiveness of eltrombopag compared with the pathway of standard care plus romiplostim in the alternative evaluation. It noted that the results of this comparison would apply only to people with severe chronic ITP and a persistent high risk of bleeding (that is, people for whom romiplostim is recommended in NICE technology appraisal guidance 221 for romiplostim).
What are the key drivers of cost effectiveness?
The key driver of cost effectiveness is the relative effect size of eltrombopag and romiplostim. The Committee did not agree with the manufacturer's assumption that eltrombopag and romiplostim were equally effective, and so considered the sensitivity analyses in which romiplostim was more effective than eltrombopag.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered the analysis that mirrored its preferred assumptions and parameters. It noted that the resulting ICERs for eltrombopag compared with romiplostim were £389,000 saved per QALY lost for patients who had had a splenectomy and £271,000 saved per QALY lost for patients who had not had a splenectomy.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer of eltrombopag has agreed a patient access scheme with the Department of Health that makes eltrombopag available with a discount. The size of the discount is commercial in confidence.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
During consultation on the second appraisal consultation document a consultee highlighted under the heading 'Unlawful discrimination or groups who will be disadvantaged?' that the 'draft guidance puts doctors in an indefensible position and lays the NHS wide open to a legal class action by patients that are forced into a surgical procedure that may not be relevant to, or in fact resolve, their ITP.' This comment does not highlight any unlawful discrimination or groups of patients with ITP that could be disadvantaged. The wording of the marketing authorisation for eltrombopag stipulates that eltrombopag should only be used if a person has had a splenectomy or has not had a splenectomy because such surgery is contraindicated. The regulatory agency has stated that the benefit-harm balance for eltrombopag could not be considered favourable for patients for whom a splenectomy remained a therapeutic option. NICE has to give recommendations in line with the marketing authorisation.
# Recommendations for further research
The Committee recommends that research should be carried out to directly compare eltrombopag with non-thrombopoietin receptor agonist treatments routinely used in UK clinical practice.
The Committee recommends research generating and analysing observational data including, but not limited to, the existing UK ITP Registry, which collects data on the long-term outcomes of patients treated with eltrombopag and romiplostim.
|
{'Guidance': 'Eltrombopag is recommended as an option for treating chronic immune thrombocytopenia in adults, only if:\n\ntheir condition is refractory to standard active treatments and rescue therapies or\n\nthey have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies. Eltrombopag is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nThese recommendations are not intended to affect treatment with eltrombopag that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Eltrombopag (Revolade, GlaxoSmithKline) increases platelet production by activating the thrombopoietin receptor, thereby stimulating platelet production and reducing bleeding. Eltrombopag has a UK marketing authorisation for the treatment of 'chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1\xa0year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins)'.\n\nEltrombopag is taken orally. The summary of product characteristics states that the recommended starting dose is 50\xa0mg once daily but that patients of East Asian ancestry should start eltrombopag at a reduced dose of 25\xa0mg once daily. It recommends that patients should take eltrombopag at least 4\xa0hours before or after antacids, dairy products (or other calcium-containing food products) or mineral supplements containing polyvalent cations (for example, iron, calcium, magnesium, aluminium, selenium and zinc). If, after initial therapy, platelet counts are below the target level (50×109\xa0per litre), the dosage may be increased to a maximum of 75\xa0mg once daily. Treatment should be stopped if the platelet count does not increase sufficiently to avoid clinically significant bleeding after 4\xa0weeks of therapy at a dosage of 75\xa0mg once daily. The summary of product characteristics stipulates that eltrombopag treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases. For full details of dosage and administration, see the summary of product characteristics.\n\nThe summary of product characteristics lists the following adverse reactions for eltrombopag as being common (1\xa0or more patient in every 100 and fewer than 1\xa0patient in every 10) or very common (1\xa0or more patient in every 10): psychiatric disorders (insomnia), nervous system disorders (headache and paraesthesia), eye disorders (cataract and dry eye), gastrointestinal disorders (nausea, diarrhoea, constipation and upper abdominal pain), hepatobiliary disorders (increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin and hyperbilirubinaemia, and abnormal hepatic function), skin and subcutaneous tissue disorders (rash, pruritus and alopecia), musculoskeletal and connective tissue disorders (arthralgia, myalgia, muscle spasm and bone pain), and general disorders (fatigue and peripheral oedema). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe 'British national formulary' (BNF; edition\xa064) states that the net price of a 28‑tablet pack of 25\xa0mg eltrombopag is £770 (a single 25\xa0mg dose costs £27.50). The net price of a 28‑tablet pack of 50\xa0mg eltrombopag is £1540 (a single 50\xa0mg dose costs £55). The cost per patient will vary with dose adjustment and treatment duration. The manufacturer indicated that the average daily cost of eltrombopag (based on the mean dose of eltrombopag in the EXTEND study of 51.3\xa0mg per day) is £56.43. The manufacturer of eltrombopag (GlaxoSmithKline) has agreed a patient access scheme with the Department of Health that makes eltrombopag available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section\xa09) considered evidence submitted by the manufacturer of eltrombopag and a review of this submission by the Evidence Review Group (ERG; section\xa010).\n\nThe manufacturer compared eltrombopag within a standard care pathway with the standard care pathway alone, and separately with romiplostim plus standard care. Standard care was defined as a pathway of care without eltrombopag or romiplostim, that is, without thrombopoietin receptor agonists (non-thrombopoietin receptor agonist pathway). It consisted of a sequence of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine. The manufacturer evaluated the clinical and cost effectiveness of eltrombopag for 2\xa0groups: patients who had had a splenectomy and patients who had not had a splenectomy.\n\n# Clinical effectiveness\n\nThe manufacturer presented clinical evidence from 3\xa0randomised controlled trials (RCTs), TRA\xa0100773A, TRA\xa0100773B and RAISE, all of which were placebo-controlled, and from an extension study (EXTEND) that followed patients who had previously participated in the RCTs. The key clinical evidence was obtained from RAISE. The manufacturer also presented a meta-analysis of the results of the 3\xa0eltrombopag RCTs (TRA\xa0100773A, and TRA\xa0100773B and RAISE), and 2\xa0indirect comparisons, 1 between eltrombopag and romiplostim, and the other between eltrombopag and standard care.\n\nRAISE was a phase\xa0IIl multicentre RCT (including 9\xa0UK centres) that evaluated the efficacy and safety of eltrombopag plus standard care compared with placebo plus standard care in adults with a platelet count of less than 30×109\xa0per litre. RAISE was a 6‑month study that followed patients for up to 4\xa0weeks after treatment had been stopped, then at 3\xa0and 6\xa0months. Investigators randomised 197\xa0patients to eltrombopag (n=135) or placebo (n=62), and stratified randomisation by baseline platelet counts (15×109\xa0per litre or less, and more than 15×109\xa0per litre), whether or not a patient had had a splenectomy, and whether or not patients were taking medication for immune thrombocytopenia (ITP) at baseline. Approximately 30% of patients had ITP that was refractory to, or had relapsed after, splenectomy. Patients randomised to either treatment group received standard care (that is, treatment with corticosteroids, non-selective immunosuppressants and rescue medication) as needed, plus either 50\xa0mg eltrombopag or placebo, and investigators adjusted the dose of eltrombopag based on individual platelet counts. Over the 6‑month study period, the mean dose of eltrombopag was 54.7\xa0mg per person per day. At the end of the study, 69% of patients randomised to the placebo group and 55% of those randomised to the eltrombopag group had received concomitant ITP medication.\n\nThe primary outcome in the RAISE trial was the odds of achieving a platelet count of 50–400×109\xa0per litre at any point during the 6‑month study period. Secondary outcomes included use of rescue treatment (defined as a composite of a newly prescribed ITP medication, an increased dose of a concomitant ITP medication, a platelet transfusion or a splenectomy), incidence and severity of bleeding, and health-related quality of life.\n\nIn RAISE, the odds ratio reflecting a response during the 6‑month study period (primary outcome) was 8.2 (99% confidence interval [CI] 3.59 to 18.73; p<0.001). At the end of the study, 52% of patients receiving eltrombopag and 17% of those receiving placebo had platelet counts of 50–400×109\xa0per litre. Once treatment was stopped, the proportions of patients with target platelet counts in the eltrombopag and placebo groups converged, reaching 20% for eltrombopag and 14% for placebo after 4\xa0weeks. The manufacturer reported that the response to eltrombopag did not depend on whether or not the patient had had a splenectomy (p value for interaction was 0.562).\n\nThe manufacturer carried out a post hoc analysis of platelet response in RAISE, that is, an analysis of how long during the study patients maintained platelet counts of 50–400×109\xa0per litre. The manufacturer categorised platelet response into 'sustained' platelet response, when a patient had a platelet count of 50–400×109\xa0per litre for at least 6 of the last 8\xa0weeks of treatment; 'transient' platelet response, when a patient had a platelet response for 4\xa0or more consecutive weeks during the treatment period; and 'overall' platelet response, when a patient had either a sustained or a transient response. The manufacturer performed the analysis on the intention-to-treat population and on the subset of patients treated with study medication for 6\xa0months or more (that is, including patients who continued taking eltrombopag after the study ended). In both groups, a higher proportion of patients receiving eltrombopag had 'sustained' and 'overall' platelet responses than patients receiving placebo, irrespective of whether or not they had had a splenectomy.\n\nThe manufacturer reported results for secondary outcomes in the RAISE trial. Fewer patients randomised to eltrombopag needed protocol-defined rescue treatments than those randomised to placebo (18% and 40% respectively). Among the safety population, the odds of experiencing bleeding (World Health Organization [WHO] grades 1–4) during the study period were 76% lower among patients who took at least 1\xa0dose of eltrombopag than in those who took at least 1\xa0dose of placebo (odds ratio [OR]\xa00.24; p<0.001; CI not given). At the end of the study, 57% of patients receiving placebo had experienced a grade 1–4 WHO bleed (any type of bleeding) compared with 27% of those receiving eltrombopag (OR\xa00.25; p>0.001; CI not given). However, a grade 2‑4 WHO bleed (clinically significant bleeding) did not differ between treatment groups (13% and 10% in the placebo and eltrombopag groups respectively). The manufacturer also performed an analysis of the risk of bleeding at least once at any point during the study, and stratified this analysis by whether or not the patient had had a splenectomy. It found that patients randomised to eltrombopag were statistically significantly less likely to have clinically significant bleeding than those randomised to placebo (33% for eltrombopag and 53% for placebo; OR 0.30; p>0.001); the results of the analysis were also statistically significantly different in favour of eltrombopag for patients who had or had not had a splenectomy.\n\nThe manufacturer reported treatment-related adverse reactions for 48\xa0patients (36%) in the eltrombopag group and 18\xa0patients (30%) in the placebo group. The most common adverse reactions experienced by patients receiving eltrombopag were headache (30%), diarrhoea (13%), nausea (12%), nasopharyngitis (10%), upper respiratory tract infection (10%) and fatigue (10%). The manufacturer also reported 2\xa0thromboembolic events in the eltrombopag group and none in the placebo group. A post hoc analysis of patients treated with concomitant medication showed a reduction in corticosteroid-related adverse reactions (including dyspepsia, peripheral oedema and hyperglycaemia) in the eltrombopag group.\n\nThe RAISE trial assessed health-related quality of life at baseline, and at 6, 14 and 26\xa0weeks using the SF‑36 instrument, which consists of 8\xa0subdomains and 2\xa0component summary scores (representing physical and mental health). In addition, investigators used subscales of the Functional Assessment of Chronic Illness Therapy for Patients with Thrombocytopenia (FACIT‑Th) and Functional Assessment of Chronic Illness Therapy (FACIT) instruments. The manufacturer reported that patients receiving eltrombopag improved more from baseline to week\xa026 across most of the SF‑36 domains for health and wellbeing than those receiving placebo. There were statistically significant differences between treatment groups in the change from baseline in the component summaries for physical role, vitality, emotional role and mental health.\n\nThe manufacturer did a meta-analysis of TRA\xa0100773A, TRA\xa0100773B and RAISE to establish whether treatment with eltrombopag improved platelet counts compared with placebo. It reported the odds ratios for attaining a platelet count of 50×109\xa0per litre or more 6\xa0weeks after the beginning of the study. In this analysis, eltrombopag was associated with higher odds of responding to treatment compared with placebo, with an odds ratio from a fixed effects model of 8.23 (95%\xa0CI 4.68 to 14.48) and an odds ratio from a random effects model of 8.16 (95%\xa0CI 4.63 to 14.37); there was little evidence of statistical heterogeneity.\n\nBecause there were no head-to-head trials comparing eltrombopag with romiplostim, the manufacturer performed an indirect comparison between the 2\xa0treatments. A systematic review by the manufacturer identified 2\xa0RCTs comparing romiplostim with placebo (both reported in Kuter et al. 2008), which the manufacturer used to compare eltrombopag with romiplostim for efficacy and rates of clinically significant bleeding. Both RCTs evaluated the safety and efficacy of romiplostim in patients with ITP; 1 enrolled 63\xa0patients who had had a splenectomy, and the other enrolled 62\xa0patients who had not. In both studies, patients had platelet counts of 30×109\xa0per litre or less and ITP that was refractory to at least 1\xa0previous treatment. Patients were randomised to either romiplostim plus standard care, or standard care alone, and they received treatment for 6\xa0months. The primary outcome in both studies was the proportion of patients with a durable platelet response (defined as a platelet count of 50×109\xa0per litre or more in 6\xa0or more weekly assessments in the last 8\xa0weeks of treatment), and who did not need rescue medication. The manufacturer combined the results of the 2\xa0studies using standard meta-analytic techniques and then treated them as a single trial to do the indirect comparison.\n\nThe manufacturer used the Bucher method in its indirect comparison between eltrombopag (data from RAISE) and romiplostim (data from the 2\xa0Kuter et al. 2008 trials), using placebo as a common comparator. It performed the comparison for the whole population, and separately for patients who had or had not had a splenectomy. The manufacturer considered 2\xa0main outcome measures: platelet response and clinically significant bleeding. The end points for platelet response differed between the eltrombopag and romiplostim trials. In Kuter et al., the primary outcome was the proportion of patients with platelet counts of 50×109\xa0per litre or more in 6\xa0or more weekly assessments during the last 8\xa0weeks of treatment without using rescue medication (durable platelet response), which the manufacturer equated to 'sustained response' as defined in the post hoc analyses of RAISE (section\xa03.6). The manufacturer further defined an 'overall response' as having either a durable response or a transient response. There were also differences in the definitions of bleeding between the eltrombopag and romiplostim trials: in RAISE, data on bleeding were collected using the WHO bleeding scale and the Common Terminology Criteria for Adverse Events (CTCAE) scale, whereas in Kuter et al., they were collected using an unnamed scale.\n\nThe manufacturer performed separate analyses for durable response and overall response. The results of the indirect comparison were framed so that odds ratios of more than\xa01.00 favoured eltrombopag. When eltrombopag was compared with romiplostim, the odds ratio for attaining a durable response was 0.32 (95%\xa0CI 0.03 to 3.14) and that for attaining an overall response was 0.22 (95%\xa0CI 0.05 to 1.02). For people who had had a splenectomy, the odds ratios were 0.50 (95%\xa0CI 0.01 to 17.3) for durable response and 0.09 (95%\xa0CI 0.00 to 2.52) for overall response; for people who had not had a splenectomy, the odds ratios were 0.41 (95%\xa0CI 0.04 to 4.80) and 0.34 (95%\xa0CI 0.06 to 2.14) for durable response and overall response respectively.\n\nThe indirect comparison of rates of bleeding showed that the point estimates favoured eltrombopag in some analyses and romiplostim in others, with no statistically significant differences between the 2\xa0treatments. When eltrombopag was compared with romiplostim, the odds ratio of a clinically significant bleed was 0.60 (95%\xa0CI 0.08 to 4.29), and that of a moderate or clinically significant bleed was 1.63 (95%\xa0CI 0.4.6 to 5.80).\n\nThe manufacturer highlighted that the indirect comparison showed no statistically significant differences between eltrombopag and romiplostim, and suggested that the differences between individual studies should be acknowledged when interpreting the results. The manufacturer indicated that patients differed between RAISE and the 2\xa0Kuter et al. (2008) trials in terms of duration of ITP, previous use of ITP medications, use of concomitant medication, and whether or not patients had had a splenectomy. It also indicated that the design of the trials was different for timing of platelet count assessments, timeframes in which patients were allowed to reduce concomitant ITP medications, definitions of response and definitions of 'period of rescue medication'. The manufacturer pointed out that 2\xa0published clinical guidelines, the 'International consensus report on the investigation and management of primary immune thrombocytopenia' (Provan et al. 2010) and 'The American Society of Haematology 2011 evidence-based practice guideline for immune thrombocytopenia' (Neunert et al. 2011), do not favour 1\xa0treatment over the other. The manufacturer concluded that its indirect comparison between eltrombopag and romiplostim did not provide evidence of clinical superiority for 1\xa0treatment over the other. In absence of evidence to the contrary, the manufacturer concluded that eltrombopag and romiplostim have 'equal efficacy' and applied this assumption to the cost-effectiveness analysis.\n\nThe manufacturer presented an indirect comparison between eltrombopag and standard care alone (excluding eltrombopag and romiplostim). In this, the manufacturer restricted the treatments used in standard care to those included in the international consensus report (that is, intravenous immunoglobulin\xa0G, anti‑D, rituximab, corticosteroids, vinca alkaloids, mycophenolate mofetil, ciclosporin, cyclophosphamide, danazol and dapsone). The manufacturer's systematic review of treatments used in standard care identified 113\xa0studies (including 20\xa0RCTs). However, the manufacturer altered its inclusion criteria after performing the search, which resulted in the exclusion of most of the identified studies. The manufacturer combined results from 37\xa0studies, including 6\xa0RCTs, to calculate weighted averages of response rate, time to response and duration of response for each drug used within the standard care pathway. The manufacturer pooled data regardless of the definition of response, and calculated the efficacy of each intervention using a simple average. The manufacturer highlighted that the results of the weighted averages for each of the included treatments were obtained mainly from non-randomised, highly heterogeneous, older trials; however, it acknowledged that the results largely reflected the response rates outlined in the international consensus report (Provan et al. 2010) and in Romiplostim for the treatment of chronic immune thrombocytopenia (NICE technology appraisal guidance 221).\n\n# Cost effectiveness\n\nThe manufacturer developed a de novo economic model to assess the cost effectiveness of eltrombopag in 2\xa0populations of chronic ITP:\n\nadults who have not had a splenectomy\n\nadults who have had a splenectomy, but whose condition is refractory to previous treatments. The manufacturer assumed that patients who have not had a splenectomy reflect those for whom splenectomy is contraindicated.\n\nThe cost-effectiveness model developed by the manufacturer is a state-transition Markov cohort model with a 4‑week cycle length. The model simulates patients with chronic ITP receiving eltrombopag plus standard care, romiplostim plus standard care, or standard care alone. The manufacturer assumed that all patients entering the model have ITP that is refractory to first-line treatment with corticosteroids or immunoglobulins and, if rituximab is considered an appropriate treatment option, patients will have already received it. For patients starting a treatment, the model permits their platelet count to reach 50×109\xa0per litre or more (equal to a response) in the first, second, third or fourth cycle, depending on the time to response associated with each treatment. When the platelet count reaches 50×109\xa0per litre, patients have a treatment-specific probability of losing the response in each cycle, and of receiving rescue therapy when bleeding occurs or a patient is deemed at high risk of bleeding. If the platelet count does not reach 50×109\xa0per litre or patients lose their response, they stop treatment but may receive rescue therapy (intravenous immunoglobulin, anti‑D and corticosteroids), which may result in a temporary platelet response lasting for 1\xa0cycle. During each cycle, a proportion of patients who experience a bleed or whose platelet count does not respond 'exit' the 'non-responder' state and move on to other treatments further down the treatment sequence. Rates of rescue treatment, rates of non-severe bleeds treated in the outpatient setting, and rates of severe bleeds treated in the inpatient setting were lower in patients whose condition responds than in those whose condition does not. Patients in the model who are less likely to bleed are less likely to die.\n\nThe economic evaluation compared 3\xa0treatment sequences: a pathway reflecting standard care without a thrombopoietin agonist (sequence 'a': azathioprine, mycophenolate mofetil, ciclosporin, danazol, dapsone, cyclophosphamide, vinblastine and vincristine), a pathway of eltrombopag with standard care (eltrombopag followed by sequence 'a'), and a pathway of romiplostim with standard care (romiplostim followed by sequence 'a'). The sequence of treatments used as standard care reflects that used by the manufacturer of romiplostim in NICE technology appraisal guidance 221, except that rituximab is removed from the sequence for the base-case analysis in the current submission. This is because, as the manufacturer explained, UK local guidance suggests that clinicians offer rituximab to patients before eltrombopag or romiplostim. The manufacturer discounted costs and benefits at an annual 3.5% rate.\n\nThe manufacturer submitted 3\xa0separate economic evaluations: a base case, an 'alternative' evaluation and a scenario analysis. In the base case, the manufacturer applied a set of assumptions it deemed most relevant to the decision problem, using NICE technology appraisal guidance 221 as its main source of data and assumptions. The only parameters in the base-case model that the manufacturer sourced from the RAISE and EXTEND trials were the thrombopoietin receptor agonist response rates and the thrombopoietin receptor agonist time on treatment. The alternative evaluation applied data from RAISE and EXTEND, along with clinical evidence retrieved from the manufacturer's systematic review for this appraisal. In the scenario analysis, the manufacturer applied all the assumptions and model inputs used in the economic evaluation for romiplostim in NICE technology appraisal guidance 221 (including those that were not used in the base case) to try to replicate as closely as possible the analysis in that technology appraisal.\n\nIn the base case and alternative evaluation, the manufacturer assumed that the response rate (attaining a platelet count of 50–400×109\xa0per litre at any time during the 6‑month study period) for eltrombopag was the same as that observed in the RAISE trial. It also assumed that, if a patient had a platelet response at any time during the 6‑month period, the patient maintained the platelet response while on treatment and had a probability of bleeding and death as if the platelet count had remained elevated. Both the base case and alternative evaluation assumed complete clinical equivalence between eltrombopag and romiplostim, and so a patient in the model taking eltrombopag had the same rate of platelet response as a patient taking romiplostim. The manufacturer assumed that the effectiveness of the 2\xa0treatments was the same because its indirect comparison had not shown that the treatments were different (section\xa03.15). However, the manufacturer performed sensitivity analyses to test the possibility that romiplostim was more effective than eltrombopag by applying the odds ratio for overall response from its indirect comparison between eltrombopag and romiplostim (0.22).\n\nFor treatments considered to be standard care, the manufacturer took response rates for the base case from NICE technology appraisal guidance 221, in which the response rates were calculated from a systematic review that the manufacturer of romiplostim had done. In the alternative evaluation, the manufacturer estimated a response rate for each treatment from its indirect comparison between eltrombopag and treatments comprising standard care (section\xa03.16).\n\nIn the base case and alternative evaluation, time to platelet response for eltrombopag was 15\xa0days (standard error 3.75\xa0days), as observed in RAISE. For romiplostim, the time to response was assumed to be 28\xa0days (standard error 7\xa0days), based on the Kuter et al. (2008) trials. For treatments comprising standard care, time to response from NICE technology appraisal guidance\xa0221 was used in the base case and, for the alternative evaluation, it was obtained from the manufacturer's indirect comparison between eltrombopag and standard care (section\xa03.16).\n\nBecause the manufacturer assumed that eltrombopag and romiplostim were equally effective, it also assumed that time on treatment was the same for eltrombopag and romiplostim. To extrapolate time on treatment over a lifetime horizon, the manufacturer modelled time on treatment as a survival variable using patient-level data on treatment discontinuation from RAISE and EXTEND, and carried out a parametric analysis. The manufacturer found that, among patients whose condition responded to treatment, those who had had a splenectomy spent less time on eltrombopag than those who had not.\n\nFor the time on treatment for therapies included in standard care, the manufacturer took values from NICE technology appraisal guidance 221 for its base case, and from the indirect comparison between eltrombopag and standard care (section\xa03.16) for its alternative evaluation. The manufacturer assumed that time on treatment for standard therapy followed an exponential distribution.\n\nThe manufacturer assumed that the risk of bleeding in the model is a function of platelet response irrespective of treatment, so patients with platelet counts of 50×109\xa0per litre or more were at risk of non-severe bleeds (treated as an outpatient), and patients with platelet counts of less than 50×109\xa0per litre had a risk of severe (needing inpatient care) or non-severe bleeds. For its base case, the manufacturer applied the rates of bleeding previously used in NICE technology appraisal guidance 221 for romiplostim. For patients who did not have a platelet response, the rate of severe bleeds applied in the base-case model was 4.3% per month. For its alternative evaluation, the manufacturer used the rate of severe bleeds from RAISE and EXTEND (0.8% per month). The manufacturer assumed that patients whose condition is refractory to all previous treatments are twice as likely to bleed as patients whose condition does not respond to treatment but who are between treatments. The manufacturer took this assumption from NICE technology appraisal guidance 221.\n\nThe manufacturer modelled mortality from chronic ITP as a function of severe bleeds in the base case and alternative evaluation. For each bleed for which a patient needed to be hospitalised, the manufacturer applied a mortality rate from Danese et al. (2009), and assumed that this rate doubles for patients whose condition is refractory to all previous treatments. The manufacturer considered that patients would need to be hospitalised for the following categories of bleeds: gastrointestinal haemorrhage, intracranial haemorrhage and haemorrhage resulting from a 'coagulation disorder'.\n\nFor the base case, the modelling assumed that only patients with platelet counts of less than 50×109\xa0per litre receive rescue medication, the types and rates of which were used in NICE technology appraisal guidance 221. The rate of rescue therapy for patients who had had a splenectomy was 68% and, for patients who had not had splenectomy, it was 33%. Rescue medications included intravenous immunoglobulin, anti‑D and corticosteroids, and the proportions in which patients received these medications in the model were based on a survey of 169\xa0UK haematologists that the manufacturer of romiplostim did for NICE technology appraisal guidance 221. To estimate the rate of rescue for patients with platelet counts above and below 50×109\xa0per litre for its alternative evaluation, the manufacturer used data from RAISE and EXTEND limited to countries with healthcare resources comparable to the UK.\n\nAdverse events in the model were considered as either severe or 'other'. In the base case and alternative evaluation, the manufacturer assumed that the rates of adverse events for eltrombopag and romiplostim were equivalent and used the rates from NICE technology appraisal guidance 221. The manufacturer estimated adverse event rates for treatments included in standard care from the same technology appraisal.\n\nAlthough RAISE and EXTEND collected health-related quality-of-life data, the manufacturer chose to use utility data for the base case and alternative evaluation from a study it had identified (Szende et al. 2010). This study developed 6\xa0ITP-related health states that investigators had evaluated using the time trade-off method in 359\xa0members of the UK general public.\n\nThe manufacturer did not identify any resource-use studies relevant to the UK from its systematic review of the literature. Therefore, it used unpublished data to estimate costs including the costs of acquisition and administration of the intervention and comparators, and the costs of the rescue medication, as well as the costs of monitoring. The manufacturer took the list prices of the different drugs from the 'British national formulary' (BNF) edition\xa063 and applied the patient access schemes for eltrombopag and romiplostim. It calculated the average doses of eltrombopag from RAISE and, after the 6‑month study period, it estimated a stable dose from the EXTEND study. For romiplostim, the manufacturer calculated the average doses from Kuter et al. (2008) and assumed that the dose on which a patient is likely to remain (the stable dose) equals the last dose used in the trials (last dose carried forward). Dosages of drugs other than romiplostim and eltrombopag were taken from Provan et al. (2010), the international consensus report, or NICE technology appraisal guidance 221. Eltrombopag and other oral treatments did not have administration costs. Because romiplostim is injected subcutaneously, it can be administered at home or in hospital; the manufacturer assumed that costs were incurred only when the drug was administered in hospital. The cost of bleeds covered drug costs, hospitalisation and follow-up. The manufacturer assumed that all patients, regardless of treatment, needed monitoring by a haematologist and 2\xa0laboratory tests every 4\xa0weeks.\n\nIn the manufacturer's base-case analysis, eltrombopag dominated romiplostim (that is, was more effective and less costly) for patients who had or had not had a splenectomy. For the comparison of eltrombopag with standard care, eltrombopag dominated standard care for patients who had had a splenectomy, and its incremental cost-effectiveness ratio (ICER) for patients who had not had a splenectomy was £15,105 per quality-adjusted life year (QALY) gained.\n\nThe manufacturer carried out a wide range of sensitivity analyses on the base case, varying 1\xa0parameter at a time. It did not perform one‑way sensitivity analyses on the results of the alternative evaluation or the scenario analysis.\n\nFor patients who had had a splenectomy, eltrombopag dominated the standard care pathway in all analyses explored. In comparison with romiplostim, eltrombopag dominated in all analyses except when the model incorporated the odds ratio for overall response between eltrombopag and romiplostim from the manufacturer's indirect comparison (0.22, section\xa03.13). In this scenario, romiplostim gave 0.56\xa0additional QALYs compared with eltrombopag, but at an additional cost of £95,649; the resulting ICER for eltrombopag compared with romiplostim was £171,156 saved per QALY lost (that is, eltrombopag was less effective but also less expensive than romiplostim).\n\nFor patients who had not had a splenectomy, the ICER for eltrombopag compared with standard care remained below £33,000 per QALY gained in all scenarios except when a 6‑month time horizon was used, in which case the ICER for eltrombopag compared with standard care was £74,250 per QALY gained. For the comparison of eltrombopag with romiplostim, eltrombopag dominated romiplostim in all sensitivity analyses, except when the odds ratio for overall response from the indirect comparison was used to estimate the relative efficacy of eltrombopag and romiplostim (OR\xa00.22, section\xa03.13). In this scenario, romiplostim offered 0.46\xa0additional QALYs compared with eltrombopag, but at an additional cost of £51,416. This gave an ICER for eltrombopag compared with romiplostim of £110,983 saved per QALY lost.\n\nThe manufacturer carried out probabilistic sensitivity analyses to summarise the uncertainty in the base-case ICER. This showed that, for patients who had had a splenectomy, there was a 65% probability of eltrombopag being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and a 70% probability of it being cost effective if the maximum acceptable ICER was £30,000 per QALY gained. For patients who had not had a splenectomy, there was a 54% probability of eltrombopag being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and a 63% probability of it being cost effective if the maximum acceptable ICER was £30,000 per QALY gained.\n\nIn the manufacturer's alternative evaluation, eltrombopag dominated romiplostim in the analyses for patients who had or had not had a splenectomy. When eltrombopag was compared with standard care, the ICER for eltrombopag was £61,337 per QALY gained for patients who had had a splenectomy and £95,536 per QALY gained for patients who had not had a splenectomy.\n\nThe manufacturer presented a scenario analysis to replicate the analysis for NICE technology appraisal guidance 221. In this, the manufacturer:\n\nassumed that eltrombopag and romiplostim are administered before rituximab in the treatment pathway\n\nassumed that time on treatment followed an exponential distribution (instead of a log‑normal distribution for the base case)\n\nremodelled the response rates for eltrombopag and romiplostim to exclude patients whose condition responded to unlicensed doses\n\ncalibrated rescue rates to produce rates when the treatment pathway is set to exclude maintenance treatments\n\nbased utility values on pooled EQ‑5D and vignette utility data as per NICE technology appraisal guidance 221\n\nestimated the number of vials of romiplostim needed from NICE technology appraisal guidance 221\n\nset administration costs to £262 per cycle for all treatments and assumed that romiplostim did not incur further costs of administration.\n\nIn the scenario analysis, eltrombopag dominated both romiplostim and standard care for all patients.\n\n# Evidence Review Group critique and exploratory analyses\n\nThe ERG stated that the manufacturer identified all relevant studies comparing eltrombopag with placebo and presented a suitable meta-analysis. It also considered that the literature review carried out by the manufacturer to estimate the efficacy of standard care was reasonable.\n\nFor the indirect comparison of eltrombopag with romiplostim, the manufacturer used a Mantel‑Haenszel fixed-effect approach to combine the results of the 2\xa0Kuter et al. (2008) trials and then used the Bucher method. The ERG expressed the following concerns about this methodology:\n\nHeterogeneity exists between the 2\xa0Kuter et al. trials, and pooling their results may have introduced bias.\n\nAlthough differences exist between RAISE and the 2\xa0Kuter et al. trials (section\xa03.15), the ERG felt that it was reasonable that the manufacturer had proceeded with the indirect comparison, but advised caution with respect to the results.\n\nBecause the manufacturer had presented the indirect comparison stratified by splenectomy status, the analyses did not preserve randomisation in RAISE, and the ERG considered them to be observational analyses.\n\nThe ERG performed an exploratory indirect comparison between eltrombopag and romiplostim for the outcomes of durable and overall response, and for clinically significant and moderate bleeds using a Bayesian network meta-analysis to account for the heterogeneity between the 2 Kuter et al. (2008) studies. For durable response and bleeding, the ERG found similar results to those of the manufacturer. For overall response, the manufacturer had found no statistically significant difference between treatments (OR\xa00.22; 95%\xa0CI 0.05 to 1.02), but the ERG found a statistically significant difference in favour of romiplostim (OR\xa00.15; 95% credible interval 0.02 to 0.84).\n\nFor the indirect comparison of eltrombopag with standard care, the ERG expressed concerns about the methodological rigor of the manufacturer's approach. Because the manufacturer excluded studies from the systematic review after the review had been performed, and had pooled response estimates using a simple weighted average regardless of the definition of response, the ERG considered that bias may exist. The ERG recommended caution when considering the results of this indirect comparison.\n\nThe ERG noted that a major weakness in the base-case analysis was that the manufacturer chose not to use data from the eltrombopag RCTs or from its systematic review of the literature, and instead opted to populate the base-case model with estimates from NICE technology appraisal guidance 221 for romiplostim. Because of this, the ERG considered the alternative evaluation to be more appropriate.\n\nThe ERG had concerns about the manufacturer's assumption that eltrombopag and romiplostim are equally effective, given the uncertainty around the results of the indirect comparison between eltrombopag and romiplostim (section\xa03.15).\n\nThe ERG noted that the manufacturer did not address the optimal positioning of eltrombopag and romiplostim within the treatment sequence in the model. The manufacturer assumed that eltrombopag and romiplostim followed after rituximab, but preceded other drugs used in standard care. In addition, the ERG pointed out that there is uncertainty about the optimal place of eltrombopag and romiplostim if one is assumed to be more effective than the other. The ERG stated that the manufacturer should have explored additional sequences of treatment.\n\nThe ERG had concerns about the manufacturer's assumption that 'response' and 'platelet response' are the same. The ERG noted that, in RAISE, only 60–80% of patients whose condition responded to eltrombopag had a sustained platelet response of more than 50×109\xa0per litre. Because platelet counts drive bleeding rates and mortality in the model, the ERG stated that the manufacturer's assumption would improve the ICERs for eltrombopag and romiplostim.\n\nThe manufacturer averaged eltrombopag and romiplostim doses from the relevant trials across patients whose condition had responded and those whose condition had not. The ERG noted that, in the Kuter et al. (2008) trials, the median dose of romiplostim in patients whose condition had responded was 40–60% lower than that across the trial as a whole. The ERG stated that eltrombopag and romiplostim doses should be response-specific.\n\nTo model utility, the ERG considered that the manufacturer, in its cost-effectiveness analysis, should have used the SF‑6D health-related quality-of-life data collected from the RAISE and EXTEND trials, which are derived from a validated generic instrument.\n\nThe ERG questioned the manufacturer's assumption that the rate of severe bleeding doubles for patients whose ITP is refractory to all previous treatments, noting that these rates were high.\n\nThe ERG undertook exploratory sensitivity analyses, varying 1\xa0parameter at a time, on both the base case and alternative evaluation; these included the following:\n\nApplying the overall response rates from the manufacturer's indirect comparison (60% for eltrombopag and 94% for romiplostim for people who had had a splenectomy [OR\xa00.09], and 72% for eltrombopag and 88% for romiplostim for people who had not had a splenectomy [OR\xa00.34]).\n\n\n\nIn the comparison of eltrombopag with romiplostim, eltrombopag was associated with both fewer QALYs and lower costs than romiplostim. For the base-case analysis, the ICERs suggested savings of £174,503 per QALY lost for people who had had a splenectomy when using eltrombopag instead of romiplostim. The ERG did not explicitly report ICERs for people who had not had a splenectomy from its analyses on the base case, nor did it report the ICERs for any of the subpopulations from its analyses on the alternative evaluation.\n\nIn the comparison of eltrombopag with standard care, the ERG reported costs and QALYs for the base-case analysis only for people who had not had a splenectomy, and for the alternative evaluation both for people who had or had not had a splenectomy. In the base-case analysis, eltrombopag dominated standard care for people who had had a splenectomy. For those who had not had a splenectomy, the ICER for eltrombopag compared with standard care was £15,843 per QALY gained. In the alternative evaluation, the ICERs for eltrombopag compared with standard care were £73,335 and £108,336 per QALY gained for people who had and had not had a splenectomy respectively.\n\n\n\nApplying the SF‑6D utility data collected from RAISE and EXTEND.\n\n\n\nIn the comparison of eltrombopag with romiplostim, the ERG found that eltrombopag dominated romiplostim for both the base case and alternative evaluation, irrespective of whether or not the person had had a splenectomy.\n\nFor the comparison of eltrombopag with standard care in the base-case analysis, eltrombopag was dominant for people who had had a splenectomy, and gave an ICER of £18,489 per QALY gained for people who had not had a splenectomy. When the ERG applied the utility values to the alternative evaluation, eltrombopag was associated with ICERs of £90,753 and £133,508 per QALY gained for people who had and had not had a splenectomy respectively.\n\n\n\nReducing modelled doses of romiplostim by 40% for people who had had a splenectomy and 60% for people who had not had a splenectomy.\n\n\n\nIn the comparison of eltrombopag with romiplostim, the ERG found that, despite the lower cost of romiplostim, eltrombopag dominated romiplostim in both the base case and alternative evaluation, irrespective of whether or not people had had a splenectomy.\n\n\n\nIn response to comments received during consultation on the first appraisal consultation document, the ERG carried out additional exploratory sensitivity analyses on the alternative evaluation, varying 1\xa0parameter at a time, and then varying multiple parameters simultaneously. The ERG stated that, in its opinion, the alternative parameter inputs used in these analyses did not necessarily reflect the most reasonable assumptions. For the following parameters, the ERG:\n\na. applied the odds ratio of 0.22 for overall response from the manufacturer's indirect comparison between eltrombopag and romiplostim (section\xa03.13). The resulting overall response rates were 60% for eltrombopag and 87% for romiplostim for patients who had had a splenectomy, and 72% for eltrombopag and 92% for romiplostim for patients who had not had a splenectomy\n\nb. applied the SF‑6D utility data collected from RAISE\n\nc. removed anti‑D treatment from the rescue therapies for patients who had not had a splenectomy\n\nd. applied the odds ratio of 0.15 for overall response from the ERG's indirect comparison between eltrombopag and romiplostim, for which the ERG had used a Bayesian approach (section\xa03.40). The resulting overall response rates were 60% for eltrombopag and 91% for romiplostim for patients who had had a splenectomy, and 72% for eltrombopag and 94% for romiplostim for patients who had not had a splenectomy\n\ne. applied a dose of romiplostim of 1.54\xa0vials for patients who had had a splenectomy and 1.10\xa0vials for patients who had not had a splenectomy, as calculated by the manufacturer of romiplostim\n\nf. applied a cost per administration of romiplostim equal to £11.50, as suggested by the manufacturer of romiplostim\n\ng. applied the above-listed sensitivity analyses b and c simultaneously\n\nh. applied the above-listed sensitivity analyses b, c and d simultaneously\n\ni. applied the above-listed sensitivity analyses b, c, d and e simultaneously\n\nj. applied the above-listed sensitivity analyses b, c, d, e and f simultaneously.The ERG found that, when varying 1\xa0parameter at a time, eltrombopag dominated romiplostim (that is, gave the same QALYs as romiplostim but at a lower cost) for patients who had or had not had a splenectomy in all analyses, except when the odds ratio of 0.22 or 0.15 was applied for overall response. In these instances, eltrombopag was associated with fewer QALYs and lower costs compared with romiplostim; when the ERG applied the odds ratio of 0.22, the corresponding ICERs suggested savings of £689,084 and £372,782 per QALY lost for patients who had and had not had a splenectomy respectively; when the odds ratio of 0.15 was applied, the ICERs were savings of £638,042 and £350,685 per QALY lost for patients who had and had not had a splenectomy respectively. The ERG estimated from the analyses in which it varied multiple parameters simultaneously that eltrombopag compared with romiplostim was associated with savings per QALY lost greater than £250,000 in all analyses, irrespective of whether or not the patient had had a splenectomy. The ICER from the sensitivity analysis in which all parameters were varied simultaneously (sensitivity analysis j) was £388,799 saved per QALY lost for patients who had had a splenectomy and £270,694 saved per QALY lost for patients who had not had a splenectomy.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of eltrombopag, having considered evidence on the nature of chronic immune thrombocytopenia (ITP) and the value placed on the benefits of eltrombopag by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the nature of the condition with patient experts and clinical specialists, and heard that chronic ITP impacts on quality of life by affecting both the physical and emotional wellbeing of people with the condition. The Committee heard from clinical specialists that the signs and symptoms associated with chronic ITP vary; some people may not have any signs or symptoms, while others may have fatigue and bruise easily. It also heard from patient experts that chronic ITP may cause a patient to worry about the risk of bleeding because significant bleeding would normally cause a person to seek medical care, receive rescue treatment and possibly be hospitalised. The Committee recognised that anxiety related to bleeding may affect work or leisure activities, and, in extreme situations, causes people to become housebound. The Committee heard that family members may also worry on behalf of their relatives about the complications that may result from low platelet counts. The Committee noted that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the calculation of the quality-adjusted life year (QALY).\n\nThe Committee discussed the clinical management of chronic ITP. The clinical specialists explained that managing ITP depends on individual circumstances, and the specialists could not define a single treatment pathway as routine practice. The Committee understood that, although clinicians tend to offer active treatment to patients with low platelet counts or before surgery, treatment would not normally be determined solely on the platelet count. The Committee heard that splenectomy would be considered as first-line, second-line or subsequent-line treatment, and that approximately two‑thirds of patients can expect remission after splenectomy. The Committee was aware that splenectomy might be contraindicated in patients at greater risk of bleeding, but that laparoscopic procedures for splenectomy have lowered the risk of bleeding.\n\nThe Committee heard from patient experts about the perceived benefits of eltrombopag for patients with chronic ITP. It understood that the adverse reactions of most standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that thrombopoietin receptor agonists (eltrombopag and romiplostim) had a different mode of action and a better adverse reaction profile than these standard treatments. It also understood that eltrombopag, as a daily oral treatment, would represent significant value for some patients with chronic ITP, while other patients would prefer romiplostim administered weekly by subcutaneous injections. The Committee heard from patient experts that some patients take a tablet of eltrombopag only once every 3\xa0days rather than daily. The Committee noted that the summary of product characteristics states potential interactions of eltrombopag with dairy or calcium-containing products. The patient experts felt that, given the severity of ITP and the alternative treatment options available, few patients would have difficulties adhering to eltrombopag's dosage regimen because most would take it before bedtime to minimise the impact of dairy or calcium-containing foods on absorption. The Committee recognised that an oral treatment would add value for patients who have an aversion to needles.\n\nThe Committee considered the place of eltrombopag in the treatment pathway for people with chronic ITP and discussed the appropriate comparators, noting the licensed indications for eltrombopag. The Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP, and the specialists' view was that eltrombopag represents an effective approach. The Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab, although rituximab is not licensed for the treatment of chronic ITP.\n\nThe Committee discussed the manufacturer's decision problem, noting that the manufacturer compared a pathway of eltrombopag plus standard care with a pathway of standard care alone, and separately with a pathway of romiplostim plus standard care. In all 3\xa0pathways, the manufacturer defined standard care as sequential use of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine. The Committee considered the relevance of the 2\xa0comparator pathways (that is, the pathway of standard care alone, and the pathway of romiplostim plus standard care) in relation to the population in the RAISE trial. The Committee was aware that, since the publication of NICE technology appraisal guidance 221, romiplostim had been introduced into standard care in the NHS in England and Wales, and it was aware that the clinical specialists had indicated that eltrombopag was likely to be used in the same position as romiplostim in the treatment pathway. The Committee noted that the RAISE trial had included all patients with chronic ITP with a low platelet count for whom other treatments had failed, and not only those with severe chronic ITP who are at high risk of bleeding and need frequent courses of rescue therapy (that is, the population for which romiplostim is recommended in NICE technology appraisal guidance\xa0221). The Committee agreed that comparing eltrombopag with the pathway including romiplostim plus standard care would be appropriate only for the same population for which romiplostim is recommended in NICE technology appraisal guidance\xa0221. It also agreed that, for the population in the RAISE trial for which romiplostim is not recommended in NICE technology appraisal guidance\xa0221 (that is, patients who did not have severe disease and a high risk of bleeding), comparing eltrombopag with the pathway of standard care alone would be appropriate. The Committee therefore concluded that both comparator pathways described in the manufacturer's decision problem were appropriate, but for 2\xa0different populations.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of eltrombopag, noting that the evidence was derived mainly from the RAISE trial. It noted that the available evidence showed that, for people with chronic ITP for whom other treatments had failed, eltrombopag was clinically effective when compared with placebo in attaining the target platelet count and reducing the need for rescue therapy.\n\nThe Committee discussed the safety and tolerability of eltrombopag and noted that the adverse reactions other than bleeding were similar between people who took eltrombopag or placebo in the RAISE trial. The Committee noted the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had better safety profiles than most standard treatments for chronic ITP.\n\nThe Committee discussed whether the manufacturer's indirect comparison between eltrombopag and romiplostim was appropriate. The Committee was aware that both the manufacturer and the Evidence Review Group (ERG) had advised caution when interpreting the results of the indirect comparison because of differences in baseline patient characteristics between RAISE and the 2\xa0Kuter et al. (2008) trials for: duration of ITP, the proportion of patients who had received more than 3\xa0prior ITP therapies, and the proportion of patients receiving concomitant ITP medication at baseline. The Committee discussed the sources of heterogeneity between the trials, and heard from the clinical specialists that the romiplostim trials were conducted before the eltrombopag trials; the Committee recognised that this may have caused more patients with severe chronic ITP to be enrolled into the earlier romiplostim trials. The Committee agreed that the differences between the RAISE trial and the 2\xa0Kuter et al. trials may have introduced bias in the indirect comparison, but it concluded that it would be appropriate to perform an indirect comparison between the 2 treatments.\n\nThe Committee considered the manufacturer's indirect comparison and the ERG's exploratory analysis between eltrombopag and romiplostim, noting the different statistical approaches used to estimate the results. The Committee noted that, for the outcomes durable response and overall response, the manufacturer's indirect comparison gave odds ratios lower than 1 (favouring romiplostim), but the confidence intervals around those odds ratios suggested that the differences between eltrombopag and romiplostim were not statistically significant; for example, the odds ratio for overall response was 0.22 (in favour of romiplostim) with an upper limit of the 95% confidence interval of 1.02. The Committee understood that the statistical approach used by the manufacturer did not account for the heterogeneity between the 2\xa0Kuter et al. (2008) trials, whereas the ERG's exploratory indirect comparison, which used a Bayesian approach, treated the Kuter et al. trials separately. The Committee noted that, for overall response, the ERG's indirect comparison suggested a statistically significant difference in favour of romiplostim (odds ratio\xa00.15). For durable response, the Committee noted that the ERG found non-significant differences similar to those found by the manufacturer. The Committee was aware that the ERG's results depended on the degree of heterogeneity it assumed. The Committee agreed that the point estimates in both the manufacturer's and the ERG's analyses were associated with considerable uncertainty.\n\nThe Committee considered the relative effectiveness of eltrombopag and romiplostim in light of the manufacturer's indirect comparison and the ERG's exploratory analysis. It noted that the manufacturer interpreted the effectiveness of the 2\xa0drugs as the same (that is, not different) on the basis that its indirect comparison did not show a statistically significant difference between them. The Committee heard from the clinical specialists that, while it is difficult to know whether 1\xa0treatment is superior to the other, the use of eltrombopag and romiplostim in clinical practice is broadly interchangeable. The Committee accepted that the manufacturer's indirect comparison may have underestimated the clinical effectiveness of romiplostim given that the romiplostim trials preceded those for eltrombopag, and so the clinical trials for romiplostim may have enrolled patients whose condition was relatively more severe. The Committee noted that more patients in the romiplostim trials had received multiple previous therapies, which suggests that they better reflected patients whose condition had not responded than those in the eltrombopag trials. The Committee agreed that the available evidence suggested that romiplostim was likely to be more effective than eltrombopag rather than equally effective, and so it did not agree with the manufacturer's assumption used for the modelling that the treatments were equally effective. The Committee concluded that the most plausible odds ratio for overall response for eltrombopag compared with romiplostim would be less than 1.00 but, given the uncertainty around the point estimates obtained from the indirect comparison, it could not determine the likely value of this ratio.\n\nThe Committee considered the clinical effectiveness of eltrombopag compared with the pathway of standard care alone. The Committee understood that there was no direct evidence comparing eltrombopag with standard care, and so discussed the manufacturer's indirect comparison (section\xa03.16). The Committee noted that the evidence for treatments used in standard care was derived mainly from non-randomised, highly heterogeneous trials. It also noted that the manufacturer had altered its inclusion criteria after performing the literature review, and pooled response estimates using a simple weighted average of treatment groups. The Committee agreed that the indirect comparison lacked methodological rigor, and concluded that the results of the indirect comparison were not sufficiently robust to compare eltrombopag with the pathway of standard care alone.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's cost-effectiveness analyses, and the ERG's critique of the analyses. The Committee agreed that, of the 3\xa0economic evaluations (the base case, the alternative evaluation and the scenario analysis), the alternative evaluation represented the most valid analysis because the modelling applied data derived directly from the pivotal trials of eltrombopag and the manufacturer's own systematic review.\n\nThe Committee considered the cost effectiveness of eltrombopag compared with the pathway of standard care alone in the alternative evaluation, that is, for people with ITP for whom romiplostim is not recommended. It noted that the manufacturer had estimated response rates and time on treatment for drugs used in standard care from its indirect comparison of treatments used in standard care (section\xa03.22), and used the estimates in the alternative evaluation. The Committee, however, agreed that the indirect comparison lacked methodological rigor (section\xa04.12), and that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone. The Committee concluded that it could not recommend eltrombopag for patients who do not have severe disease and a high risk of bleeding.\n\nThe Committee then considered the cost effectiveness of eltrombopag compared with the pathway of standard care plus romiplostim in the alternative evaluation. It noted that the results of this comparison would apply only to people with severe chronic ITP and a persistent high risk of bleeding (that is, people for whom romiplostim is recommended in NICE technology appraisal guidance\xa0221 for romiplostim). The Committee considered the sensitivity analyses in which romiplostim was more effective than eltrombopag, and noted that neither the manufacturer nor the ERG had provided incremental cost-effectiveness ratios (ICERs) for eltrombopag compared with romiplostim. However, from the costs and QALYs presented by the ERG from its exploratory sensitivity analyses on the alternative evaluation (section\xa03.49), the Committee initially estimated that the ICERs would be more than £400,000 saved per QALY lost for patients who had or had not had a splenectomy. The Committee noted that a comment received during consultation on the first appraisal consultation document indicated that it would be more appropriate to include in the sensitivity analyses the odds ratio for overall response of 0.15 estimated from the ERG's indirect comparison (section\xa03.40). The Committee heard from the ERG that, in response to this comment, it had carried out sensitivity analyses within the alternative evaluation, varying the parameter for overall response rate in the model (section\xa03.50). The Committee noted that, when the ERG applied an odds ratio of 0.22 to derive overall response rates, the ICERs for eltrombopag compared with romiplostim were savings of £689,000 and £373,000 per QALY lost for patients who had and had not had a splenectomy respectively; when the ERG applied an odds ratio of 0.15, these ICERs decreased to £638,000 and £351,000 per QALY lost respectively. The Committee was aware that the clinical specialists felt that eltrombopag and romiplostim were broadly interchangeable (section\xa04.11), and it concluded that, if the odds ratio for overall response moved towards 1.0 (as implied by the clinical specialists' willingness to substitute 1\xa0treatment for another), the ICERs would further increase leading to further savings per QALY lost.\n\nThe Committee noted that the ERG questioned the source of the data on health-related quality of life used in the manufacturer's model because the manufacturer did not use the SF‑36 health-related quality-of-life data collected from RAISE and EXTEND that it had mapped on to the SF‑6D. The Committee noted that the manufacturer applied the SF‑6D utility data in a sensitivity analysis within the base case, but not within the alternative evaluation favoured by the Committee. The Committee noted comments received during consultation on the second appraisal consultation document suggesting that it would be more appropriate to use, in sensitivity analyses within the alternative evaluation, EQ‑5D utility data obtained either from mapping SF‑36 data on to the EQ‑5D or from other studies from the literature identified by the manufacturer (such as Szende et al. 2010). The Committee heard that mathematical algorithms exist to map from SF‑36 (used in RAISE and EXTEND) on to EQ‑5D, and that, because no single algorithm is considered more valid than others, the EQ‑5D data obtained from using a particular algorithm would be associated with further uncertainty. It also heard from the ERG that the Szende et al. study used by the manufacturer in its base-case analysis did not report EQ‑5D utility values. The Committee was aware that the reference case outlined in NICE's Guide to the methods of technology appraisal states that EQ‑5D is the preferred measure of health-related quality of life in adults. However, in the absence of EQ‑5D data, the Committee concluded that, of the utility data available, the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.\n\nThe Committee discussed the ERG's concern about the dosing of romiplostim in the analyses (section\xa03.46). It noted that the doses of romiplostim used in the manufacturer's model did not depend on whether or not the patient's condition had responded, whereas in the Kuter et al. (2008) trials, the median dose of romiplostim in patients whose condition had responded was 40–60% lower than that across the trial as a whole. The Committee noted a comment received during consultation on the second appraisal consultation document suggesting to set the dose of eltrombopag after 24\xa0weeks of treatment equal to the average dose from week\xa012 to week\xa023 in the RAISE trial (which was 7–12% higher than the originally modelled doses) to link the doses of eltrombopag with the modelled response rates from RAISE. The Committee discussed the impact of this suggestion on the cost effectiveness of eltrombopag compared with romiplostim, and heard from the ERG that the proposed dosing for eltrombopag would only minimally affect the relative cost effectiveness of the 2\xa0treatments. In addition, the Committee was aware that patient experts indicated that some patients take a tablet of eltrombopag only once every 3\xa0days rather than daily (section\xa04.4), which implies that the dose of eltrombopag in clinical practice might in fact be lower than that observed in the RAISE trial. The Committee concluded that it was appropriate to use a median dose of romiplostim that is 40–60% lower than that used in the Kuter et al. trials and that the dose of eltrombopag used in the model was appropriate.\n\nThe Committee noted that comments received during consultation on the first appraisal consultation document raised concerns about some of the parameters used in the model, namely that the duration of treatment for romiplostim is longer than that for eltrombopag; that doses of romiplostim should be calculated in line with the approach used for NICE technology appraisal guidance 221 (that is, 1.54\xa0vials for patients who had had a splenectomy and 1.10\xa0vials for patients who had not had a splenectomy); that time to response for eltrombopag should be equal to that for romiplostim; that an in-hospital cost of £11.75 per administration for romiplostim should be used; and that anti‑D should be excluded as a rescue therapy for patients who had not had a splenectomy.\n\nThe Committee considered these comments as follows:\n\nWith regard to duration of treatment, the Committee heard from the ERG that the curves used to determine time on treatment within the model are specific to patients whose condition responded to eltrombopag; and, even if response rates differ between eltrombopag and romiplostim, it may still be reasonable to assume that duration of treatment is similar for both drugs. The ERG explained that the assumption of equal duration of treatment does not rely on the assumption of equal response rates and that, in the absence of other robust evidence, it was acceptable to assume equal time on treatment. The Committee concluded that no sensitivity analyses varying the duration of treatment parameter were needed.\n\nWith regard to time to response, the Committee heard from the ERG that, in the model, for both eltrombopag and romiplostim, all patients receive 1\xa0full 4‑week cycle of treatment, at the end of which patients whose condition does not respond stop treatment. The ERG indicated that the assumption about time to response does not affect the relative costs and QALYs associated with eltrombopag and romiplostim in the model. The Committee accepted that the ICERs were not sensitive to the assumptions underlying time to response, and concluded that it did not need to consider those assumptions further.\n\nWith regard to the cost of administering romiplostim, the Committee noted that the model included an average in-hospital cost of £204.81 per administration. The Committee was aware that the manufacturer of eltrombopag assumed that patients receive romiplostim in hospital for the first 4\xa0weeks, and that 72% self-administer thereafter. Although the Committee agreed that the cost of administering romiplostim used in the model was likely to be an overestimate, it considered the alternative cost of £11.75, as suggested in the comments received during consultation on the first appraisal consultation document, to be too low.\n\nWith regard to the use of anti‑D as a rescue therapy, the Committee agreed that it would be appropriate to exclude it from the model.\n\nThe Committee noted the comment received during consultation on the second appraisal consultation document, which suggested that it would be more appropriate to model higher rates of bleed and rescue therapy from the Kuter et al. (2008) trial to reflect the severely affected population for which romiplostim is recommended. The Committee recognised that rates of bleeding and use of rescue therapies are important parameters in the model. It noted that both rates were higher in the romiplostim trials (Kuter et al.) than in the eltrombopag trials (RAISE and EXTEND). It heard from the ERG that the SF‑6D utility data (favoured by the Committee, section\xa04.16) for bleeding events were aligned with the definition of bleeds in RAISE, but not with the definition in the Kuter et al. trials. The Committee was aware that neither the manufacturer nor the ERG applied the bleed and rescue rates from Kuter et al. in sensitivity analyses within the alternative evaluation favoured by the Committee. The Committee noted that there was no information available on bleeding and rescue rates in clinical practice, but it heard from the ERG that including the higher rates from Kuter et al. would not lower the cost effectiveness of eltrombopag compared with romiplostim below £30,000 saved per QALY lost. It accepted that, if the higher rates of bleeds and rescue therapy from Kuter et al. were more pertinent to the population with severe ITP for which romiplostim is recommended and for which eltrombopag was being considered, this would have an impact on the ICERs in favour of romiplostim, but it would be extremely unlikely to affect the relative cost effectiveness of eltrombopag and romiplostim to a degree where the Committee would change its recommendations. The Committee concluded that it did not need to consider further sensitivity analyses incorporating the higher bleed and rescue rates from the Kuter et al. trials.\n\nThe Committee discussed the most plausible ICERs for eltrombopag compared with romiplostim. The Committee noted that the ERG did not initially report ICERs for eltrombopag compared with romiplostim from its exploratory sensitivity analyses within the alternative evaluation. It was also aware that no ICERs were available that incorporated all the parameter inputs favoured by the Committee within a single analysis. Therefore, the Committee considered the additional sensitivity analyses carried out by the ERG in response to comments on the first appraisal consultation document (section\xa04.18). The Committee agreed that romiplostim is likely to be more clinically effective than eltrombopag; that it was appropriate to use the SF‑6D utility data collected from RAISE and EXTEND, a lower romiplostim dose and a lower administration cost for romiplostim, and to exclude anti‑D. The Committee considered the analysis that mirrored this, and noted that the resulting ICERs for eltrombopag compared with romiplostim were £389,000 saved per QALY lost for patients who had had a splenectomy and £271,000 saved per QALY lost for patients who had not had a splenectomy. The Committee acknowledged that these ICERs are associated with considerable uncertainty. It accepted that the ICERs would be higher (in favour of eltrombopag) when accounting for a romiplostim administration cost in hospital of more than £11.50, or if romiplostim relative to eltrombopag was less effective (that is, if the odds ratio for overall response was greater than the 0.15 used in the ERG's analyses). The Committee also accepted that the ICER would be lower (in favour of romiplostim) if the rates of bleeding and rescue therapy in clinical practice were higher than those applied in the cost-effectiveness analysis. The Committee accepted that there was a degree of uncertainty surrounding the ICER for eltrombopag compared with romiplostim. However, it was satisfied that, based on the evidence it had seen and the comments received during consultation on 2\xa0appraisal consultation documents, eltrombopag can be considered a cost-effective use of NHS resources. The Committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The Committee concluded that eltrombopag should be recommended as specified in its marketing authorisation (that is, in adults who have had a splenectomy and whose condition is refractory to other treatments, or as a second-line treatment in adults who have not had a splenectomy because surgery is contraindicated) as an option for treating adults with chronic ITP, but only if their condition is refractory to standard active treatments and rescue therapies, or they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and the manufacturer provides eltrombopag with the discount agreed in the patient access scheme.\n\nThe Committee noted that comments received in response to consultation on the appraisal consultation documents suggested that a specialist haematologist should supervise treatment with eltrombopag. The Committee agreed that, because the summary of product characteristics stipulates that eltrombopag treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases (section\xa02.2), it did not need to repeat this in its recommendations.\n\nThe Committee was aware of comments received in response to the consultation on the appraisal consultation documents expressing concerns about the wording of the preliminary recommendation for eltrombopag, which, unlike the recommendation for romiplostim in NICE technology appraisal guidance 221, included reference to whether a person had or had not had a splenectomy. While the Committee appreciated the concerns raised, it was aware that the wording of the marketing authorisations for eltrombopag and romiplostim stipulates that both of these treatments should only be used if a person has had a splenectomy or has not had a splenectomy because such surgery is contraindicated. The Committee acknowledged that NICE cannot recommend a treatment outside its marketing authorisation, and agreed that the wording of the recommendation in section\xa01 should reflect the wording of the marketing authorisation for eltrombopag.\n\nThe Committee discussed the limited published data on the long-term safety and effectiveness for both eltrombopag and romiplostim (sections\xa04.8 and 4.11), and on observed rates of bleeding and rescue therapy in clinical practice (section\xa04.20). The Committee considered that the collection of more data on the clinical effectiveness of both eltrombopag and romiplostim would be useful for future appraisals of treatments for chronic ITP because it would enable a more robust estimate of the clinical and cost effectiveness of the treatments. Given the difficulties of conducting randomised controlled trials and in generalising their results to clinical practice, the Committee supported generating and analysing observational data including, but not limited to, the existing UK ITP Registry, which collects data on the long-term outcomes of patients treated with eltrombopag and romiplostim.\n\nThe Committee discussed the differences in the wording of the guidance developed in this appraisal and the wording in the recommendations for romiplostim in NICE technology appraisal guidance 221, the latter of which were developed some time ago. The Committee concluded that it is necessary to ensure clarity around the fact that the recommendations for eltrombopag and romiplostim are for exactly the same patient population.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA293\n\nAppraisal title: Eltrombopag for treating chronic immune thrombocytopenia (review of technology appraisal 205)\n\nSection\n\nKey conclusion\n\nEltrombopag is recommended as an option for treating adults with chronic immune thrombocytopenia, only if:\n\ntheir condition is refractory to standard active treatments and rescue therapies or\n\nthey have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies.\n\n\n\nEltrombopag is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\n\n\n\n\nFor people with severe chronic ITP who are at high risk of bleeding and need frequent courses of rescue therapy (that is, the population for which romiplostim is recommended in NICE technology appraisal guidance 221), the Committee agreed that eltrombopag was less effective and less costly than romiplostim. The analysis that mirrored the Committee's preferred assumptions gave ICERs of more than £250,000 saved per QALY lost. The Committee noted that, in this situation, the higher the ICER, the more cost effective a treatment becomes. The Committee therefore concluded that eltrombopag can be considered a cost-effective use of NHS resources in this population.\n\n\n\n, 4.20\n\nThe Committee agreed that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone. Therefore, it concluded that it could not recommend eltrombopag for patients who do not have severe disease and a high risk of bleeding (that is, the population for which romiplostim is not recommended in NICE technology appraisal guidance 221).\n\n\n\n, 4.14\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical specialists indicated that the signs and symptoms associated with chronic ITP vary. Chronic ITP may cause a patient to worry about the risk of bleeding, which may affect the ability of patients with chronic ITP to lead a normal life. The Committee recognised that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives.\n\n\n\nThe Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee understood that eltrombopag had a better adverse reaction profile than most standard treatments.\n\n\n\nThe Committee understood that a daily oral treatment would represent significant value for some patients with chronic ITP.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab.\n\n\n\nAdverse reactions\n\nThe Committee understood that the adverse reactions of most standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that eltrombopag had a better adverse reaction profile than those standard treatments.\n\n\n\nThe Committee noted the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had better safety profiles than most standard treatments for chronic ITP.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence on the clinical effectiveness of eltrombopag was derived mainly from the RAISE trial.\n\n\n\nIn the manufacturer's indirect comparison between eltrombopag and romiplostim, the Committee agreed that heterogeneity exists between RAISE and the 2 Kuter et al. (2008) trials, which may have introduced bias in the indirect comparison. However, the Committee concluded that it would be appropriate to perform an indirect comparison between both treatments.\n\n, 4.10\n\nRelevance to general clinical practice in the NHS\n\nNo specific Committee considerations on the relevance to general clinical practice in the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee heard from the clinical specialists that the romiplostim trials were conducted before the eltrombopag trials; the Committee recognised that this may have caused more patients with severe chronic ITP to be enrolled into the earlier romiplostim trials. The Committee also heard that the use of eltrombopag and romiplostim in clinical practice is broadly interchangeable.\n\n, 4.11\n\nThe Committee noted that the different statistical approaches used to perform an indirect comparison between eltrombopag and romiplostim gave an odds ratio for overall response that was statistically significantly in favour of romiplostim in the ERG's analysis but not in the manufacturer's. The Committee understood that the statistical approach used by the manufacturer did not account for heterogeneity between the 2\xa0Kuter et al. (2008) trials, and that the ERG's results depended on the degree of heterogeneity it assumed. The Committee agreed that the point estimates in both the manufacturer's and the ERG's analyses were associated with considerable uncertainty.\n\n\n\nThe Committee agreed that the manufacturer's indirect comparison between eltrombopag and the pathway of standard care alone was not sufficiently robust to compare eltrombopag with the pathway of standard care alone.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe available evidence showed that eltrombopag was clinically effective when compared with placebo.\n\n\n\nThe odds ratio for overall response from the manufacturer's indirect comparison between eltrombopag and romiplostim was 0.22, and that from the ERG's indirect comparison was 0.15. Only the latter was statistically significant.\n\n\n\nThe Committee concluded that the most plausible odds ratio for overall response for eltrombopag compared with romiplostim would be less than 1.00 but, given the uncertainty around the point estimates obtained from the indirect comparison, it could not determine the likely value of this ratio.\n\n\n\nFor the comparison of eltrombopag with the pathway of standard care alone, the Committee concluded that the results of the indirect comparison between the 2 pathways of care were not sufficiently robust to estimate a relative effect size.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer presented 3 economic analyses: a base case, an alternative evaluation and a scenario analysis. In all 3 analyses, the manufacturer compared eltrombopag with a pathway of standard care alone, and separately with a pathway of romiplostim plus standard care.\n\n\n\nThe Committee agreed that the alternative evaluation represented the most valid analysis because the modelling applied data derived directly from the pivotal trials of eltrombopag and the manufacturer's own systematic review.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered that there was no sufficiently robust cost-effectiveness evidence to make a recommendation for eltrombopag compared with the pathway of standard care alone because the model incorporated data based on the manufacturer's indirect comparison of treatments used in standard care that, in the Committee's opinion, lacked methodological rigor.\n\n, 4.15, 4.17\n\nThe Committee agreed that romiplostim is likely to be more clinically effective than eltrombopag, that it was appropriate to use the SF‑6D utility data collected from RAISE and EXTEND, a lower romiplostim dose and a lower administration cost for romiplostim, and to exclude anti‑D. The Committee acknowledged that the ICERs, even those reflecting its favoured parameters and assumptions, are associated with considerable uncertainty.\n\n, 4.19, 4.21\n\nThe Committee noted that there was no information available on bleeding and rescue rates observed in clinical practice. It accepted that, if these rates are higher than those applied in the model, this would have an impact on the ICERs in favour of romiplostim, but it would be extremely unlikely to affect the relative cost effectiveness of eltrombopag and romiplostim to a degree where the Committee would change its recommendations.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the manufacturer did not use the health-related quality-of-life data collected from RAISE and EXTEND. The Committee concluded that, of the utility data available, the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.\n\n\n\nThe Committee considered that the EQ‑5D data obtained from using a particular mapping algorithm would be associated with further uncertainty and, in the absence of other EQ‑5D data, the Committee concluded that the SF‑6D data provided by the manufacturer were the most appropriate to use within the alternative evaluation.\n\n\n\nThe Committee noted that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the calculation of the QALY.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee considered the cost effectiveness of eltrombopag compared with the pathway of standard care plus romiplostim in the alternative evaluation. It noted that the results of this comparison would apply only to people with severe chronic ITP and a persistent high risk of bleeding (that is, people for whom romiplostim is recommended in NICE technology appraisal guidance 221 for romiplostim).\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key driver of cost effectiveness is the relative effect size of eltrombopag and romiplostim. The Committee did not agree with the manufacturer's assumption that eltrombopag and romiplostim were equally effective, and so considered the sensitivity analyses in which romiplostim was more effective than eltrombopag.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee considered the analysis that mirrored its preferred assumptions and parameters. It noted that the resulting ICERs for eltrombopag compared with romiplostim were £389,000 saved per QALY lost for patients who had had a splenectomy and £271,000 saved per QALY lost for patients who had not had a splenectomy.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of eltrombopag has agreed a patient access scheme with the Department of Health that makes eltrombopag available with a discount. The size of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nDuring consultation on the second appraisal consultation document a consultee highlighted under the heading 'Unlawful discrimination or groups who will be disadvantaged?' that the 'draft guidance puts doctors in an indefensible position and lays the NHS wide open to a legal class action by patients that are forced into a surgical procedure [splenectomy] that may not be relevant to, or in fact resolve, their ITP.' This comment does not highlight any unlawful discrimination or groups of patients with ITP that could be disadvantaged. The wording of the marketing authorisation for eltrombopag stipulates that eltrombopag should only be used if a person has had a splenectomy or has not had a splenectomy because such surgery is contraindicated. The regulatory agency has stated that the benefit-harm balance for eltrombopag could not be considered favourable for patients for whom a splenectomy remained a therapeutic option. NICE has to give recommendations in line with the marketing authorisation.\n\n", 'Recommendations for further research': 'The Committee recommends that research should be carried out to directly compare eltrombopag with non-thrombopoietin receptor agonist treatments routinely used in UK clinical practice.\n\nThe Committee recommends research generating and analysing observational data including, but not limited to, the existing UK ITP Registry, which collects data on the long-term outcomes of patients treated with eltrombopag and romiplostim.'}
|
https://www.nice.org.uk/guidance/ta293
|
Evidence-based recommendations on eltrombopag (Revolade) for treating chronic immune thrombocytopenia in adults.
|
2dcc471a5e7dfdf564ae56081031c41e810dfa87
|
nice
|
Myeloma: diagnosis and management
|
Myeloma: diagnosis and management
This guideline covers the diagnosing and managing of myeloma (including smouldering myeloma and primary plasma cell leukaemia) in people aged 16 and over. It aims to improve care for people with myeloma by promoting the most effective tests and treatments for myeloma and its complications.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Communication and support
Provide information and support to people with myeloma or primary plasma cell leukaemia and their family members or carers (as appropriate), particularly at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.
Consider providing the following information in an individualised manner to people with myeloma and their family members or carers (as appropriate):
the disease process, relapse and remission cycle, and the person's overall prognosis
the treatment plan, including (if appropriate) the process and the potential benefits, risks and complications of stem cell transplantation
symptoms of myeloma and treatment‑related side effects (including steroid‑related side effects, infection and neuropathy)
lifestyle measures to optimise bone health and renal function
how to identify and report new symptoms (especially pain and spinal cord compression)
the role of supportive and palliative care
how to access peer support and patient support groups.
Offer prompt psychological assessment and support to people with myeloma at diagnosis and (as appropriate) at the beginning and end of each treatment, at disease progression and at transition to end of life care.
Refer people who are assessed as needing further psychological support to psychological services.
Advise family members or carers (as appropriate) about the range of available local and national support services at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.
For guidance on communication and patient‑centred care see the NICE guideline on patient experience in adult NHS services.
# Laboratory investigations
## Laboratory investigations for people with suspected myeloma
Use serum protein electrophoresis and serum‑free light‑chain assay to confirm the presence of a paraprotein indicating possible myeloma or monoclonal gammopathy of undetermined significance (MGUS).
If serum protein electrophoresis is abnormal, use serum immunofixation to confirm the presence of a paraprotein indicating possible myeloma or MGUS.
Do not use serum protein electrophoresis, serum immunofixation, serum‑free light‑chain assay or urine electrophoresis (urine Bence–Jones protein assessment) alone to exclude a diagnosis of myeloma.
When performing a bone marrow aspirate and trephine biopsy to confirm a diagnosis of myeloma, use morphology to determine plasma cell percentage and flow cytometry to determine plasma cell phenotype.
For guidance on the setup of laboratory diagnostic services see the NICE cancer service guidance on improving outcomes in haematological cancers.
## Laboratory investigations to provide prognostic information
Use the same sample for all diagnostic and prognostic tests on bone marrow, so people only have to have one bone marrow aspirate and trephine biopsy.
When performing a bone marrow aspirate and trephine biopsy to provide prognostic information:
Perform fluorescence in‑situ hybridisation (FISH) on CD138‑selected bone marrow plasma cells to identify the adverse risk abnormalities t(4;14), t(14;16), 1q gain, del(1p) and del(17p)(TP53 deletion). Use these abnormalities alongside International Staging System (ISS) scores to identify people with high‑risk myeloma.
Consider performing FISH on CD138‑selected bone marrow plasma cells to identify the adverse risk abnormality t(14;20), and the standard risk abnormalities t(11;14) and hyperdiploidy.
Consider performing immunophenotyping of bone marrow to identify plasma cell phenotype, and to inform subsequent monitoring.
Consider performing immunohistochemistry (including Ki‑67 staining and p53 expression) on the trephine biopsy to identify plasma cell phenotype and give an indication of cell proliferation, to provide further prognostic information.
Perform serum‑free light‑chain assay and use serum‑free light‑chain ratio to assess prognosis.
# Imaging investigations
## Imaging for people with suspected myeloma
Offer imaging to all people with a plasma cell disorder suspected to be myeloma.
Consider whole‑body MRI as first‑line imaging.
Consider whole‑body low‑dose CT as first‑line imaging if whole‑body MRI is unsuitable or the person declines it.
Only consider skeletal survey as first‑line imaging if whole‑body MRI and whole‑body low‑dose CT are unsuitable or the person declines them.
Do not use isotope bone scans to identify myeloma‑related bone disease in people with a plasma cell disorder suspected to be myeloma.
## Imaging for people with newly diagnosed myeloma
For people with newly diagnosed myeloma or smouldering myeloma who have not had whole‑body imaging with 1 of the following, consider whole‑body imaging to assess for myeloma‑related bone disease and extra‑medullary plasmacytomas with one of:
MRI
CT
fluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).
For guidance on imaging for people with suspected spinal cord compression, see the NICE guideline on metastatic spinal cord compression.
Consider baseline whole‑body imaging with MRI or FDG PET‑CT for people who have non‑secretory myeloma or suspected or confirmed soft tissue plasmacytomas and have not already had either of these tests.
# Service organisation
For guidance on the facilities needed to provide intensive inpatient chemotherapy and transplants for people with myeloma, and the structure and function of multidisciplinary teams (MDTs), see the NICE cancer service guidance on improving outcomes in haematological cancers.
For guidance on service organisation for young people see the NICE cancer service guidance on improving outcomes in children and young people with cancer.
Each hospital treating people with myeloma who are not receiving intensive inpatient chemotherapy or a transplant should provide local access to:
an MDT specialising in myeloma
supportive and palliative care, supported by:
psychological support services
a 24‑hour acute oncology and/or haematology helpline
physiotherapy
-ccupational therapy
dietetics
medical social services
critical care
clinical trials via the MDT specialising in myeloma
dental services.
Each hospital treating people with myeloma should provide regional access through its network to:
facilities for intensive inpatient chemotherapy or transplantation
renal support
spinal disease management
specialised pain management
therapeutic apheresis
radiotherapy
restorative dentistry and oral surgery
clinical trials, in particular early phase trials.
# Managing newly diagnosed myeloma
## First‑line treatment
NICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myeloma‑related subgroups are not included.
Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high‑dose chemotherapy with haematopoietic stem cell transplantation.
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first‑line treatment of multiple myeloma in people for whom high‑dose chemotherapy with stem cell transplantation is considered inappropriate.
Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first‑line treatment of multiple myeloma if:
high‑dose chemotherapy with stem cell transplantation is considered inappropriate and
the person is unable to tolerate or has contraindications to thalidomide.
Consider using frailty and performance status measures that include comorbidities to assess the suitability of people with myeloma for first autologous stem cell transplant.
Do not use age or the level of renal impairment alone to assess the suitability of people with myeloma for first autologous stem cell transplant.
Take into account that only a small number of people with myeloma are suitable for allogeneic stem cell transplantation.
When assessing whether people with myeloma are suitable for an allogeneic stem cell transplant, take into account:
whether the person has chemosensitive disease
how many previous lines of treatment they have had
whether a fully human leukocyte antigen (HLA) matched donor is available
how graft‑versus‑host disease (GvHD) and other complications may get worse with age
the risk of higher transplant‑related mortality and morbidity, versus the potential for long‑term disease‑free survival
improving outcomes with other newer treatments
the person's understanding of the procedure and its risks and benefits.
Consider allogeneic stem cell transplantation as part of a clinical trial if one is available.
## Primary plasma cell leukaemia
Consider bortezomib‑based and/or lenalidomide‑based combination induction chemotherapy for people with primary plasma cell leukaemia.
Consider high‑dose melphalan‑based autologous stem cell transplantation for people with primary plasma cell leukaemia if they are suitable.
# Managing acute renal disease caused by myeloma
Consider immediately starting a bortezomib‑ and dexamethasone‑based combination regimen for people with untreated, newly diagnosed, myeloma‑induced acute renal disease.
If a bortezomib‑based combination regimen is unsuitable for people with untreated, newly diagnosed, myeloma‑induced acute renal disease, consider immediately starting a thalidomide‑ and dexamethasone‑based combination regimen.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Do not perform plasma exchange for myeloma‑induced acute renal disease.
# Preventing and managing bone disease
## Preventing bone disease
To prevent bone disease, offer people with myeloma:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.
Consider immediately referring people with myeloma for dental assessment and treatment before starting zoledronic acid or disodium pamidronate.
For people who need urgent myeloma treatment, consider referring for dental assessment and treatment as soon as possible after they start treatment.
## Managing non‑spinal bone disease
Offer people with myeloma and non‑spinal bone disease who have not already started bisphosphonates:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.
Assess the risk of fracture (in line with the NICE guideline on assessing the risk of fragility fractures in osteoporosis) in people with myeloma and non‑spinal bone disease.
Consider surgical stabilisation followed by radiotherapy for non‑spinal bones that have fractured or are at high risk of fractures.
Consider radiotherapy for non‑spinal bones that have fractured or are at high risk of fracture if surgical intervention is unsuitable or not immediately needed.
Consider radiotherapy for people with myeloma and non‑spinal bone disease who need additional pain relief if:
chemotherapy and initial pain management has not led to prompt improvement in pain control
chemotherapy is unsuitable and current pain medication is not working.
Consider re‑treatment with radiotherapy if pain recurs or if there is regrowth of a previously treated lesion.
Consider seeking advice from or referral to specialists in palliative care or pain medicine for people with complex non‑spinal bone disease.
## Managing spinal bone disease
For guidance on treating metastatic spinal cord compression, see the NICE guideline on metastatic spinal cord compression.
Offer all people with myeloma and spinal bone disease:
bisphosphonates as follows, if not already started:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or unsuitable
systemic pain control, when relevant using the NICE guidelines on neuropathic pain and opioids in palliative care.
Consider the following as adjuncts to other treatments for all people with myeloma and spinal bone disease:
interventional pain management
bracing.
In people with radiological evidence of myeloma‑related spinal instability, consider immediate intervention with:
spinal surgery, with or without radiotherapy
cement augmentation, with or without radiotherapy
radiotherapy alone, if spinal intervention is unsuitable or not currently needed.
In people with radiological evidence of myeloma‑related spinal bone disease without instability, consider:
cement augmentation, with or without radiotherapy
radiotherapy alone.
# Preventing and managing complications
## Preventing infection
Offer people with myeloma the seasonal influenza vaccination.
Consider extending the pneumococcal vaccination to people with myeloma who are under 65.
Consider intravenous immunoglobulin replacement therapy for people who have hypogammaglobulinaemia and recurrent infections.
Consider continuing aciclovir or equivalent antiviral prophylaxis after treatment with bortezomib or other proteasome inhibitors ends.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Consider aciclovir or equivalent antiviral prophylaxis for people who are taking both immunomodulatory drugs and high‑dose steroids.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Consider testing for hepatitis B, hepatitis C and HIV before starting myeloma treatment.
## Managing peripheral neuropathy
For guidance on the pharmacological management of neuropathic pain see the NICE guideline on neuropathic pain in adults.
Explain the symptoms of neuropathy to people with myeloma, and encourage them to tell their clinical team about any new, different or worsening neuropathic symptoms immediately.
If people who are receiving bortezomib develop neuropathic symptoms, consider immediately:
switching to subcutaneous injections and/or
reducing to weekly doses and/or
reducing the dose.
Consider reducing the dose if people are taking a drug other than bortezomib and develop neuropathic symptoms.
Temporarily stop neuropathy‑inducing myeloma treatments if people develop either of the following:
grade 2 neuropathy with pain
grade 3 or 4 neuropathy.
If neuropathy does not improve despite stopping myeloma treatment and further treatment is needed, consider switching to myeloma treatments less likely to induce neuropathy.
## Preventing thrombosis
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
## Managing fatigue
If other treatable causes of anaemia have been excluded, consider erythropoietin analogues (adjusted to maintain a steady state of haemoglobin at 110–120 g/litre) to improve fatigue in people with myeloma who have symptomatic anaemia.
# Monitoring
Monitor people with smouldering myeloma every 3 months for the first 5 years, and then decide the frequency of further monitoring based on the long‑term stability of the disease.
Monitor people who have completed myeloma treatment and recovered at least every 3 months. Take into account any risk factors for progression, such as:
high‑risk fluorescence in‑situ hybridisation (FISH)
impaired renal function
disease presentation.
Monitoring for myeloma and smouldering myeloma should include:
assessment of symptoms related to myeloma and myeloma treatment and
the following laboratory tests:
full blood count
renal function
bone profile
serum immunoglobulins and serum protein electrophoresis
serum‑free light‑chain assay, if appropriate.
Do not offer people with myeloma or smouldering myeloma routine skeletal surveys for disease monitoring.
Consider symptom‑directed imaging for people with myeloma or smouldering myeloma if any new bone symptoms develop.
For people with myeloma and serological relapse or disease progression, consider one of the following (taking into consideration previous imaging tests):
whole‑body MRI
spinal MRI
fluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).
For people with smouldering myeloma and disease progression, consider one of the following (taking into consideration previous imaging tests):
whole‑body MRI
whole‑body low‑dose CT
whole‑body CT
spinal MRI
fluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).
# Managing relapsed myeloma
## First relapse
NICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myeloma‑related subgroups are not included.
Bortezomib monotherapy is recommended as an option for the treatment of progressive multiple myeloma in people who are at first relapse having received 1 prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation, under the following circumstances:
the response to bortezomib is measured using serum M protein after a maximum of 4 cycles of treatment, and treatment is continued only in people who have a complete or partial response (that is, reduction in serum M protein of 50% or more or, where serum M protein is not measurable, an appropriate alternative biochemical measure of response), and
the manufacturer rebates the full cost of bortezomib for people who, after a maximum of 4 cycles of treatment, have less than a partial response (as defined above).
People currently receiving bortezomib monotherapy who do not meet the criteria in recommendation 1.10.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
## Second autologous stem cell transplantation
Offer a second autologous stem cell transplant to people with relapsed myeloma who are suitable and who have:
completed re‑induction therapy without disease progression and
had a response duration of more than 24 months after their first autologous stem cell transplant.
Consider a second autologous stem cell transplant for people with relapsed myeloma who are suitable and who have:
completed reinduction therapy without disease progression and
had a response duration of between 12 and 24 months after their first autologous stem cell transplant.
Be aware that people with relapsed myeloma are more likely to be suitable for a second autologous stem cell transplant if they have:
had a good response to the first autologous stem cell transplant
a lower International Staging System (ISS) stage
not had many prior treatments
good overall fitness, based on resilience, frailty and performance status
no adverse fluorescence in‑situ hybridisation (FISH) results.
## Subsequent therapy
Lenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of multiple myeloma only in people who have received two or more prior therapies, with the following condition:
The drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for more than 26 cycles (each of 28 days; normally a period of 2 years) will be met by the manufacturer.
People currently receiving lenalidomide for the treatment of multiple myeloma, but who have not received 2 or more prior therapies, should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
Pomalidomide, in combination with dexamethasone, is not recommended within its marketing authorisation for treating relapsed and refractory multiple myeloma in adults who have had at least 2 previous treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.
People whose treatment with pomalidomide was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
# Terms used in this guideline
## Smouldering myeloma
In this guideline, only recommendations that specifically refer to smouldering myeloma apply to this condition.
To find out what NICE has said on topics related to this guideline, see our web pages on blood and bone marrow cancers, complications of cancer, embolism and thrombosis and end of life care.# Context
Myeloma is a malignancy of the plasma cells that normally produce immunoglobulin. It affects multiple organs and systems, including the bones, kidneys, blood and immune systems.
Myeloma is the seventeenth most common cancer in the UK. In 2010, 4672 people in the UK were diagnosed with myeloma. It occurs more frequently in men and in people of African–Caribbean family origin. Diagnosis is often delayed because the symptoms are not specific to myeloma, and this leads to significant early morbidity and mortality.
Myeloma management is complex and challenging. Effective treatments have been developed over the past 15 years, and although myeloma is still incurable these treatments have led to improvements in overall survival and quality of life. However, myeloma treatment increasingly involves expensive drugs and frequent hospital visits. Complications of myeloma and myeloma treatment cause an increasing long‑term strain on supportive and palliative care services, and on carers.
This guideline covers areas in which there is uncertainty or variation in practice. It contains recommendations on:
communication and support
laboratory investigations and imaging to diagnose myeloma and determine further treatment
managing bone disease and acute renal disease
autologous and allogeneic stem cell transplantation
preventing and managing myeloma‑ and treatment‑induced complications
monitoring for people with smouldering myeloma and myeloma.
Because of the changes to the International Myeloma Working Group definition of smouldering myeloma, it was not possible to make any recommendations for clinical practice on managing this condition. The new definition has changed how smouldering myeloma and myeloma are differentiated, and there is currently no evidence available that is using the new definitions.
This guideline covers adults (aged 16 years and over):
who are referred to secondary care with suspected myeloma
with newly diagnosed or relapsed myeloma (including high‑risk myeloma and primary plasma cell leukaemia).
This guideline does not cover people who have:
a solitary plasmacytoma without myeloma
amyloid light‑chain amyloidosis in the absence of myeloma
paraproteins secondary to other conditions.# Recommendations for research
The Guideline Committee has made the following recommendations for research. The Committee's full set of research recommendations is detailed in the full guideline.
# Diagnostic investigations to predict treatment outcomes
What is the prognostic value of the Hevylite assay and ratio compared with other prognostic factors and tests, including the serum‑free light‑chain assay and fluorescence in‑situ hybridisation (FISH), in people with newly diagnosed myeloma who are starting treatment?
## Why this is important
Hevylite is a new assay that some studies have indicated is a useful prognostic tool. However, it is not clear how robustly it has been evaluated against other prognostic factors and tests, or whether it is an independent prognostic factor. The Hevylite assay should be evaluated in an accredited centralised laboratory independent of links with the manufacturer. Outcomes of interest are overall response, complete response, minimal residual disease, progression‑free survival, overall survival and resource use.
# Imaging investigations for newly diagnosed myeloma
What is the comparative effectiveness of whole‑body MRI, fluorodeoxyglucose positron emission tomography CT (FDG PET‑CT) and whole‑body low‑dose CT in detecting lesions that may determine the start of treatment for people with newly diagnosed myeloma?
## Why this is important
Newer imaging techniques are replacing skeletal surveys for assessing myeloma‑related bone disease in people with newly diagnosed myeloma. However, the most effective technique is not known. Outcomes of interest are lesion detection, sensitivity and specificity for myeloma‑related bone disease, patient acceptability, incremental upstaging, radiation exposure, risk of second primary cancer, the impact of additional information on predicting progression‑free survival, overall survival and skeletal‑related events.
# Management of smouldering myeloma
Which combinations of FISH, molecular technologies, bone marrow plasma cell percentage, whole‑body imaging, immunophenotype, serum‑free light‑chain levels or ratio, Hevylite, paraprotein levels, immunoparesis, and International Staging System (ISS) are most effective at risk stratification for people with smouldering myeloma?
What is the comparative effectiveness of fixed duration treatment (with or without bone‑directed therapy), continuous treatment (with or without bone‑directed therapy) and no treatment (with or without bone‑directed therapy) for people with smouldering myeloma?
## Why this is important
Changes to the International Myeloma Working Group definitions of smouldering myeloma and myeloma have affected the risk stratification process for smouldering myeloma. It is unclear if the previous risk stratification approach remains valid. It is also unclear if earlier treatment will be of benefit to people with smouldering myeloma. This study should be a randomised multi‑centre prospective trial for patients with newly diagnosed smouldering myeloma (as defined by the International Myeloma Working Group 2014 classification). Outcomes of interest are time to biochemical and/or clinical progression, overall survival, adverse events, quality of life and resource use.
# Allogeneic stem cell transplantation
What is the effectiveness of combined autologous–allogeneic stem cell transplantation compared with autologous stem cell transplantation, plus consolidation and maintenance treatment in chemosensitive patients at first response or first relapse?
## Why this is important
There are conflicting data from a small number of studies on long‑term survival following auto/allo stem cell transplantation compared with autologous stem cell transplantation. These studies were performed before thalidomide, bortezomib and lenalidomide were used as myeloma treatments. These drugs produce better responses and also have the capacity to affect immunological responses after the transplant. Research is needed to see if there is a role for auto/allo stem cell transplant in the ongoing treatment of myeloma. Outcomes of interest are progression‑free survival, overall survival, transplant‑related mortality, quality of life, early and late toxicity including graft‑versus‑host‑disease (GvHD) and resource use. This research should be included as an option in appropriate mainstream clinical trials for myeloma.
# Bisphosphonates for the prevention of bone disease
What is the effectiveness of monthly zoledronic acid given indefinitely compared with zoledronic acid given for a fixed duration in patients with myeloma?
## Why this is important
There is good‑quality evidence to support the use of zoledronic acid to prevent bone disease in people with myeloma. However, the optimal frequency and duration of treatment is not clearly defined and needs further research, particularly given the quality‑of‑life implications for people needing regular, life‑long visits to hospital. This study should be a randomised controlled trial. Outcomes of interest are skeletal‑related events, progression‑free survival, overall survival, utility of bone biomarkers, incidence of osteonecrosis of the jaw, quality of life and resource use.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Communication and support\n\nProvide information and support to people with myeloma or primary plasma cell leukaemia and their family members or carers (as appropriate), particularly at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.\n\nConsider providing the following information in an individualised manner to people with myeloma and their family members or carers (as appropriate):\n\nthe disease process, relapse and remission cycle, and the person's overall prognosis\n\nthe treatment plan, including (if appropriate) the process and the potential benefits, risks and complications of stem cell transplantation\n\nsymptoms of myeloma and treatment‑related side effects (including steroid‑related side effects, infection and neuropathy)\n\nlifestyle measures to optimise bone health and renal function\n\nhow to identify and report new symptoms (especially pain and spinal cord compression)\n\nthe role of supportive and palliative care\n\nhow to access peer support and patient support groups.\n\nOffer prompt psychological assessment and support to people with myeloma at diagnosis and (as appropriate) at the beginning and end of each treatment, at disease progression and at transition to end of life care.\n\nRefer people who are assessed as needing further psychological support to psychological services.\n\nAdvise family members or carers (as appropriate) about the range of available local and national support services at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.\n\nFor guidance on communication and patient‑centred care see the NICE guideline on patient experience in adult NHS services.\n\n# Laboratory investigations\n\n## Laboratory investigations for people with suspected myeloma\n\nUse serum protein electrophoresis and serum‑free light‑chain assay to confirm the presence of a paraprotein indicating possible myeloma or monoclonal gammopathy of undetermined significance (MGUS).\n\nIf serum protein electrophoresis is abnormal, use serum immunofixation to confirm the presence of a paraprotein indicating possible myeloma or MGUS.\n\nDo not use serum protein electrophoresis, serum immunofixation, serum‑free light‑chain assay or urine electrophoresis (urine Bence–Jones protein assessment) alone to exclude a diagnosis of myeloma.\n\nWhen performing a bone marrow aspirate and trephine biopsy to confirm a diagnosis of myeloma, use morphology to determine plasma cell percentage and flow cytometry to determine plasma cell phenotype.\n\nFor guidance on the setup of laboratory diagnostic services see the NICE cancer service guidance on improving outcomes in haematological cancers.\n\n## Laboratory investigations to provide prognostic information\n\nUse the same sample for all diagnostic and prognostic tests on bone marrow, so people only have to have one bone marrow aspirate and trephine biopsy.\n\nWhen performing a bone marrow aspirate and trephine biopsy to provide prognostic information:\n\nPerform fluorescence in‑situ hybridisation (FISH) on CD138‑selected bone marrow plasma cells to identify the adverse risk abnormalities t(4;14), t(14;16), 1q gain, del(1p) and del(17p)(TP53 deletion). Use these abnormalities alongside International Staging System (ISS) scores to identify people with high‑risk myeloma.\n\nConsider performing FISH on CD138‑selected bone marrow plasma cells to identify the adverse risk abnormality t(14;20), and the standard risk abnormalities t(11;14) and hyperdiploidy.\n\nConsider performing immunophenotyping of bone marrow to identify plasma cell phenotype, and to inform subsequent monitoring.\n\nConsider performing immunohistochemistry (including Ki‑67 staining and p53 expression) on the trephine biopsy to identify plasma cell phenotype and give an indication of cell proliferation, to provide further prognostic information.\n\nPerform serum‑free light‑chain assay and use serum‑free light‑chain ratio to assess prognosis.\n\n# Imaging investigations\n\n## Imaging for people with suspected myeloma\n\nOffer imaging to all people with a plasma cell disorder suspected to be myeloma.\n\nConsider whole‑body MRI as first‑line imaging.\n\nConsider whole‑body low‑dose CT as first‑line imaging if whole‑body MRI is unsuitable or the person declines it.\n\nOnly consider skeletal survey as first‑line imaging if whole‑body MRI and whole‑body low‑dose CT are unsuitable or the person declines them.\n\nDo not use isotope bone scans to identify myeloma‑related bone disease in people with a plasma cell disorder suspected to be myeloma.\n\n## Imaging for people with newly diagnosed myeloma\n\nFor people with newly diagnosed myeloma or smouldering myeloma who have not had whole‑body imaging with 1\xa0of the following, consider whole‑body imaging to assess for myeloma‑related bone disease and extra‑medullary plasmacytomas with one of:\n\nMRI\n\nCT\n\nfluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).\n\nFor guidance on imaging for people with suspected spinal cord compression, see the NICE guideline on metastatic spinal cord compression.\n\nConsider baseline whole‑body imaging with MRI or FDG PET‑CT for people who have non‑secretory myeloma or suspected or confirmed soft tissue plasmacytomas and have not already had either of these tests.\n\n# Service organisation\n\nFor guidance on the facilities needed to provide intensive inpatient chemotherapy and transplants for people with myeloma, and the structure and function of multidisciplinary teams (MDTs), see the NICE cancer service guidance on improving outcomes in haematological cancers.\n\nFor guidance on service organisation for young people see the NICE cancer service guidance on improving outcomes in children and young people with cancer.\n\nEach hospital treating people with myeloma who are not receiving intensive inpatient chemotherapy or a transplant should provide local access to:\n\nan MDT specialising in myeloma\n\nsupportive and palliative care, supported by:\n\n\n\npsychological support services\n\na 24‑hour acute oncology and/or haematology helpline\n\nphysiotherapy\n\noccupational therapy\n\ndietetics\n\nmedical social services\n\ncritical care\n\n\n\nclinical trials via the MDT specialising in myeloma\n\ndental services.\n\nEach hospital treating people with myeloma should provide regional access through its network to:\n\nfacilities for intensive inpatient chemotherapy or transplantation\n\nrenal support\n\nspinal disease management\n\nspecialised pain management\n\ntherapeutic apheresis\n\nradiotherapy\n\nrestorative dentistry and oral surgery\n\nclinical trials, in particular early phase trials.\n\n# Managing newly diagnosed myeloma\n\n## First‑line treatment\n\nNICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myeloma‑related subgroups are not included.\n\nBortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high‑dose chemotherapy with haematopoietic stem cell transplantation. [This recommendation is from NICE technology appraisal guidance on bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation.]\n\nThalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first‑line treatment of multiple myeloma in people for whom high‑dose chemotherapy with stem cell transplantation is considered inappropriate. [This recommendation is from NICE technology appraisal guidance on bortezomib and thalidomide for the first-line treatment of multiple myeloma.]\n\nBortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first‑line treatment of multiple myeloma if:\n\nhigh‑dose chemotherapy with stem cell transplantation is considered inappropriate and\n\nthe person is unable to tolerate or has contraindications to thalidomide. [This recommendation is from NICE technology appraisal guidance on bortezomib and thalidomide for the first-line treatment of multiple myeloma.]\n\nConsider using frailty and performance status measures that include comorbidities to assess the suitability of people with myeloma for first autologous stem cell transplant.\n\nDo not use age or the level of renal impairment alone to assess the suitability of people with myeloma for first autologous stem cell transplant.\n\nTake into account that only a small number of people with myeloma are suitable for allogeneic stem cell transplantation.\n\nWhen assessing whether people with myeloma are suitable for an allogeneic stem cell transplant, take into account:\n\nwhether the person has chemosensitive disease\n\nhow many previous lines of treatment they have had\n\nwhether a fully human leukocyte antigen (HLA) matched donor is available\n\nhow graft‑versus‑host disease (GvHD) and other complications may get worse with age\n\nthe risk of higher transplant‑related mortality and morbidity, versus the potential for long‑term disease‑free survival\n\nimproving outcomes with other newer treatments\n\nthe person's understanding of the procedure and its risks and benefits.\n\nConsider allogeneic stem cell transplantation as part of a clinical trial if one is available.\n\n## Primary plasma cell leukaemia\n\nConsider bortezomib‑based and/or lenalidomide‑based combination induction chemotherapy for people with primary plasma cell leukaemia.\n\nConsider high‑dose melphalan‑based autologous stem cell transplantation for people with primary plasma cell leukaemia if they are suitable.\n\n# Managing acute renal disease caused by myeloma\n\nConsider immediately starting a bortezomib‑ and dexamethasone‑based combination regimen for people with untreated, newly diagnosed, myeloma‑induced acute renal disease.\n\nIf a bortezomib‑based combination regimen is unsuitable for people with untreated, newly diagnosed, myeloma‑induced acute renal disease, consider immediately starting a thalidomide‑ and dexamethasone‑based combination regimen.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.\n\nDo not perform plasma exchange for myeloma‑induced acute renal disease.\n\n# Preventing and managing bone disease\n\n## Preventing bone disease\n\nTo prevent bone disease, offer people with myeloma:\n\nzoledronic acid or\n\ndisodium pamidronate, if zoledronic acid is contraindicated or not tolerated or\n\nsodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.\n\nConsider immediately referring people with myeloma for dental assessment and treatment before starting zoledronic acid or disodium pamidronate.\n\nFor people who need urgent myeloma treatment, consider referring for dental assessment and treatment as soon as possible after they start treatment.\n\n## Managing non‑spinal bone disease\n\nOffer people with myeloma and non‑spinal bone disease who have not already started bisphosphonates:\n\nzoledronic acid or\n\ndisodium pamidronate, if zoledronic acid is contraindicated or not tolerated or\n\nsodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.\n\nAssess the risk of fracture (in line with the NICE guideline on assessing the risk of fragility fractures in osteoporosis) in people with myeloma and non‑spinal bone disease.\n\nConsider surgical stabilisation followed by radiotherapy for non‑spinal bones that have fractured or are at high risk of fractures.\n\nConsider radiotherapy for non‑spinal bones that have fractured or are at high risk of fracture if surgical intervention is unsuitable or not immediately needed.\n\nConsider radiotherapy for people with myeloma and non‑spinal bone disease who need additional pain relief if:\n\nchemotherapy and initial pain management has not led to prompt improvement in pain control\n\nchemotherapy is unsuitable and current pain medication is not working.\n\nConsider re‑treatment with radiotherapy if pain recurs or if there is regrowth of a previously treated lesion.\n\nConsider seeking advice from or referral to specialists in palliative care or pain medicine for people with complex non‑spinal bone disease.\n\n## Managing spinal bone disease\n\nFor guidance on treating metastatic spinal cord compression, see the NICE guideline on metastatic spinal cord compression.\n\nOffer all people with myeloma and spinal bone disease:\n\nbisphosphonates as follows, if not already started:\n\n\n\nzoledronic acid or\n\ndisodium pamidronate, if zoledronic acid is contraindicated or not tolerated or\n\nsodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or unsuitable\n\n\n\nsystemic pain control, when relevant using the NICE guidelines on neuropathic pain and opioids in palliative care.\n\nConsider the following as adjuncts to other treatments for all people with myeloma and spinal bone disease:\n\ninterventional pain management\n\nbracing.\n\nIn people with radiological evidence of myeloma‑related spinal instability, consider immediate intervention with:\n\nspinal surgery, with or without radiotherapy\n\ncement augmentation, with or without radiotherapy\n\nradiotherapy alone, if spinal intervention is unsuitable or not currently needed.\n\nIn people with radiological evidence of myeloma‑related spinal bone disease without instability, consider:\n\ncement augmentation, with or without radiotherapy\n\nradiotherapy alone.\n\n# Preventing and managing complications\n\n## Preventing infection\n\nOffer people with myeloma the seasonal influenza vaccination.\n\nConsider extending the pneumococcal vaccination to people with myeloma who are under\xa065.\n\nConsider intravenous immunoglobulin replacement therapy for people who have hypogammaglobulinaemia and recurrent infections.\n\nConsider continuing aciclovir or equivalent antiviral prophylaxis after treatment with bortezomib or other proteasome inhibitors ends.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.\n\nConsider aciclovir or equivalent antiviral prophylaxis for people who are taking both immunomodulatory drugs and high‑dose steroids.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.\n\nConsider testing for hepatitis\xa0B, hepatitis\xa0C and HIV before starting myeloma treatment.\n\n## Managing peripheral neuropathy\n\nFor guidance on the pharmacological management of neuropathic pain see the NICE guideline on neuropathic pain in adults.\n\nExplain the symptoms of neuropathy to people with myeloma, and encourage them to tell their clinical team about any new, different or worsening neuropathic symptoms immediately.\n\nIf people who are receiving bortezomib develop neuropathic symptoms, consider immediately:\n\nswitching to subcutaneous injections and/or\n\nreducing to weekly doses and/or\n\nreducing the dose.\n\nConsider reducing the dose if people are taking a drug other than bortezomib and develop neuropathic symptoms.\n\nTemporarily stop neuropathy‑inducing myeloma treatments if people develop either of the following:\n\ngrade\xa02 neuropathy with pain\n\ngrade\xa03 or 4 neuropathy.\n\nIf neuropathy does not improve despite stopping myeloma treatment and further treatment is needed, consider switching to myeloma treatments less likely to induce neuropathy.\n\n## Preventing thrombosis\n\nThis recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.\n\nThis recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.\n\nThis recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.\n\nThis recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.\n\nThis recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.\n\n## Managing fatigue\n\nIf other treatable causes of anaemia have been excluded, consider erythropoietin analogues (adjusted to maintain a steady state of haemoglobin at 110–120\xa0g/litre) to improve fatigue in people with myeloma who have symptomatic anaemia.\n\n# Monitoring\n\nMonitor people with smouldering myeloma every 3\xa0months for the first 5\xa0years, and then decide the frequency of further monitoring based on the long‑term stability of the disease.\n\nMonitor people who have completed myeloma treatment and recovered at least every 3\xa0months. Take into account any risk factors for progression, such as:\n\nhigh‑risk fluorescence in‑situ hybridisation (FISH)\n\nimpaired renal function\n\ndisease presentation.\n\nMonitoring for myeloma and smouldering myeloma should include:\n\nassessment of symptoms related to myeloma and myeloma treatment and\n\nthe following laboratory tests:\n\n\n\nfull blood count\n\nrenal function\n\nbone profile\n\nserum immunoglobulins and serum protein electrophoresis\n\nserum‑free light‑chain assay, if appropriate.\n\n\n\nDo not offer people with myeloma or smouldering myeloma routine skeletal surveys for disease monitoring.\n\nConsider symptom‑directed imaging for people with myeloma or smouldering myeloma if any new bone symptoms develop.\n\nFor people with myeloma and serological relapse or disease progression, consider one of the following (taking into consideration previous imaging tests):\n\nwhole‑body MRI\n\nspinal MRI\n\nfluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).\n\nFor people with smouldering myeloma and disease progression, consider one of the following (taking into consideration previous imaging tests):\n\nwhole‑body MRI\n\nwhole‑body low‑dose CT\n\nwhole‑body CT\n\nspinal MRI\n\nfluorodeoxyglucose positron emission tomography CT (FDG PET‑CT).\n\n# Managing relapsed myeloma\n\n## First relapse\n\nNICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myeloma‑related subgroups are not included.\n\nBortezomib monotherapy is recommended as an option for the treatment of progressive multiple myeloma in people who are at first relapse having received 1 prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation, under the following circumstances:\n\nthe response to bortezomib is measured using serum\xa0M protein after a maximum of 4 cycles of treatment, and treatment is continued only in people who have a complete or partial response (that is, reduction in serum\xa0M protein of 50% or more or, where serum\xa0M protein is not measurable, an appropriate alternative biochemical measure of response), and\n\nthe manufacturer rebates the full cost of bortezomib for people who, after a maximum of 4 cycles of treatment, have less than a partial response (as defined above). [This recommendation is from NICE technology appraisal guidance on bortezomib monotherapy for relapsed multiple myeloma.]\n\nPeople currently receiving bortezomib monotherapy who do not meet the criteria in recommendation 1.10.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop. [This recommendation is from NICE technology appraisal guidance on bortezomib monotherapy for relapsed multiple myeloma.]\n\n## Second autologous stem cell transplantation\n\nOffer a second autologous stem cell transplant to people with relapsed myeloma who are suitable and who have:\n\ncompleted re‑induction therapy without disease progression and\n\nhad a response duration of more than 24\xa0months after their first autologous stem cell transplant.\n\nConsider a second autologous stem cell transplant for people with relapsed myeloma who are suitable and who have:\n\ncompleted reinduction therapy without disease progression and\n\nhad a response duration of between 12 and 24\xa0months after their first autologous stem cell transplant.\n\nBe aware that people with relapsed myeloma are more likely to be suitable for a second autologous stem cell transplant if they have:\n\nhad a good response to the first autologous stem cell transplant\n\na lower International Staging System (ISS) stage\n\nnot had many prior treatments\n\ngood overall fitness, based on resilience, frailty and performance status\n\nno adverse fluorescence in‑situ hybridisation (FISH) results.\n\n## Subsequent therapy\n\nLenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of multiple myeloma only in people who have received two or more prior therapies, with the following condition:\n\nThe drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for more than 26\xa0cycles (each of 28\xa0days; normally a period of 2\xa0years) will be met by the manufacturer. [This recommendation is from NICE technology appraisal guidance on lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy.]\n\nPeople currently receiving lenalidomide for the treatment of multiple myeloma, but who have not received 2 or more prior therapies, should have the option to continue therapy until they and their clinicians consider it appropriate to stop. [This recommendation is from NICE technology appraisal guidance on lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy.]\n\nPomalidomide, in combination with dexamethasone, is not recommended within its marketing authorisation for treating relapsed and refractory multiple myeloma in adults who have had at least 2\xa0previous treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy. [This recommendation is from NICE technology appraisal guidance on pomalidomide for relapsed and refractory multiple myeloma previously treated with lenalidomide and bortezomib.]\n\nPeople whose treatment with pomalidomide was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. [This recommendation is from NICE technology appraisal guidance on pomalidomide for relapsed and refractory multiple myeloma previously treated with lenalidomide and bortezomib.]\n\n# Terms used in this guideline\n\n## Smouldering myeloma\n\nIn this guideline, only recommendations that specifically refer to smouldering myeloma apply to this condition.\n\nTo find out what NICE has said on topics related to this guideline, see our web pages on blood and bone marrow cancers, complications of cancer, embolism and thrombosis and end of life care.", 'Context': 'Myeloma is a malignancy of the plasma cells that normally produce immunoglobulin. It affects multiple organs and systems, including the bones, kidneys, blood and immune systems.\n\nMyeloma is the seventeenth most common cancer in the UK. In 2010, 4672 people in the UK were diagnosed with myeloma. It occurs more frequently in men and in people of African–Caribbean family origin. Diagnosis is often delayed because the symptoms are not specific to myeloma, and this leads to significant early morbidity and mortality.\n\nMyeloma management is complex and challenging. Effective treatments have been developed over the past 15\xa0years, and although myeloma is still incurable these treatments have led to improvements in overall survival and quality of life. However, myeloma treatment increasingly involves expensive drugs and frequent hospital visits. Complications of myeloma and myeloma treatment cause an increasing long‑term strain on supportive and palliative care services, and on carers.\n\nThis guideline covers areas in which there is uncertainty or variation in practice. It contains recommendations on:\n\ncommunication and support\n\nlaboratory investigations and imaging to diagnose myeloma and determine further treatment\n\nmanaging bone disease and acute renal disease\n\nautologous and allogeneic stem cell transplantation\n\npreventing and managing myeloma‑ and treatment‑induced complications\n\nmonitoring for people with smouldering myeloma and myeloma.\n\nBecause of the changes to the International Myeloma Working Group definition of smouldering myeloma, it was not possible to make any recommendations for clinical practice on managing this condition. The new definition has changed how smouldering myeloma and myeloma are differentiated, and there is currently no evidence available that is using the new definitions.\n\nThis guideline covers adults (aged 16\xa0years and over):\n\nwho are referred to secondary care with suspected myeloma\n\nwith newly diagnosed or relapsed myeloma (including high‑risk myeloma and primary plasma cell leukaemia).\n\nThis guideline does not cover people who have:\n\na solitary plasmacytoma without myeloma\n\namyloid light‑chain amyloidosis in the absence of myeloma\n\nparaproteins secondary to other conditions.', 'Recommendations for research': "The Guideline Committee has made the following recommendations for research. The Committee's full set of research recommendations is detailed in the full guideline.\n\n# Diagnostic investigations to predict treatment outcomes\n\nWhat is the prognostic value of the Hevylite assay and ratio compared with other prognostic factors and tests, including the serum‑free light‑chain assay and fluorescence in‑situ hybridisation (FISH), in people with newly diagnosed myeloma who are starting treatment?\n\n## Why this is important\n\nHevylite is a new assay that some studies have indicated is a useful prognostic tool. However, it is not clear how robustly it has been evaluated against other prognostic factors and tests, or whether it is an independent prognostic factor. The Hevylite assay should be evaluated in an accredited centralised laboratory independent of links with the manufacturer. Outcomes of interest are overall response, complete response, minimal residual disease, progression‑free survival, overall survival and resource use.\n\n# Imaging investigations for newly diagnosed myeloma\n\nWhat is the comparative effectiveness of whole‑body MRI, fluorodeoxyglucose positron emission tomography CT (FDG PET‑CT) and whole‑body low‑dose CT in detecting lesions that may determine the start of treatment for people with newly diagnosed myeloma?\n\n## Why this is important\n\nNewer imaging techniques are replacing skeletal surveys for assessing myeloma‑related bone disease in people with newly diagnosed myeloma. However, the most effective technique is not known. Outcomes of interest are lesion detection, sensitivity and specificity for myeloma‑related bone disease, patient acceptability, incremental upstaging, radiation exposure, risk of second primary cancer, the impact of additional information on predicting progression‑free survival, overall survival and skeletal‑related events.\n\n# Management of smouldering myeloma\n\nWhich combinations of FISH, molecular technologies, bone marrow plasma cell percentage, whole‑body imaging, immunophenotype, serum‑free light‑chain levels or ratio, Hevylite, paraprotein levels, immunoparesis, and International Staging System (ISS) are most effective at risk stratification for people with smouldering myeloma?\n\nWhat is the comparative effectiveness of fixed duration treatment (with or without bone‑directed therapy), continuous treatment (with or without bone‑directed therapy) and no treatment (with or without bone‑directed therapy) for people with smouldering myeloma?\n\n## Why this is important\n\nChanges to the International Myeloma Working Group definitions of smouldering myeloma and myeloma have affected the risk stratification process for smouldering myeloma. It is unclear if the previous risk stratification approach remains valid. It is also unclear if earlier treatment will be of benefit to people with smouldering myeloma. This study should be a randomised multi‑centre prospective trial for patients with newly diagnosed smouldering myeloma (as defined by the International Myeloma Working Group 2014 classification). Outcomes of interest are time to biochemical and/or clinical progression, overall survival, adverse events, quality of life and resource use.\n\n# Allogeneic stem cell transplantation\n\nWhat is the effectiveness of combined autologous–allogeneic stem cell transplantation compared with autologous stem cell transplantation, plus consolidation and maintenance treatment in chemosensitive patients at first response or first relapse?\n\n## Why this is important\n\nThere are conflicting data from a small number of studies on long‑term survival following auto/allo stem cell transplantation compared with autologous stem cell transplantation. These studies were performed before thalidomide, bortezomib and lenalidomide were used as myeloma treatments. These drugs produce better responses and also have the capacity to affect immunological responses after the transplant. Research is needed to see if there is a role for auto/allo stem cell transplant in the ongoing treatment of myeloma. Outcomes of interest are progression‑free survival, overall survival, transplant‑related mortality, quality of life, early and late toxicity including graft‑versus‑host‑disease (GvHD) and resource use. This research should be included as an option in appropriate mainstream clinical trials for myeloma.\n\n# Bisphosphonates for the prevention of bone disease\n\nWhat is the effectiveness of monthly zoledronic acid given indefinitely compared with zoledronic acid given for a fixed duration in patients with myeloma?\n\n## Why this is important\n\nThere is good‑quality evidence to support the use of zoledronic acid to prevent bone disease in people with myeloma. However, the optimal frequency and duration of treatment is not clearly defined and needs further research, particularly given the quality‑of‑life implications for people needing regular, life‑long visits to hospital. This study should be a randomised controlled trial. Outcomes of interest are skeletal‑related events, progression‑free survival, overall survival, utility of bone biomarkers, incidence of osteonecrosis of the jaw, quality of life and resource use."}
|
https://www.nice.org.uk/guidance/ng35
|
This guideline covers the diagnosing and managing of myeloma (including smouldering myeloma and primary plasma cell leukaemia) in people aged 16 and over. It aims to improve care for people with myeloma by promoting the most effective tests and treatments for myeloma and its complications.
|
b5d4eb340ae2f5e9cd10f6baae4ac7166d41bfbf
|
nice
|
Lyme disease
|
Lyme disease
This guideline covers diagnosing and managing Lyme disease. It aims to raise awareness of when Lyme disease should be suspected and ensure that people have prompt and consistent diagnosis and treatment. It does not cover preventing Lyme disease.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Awareness of Lyme disease
Be aware that:
the bacteria that cause Lyme disease are transmitted by the bite of an infected tick
ticks are mainly found in grassy and wooded areas, including urban gardens and parks
tick bites may not always be noticed
infected ticks are found throughout the UK and Ireland, and although some areas appear to have a higher prevalence of infected ticks, prevalence data are incomplete
particularly high-risk areas are the South of England and Scottish Highlands but infection can occur in many areas
Lyme disease may be more prevalent in parts of central, eastern and northern Europe (including Scandinavia) and parts of Asia, the US and Canada.
Be aware that most tick bites do not transmit Lyme disease and that prompt, correct removal of the tick reduces the risk of transmission.
Give people advice about:
where ticks are commonly found (such as grassy and wooded areas, including urban gardens and parks)
the importance of prompt, correct tick removal and how to do this (see Public Health England's information on removing ticks)
covering exposed skin and using insect repellents that protect against ticks
how to check themselves and their children for ticks on the skin
sources of information on Lyme disease, such as Public Health England's resources and guidance on Lyme disease and organisations providing information and support, such as patient charities.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on awareness of Lyme disease .
Full details of the evidence and the committee's discussion are in evidence review A: awareness of Lyme disease.
Loading. Please wait.
# Diagnosis
## Clinical assessment
Diagnose Lyme disease in people with erythema migrans, a red rash that:
increases in size and may sometimes have a central clearing
is not usually itchy, hot or painful
usually becomes visible from 1 to 4 weeks (but can appear from 3 days to 3 months) after a tick bite and lasts for several weeks
is usually at the site of a tick bite.See also NICE's resource on different presentations of erythema migrans.
Be aware that a rash, which is not erythema migrans, can develop as a reaction to a tick bite that:
usually develops and recedes during 48 hours from the time of the tick bite
is more likely than erythema migrans to be hot, itchy or painful
may be caused by an inflammatory reaction or infection with a common skin pathogen.
Consider the possibility of Lyme disease in people presenting with several of the following symptoms, because Lyme disease is a possible but uncommon cause of:
fever and sweats
swollen glands
malaise
fatigue
neck pain or stiffness
migratory joint or muscle aches and pain
cognitive impairment, such as memory problems and difficulty concentrating (sometimes described as 'brain fog')
headache
paraesthesia.
Consider the possibility of Lyme disease in people presenting with symptoms and signs relating to 1 or more organ systems (focal symptoms) because Lyme disease is a possible but uncommon cause of:
neurological symptoms, such as facial palsy or other unexplained cranial nerve palsies, meningitis, mononeuritis multiplex or other unexplained radiculopathy; or rarely encephalitis, neuropsychiatric presentations or unexplained white matter changes on brain imaging
inflammatory arthritis affecting 1 or more joints that may be fluctuating and migratory
cardiac problems, such as heart block or pericarditis
eye symptoms, such as uveitis or keratitis
skin rashes such as acrodermatitis chronica atrophicans or lymphocytoma.
If a person presents with symptoms that suggest the possibility of Lyme disease, explore how long the person has had symptoms and their history of possible tick exposure, for example, ask about:
activities that might have exposed them to ticks
travel to areas where Lyme disease is known to be highly prevalent.
Do not rule out the possibility of Lyme disease in people with symptoms but no clear history of tick exposure.
Do not diagnose Lyme disease in people without symptoms, even if they have had a tick bite.
Be cautious about diagnosing Lyme disease in people without a supportive history or positive serological testing because of the risk of:
missing an alternative diagnosis
providing inappropriate treatment.
Follow usual clinical practice to manage symptoms, for example, pain relief for headaches or muscle pain, in people being assessed for Lyme disease.
Take into account that people with Lyme disease may have symptoms of cognitive impairment and may have difficulty explaining their symptoms. For adults, follow the recommendations in NICE's guideline on patient experience in adult NHS services.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on clinical assessment .
Full details of the evidence and the committee's discussion are in evidence review B: diagnostic accuracy of signs and symptoms.
Loading. Please wait.
## Laboratory investigations to support diagnosis
We have also produced a NICE visual summary of the recommendations on testing for Lyme disease.
Diagnose and treat Lyme disease without laboratory testing in people with erythema migrans.
Use a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans. Do not rule out diagnosis if tests are negative but there is high clinical suspicion of Lyme disease.
If there is a clinical suspicion of Lyme disease in people without erythema migrans:
-ffer an enzyme-linked immunosorbent assay (ELISA) test for Lyme disease and
consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion.
Test for both IgM and IgG antibodies using ELISAs based on purified or recombinant antigens derived from the VlsE protein or its IR6 domain peptide (such as C6 ELISA).
If the ELISA is positive or equivocal:
perform an immunoblot test for Lyme disease and
consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion of Lyme disease.
If the ELISA for Lyme disease is negative and the person still has symptoms, review their history and symptoms, and think about the possibility of an alternative diagnosis.
If Lyme disease is still suspected in people with a negative ELISA who were tested within 4 weeks from symptom onset, repeat the ELISA 4 to 6 weeks after the first ELISA test.
If Lyme disease is still suspected in people with a negative ELISA who have had symptoms for 12 weeks or more, perform an immunoblot test.
Diagnose Lyme disease in people with symptoms of Lyme disease and a positive immunoblot test.
If the immunoblot test for Lyme disease is negative (regardless of the ELISA result) but symptoms persist, consider a discussion with or referral to a specialist, to:
review whether further tests may be needed for suspected Lyme disease, for example, synovial fluid aspirate or biopsy, or lumbar puncture for cerebrospinal fluid analysis or
consider alternative diagnoses (both infectious, including other tick-borne diseases, and non-infectious diseases).Choose a specialist appropriate for the person's history or symptoms, for example, an adult or paediatric infection specialist, rheumatologist or neurologist.
If the immunoblot test for Lyme disease is negative and symptoms have resolved, explain to the person that no treatment is required.
Carry out tests for Lyme disease only at laboratories that:
are accredited by the UK accreditation service (UKAS) and
use validated tests (validation should include published evidence on the test methodology, its relation to Lyme disease and independent reports of performance) and
participate in a formal external quality assurance programme.
Do not routinely diagnose Lyme disease based only on tests done outside the NHS, unless the laboratory used is accredited, participates in formal external quality assurance programmes and uses validated tests (see recommendation 1.2.22). If there is any doubt about tests:
review the person's clinical presentation and
carry out testing again using a UKAS-accredited laboratory and/or seek advice from a national reference laboratory.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on laboratory investigations .
Full details of the evidence and the committee's discussion are in evidence review C: diagnostic tests.
Loading. Please wait.
## Information for people being tested for Lyme disease
Tell people that tests for Lyme disease have limitations. Explain that both false-positive and false-negative results can occur and what this means.
Explain to people that most tests for Lyme disease assess for the presence of antibodies and that the accuracy of tests may be reduced if:
testing is carried out too early (before antibodies have developed)
the person has reduced immunity, for example, people on immunosuppressant treatments, which might affect the development of antibodies.
Advise people that tests from non-UKAS laboratories may not have been fully evaluated to diagnose Lyme disease.
Explain to people that:
the symptoms and signs associated with Lyme disease overlap with those of other conditions
they will be assessed for alternative diagnoses if their tests are negative and their symptoms have not resolved
symptoms such as tiredness, headache and muscle pain are common, and a specific medical cause is often not found.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information .
Full details of the evidence and the committee's discussion are in evidence review N: information needs.
Loading. Please wait.
# Management
## Emergency referral
Follow usual clinical practice for emergency referrals, for example, in people with symptoms that suggest central nervous system infection, uveitis or cardiac complications such as complete heart block, even if Lyme disease is suspected.
## Specialist advice
Discuss the diagnosis and management of Lyme disease in children and young people under 18 years with a specialist, unless they have a single erythema migrans lesion and no other symptoms. Choose a specialist appropriate for the child or young person's symptoms dependent on availability, for example, a paediatrician, paediatric infectious disease specialist or a paediatric neurologist.
If an adult with Lyme disease has focal symptoms, consider a discussion with or referral to a specialist, without delaying treatment. Choose a specialist appropriate for the person's symptoms, for example, an adult infection specialist, rheumatologist or neurologist.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on emergency referral and specialist advice .
Full details of the evidence and the committee's discussion are in evidence review D: management of erythema migrans.
Loading. Please wait.
## Antibiotic treatment
For adults and young people (aged 12 and over) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in table 1. (Note that for Lyme disease suspected during pregnancy, use appropriate antibiotics for the stage of pregnancy (see the recommendation on assessing and diagnosing Lyme disease in the section on management for women with Lyme disease during pregnancy and their babies.)
For children (under 12) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in table 2. (Note that management of Lyme disease in children and young people should be discussed with a specialist in line with recommendation 1.3.2.)
Ask women (including young women under 18) if they might be pregnant before offering antibiotic treatment for Lyme disease (see the recommendation on assessing and diagnosing Lyme disease in the section on management for women with Lyme disease during pregnancy and their babies).
If symptoms worsen during treatment for Lyme disease, assess for an allergic reaction to the antibiotic. Be aware that a Jarisch–Herxheimer reaction may cause an exacerbation of symptoms but does not usually warrant stopping treatment.
Consider clinical review during or after treatment for Lyme disease to assess for possible side effects and response to treatment.
Symptoms
Treatment
First alternative
Second alternative
Lyme disease without focal symptoms but with erythema migrans and/or non-focal symptoms
Oral doxycycline:
mg twice per day or 200 mg once per day for 21 days
Oral amoxicillin:
g 3 times per day for 21 days
Oral azithromycin:
mg daily for 17 days
Note: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.
Lyme disease affecting the cranial nerves or peripheral nervous system
Oral doxycycline:
mg twice per day or 200 mg once per day for 21 days
Oral amoxicillin:
g 3 times per day for 21 days
Lyme disease affecting the central nervous system
Intravenous ceftriaxone:
g twice per day or 4 g once per day for 21 days (when an oral switch is being considered, use doxycycline)
Oral doxycycline:
mg twice per day or 400 mg once per day for 21 days
Lyme disease with arthritis
Oral doxycycline:
mg twice per day or 200 mg once per day for 28 days
Oral amoxicillin:
g 3 times per day for 28 days
Intravenous ceftriaxone:
g once per day for 28 days
Lyme disease with acrodermatitis chronica atrophicans
Oral doxycycline:
mg twice per day or 200 mg once per day for 28 days
Oral amoxicillin:
g 3 times per day for 28 days
Intravenous ceftriaxone:
g once per day for 28 days
Lyme disease with Lyme carditis
Oral doxycycline:
mg twice per day or 200 mg once per day for 21 days
Intravenous ceftriaxone:
g once per day for 21 days
Lyme disease with Lyme carditis and haemodynamically unstable
Intravenous ceftriaxone:
g once per day for 21 days (when an oral switch is being considered, use doxycycline)
Note: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.
Symptoms
Age
Treatment
First alternative
Second alternative
Lyme disease without focal symptoms but with erythema migrans and/or non-focal symptoms
–12 years
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 21 days
For severe infections, up to 5 mg/kg daily for 21 days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Oral amoxicillin for children 33 kg and under:
mg/kg 3 times per day for 21 days
Oral azithromycin for children 50 kg and under:
mg/kg daily for 17 days
In April 2018, this use of azithromycin was off-label in children under 12 years. See NICE's information on prescribing medicines
Note: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval
Lyme disease without focal symptoms with erythema migrans and/or non-focal symptoms
Under 9
Oral amoxicillin for children 33 kg and under: 30 mg/kg 3 times per day for 21 days
Oral azithromycin for children 50 kg and under:
mg/kg daily for 17 days
In April 2018, this use of azithromycin was off-label in children under 12 years. See NICE's information on prescribing medicines
Note: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval
Lyme disease affecting the cranial nerves or peripheral nervous system
–12 years
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 21 days
For severe infections, up to 5 mg/kg daily for 21 days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Oral amoxicillin for children 33 kg and under:
mg/kg 3 times per day for 21 days
Lyme disease affecting the cranial nerves or peripheral nervous system
Under 9
Oral amoxicillin for children 33 kg and under:
mg/kg 3 times per day for 21 days
Lyme disease affecting the central nervous system
–12 years
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 4 g) once per day for 21 days
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 21 days
For severe infections, up to 5 mg/kg daily (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Lyme disease affecting the central nervous system
Under 9
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 4 g) once per day for 21 days
Lyme disease with arthritis or acrodermatitis chronica atrophicans
–12 years
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 28 days
For severe infections, up to 5 mg/kg daily for 28 days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Oral amoxicillin for children 33 kg and under:
mg/kg 3 times per day 28 days
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 28 days
Lyme disease with arthritis or acrodermatitis chronica atrophicans
Under 9
Oral amoxicillin for children, 33 kg and under:
mg/kg 3 times per day for 28 days
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 28 days
Lyme disease with Lyme carditis and haemodynamically stable
–12 years
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 21 days
For severe infections, up to 5 mg/kg daily for 21 days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 21 days
Lyme disease with Lyme carditis and haemodynamically stable
Under 9
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 21 days
Lyme disease with Lyme carditis and haemodynamically unstable
–12 years
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 21 days
Oral doxycycline for children under 45 kg:
mg/kg in 2 divided doses on day 1 followed by 2.5 mg/kg daily in 1 or 2 divided doses for a total of 21 days
For severe infections, up to 5 mg/kg daily for 21 days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)
In April 2018, this use of doxycycline was off-label in children under 12 years. See NICE's information on prescribing medicines
Lyme carditis and haemodynamically unstablef
Under 9
Intravenous ceftriaxone for children under 50 kg:
mg/kg (up to 2 g) once per day for 21 days
Notes:
Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.
Children weighing more than the amounts specified should be treated according to table 1.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antibiotic treatment .
Full details of the evidence and the committee's discussion are in:
evidence review D: management of erythema migrans
evidence review E: management of non-specific symptoms
evidence review F: management of neuroborreliosis
evidence review G: management of arthritis
evidence review H: management of acrodermatitis chronica atrophicans
evidence review I: management of carditis
evidence review J: management of lymphocytoma
evidence review K: management of ocular symptoms.
Loading. Please wait.
## Ongoing symptoms after a course of antibiotics
If symptoms that may be related to Lyme disease persist, do not continue to improve or worsen after antibiotic treatment, review the person's history and symptoms to explore:
possible alternative causes of the symptoms
if re‑infection may have occurred
if treatment may have failed
details of any previous treatment, including whether the course of antibiotics was completed without interruption
if symptoms may be related to organ damage caused by Lyme disease, for example, nerve palsy.
If the person's history suggests re‑infection, offer antibiotic treatment for Lyme disease according to their symptoms (see tables 1 and 2).
Consider a second course of antibiotics for people with ongoing symptoms if treatment may have failed. Use an alternative antibiotic to the initial course, for example, for adults with Lyme disease and arthritis, offer amoxicillin if the person has completed an initial course of doxycycline.
If a person has ongoing symptoms following 2 completed courses of antibiotics for Lyme disease:
do not routinely offer further antibiotics and
consider discussion with a national reference laboratory or discussion or referral to a specialist as outlined in the recommendation on when the immunoblot test for Lyme disease is negative but symptoms persist in the section on laboratory investigations to support diagnosis.
Explain to people with ongoing symptoms following antibiotic treatment for Lyme disease that:
continuing symptoms may not mean they still have an active infection
symptoms of Lyme disease may take months or years to resolve even after treatment
some symptoms may be a consequence of permanent damage from infection
there is no test to assess for active infection and an alternative diagnosis may explain their symptoms.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on ongoing symptoms after a course of antibiotics .
Full details of the evidence and the committee's discussion are in evidence review L: management of ongoing symptoms.
Loading. Please wait.
## Non-antibiotic management of ongoing symptoms
Offer regular clinical review and reassessment to people with ongoing symptoms, including people who have no confirmed diagnosis.
Explore any ongoing symptoms with the person and offer additional treatment if needed following usual clinical practice.
Be alert to the possibility of symptoms related to Lyme disease that may need assessment and management, including:
chronic pain
depression and anxiety (see NICE's guideline on common mental health problems)
fatigue
sleep disturbance.
Support people who have ongoing symptoms after treatment for Lyme disease by:
encouraging and helping them to access additional services, including referring to adult social care for a care and support needs assessment, if they would benefit from these
communicating with children and families' social care, schools and higher education, and employers about the person's need for a gradual return to activities, if relevant.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on non-antibiotic management of ongoing symptoms .
Full details of the evidence and the committee's discussion are in evidence review L: management of ongoing symptoms.
Loading. Please wait.
## Management for women with Lyme disease during pregnancy and their babies
Assess and diagnose Lyme disease during pregnancy in the same way as for people who are not pregnant. Treat Lyme disease in pregnant women using appropriate antibiotics for the stage of pregnancy. (For more information on antibiotic use during pregnancy, see the British national formulary's information on specific antibiotics for Lyme disease.)
Tell women with Lyme disease during pregnancy that they are unlikely to pass the infection to their baby and emphasise the importance of completing the full course of antibiotic treatment.
Advise women who had Lyme disease during pregnancy to tell this to their healthcare professional if they have any concerns about their baby. In this situation, healthcare professionals should discuss the history with a paediatric infectious disease specialist and seek advice on what investigations to perform.
Start treatment for Lyme disease under specialist care for babies of women treated for Lyme disease during pregnancy if the baby has IgM antibodies specific for Lyme disease or there is any suspicion the baby may be infected.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management for women with Lyme disease during pregnancy and their babies .
Full details of the evidence and the committee's discussion are in evidence review M: transmission.
Loading. Please wait.
# Information for people with Lyme disease
Explain to people diagnosed with Lyme disease that:
Lyme disease is a bacterial infection treated with antibiotics
most people recover completely
prompt antibiotic treatment reduces the risk of further symptoms developing and increases the chance of complete recovery
it may take time to get better, but their symptoms should continue to improve in the months after antibiotic treatment
they may need additional treatment for symptom relief.
Tell people who are starting antibiotics for Lyme disease that some people may have a Jarisch–Herxheimer reaction to treatment. Explain that:
this causes a worsening of symptoms early in treatment
it can happen when large numbers of bacteria in the body are killed
it does not happen to everyone treated for Lyme disease
they should contact their doctor and keep taking their antibiotics if their symptoms worsen.
Advise people with Lyme disease to talk to their doctor if their symptoms have not improved or if symptoms return after completing treatment.
Explain to people with Lyme disease that infection does not give them lifelong immunity and that it is possible for them to be re‑infected and develop Lyme disease again.
For a short explanation of why the committee made the recommendations, see the rationale and impact section on information .
Full details of the evidence and the committee's discussion are in evidence review N: information needs.
Loading. Please wait.
# Terms used in this guideline
## Test for Lyme disease
Lyme disease is caused by infection with bacteria from different species of Borrelia. The majority of tests for Lyme disease detect antibodies produced in response to infection by bacteria.
The term Lyme disease is used when referring to both the disease and to tests for an antibody response. This reflects the terminology used in clinical practice.
## Jarisch–Herxheimer reaction
This is a systemic reaction, thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria. Symptoms include a worsening of fever, chills, muscle pains and headache. The reaction can start between 1 and 12 hours after antibiotics are started but can also occur later and can last for a few hours or 1 or 2 days. The reaction is self-limiting and usually resolves within 24 to 48 hours.
It was originally reported in the treatment of syphilis but has been documented in tick-borne diseases including Lyme disease, leptospirosis and relapsing fever.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Core outcome set for studies of management of Lyme disease
Can a core outcome set be developed for clinical trials of management of Lyme disease?
## Why this is important
Antibiotic treatment is the mainstay of management for Lyme disease. The studies published on the management of Lyme disease use differing outcomes, which are often poorly defined. The development of a core outcome set has been identified as a high priority because it would allow comparison across trials and allow appropriate meta-analysis to strengthen results. The methods used should be patient-focused and include patient input on priority outcomes and how they should be measured.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on antibiotic treatment .
Full details of the evidence and the committee's discussion are in:
evidence review D: management of erythema migrans
evidence review E: management of non-specific symptoms
evidence review F: management of neuroborreliosis
evidence review G: management of arthritis
evidence review H: management of acrodermatitis chronica atrophicans
evidence review I: management of carditis
evidence review J: management of lymphocytoma
evidence review K: management of ocular symptoms.
Loading. Please wait.
# Clinical epidemiology of Lyme disease in the UK
What are the incidence, presenting features, management and outcome of Lyme disease in the UK?
## Why this is important
There is a lack of robust epidemiological data on Lyme disease in the UK population. A large clinico-epidemiological study to collect data on incidence, presenting clinical features, management and outcome of Lyme disease in community and hospital settings in the UK would generate population-based statistics. These statistics would enable interventions such as antibiotic treatment and service improvements to be assessed properly and for services to be tailored so they best serve people with Lyme disease; this was felt to be of high priority. There is no current requirement to notify cases of Lyme disease; therefore, current data are likely to underestimate the number of cases.
For a short explanation of why the committee made the recommendation for research, see the rationale on awareness of Lyme disease .
Full details of the evidence and the committee's discussion are in evidence review A: awareness of Lyme disease.
Loading. Please wait.
# Seroprevalence of Lyme disease-specific antibodies and other tick-borne infections in the UK population
What is the current seroprevalence of Lyme disease-specific antibodies and other tick-borne infections in people in the UK?
## Why this is important
This information is not currently available and is of high priority. Without understanding the underlying population's seroprevalence of Lyme disease-specific antibodies in the UK, it is impossible to interpret incidence data accurately or to understand fully the epidemiology of Lyme disease in the UK. The available data suggest there are areas of higher and lower prevalence in the UK but there are many gaps in knowledge. This study is needed to act as a basis for future studies. The information may also help interpret serology of individuals living in endemic areas where positive serological results may be more common and may not always indicate an acute or recent infection.
Data now may also act as a baseline to help determine whether Lyme disease is spreading and becoming more common. This will be of benefit to patients affected by Lyme disease and healthcare workers treating it in the UK. Many people are concerned about the possible presence of co‑infections transmitted by ticks; these are thought to be rare in the UK (compared with other parts of the world) but there are insufficient data to confirm or refute this. Better evidence may improve diagnostic and treatment decisions.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on laboratory investigations .
Full details of the evidence and the committee's discussion are in evidence review C: diagnostic tests.
Loading. Please wait.
# Antimicrobial management of Lyme disease
What are the most clinically and cost-effective treatment options for different clinical presentations of Lyme disease in the UK?
## Why this is important
The evidence on the effectiveness of antimicrobial treatment regimens used in different presentations of Lyme diseases is of poor quality, out-dated and often based on small studies. No relevant cost-effectiveness evidence was identified. A series of prospective multicentre studies is needed to compare the clinical and cost effectiveness of different dosages and length of treatments needed and the clinical and cost effectiveness of oral compared with intravenous treatments for different presentations of Lyme disease. This is felt to be of high priority because it has enormous implications for people with Lyme disease and for NHS costs.
There is currently insufficient quality evidence on the most effective drug and dose, and the effectiveness of extended treatment or retreatment regimens in those with continuing symptoms remains uncertain, leading to multiple referrals in search of alternative diagnoses. Clarification could improve outcomes, reduce costs and may minimise unnecessary treatment.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on antibiotic treatment .
Full details of the evidence and the committee's discussion are in:
evidence review D: management of erythema migrans
evidence review E: management of non-specific symptoms
evidence review F: management of neuroborreliosis
evidence review G: management of arthritis
evidence review H: management of acrodermatitis chronica atrophicans
evidence review I: management of carditis
evidence review J: management of lymphocytoma
evidence review K: management of ocular symptoms.
Loading. Please wait.
# Laboratory tests to diagnose initial and ongoing infection and determine re‑infection in the different presentations of Lyme disease in the UK
What is the most clinically and cost-effective serological antibody-based test, biomarker or other test for diagnosing Lyme disease in the UK at all stages, including re‑infection?
## Why this is important
Determining the most clinically and cost-effective diagnostic tests for Lyme disease will improve patient care and is a high priority. The clinical presentation of Lyme disease is variable with the diagnosis of all presentations, except erythema migrans, relying in part on laboratory testing. Current literature suggests that a combined IgG/IgM enzyme-linked immunosorbent assay (ELISA) based on the IR6 peptide and immunoblot are useful; however, published evidence is of either low or very low quality and is not UK based. There is evidence of variation in the IR6 peptide between the principal Borrelia genospecies in UK ticks and a combination of ELISAs may improve sensitivity.
A 'test of cure' for Lyme disease does not exist and, consistent with most other infectious diseases, serology is likely to remain positive for some time following successful treatment of infection in most patients. However, little is known about the evolution of antibody titres over time in those who have been treated successfully and in those who have ongoing symptoms.
It is frequently stated that early antibiotic treatment of Lyme disease abrogates the immune response, so that serology remains or becomes negative. This is not a common occurrence in other infections but there are inadequate prospective data on whether it occurs in people with Lyme disease. Observational studies to clarify this would be helpful. In addition, understanding the natural course of Lyme disease serology, and non-serological tests over time, may assist in the interpretation of test results in patients who remain symptomatic and in those who are high risk for re‑infection, such as those with occupational exposure.
In particular, further research into the value of novel biomarkers (for example, CXCL13 and others) and other types of tests may be helpful to support the current low-quality evidence. The examples of tests included in this research recommendation reflect those included in this guideline. However, other novel biomarkers are likely to be developed and require similar assessment.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on laboratory investigations .
Full details of the evidence and the committee's discussion are in evidence review C: diagnostic tests.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Awareness of Lyme disease
Recommendations 1.1.1 to 1.1.3
## Why the committee made the recommendations
The committee agreed that raising awareness is important to improve diagnosis and management of Lyme disease. Based on the committee's knowledge and experience, and some limited evidence on UK incidence, they agreed to highlight how infection occurs, typical tick habitats and areas of higher risk. This may help to guide healthcare professionals, for example, in recognising the possibility of Lyme disease when a person is unaware that they have been bitten by a tick or in areas where ticks are found but Lyme disease is not highly prevalent.
The committee also agreed that people who may have been exposed to ticks should be given advice to help avoid Lyme disease in the future.
Because of the lack of evidence in this area, the committee also developed a research recommendation on the clinical epidemiology of Lyme disease in the UK.
## How the recommendations might affect practice
The recommendations aim to improve awareness of Lyme disease, to promote early investigation and treatment, and to optimise outcomes in people with Lyme disease. They will change current practice by prompting healthcare professionals to think about the possibility of Lyme disease. This may result in an increase in testing and treatment, but the cost of this is likely to be balanced by the benefits of improved recognition and early treatment.
Return to recommendations
# Clinical assessment
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
The committee reviewed evidence on the diagnostic accuracy of some specific signs and symptoms (erythema migrans, facial palsy, lymphocytoma, acrodermatitis chronica atrophicans and heart block or arrhythmias) to assess if any could be used to diagnose Lyme disease or to indicate that testing should be carried out.
Erythema migrans only occurs in Lyme disease and may be used to diagnose Lyme disease. The committee agreed that the evidence, although limited, supported this. Some healthcare professionals may not be familiar with erythema migrans, so a description of the rash and its characteristics was included.
Lyme disease has a varied presentation and erythema migrans is not always present, so the assessment of other signs and symptoms is important. The evidence was not strong enough for the committee to recommend diagnosis, testing or treatment based on any other symptom or sign alone. However, the committee noted a number of potential presentations of Lyme disease that should alert healthcare professionals to consider the possibility of Lyme disease and prompt a discussion about the possibility of tick exposure. Based on their knowledge and experience, the committee agreed to highlight factors to consider in history and presentation to help with clinical decision-making.
## How the recommendations might affect practice
Current practice is to diagnose and treat Lyme disease in people with erythema migrans. People who present without erythema migrans but whose history and presentation are consistent with Lyme disease are offered testing. The recommendations will not change current practice but should serve as a reminder to healthcare professionals, particularly in areas where Lyme disease is less common, to think about Lyme disease as a differential diagnosis. Implementing these recommendations is unlikely to involve additional costs and may improve recognition and diagnosis.
Return to recommendations
# Laboratory investigations
Recommendations 1.2.11 to 1.2.23
## Why the committee made the recommendations
The committee agreed that laboratory testing is unnecessary for people presenting with erythema migrans, because the rash is very specific to Lyme disease and prompt treatment will prevent further symptoms developing. However, most other symptoms associated with Lyme disease have other more common causes, so testing may be helpful to ensure accurate diagnosis and appropriate treatment.
Based on the evidence on test accuracy, the committee agreed that test results need careful interpretation alongside clinical assessment to guide diagnosis. Because of the limitations of tests, Lyme disease should not be ruled out by negative tests if it is strongly suggested by the clinical assessment. The committee decided that treatment could be started at the same time as testing if clinical assessment strongly suggests Lyme disease because prompt treatment is important.
The committee agreed a strategy of 2‑tier testing (an initial and confirmatory test), which the evidence indicated was potentially cost saving. Initial testing with a combination IgM and IgG enzyme-linked immunosorbent assay (ELISA) for Lyme disease should be offered because the evidence generally showed better accuracy (both sensitivity and specificity) for combined tests compared to IgM‑only and IgG‑only tests. The evidence was best for tests based on purified or recombinant antigens derived from the VlsE protein or its IR6 domain peptide (such as a C6).
For people with a negative ELISA result who continue to have symptoms, the committee agreed that clinical review would ensure that alternative diagnoses are not missed. In addition, because antibodies take some time to develop, repeat testing would be warranted for people who may have had the initial test too early, before an immune response has developed. If symptoms have been present for 12 weeks, the committee agreed that an immunoblot would help rule out or confirm diagnosis where uncertainty still remains.
The committee agreed that for people with negative test results who continue to have symptoms, discussion with or referral to a specialist for further review might be beneficial.
The committee agreed that testing should be done in UKAS-accredited laboratories and that any tests used for diagnosis should be validated before they are used to diagnose Lyme disease to avoid unreliable and misleading results, which may lead to misdiagnosis.
Based on their knowledge and experience, the committee agreed that Borrelia burgdorferi sensu lato (sl) infection does not behave differently in children than adults, but acknowledged that a young child's immune responses might not be as rapid and effective. The limited evidence in children did not show a noticeable difference in test accuracy compared with adults. Therefore, the committee decided that separate recommendations for testing in children were unnecessary.
The committee considered it important that people being tested for Lyme disease understand how the tests work, their limitations and the importance of basing decisions on tests that are valid.
The committee noted that further research would be helpful and agreed to make research recommendations to determine the seroprevalence of antibodies to tick-borne infections in the UK and to clarify further the most effective laboratory tests at different stages of Lyme disease.
## How the recommendations might affect practice
A 2‑tiered testing system is used in current practice, in which a positive result on an initial ELISA leads to a confirmatory immunoblot test. A negative result on an initial ELISA would not usually lead to a confirmatory immunoblot test. Therefore, the recommendation to carry out an immunoblot test, despite an initial negative ELISA when there is clinical suspicion of Lyme disease would be a change to practice and increase the number of people receiving this test. However, this would only apply to a small population, so this recommendation is not likely to have a significant resource impact.
Return to recommendations
# Emergency referral and specialist advice
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
Lyme disease will not usually be considered as the most likely cause when people present with neurological and other symptoms that need emergency referral (such as central nervous system infection or heart block). However, the committee wanted to emphasise that if the history and physical findings suggest Lyme disease, usual clinical practice is still appropriate, because people may need additional supportive treatment from specialist services as well as appropriate antibiotics.
The type of problems that children with Lyme disease may develop, such as arthritis or facial palsy, are uncommon and the committee decided to recommend that management for children and young people with presentations other than uncomplicated erythema migrans (a single lesion with no other symptoms) should be discussed with a specialist to ensure the diagnosis is correct and for advice on antibiotic treatment.
For adults with focal symptoms such as arthritis, the committee agreed that a discussion with a specialist may be considered, but that treatment can be started.
## How the recommendations might affect practice
People who are systemically unwell with neurological or cardiac disease are referred to hospital for urgent treatment, so this recommendation should not lead to a change in existing practice.
The occurrence of symptoms such as arthritis and facial palsy are uncommon in children, so it is expected that most children with these symptoms are already seen in specialist services; therefore, this recommendation should not result in a large change of practice.
Return to recommendations
# Antibiotic treatment
Recommendations 1.3.4 to 1.3.8
## Why the committee made the recommendations
A number of studies examined antibiotic treatment of Lyme disease with erythema migrans using different antibiotics, doses and durations of treatment. However, many of the studies did not reflect current prescribing practices and the evidence was of poor quality.
For adults, there was evidence that doxycycline is more clinically effective than some other antibiotics. However, the evidence showed no clear difference in effectiveness between doxycycline, an amoxicillin/probenecid combination and azithromycin. The evidence also showed no benefit of intravenous or intramuscular cephalosporin over doxycycline. It was noted that doxycycline and amoxicillin are able to penetrate the blood–cerebrospinal fluid barrier and pass into the central nervous system, whereas azithromycin cannot. This may be important to prevent the development of further symptoms. Doxycycline can also be taken in a single daily dose, which may help with adherence.
Based on these factors, along with their knowledge and experience, the committee agreed on doxycycline as the initial treatment for adults and young people (aged 12 and over), with amoxicillin as an alternative, and azithromycin as a third option when both doxycycline and amoxicillin are contraindicated.
The committee acknowledged that infectious disease specialists currently treat Lyme disease in children aged 9 and above with doxycycline, although it is not licensed in the UK for children under 12, and it is contraindicated in this age group because of side effects, such as teeth staining. Based on their experience and knowledge, feedback from stakeholders, and the evidence for adults, the committee agreed that doxycycline is the most effective treatment for Lyme disease and that the risk of dental problems in children is low when it is used for short-term treatment (28 days or less). Therefore, doxycycline can be used as the initial treatment for Lyme disease in children aged 9 and above. The committee agreed on doxycycline doses based on their knowledge and experience of current practice both in the UK and the US.
The use of doxycycline in children under 9 years is currently limited by licensing and clinical experience. There was some evidence that amoxicillin and azithromycin were equally effective in children. Because of its ability to penetrate the blood–cerebrospinal fluid barrier, the committee agreed that children under 9 should be offered amoxicillin as the initial treatment, with azithromycin as an alternative treatment option, and that doses should be adjusted by weight.
Current guidelines give ranges for treatment duration, generally between 10 and 21 days, without guidance on when to use a longer or shorter course. The committee agreed that this is not clear enough for generalists. The evidence for treatment duration was limited. The committee decided that longer courses of 21 days of treatment should be offered as standard because of their concern at low cure rates in some studies and the lack of clear evidence for shorter courses. They also agreed that a longer course may be reassuring for people being treated for Lyme disease who continue to have symptoms. The evidence showed adverse event rates were not increased for longer courses.
The committee agreed that further research would be helpful and agreed to make research recommendations to develop a core outcome set for clinical trials and to determine the most effective antibiotic treatment for different presentations of Lyme disease.
No studies were identified comparing different antibiotics for managing Lyme disease in people with non-focal symptoms (symptoms such as fever, sweats and muscle pain, which are not specific to an organ system). However, the committee reviewed the evidence available for treating other symptoms and, based on this and their knowledge and experience, agreed that people with non-focal symptoms should be given the same treatment as people with erythema migrans.
Because of the uncertainties about diagnosis and management, the committee agreed that care of children and young people under 18 with Lyme disease and non‑erythema migrans presentations should have their care discussed with a specialist.
The evidence for antibiotic treatment of Lyme disease affecting the nervous system was limited. One study showed a greater benefit with oral doxycycline than intravenous ceftriaxone in treating Lyme disease affecting the peripheral nervous system. However, both treatments showed low rates of cure (full resolution of neurological symptoms). The committee also noted that the study used a 14‑day course of antibiotics, which is below the maximum treatment durations recommended by some current guidelines.
The committee agreed that people presenting with meningitis or encephalitis (before a diagnosis of Lyme disease) would receive treatment with intravenous ceftriaxone, and that intravenous treatment would achieve adequate concentrations in the central nervous system more rapidly than oral treatment.
The committee also discussed the management of neurosyphilis, which has similar central nervous system involvement. The committee considered that, although the evidence was limited, central nervous system symptoms in Lyme disease should be treated with a similar antibiotic dose to that recommended for neurosyphilis.
Once-daily ceftriaxone has the advantage of being given more easily as an outpatient treatment than other intravenous options, which allows completion of the course as an outpatient.
Taking these factors into account and based on their knowledge and experience, the committee agreed on a 21‑day course of intravenous ceftriaxone 4 g daily as the initial treatment for adults and young people (aged 12 and over) with Lyme disease affecting the central nervous system, with a 21‑day course of doxycycline 400 mg daily recommended as an alternative treatment. The higher dose (4 g) is the recommended dose for bacterial meningitis. For Lyme disease affecting the cranial nerves or the peripheral nervous system, the committee agreed on a 21‑day course of doxycycline 200 mg daily as the initial treatment for adults and young people (aged 12 and over), with amoxicillin recommended as an alternative treatment.
No studies were identified for nervous system symptoms in children. However, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9 to 12 years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9 years is currently limited by licensing and clinical experience.
Because of the importance of diagnosis and management, the committee also agreed that care of children and young people under 18 should be discussed with a specialist.
The studies identified looked at antibiotic treatment in children, young people and adults with Lyme arthritis (inflammation affecting 1 or more joints). Evidence from 1 study showed that a 30‑day course of doxycycline resulted in fewer symptom relapses and adverse events than 30 days of amoxicillin plus probenecid.
The committee agreed that longer courses of treatment are appropriate when treating Lyme arthritis because it is difficult for antibiotics to penetrate to the synovium and synovial fluid.
Taking these factors into account, the committee decided that a 28‑day course of antibiotics would be appropriate and also practical, because antibiotics are available in weekly packs.
Because the evidence was limited, the committee also took into account evidence for other presentations of Lyme disease. Based on this, along with their knowledge and experience of current practice, the committee agreed that doxycycline should be offered to adults and young people (aged 12 and over) as the initial treatment, with amoxicillin recommended as an alternative treatment. The committee also agreed that if oral doxycycline and amoxicillin are contraindicated or unsuitable, 28 days of intravenous ceftriaxone should be offered.
Although there was no evidence for treating Lyme arthritis in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9 to 12 years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9 years is currently limited by licensing and clinical experience.
Because of the importance of correct diagnosis and management, the committee agreed that care of children and young people under 18 with Lyme disease and non‑erythema migrans presentations should be discussed with a specialist.
One study suggested that a 30‑day course of doxycycline was better for treating acrodermatitis chronica atrophicans than a 20‑day course of treatment. Oral doxycycline given for 30 days was also more effective than a 15‑day course of intravenous ceftriaxone. The committee agreed that a longer course of treatment might be beneficial because it is difficult for antibiotics to penetrate the affected skin. They also took into account evidence for Lyme arthritis, which justified a longer treatment course to allow penetration into joints. The committee decided that a 28‑day course of antibiotics would be appropriate and practical, because antibiotics are available in weekly packs.
The evidence for antibiotics was very limited, so the committee also took into account evidence for other presentations of Lyme disease and their experience and knowledge of current practice. The committee agreed that doxycycline should be offered to adults and young people (aged 12 and over) as the initial treatment, with amoxicillin recommended as an alternative treatment. The committee also agreed that if oral doxycycline and amoxicillin are contraindicated or unsuitable, intravenous ceftriaxone could be offered.
Although there was no evidence for treating acrodermatitis chronica atrophicans in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9 to 12 years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9 years is currently limited by licensing and clinical experience.
Because of the importance of correct diagnosis and management, the committee agreed that care of children and young people under 18 with Lyme disease and non-erythema migrans presentations should be discussed with a specialist.
No studies of antibiotic treatment for heart problems caused by Lyme disease were identified. Therefore, the committee reviewed the evidence available for treating other symptoms of Lyme disease and used this, their experience of current practice and their knowledge of care for people with heart problems, to develop the recommendations.
The committee decided that a 21‑day course of doxycycline would be appropriate as the initial treatment for adults and young people (aged 12 and over) with carditis who are stable, with a 21‑day course of intravenous ceftriaxone recommended as an alternative treatment.
The committee noted that people with severe heart problems are likely to need treatment in hospital from cardiologists. They agreed that intravenous ceftriaxone for 21 days would therefore be suitable as the initial treatment for people with carditis who are haemodynamically unstable.
Because of the lack of evidence for treatment in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9 to 12 years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9 years is currently limited by licensing and clinical experience.
Because of the importance of correct diagnosis and management, the committee agreed that care of children and young people under 18 with Lyme disease and focal symptoms such as carditis should be discussed with a specialist.
The committee also noted that azithromycin should not be used to treat people with cardiac abnormalities because of its effect on the QT interval.
No evidence was identified for the antibiotic treatment of lymphocytoma related to Lyme disease. Lymphocytoma is a very rare early presentation of Lyme disease and the committee agreed that most people presenting with lymphocytoma only would be referred for specialist investigation of lesions to establish the diagnosis. People with lymphocytoma and other symptoms of Lyme disease would receive treatment appropriate for their other symptoms on diagnosis. Therefore, they decided not to make a recommendation and that further research in this area was not a priority.
No evidence was identified for the antibiotic treatment of non-neurological ocular symptoms related to Lyme disease. The committee agreed that people presenting with severe ocular symptoms would be referred for specialist investigation. The committee noted that it is difficult to diagnose Lyme disease as a cause of ocular symptoms unless there is a supportive history and other symptoms of Lyme disease, but that people with other symptoms of Lyme disease would receive treatment appropriate for their other symptoms on diagnosis. Therefore, they decided not to make a recommendation and that further research in this area was not a priority.
## How the recommendations might affect practice
The recommendations aim to standardise antibiotic treatment and to provide a consistent framework for good practice in managing Lyme disease. Overall, there may be changes to prescribing practices, but the impact is likely to be small.
Full details of the evidence and the committee's discussion are in the evidence reviews.
Return to recommendations
# Ongoing symptoms after a course of antibiotics
Recommendations 1.3.9 to 1.3.13
## Why the committee made the recommendations
People who have had treatment for Lyme disease sometimes report ongoing symptoms. The cause is often not clear and includes re‑infection, or organ damage caused by Lyme disease, which may take a long time to heal or may even be permanent.
The evidence available for treating ongoing symptoms did not show benefit from prolonged treatment with antibiotics. However, based on their knowledge and experience, the committee agreed that treatment failure could occur and that a second course of an alternative antibiotic might sometimes be appropriate. The committee noted the importance of considering alternative diagnoses to prevent inappropriate antibiotic treatment and misdiagnosis.
The committee agreed that people with ongoing symptoms should not routinely be offered more than 2 courses of antibiotics because of lack of evidence of benefit. However, discussion with a specialist or referral should be considered for some people, and discussion with the UK national reference laboratory might be helpful, for example, if a different tick-borne disease is possible.
People who have a slow recovery from Lyme disease may need additional support and access to social care. The committee agreed that it was important that healthcare professionals help people with long-term symptoms related to Lyme disease to access support if needed.
## How the recommendations might affect practice
Current treatment for Lyme disease is a single course of antibiotics. Treatment for ongoing symptoms is unclear and practice varies. Further antibiotic treatment is now recommended as an option if persisting infection is a possibility. This will standardise practice, but may cause an increase in antibiotic prescribing in a small number of patients. The committee agreed that this change in practice would not result in a significant resource impact given the small number of people with treatment failure.
Return to recommendations
# Non-antibiotic management of ongoing symptoms
Recommendations 1.3.14 to 1.3.17
## Why the committee made the recommendations
No specific evidence review was carried out to inform recommendations on support, referral to social services or the need to consider assessing and managing other symptoms related to Lyme disease, such as chronic pain, fatigue or depression. The committee, however, acknowledged that some people with Lyme disease experience a slow recovery and may need professional support. Some people with Lyme disease feel that their needs are not considered in an appropriate way. Based on their knowledge and clinical experience, the committee agreed that healthcare professionals should consider the possibility of such needs and provide support if needed, including regular review for people with ongoing symptoms.
## How the recommendations might affect practice
Some people with Lyme disease may need support or social services, especially when they have a slow recovery. Social services needs assessments are carried out by local authorities and will not affect NHS practice.
Some people with Lyme disease may also present with related symptoms, such as chronic pain, depression or fatigue. Guidance for managing these symptoms already exists and therefore there will be no change to existing clinical practice.
Return to recommendations
# Management for women with Lyme disease during pregnancy and their babies
Recommendations 1.3.18 to 1.3.21
## Why the committee made the recommendations
The committee acknowledged that mother-to-baby transmission of Lyme disease is possible in theory. There was an absence of evidence, but the risk appears to be very low. The committee decided that women could be reassured that pregnancy and their baby are unlikely to be affected, and highlighted the importance of completing treatment. It was also agreed that pregnant women should be treated following usual practice, but using antibiotics suitable in pregnancy.
Given the absence of evidence and the lack of a standard approach to care, the committee agreed that care of babies born to mothers with Lyme disease during pregnancy should be discussed with a paediatric infectious disease specialist if the mother has concerns about her baby. In addition, to ensure that babies with Lyme disease do not go untreated, the committee agreed that babies should receive treatment if they have serology showing IgM antibodies specific to Lyme disease or symptoms that might be caused by Lyme disease.
The committee agreed that more evidence on Lyme disease in pregnancy would be helpful to inform future guidance. Pregnant women with Lyme disease or suspected Lyme disease are a population of particular interest in the research recommendation on the clinical epidemiology of Lyme disease in the UK.
No evidence was found for transmission of Lyme disease through sexual contact or blood products and the committee agreed that they could not make recommendations in these areas.
## How the recommendations might affect practice
There is no standardised approach to the care of babies born to mothers who had Lyme disease in pregnancy. The recommendations are unlikely to have a big impact on practice, but should reduce variation and provide guidance to reassure women and healthcare professionals.
Return to recommendations
# Information for people with Lyme disease
Recommendations 1.2.24 to 1.2.27 and 1.4.1 to 1.4.4
## Why the committee made the recommendations
There was a lack of evidence identified on the information needs of people with suspected or confirmed Lyme disease, or specific Lyme disease presentations. However, some evidence was identified that highlighted the need for information addressing the medical uncertainties of Lyme disease.
The guideline committee used this evidence, the evidence reviews on diagnosis and management, and their experience to make recommendations to inform people being investigated for and diagnosed with Lyme disease. The committee agreed that people would benefit from a better understanding of the nature of Lyme disease, the accuracy and limitations of testing, and issues with treatment and follow‑up.
## How the recommendations might affect practice
The recommendations standardise and reinforce current good practice. Many healthcare professionals will not need to change their current practice.
Return to recommendations 1.2.24 to 1.2.27 and 1.4.1 to 1.4.4.# Context
Lyme disease (Lyme borreliosis) is a tick-borne infectious disease. It is caused by different genospecies of Borrelia including B. burgdorferi sensu strictu (ss), B. afzelii and B. garinii, which can be transmitted to humans through a bite from an infected tick. Infection is more likely the longer a tick is attached to the skin. Ticks live in grassy and wooded areas, both in rural and urban locations. People who spend time in these areas for work or recreation are at increased risk of tick exposure.
Lyme disease can occur anywhere in the UK, although some areas have a higher reported incidence. Approximately 50% of laboratory-confirmed cases are diagnosed in the South East and South West of England. High incidence is also reported in Scotland. Worldwide, Lyme disease occurs mainly in the northern hemisphere, and travellers to areas of Europe, North America and elsewhere may be at risk. However, the true incidence of Lyme disease is unknown.
Although the disease has been recognised in mainland Europe for more than a century, it was first reported in England and Wales in the 1980s. Public Health England (PHE) reports that there are approximately 1,000 serologically confirmed cases of Lyme disease each year in England and Wales. Many diagnoses will also be made clinically without laboratory testing. The true number of cases is currently unknown.
In England and Wales, cases of laboratory-confirmed Lyme disease have increased. It is not certain how much of the rise is due to increased awareness and how much to the spread of the disease.
Infection with B. burgdorferisensu lato (sl) can sometimes go unremarked, with mild symptoms that are ignored by the person. When symptoms occur, this is called Lyme disease. Many people may not notice or remember a tick bite. A bite can be followed by an 'erythema migrans' rash, which is sometimes mistaken for cellulitis or ringworm, and effective treatment is delayed. If there is no erythema migrans or it is unnoticed, diagnosis can be difficult because the same symptoms may be caused by many other conditions as well as Lyme disease.
The terminology around Lyme disease is varied and many poorly defined terms are used in the literature (such as chronic Lyme disease and post-Lyme disease). This guideline has avoided using controversial definitions and has concentrated on providing advice on diagnosis and treatment based on the available evidence, according to the clinical context, presentation, symptoms and available treatments. The guideline committee has noted the poor-quality evidence available on both diagnosis and treatment.
The guideline aims to raise awareness of when Lyme disease should be suspected and to ensure that people with suspected Lyme disease are given early and consistent treatment. The guideline committee has also developed a series of research recommendations to improve basic epidemiology, understanding of the natural history of Lyme disease, and to develop diagnostic tests appropriate for UK infections.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Awareness of Lyme disease\n\nBe aware that:\n\nthe bacteria that cause Lyme disease are transmitted by the bite of an infected tick\n\nticks are mainly found in grassy and wooded areas, including urban gardens and parks\n\ntick bites may not always be noticed\n\ninfected ticks are found throughout the UK and Ireland, and although some areas appear to have a higher prevalence of infected ticks, prevalence data are incomplete\n\nparticularly high-risk areas are the South of England and Scottish Highlands but infection can occur in many areas\n\nLyme disease may be more prevalent in parts of central, eastern and northern Europe (including Scandinavia) and parts of Asia, the US and Canada.\n\nBe aware that most tick bites do not transmit Lyme disease and that prompt, correct removal of the tick reduces the risk of transmission.\n\nGive people advice about:\n\nwhere ticks are commonly found (such as grassy and wooded areas, including urban gardens and parks)\n\nthe importance of prompt, correct tick removal and how to do this (see Public Health England's information on removing ticks)\n\ncovering exposed skin and using insect repellents that protect against ticks\n\nhow to check themselves and their children for ticks on the skin\n\nsources of information on Lyme disease, such as Public Health England's resources and guidance on Lyme disease and organisations providing information and support, such as patient charities.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on awareness of Lyme disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: awareness of Lyme disease.\n\nLoading. Please wait.\n\n# Diagnosis\n\n## Clinical assessment\n\nDiagnose Lyme disease in people with erythema migrans, a red rash that:\n\nincreases in size and may sometimes have a central clearing\n\nis not usually itchy, hot or painful\n\nusually becomes visible from 1\xa0to\xa04\xa0weeks (but can appear from 3\xa0days to 3\xa0months) after a tick bite and lasts for several weeks\n\nis usually at the site of a tick bite.See also NICE's resource on different presentations of erythema migrans.\n\nBe aware that a rash, which is not erythema migrans, can develop as a reaction to a tick bite that:\n\nusually develops and recedes during 48\xa0hours from the time of the tick bite\n\nis more likely than erythema migrans to be hot, itchy or painful\n\nmay be caused by an inflammatory reaction or infection with a common skin pathogen.\n\nConsider the possibility of Lyme disease in people presenting with several of the following symptoms, because Lyme disease is a possible but uncommon cause of:\n\nfever and sweats\n\nswollen glands\n\nmalaise\n\nfatigue\n\nneck pain or stiffness\n\nmigratory joint or muscle aches and pain\n\ncognitive impairment, such as memory problems and difficulty concentrating (sometimes described as 'brain fog')\n\nheadache\n\nparaesthesia.\n\nConsider the possibility of Lyme disease in people presenting with symptoms and signs relating to 1\xa0or more organ systems (focal symptoms) because Lyme disease is a possible but uncommon cause of:\n\nneurological symptoms, such as facial palsy or other unexplained cranial nerve palsies, meningitis, mononeuritis multiplex or other unexplained radiculopathy; or rarely encephalitis, neuropsychiatric presentations or unexplained white matter changes on brain imaging\n\ninflammatory arthritis affecting 1\xa0or more joints that may be fluctuating and migratory\n\ncardiac problems, such as heart block or pericarditis\n\neye symptoms, such as uveitis or keratitis\n\nskin rashes such as acrodermatitis chronica atrophicans or lymphocytoma.\n\nIf a person presents with symptoms that suggest the possibility of Lyme disease, explore how long the person has had symptoms and their history of possible tick exposure, for example, ask about:\n\nactivities that might have exposed them to ticks\n\ntravel to areas where Lyme disease is known to be highly prevalent.\n\nDo not rule out the possibility of Lyme disease in people with symptoms but no clear history of tick exposure.\n\nDo not diagnose Lyme disease in people without symptoms, even if they have had a tick bite.\n\nBe cautious about diagnosing Lyme disease in people without a supportive history or positive serological testing because of the risk of:\n\nmissing an alternative diagnosis\n\nproviding inappropriate treatment.\n\nFollow usual clinical practice to manage symptoms, for example, pain relief for headaches or muscle pain, in people being assessed for Lyme disease.\n\nTake into account that people with Lyme disease may have symptoms of cognitive impairment and may have difficulty explaining their symptoms. For adults, follow the recommendations in NICE's guideline on patient experience in adult NHS services.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on clinical assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: diagnostic accuracy of signs and symptoms.\n\nLoading. Please wait.\n\n## Laboratory investigations to support diagnosis\n\nWe have also produced a NICE visual summary of the recommendations on testing for Lyme disease.\n\nDiagnose and treat Lyme disease without laboratory testing in people with erythema migrans.\n\nUse a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans. Do not rule out diagnosis if tests are negative but there is high clinical suspicion of Lyme disease.\n\nIf there is a clinical suspicion of Lyme disease in people without erythema migrans:\n\noffer an enzyme-linked immunosorbent assay (ELISA) test for Lyme disease and\n\nconsider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion.\n\nTest for both IgM and IgG antibodies using ELISAs based on purified or recombinant antigens derived from the VlsE protein or its IR6\xa0domain peptide (such as C6\xa0ELISA).\n\nIf the ELISA is positive or equivocal:\n\nperform an immunoblot test for Lyme disease and\n\nconsider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion of Lyme disease.\n\nIf the ELISA for Lyme disease is negative and the person still has symptoms, review their history and symptoms, and think about the possibility of an alternative diagnosis.\n\nIf Lyme disease is still suspected in people with a negative ELISA who were tested within 4\xa0weeks from symptom onset, repeat the ELISA 4\xa0to 6\xa0weeks after the first ELISA test.\n\nIf Lyme disease is still suspected in people with a negative ELISA who have had symptoms for 12\xa0weeks or more, perform an immunoblot test.\n\nDiagnose Lyme disease in people with symptoms of Lyme disease and a positive immunoblot test.\n\nIf the immunoblot test for Lyme disease is negative (regardless of the ELISA result) but symptoms persist, consider a discussion with or referral to a specialist, to:\n\nreview whether further tests may be needed for suspected Lyme disease, for example, synovial fluid aspirate or biopsy, or lumbar puncture for cerebrospinal fluid analysis or\n\nconsider alternative diagnoses (both infectious, including other tick-borne diseases, and non-infectious diseases).Choose a specialist appropriate for the person's history or symptoms, for example, an adult or paediatric infection specialist, rheumatologist or neurologist.\n\nIf the immunoblot test for Lyme disease is negative and symptoms have resolved, explain to the person that no treatment is required.\n\nCarry out tests for Lyme disease only at laboratories that:\n\nare accredited by the UK accreditation service (UKAS) and\n\nuse validated tests (validation should include published evidence on the test methodology, its relation to Lyme disease and independent reports of performance) and\n\nparticipate in a formal external quality assurance programme.\n\nDo not routinely diagnose Lyme disease based only on tests done outside the NHS, unless the laboratory used is accredited, participates in formal external quality assurance programmes and uses validated tests (see recommendation\xa01.2.22). If there is any doubt about tests:\n\nreview the person's clinical presentation and\n\ncarry out testing again using a UKAS-accredited laboratory and/or seek advice from a national reference laboratory.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on laboratory investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnostic tests.\n\nLoading. Please wait.\n\n## Information for people being tested for Lyme disease\n\nTell people that tests for Lyme disease have limitations. Explain that both false-positive and false-negative results can occur and what this means.\n\nExplain to people that most tests for Lyme disease assess for the presence of antibodies and that the accuracy of tests may be reduced if:\n\ntesting is carried out too early (before antibodies have developed)\n\nthe person has reduced immunity, for example, people on immunosuppressant treatments, which might affect the development of antibodies.\n\nAdvise people that tests from non-UKAS laboratories may not have been fully evaluated to diagnose Lyme disease.\n\nExplain to people that:\n\nthe symptoms and signs associated with Lyme disease overlap with those of other conditions\n\nthey will be assessed for alternative diagnoses if their tests are negative and their symptoms have not resolved\n\nsymptoms such as tiredness, headache and muscle pain are common, and a specific medical cause is often not found.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: information needs.\n\nLoading. Please wait.\n\n# Management\n\n## Emergency referral\n\nFollow usual clinical practice for emergency referrals, for example, in people with symptoms that suggest central nervous system infection, uveitis or cardiac complications such as complete heart block, even if Lyme disease is suspected.\n\n## Specialist advice\n\nDiscuss the diagnosis and management of Lyme disease in children and young people under 18\xa0years with a specialist, unless they have a single erythema migrans lesion and no other symptoms. Choose a specialist appropriate for the child or young person's symptoms dependent on availability, for example, a paediatrician, paediatric infectious disease specialist or a paediatric neurologist.\n\nIf an adult with Lyme disease has focal symptoms, consider a discussion with or referral to a specialist, without delaying treatment. Choose a specialist appropriate for the person's symptoms, for example, an adult infection specialist, rheumatologist or neurologist.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on emergency referral and specialist advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: management of erythema migrans.\n\nLoading. Please wait.\n\n## Antibiotic treatment\n\nFor adults and young people (aged 12\xa0and over) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in table\xa01. (Note that for Lyme disease suspected during pregnancy, use appropriate antibiotics for the stage of pregnancy (see the recommendation on assessing and diagnosing Lyme disease in the section on management for women with Lyme disease during pregnancy and their babies.)\n\nFor children (under\xa012) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in table\xa02. (Note that management of Lyme disease in children and young people should be discussed with a specialist in line with recommendation\xa01.3.2.)\n\nAsk women (including young women under\xa018) if they might be pregnant before offering antibiotic treatment for Lyme disease (see the recommendation on assessing and diagnosing Lyme disease in the section on management for women with Lyme disease during pregnancy and their babies).\n\nIf symptoms worsen during treatment for Lyme disease, assess for an allergic reaction to the antibiotic. Be aware that a Jarisch–Herxheimer reaction may cause an exacerbation of symptoms but does not usually warrant stopping treatment.\n\nConsider clinical review during or after treatment for Lyme disease to assess for possible side effects and response to treatment.\n\nSymptoms\n\nTreatment\n\nFirst alternative\n\nSecond alternative\n\nLyme disease without focal symptoms but with erythema migrans and/or non-focal symptoms\n\nOral doxycycline:\n\nmg twice per day or 200\xa0mg once per day for 21\xa0days\n\nOral amoxicillin:\n\ng 3\xa0times per day for 21\xa0days\n\nOral azithromycin:\n\nmg daily for 17\xa0days\n\nNote: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.\n\nLyme disease affecting the cranial nerves or peripheral nervous system\n\nOral doxycycline:\n\nmg twice per day or 200\xa0mg once per day for 21\xa0days\n\nOral amoxicillin:\n\ng 3\xa0times per day for 21\xa0days\n\n–\n\nLyme disease affecting the central nervous system\n\nIntravenous ceftriaxone:\n\ng twice per day or 4\xa0g once per day for 21\xa0days (when an oral switch is being considered, use doxycycline)\n\nOral doxycycline:\n\nmg twice per day or 400\xa0mg once per day for 21\xa0days\n\n–\n\nLyme disease with arthritis\n\nOral doxycycline:\n\nmg twice per day or 200\xa0mg once per day for 28\xa0days\n\nOral amoxicillin:\n\ng 3\xa0times per day for 28\xa0days\n\nIntravenous ceftriaxone:\n\ng once per day for 28\xa0days\n\nLyme disease with acrodermatitis chronica atrophicans\n\nOral doxycycline:\n\nmg twice per day or 200\xa0mg once per day for 28\xa0days\n\nOral amoxicillin:\n\ng 3\xa0times per day for 28\xa0days\n\nIntravenous ceftriaxone:\n\ng once per day for 28\xa0days\n\nLyme disease with Lyme carditis\n\n\n\nOral doxycycline:\n\nmg twice per day or 200\xa0mg once per day for 21\xa0days\n\nIntravenous ceftriaxone:\n\ng once per day for 21\xa0days\n\n–\n\nLyme disease with Lyme carditis and haemodynamically unstable\n\n\n\nIntravenous ceftriaxone:\n\ng once per day for 21\xa0days (when an oral switch is being considered, use doxycycline)\n\n–\n\n–\n\nNote: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.\n\nSymptoms\n\nAge\n\nTreatment\n\nFirst alternative\n\nSecond alternative\n\nLyme disease without focal symptoms but with erythema migrans and/or non-focal symptoms\n\n–12 years\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 21\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily for 21\xa0days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nOral amoxicillin for children 33\xa0kg and under:\n\nmg/kg 3\xa0times per day for 21\xa0days\n\nOral azithromycin for children 50\xa0kg and under:\n\nmg/kg daily for 17\xa0days\n\nIn April 2018, this use of azithromycin was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nNote: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval\n\nLyme disease without focal symptoms with erythema migrans and/or non-focal symptoms\n\nUnder 9\n\nOral amoxicillin for children 33\xa0kg and under: 30\xa0mg/kg 3\xa0times per day for 21\xa0days\n\nOral azithromycin for children 50\xa0kg and under:\n\nmg/kg daily for 17\xa0days\n\nIn April 2018, this use of azithromycin was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nNote: Do not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval\n\n–\n\nLyme disease affecting the cranial nerves or peripheral nervous system\n\n–12 years\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 21\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily for 21\xa0days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nOral amoxicillin for children 33\xa0kg and under:\n\nmg/kg 3\xa0times per day for 21\xa0days\n\n–\n\nLyme disease affecting the cranial nerves or peripheral nervous system\n\nUnder 9\n\nOral amoxicillin for children 33\xa0kg and under:\n\nmg/kg 3\xa0times per day for 21\xa0days\n\n–\n\n–\n\nLyme disease affecting the central nervous system\n\n–12 years\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 4\xa0g) once per day for 21\xa0days\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 21\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\n–\n\nLyme disease affecting the central nervous system\n\nUnder 9\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 4\xa0g) once per day for 21\xa0days\n\n–\n\n–\n\nLyme disease with arthritis or acrodermatitis chronica atrophicans\n\n–12 years\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 28\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily for 28\xa0days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nOral amoxicillin for children 33\xa0kg and under:\n\nmg/kg 3\xa0times per day 28\xa0days\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 28\xa0days\n\nLyme disease with arthritis or acrodermatitis chronica atrophicans\n\nUnder 9\n\nOral amoxicillin for children, 33\xa0kg and under:\n\nmg/kg 3\xa0times per day for 28\xa0days\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 28\xa0days\n\n–\n\nLyme disease with Lyme carditis and haemodynamically stable\n\n–12 years\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 21\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily for 21\xa0days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 21\xa0days\n\n–\n\nLyme disease with Lyme carditis and haemodynamically stable\n\nUnder 9\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 21\xa0days\n\n–\n\n–\n\nLyme disease with Lyme carditis and haemodynamically unstable\n\n–12 years\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 21\xa0days\n\n\n\nOral doxycycline for children under 45\xa0kg:\n\nmg/kg in 2\xa0divided doses on day\xa01 followed by 2.5\xa0mg/kg daily in 1\xa0or 2\xa0divided doses for a total of 21\xa0days\n\nFor severe infections, up to 5\xa0mg/kg daily for 21\xa0days (Use clinical judgement to determine doses of doxycycline for children under 12 years with severe infections)\n\nIn April 2018, this use of doxycycline was off-label in children under 12\xa0years. See NICE's information on prescribing medicines\n\n–\n\nLyme carditis and haemodynamically unstablef\n\nUnder 9\n\nIntravenous ceftriaxone for children under 50\xa0kg:\n\nmg/kg (up to 2\xa0g) once per day for 21\xa0days\n\n\n\n\n\nNotes:\n\nDo not use azithromycin to treat people with cardiac abnormalities associated with Lyme disease because of its effect on QT interval.\n\nChildren weighing more than the amounts specified should be treated according to table\xa01.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antibiotic treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: management of erythema migrans\n\nevidence review\xa0E: management of non-specific symptoms\n\nevidence review\xa0F: management of neuroborreliosis\n\nevidence review\xa0G: management of arthritis\n\nevidence review\xa0H: management of acrodermatitis chronica atrophicans\n\nevidence review\xa0I: management of carditis\n\nevidence review\xa0J: management of lymphocytoma\n\nevidence review\xa0K: management of ocular symptoms.\n\nLoading. Please wait.\n\n## Ongoing symptoms after a course of antibiotics\n\nIf symptoms that may be related to Lyme disease persist, do not continue to improve or worsen after antibiotic treatment, review the person's history and symptoms to explore:\n\npossible alternative causes of the symptoms\n\nif re‑infection may have occurred\n\nif treatment may have failed\n\ndetails of any previous treatment, including whether the course of antibiotics was completed without interruption\n\nif symptoms may be related to organ damage caused by Lyme disease, for example, nerve palsy.\n\nIf the person's history suggests re‑infection, offer antibiotic treatment for Lyme disease according to their symptoms (see tables\xa01 and\xa02).\n\nConsider a second course of antibiotics for people with ongoing symptoms if treatment may have failed. Use an alternative antibiotic to the initial course, for example, for adults with Lyme disease and arthritis, offer amoxicillin if the person has completed an initial course of doxycycline.\n\nIf a person has ongoing symptoms following 2\xa0completed courses of antibiotics for Lyme disease:\n\ndo not routinely offer further antibiotics and\n\nconsider discussion with a national reference laboratory or discussion or referral to a specialist as outlined in the recommendation on when the immunoblot test for Lyme disease is negative but symptoms persist in the section on laboratory investigations to support diagnosis.\n\nExplain to people with ongoing symptoms following antibiotic treatment for Lyme disease that:\n\ncontinuing symptoms may not mean they still have an active infection\n\nsymptoms of Lyme disease may take months or years to resolve even after treatment\n\nsome symptoms may be a consequence of permanent damage from infection\n\nthere is no test to assess for active infection and an alternative diagnosis may explain their symptoms.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on ongoing symptoms after a course of antibiotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: management of ongoing symptoms.\n\nLoading. Please wait.\n\n## Non-antibiotic management of ongoing symptoms\n\nOffer regular clinical review and reassessment to people with ongoing symptoms, including people who have no confirmed diagnosis.\n\nExplore any ongoing symptoms with the person and offer additional treatment if needed following usual clinical practice.\n\nBe alert to the possibility of symptoms related to Lyme disease that may need assessment and management, including:\n\nchronic pain\n\ndepression and anxiety (see NICE's guideline on common mental health problems)\n\nfatigue\n\nsleep disturbance.\n\nSupport people who have ongoing symptoms after treatment for Lyme disease by:\n\nencouraging and helping them to access additional services, including referring to adult social care for a care and support needs assessment, if they would benefit from these\n\ncommunicating with children and families' social care, schools and higher education, and employers about the person's need for a gradual return to activities, if relevant.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on non-antibiotic management of ongoing symptoms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: management of ongoing symptoms.\n\nLoading. Please wait.\n\n## Management for women with Lyme disease during pregnancy and their babies\n\nAssess and diagnose Lyme disease during pregnancy in the same way as for people who are not pregnant. Treat Lyme disease in pregnant women using appropriate antibiotics for the stage of pregnancy. (For more information on antibiotic use during pregnancy, see the British national formulary's information on specific antibiotics for Lyme disease.)\n\nTell women with Lyme disease during pregnancy that they are unlikely to pass the infection to their baby and emphasise the importance of completing the full course of antibiotic treatment.\n\nAdvise women who had Lyme disease during pregnancy to tell this to their healthcare professional if they have any concerns about their baby. In this situation, healthcare professionals should discuss the history with a paediatric infectious disease specialist and seek advice on what investigations to perform.\n\nStart treatment for Lyme disease under specialist care for babies of women treated for Lyme disease during pregnancy if the baby has IgM antibodies specific for Lyme disease or there is any suspicion the baby may be infected.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management for women with Lyme disease during pregnancy and their babies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: transmission.\n\nLoading. Please wait.\n\n# Information for people with Lyme disease\n\nExplain to people diagnosed with Lyme disease that:\n\nLyme disease is a bacterial infection treated with antibiotics\n\nmost people recover completely\n\nprompt antibiotic treatment reduces the risk of further symptoms developing and increases the chance of complete recovery\n\nit may take time to get better, but their symptoms should continue to improve in the months after antibiotic treatment\n\nthey may need additional treatment for symptom relief.\n\nTell people who are starting antibiotics for Lyme disease that some people may have a Jarisch–Herxheimer reaction to treatment. Explain that:\n\nthis causes a worsening of symptoms early in treatment\n\nit can happen when large numbers of bacteria in the body are killed\n\nit does not happen to everyone treated for Lyme disease\n\nthey should contact their doctor and keep taking their antibiotics if their symptoms worsen.\n\nAdvise people with Lyme disease to talk to their doctor if their symptoms have not improved or if symptoms return after completing treatment.\n\nExplain to people with Lyme disease that infection does not give them lifelong immunity and that it is possible for them to be re‑infected and develop Lyme disease again.\n\nFor a short explanation of why the committee made the recommendations, see the rationale and impact section on information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: information needs.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Test for Lyme disease\n\nLyme disease is caused by infection with bacteria from different species of Borrelia. The majority of tests for Lyme disease detect antibodies produced in response to infection by bacteria.\n\nThe term Lyme disease is used when referring to both the disease and to tests for an antibody response. This reflects the terminology used in clinical practice.\n\n## Jarisch–Herxheimer reaction\n\nThis is a systemic reaction, thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria. Symptoms include a worsening of fever, chills, muscle pains and headache. The reaction can start between 1\xa0and 12\xa0hours after antibiotics are started but can also occur later and can last for a few hours or 1\xa0or 2\xa0days. The reaction is self-limiting and usually resolves within 24\xa0to 48\xa0hours.\n\nIt was originally reported in the treatment of syphilis but has been documented in tick-borne diseases including Lyme disease, leptospirosis and relapsing fever.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Core outcome set for studies of management of Lyme disease\n\nCan a core outcome set be developed for clinical trials of management of Lyme disease?\n\n## Why this is important\n\nAntibiotic treatment is the mainstay of management for Lyme disease. The studies published on the management of Lyme disease use differing outcomes, which are often poorly defined. The development of a core outcome set has been identified as a high priority because it would allow comparison across trials and allow appropriate meta-analysis to strengthen results. The methods used should be patient-focused and include patient input on priority outcomes and how they should be measured.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on antibiotic treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: management of erythema migrans\n\nevidence review\xa0E: management of non-specific symptoms\n\nevidence review\xa0F: management of neuroborreliosis\n\nevidence review\xa0G: management of arthritis\n\nevidence review\xa0H: management of acrodermatitis chronica atrophicans\n\nevidence review\xa0I: management of carditis\n\nevidence review\xa0J: management of lymphocytoma\n\nevidence review\xa0K: management of ocular symptoms.\n\nLoading. Please wait.\n\n# Clinical epidemiology of Lyme disease in the UK\n\nWhat are the incidence, presenting features, management and outcome of Lyme disease in the UK?\n\n## Why this is important\n\nThere is a lack of robust epidemiological data on Lyme disease in the UK population. A large clinico-epidemiological study to collect data on incidence, presenting clinical features, management and outcome of Lyme disease in community and hospital settings in the UK would generate population-based statistics. These statistics would enable interventions such as antibiotic treatment and service improvements to be assessed properly and for services to be tailored so they best serve people with Lyme disease; this was felt to be of high priority. There is no current requirement to notify cases of Lyme disease; therefore, current data are likely to underestimate the number of cases.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on awareness of Lyme disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: awareness of Lyme disease.\n\nLoading. Please wait.\n\n# Seroprevalence of Lyme disease-specific antibodies and other tick-borne infections in the UK population\n\nWhat is the current seroprevalence of Lyme disease-specific antibodies and other tick-borne infections in people in the UK?\n\n## Why this is important\n\nThis information is not currently available and is of high priority. Without understanding the underlying population's seroprevalence of Lyme disease-specific antibodies in the UK, it is impossible to interpret incidence data accurately or to understand fully the epidemiology of Lyme disease in the UK. The available data suggest there are areas of higher and lower prevalence in the UK but there are many gaps in knowledge. This study is needed to act as a basis for future studies. The information may also help interpret serology of individuals living in endemic areas where positive serological results may be more common and may not always indicate an acute or recent infection.\n\nData now may also act as a baseline to help determine whether Lyme disease is spreading and becoming more common. This will be of benefit to patients affected by Lyme disease and healthcare workers treating it in the UK. Many people are concerned about the possible presence of co‑infections transmitted by ticks; these are thought to be rare in the UK (compared with other parts of the world) but there are insufficient data to confirm or refute this. Better evidence may improve diagnostic and treatment decisions.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on laboratory investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnostic tests.\n\nLoading. Please wait.\n\n# Antimicrobial management of Lyme disease\n\nWhat are the most clinically and cost-effective treatment options for different clinical presentations of Lyme disease in the UK?\n\n## Why this is important\n\nThe evidence on the effectiveness of antimicrobial treatment regimens used in different presentations of Lyme diseases is of poor quality, out-dated and often based on small studies. No relevant cost-effectiveness evidence was identified. A series of prospective multicentre studies is needed to compare the clinical and cost effectiveness of different dosages and length of treatments needed and the clinical and cost effectiveness of oral compared with intravenous treatments for different presentations of Lyme disease. This is felt to be of high priority because it has enormous implications for people with Lyme disease and for NHS costs.\n\nThere is currently insufficient quality evidence on the most effective drug and dose, and the effectiveness of extended treatment or retreatment regimens in those with continuing symptoms remains uncertain, leading to multiple referrals in search of alternative diagnoses. Clarification could improve outcomes, reduce costs and may minimise unnecessary treatment.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on antibiotic treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: management of erythema migrans\n\nevidence review\xa0E: management of non-specific symptoms\n\nevidence review\xa0F: management of neuroborreliosis\n\nevidence review\xa0G: management of arthritis\n\nevidence review\xa0H: management of acrodermatitis chronica atrophicans\n\nevidence review\xa0I: management of carditis\n\nevidence review\xa0J: management of lymphocytoma\n\nevidence review\xa0K: management of ocular symptoms.\n\nLoading. Please wait.\n\n# Laboratory tests to diagnose initial and ongoing infection and determine re‑infection in the different presentations of Lyme disease in the UK\n\nWhat is the most clinically and cost-effective serological antibody-based test, biomarker or other test for diagnosing Lyme disease in the UK at all stages, including re‑infection?\n\n## Why this is important\n\nDetermining the most clinically and cost-effective diagnostic tests for Lyme disease will improve patient care and is a high priority. The clinical presentation of Lyme disease is variable with the diagnosis of all presentations, except erythema migrans, relying in part on laboratory testing. Current literature suggests that a combined IgG/IgM enzyme-linked immunosorbent assay (ELISA) based on the IR6\xa0peptide and immunoblot are useful; however, published evidence is of either low or very low quality and is not UK based. There is evidence of variation in the IR6\xa0peptide between the principal Borrelia genospecies in UK ticks and a combination of ELISAs may improve sensitivity.\n\nA 'test of cure' for Lyme disease does not exist and, consistent with most other infectious diseases, serology is likely to remain positive for some time following successful treatment of infection in most patients. However, little is known about the evolution of antibody titres over time in those who have been treated successfully and in those who have ongoing symptoms.\n\nIt is frequently stated that early antibiotic treatment of Lyme disease abrogates the immune response, so that serology remains or becomes negative. This is not a common occurrence in other infections but there are inadequate prospective data on whether it occurs in people with Lyme disease. Observational studies to clarify this would be helpful. In addition, understanding the natural course of Lyme disease serology, and non-serological tests over time, may assist in the interpretation of test results in patients who remain symptomatic and in those who are high risk for re‑infection, such as those with occupational exposure.\n\nIn particular, further research into the value of novel biomarkers (for example, CXCL13 and others) and other types of tests may be helpful to support the current low-quality evidence. The examples of tests included in this research recommendation reflect those included in this guideline. However, other novel biomarkers are likely to be developed and require similar assessment.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on laboratory investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: diagnostic tests.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Awareness of Lyme disease\n\nRecommendations 1.1.1 to 1.1.3\n\n## Why the committee made the recommendations\n\nThe committee agreed that raising awareness is important to improve diagnosis and management of Lyme disease. Based on the committee's knowledge and experience, and some limited evidence on UK incidence, they agreed to highlight how infection occurs, typical tick habitats and areas of higher risk. This may help to guide healthcare professionals, for example, in recognising the possibility of Lyme disease when a person is unaware that they have been bitten by a tick or in areas where ticks are found but Lyme disease is not highly prevalent.\n\nThe committee also agreed that people who may have been exposed to ticks should be given advice to help avoid Lyme disease in the future.\n\nBecause of the lack of evidence in this area, the committee also developed a research recommendation on the clinical epidemiology of Lyme disease in the UK.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to improve awareness of Lyme disease, to promote early investigation and treatment, and to optimise outcomes in people with Lyme disease. They will change current practice by prompting healthcare professionals to think about the possibility of Lyme disease. This may result in an increase in testing and treatment, but the cost of this is likely to be balanced by the benefits of improved recognition and early treatment.\n\nReturn to recommendations\n\n# Clinical assessment\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nThe committee reviewed evidence on the diagnostic accuracy of some specific signs and symptoms (erythema migrans, facial palsy, lymphocytoma, acrodermatitis chronica atrophicans and heart block or arrhythmias) to assess if any could be used to diagnose Lyme disease or to indicate that testing should be carried out.\n\nErythema migrans only occurs in Lyme disease and may be used to diagnose Lyme disease. The committee agreed that the evidence, although limited, supported this. Some healthcare professionals may not be familiar with erythema migrans, so a description of the rash and its characteristics was included.\n\nLyme disease has a varied presentation and erythema migrans is not always present, so the assessment of other signs and symptoms is important. The evidence was not strong enough for the committee to recommend diagnosis, testing or treatment based on any other symptom or sign alone. However, the committee noted a number of potential presentations of Lyme disease that should alert healthcare professionals to consider the possibility of Lyme disease and prompt a discussion about the possibility of tick exposure. Based on their knowledge and experience, the committee agreed to highlight factors to consider in history and presentation to help with clinical decision-making.\n\n## How the recommendations might affect practice\n\nCurrent practice is to diagnose and treat Lyme disease in people with erythema migrans. People who present without erythema migrans but whose history and presentation are consistent with Lyme disease are offered testing. The recommendations will not change current practice but should serve as a reminder to healthcare professionals, particularly in areas where Lyme disease is less common, to think about Lyme disease as a differential diagnosis. Implementing these recommendations is unlikely to involve additional costs and may improve recognition and diagnosis.\n\nReturn to recommendations\n\n# Laboratory investigations\n\nRecommendations 1.2.11 to 1.2.23\n\n## Why the committee made the recommendations\n\nThe committee agreed that laboratory testing is unnecessary for people presenting with erythema migrans, because the rash is very specific to Lyme disease and prompt treatment will prevent further symptoms developing. However, most other symptoms associated with Lyme disease have other more common causes, so testing may be helpful to ensure accurate diagnosis and appropriate treatment.\n\nBased on the evidence on test accuracy, the committee agreed that test results need careful interpretation alongside clinical assessment to guide diagnosis. Because of the limitations of tests, Lyme disease should not be ruled out by negative tests if it is strongly suggested by the clinical assessment. The committee decided that treatment could be started at the same time as testing if clinical assessment strongly suggests Lyme disease because prompt treatment is important.\n\nThe committee agreed a strategy of 2‑tier testing (an initial and confirmatory test), which the evidence indicated was potentially cost saving. Initial testing with a combination IgM and IgG enzyme-linked immunosorbent assay (ELISA) for Lyme disease should be offered because the evidence generally showed better accuracy (both sensitivity and specificity) for combined tests compared to IgM‑only and IgG‑only tests. The evidence was best for tests based on purified or recombinant antigens derived from the VlsE protein or its IR6\xa0domain peptide (such as a\xa0C6).\n\nFor people with a negative ELISA result who continue to have symptoms, the committee agreed that clinical review would ensure that alternative diagnoses are not missed. In addition, because antibodies take some time to develop, repeat testing would be warranted for people who may have had the initial test too early, before an immune response has developed. If symptoms have been present for 12\xa0weeks, the committee agreed that an immunoblot would help rule out or confirm diagnosis where uncertainty still remains.\n\nThe committee agreed that for people with negative test results who continue to have symptoms, discussion with or referral to a specialist for further review might be beneficial.\n\nThe committee agreed that testing should be done in UKAS-accredited laboratories and that any tests used for diagnosis should be validated before they are used to diagnose Lyme disease to avoid unreliable and misleading results, which may lead to misdiagnosis.\n\nBased on their knowledge and experience, the committee agreed that Borrelia burgdorferi sensu lato (sl) infection does not behave differently in children than adults, but acknowledged that a young child's immune responses might not be as rapid and effective. The limited evidence in children did not show a noticeable difference in test accuracy compared with adults. Therefore, the committee decided that separate recommendations for testing in children were unnecessary.\n\nThe committee considered it important that people being tested for Lyme disease understand how the tests work, their limitations and the importance of basing decisions on tests that are valid.\n\nThe committee noted that further research would be helpful and agreed to make research recommendations to determine the seroprevalence of antibodies to tick-borne infections in the UK and to clarify further the most effective laboratory tests at different stages of Lyme disease.\n\n## How the recommendations might affect practice\n\nA 2‑tiered testing system is used in current practice, in which a positive result on an initial ELISA leads to a confirmatory immunoblot test. A negative result on an initial ELISA would not usually lead to a confirmatory immunoblot test. Therefore, the recommendation to carry out an immunoblot test, despite an initial negative ELISA when there is clinical suspicion of Lyme disease would be a change to practice and increase the number of people receiving this test. However, this would only apply to a small population, so this recommendation is not likely to have a significant resource impact.\n\nReturn to recommendations\n\n# Emergency referral and specialist advice\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nLyme disease will not usually be considered as the most likely cause when people present with neurological and other symptoms that need emergency referral (such as central nervous system infection or heart block). However, the committee wanted to emphasise that if the history and physical findings suggest Lyme disease, usual clinical practice is still appropriate, because people may need additional supportive treatment from specialist services as well as appropriate antibiotics.\n\nThe type of problems that children with Lyme disease may develop, such as arthritis or facial palsy, are uncommon and the committee decided to recommend that management for children and young people with presentations other than uncomplicated erythema migrans (a single lesion with no other symptoms) should be discussed with a specialist to ensure the diagnosis is correct and for advice on antibiotic treatment.\n\nFor adults with focal symptoms such as arthritis, the committee agreed that a discussion with a specialist may be considered, but that treatment can be started.\n\n## How the recommendations might affect practice\n\nPeople who are systemically unwell with neurological or cardiac disease are referred to hospital for urgent treatment, so this recommendation should not lead to a change in existing practice.\n\nThe occurrence of symptoms such as arthritis and facial palsy are uncommon in children, so it is expected that most children with these symptoms are already seen in specialist services; therefore, this recommendation should not result in a large change of practice.\n\nReturn to recommendations\n\n# Antibiotic treatment\n\nRecommendations 1.3.4 to 1.3.8\n\n## Why the committee made the recommendations\n\nA number of studies examined antibiotic treatment of Lyme disease with erythema migrans using different antibiotics, doses and durations of treatment. However, many of the studies did not reflect current prescribing practices and the evidence was of poor quality.\n\nFor adults, there was evidence that doxycycline is more clinically effective than some other antibiotics. However, the evidence showed no clear difference in effectiveness between doxycycline, an amoxicillin/probenecid combination and azithromycin. The evidence also showed no benefit of intravenous or intramuscular cephalosporin over doxycycline. It was noted that doxycycline and amoxicillin are able to penetrate the blood–cerebrospinal fluid barrier and pass into the central nervous system, whereas azithromycin cannot. This may be important to prevent the development of further symptoms. Doxycycline can also be taken in a single daily dose, which may help with adherence.\n\nBased on these factors, along with their knowledge and experience, the committee agreed on doxycycline as the initial treatment for adults and young people (aged 12\xa0and over), with amoxicillin as an alternative, and azithromycin as a third option when both doxycycline and amoxicillin are contraindicated.\n\nThe committee acknowledged that infectious disease specialists currently treat Lyme disease in children aged 9\xa0and above with doxycycline, although it is not licensed in the UK for children under\xa012, and it is contraindicated in this age group because of side effects, such as teeth staining. Based on their experience and knowledge, feedback from stakeholders, and the evidence for adults, the committee agreed that doxycycline is the most effective treatment for Lyme disease and that the risk of dental problems in children is low when it is used for short-term treatment (28\xa0days or less). Therefore, doxycycline can be used as the initial treatment for Lyme disease in children aged 9\xa0and above. The committee agreed on doxycycline doses based on their knowledge and experience of current practice both in the UK and the US.\n\nThe use of doxycycline in children under 9\xa0years is currently limited by licensing and clinical experience. There was some evidence that amoxicillin and azithromycin were equally effective in children. Because of its ability to penetrate the blood–cerebrospinal fluid barrier, the committee agreed that children under\xa09 should be offered amoxicillin as the initial treatment, with azithromycin as an alternative treatment option, and that doses should be adjusted by weight.\n\nCurrent guidelines give ranges for treatment duration, generally between 10\xa0and 21\xa0days, without guidance on when to use a longer or shorter course. The committee agreed that this is not clear enough for generalists. The evidence for treatment duration was limited. The committee decided that longer courses of 21\xa0days of treatment should be offered as standard because of their concern at low cure rates in some studies and the lack of clear evidence for shorter courses. They also agreed that a longer course may be reassuring for people being treated for Lyme disease who continue to have symptoms. The evidence showed adverse event rates were not increased for longer courses.\n\nThe committee agreed that further research would be helpful and agreed to make research recommendations to develop a core outcome set for clinical trials and to determine the most effective antibiotic treatment for different presentations of Lyme disease.\n\nNo studies were identified comparing different antibiotics for managing Lyme disease in people with non-focal symptoms (symptoms such as fever, sweats and muscle pain, which are not specific to an organ system). However, the committee reviewed the evidence available for treating other symptoms and, based on this and their knowledge and experience, agreed that people with non-focal symptoms should be given the same treatment as people with erythema migrans.\n\nBecause of the uncertainties about diagnosis and management, the committee agreed that care of children and young people under\xa018 with Lyme disease and non‑erythema migrans presentations should have their care discussed with a specialist.\n\nThe evidence for antibiotic treatment of Lyme disease affecting the nervous system was limited. One study showed a greater benefit with oral doxycycline than intravenous ceftriaxone in treating Lyme disease affecting the peripheral nervous system. However, both treatments showed low rates of cure (full resolution of neurological symptoms). The committee also noted that the study used a 14‑day course of antibiotics, which is below the maximum treatment durations recommended by some current guidelines.\n\nThe committee agreed that people presenting with meningitis or encephalitis (before a diagnosis of Lyme disease) would receive treatment with intravenous ceftriaxone, and that intravenous treatment would achieve adequate concentrations in the central nervous system more rapidly than oral treatment.\n\nThe committee also discussed the management of neurosyphilis, which has similar central nervous system involvement. The committee considered that, although the evidence was limited, central nervous system symptoms in Lyme disease should be treated with a similar antibiotic dose to that recommended for neurosyphilis.\n\nOnce-daily ceftriaxone has the advantage of being given more easily as an outpatient treatment than other intravenous options, which allows completion of the course as an outpatient.\n\nTaking these factors into account and based on their knowledge and experience, the committee agreed on a 21‑day course of intravenous ceftriaxone 4\xa0g daily as the initial treatment for adults and young people (aged 12\xa0and over) with Lyme disease affecting the central nervous system, with a 21‑day course of doxycycline 400\xa0mg daily recommended as an alternative treatment. The higher dose (4\xa0g) is the recommended dose for bacterial meningitis. For Lyme disease affecting the cranial nerves or the peripheral nervous system, the committee agreed on a 21‑day course of doxycycline 200\xa0mg daily as the initial treatment for adults and young people (aged 12\xa0and over), with amoxicillin recommended as an alternative treatment.\n\nNo studies were identified for nervous system symptoms in children. However, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9\xa0to\xa012\xa0years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9\xa0years is currently limited by licensing and clinical experience.\n\nBecause of the importance of diagnosis and management, the committee also agreed that care of children and young people under\xa018 should be discussed with a specialist.\n\nThe studies identified looked at antibiotic treatment in children, young people and adults with Lyme arthritis (inflammation affecting 1\xa0or more joints). Evidence from 1\xa0study showed that a 30‑day course of doxycycline resulted in fewer symptom relapses and adverse events than 30\xa0days of amoxicillin plus probenecid.\n\nThe committee agreed that longer courses of treatment are appropriate when treating Lyme arthritis because it is difficult for antibiotics to penetrate to the synovium and synovial fluid.\n\nTaking these factors into account, the committee decided that a 28‑day course of antibiotics would be appropriate and also practical, because antibiotics are available in weekly packs.\n\nBecause the evidence was limited, the committee also took into account evidence for other presentations of Lyme disease. Based on this, along with their knowledge and experience of current practice, the committee agreed that doxycycline should be offered to adults and young people (aged 12\xa0and over) as the initial treatment, with amoxicillin recommended as an alternative treatment. The committee also agreed that if oral doxycycline and amoxicillin are contraindicated or unsuitable, 28\xa0days of intravenous ceftriaxone should be offered.\n\nAlthough there was no evidence for treating Lyme arthritis in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9\xa0to\xa012\xa0years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9\xa0years is currently limited by licensing and clinical experience.\n\nBecause of the importance of correct diagnosis and management, the committee agreed that care of children and young people under\xa018 with Lyme disease and non‑erythema migrans presentations should be discussed with a specialist.\n\nOne study suggested that a 30‑day course of doxycycline was better for treating acrodermatitis chronica atrophicans than a 20‑day course of treatment. Oral doxycycline given for 30\xa0days was also more effective than a 15‑day course of intravenous ceftriaxone. The committee agreed that a longer course of treatment might be beneficial because it is difficult for antibiotics to penetrate the affected skin. They also took into account evidence for Lyme arthritis, which justified a longer treatment course to allow penetration into joints. The committee decided that a 28‑day course of antibiotics would be appropriate and practical, because antibiotics are available in weekly packs.\n\nThe evidence for antibiotics was very limited, so the committee also took into account evidence for other presentations of Lyme disease and their experience and knowledge of current practice. The committee agreed that doxycycline should be offered to adults and young people (aged 12\xa0and over) as the initial treatment, with amoxicillin recommended as an alternative treatment. The committee also agreed that if oral doxycycline and amoxicillin are contraindicated or unsuitable, intravenous ceftriaxone could be offered.\n\nAlthough there was no evidence for treating acrodermatitis chronica atrophicans in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9\xa0to\xa012\xa0years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9\xa0years is currently limited by licensing and clinical experience.\n\nBecause of the importance of correct diagnosis and management, the committee agreed that care of children and young people under\xa018 with Lyme disease and non-erythema migrans presentations should be discussed with a specialist.\n\nNo studies of antibiotic treatment for heart problems caused by Lyme disease were identified. Therefore, the committee reviewed the evidence available for treating other symptoms of Lyme disease and used this, their experience of current practice and their knowledge of care for people with heart problems, to develop the recommendations.\n\nThe committee decided that a 21‑day course of doxycycline would be appropriate as the initial treatment for adults and young people (aged 12\xa0and over) with carditis who are stable, with a 21‑day course of intravenous ceftriaxone recommended as an alternative treatment.\n\nThe committee noted that people with severe heart problems are likely to need treatment in hospital from cardiologists. They agreed that intravenous ceftriaxone for 21\xa0days would therefore be suitable as the initial treatment for people with carditis who are haemodynamically unstable.\n\nBecause of the lack of evidence for treatment in children, the committee agreed that the evidence for adults and young people could be used to support similar treatment for children aged 9\xa0to\xa012\xa0years, with the same antibiotics and duration of treatment but with doses adjusted by weight. The use of doxycycline in children under 9\xa0years is currently limited by licensing and clinical experience.\n\nBecause of the importance of correct diagnosis and management, the committee agreed that care of children and young people under\xa018 with Lyme disease and focal symptoms such as carditis should be discussed with a specialist.\n\nThe committee also noted that azithromycin should not be used to treat people with cardiac abnormalities because of its effect on the QT\xa0interval.\n\nNo evidence was identified for the antibiotic treatment of lymphocytoma related to Lyme disease. Lymphocytoma is a very rare early presentation of Lyme disease and the committee agreed that most people presenting with lymphocytoma only would be referred for specialist investigation of lesions to establish the diagnosis. People with lymphocytoma and other symptoms of Lyme disease would receive treatment appropriate for their other symptoms on diagnosis. Therefore, they decided not to make a recommendation and that further research in this area was not a priority.\n\nNo evidence was identified for the antibiotic treatment of non-neurological ocular symptoms related to Lyme disease. The committee agreed that people presenting with severe ocular symptoms would be referred for specialist investigation. The committee noted that it is difficult to diagnose Lyme disease as a cause of ocular symptoms unless there is a supportive history and other symptoms of Lyme disease, but that people with other symptoms of Lyme disease would receive treatment appropriate for their other symptoms on diagnosis. Therefore, they decided not to make a recommendation and that further research in this area was not a priority.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to standardise antibiotic treatment and to provide a consistent framework for good practice in managing Lyme disease. Overall, there may be changes to prescribing practices, but the impact is likely to be small.\n\nFull details of the evidence and the committee's discussion are in the evidence reviews.\n\nReturn to recommendations\n\n# Ongoing symptoms after a course of antibiotics\n\nRecommendations 1.3.9 to 1.3.13\n\n## Why the committee made the recommendations\n\nPeople who have had treatment for Lyme disease sometimes report ongoing symptoms. The cause is often not clear and includes re‑infection, or organ damage caused by Lyme disease, which may take a long time to heal or may even be permanent.\n\nThe evidence available for treating ongoing symptoms did not show benefit from prolonged treatment with antibiotics. However, based on their knowledge and experience, the committee agreed that treatment failure could occur and that a second course of an alternative antibiotic might sometimes be appropriate. The committee noted the importance of considering alternative diagnoses to prevent inappropriate antibiotic treatment and misdiagnosis.\n\nThe committee agreed that people with ongoing symptoms should not routinely be offered more than 2\xa0courses of antibiotics because of lack of evidence of benefit. However, discussion with a specialist or referral should be considered for some people, and discussion with the UK national reference laboratory might be helpful, for example, if a different tick-borne disease is possible.\n\nPeople who have a slow recovery from Lyme disease may need additional support and access to social care. The committee agreed that it was important that healthcare professionals help people with long-term symptoms related to Lyme disease to access support if needed.\n\n## How the recommendations might affect practice\n\nCurrent treatment for Lyme disease is a single course of antibiotics. Treatment for ongoing symptoms is unclear and practice varies. Further antibiotic treatment is now recommended as an option if persisting infection is a possibility. This will standardise practice, but may cause an increase in antibiotic prescribing in a small number of patients. The committee agreed that this change in practice would not result in a significant resource impact given the small number of people with treatment failure.\n\nReturn to recommendations\n\n# Non-antibiotic management of ongoing symptoms\n\nRecommendations 1.3.14 to 1.3.17\n\n## Why the committee made the recommendations\n\nNo specific evidence review was carried out to inform recommendations on support, referral to social services or the need to consider assessing and managing other symptoms related to Lyme disease, such as chronic pain, fatigue or depression. The committee, however, acknowledged that some people with Lyme disease experience a slow recovery and may need professional support. Some people with Lyme disease feel that their needs are not considered in an appropriate way. Based on their knowledge and clinical experience, the committee agreed that healthcare professionals should consider the possibility of such needs and provide support if needed, including regular review for people with ongoing symptoms.\n\n## How the recommendations might affect practice\n\nSome people with Lyme disease may need support or social services, especially when they have a slow recovery. Social services needs assessments are carried out by local authorities and will not affect NHS practice.\n\nSome people with Lyme disease may also present with related symptoms, such as chronic pain, depression or fatigue. Guidance for managing these symptoms already exists and therefore there will be no change to existing clinical practice.\n\nReturn to recommendations\n\n# Management for women with Lyme disease during pregnancy and their babies\n\nRecommendations 1.3.18 to 1.3.21\n\n## Why the committee made the recommendations\n\nThe committee acknowledged that mother-to-baby transmission of Lyme disease is possible in theory. There was an absence of evidence, but the risk appears to be very low. The committee decided that women could be reassured that pregnancy and their baby are unlikely to be affected, and highlighted the importance of completing treatment. It was also agreed that pregnant women should be treated following usual practice, but using antibiotics suitable in pregnancy.\n\nGiven the absence of evidence and the lack of a standard approach to care, the committee agreed that care of babies born to mothers with Lyme disease during pregnancy should be discussed with a paediatric infectious disease specialist if the mother has concerns about her baby. In addition, to ensure that babies with Lyme disease do not go untreated, the committee agreed that babies should receive treatment if they have serology showing IgM antibodies specific to Lyme disease or symptoms that might be caused by Lyme disease.\n\nThe committee agreed that more evidence on Lyme disease in pregnancy would be helpful to inform future guidance. Pregnant women with Lyme disease or suspected Lyme disease are a population of particular interest in the research recommendation on the clinical epidemiology of Lyme disease in the UK.\n\nNo evidence was found for transmission of Lyme disease through sexual contact or blood products and the committee agreed that they could not make recommendations in these areas.\n\n## How the recommendations might affect practice\n\nThere is no standardised approach to the care of babies born to mothers who had Lyme disease in pregnancy. The recommendations are unlikely to have a big impact on practice, but should reduce variation and provide guidance to reassure women and healthcare professionals.\n\nReturn to recommendations\n\n# Information for people with Lyme disease\n\nRecommendations 1.2.24 to 1.2.27 and 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThere was a lack of evidence identified on the information needs of people with suspected or confirmed Lyme disease, or specific Lyme disease presentations. However, some evidence was identified that highlighted the need for information addressing the medical uncertainties of Lyme disease.\n\nThe guideline committee used this evidence, the evidence reviews on diagnosis and management, and their experience to make recommendations to inform people being investigated for and diagnosed with Lyme disease. The committee agreed that people would benefit from a better understanding of the nature of Lyme disease, the accuracy and limitations of testing, and issues with treatment and follow‑up.\n\n## How the recommendations might affect practice\n\nThe recommendations standardise and reinforce current good practice. Many healthcare professionals will not need to change their current practice.\n\nReturn to recommendations 1.2.24 to 1.2.27 and 1.4.1 to 1.4.4.", 'Context': "Lyme disease (Lyme borreliosis) is a tick-borne infectious disease. It is caused by different genospecies of Borrelia including B.\xa0burgdorferi sensu strictu (ss), B.\xa0afzelii and B.\xa0garinii, which can be transmitted to humans through a bite from an infected tick. Infection is more likely the longer a tick is attached to the skin. Ticks live in grassy and wooded areas, both in rural and urban locations. People who spend time in these areas for work or recreation are at increased risk of tick exposure.\n\nLyme disease can occur anywhere in the UK, although some areas have a higher reported incidence. Approximately 50% of laboratory-confirmed cases are diagnosed in the South East and South West of England. High incidence is also reported in Scotland. Worldwide, Lyme disease occurs mainly in the northern hemisphere, and travellers to areas of Europe, North America and elsewhere may be at risk. However, the true incidence of Lyme disease is unknown.\n\nAlthough the disease has been recognised in mainland Europe for more than a century, it was first reported in England and Wales in the\xa01980s. Public Health England (PHE) reports that there are approximately 1,000\xa0serologically confirmed cases of Lyme disease each year in England and Wales. Many diagnoses will also be made clinically without laboratory testing. The true number of cases is currently unknown.\n\nIn England and Wales, cases of laboratory-confirmed Lyme disease have increased. It is not certain how much of the rise is due to increased awareness and how much to the spread of the disease.\n\nInfection with B. burgdorferisensu lato (sl) can sometimes go unremarked, with mild symptoms that are ignored by the person. When symptoms occur, this is called Lyme disease. Many people may not notice or remember a tick bite. A bite can be followed by an 'erythema migrans' rash, which is sometimes mistaken for cellulitis or ringworm, and effective treatment is delayed. If there is no erythema migrans or it is unnoticed, diagnosis can be difficult because the same symptoms may be caused by many other conditions as well as Lyme disease.\n\nThe terminology around Lyme disease is varied and many poorly defined terms are used in the literature (such as chronic Lyme disease and post-Lyme disease). This guideline has avoided using controversial definitions and has concentrated on providing advice on diagnosis and treatment based on the available evidence, according to the clinical context, presentation, symptoms and available treatments. The guideline committee has noted the poor-quality evidence available on both diagnosis and treatment.\n\nThe guideline aims to raise awareness of when Lyme disease should be suspected and to ensure that people with suspected Lyme disease are given early and consistent treatment. The guideline committee has also developed a series of research recommendations to improve basic epidemiology, understanding of the natural history of Lyme disease, and to develop diagnostic tests appropriate for UK infections."}
|
https://www.nice.org.uk/guidance/ng95
|
This guideline covers diagnosing and managing Lyme disease. It aims to raise awareness of when Lyme disease should be suspected and ensure that people have prompt and consistent diagnosis and treatment. It does not cover preventing Lyme disease.
|
b6ec51016bd18f1ad5e6eff26f1653f6255bb143
|
nice
|
Dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma
|
Dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma
Evidence-based recommendations on dabrafenib (Tafinlar) with trametinib (Mekinist) for resected stage III, BRAF V600 mutation-positive melanoma in adults.
# Recommendations
Dabrafenib with trametinib is recommended, within its marketing authorisation, as an option for the adjuvant treatment of resected stage III BRAF V600 mutation-positive melanoma in adults. It is recommended only if the company provides dabrafenib and trametinib with the discounts agreed in the commercial arrangements.
Why the committee made these recommendations
There are currently no adjuvant treatments available for stage III BRAF V600 mutation-positive melanoma and there is a substantial risk of the cancer returning and becoming incurable. Dabrafenib with trametinib is a new adjuvant treatment aimed at curing the cancer by reducing the likelihood that it will spread. It is therefore an important development in managing stage III melanoma.
Clinical trial evidence shows that dabrafenib with trametinib extends the length of time people have before their melanoma recurs compared with routine surveillance. Evidence from the trial and from clinical experts strongly suggests that it also increases the overall length of time people live by reducing how many people develop metastatic disease.
Cost-effectiveness estimates for dabrafenib with trametinib are in the range usually considered a cost-effective use of NHS resources. Therefore it can be recommended.# Information about dabrafenib with trametinib
Anticipated marketing
Dabrafenib (Tafinlar, Novartis Pharmaceuticals) with trametinib (Mekinist, Novartis Pharmaceuticals) is indicated for 'the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation, following complete resection'.
Dosage in the marketing authorisation
For dabrafenib, the recommended dose is 150 mg taken orally, twice daily. For trametinib, the recommended dose is 2 mg taken orally, once daily.
Price
The list price for 28 capsules of dabrafenib 75 mg is £1,400 and for 30 tablets of trametinib 2 mg is £4,800 (company submission).
The company has a commercial arrangement for each drug. This makes dabrafenib with trametinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need and current management
## People with completely resected stage III BRAF V600 mutation-positive melanoma have a high unmet clinical need
Melanoma is more common in younger people than other cancers. It has a substantial effect on patients, carers and wider society. Around half of people with stage III melanoma will experience a distant (metastatic) recurrence, for which the 5‑year survival prognosis is poor (ranging from 5% to 20%). Advanced melanoma can cause severe and debilitating symptoms and is life threatening. Standard treatment for stage III melanoma is resection of the tumour and associated lymph nodes but people are still at high risk of disease recurrence, with 5- and 10-year relapse-free survival rates of 57% and 36%. The clinical and patient experts explained that there is a need for earlier active treatment after resection to prevent both recurrence at the original site and the development of metastatic disease. The committee concluded that people with resected stage III BRAF V600 mutation-positive melanoma have a high unmet clinical need and would value new treatment options.
## Adjuvant treatment aims to cure the disease and is an important development in the management of stage III melanoma
Standard of care for people with resected stage III BRAF V600 mutation-positive melanoma is routine surveillance. This includes regular clinical review and imaging surveillance. Adjuvant radiotherapy and immunotherapy after tumour removal are not widely used in UK practice. The clinical experts explained that the aim of adjuvant treatment is to remove any residual microscopic disease after resection. This reduces the risk of relapse and progression to metastatic disease. They further explained that the biology of the disease means that relapse usually happens in the first few years after resection, but this had not been seen with dabrafenib with trametinib in the clinical trial. Their expectation is that a substantial number of people will be cured by having a course of dabrafenib with trametinib after surgical resection. The committee noted that the ERG's clinical experts suggested that adjuvant treatment may only delay disease recurrence, rather than prevent it. However, the Cancer Drugs Fund clinical lead explained that dabrafenib with trametinib taken for advanced disease is not considered curative. But, there are precedents from other malignancies in which non-curative systemic therapy for advanced disease does increase the cure rate if given at an early stage of disease post-surgery, for example breast cancer, colorectal cancer and non-small-cell lung cancer. He therefore considered it unlikely that adjuvant treatment with dabrafenib with trametinib would have no long-term survival benefit in melanoma. The committee concluded that adjuvant treatment with dabrafenib with trametinib for resected stage III BRAF V600 mutation-positive melanoma is a potentially innovative therapy. It aims to reduce the risk of relapse and death and is therefore an important development in the management of melanoma.
# Clinical evidence
## The clinical evidence is representative of clinical practice in England
The clinical evidence came from COMBI-AD, which was a double-blind randomised placebo-controlled trial. COMBI-AD assessed the clinical effectiveness of dabrafenib with trametinib in people with resected stage III BRAF V600 mutation-positive melanoma. The ERG explained that there were some limitations of the trial, but that overall it was well conducted and the baseline demographic characteristics of patients were comparable to patients in the UK. The committee understood that the American Joint Committee on Cancer (8th edition) had redefined stage III melanoma groupings and included an additional stage III‑D subgroup. The committee considered whether this would affect the generalisability of COMBI-AD (which used staging based on the 7th edition) to clinical practice in England in the future. The clinical experts explained that the new III‑D subgroup is a subset of the III‑C subgroup and therefore these patients were included in the trial. The committee concluded that COMBI-AD was well conducted and representative of clinical practice in England.
## Dabrafenib with trametinib increases relapse-free survival
Investigator assessed relapse-free survival was the primary end point in COMBI-AD. At a median follow-up of 2.8 years, median relapse-free survival in the dabrafenib with trametinib arm had not yet been reached because of the low event rate. Relapse-free survival was substantially longer in the dabrafenib with trametinib arm than in the placebo arm, representing a 53% lower risk of relapse or death (hazard ratio 0.47, 95% confidence interval 0.39 to 0.58; p<0.001). The Kaplan–Meier plot showed that relapse-free survival was higher for the treatment arm compared with placebo at all time points, suggesting an early and sustained advantage. The clinical experts explained that they expected to see continued separation of the curves with maturing data, to reflect the biology of the disease (in which the risk of relapse decreases substantially a few years after treatment). The committee concluded that dabrafenib with trametinib increases relapse-free survival compared with placebo.
## Dabrafenib with trametinib is expected to increase overall survival
Median overall survival was not reached in either arm of the trial, suggesting that more than 50% of patients were still alive at the time of data cut-off. However, the hazard ratio for death was 0.57 (95% CI 0.42 to 0.79; p=0.0006) for dabrafenib with trametinib compared with placebo. The committee considered that the results, although immature, were extremely promising and, together with the evidence from the clinical experts (see section 3.2), strongly suggest that combination adjuvant treatment with dabrafenib with trametinib will increase overall survival.
# Adverse events
## Dabrafenib and trametinib have manageable adverse-event profiles
The most frequently reported adverse events in the treatment arm were pyrexia (63% of patients), fatigue (47%), and nausea (40%). Serious adverse events happened in 36% of patients and 26% of patients permanently stopped taking dabrafenib and trametinib because of adverse events. However, the clinical and patient experts explained that dabrafenib and trametinib are generally well-tolerated. They stated that side effects are manageable with quality of life maintained, and that treatment is well adhered to. The committee therefore concluded that dabrafenib and trametinib have manageable adverse-event profiles.
# The company's economic model
## The model is appropriate for decision-making
The company presented a 4 state-transition model comparing dabrafenib with trametinib with routine surveillance. The model was divided into 2 periods: the first 50 months, corresponding to the maximum follow-up in COMBI-AD, and the period beyond this to the end of the time horizon (50 years). Different curves were fitted to the 2 time periods and the distribution of events (loco-regional recurrence, distant recurrence and deaths) in each period also differed. The committee noted the comments from the ERG that the model structure was unusual because the cost-effectiveness estimates were not reliant on any modelled overall survival even though it was anticipated that this would differ between the arms. The committee considered that the company's approach was appropriate given the immaturity of the overall-survival data at the time of the modelling and that the model was suitable for decision-making.
## The choice of curve for modelling relapse-free survival is the key driver in the economic analysis
A key uncertainty in the economic analysis was the choice of curves for modelling relapse-free survival, and the committee considered which curves were most appropriate. The company fitted different parametric functions to the trial data and considered the log-logistic unrestricted mixture model to provide the best visual and statistical fit to the relapse-free survival seen in the trial. The committee noted the ERG's comments that curve choice for extrapolation of relapse-free survival beyond the trial period is dependent on whether treatment with dabrafenib with trametinib is believed to cure disease or postpone recurrence. It recalled the views of the clinical experts that treatment is expected to cure some patients (see section 3.2). The clinical experts identified the company's log-logistic unrestricted mixture model followed by one of the alternative models presented by the ERG, the flexible parametric fit model, as the most clinically plausible because they showed continued separation of the curves. The committee acknowledged that the choice of curve had a substantial effect on the cost-effectiveness estimates and accepted the clinical experts' first preference for the log-logistic unrestricted mixture model and then the flexible parametric fit model.
## Using data from the placebo arm of a trial of adjuvant immunotherapy to model long-term relapse-free survival is not adequately justified
Beyond the first 50 months of the trial, the company extrapolated the results from COMBI-AD using the placebo arm of the international EORTC 18071 trial. This compared adjuvant ipilimumab with placebo in people with completely resected stage III melanoma. The ERG did not consider this approach appropriate because it locked in the proportionate survival gain at 50 months, with survival in the placebo arm being around 80% of survival in the treatment arm from month 50 onwards. Also, the ERG highlighted generalisability concerns about applying common risks from the placebo arm of a trial in a mixed-BRAF population to the exclusively BRAF-positive population of COMBI-AD. The company had not explored other external sources such as AVAST-M (a UK trial of adjuvant bevacizumab), which may be more generalisable to clinical practice in England than the EORTC 18071 trial. The committee noted the ERG's comments that the company had rejected a number of parameterisations of the COMBI-AD relapse-free survival data because the dabrafenib with trametinib curves fell below the placebo curve. However, the ERG considered that this was minimal and did not happen until well into extrapolation, and therefore the company had not adequately justified why these curves should be rejected. The committee concluded that using data from the placebo arm of EORTC 18071 to model long-term relapse-free survival had not been adequately justified by the company.
## The ERG's and company's base-case ICERs are very similar despite different methods of extrapolation, and fall in the range that can be considered cost effective
The ERG made a number of changes to the company's base-case model such as revised assumptions for subsequent therapy and monitoring. The committee considered that these were appropriate but that the model was not sensitive to changes in these assumptions. The main driver of the cost-effectiveness modelling is the projection of long-term relapse-free survival. The ERG used parameterised curves derived from COMBI-AD for modelling relapse-free survival and the company used the placebo arm of EORTC 18071 for relapse-free survival after 50 months (see section 3.9). Using the ERG's base-case assumptions (alongside the committee's 2 preferred curves for modelling relapse-free survival, see section 3.8), the incremental cost-effectiveness ratios (ICERs) ranged from £20,701 per quality-adjusted life year (QALY) gained for the log-logistic unrestricted mixture model and £20,167 per QALY gained for the ERG's flexible parametric fit model. The committee noted that these were almost identical to the company's base-case ICER of £20,039 per QALY gained. The committee further noted that the results were consistent across the ERG's scenario analyses and were in the range normally considered cost effective. It therefore concluded that dabrafenib with trametinib is a potentially innovative treatment for stage III melanoma and represents a cost-effective use of NHS resources. Therefore, it can be recommended for routine commissioning.
|
{'Recommendations': 'Dabrafenib with trametinib is recommended, within its marketing authorisation, as an option for the adjuvant treatment of resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma in adults. It is recommended only if the company provides dabrafenib and trametinib with the discounts agreed in the commercial arrangements.\n\nWhy the committee made these recommendations\n\nThere are currently no adjuvant treatments available for stage\xa0III BRAF\xa0V600 mutation-positive melanoma and there is a substantial risk of the cancer returning and becoming incurable. Dabrafenib with trametinib is a new adjuvant treatment aimed at curing the cancer by reducing the likelihood that it will spread. It is therefore an important development in managing stage\xa0III melanoma.\n\nClinical trial evidence shows that dabrafenib with trametinib extends the length of time people have before their melanoma recurs compared with routine surveillance. Evidence from the trial and from clinical experts strongly suggests that it also increases the overall length of time people live by reducing how many people develop metastatic disease.\n\nCost-effectiveness estimates for dabrafenib with trametinib are in the range usually considered a cost-effective use of NHS resources. Therefore it can be recommended.', 'Information about dabrafenib with trametinib': "Anticipated marketing\n\nDabrafenib (Tafinlar, Novartis Pharmaceuticals) with trametinib (Mekinist, Novartis Pharmaceuticals) is indicated for 'the adjuvant treatment of adult patients with stage\xa0III melanoma with a BRAF\xa0V600 mutation, following complete resection'.\n\nDosage in the marketing authorisation\n\nFor dabrafenib, the recommended dose is 150\xa0mg taken orally, twice daily. For trametinib, the recommended dose is 2\xa0mg taken orally, once daily.\n\nPrice\n\nThe list price for 28\xa0capsules of dabrafenib 75\xa0mg is £1,400 and for 30\xa0tablets of trametinib 2\xa0mg is £4,800 (company submission).\n\nThe company has a commercial arrangement for each drug. This makes dabrafenib with trametinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need and current management\n\n## People with completely resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma have a high unmet clinical need\n\nMelanoma is more common in younger people than other cancers. It has a substantial effect on patients, carers and wider society. Around half of people with stage\xa0III melanoma will experience a distant (metastatic) recurrence, for which the 5‑year survival prognosis is poor (ranging from 5% to 20%). Advanced melanoma can cause severe and debilitating symptoms and is life threatening. Standard treatment for stage\xa0III melanoma is resection of the tumour and associated lymph nodes but people are still at high risk of disease recurrence, with 5- and 10-year relapse-free survival rates of 57% and 36%. The clinical and patient experts explained that there is a need for earlier active treatment after resection to prevent both recurrence at the original site and the development of metastatic disease. The committee concluded that people with resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma have a high unmet clinical need and would value new treatment options.\n\n## Adjuvant treatment aims to cure the disease and is an important development in the management of stage\xa0III melanoma\n\nStandard of care for people with resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma is routine surveillance. This includes regular clinical review and imaging surveillance. Adjuvant radiotherapy and immunotherapy after tumour removal are not widely used in UK practice. The clinical experts explained that the aim of adjuvant treatment is to remove any residual microscopic disease after resection. This reduces the risk of relapse and progression to metastatic disease. They further explained that the biology of the disease means that relapse usually happens in the first few years after resection, but this had not been seen with dabrafenib with trametinib in the clinical trial. Their expectation is that a substantial number of people will be cured by having a course of dabrafenib with trametinib after surgical resection. The committee noted that the ERG's clinical experts suggested that adjuvant treatment may only delay disease recurrence, rather than prevent it. However, the Cancer Drugs Fund clinical lead explained that dabrafenib with trametinib taken for advanced disease is not considered curative. But, there are precedents from other malignancies in which non-curative systemic therapy for advanced disease does increase the cure rate if given at an early stage of disease post-surgery, for example breast cancer, colorectal cancer and non-small-cell lung cancer. He therefore considered it unlikely that adjuvant treatment with dabrafenib with trametinib would have no long-term survival benefit in melanoma. The committee concluded that adjuvant treatment with dabrafenib with trametinib for resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma is a potentially innovative therapy. It aims to reduce the risk of relapse and death and is therefore an important development in the management of melanoma.\n\n# Clinical evidence\n\n## The clinical evidence is representative of clinical practice in England\n\nThe clinical evidence came from COMBI-AD, which was a double-blind randomised placebo-controlled trial. COMBI-AD assessed the clinical effectiveness of dabrafenib with trametinib in people with resected stage\xa0III BRAF\xa0V600 mutation-positive melanoma. The ERG explained that there were some limitations of the trial, but that overall it was well conducted and the baseline demographic characteristics of patients were comparable to patients in the UK. The committee understood that the American Joint Committee on Cancer (8th edition) had redefined stage\xa0III melanoma groupings and included an additional stage\xa0III‑D subgroup. The committee considered whether this would affect the generalisability of COMBI-AD (which used staging based on the 7th edition) to clinical practice in England in the future. The clinical experts explained that the new III‑D subgroup is a subset of the III‑C subgroup and therefore these patients were included in the trial. The committee concluded that COMBI-AD was well conducted and representative of clinical practice in England.\n\n## Dabrafenib with trametinib increases relapse-free survival\n\nInvestigator assessed relapse-free survival was the primary end point in COMBI-AD. At a median follow-up of 2.8\xa0years, median relapse-free survival in the dabrafenib with trametinib arm had not yet been reached because of the low event rate. Relapse-free survival was substantially longer in the dabrafenib with trametinib arm than in the placebo arm, representing a 53% lower risk of relapse or death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39 to 0.58; p<0.001). The Kaplan–Meier plot showed that relapse-free survival was higher for the treatment arm compared with placebo at all time points, suggesting an early and sustained advantage. The clinical experts explained that they expected to see continued separation of the curves with maturing data, to reflect the biology of the disease (in which the risk of relapse decreases substantially a few years after treatment). The committee concluded that dabrafenib with trametinib increases relapse-free survival compared with placebo.\n\n## Dabrafenib with trametinib is expected to increase overall survival\n\nMedian overall survival was not reached in either arm of the trial, suggesting that more than 50% of patients were still alive at the time of data cut-off. However, the hazard ratio for death was 0.57 (95% CI 0.42 to 0.79; p=0.0006) for dabrafenib with trametinib compared with placebo. The committee considered that the results, although immature, were extremely promising and, together with the evidence from the clinical experts (see section\xa03.2), strongly suggest that combination adjuvant treatment with dabrafenib with trametinib will increase overall survival.\n\n# Adverse events\n\n## Dabrafenib and trametinib have manageable adverse-event profiles\n\nThe most frequently reported adverse events in the treatment arm were pyrexia (63% of patients), fatigue (47%), and nausea (40%). Serious adverse events happened in 36% of patients and 26% of patients permanently stopped taking dabrafenib and trametinib because of adverse events. However, the clinical and patient experts explained that dabrafenib and trametinib are generally well-tolerated. They stated that side effects are manageable with quality of life maintained, and that treatment is well adhered to. The committee therefore concluded that dabrafenib and trametinib have manageable adverse-event profiles.\n\n# The company's economic model\n\n## The model is appropriate for decision-making\n\nThe company presented a 4\xa0state-transition model comparing dabrafenib with trametinib with routine surveillance. The model was divided into 2\xa0periods: the first 50\xa0months, corresponding to the maximum follow-up in COMBI-AD, and the period beyond this to the end of the time horizon (50\xa0years). Different curves were fitted to the 2\xa0time periods and the distribution of events (loco-regional recurrence, distant recurrence and deaths) in each period also differed. The committee noted the comments from the ERG that the model structure was unusual because the cost-effectiveness estimates were not reliant on any modelled overall survival even though it was anticipated that this would differ between the arms. The committee considered that the company's approach was appropriate given the immaturity of the overall-survival data at the time of the modelling and that the model was suitable for decision-making.\n\n## The choice of curve for modelling relapse-free survival is the key driver in the economic analysis\n\nA key uncertainty in the economic analysis was the choice of curves for modelling relapse-free survival, and the committee considered which curves were most appropriate. The company fitted different parametric functions to the trial data and considered the log-logistic unrestricted mixture model to provide the best visual and statistical fit to the relapse-free survival seen in the trial. The committee noted the ERG's comments that curve choice for extrapolation of relapse-free survival beyond the trial period is dependent on whether treatment with dabrafenib with trametinib is believed to cure disease or postpone recurrence. It recalled the views of the clinical experts that treatment is expected to cure some patients (see section\xa03.2). The clinical experts identified the company's log-logistic unrestricted mixture model followed by one of the alternative models presented by the ERG, the flexible parametric fit model, as the most clinically plausible because they showed continued separation of the curves. The committee acknowledged that the choice of curve had a substantial effect on the cost-effectiveness estimates and accepted the clinical experts' first preference for the log-logistic unrestricted mixture model and then the flexible parametric fit model.\n\n## Using data from the placebo arm of a trial of adjuvant immunotherapy to model long-term relapse-free survival is not adequately justified\n\nBeyond the first 50\xa0months of the trial, the company extrapolated the results from COMBI-AD using the placebo arm of the international EORTC\xa018071 trial. This compared adjuvant ipilimumab with placebo in people with completely resected stage\xa0III melanoma. The ERG did not consider this approach appropriate because it locked in the proportionate survival gain at 50\xa0months, with survival in the placebo arm being around 80% of survival in the treatment arm from month\xa050 onwards. Also, the ERG highlighted generalisability concerns about applying common risks from the placebo arm of a trial in a mixed-BRAF population to the exclusively BRAF-positive population of COMBI-AD. The company had not explored other external sources such as AVAST-M (a UK trial of adjuvant bevacizumab), which may be more generalisable to clinical practice in England than the EORTC\xa018071 trial. The committee noted the ERG's comments that the company had rejected a number of parameterisations of the COMBI-AD relapse-free survival data because the dabrafenib with trametinib curves fell below the placebo curve. However, the ERG considered that this was minimal and did not happen until well into extrapolation, and therefore the company had not adequately justified why these curves should be rejected. The committee concluded that using data from the placebo arm of EORTC\xa018071 to model long-term relapse-free survival had not been adequately justified by the company.\n\n## The ERG's and company's base-case ICERs are very similar despite different methods of extrapolation, and fall in the range that can be considered cost effective\n\nThe ERG made a number of changes to the company's base-case model such as revised assumptions for subsequent therapy and monitoring. The committee considered that these were appropriate but that the model was not sensitive to changes in these assumptions. The main driver of the cost-effectiveness modelling is the projection of long-term relapse-free survival. The ERG used parameterised curves derived from COMBI-AD for modelling relapse-free survival and the company used the placebo arm of EORTC\xa018071 for relapse-free survival after 50\xa0months (see section\xa03.9). Using the ERG's base-case assumptions (alongside the committee's 2\xa0preferred curves for modelling relapse-free survival, see section\xa03.8), the incremental cost-effectiveness ratios (ICERs) ranged from £20,701 per quality-adjusted life year (QALY) gained for the log-logistic unrestricted mixture model and £20,167 per QALY gained for the ERG's flexible parametric fit model. The committee noted that these were almost identical to the company's base-case ICER of £20,039 per QALY gained. The committee further noted that the results were consistent across the ERG's scenario analyses and were in the range normally considered cost effective. It therefore concluded that dabrafenib with trametinib is a potentially innovative treatment for stage\xa0III melanoma and represents a cost-effective use of NHS resources. Therefore, it can be recommended for routine commissioning."}
|
https://www.nice.org.uk/guidance/ta544
|
Evidence-based recommendations on dabrafenib (Tafinlar) with trametinib (Mekinist) for resected stage III, BRAF V600 mutation-positive melanoma in adults.
|
8f0bf94a57ae15c6e0146564ff3f65ea7abb508f
|
nice
|
Decision-making and mental capacity
|
Decision-making and mental capacity
This guideline covers decision-making in people 16 years and over who may lack capacity now or in the future. It aims to help health and social care practitioners support people to make their own decisions where they have the capacity to do so. It also helps practitioners to keep people who lack capacity at the centre of the decision-making process.
# Context
The Care Quality Commission (CQC) estimates that around 2 million people in England and Wales may lack the capacity to make certain decisions for themselves at some point because of illness, injury or disability. The Mental Capacity Act 2005 was designed to empower and protect individuals in these circumstances. However, the CQC identified serious issues with the practical implementation of the Act. This subject was subsequently reported on by a House of Lords Select Committee in 2014, adding further momentum towards the need for improvement in practice.
It is in this context that the Department of Health commissioned this guideline, which makes recommendations for best practice in assessing and supporting people aged 16 years and older with decision-making activities. It helps to ensure that people are supported to make decisions for themselves when they have the mental capacity to do so, and where they lack the mental capacity to make specific decisions, they remain at the centre of the decision-making process. The guideline supports the empowering ethos and principles introduced by the Mental Capacity Act 2005 and explained in the Mental Capacity Act Code of Practice. These are:
. A person must be assumed to have capacity unless it is established that he lacks capacity.
. A person is not to be treated as unable to make a decision unless all practicable steps to help him to do so have been taken without success.
. A person is not to be treated as unable to make a decision merely because he makes an unwise decision.
. An act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interests.
. Before the act is done, or the decision is made, regard must be had to whether the purpose for which it is needed can be as effectively achieved in a way that is less restrictive of the person's rights and freedom of action.
The guideline helps health and social care practitioners to implement these principles and improve the quality of the decision-making support they provide. It applies to a range of decisions, including care, support and treatment, financial matters and day-to-day living, and aims to be proportionate, recognising that practitioners may need to provide rapid assistance in emergencies.
The guideline is based on the best available evidence from research, expert testimony, expert consensus and developments in law. It also identifies where evidence is lacking and makes recommendations for future research. The recommendations for research address the following: training and support for practitioners, interventions to support and improve decision-making capacity for treatment, advocacy and support for decision-making, mental capacity assessment tools, and the components of a mental capacity assessment.
The guideline applies to, and reinforces, the assessment, support and exercise of capacity whenever this is required by legislation, including but not confined to the Mental Capacity Act 2005, Mental Health Act 1983 and Care Act 2014. Practitioners should use the guideline to enhance the specific requirements of such legislation, codes of practice and other guidance relevant to their work. The guideline does not seek to repeat these, or be a step-by-step guide to their implementation.
Decision-making and mental capacity can be a particularly complex area for young people aged 16–18 years. A detailed overview of the legal provisions relating to the care and treatment of young people falls outside the scope of this guideline. However, the Children Act 1989 and Children and Families Act 2014 interface with the other Acts referred to above and in some circumstances provide an additional framework for the way in which young people should be involved in decision-making about their lives.
Where a young person over 16 is found to lack capacity to make a particular decision, it is important that the best interests process under the Mental Capacity Act 2005 is followed and that young people are as involved as possible in decisions made on their behalf.
In some cases, it will be possible for someone with parental responsibility to make a decision on behalf of the young person who lacks capacity. However, this will not always be appropriate. In these circumstances, the Mental Capacity Act Code of Practice should be followed to determine who should lead the best interests process.
Effective safeguarding identification and processes must always be followed, with acute awareness necessary among practitioners about the more subtle forms of abuse such as coercion. Practitioners must always refer to local safeguarding procedures.
The guideline focuses on the following key areas:
advance care planning
supporting decision-making
assessment of mental capacity to make specific decisions at a particular time
best interests decision-making for individuals who are assessed as lacking capacity to make a particular decision at a particular time.
The structure of the guideline is as follows:
Section 1.1 overarching principles
Section 1.2 supporting decision-making
Section 1.3 advance care planning
Section 1.4 assessment of mental capacity
Section 1.5 best interests decision-making.
Sections 1.2, 1.4 and 1.5 each begin by citing the relevant principle from the Mental Capacity Act 2005 along with an explanatory note about the practical application of the principle. This helps to ensure that the recommendations are interpreted within the framework of the Mental Capacity Act and Code of Practice.
The guideline does not cover:
decision-making activities and support for children under 16 years
the issue of deprivation of liberty and the Deprivation of Liberty Safeguards processes.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Overarching principles
## Recommendations for service providers and commissioners
Service providers and commissioners should ensure that practitioners undergo training to help them to apply the Mental Capacity Act 2005 and its Code of Practice. Training should be tailored to the role and responsibilities of the practitioner and cover new staff, pre‑registration, and continuing development and practice supervision for existing staff. Where appropriate, training should be interdisciplinary, involve experts by experience and include:
the statutory principles of the Mental Capacity Act 2005
the importance of seeking consent, and how to proceed if a person might lack capacity to give or refuse their consent to any proposed intervention
how and when to have potentially difficult conversations about loss of autonomy, advance care planning or death
required communication skills for building trust and working with people who may lack capacity
clarity on roles and responsibilities
the advantages, challenges and ethics of advance care planning, and how to discuss these with the person and their carers, family and friends
the processes and law surrounding advance decisions to refuse treatment and lasting powers of attorney/court appointed deputies
condition-specific knowledge related to advance care planning, where appropriate
the conduct of decision- and time-specific capacity assessments
the process of best interests decision-making in the context of section 4 of the Mental Capacity Act 2005 and associated guidance
the role of Independent Mental Capacity Advocates in best interests decision-making
how to direct people to sources of advice and information.
All health and social care organisations should:
develop local policy and guidance about which interventions, tools and approaches will be used to support decision-making
identify or devise specific tools to help health and social care practitioners assess where appropriate and necessary the mental capacity of the people they are working with and audit the tools against adherence to the Mental Capacity Act Code of Practice
train relevant practitioners in the use of these tools.
Co-develop policies and Mental Capacity Act 2005 training programmes with people who have experience of supported decision-making and of having their mental capacity assessed, and their carers, family and friends.
## Recommendations for individual practitioners
Practitioners involved in making decisions regarding individuals who lack capacity or supporting decision-making in individuals who have capacity must follow the 5 key principles set out in section 1 of the Mental Capacity Act 2005. As a starting point they must assume capacity unless there is evidence to suggest an assessment is required.
When giving information about a decision to the person:
it must be accessible, relevant and tailored to their specific needs
it should be sufficient to allow the person to make an informed choice about the specific decision in question
it should be supported by tools such as visual materials, visual aids, communication aids and hearing aids, as appropriate.
Record and update information about people's past and present wishes, beliefs and preferences in a way that practitioners from multiple areas (for example care and support staff, paramedics) can access and update. This information should be used to inform advance planning, supported decision-making and best interests decision-making.
## Using advocacy to support decision-making and assessment under the Mental Capacity Act
Practitioners should tell people about advocacy services as a potential source of support for decision-making, including:
enabling them to make their own key decisions, for example, about their personal welfare, medical treatment, property or affairs
facilitating their involvement in decisions that may be made, or are being made under the Mental Capacity Act 2005.
As a minimum, independent advocacy must be offered by local authorities as described in the Care Act 2014, Mental Capacity Act 2005 and Mental Health Act 2007. This recommendation is adapted from the NICE guideline on learning disabilities and behaviour that challenges: service design and delivery.
Consider expanding the commissioning of statutory Independent Mental Capacity Advocates.
Commissioners, public bodies and providers of statutory advocacy services should work closely to ensure that:
statutory duties on public bodies to refer to and involve advocacy are consistently adhered to and monitored and
failures in the duty to refer to statutory advocacy are addressed.
Relevant commissioners and providers should work with public bodies and providers to increase investment in training for statutory independent mental capacity and other statutory advocates in key areas, in order to ensure they are able to support:
people who have communication difficulties and
Independent Mental Capacity Advocates to have expertise in specific areas that require additional skills and knowledge – for example working with people with impaired executive function arising from acquired brain injury, mental illness, dementia or other illness.
# Supporting decision-making
'A person is not to be treated as unable to make a decision unless all practicable steps to help him do so have been taken without success.' (Principle 2, section 1(3), Mental Capacity Act 2005)
Principle 2 of the Mental Capacity Act 2005 requires practitioners to help a person make their own decision, before deciding that they are unable to make a decision. Supporting decision-making capacity effectively requires a collaborative and trusting relationship between the practitioner and the person. It does not involve trying to persuade or coerce a person into making a particular decision, and must be conducted in a non-discriminatory way. It requires practitioners to understand what is involved in a particular decision, and to understand what aspects of decision-making a person may need support with, and why.
This may mean helping a person with their memory or communication, helping them understand and weigh up the information relevant to a decision, or helping to reduce their distress. Various ways to support decision-making capacity are described in Chapter 3 of the Mental Capacity Act 2005 Code of Practice.
Find out from the person how they want to be supported in decision-making in accordance with principle 2 of the Mental Capacity Act 2005. If they would like someone to support them, find out from the person who needs support who this should be. Be aware of the possibility that the nominated person may be exercising undue influence, duress or coercion regarding the decision, and take advice from a safeguarding lead if there is a concern.
At times, the person being supported may wish to make a decision that appears unwise. As confirmed by the third key principle of the Mental Capacity Act 2005, a person is not to be treated as unable to make a decision merely because he or she makes an unwise decision.
Practitioners supporting a person's decision-making should build and maintain a trusting relationship with the person they are supporting.
Practitioners should take a personalised approach, accounting for any reasonable adjustments and the wide range of factors that can have an impact on a person's ability to make a decision. These should include:
the person's physical and mental health condition
the person's communication needs
the person's previous experience (or lack of experience) in making decisions
the involvement of others and being aware of the possibility that the person may be subject to undue influence, duress or coercion regarding the decision
situational, social and relational factors
cultural, ethnic and religious factors
cognitive (including the person's awareness of their ability to make decisions), emotional and behavioural factors, or those related to symptoms
the effects of prescribed drugs or other substances.They should use this knowledge to develop a shared and personalised understanding of the factors that may help or hinder a person's decision-making, which can be used to identify ways in which the person's decision-making can be supported.
## Providing information to support decision-making
At the start of the decision-making process, practitioners should clearly determine what information they need to cover the salient details of the decision they are supporting the person to make. This will depend on the nature and complexity of the decision itself.
Offer tailored, accessible information to the person being supported. This should be about the process and principles of supported decision-making as well as about the specific decision.
When providing the person with information to support a particular decision:
do so in line with the NHS Accessible Information Standard
support them to identify, express and document their own communication needs
ensure that options are presented in a balanced and non-leading way.
Record the information that is given to the person during decision-making. Give the person an opportunity to review and comment on what is recorded and write down their views.
Consider tailored training programmes for the person, to provide information for specific decisions – for example sexual education programmes and medication management.
## Supporting decision-making
Support people to communicate so that they can take part in decision-making. Use strategies to support the person's understanding and ability to express themselves in accordance with paragraphs 3.10 and 3.11 of the Mental Capacity Act Code of Practice.
Involve significant and trusted people in supporting decision-making, in line with the person's preferences and:
have due regard for the principle of confidentiality set out in paragraph 3.15 of the Mental Capacity Act Code of Practice
ensure that this support is free from coercion or undue influence, for example that it does not undermine the person's ability to understand, retain, use and weigh information and express a choice. If there are no significant trusted people, or no-one willing to take on this role, think about involving an advocate.
Practitioners should be aware of the pros and cons of supporting decision-making and be prepared to discuss these with the person concerned. The benefits could include increased autonomy, being better informed and sharing decisions with people interested in their welfare. However, practitioners should also be aware that talking about potentially upsetting issues including declining health or end of life can be potentially distressing, and a person may feel overwhelmed with having to make a difficult decision at a difficult time and having to deal with possibly conflicting opinions.
Give people time during the decision-making process to communicate their needs and feel listened to. Be aware that this may mean meeting with the person for more than 1 session.
Practitioners should increase the person's involvement in decision-making discussions by using a range of interventions focused on improving supported decision-making.
Where possible and relevant, ensure that the same practitioner provides continuous support to the person as they make different decisions at different points in time.
Health and social care practitioners should refer to other services (for example speech and language therapy, clinical psychology and liaison psychiatry) that could enable the person to make their decision when their level of need requires specialist input. This is especially important:
when the person's needs in relation to decision-making are complex
if the consequences of the decision would be significant (for example a decision about a highly complex treatment that carries significant risk).
Practitioners should make a written record of the decision-making process, which is proportionate to the decision being made. Share the record with the person and, with their consent, other appropriate people. Include:
what the person is being asked to decide
how the person wishes to be supported to make the decision
steps taken to help the person make the decision
-ther people involved in supporting the decision
information given to the person
whether on the balance of probabilities a person lacks capacity to make a decision
key considerations for the person in making the decision
the person's expressed preference and the decision reached
needs identified as a result of the decision
any further actions arising from the decision
any actions not applied and the reasons why not.
Organisations should ensure they can demonstrate compliance with principle 2, section 1(3) of the Mental Capacity Act 2005 by monitoring and auditing:
person-reported outcomes, including the extent to which the person experiences collaboration and empowerment when making important decisions and the extent to which they experience support for their decision-making
practitioner-reported outcomes, including the frequency and quality of steps they have taken to support decision-making
process outcomes, including the frequency and quality of formal recording of steps taken to support decision-making and the use of overt and covert coercion during decision-making.
# Advance care planning
Advance care planning involves helping people to plan for their future care and support needs, including medical treatment, and therefore to exercise their personal autonomy as far as possible. This should be offered to everyone who is at risk of losing capacity (for example through progressive illness), as well as those who have fluctuating capacity (for example through mental illness).
Some approaches involve the production of legally binding advance decisions, which only cover decisions to refuse medical treatment, or the appointment of an attorney. Others, such as joint crisis planning and advance statements, which can include any information a person considers important to their health and care, do not have legal force, but practitioners must consider them carefully when future decisions are being made, and need to be able to justify not adhering to them.
People can initiate advance care planning (such as advance statements) independently, without the input of practitioners. However, in some circumstances, professional input from a clinician with the appropriate expertise may assist a person to consider the matters they wish to address either by way of an advance care plan, an advance refusal of treatment and/or creation of a formal proxy decision-making mechanism such as a Lasting Power of Attorney. Skilled practitioners need to be able to have sensitive conversations with people in the context of a trusting and collaborative relationship, and provide the person with clear and accessible information to help them make these important decisions.
## Helping practitioners to undertake advance care planning
Healthcare commissioners and providers should:
develop standard protocols and plans for joint working and sharing of information on advance care plans between practitioners, people and families
ensure that protocols and plans reflect the optional nature of advance care planning
commission training on advance care planning, including advance decisions to refuse treatment and a Lasting Power of Attorney
demonstrate that protocols are in place and training is available by including advance care planning in audits.
## Providing information about advance care planning
Offer people accessible verbal and written information about advance care planning, including how it relates to their own circumstances and conditions. All information sharing must fulfil the requirements of the NHS Accessible Information Standard.
If a person has recently been diagnosed with a long-term or life-limiting condition, give them information on:
their condition
the process of advance care planning
how they can change their minds or amend the decisions they make while they retain capacity to make them
the impact that a subsequent loss of capacity may have on decisions made
services that will help in advance care planning.
## Developing advance care plans collaboratively
All health and social care practitioners who come into contact with the person after diagnosis should help them to make an informed choice about participating in advance care planning. If the person wishes to engage in advance care planning, enable them to do so.
Offer the person a discussion about advance care planning:
at the most suitable time once they receive a diagnosis likely to make advance care planning useful and
at other times, allowing people to think through and address different issues in their own time.
Practitioners involved in advance care planning should ensure that they have access to information about the person's medical condition that helps them to support the advance care planning process. It is the practitioner's responsibility to identify what information they need.
When approaching discussions about advance care planning, practitioners should:
be sensitive, recognising that some people may prefer not to talk about this, or prefer not to have an advance care plan
be prepared to postpone discussions until a later date, if the person wishes
recognise that people have different needs for knowledge, autonomy and control
talk about the purpose, advantages and challenges of this type of planning
consider the use of checklists to support discussions.
If the person has given consent for carers, family and friends or advocates to be involved in discussions about advance care planning, practitioners should take reasonable steps to include them.
Health and social care practitioners should help everyone to take part in advance care planning and co‑produce their advance care plan if they choose to have one (including people with fluctuating or progressive conditions). They should:
work with the person to identify any barriers to their involvement, and investigate how to overcome these
help them to communicate by providing communication support appropriate to their needs (for example communication aids, advocacy support, interpreters, specialist speech and language therapy support, involvement of family members or friends).
During advance care planning discussions, practitioners should:
take into account the person's history, social circumstances, wishes and feelings, values and beliefs (including religious, cultural and ethnic factors), aspirations and any other factors they may consider important to them
help the person to anticipate how their needs may change in the future.
Practitioners must ensure that all notes made on advance care planning are contemporaneous. In addition:
notes should be agreed with the person at the time and
consent should be sought from the person to share the information with other people as appropriate.
Provide the person with an accessible document that records their wishes, beliefs and preferences in relation to advance care planning and which they may take with them to show different services. It may include who the person wants to have involved in decision-making or their preferences for issues such as treatment, support or accommodation.
Practitioners should share any advance care plans in a clear and simple format with everyone involved in the person's care, if the person has given consent.
Practitioners should ensure that information about a person's advance care plan is, with their consent, transferred between services when their care provider changes.
Review advance care plans at reviews of treatment or support, while the person has capacity, and amend as necessary, if the person wishes.
When people are reaching the end of life, give them the opportunity to review or develop an advance care plan if they haven't already done so.
## Joint crisis planning
Practitioners and individuals may wish to consider the use of advance care planning in the context of joint crisis planning.
Offer joint crisis planning to anyone who has been diagnosed with a mental disorder and has an assessed risk of relapse or deterioration, and anyone who is in contact with specialist mental health services. The offer should be documented and, if the person accepts it, the plan should be recorded.
# Assessment of mental capacity
'A person must be assumed to have capacity unless it is established that he lacks capacity.' (Principle 1, section 1(2), Mental Capacity Act 2005.)
Mental capacity within the meaning of the Mental Capacity Act 2005 involves being able to make a particular decision at the time it needs to be made (section 2 of the Mental Capacity Act 2005, and Chapter 4 of the Mental Capacity Act Code of Practice).
Under the Mental Capacity Act 2005, capacity is decision-specific, and an individual is assumed to have capacity unless, on the balance of probabilities, proven otherwise. The concept of capacity under the Mental Capacity Act 2005 is relevant to many decisions including care, support and treatment, financial matters and day-to-day living. However, the Mental Capacity Act 2005 does not cover all decisions, and there are some decisions that are subject to a separate capacity test.
To lack capacity within the meaning of the Mental Capacity Act 2005, a person must be unable to make a decision because of an impairment or disturbance in the functioning of the mind or brain. That is, the impairment or disturbance must be the reason why the person is unable to make the decision, for the person to lack capacity within the meaning of the Mental Capacity Act 2005. The inability to make a decision must not be due to other factors, for example because of undue influence, coercion or pressure, or feeling overwhelmed by the suddenness and seriousness of a decision.
A lack of capacity cannot be established based merely by reference to the person's condition or behaviour. It can only be established if their condition also prevents them from understanding or retaining information about the decision, using or weighing it, or communicating their decision. It cannot be established unless everything practicable has been done to support the person to have capacity, and it should never be based on the perceived wisdom of the decision the person wishes to make.
Effective assessments are thorough, proportionate to the complexity, importance and urgency of the decision, and performed in the context of a trusting and collaborative relationship.
Health and social care organisations should monitor and audit the quality of mental capacity assessments, taking into account the degree to which they are collaborative, person centred, thorough and aligned with the Mental Capacity Act 2005 and Code of Practice.
Include people's views and experiences in data collected for monitoring an organisation's mental capacity assessment activity.
Organisations should ensure that assessors can seek advice from people with specialist condition-specific knowledge to help them assess whether, on the balance of probabilities, there is evidence that the person lacks capacity – for example clinical psychologists and speech and language therapists.
Organisations with responsibility for care and support plans should record whether a person has capacity to consent to any aspect of the care and support plan.
Organisations should have clear policies or guidance on how to resolve disputes about the outcome of the capacity assessment, including how to inform the person and others affected by the outcome of the assessment.
## Conducting an assessment of mental capacity
Assess mental capacity in line with the process set out in section 2 of the Mental Capacity Act 2005 and section 3 of the Mental Capacity Act 2005.
While the process applies to all decisions that fall within the scope of the Mental Capacity Act 2005, both large and small, the nature of the assessment and the recording of it should be proportionate to the complexity and significance of that decision.
Assessors should have sufficient knowledge of the person being assessed (except in emergencies or where services have had no previous contact with the person) to be able to:
recognise the best time to make the decision
provide tailored information, including information about the consequences of making the decision or of not making the decision
know whether the person would be likely to attach particular importance to any key considerations relating to the decision.
Practitioners should be aware that people can be distressed by having their capacity questioned, particularly if they strongly disagree that there is a reason to doubt their capacity.
In preparing for an assessment, the assessor should be clear about:
the decision to be made
if any inability to make a decision is caused by any impairment of or disturbance in the functioning of the mind or brain in that person
the options available to the person in relation to the decision
what information (the salient factors) the person needs in order to be able to explore their options and make a decision
what the person needs in order to understand, retain, weigh up and use relevant information in relation to this decision, including the use of communication aids
how to allow enough time for the assessment, giving people with communication needs more time if needed
how to introduce the assessment and conduct it in a way that is respectful, collaborative, non-judgmental and preserves the person's dignity
how to make reasonable adjustments including, for example, delaying the assessment until a time when the person feels less anxious or distressed and more able to make the decision
how to ensure that the assessment takes place at a location and in an environment and through a means of communication with which the person is comfortable
how to identify the steps a person is unable to carry out even with all practicable support
whether involving people with whom the person has a trusted relationship would help the assessment.
The assessor should take into account the person's decision-making history when preparing for an assessment, including the extent to which the person felt involved and listened to, the possible outcomes of that assessment, and the nature and outcome of the decisions they reached.
Practitioners must take all reasonable steps to minimise distress and encourage participation.
Where consent has been provided, health and social care practitioners should identify people who could be spoken with in order to inform the capacity assessment. For example, this may include the individual's family or friends.
Practitioners should use accessible language or information in an accessible format to explain to the person:
that their capacity to make a particular decision is being assessed
why their capacity is being assessed
the outcome of that assessment
what they can do if they are unhappy with the outcome.
Health and social care practitioners should take a structured, person-centred, empowering and proportionate approach to assessing a person's capacity to make decisions, including everyday decisions. If the assessment concludes that a person would, with appropriate support, have capacity to make their own decisions, the assessment should establish which elements of the decision-making process the person requires assistance with, in order to identify how decision-making can be supported.
Use of single tools (such as the Mini-Mental State Examination) that are not designed to assess capacity may yield information that is relevant to the assessment, but practitioners should be aware that these should not be used as the basis for assessing capacity.
Health and social care practitioners must take a collaborative approach to assessing capacity, where possible, working with the person to produce a shared understanding of what may help or hinder their communication and decision-making. This may include involving an interpreter, speech and language therapist, someone with sensory or specialist communication skills, clinical psychologists or other professionals to support communication during an assessment of capacity.
Where the person has identified communication needs, the assessor should also think about using communication tools to help with the assessment.
Practitioners should be aware that it may be more difficult to assess capacity in people with executive dysfunction – for example people with traumatic brain injury. Structured assessments of capacity for individuals in this group (for example, by way of interview) may therefore need to be supplemented by real-world observation of the person's functioning and decision-making ability in order to provide the assessor with a complete picture of an individual's decision-making ability. In all cases, it is necessary for the legal test for capacity as set out in section 2 and section 3 of the Mental Capacity Act 2005 to be applied.
If a person refuses to engage in some or all aspects of a capacity assessment, the assessor should try to establish the reasons for this and identify what can be done to help them participate fully. This may involve consulting with others involved in their care and support, reviewing records or giving the person a choice about who else can be involved.
Information gathered from support workers, carers, family and friends and advocates should be used to help create a complete picture of the person's capacity to make a specific decision and act on it.
When assessing capacity, practitioners must take account of the principle enshrined in section 1(4) of the Mental Capacity Act 2005 and not assume that the person lacks capacity because they have made a decision that the practitioner perceives as risky or unwise.
Practitioners should understand that the person has to retain information only for the purposes of making the specific decision in question, and for the period of time necessary to make the decision.
Practitioners should be aware that a person may have decision-making capacity even if they are described as lacking 'insight' into their condition. Capacity and insight are 2 distinct concepts. If a practitioner believes a person's insight/lack of insight is relevant to their assessment of the person's capacity, they must clearly record what they mean by insight/lack of insight in this context and how they believe it affects/does not affect the person's capacity.
## Recording the outcome of the assessment
The assessor should record any differing views on the person's capacity and how the outcome of the assessment addresses or answers those differing views.
If, following the assessment of capacity, the practitioner finds no evidence to displace the assumption of capacity, this should be documented.
If the outcome of the assessment is that the person lacks capacity, the practitioner should clearly document the reasons for this. The documentation should also make clear what impairment/disturbance of the mind or brain has been identified, the reasons why the person is unable to make a decision (with reference to section 3 of the Mental Capacity Act 2005) and the fact that the person's inability to make a decision is a direct consequence of the impairment or disturbance identified.
The person assessing mental capacity should record:
the practicable steps they have taken to help the person make the relevant decision for themselves and any steps taken by other parties involved
whether the person has capacity to make the decision
if the person is assessed as lacking capacity, why the practitioner considers this to be an incapacitous decision as opposed to an unwise decision.
All assessments of mental capacity must be recorded at an appropriate level to the complexity of the specific decision being made at a particular time. This may be as a stand-alone assessment document, contained within the individual's health or social care record or in care and support plans, following local policy. The timescale for review of the assessment should be specified and recorded.
## After the assessment
Provide the person with emotional support and information after the assessment, being aware that the assessment process could cause distress and disempowerment.
# Best interests decision-making
'An act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interests.' (Principle 4, section 1(5), Mental Capacity Act 2005)
When a person does not have capacity to make a decision, all actions and decisions taken by practitioners or their attorney or Court Appointed Deputy must be done or made in the person's best interests. Any advance statements expressing the individual's views about the decision in question should be taken into account and given appropriate weight.
When making a decision under the Mental Capacity Act 2005, a decision maker must be identified. This could be an attorney appointed by the individual or a Court Appointed Deputy with relevant decision-making powers, or the practitioner or team who is responsible for providing a health or social care intervention.
The decision maker is responsible for determining the person's best interests. They must be able to demonstrate they have adhered to all the requirements of section 4 of the Mental Capacity Act 2005 and Chapter 5 of the Mental Capacity Act Code of Practice. Wherever possible, this means helping the person who lacks capacity to be involved in the decision-making process, consulting with their family, carers and Independent Mental Capacity Advocates, and seeking or establishing the person's known wishes, preferences and values, placing these at the heart of the decision-making process where possible.
Depending on the complexity, urgency and importance of the decision, and the extent to which there is agreement or disagreement between an attorney or Court Appointed Deputy and/or other people involved in the person's care, it would be advisable to convene a meeting at which a decision regarding appropriate next steps can be made. This may include considering possible ways of resolving any disputes.
The Mental Capacity Act 2005 excludes some decisions from its remit, for example, those relating to voting and family relationships. It is therefore not possible for best interests decisions to be made in respect of the excluded issues.
## Helping practitioners to deliver best interests decision-making
In line with the Mental Capacity Act 2005, practitioners must conduct a capacity assessment, and a decision must be made and recorded that a person lacks capacity to make the decision in question, before a best interests decision can be made. Except in emergency situations, this assessment must be recorded before the best interests decision is made.
Ensure that everyone involved in the best interests decision-making process knows and agrees who the decision maker is.
As part of the best interests decision-making process, practitioners must take all reasonable steps to help the person to provide their own views on the decision.
Health and social care services must ensure that best interests decisions are being made in line with the Mental Capacity Act 2005.
Health and social care services should:
implement a service-wide process for recording best interests decisions and ensure that staff are aware of this and
have clear systems in place to support practitioners to identify and locate any relevant written statement made by the person when they had capacity, at the earliest possible time.
Health and social care services should have clear systems in place to obtain and record the person's wishes and feelings in relation to a relevant decision, as well as their values and beliefs, or any other factor that would be likely to influence such a decision. Services should:
have mechanisms in place to make these available in a timely way
ensure that the person's personal history and personality is represented in the above.
## Involving family members or other people involved in a person's care in best interests decision-making
Unless it would be contrary to the person's best interests to do so, health and social care practitioners should work with carers, family and friends, advocates, attorneys and deputies, to find out the person's values, feelings, beliefs, wishes and preferences in relation to the specific decision and to understand the person's decision-making history.
In some cases, the views of the interested parties may differ from those of the person or the decision maker. However, this does not necessarily mean it would be contrary to the person's best interests to consult them.
If a decision maker considers it helpful or necessary to convene a meeting with the relevant consultees to assist with the decision-making process, they should:
Involve the person themselves, unless a decision is made that it would be contrary to their best interests for them to attend the meeting. Where this is the case, this decision and the reasons for it should be recorded.
Consult carers, family, friends, advocates and any attorney or deputy about the meeting in advance, giving them time to ask questions and give their opinions, for example about how to include the person in decision-making.
Make it clear that the purpose of the meeting is to assist the decision maker in making a decision in the person's best interests.
Clarify the role of each person attending the meeting, especially the identities of the decision maker and the meeting chair, as these may be different people.
Provide all information in an accessible format.
Practitioners should access information about the person informally if needed, as well as through any formal meetings.
The decision maker should ensure that all people consulted as part of the best interests decision have their views encouraged, respected and heard. This does not mean that the views of consultees should necessarily be followed; the decision maker is ultimately responsible for deciding what course of action would be in the person's best interests.
## Undertaking best interests decision-making
When making a decision on behalf of the person who lacks capacity, practitioners should use a range of approaches, as needed, to ensure that the person's best interests are served. This might include:
a less formalised approach for day-to-day decisions – that is, recurring decisions being recorded in support or care plans
a decision-making approach appropriate to the circumstances and personalised to the individual, making all reasonable adjustments
formal best interests meetings for significant decisions:
if this is the most appropriate way to undertake the required consultation or
if the outcome of the decision is likely to have a serious impact on the person's health or wellbeing or
if there are likely to be conflicting opinions about the person's best interests.
Carers and practitioners must, wherever possible, find out the person's wishes and feelings in order to ensure any best interests decision made reflects those wishes and feelings unless it is not possible/appropriate to do so. Where the best interests decision ultimately made does not accord with the person's wishes and feelings, the reasons for this should be clearly documented and an explanation given. The documentation of the assessment should also make clear what steps have been taken to ascertain the person's wishes and feelings and where it has not been possible to do this, the reasons for this should be explained.
Health and social care organisations should provide toolkits to support staff to carry out and record best interests decisions. These toolkits should include:
how to identify any decision-making instruments that would have an impact on best interests decision-making occurring (for example a Lasting Power of Attorney, advance decisions to refuse treatment, court orders)
when to instruct an Independent Mental Capacity Advocate
a prompt to consult interested parties (for example families, friends, advocates and relevant professionals) and a record of who they are
guidance about recording the best interests process and decision. This may include, for example, a balance sheet, which may assist in documenting the risks and benefits of a particular decision
instructions on what information to record, ensuring this covers:
a clear explanation of the decision to be made
the steps that have been taken to help the person make the decision themselves
a current assessment concluding that the person lacks the capacity to make this decision, evidencing each element of the assessment
a clear record of the person's wishes, feelings, cultural preferences, values and beliefs, including any advance statements
the concrete choices that have been put to the person
the salient details the person needs to understand
the best interests decision made, with reasons.
When making best interests decisions, explore whether there are less restrictive options that will meet the person's needs. Take into account:
what the person would prefer, including their past and present wishes and feelings, based on past conversations, actions, choices, values or known beliefs
what decision the person who lacks capacity would have made if they were able to do so
all the different options
the restrictions and freedoms associated with each option (including possible human rights infringements)
the likely risks associated with each option (including the potential negative effects on the person who lacks capacity to make a decision – for example trauma or disempowerment).
When an Independent Mental Capacity Advocate has been instructed, they should be involved in the process until a decision has been made and implemented fully.
As people's circumstances change, review the decisions regularly to ensure that they remain in a person's best interests.
After the outcome has been decided, the decision maker should ensure that it is recorded and communicated to everyone involved and that there is opportunity for all participants to offer feedback or raise objections.
If there is a dispute about a person's best interests, resolve this, where possible, before the decision is implemented – for example through further meetings or mediation. If a dispute cannot be resolved locally, it may be necessary for the matter to be referred to the Court of Protection for a determination of the person's best interests.
Decision makers should specify a timely review of the implementation of the actions resulting from the best interests decision. If the review establishes that the best interests decision was not successfully actioned, the decision maker should take suitable steps such as:
convening a multi-agency meeting to resolve issues leading to the best interests decision not being successfully implemented or
reassessing and making a new best interests decision that is more achievable or
taking steps to refer the decision to the Court of Protection or
re-considering whether any further action is appropriate.
# Terms used in this guideline
## Advance care planning
Advance care planning with people who may lack mental capacity in the future is a voluntary process of discussion about future care between the person and their care providers. If the person wishes, their family and friends may be included in the discussion. With the person's agreement this discussion is documented, regularly reviewed and communicated to key persons involved in their care.
## Advance decisions to refuse treatment
An advance decision to refuse treatment (sometimes referred to as a living will and sometimes abbreviated to ADRT) is a decision an individual can make when they have capacity to refuse a specific type of treatment, to apply at some time in the future when they have lost capacity. It means that families and health professionals will know the person's decisions about refusing treatment if they are unable to make or communicate the decisions themselves.
An advance decision must be valid and applicable before it can be legally binding. For example, one of the conditions is that the individual is aged 18 or over at the time the decision is made. To establish whether an advance decision to refuse treatment is valid and applicable, practitioners must have regard to sections 24 to 26 of the Mental Capacity Act 2005. If the advance decision purports to refuse life-sustaining treatment, additional requirements apply. (See Chapter 9 of the Mental Capacity Act Code of Practice.)
## Capacitous
Where used in this guideline, the term 'capacitous' is used to reflect the status of someone who has capacity to make decisions regarding their care and treatment – that is, those matters to which the Mental Capacity Act 2005 applies. This could be someone for whom there is no evidence to suggest the presumption of capacity should be displaced, or someone whose capacity to make decisions regarding their care and treatment has been formally assessed and who has been found to have capacity to make those decisions.
## Contemporaneous
This is being used to describe how, during advance care planning, the practitioner should take notes of the discussions and decisions reached at the same time as those discussions are taking place.
## Consent
The voluntary and continuing permission of the person to receive particular treatment or care and support, based on an adequate knowledge of the purpose, nature, likely effects and risks including the likelihood of success, any alternatives to it and what will happen if the treatment does not go ahead. Permission given under any unfair or undue pressure is not consent. By definition, a person who lacks capacity to consent cannot consent to treatment or care and support, even if they cooperate with the treatment or actively seek it.
## Court Appointed Deputy
A person appointed by the Court of Protection who is authorised to make decisions (relating to the person's health, welfare, property or financial affairs) on behalf of someone who lacks mental capacity and who cannot make a decision for themselves at the time it needs to be made.
## Executive dysfunction
The completion of tasks that involve several steps or decisions normally involves the operation of mental processes known as 'executive functions'. If these executive functions do not develop normally, or are damaged by brain injury or illness, this can cause something called 'executive dysfunction'. This involves a range of difficulties in everyday planning and decision-making, which can be sometimes hard to detect using standard clinical tests and assessments.
## Independent advocacy
Independent advocates can have a role in promoting social inclusion, equality and social justice and can provide a safeguard against the abuse of vulnerable people. Independent advocates take action to act to help people say what they want, secure their rights, represent their interests and obtain the services they need. Together with their provider organisations they work in partnership with the people they support and speak out on their behalf.
## Joint crisis planning
A joint crisis plan enables the person and services to learn from experience and make plans about what to do in the event of another crisis. It is developed by seeking agreement between the person who may lack mental capacity now or in future and their mental health team about what to do if they become unwell in the future. When the person lacks capacity to make decisions regarding their care and treatment and is unlikely to gain or regain capacity, a joint crisis plan about what to do in the event of a future crisis may be developed through a best interests decision-making process. A joint crisis plan does not have the same legal status as an advance decision to refuse treatment.
## Lasting Power of Attorney
A legal instrument that allows a person (the 'donor') to appoint one or more people (known as 'attorneys') to make decisions on their behalf. There are 2 types: health and welfare, and property and financial affairs, and either one or both of these can be made. To have legal force, lasting powers of attorney must be created in accordance with section 9 and section 10 of the Mental Capacity Act 2005. The attorney must have regard to section 4 of the Mental Capacity Act 2005, the Mental Capacity Act Code of Practice, and must make decisions in the best interests of the person.
## Mental Capacity Act 2005
The Mental Capacity Act 2005 is designed to protect and empower people who may lack capacity to make their own decisions about their care and treatment. It is a law that applies to people aged 16 and over in England and Wales and provides a framework for decision-making for people unable to make some or all decisions for themselves.
## Mental Health Act 1983
The Mental Health Act 1983 provides for the detention of persons in hospital for assessment and/or treatment of mental disorder and for treatment in the community in some circumstances. The Act provides for the process of assessing individuals and bringing them within the scope of the Act, for treatment of individuals subject to the Act's provisions and sets out the rights and safeguards afforded to individuals who are subject to the Act's powers.
## Practicable steps
'Practicable steps' links to principle 2 of the Mental Capacity Act (and Chapter 3 of the Mental Capacity Act Code of Practice), which states that 'all practicable steps' should be taken to help a person make a decision before being treated as though they are unable to make the decision. There are obvious steps a person might take, proportionate to the urgency, type and importance of the decision including the use of specific types of communication equipment or types of languages such as Makaton or the use of specialist services, such as a speech and language therapist or clinical psychologist. Practicable steps could also involve ensuring the best environment in which people are expected to make often life-changing decisions – for example giving them privacy and peace and quiet, or ensuring they have a family member or other trusted person to provide support during decision-making, if this is their wish.
## Salient factors
Section 3(1) of the Mental Capacity Act 2005 makes clear that a person will be unable to make a decision for themselves if they are unable to understand the information relevant to the decision. Case law has confirmed that the information to be provided to the person regarding the decision does not have to include every single detail relating to the decision, but must include the 'salient factors'. The salient factors are those which are most important to the decision to be made. This would include information that is subjectively important to the person being assessed (for example information relating to the likely level of disability a person would have if they did/did not undergo the treatment in question) and also key pieces of objective/factual information relevant to the decision to be made (for example the side effects of a particular treatment, or the known complications or survival rates of a particular surgical procedure). The seriousness of the decision, and the timeframe within which it must be made, will impact on the nature and amount of information that will need to be provided to the person.
For other social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Training and support for practitioners
What is the effectiveness and cost effectiveness of different training programmes on the Mental Capacity Act 2005 at improving practice for practitioners involved in supporting decision-making, conducting capacity assessments and making best interests decisions?
## Why this is important
The guideline committee agreed that effective training and support on the Mental Capacity Act 2005 and how to apply its principles in practice is essential for practitioners working with people who may lack capacity to make a decision. The evidence the committee reviewed often referred to training and support, but very few studies looked at this area specifically. Some of the evidence suggested that practitioners did not always understand the requirements of the Act and that their practice did not always comply with these. Much of the evidence was of low to moderate quality and there was no good-quality evidence evaluating the effectiveness of training and support in relation to the Act.
A better understanding of what training and support increases compliance with the Act could improve outcomes for people who may lack capacity to make a decision. Qualitative studies exploring the current barriers to delivering effective training and support and the challenges that practitioners face in using this learning in practice would help to inform measures for improvement.
Comparative studies are needed to determine the effectiveness and cost effectiveness of different approaches for delivering training and support to practitioners. Evaluating whether these increase compliance with the requirements of the Act would be especially informative.
# Targeted interventions to support and improve decision-making capacity for treatment
What is the effectiveness and cost effectiveness of different targeted interventions (speech and language therapy and psychological and psychosocial interventions) to support and improve decision-making capacity for treatment in specific groups?
## Why this is important
Evidence suggests that tailored approaches such as speech and language therapy and psychological and psychosocial interventions can lead to improvements in a person's capacity to make a decision. However, the studies were limited in number and generally of low quality. The guideline committee agreed that further research in this area would be valuable, particularly in relation to the decision-making capacity for treatment of people with dementia, a learning disability, an acquired brain injury or a mental illness. Interventions should be designed to address the needs of those cohorts, should take into account the natural course of capacity (whether stable or fluctuating) and should be underpinned by a comprehensive understanding of the needs associated with each condition.
High-quality comparative studies evaluating the effectiveness of these different types of interventions (including participant experience of the interventions) are needed to help ensure that practitioners refer people to the most appropriate programmes. This would empower people to make their own decisions about their treatment wherever possible.
# Advocacy and support for decision-making
What is the effectiveness, cost effectiveness and acceptability of advocacy as a means of supporting people to make decisions?
## Why this is important
The evidence reviewed did not include any studies that evaluated the effectiveness or acceptability of advocacy as a means of supporting people to make decisions. However, the guideline committee thought that this was an area in which emerging practice shows promise. Expert witness testimony highlighting the Swedish 'Personal Ombudsman' peer support scheme also suggested that further research into the use of advocacy as a means of supporting decision-making might be useful. Although provision for advocacy already exists for people assessed as lacking capacity to make a decision (through an Independent Mental Capacity Advocate), this type of support could also benefit people who, although retaining capacity, may need support to make a decision.
High-quality mixed methods studies with a controlled effectiveness component (preferably randomised) are needed to evaluate the effectiveness and cost effectiveness of advocacy as a tool to support the decision-making of people who may need support to make a decision. The effectiveness component will ideally include 3 arms: usual care, usual care plus advocacy, and usual care plus support with enhanced advocacy. Studies should also include a qualitative component that explores whether advocacy as a means of support to make decisions is acceptable to people using services and valued by practitioners.
# Using mental capacity assessment tools to assess capacity
What is the accuracy and/or effectiveness, cost effectiveness and acceptability of mental capacity assessment tools that are compliant with the Mental Capacity Act 2005?
## Why this is important
There is a lack of evidence from the UK on the effectiveness and acceptability of approaches to capacity assessment that are in line with the meaning of mental capacity as outlined in the Mental Capacity Act 2005. Although the guideline committee reviewed some evidence evaluating the accuracy of specific tools, these are not necessarily compatible with the definition of mental capacity.
There is a need for high-quality mixed methods studies that evaluate the accuracy or effectiveness of mental capacity assessment tools that are compliant with the Act. The controlled effectiveness component will ideally include 3 arms: usual care, usual care plus mental capacity assessment tools, and usual care plus support with enhanced assessment tools. Studies should also include a qualitative component that explores whether such tools and approaches are acceptable to people using services and valued by practitioners.
# Components of a mental capacity assessment
What are the components of an effective assessment of mental capacity to make a decision (for example checklists, memory aids or standardised documentation)?
## Why this is important
Although the Mental Capacity Act Code of Practice provides some fundamental guidance on conducting and recording capacity assessments, there is a lack of clarity about the way in which practitioners actually conduct assessments of capacity to make a decision and how the process and outcomes of these assessments are being recorded. The guideline committee reviewed the small amount of available evidence suggesting that practice may be improved through the use of standardised forms. However, these studies tended to be poorly designed – for example, relying on audit data.
There is a need for high-quality research that explores in detail how to conduct an effective capacity assessment. This could include studies comparing one‑off capacity assessments with multiple assessments, and comparative studies evaluating whether certain approaches or tools are appropriate.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Ensuring a greater focus on supported decision-making. Underpinned by principles 1 and 2 of the Mental Capacity Act 2005, supported decision-making is fundamental to:
effective implementation of the legislation
empowering people who have difficulties making their own decisions independently. Alongside local policies and training, organisations need to ensure that their procedures and forms for capacity and best interests assessments are congruent with an emphasis on supported decision-making.
Ensuring a workforce that is well-trained and well-developed in supporting decision-making and in implementing the Act. Practitioners need to understand the status of the person's decision-making capacity at that specific point in time and how their particular impairment of the mind or brain affects their current ability to make decisions. Training should be delivered with input from people who use services. It should start with basic training and continue throughout an individual's employment, particularly whenever legislation is updated.
Access to independent advocacy. This is affected by a range of factors, including:
a shortage of well-trained advocates
practitioner knowledge of the different types of advocacy
practitioners being unaware of the duty to refer for advocacy
advocacy services being under-resourced and in high demand.Additionally, there is consistent evidence of a lack of understanding among commissioners, public bodies, practitioners and people who use services of the critical role that independent advocacy can play in upholding rights and providing an ultimate safeguard from abuse. Consequently, ensuring the recommendations relating to independent advocacy are acted on will be a challenge of communication and persuasion beyond statutory requirements, and they will require a concerted effort to implement effectively.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.
|
{'Context': "The Care Quality Commission (CQC) estimates that around 2\xa0million people in England and Wales may lack the capacity to make certain decisions for themselves at some point because of illness, injury or disability. The Mental Capacity Act\xa02005 was designed to empower and protect individuals in these circumstances. However, the CQC identified serious issues with the practical implementation of the Act. This subject was subsequently reported on by a House of Lords Select Committee in\xa02014, adding further momentum towards the need for improvement in practice.\n\nIt is in this context that the Department of Health commissioned this guideline, which makes recommendations for best practice in assessing and supporting people aged 16\xa0years and older with decision-making activities. It helps to ensure that people are supported to make decisions for themselves when they have the mental capacity to do so, and where they lack the mental capacity to make specific decisions, they remain at the centre of the decision-making process. The guideline supports the empowering ethos and principles introduced by the Mental Capacity Act\xa02005 and explained in the Mental Capacity Act Code of Practice. These are:\n\n. A person must be assumed to have capacity unless it is established that he lacks capacity.\n\n. A person is not to be treated as unable to make a decision unless all practicable steps to help him to do so have been taken without success.\n\n. A person is not to be treated as unable to make a decision merely because he makes an unwise decision.\n\n. An act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interests.\n\n. Before the act is done, or the decision is made, regard must be had to whether the purpose for which it is needed can be as effectively achieved in a way that is less restrictive of the person's rights and freedom of action.\n\nThe guideline helps health and social care practitioners to implement these principles and improve the quality of the decision-making support they provide. It applies to a range of decisions, including care, support and treatment, financial matters and day-to-day living, and aims to be proportionate, recognising that practitioners may need to provide rapid assistance in emergencies.\n\nThe guideline is based on the best available evidence from research, expert testimony, expert consensus and developments in law. It also identifies where evidence is lacking and makes recommendations for future research. The recommendations for research address the following: training and support for practitioners, interventions to support and improve decision-making capacity for treatment, advocacy and support for decision-making, mental capacity assessment tools, and the components of a mental capacity assessment.\n\nThe guideline applies to, and reinforces, the assessment, support and exercise of capacity whenever this is required by legislation, including but not confined to the Mental Capacity Act\xa02005, Mental Health Act\xa01983 and Care Act\xa02014. Practitioners should use the guideline to enhance the specific requirements of such legislation, codes of practice and other guidance relevant to their work. The guideline does not seek to repeat these, or be a step-by-step guide to their implementation.\n\nDecision-making and mental capacity can be a particularly complex area for young people aged 16–18\xa0years. A detailed overview of the legal provisions relating to the care and treatment of young people falls outside the scope of this guideline. However, the Children Act\xa01989 and Children and Families Act\xa02014 interface with the other Acts referred to above and in some circumstances provide an additional framework for the way in which young people should be involved in decision-making about their lives.\n\nWhere a young person over\xa016 is found to lack capacity to make a particular decision, it is important that the best interests process under the Mental Capacity Act\xa02005 is followed and that young people are as involved as possible in decisions made on their behalf.\n\nIn some cases, it will be possible for someone with parental responsibility to make a decision on behalf of the young person who lacks capacity. However, this will not always be appropriate. In these circumstances, the Mental Capacity Act Code of Practice should be followed to determine who should lead the best interests process.\n\nEffective safeguarding identification and processes must always be followed, with acute awareness necessary among practitioners about the more subtle forms of abuse such as coercion. Practitioners must always refer to local safeguarding procedures.\n\nThe guideline focuses on the following key areas:\n\nadvance care planning\n\nsupporting decision-making\n\nassessment of mental capacity to make specific decisions at a particular time\n\nbest interests decision-making for individuals who are assessed as lacking capacity to make a particular decision at a particular time.\n\nThe structure of the guideline is as follows:\n\nSection 1.1 overarching principles\n\nSection 1.2 supporting decision-making\n\nSection 1.3 advance care planning\n\nSection 1.4 assessment of mental capacity\n\nSection 1.5 best interests decision-making.\n\nSections 1.2, 1.4 and\xa01.5 each begin by citing the relevant principle from the Mental Capacity Act\xa02005 along with an explanatory note about the practical application of the principle. This helps to ensure that the recommendations are interpreted within the framework of the Mental Capacity Act and Code of Practice.\n\nThe guideline does not cover:\n\ndecision-making activities and support for children under 16\xa0years\n\nthe issue of deprivation of liberty and the Deprivation of Liberty Safeguards processes.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Overarching principles\n\n## Recommendations for service providers and commissioners\n\nService providers and commissioners should ensure that practitioners undergo training to help them to apply the Mental Capacity Act\xa02005 and its Code of Practice. Training should be tailored to the role and responsibilities of the practitioner and cover new staff, pre‑registration, and continuing development and practice supervision for existing staff. Where appropriate, training should be interdisciplinary, involve experts by experience and include:\n\nthe statutory principles of the Mental Capacity Act\xa02005\n\nthe importance of seeking consent, and how to proceed if a person might lack capacity to give or refuse their consent to any proposed intervention\n\nhow and when to have potentially difficult conversations about loss of autonomy, advance care planning or death\n\nrequired communication skills for building trust and working with people who may lack capacity\n\nclarity on roles and responsibilities\n\nthe advantages, challenges and ethics of advance care planning, and how to discuss these with the person and their carers, family and friends\n\nthe processes and law surrounding advance decisions to refuse treatment and lasting powers of attorney/court appointed deputies\n\ncondition-specific knowledge related to advance care planning, where appropriate\n\nthe conduct of decision- and time-specific capacity assessments\n\nthe process of best interests decision-making in the context of section\xa04 of the Mental Capacity Act 2005 and associated guidance\n\nthe role of Independent Mental Capacity Advocates in best interests decision-making\n\nhow to direct people to sources of advice and information.\n\nAll health and social care organisations should:\n\ndevelop local policy and guidance about which interventions, tools and approaches will be used to support decision-making\n\nidentify or devise specific tools to help health and social care practitioners assess where appropriate and necessary the mental capacity of the people they are working with and audit the tools against adherence to the Mental Capacity Act Code of Practice\n\ntrain relevant practitioners in the use of these tools.\n\nCo-develop policies and Mental Capacity Act\xa02005 training programmes with people who have experience of supported decision-making and of having their mental capacity assessed, and their carers, family and friends.\n\n## Recommendations for individual practitioners\n\nPractitioners involved in making decisions regarding individuals who lack capacity or supporting decision-making in individuals who have capacity must follow the 5\xa0key principles set out in section\xa01 of the Mental Capacity Act 2005. As a starting point they must assume capacity unless there is evidence to suggest an assessment is required.\n\nWhen giving information about a decision to the person:\n\nit must be accessible, relevant and tailored to their specific needs\n\nit should be sufficient to allow the person to make an informed choice about the specific decision in question\n\nit should be supported by tools such as visual materials, visual aids, communication aids and hearing aids, as appropriate.\n\nRecord and update information about people's past and present wishes, beliefs and preferences in a way that practitioners from multiple areas (for example care and support staff, paramedics) can access and update. This information should be used to inform advance planning, supported decision-making and best interests decision-making.\n\n## Using advocacy to support decision-making and assessment under the Mental Capacity Act\n\nPractitioners should tell people about advocacy services as a potential source of support for decision-making, including:\n\nenabling them to make their own key decisions, for example, about their personal welfare, medical treatment, property or affairs\n\nfacilitating their involvement in decisions that may be made, or are being made under the Mental Capacity Act\xa02005.\n\nAs a minimum, independent advocacy must be offered by local authorities as described in the Care Act\xa02014, Mental Capacity Act\xa02005 and Mental Health Act\xa02007. This recommendation is adapted from the NICE guideline on learning disabilities and behaviour that challenges: service design and delivery.\n\nConsider expanding the commissioning of statutory Independent Mental Capacity Advocates.\n\nCommissioners, public bodies and providers of statutory advocacy services should work closely to ensure that:\n\nstatutory duties on public bodies to refer to and involve advocacy are consistently adhered to and monitored and\n\nfailures in the duty to refer to statutory advocacy are addressed.\n\nRelevant commissioners and providers should work with public bodies and providers to increase investment in training for statutory independent mental capacity and other statutory advocates in key areas, in order to ensure they are able to support:\n\npeople who have communication difficulties and\n\nIndependent Mental Capacity Advocates to have expertise in specific areas that require additional skills and knowledge – for example working with people with impaired executive function arising from acquired brain injury, mental illness, dementia or other illness.\n\n# Supporting decision-making\n\n'A person is not to be treated as unable to make a decision unless all practicable steps to help him do so have been taken without success.' (Principle\xa02, section\xa01(3), Mental Capacity Act\xa02005)\n\nPrinciple\xa02 of the Mental Capacity Act\xa02005 requires practitioners to help a person make their own decision, before deciding that they are unable to make a decision. Supporting decision-making capacity effectively requires a collaborative and trusting relationship between the practitioner and the person. It does not involve trying to persuade or coerce a person into making a particular decision, and must be conducted in a non-discriminatory way. It requires practitioners to understand what is involved in a particular decision, and to understand what aspects of decision-making a person may need support with, and why.\n\nThis may mean helping a person with their memory or communication, helping them understand and weigh up the information relevant to a decision, or helping to reduce their distress. Various ways to support decision-making capacity are described in Chapter\xa03 of the Mental Capacity Act 2005 Code of Practice.\n\nFind out from the person how they want to be supported in decision-making in accordance with principle\xa02 of the Mental Capacity Act\xa02005. If they would like someone to support them, find out from the person who needs support who this should be. Be aware of the possibility that the nominated person may be exercising undue influence, duress or coercion regarding the decision, and take advice from a safeguarding lead if there is a concern.\n\nAt times, the person being supported may wish to make a decision that appears unwise. As confirmed by the third key principle of the Mental Capacity Act\xa02005, a person is not to be treated as unable to make a decision merely because he or she makes an unwise decision.\n\nPractitioners supporting a person's decision-making should build and maintain a trusting relationship with the person they are supporting.\n\nPractitioners should take a personalised approach, accounting for any reasonable adjustments and the wide range of factors that can have an impact on a person's ability to make a decision. These should include:\n\nthe person's physical and mental health condition\n\nthe person's communication needs\n\nthe person's previous experience (or lack of experience) in making decisions\n\nthe involvement of others and being aware of the possibility that the person may be subject to undue influence, duress or coercion regarding the decision\n\nsituational, social and relational factors\n\ncultural, ethnic and religious factors\n\ncognitive (including the person's awareness of their ability to make decisions), emotional and behavioural factors, or those related to symptoms\n\nthe effects of prescribed drugs or other substances.They should use this knowledge to develop a shared and personalised understanding of the factors that may help or hinder a person's decision-making, which can be used to identify ways in which the person's decision-making can be supported.\n\n## Providing information to support decision-making\n\nAt the start of the decision-making process, practitioners should clearly determine what information they need to cover the salient details of the decision they are supporting the person to make. This will depend on the nature and complexity of the decision itself.\n\nOffer tailored, accessible information to the person being supported. This should be about the process and principles of supported decision-making as well as about the specific decision.\n\nWhen providing the person with information to support a particular decision:\n\ndo so in line with the NHS Accessible Information Standard\n\nsupport them to identify, express and document their own communication needs\n\nensure that options are presented in a balanced and non-leading way.\n\nRecord the information that is given to the person during decision-making. Give the person an opportunity to review and comment on what is recorded and write down their views.\n\nConsider tailored training programmes for the person, to provide information for specific decisions – for example sexual education programmes and medication management.\n\n## Supporting decision-making\n\nSupport people to communicate so that they can take part in decision-making. Use strategies to support the person's understanding and ability to express themselves in accordance with paragraphs\xa03.10 and\xa03.11 of the Mental Capacity Act Code of Practice.\n\nInvolve significant and trusted people in supporting decision-making, in line with the person's preferences and:\n\nhave due regard for the principle of confidentiality set out in paragraph\xa03.15 of the Mental Capacity Act Code of Practice\n\nensure that this support is free from coercion or undue influence, for example that it does not undermine the person's ability to understand, retain, use and weigh information and express a choice. If there are no significant trusted people, or no-one willing to take on this role, think about involving an advocate.\n\nPractitioners should be aware of the pros and cons of supporting decision-making and be prepared to discuss these with the person concerned. The benefits could include increased autonomy, being better informed and sharing decisions with people interested in their welfare. However, practitioners should also be aware that talking about potentially upsetting issues including declining health or end of life can be potentially distressing, and a person may feel overwhelmed with having to make a difficult decision at a difficult time and having to deal with possibly conflicting opinions.\n\nGive people time during the decision-making process to communicate their needs and feel listened to. Be aware that this may mean meeting with the person for more than 1\xa0session.\n\nPractitioners should increase the person's involvement in decision-making discussions by using a range of interventions focused on improving supported decision-making.\n\nWhere possible and relevant, ensure that the same practitioner provides continuous support to the person as they make different decisions at different points in time.\n\nHealth and social care practitioners should refer to other services (for example speech and language therapy, clinical psychology and liaison psychiatry) that could enable the person to make their decision when their level of need requires specialist input. This is especially important:\n\nwhen the person's needs in relation to decision-making are complex\n\nif the consequences of the decision would be significant (for example a decision about a highly complex treatment that carries significant risk).\n\nPractitioners should make a written record of the decision-making process, which is proportionate to the decision being made. Share the record with the person and, with their consent, other appropriate people. Include:\n\nwhat the person is being asked to decide\n\nhow the person wishes to be supported to make the decision\n\nsteps taken to help the person make the decision\n\nother people involved in supporting the decision\n\ninformation given to the person\n\nwhether on the balance of probabilities a person lacks capacity to make a decision\n\nkey considerations for the person in making the decision\n\nthe person's expressed preference and the decision reached\n\nneeds identified as a result of the decision\n\nany further actions arising from the decision\n\nany actions not applied and the reasons why not.\n\nOrganisations should ensure they can demonstrate compliance with principle\xa02, section\xa01(3) of the Mental Capacity Act 2005 by monitoring and auditing:\n\nperson-reported outcomes, including the extent to which the person experiences collaboration and empowerment when making important decisions and the extent to which they experience support for their decision-making\n\npractitioner-reported outcomes, including the frequency and quality of steps they have taken to support decision-making\n\nprocess outcomes, including the frequency and quality of formal recording of steps taken to support decision-making and the use of overt and covert coercion during decision-making.\n\n# Advance care planning\n\nAdvance care planning involves helping people to plan for their future care and support needs, including medical treatment, and therefore to exercise their personal autonomy as far as possible. This should be offered to everyone who is at risk of losing capacity (for example through progressive illness), as well as those who have fluctuating capacity (for example through mental illness).\n\nSome approaches involve the production of legally binding advance decisions, which only cover decisions to refuse medical treatment, or the appointment of an attorney. Others, such as joint crisis planning and advance statements, which can include any information a person considers important to their health and care, do not have legal force, but practitioners must consider them carefully when future decisions are being made, and need to be able to justify not adhering to them.\n\nPeople can initiate advance care planning (such as advance statements) independently, without the input of practitioners. However, in some circumstances, professional input from a clinician with the appropriate expertise may assist a person to consider the matters they wish to address either by way of an advance care plan, an advance refusal of treatment and/or creation of a formal proxy decision-making mechanism such as a Lasting Power of Attorney. Skilled practitioners need to be able to have sensitive conversations with people in the context of a trusting and collaborative relationship, and provide the person with clear and accessible information to help them make these important decisions.\n\n## Helping practitioners to undertake advance care planning\n\nHealthcare commissioners and providers should:\n\ndevelop standard protocols and plans for joint working and sharing of information on advance care plans between practitioners, people and families\n\nensure that protocols and plans reflect the optional nature of advance care planning\n\ncommission training on advance care planning, including advance decisions to refuse treatment and a Lasting Power of Attorney\n\ndemonstrate that protocols are in place and training is available by including advance care planning in audits.\n\n## Providing information about advance care planning\n\nOffer people accessible verbal and written information about advance care planning, including how it relates to their own circumstances and conditions. All information sharing must fulfil the requirements of the NHS Accessible Information Standard.\n\nIf a person has recently been diagnosed with a long-term or life-limiting condition, give them information on:\n\ntheir condition\n\nthe process of advance care planning\n\nhow they can change their minds or amend the decisions they make while they retain capacity to make them\n\nthe impact that a subsequent loss of capacity may have on decisions made\n\nservices that will help in advance care planning.\n\n## Developing advance care plans collaboratively\n\nAll health and social care practitioners who come into contact with the person after diagnosis should help them to make an informed choice about participating in advance care planning. If the person wishes to engage in advance care planning, enable them to do so.\n\nOffer the person a discussion about advance care planning:\n\nat the most suitable time once they receive a diagnosis likely to make advance care planning useful and\n\nat other times, allowing people to think through and address different issues in their own time.\n\nPractitioners involved in advance care planning should ensure that they have access to information about the person's medical condition that helps them to support the advance care planning process. It is the practitioner's responsibility to identify what information they need.\n\nWhen approaching discussions about advance care planning, practitioners should:\n\nbe sensitive, recognising that some people may prefer not to talk about this, or prefer not to have an advance care plan\n\nbe prepared to postpone discussions until a later date, if the person wishes\n\nrecognise that people have different needs for knowledge, autonomy and control\n\ntalk about the purpose, advantages and challenges of this type of planning\n\nconsider the use of checklists to support discussions.\n\nIf the person has given consent for carers, family and friends or advocates to be involved in discussions about advance care planning, practitioners should take reasonable steps to include them.\n\nHealth and social care practitioners should help everyone to take part in advance care planning and co‑produce their advance care plan if they choose to have one (including people with fluctuating or progressive conditions). They should:\n\nwork with the person to identify any barriers to their involvement, and investigate how to overcome these\n\nhelp them to communicate by providing communication support appropriate to their needs (for example communication aids, advocacy support, interpreters, specialist speech and language therapy support, involvement of family members or friends).\n\nDuring advance care planning discussions, practitioners should:\n\ntake into account the person's history, social circumstances, wishes and feelings, values and beliefs (including religious, cultural and ethnic factors), aspirations and any other factors they may consider important to them\n\nhelp the person to anticipate how their needs may change in the future.\n\nPractitioners must ensure that all notes made on advance care planning are contemporaneous. In addition:\n\nnotes should be agreed with the person at the time and\n\nconsent should be sought from the person to share the information with other people as appropriate.\n\nProvide the person with an accessible document that records their wishes, beliefs and preferences in relation to advance care planning and which they may take with them to show different services. It may include who the person wants to have involved in decision-making or their preferences for issues such as treatment, support or accommodation.\n\nPractitioners should share any advance care plans in a clear and simple format with everyone involved in the person's care, if the person has given consent.\n\nPractitioners should ensure that information about a person's advance care plan is, with their consent, transferred between services when their care provider changes.\n\nReview advance care plans at reviews of treatment or support, while the person has capacity, and amend as necessary, if the person wishes.\n\nWhen people are reaching the end of life, give them the opportunity to review or develop an advance care plan if they haven't already done so.\n\n## Joint crisis planning\n\nPractitioners and individuals may wish to consider the use of advance care planning in the context of joint crisis planning.\n\nOffer joint crisis planning to anyone who has been diagnosed with a mental disorder and has an assessed risk of relapse or deterioration, and anyone who is in contact with specialist mental health services. The offer should be documented and, if the person accepts it, the plan should be recorded.\n\n# Assessment of mental capacity\n\n'A person must be assumed to have capacity unless it is established that he lacks capacity.' (Principle\xa01, section\xa01(2), Mental Capacity Act 2005.)\n\nMental capacity within the meaning of the Mental Capacity Act\xa02005 involves being able to make a particular decision at the time it needs to be made (section\xa02 of the Mental Capacity Act\xa02005, and Chapter\xa04 of the Mental Capacity Act Code of Practice).\n\nUnder the Mental Capacity Act\xa02005, capacity is decision-specific, and an individual is assumed to have capacity unless, on the balance of probabilities, proven otherwise. The concept of capacity under the Mental Capacity Act\xa02005 is relevant to many decisions including care, support and treatment, financial matters and day-to-day living. However, the Mental Capacity Act\xa02005 does not cover all decisions, and there are some decisions that are subject to a separate capacity test.\n\nTo lack capacity within the meaning of the Mental Capacity Act\xa02005, a person must be unable to make a decision because of an impairment or disturbance in the functioning of the mind or brain. That is, the impairment or disturbance must be the reason why the person is unable to make the decision, for the person to lack capacity within the meaning of the Mental Capacity Act\xa02005. The inability to make a decision must not be due to other factors, for example because of undue influence, coercion or pressure, or feeling overwhelmed by the suddenness and seriousness of a decision.\n\nA lack of capacity cannot be established based merely by reference to the person's condition or behaviour. It can only be established if their condition also prevents them from understanding or retaining information about the decision, using or weighing it, or communicating their decision. It cannot be established unless everything practicable has been done to support the person to have capacity, and it should never be based on the perceived wisdom of the decision the person wishes to make.\n\nEffective assessments are thorough, proportionate to the complexity, importance and urgency of the decision, and performed in the context of a trusting and collaborative relationship.\n\nHealth and social care organisations should monitor and audit the quality of mental capacity assessments, taking into account the degree to which they are collaborative, person centred, thorough and aligned with the Mental Capacity Act\xa02005 and Code of Practice.\n\nInclude people's views and experiences in data collected for monitoring an organisation's mental capacity assessment activity.\n\nOrganisations should ensure that assessors can seek advice from people with specialist condition-specific knowledge to help them assess whether, on the balance of probabilities, there is evidence that the person lacks capacity – for example clinical psychologists and speech and language therapists.\n\nOrganisations with responsibility for care and support plans should record whether a person has capacity to consent to any aspect of the care and support plan.\n\nOrganisations should have clear policies or guidance on how to resolve disputes about the outcome of the capacity assessment, including how to inform the person and others affected by the outcome of the assessment.\n\n## Conducting an assessment of mental capacity\n\nAssess mental capacity in line with the process set out in section\xa02 of the Mental Capacity Act 2005 and section\xa03 of the Mental Capacity Act 2005.\n\nWhile the process applies to all decisions that fall within the scope of the Mental Capacity Act\xa02005, both large and small, the nature of the assessment and the recording of it should be proportionate to the complexity and significance of that decision.\n\nAssessors should have sufficient knowledge of the person being assessed (except in emergencies or where services have had no previous contact with the person) to be able to:\n\nrecognise the best time to make the decision\n\nprovide tailored information, including information about the consequences of making the decision or of not making the decision\n\nknow whether the person would be likely to attach particular importance to any key considerations relating to the decision.\n\nPractitioners should be aware that people can be distressed by having their capacity questioned, particularly if they strongly disagree that there is a reason to doubt their capacity.\n\nIn preparing for an assessment, the assessor should be clear about:\n\nthe decision to be made\n\nif any inability to make a decision is caused by any impairment of or disturbance in the functioning of the mind or brain in that person\n\nthe options available to the person in relation to the decision\n\nwhat information (the salient factors) the person needs in order to be able to explore their options and make a decision\n\nwhat the person needs in order to understand, retain, weigh up and use relevant information in relation to this decision, including the use of communication aids\n\nhow to allow enough time for the assessment, giving people with communication needs more time if needed\n\nhow to introduce the assessment and conduct it in a way that is respectful, collaborative, non-judgmental and preserves the person's dignity\n\nhow to make reasonable adjustments including, for example, delaying the assessment until a time when the person feels less anxious or distressed and more able to make the decision\n\nhow to ensure that the assessment takes place at a location and in an environment and through a means of communication with which the person is comfortable\n\nhow to identify the steps a person is unable to carry out even with all practicable support\n\nwhether involving people with whom the person has a trusted relationship would help the assessment.\n\nThe assessor should take into account the person's decision-making history when preparing for an assessment, including the extent to which the person felt involved and listened to, the possible outcomes of that assessment, and the nature and outcome of the decisions they reached.\n\nPractitioners must take all reasonable steps to minimise distress and encourage participation.\n\nWhere consent has been provided, health and social care practitioners should identify people who could be spoken with in order to inform the capacity assessment. For example, this may include the individual's family or friends.\n\nPractitioners should use accessible language or information in an accessible format to explain to the person:\n\nthat their capacity to make a particular decision is being assessed\n\nwhy their capacity is being assessed\n\nthe outcome of that assessment\n\nwhat they can do if they are unhappy with the outcome.\n\nHealth and social care practitioners should take a structured, person-centred, empowering and proportionate approach to assessing a person's capacity to make decisions, including everyday decisions. If the assessment concludes that a person would, with appropriate support, have capacity to make their own decisions, the assessment should establish which elements of the decision-making process the person requires assistance with, in order to identify how decision-making can be supported.\n\nUse of single tools (such as the Mini-Mental State Examination) that are not designed to assess capacity may yield information that is relevant to the assessment, but practitioners should be aware that these should not be used as the basis for assessing capacity.\n\nHealth and social care practitioners must take a collaborative approach to assessing capacity, where possible, working with the person to produce a shared understanding of what may help or hinder their communication and decision-making. This may include involving an interpreter, speech and language therapist, someone with sensory or specialist communication skills, clinical psychologists or other professionals to support communication during an assessment of capacity.\n\nWhere the person has identified communication needs, the assessor should also think about using communication tools to help with the assessment.\n\nPractitioners should be aware that it may be more difficult to assess capacity in people with executive dysfunction – for example people with traumatic brain injury. Structured assessments of capacity for individuals in this group (for example, by way of interview) may therefore need to be supplemented by real-world observation of the person's functioning and decision-making ability in order to provide the assessor with a complete picture of an individual's decision-making ability. In all cases, it is necessary for the legal test for capacity as set out in section\xa02 and section\xa03 of the Mental Capacity Act 2005 to be applied.\n\nIf a person refuses to engage in some or all aspects of a capacity assessment, the assessor should try to establish the reasons for this and identify what can be done to help them participate fully. This may involve consulting with others involved in their care and support, reviewing records or giving the person a choice about who else can be involved.\n\nInformation gathered from support workers, carers, family and friends and advocates should be used to help create a complete picture of the person's capacity to make a specific decision and act on it.\n\nWhen assessing capacity, practitioners must take account of the principle enshrined in section\xa01(4) of the Mental Capacity Act 2005 and not assume that the person lacks capacity because they have made a decision that the practitioner perceives as risky or unwise.\n\nPractitioners should understand that the person has to retain information only for the purposes of making the specific decision in question, and for the period of time necessary to make the decision.\n\nPractitioners should be aware that a person may have decision-making capacity even if they are described as lacking 'insight' into their condition. Capacity and insight are 2\xa0distinct concepts. If a practitioner believes a person's insight/lack of insight is relevant to their assessment of the person's capacity, they must clearly record what they mean by insight/lack of insight in this context and how they believe it affects/does not affect the person's capacity.\n\n## Recording the outcome of the assessment\n\nThe assessor should record any differing views on the person's capacity and how the outcome of the assessment addresses or answers those differing views.\n\nIf, following the assessment of capacity, the practitioner finds no evidence to displace the assumption of capacity, this should be documented.\n\nIf the outcome of the assessment is that the person lacks capacity, the practitioner should clearly document the reasons for this. The documentation should also make clear what impairment/disturbance of the mind or brain has been identified, the reasons why the person is unable to make a decision (with reference to section\xa03 of the Mental Capacity Act 2005) and the fact that the person's inability to make a decision is a direct consequence of the impairment or disturbance identified.\n\nThe person assessing mental capacity should record:\n\nthe practicable steps they have taken to help the person make the relevant decision for themselves and any steps taken by other parties involved\n\nwhether the person has capacity to make the decision\n\nif the person is assessed as lacking capacity, why the practitioner considers this to be an incapacitous decision as opposed to an unwise decision.\n\nAll assessments of mental capacity must be recorded at an appropriate level to the complexity of the specific decision being made at a particular time. This may be as a stand-alone assessment document, contained within the individual's health or social care record or in care and support plans, following local policy. The timescale for review of the assessment should be specified and recorded.\n\n## After the assessment\n\nProvide the person with emotional support and information after the assessment, being aware that the assessment process could cause distress and disempowerment.\n\n# Best interests decision-making\n\n'An act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interests.' (Principle\xa04, section\xa01(5), Mental Capacity Act 2005)\n\nWhen a person does not have capacity to make a decision, all actions and decisions taken by practitioners or their attorney or Court Appointed Deputy must be done or made in the person's best interests. Any advance statements expressing the individual's views about the decision in question should be taken into account and given appropriate weight.\n\nWhen making a decision under the Mental Capacity Act\xa02005, a decision maker must be identified. This could be an attorney appointed by the individual or a Court Appointed Deputy with relevant decision-making powers, or the practitioner or team who is responsible for providing a health or social care intervention.\n\nThe decision maker is responsible for determining the person's best interests. They must be able to demonstrate they have adhered to all the requirements of section\xa04 of the Mental Capacity Act 2005 and Chapter\xa05 of the Mental Capacity Act Code of Practice. Wherever possible, this means helping the person who lacks capacity to be involved in the decision-making process, consulting with their family, carers and Independent Mental Capacity Advocates, and seeking or establishing the person's known wishes, preferences and values, placing these at the heart of the decision-making process where possible.\n\nDepending on the complexity, urgency and importance of the decision, and the extent to which there is agreement or disagreement between an attorney or Court Appointed Deputy and/or other people involved in the person's care, it would be advisable to convene a meeting at which a decision regarding appropriate next steps can be made. This may include considering possible ways of resolving any disputes.\n\nThe Mental Capacity Act\xa02005 excludes some decisions from its remit, for example, those relating to voting and family relationships. It is therefore not possible for best interests decisions to be made in respect of the excluded issues.\n\n## Helping practitioners to deliver best interests decision-making\n\nIn line with the Mental Capacity Act\xa02005, practitioners must conduct a capacity assessment, and a decision must be made and recorded that a person lacks capacity to make the decision in question, before a best interests decision can be made. Except in emergency situations, this assessment must be recorded before the best interests decision is made.\n\nEnsure that everyone involved in the best interests decision-making process knows and agrees who the decision maker is.\n\nAs part of the best interests decision-making process, practitioners must take all reasonable steps to help the person to provide their own views on the decision.\n\nHealth and social care services must ensure that best interests decisions are being made in line with the Mental Capacity Act\xa02005.\n\nHealth and social care services should:\n\nimplement a service-wide process for recording best interests decisions and ensure that staff are aware of this and\n\nhave clear systems in place to support practitioners to identify and locate any relevant written statement made by the person when they had capacity, at the earliest possible time.\n\nHealth and social care services should have clear systems in place to obtain and record the person's wishes and feelings in relation to a relevant decision, as well as their values and beliefs, or any other factor that would be likely to influence such a decision. Services should:\n\nhave mechanisms in place to make these available in a timely way\n\nensure that the person's personal history and personality is represented in the above.\n\n## Involving family members or other people involved in a person's care in best interests decision-making\n\nUnless it would be contrary to the person's best interests to do so, health and social care practitioners should work with carers, family and friends, advocates, attorneys and deputies, to find out the person's values, feelings, beliefs, wishes and preferences in relation to the specific decision and to understand the person's decision-making history.\n\nIn some cases, the views of the interested parties may differ from those of the person or the decision maker. However, this does not necessarily mean it would be contrary to the person's best interests to consult them.\n\nIf a decision maker considers it helpful or necessary to convene a meeting with the relevant consultees to assist with the decision-making process, they should:\n\nInvolve the person themselves, unless a decision is made that it would be contrary to their best interests for them to attend the meeting. Where this is the case, this decision and the reasons for it should be recorded.\n\nConsult carers, family, friends, advocates and any attorney or deputy about the meeting in advance, giving them time to ask questions and give their opinions, for example about how to include the person in decision-making.\n\nMake it clear that the purpose of the meeting is to assist the decision maker in making a decision in the person's best interests.\n\nClarify the role of each person attending the meeting, especially the identities of the decision maker and the meeting chair, as these may be different people.\n\nProvide all information in an accessible format.\n\nPractitioners should access information about the person informally if needed, as well as through any formal meetings.\n\nThe decision maker should ensure that all people consulted as part of the best interests decision have their views encouraged, respected and heard. This does not mean that the views of consultees should necessarily be followed; the decision maker is ultimately responsible for deciding what course of action would be in the person's best interests.\n\n## Undertaking best interests decision-making\n\nWhen making a decision on behalf of the person who lacks capacity, practitioners should use a range of approaches, as needed, to ensure that the person's best interests are served. This might include:\n\na less formalised approach for day-to-day decisions – that is, recurring decisions being recorded in support or care plans\n\na decision-making approach appropriate to the circumstances and personalised to the individual, making all reasonable adjustments\n\nformal best interests meetings for significant decisions:\n\n\n\nif this is the most appropriate way to undertake the required consultation or\n\nif the outcome of the decision is likely to have a serious impact on the person's health or wellbeing or\n\nif there are likely to be conflicting opinions about the person's best interests.\n\n\n\nCarers and practitioners must, wherever possible, find out the person's wishes and feelings in order to ensure any best interests decision made reflects those wishes and feelings unless it is not possible/appropriate to do so. Where the best interests decision ultimately made does not accord with the person's wishes and feelings, the reasons for this should be clearly documented and an explanation given. The documentation of the assessment should also make clear what steps have been taken to ascertain the person's wishes and feelings and where it has not been possible to do this, the reasons for this should be explained.\n\nHealth and social care organisations should provide toolkits to support staff to carry out and record best interests decisions. These toolkits should include:\n\nhow to identify any decision-making instruments that would have an impact on best interests decision-making occurring (for example a Lasting Power of Attorney, advance decisions to refuse treatment, court orders)\n\nwhen to instruct an Independent Mental Capacity Advocate\n\na prompt to consult interested parties (for example families, friends, advocates and relevant professionals) and a record of who they are\n\nguidance about recording the best interests process and decision. This may include, for example, a balance sheet, which may assist in documenting the risks and benefits of a particular decision\n\ninstructions on what information to record, ensuring this covers:\n\n\n\na clear explanation of the decision to be made\n\nthe steps that have been taken to help the person make the decision themselves\n\na current assessment concluding that the person lacks the capacity to make this decision, evidencing each element of the assessment\n\na clear record of the person's wishes, feelings, cultural preferences, values and beliefs, including any advance statements\n\nthe concrete choices that have been put to the person\n\nthe salient details the person needs to understand\n\nthe best interests decision made, with reasons.\n\n\n\nWhen making best interests decisions, explore whether there are less restrictive options that will meet the person's needs. Take into account:\n\nwhat the person would prefer, including their past and present wishes and feelings, based on past conversations, actions, choices, values or known beliefs\n\nwhat decision the person who lacks capacity would have made if they were able to do so\n\nall the different options\n\nthe restrictions and freedoms associated with each option (including possible human rights infringements)\n\nthe likely risks associated with each option (including the potential negative effects on the person who lacks capacity to make a decision – for example trauma or disempowerment).\n\nWhen an Independent Mental Capacity Advocate has been instructed, they should be involved in the process until a decision has been made and implemented fully.\n\nAs people's circumstances change, review the decisions regularly to ensure that they remain in a person's best interests.\n\nAfter the outcome has been decided, the decision maker should ensure that it is recorded and communicated to everyone involved and that there is opportunity for all participants to offer feedback or raise objections.\n\nIf there is a dispute about a person's best interests, resolve this, where possible, before the decision is implemented – for example through further meetings or mediation. If a dispute cannot be resolved locally, it may be necessary for the matter to be referred to the Court of Protection for a determination of the person's best interests.\n\nDecision makers should specify a timely review of the implementation of the actions resulting from the best interests decision. If the review establishes that the best interests decision was not successfully actioned, the decision maker should take suitable steps such as:\n\nconvening a multi-agency meeting to resolve issues leading to the best interests decision not being successfully implemented or\n\nreassessing and making a new best interests decision that is more achievable or\n\ntaking steps to refer the decision to the Court of Protection or\n\nre-considering whether any further action is appropriate.\n\n# Terms used in this guideline\n\n## Advance care planning\n\nAdvance care planning with people who may lack mental capacity in the future is a voluntary process of discussion about future care between the person and their care providers. If the person wishes, their family and friends may be included in the discussion. With the person's agreement this discussion is documented, regularly reviewed and communicated to key persons involved in their care.\n\n## Advance decisions to refuse treatment\n\nAn advance decision to refuse treatment (sometimes referred to as a living will and sometimes abbreviated to ADRT) is a decision an individual can make when they have capacity to refuse a specific type of treatment, to apply at some time in the future when they have lost capacity. It means that families and health professionals will know the person's decisions about refusing treatment if they are unable to make or communicate the decisions themselves.\n\nAn advance decision must be valid and applicable before it can be legally binding. For example, one of the conditions is that the individual is aged 18\xa0or over at the time the decision is made. To establish whether an advance decision to refuse treatment is valid and applicable, practitioners must have regard to sections\xa024 to 26 of the Mental Capacity Act 2005. If the advance decision purports to refuse life-sustaining treatment, additional requirements apply. (See Chapter 9 of the Mental Capacity Act Code of Practice.)\n\n## Capacitous\n\nWhere used in this guideline, the term 'capacitous' is used to reflect the status of someone who has capacity to make decisions regarding their care and treatment – that is, those matters to which the Mental Capacity Act\xa02005 applies. This could be someone for whom there is no evidence to suggest the presumption of capacity should be displaced, or someone whose capacity to make decisions regarding their care and treatment has been formally assessed and who has been found to have capacity to make those decisions.\n\n## Contemporaneous\n\nThis is being used to describe how, during advance care planning, the practitioner should take notes of the discussions and decisions reached at the same time as those discussions are taking place.\n\n## Consent\n\nThe voluntary and continuing permission of the person to receive particular treatment or care and support, based on an adequate knowledge of the purpose, nature, likely effects and risks including the likelihood of success, any alternatives to it and what will happen if the treatment does not go ahead. Permission given under any unfair or undue pressure is not consent. By definition, a person who lacks capacity to consent cannot consent to treatment or care and support, even if they cooperate with the treatment or actively seek it.\n\n## Court Appointed Deputy\n\nA person appointed by the Court of Protection who is authorised to make decisions (relating to the person's health, welfare, property or financial affairs) on behalf of someone who lacks mental capacity and who cannot make a decision for themselves at the time it needs to be made.\n\n## Executive dysfunction\n\nThe completion of tasks that involve several steps or decisions normally involves the operation of mental processes known as 'executive functions'. If these executive functions do not develop normally, or are damaged by brain injury or illness, this can cause something called 'executive dysfunction'. This involves a range of difficulties in everyday planning and decision-making, which can be sometimes hard to detect using standard clinical tests and assessments.\n\n## Independent advocacy\n\nIndependent advocates can have a role in promoting social inclusion, equality and social justice and can provide a safeguard against the abuse of vulnerable people. Independent advocates take action to act to help people say what they want, secure their rights, represent their interests and obtain the services they need. Together with their provider organisations they work in partnership with the people they support and speak out on their behalf.\n\n## Joint crisis planning\n\nA joint crisis plan enables the person and services to learn from experience and make plans about what to do in the event of another crisis. It is developed by seeking agreement between the person who may lack mental capacity now or in future and their mental health team about what to do if they become unwell in the future. When the person lacks capacity to make decisions regarding their care and treatment and is unlikely to gain or regain capacity, a joint crisis plan about what to do in the event of a future crisis may be developed through a best interests decision-making process. A joint crisis plan does not have the same legal status as an advance decision to refuse treatment.\n\n## Lasting Power of Attorney\n\nA legal instrument that allows a person (the 'donor') to appoint one or more people (known as 'attorneys') to make decisions on their behalf. There are 2\xa0types: health and welfare, and property and financial affairs, and either one or both of these can be made. To have legal force, lasting powers of attorney must be created in accordance with section\xa09 and section\xa010 of the Mental Capacity Act 2005. The attorney must have regard to section\xa04 of the Mental Capacity Act 2005, the Mental Capacity Act Code of Practice, and must make decisions in the best interests of the person.\n\n## Mental Capacity Act\xa02005\n\nThe Mental Capacity Act\xa02005 is designed to protect and empower people who may lack capacity to make their own decisions about their care and treatment. It is a law that applies to people aged 16\xa0and over in England and Wales and provides a framework for decision-making for people unable to make some or all decisions for themselves.\n\n## Mental Health Act\xa01983\n\nThe Mental Health Act\xa01983 provides for the detention of persons in hospital for assessment and/or treatment of mental disorder and for treatment in the community in some circumstances. The Act provides for the process of assessing individuals and bringing them within the scope of the Act, for treatment of individuals subject to the Act's provisions and sets out the rights and safeguards afforded to individuals who are subject to the Act's powers.\n\n## Practicable steps\n\n'Practicable steps' links to principle\xa02 of the Mental Capacity Act (and Chapter\xa03 of the Mental Capacity Act Code of Practice), which states that 'all practicable steps' should be taken to help a person make a decision before being treated as though they are unable to make the decision. There are obvious steps a person might take, proportionate to the urgency, type and importance of the decision including the use of specific types of communication equipment or types of languages such as Makaton or the use of specialist services, such as a speech and language therapist or clinical psychologist. Practicable steps could also involve ensuring the best environment in which people are expected to make often life-changing decisions – for example giving them privacy and peace and quiet, or ensuring they have a family member or other trusted person to provide support during decision-making, if this is their wish.\n\n## Salient factors\n\nSection\xa03(1) of the Mental Capacity Act 2005 makes clear that a person will be unable to make a decision for themselves if they are unable to understand the information relevant to the decision. Case law has confirmed that the information to be provided to the person regarding the decision does not have to include every single detail relating to the decision, but must include the 'salient factors'. The salient factors are those which are most important to the decision to be made. This would include information that is subjectively important to the person being assessed (for example information relating to the likely level of disability a person would have if they did/did not undergo the treatment in question) and also key pieces of objective/factual information relevant to the decision to be made (for example the side effects of a particular treatment, or the known complications or survival rates of a particular surgical procedure). The seriousness of the decision, and the timeframe within which it must be made, will impact on the nature and amount of information that will need to be provided to the person.\n\nFor other social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Training and support for practitioners\n\nWhat is the effectiveness and cost effectiveness of different training programmes on the Mental Capacity Act\xa02005 at improving practice for practitioners involved in supporting decision-making, conducting capacity assessments and making best interests decisions?\n\n## Why this is important\n\nThe guideline committee agreed that effective training and support on the Mental Capacity Act\xa02005 and how to apply its principles in practice is essential for practitioners working with people who may lack capacity to make a decision. The evidence the committee reviewed often referred to training and support, but very few studies looked at this area specifically. Some of the evidence suggested that practitioners did not always understand the requirements of the Act and that their practice did not always comply with these. Much of the evidence was of low to moderate quality and there was no good-quality evidence evaluating the effectiveness of training and support in relation to the Act.\n\nA better understanding of what training and support increases compliance with the Act could improve outcomes for people who may lack capacity to make a decision. Qualitative studies exploring the current barriers to delivering effective training and support and the challenges that practitioners face in using this learning in practice would help to inform measures for improvement.\n\nComparative studies are needed to determine the effectiveness and cost effectiveness of different approaches for delivering training and support to practitioners. Evaluating whether these increase compliance with the requirements of the Act would be especially informative.\n\n# Targeted interventions to support and improve decision-making capacity for treatment\n\nWhat is the effectiveness and cost effectiveness of different targeted interventions (speech and language therapy and psychological and psychosocial interventions) to support and improve decision-making capacity for treatment in specific groups?\n\n## Why this is important\n\nEvidence suggests that tailored approaches such as speech and language therapy and psychological and psychosocial interventions can lead to improvements in a person's capacity to make a decision. However, the studies were limited in number and generally of low quality. The guideline committee agreed that further research in this area would be valuable, particularly in relation to the decision-making capacity for treatment of people with dementia, a learning disability, an acquired brain injury or a mental illness. Interventions should be designed to address the needs of those cohorts, should take into account the natural course of capacity (whether stable or fluctuating) and should be underpinned by a comprehensive understanding of the needs associated with each condition.\n\nHigh-quality comparative studies evaluating the effectiveness of these different types of interventions (including participant experience of the interventions) are needed to help ensure that practitioners refer people to the most appropriate programmes. This would empower people to make their own decisions about their treatment wherever possible.\n\n# Advocacy and support for decision-making\n\nWhat is the effectiveness, cost effectiveness and acceptability of advocacy as a means of supporting people to make decisions?\n\n## Why this is important\n\nThe evidence reviewed did not include any studies that evaluated the effectiveness or acceptability of advocacy as a means of supporting people to make decisions. However, the guideline committee thought that this was an area in which emerging practice shows promise. Expert witness testimony highlighting the Swedish 'Personal Ombudsman' peer support scheme also suggested that further research into the use of advocacy as a means of supporting decision-making might be useful. Although provision for advocacy already exists for people assessed as lacking capacity to make a decision (through an Independent Mental Capacity Advocate), this type of support could also benefit people who, although retaining capacity, may need support to make a decision.\n\nHigh-quality mixed methods studies with a controlled effectiveness component (preferably randomised) are needed to evaluate the effectiveness and cost effectiveness of advocacy as a tool to support the decision-making of people who may need support to make a decision. The effectiveness component will ideally include 3\xa0arms: usual care, usual care plus advocacy, and usual care plus support with enhanced advocacy. Studies should also include a qualitative component that explores whether advocacy as a means of support to make decisions is acceptable to people using services and valued by practitioners.\n\n# Using mental capacity assessment tools to assess capacity\n\nWhat is the accuracy and/or effectiveness, cost effectiveness and acceptability of mental capacity assessment tools that are compliant with the Mental Capacity Act\xa02005?\n\n## Why this is important\n\nThere is a lack of evidence from the UK on the effectiveness and acceptability of approaches to capacity assessment that are in line with the meaning of mental capacity as outlined in the Mental Capacity Act\xa02005. Although the guideline committee reviewed some evidence evaluating the accuracy of specific tools, these are not necessarily compatible with the definition of mental capacity.\n\nThere is a need for high-quality mixed methods studies that evaluate the accuracy or effectiveness of mental capacity assessment tools that are compliant with the Act. The controlled effectiveness component will ideally include 3\xa0arms: usual care, usual care plus mental capacity assessment tools, and usual care plus support with enhanced assessment tools. Studies should also include a qualitative component that explores whether such tools and approaches are acceptable to people using services and valued by practitioners.\n\n# Components of a mental capacity assessment\n\nWhat are the components of an effective assessment of mental capacity to make a decision (for example checklists, memory aids or standardised documentation)?\n\n## Why this is important\n\nAlthough the Mental Capacity Act Code of Practice provides some fundamental guidance on conducting and recording capacity assessments, there is a lack of clarity about the way in which practitioners actually conduct assessments of capacity to make a decision and how the process and outcomes of these assessments are being recorded. The guideline committee reviewed the small amount of available evidence suggesting that practice may be improved through the use of standardised forms. However, these studies tended to be poorly designed – for example, relying on audit data.\n\nThere is a need for high-quality research that explores in detail how to conduct an effective capacity assessment. This could include studies comparing one‑off capacity assessments with multiple assessments, and comparative studies evaluating whether certain approaches or tools are appropriate.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nEnsuring a greater focus on supported decision-making. Underpinned by principles\xa01 and\xa02 of the Mental Capacity Act\xa02005, supported decision-making is fundamental to:\n\n\n\neffective implementation of the legislation\n\nempowering people who have difficulties making their own decisions independently. Alongside local policies and training, organisations need to ensure that their procedures and forms for capacity and best interests assessments are congruent with an emphasis on supported decision-making.\n\n\n\nEnsuring a workforce that is well-trained and well-developed in supporting decision-making and in implementing the Act. Practitioners need to understand the status of the person's decision-making capacity at that specific point in time and how their particular impairment of the mind or brain affects their current ability to make decisions. Training should be delivered with input from people who use services. It should start with basic training and continue throughout an individual's employment, particularly whenever legislation is updated.\n\nAccess to independent advocacy. This is affected by a range of factors, including:\n\n\n\na shortage of well-trained advocates\n\npractitioner knowledge of the different types of advocacy\n\npractitioners being unaware of the duty to refer for advocacy\n\nadvocacy services being under-resourced and in high demand.Additionally, there is consistent evidence of a lack of understanding among commissioners, public bodies, practitioners and people who use services of the critical role that independent advocacy can play in upholding rights and providing an ultimate safeguard from abuse. Consequently, ensuring the recommendations relating to independent advocacy are acted on will be a challenge of communication and persuasion beyond statutory requirements, and they will require a concerted effort to implement effectively.\n\n\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley."}
|
https://www.nice.org.uk/guidance/ng108
|
This guideline covers decision-making in people 16 years and over who may lack capacity now or in the future. It aims to help health and social care practitioners support people to make their own decisions where they have the capacity to do so. It also helps practitioners to keep people who lack capacity at the centre of the decision-making process.
|
6eb7402198fa9254ba544b6a66e2d3705780f244
|
nice
|
Renal replacement therapy and conservative management
|
Renal replacement therapy and conservative management
This guideline covers renal replacement therapy (dialysis and transplantation) and conservative management for people with chronic kidney disease stages 4 and 5. It aims to improve quality of life by making recommendations on planning, starting and switching treatments, and coordinating care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Indications for starting dialysis
Follow the recommendations on referral criteria in NICE's guideline on chronic kidney disease.
Consider starting dialysis when indicated by the impact of symptoms of uraemia on daily living, or biochemical measures or uncontrollable fluid overload, or at an estimated glomerular filtration rate (eGFR) of around 5 to 7 ml/min/1.73 m2 if there are no symptoms.
Ensure the decision to start dialysis is made jointly by the person (or, where appropriate, their family members or carers) and their healthcare team.
Before starting dialysis in response to symptoms, be aware that some symptoms may be caused by non-renal conditions.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for starting renal replacement therapy .
Full details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.
Loading. Please wait.
# Preparing for renal replacement therapy or conservative management
## When to assess
Start assessment for renal replacement therapy (RRT) or conservative management at least 1 year before therapy is likely to be needed, including for those with a failing transplant.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on preparing for renal replacement therapy or conservative management – when to assess .
Full details of the evidence and the committee's discussion are in evidence review E: when to assess for renal replacement therapy.
Loading. Please wait.
## How to assess
Involve the person and their family members or carers (as appropriate) in shared decision-making over the course of assessment to include:
clinical preparation
psychosocial evaluation, preparation and support
the person's individual preferences for type of RRT and when to start
how decisions are likely to affect daily life.
Consider further assessment by a clinical psychologist or psychiatrist for:
all children and young people being considered for a transplant, and
adults being considered for a transplant if risk factors for poor outcomes have been identified; these may include:
lack of social support
neurocognitive issues
non-adherence (medicines, diet, hospital appointments)
poor understanding of process and complexities of treatment
poorly controlled mental health conditions or severe mental illness
substance misuse or dependence.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preparing for renal replacement therapy or conservative management – how to assess .
Full details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.
Loading. Please wait.
# Choosing modalities of renal replacement therapy or conservative management
Offer a choice of RRT or conservative management to people who are likely to need RRT. Conservative management for children should only be considered within appropriate regulatory frameworks. See NICE's guideline on end of life care for children and young people with life-limiting conditions.
Ensure that decisions about RRT modalities or conservative management are made jointly with the person (or with their family members or carers for children or adults lacking capacity) and healthcare team, taking into account:
predicted quality of life
predicted life expectancy
the person's preferences (see the recommendations on information, education and support)
-ther factors such as co-existing conditions.
Offer people (and their family members or carers, as appropriate) regular opportunities:
to review the decision regarding RRT modalities or conservative management
to discuss any concerns or changes in their preferences.
## Transplantation
Discuss the individual factors that affect the risks and benefits of transplantation with all people who are likely to need RRT, and their family members or carers (as appropriate).
Include living donor transplantation in the full informed discussion of options for RRT.
Offer a pre-emptive living donor transplant (when there is a suitable living donor) or pre-emptive listing for deceased donor transplantation to people considered eligible after a full assessment.
Do not exclude people from receiving a kidney transplant based on BMI alone.
## Choice of dialysis modalities
Offer a choice of dialysis modalities at home or in centre ensuring that the decision is informed by clinical considerations and patient preferences (see recommendation 1.3.2).
Offer all people who choose peritoneal dialysis a choice of continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD), if this is medically appropriate.
Consider peritoneal dialysis as the first choice for children 2 years or under.
For people who choose haemodialysis/haemodiafiltration (HD/HDF):
Consider HDF rather than HD if in centre (hospital or satellite unit).
Consider HDF or HD at home, taking into account the suitability of the space and facilities.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on choosing modalities of renal replacement therapy or conservative management .
Full details of the evidence and the committee's discussion are in evidence review B: modalities of renal replacement therapy and evidence review C: sequencing modalities of renal replacement therapy.
Loading. Please wait.
# Planning dialysis access formation
Discuss with the person, their family members and carers (as appropriate) the risk and benefits of the different types of dialysis access, for example, fistula, graft, central venous or peritoneal dialysis catheter.
When peritoneal dialysis is planned via a catheter placed by an open surgical technique, aim to create the access around 2 weeks before the anticipated start of dialysis.
When HDF or HD is planned via an arteriovenous fistula, aim to create the fistula around 6 months before the anticipated start of dialysis to allow for maturation. When deciding on timing, take into account the possibility of the first fistula failing or needing further interventions before use.
Offer ultrasound scanning to determine vascular access sites for creating arteriovenous fistulae for HDF or HD.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on planning dialysis access formation .
Full details of the evidence and the committee's discussion are in evidence review D: when to create access formation and/or list for transplantation and evidence review F: how to assess people for renal replacement therapy.
Loading. Please wait.
# Indications for switching or stopping renal replacement therapy
Offer information on all medically appropriate treatment options when discussing switching RRT modality.
Consider switching treatment modality or stopping RRT if medically indicated or if the person (or, where appropriate, their family members or carers) asks.
Plan switching treatment modality or stopping RRT in advance wherever possible.
Do not routinely switch people on peritoneal dialysis to a different treatment modality in anticipation of potential future complications such as encapsulating peritoneal sclerosis. However, monitor risk factors, such as loss of ultrafiltration.
Seek specialist advice on the need for switching treatment modality when women become pregnant or wish to become pregnant.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for switching or stopping renal replacement therapy .
Full details of the evidence and the committee's discussion are in evidence review G: indicators for transferring or discontinuing renal replacement therapy.
Loading. Please wait.
# Recognising symptoms
Recognise that people on RRT or receiving conservative management may have the symptoms in box 1 and that these may affect their day-to-day life.
## Box 1 Possible symptoms in people on renal replacement therapy or conservative management
General symptoms:
breathlessness
fatigue
insomnia
itching
lethargy
pain
poor appetite
swelling
taste changes
thirst
weakness
weight loss/gain.
Gastro-intestinal/urological symptoms:
abdominal cramps
change in bowel or urinary habits
nausea.
Musculoskeletal symptoms:
muscle cramps
restless legs.
Neurological symptoms:
cognitive impairment
dizziness
headaches.
Psychological/behavioural symptoms:
anxiety
body image concerns
depression
mood disturbances/fluctuations
sexual dysfunction.
Throughout the course of RRT and conservative management:
Ask people about any symptoms they have.
Explore whether symptoms are due to the renal condition, treatment or another cause.
Explain the likely cause of the symptoms and how well treatment may be expected to control them.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on recognising symptoms .
Full details of the evidence and the committee's discussion are in evidence review H: symptom recognition.
Loading. Please wait.
# Diet and fluids
Offer a full dietary assessment by a specialist renal dietitian to people starting dialysis or conservative management. This should include:
weight history
fluid intake
sodium
potassium
phosphate
protein
calories
micronutrients (vitamin and minerals).
After transplantation, offer dietary advice from a healthcare professional with training and skills in this area.
Re-assess dietary management and fluid allowance when:
a person's circumstances change (for example, when switching RRT modality), or
biochemical measures or body composition measures (for example, unintentional weight loss) indicate, or
the person (or, where appropriate, their family members or carers) asks.
Provide individualised information, advice and ongoing support on dietary management and fluid allowance to the person and their family members or carers (as appropriate). The information should be in an accessible format and be sensitive to the person's cultural needs and beliefs.
Follow the recommendations on dietary management and phosphate binders in NICE's guideline on chronic kidney disease.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and fluids .
Full details of the evidence and the committee's discussion are in evidence review I: dietary management and fluid restriction.
Loading. Please wait.
# Information, education and support
To enable people, and their families and carers (as appropriate), to make informed decisions, offer balanced and accurate information about:
all treatments available to them (including RRT modalities and conservative management), and
how the treatments may affect their lives.See box 2 for more details.
## Box 2 Information about treatments and how they may affect lifestyle
Information about treatments, including RRT, conservative management and dietary intervention:
What they involve, for example, availability of assistance, time that treatment takes place, and number of sessions per day/week
Potential benefits.
The benefits of adherence to treatment regimens and the potential consequences of non-adherence.
Potential adverse effects, their severity and how they may be managed.
The likely prognosis on dialysis, after transplant or with conservative management.
The transplant listing process (when appropriate).
Switching the modality of RRT and the possible consequences (that is, the impact on the person's life or how this may affect future treatment or outcomes).
Reviewing treatment decisions.
Stopping treatment and planning end of life care.
Information about how treatments may affect lifestyle:
The person or carer's ability to carry out and adjust the treatment themselves.
The possible impact of dietary management and management of fluid allowance.
How treatment may fit in with daily activities such as work, school, hobbies, family commitments and travel for work or leisure.
How treatment may affect sexual function, fertility and family planning.
Opportunities to maintain social interaction.
How treatment may affect body image.
How treatment may affect physical activity (for example, whether contact sports should be avoided after transplantation, whether swimming should be avoided with peritoneal dialysis).
Whether a person's home will need to be modified to accommodate treatment.
How much time and travel treatment or training will involve.
The availability of transport.
The flexibility of the treatment regimen.
Whether any additional support or services might be needed.
Recognise the psychological impact of a person being offered RRT or conservative management and discuss what psychological support may be available to help with decision-making.
Discuss with people which treatment options are available to them and explain why any options may be inappropriate or not advised.
Offer oral and written information and support early enough to allow time for people to fully understand their treatment options and make informed decisions. Information should be in an accessible format.
Direct people to other sources of information and support (for example, online resources, pre-dialysis classes and peer support).
Remember that some decisions must be made months before RRT is needed (for example, a fistula is created at least 6 months before starting dialysis).
Be prepared to discuss the information provided both before and after decisions are made, in line with the person's wishes.
Take into account information the person has obtained from other sources (such as family members and carers) and how this information has influenced their decision.
Ensure that healthcare professionals offering information have specialist knowledge about late stage chronic kidney disease and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage).
Offer people who have presented late, or who started dialysis in an unplanned way, the same information as people who present at an earlier stage.
Follow the recommendations on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services and on information and education in NICE's guideline on chronic kidney disease. See also NICE's guideline on shared decision making.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information, education and support .
Full details of the evidence and the committee's discussion are in evidence review K: information, education and support.
Loading. Please wait.
# Coordinating care
Provide the person with the contact details of the healthcare professional responsible for their overall renal care:
before they start RRT or conservative management, and
when they switch from one modality to another.
Coordinate care to reduce its effect on day-to-day life and wellbeing (treatment burden). For example, take account of people's preferences and avoid scheduling appointments on non-dialysis days for people on hospital dialysis wherever possible.
Follow the recommendations on:
delivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity, and
continuity of care and relationships, and enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordinating care .
Full details of the evidence and the committee's discussion are in evidence review M: coordinating care.
Loading. Please wait.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Cardiac assessment
What is the clinical and cost effectiveness of cardiac assessment before transplantation?
For a short explanation of why the committee made the recommendation for research, see the rationale section on preparing for renal replacement therapy or conservative management – how to assess .
Full details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.
Loading. Please wait.
## Timing of pre-emptive transplant
What is the most clinical and cost-effective strategy for timing of pre-emptive transplantation?
For a short explanation of why the committee made the recommendation for research, see the rationale section on indications for starting renal replacement therapy .
Full details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.
Loading. Please wait.
## Acute haemodialysis versus acute peritoneal dialysis
What is the clinical and cost effectiveness of initial haemodialysis versus initial peritoneal dialysis for people who start dialysis in an unplanned way?
For a short explanation of why the committee made the recommendation for research, see the rationale section on choosing modalities of renal replacement therapy or conservative management .
Full details of the evidence and the committee's discussion are in evidence review B: modalities of renal replacement therapy and evidence review C: sequencing modalities of renal replacement therapy.
Loading. Please wait.
## Frequency of review
What is the most clinical and cost-effective frequency of review for people on peritoneal dialysis, haemodiafiltration, haemodialysis or conservative management?
For a short explanation of why the committee made the recommendation for research, see the rationale section on frequency of review .
Full details of the evidence and the committee's discussion are in evidence review J: frequency of review.
Loading. Please wait.
## Coordinating care
What is the clinical and cost effectiveness of having keyworkers present in the context of renal replacement therapy (RRT)?
For a short explanation of why the committee made the recommendation for research, see the rationale section on coordinating care .
Full details of the evidence and the committee's discussion are in evidence review M: coordinating care.
Loading. Please wait.
# Other recommendations for research
What is the clinical and cost effectiveness of strategies for switching RRT modality?
What is the clinical and cost effectiveness of using decision aids in the context of RRT?
For a short explanation of why the committee made the recommendation for research, see the rationale section on decision support interventions .
Full details of the evidence and the committee's discussion are in evidence review L: decision support interventions.
Loading. Please wait.
What is the optimum timing of laparoscopic and percutaneous peritoneal dialysis access creation?
What is the clinical and cost effectiveness of conservative management versus dialysis in frail, older people?
What is the clinical and cost effectiveness of home haemodiafiltration versus home haemodialysis, taking into account the impact of frequency?
What is the clinical and cost effectiveness of haemodialysis/haemodiafiltration before peritoneal dialysis versus peritoneal dialysis before haemodialysis/haemodiafiltration?
What is the optimum timing of listing for transplantation?# Rationale and impact
# Indications for starting renal replacement therapy
Recommendations 1.1.1 to 1.1.4
## Why the committee made the recommendations
The committee agreed that when to start dialysis is a complex decision that should take into account a number of factors (symptoms, patient preference, biochemistry, fluid overload and estimated glomerular filtration rate ). Most people start dialysis due to symptoms, but evidence suggested that there was no overall harm or benefit of starting dialysis at an eGFR of around 5 to 7 ml/min/1.73 m2 in the absence of symptoms. However, there was evidence that starting dialysis when there are symptoms or the eGFR reaches 5 to 7 ml/min per 1.73 m2 was cost saving compared with an earlier start. The committee noted that some people prefer to have an agreed starting point (eGFR), but may need dialysis before this because symptoms are affecting normal daily activities. Some people with slowly progressing chronic kidney disease may not recognise and report symptoms that indicate dialysis is needed. Taking all this information together, the committee acknowledged several indications for starting dialysis and agreed that these should be considered on an individual basis.
The committee agreed that it is important to establish whether symptoms (for example, fatigue and depression) are due to uraemia or not, and to discuss their impact on daily life.
Evidence on the timing of pre-emptive transplant was limited and contradictory, with one study showing a clinically important benefit of transplanting at an eGFR of less than 10 ml/min/1.73 m2 but another showing no difference. The committee agreed to make a recommendation for research on this to guide future practice.
## How the recommendations might affect practice
The recommendations reflect common practice for adults and children, and so are not likely to involve a change of practice for most NHS providers or have a substantial resource impact for the NHS in England. If providers need to change from an earlier to a later initiation strategy, this is likely to be cost saving due to a reduction in time on dialysis.
Full details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.
Return to recommendations
# Preparing for renal replacement therapy or conservative management – when to assess
Recommendation 1.2.1
## Why the committee made the recommendation
Some evidence indicated that earlier referral to nephrology services improved survival on RRT at 90 days. The committee were interested in the timing of referral for assessment for RRT and used their experience to recommend that this should be at least 1 year before RRT is likely to be needed. They agreed that this would provide time for clinical and psychological preparation for dialysis or pre-emptive transplantation, and give the person, family members and carers enough time to think about the options. The committee acknowledged that there might be possible harms and costs for people who were referred but did not go on to need RRT, but they agreed that these were outweighed by the benefits of early referral for most people.
## How the recommendation might affect practice
The recommendation generally reflects current practice so there should be no significant change in practice or substantial resource impact to the NHS in England.
Full details of the evidence and the committee's discussion are in evidence review E: when to assess for renal replacement therapy.
Return to the recommendation
# Preparing for renal replacement therapy or conservative management – how to assess
## Why the committee made the recommendations
Recommendations 1.2.2 to 1.2.3
The committee recognised that an assessment should involve preparing people for RRT, for example, by explaining the procedures to create vascular access and checking heart function and immunity. Psychosocial preparation is also important for reducing non-adherence and improving outcomes. They also highlighted the importance of discussing a person's preferences and understanding how decisions on RRT or conservative management are likely to affect a person's everyday life.
No evidence was identified on the psychological assessment of transplant recipients or donors. The committee agreed that there were likely benefits for identifying risk factors for non-adherence or morbidity after the operation. These could include substance misuse, current non-adherence or a previous or current mental health condition. Given the lack of evidence and potential resource impact, the committee agreed that assessment could be considered for specific high-risk groups.
There was no evidence on cardiac assessment before transplantation. The committee discussed current practice and agreed it is very variable. They therefore decided to make a recommendation for research to inform future practice.
## How the recommendations might affect practice
Psychological assessment in people at high risk of non-adherence or morbidity is current practice in many areas. The recommendation is likely to lead to better targeting of psychological assessment in other areas. The recommendation was not considered likely to have a substantial resource impact overall.
Full details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.
Return to the recommendations
# Choosing modalities of renal replacement therapy or conservative management
Recommendations 1.3.1 to 1.3.11
## Why the committee made the recommendations
People who are likely to need RRT should be supported to make decisions about treatment options, including conservative management. There was no evidence of differential benefits or harms in any specific group of people and the committee agreed that the decision needs to be based on individual factors (such as frailty, cognitive impairment and multimorbidity) and patient preference.
Evidence showed that if RRT is chosen, transplantation offers a clear advantage over dialysis in terms of extending life. This benefit was observed in each age group. In the committee's experience, quality of life and hospitalisation are also likely to be improved by transplantation. However, the individual factors that affect the risks and benefits of transplantation, for example, comorbidities, should be discussed. There was no evidence on cost effectiveness but the committee considered transplantation likely to have a lower cost over the long term due to the cost of avoiding dialysis. The committee agreed to recommend pre-emptive transplantation with a living donor or, if this is not an option, a transplant from a deceased donor.
The committee noted that the only available evidence suggested that people with a BMI greater than 30 benefited from transplant (as opposed to dialysis) to a similar degree as people with a BMI of 30 or under, in terms of mortality. The committee agreed to recommend that healthcare professionals do not exclude people from transplantation based on BMI alone.
Limited evidence showed that if a transplant is not possible, peritoneal dialysis and haemodialysis (HD) offered similar benefits and equivalent harms. There was uncertainty about the differences in costs between peritoneal dialysis and HD due to uncertainty in current UK dialysis costs and transport costs. There was no evidence comparing haemodiafiltration (HDF) and peritoneal dialysis. The committee agreed that peritoneal dialysis and HD/HDF may have quite different effects on a person's life (for example, affecting their ability to travel and the need for self-care) so they agreed that a person should be able to choose the type of dialysis most suitable for them. Peritoneal dialysis should be considered for children under 2 years due to difficulties with vascular access and extracorporeal blood volume.
There was no evidence to suggest clear differences between home and in-centre (hospital or satellite unit) HD/HDF. There is uncertainty in current UK dialysis costs but they may be lower at home. The committee acknowledged that these treatments can have very different effects on lifestyle and recommended patient choice.
Evidence suggested that in-centre HDF was more effective than in-centre HD and was cost effective, so the committee agreed that HDF rather than HD should be recommended when dialysis was in centre. However, they were aware of an ongoing trial H4RT comparing high-volume HDF with high-flux HD and, following stakeholder consultation, changed the recommendation to consider HDF rather than HD for in-centre dialysis. The committee noted that HD may be done more frequently at home than in centre. The benefits of HDF are unknown in people who dialyse more frequently. There was no evidence on the efficacy of HDF at home. The committee was aware that some centres offer home HDF, although some people opt for transportable dialysis machines (which cannot do HDF currently) and these centres also provide home HD. Taking all of this information together the committee could not recommend one option over another for HD/HDF at home. They decided that either HD or HDF could be considered.
There was no evidence comparing HD/HDF and peritoneal dialysis as initial therapy for people who start dialysis in an unplanned way. The committee agreed to make a recommendation for research on this to inform future guidance.
There was no evidence to suggest clear differences between automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). Again the committee acknowledged that these treatments can have very different effects on lifestyle and recommended patient choice.
The committee agreed that people should have regular opportunities to review treatment options.
There was not enough evidence to recommend any particular sequence of RRT modalities. The committee agreed that decisions about sequence would mostly be guided by personal circumstances.
## How the recommendations might affect practice
Currently there is a mix of HDF and HD provision in the NHS in England. The recommendation to consider HDF over HD for in-centre dialysis may affect resource use in areas where this is a change in practice. There are likely to be additional costs relating to consumables and water consumption with HDF compared with HD, but these may be partly offset by reduced use of erythropoietin-stimulating agent (ESA). There may be additional costs for machines where HDF-capable machines are not currently used. However, most centres already have some HDF-capable machines. This will enable them to accommodate any initial increased demand for HDF. Provision can be expanded if demand increases within the usual replacement cycles. These additional costs may result in a substantial resource impact to the NHS in England overall. However, this is uncertain as it is not possible to accurately predict how widely additional use of HDF will be considered.
Although use of different RRT modalities and conservative management varies between areas, other recommendations reinforce current good practice to offer people a choice of modalities and settings, and conservative management, and so are not expected to have a substantial resource impact.
The committee agreed that people are often not offered regular opportunities to discuss the option of switching treatment modality or stopping RRT and so this may be a change in practice in many areas. However, these discussions could form part of current patient reviews and so would not mean a difference in resource use. More regular discussions may lead to more people switching or stopping RRT but this is not expected to result in a substantial resource impact overall.
Full details of the evidence and the committee's discussion are in evidence review B: modalities of renal replacement therapy and evidence review C: sequencing modalities of renal replacement therapy.
Return to the recommendations
# Planning dialysis access formation
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
The committee highlighted the importance of discussing with the person the different types of dialysis and their access and the impacts of these on everyday life.
Evidence suggested that the best time for creating access for peritoneal dialysis by open surgery is around 2 weeks before starting dialysis. There was no evidence on the best time for creating other types of peritoneal access so the committee decided to make a recommendation for research to inform future guidance.
Evidence suggested that the best time for creating an arteriovenous fistula (AVF) for vascular access was 3 to 6 months before starting HD or HDF. It suggested that earlier AVF creation may increase the rate of AVF success. The committee agreed that doing this early (around 6 months) reduced the need for additional access procedures. However, when a fistula is created early, some people may never need it, for example, because they have a pre-emptive transplant. The committee agreed that the benefits of establishing a fistula around 6 months before starting dialysis, including the cost savings associated with avoiding additional access procedures, were likely to outweigh the potential disadvantages and increased costs associated with unused fistulae. The committee noted that the precise timing will vary from person to person, depending on the likely success of fistula creation.
Evidence showed a benefit of routine ultrasound scanning in terms of reduced failure of AVF. Cost calculations based on the clinical evidence suggested that routine scanning is likely to reduce overall costs because of fewer repeat interventions. The committee agreed to recommend routine ultrasound scanning to determine vascular access sites.
The committee noted that there was no evidence to guide the optimum timing of transplant listing and therefore made a recommendation for research in this area.
## How the recommendations might affect practice
Current practice for creating vascular access is variable. A minimum timing from creation to use of 6 weeks has been suggested – however, the committee agreed that creation around 6 months reflected common practice. The recommendation is not expected to have a significant impact on practice, but should standardise some current variability. It is not expected to have a substantial resource impact to the NHS in England.
Current practice for creating peritoneal dialysis access via open surgery is broadly in line with the recommendation (that is, 2 weeks before use) and so this recommendation is not expected to have a substantial resource impact to the NHS in England.
Current practice regarding ultrasound scanning to determine access sites is variable; some centres use routine ultrasound scanning but others offer a more selective approach. The recommendation would not involve a large change in practice and is likely to be cost saving because of the reduced need for repeat intervention. It is not expected to have a substantial resource impact to the NHS in England.
Full details of the evidence and the committee's discussion are in evidence review D: when to create access formation and/or list for transplantation and evidence review F: how to assess people for renal replacement therapy.
Return to the recommendations
# Indications for switching or stopping renal replacement therapy
Recommendations 1.5.1 to 1.5.5
## Why the committee made the recommendations
There was no evidence on indications for switching treatment and the committee agreed to make recommendations for research on possible indicators to inform future guidance. There was no evidence that people on peritoneal dialysis should switch modality in anticipation of future complications such as encapsulating peritoneal sclerosis and the committee agreed this should not be routine. They highlighted that healthcare professionals should monitor for risk factors predicting complications (for example, loss of ultrafiltration).
There was also no evidence to support a switch from peritoneal dialysis to HD/HDF for women who become or wish to become pregnant. The committee agreed that the need for a switch would depend on the adequacy of dialysis, the health of the fetus and the control of urea. They recommended that specialist advice should be sought before any decisions were made.
## How the recommendations might affect practice
The recommendations broadly reflect current good practice and are not expected to have a resource impact to the NHS in England.
Full details of the evidence and the committee's discussion are in evidence review G: indicators for transferring or discontinuing renal replacement therapy.
Return to the recommendations
# Recognising symptoms
Recommendations 1.6.1 to 1.6.2
## Why the committee made the recommendations
Evidence identified symptoms that people approaching the need for RRT or receiving RRT or conservative management frequently report as affecting their lives. The committee also identified others (for example, change in urinary habits). People may feel uncomfortable talking about some symptoms (for example, sexual dysfunction) and may not associate them with their condition or its treatment. The committee agreed that healthcare professionals should ask people about symptoms and determine the likely cause. It is important that people understand which symptoms they may experience, which may need further management and if treatment will control them.
## How the recommendations might affect practice
Currently, not all healthcare professionals ask people about all of the symptoms they are experiencing. They may only ask about specific symptoms and not explore all of them. Healthcare professionals should ascertain whether symptoms are due to the person's renal condition or not and explain this to them. This may be a change in practice for some, but is not expected to have a substantial resource impact to the NHS in England.
Full details of the evidence and the committee's discussion are in evidence review H: symptom recognition.
Return to the recommendations
# Diet and fluids
Recommendations 1.7.1 to 1.7.5
## Why the committee made the recommendations
Limited evidence, including in people with a transplant, indicated that people receiving RRT or conservative management may benefit from dietary and/or fluid management. The committee agreed that current practice is for people receiving dialysis or conservative management to have an assessment by a specialist dietitian. NICE's guideline on managing hyperphosphataemia in chronic kidney disease recommends assessment by a specialist renal dietitian for those at risk of hyperphosphataemia, which would include these groups of people. They also considered it current practice for dietary advice to be given after transplantation, although this advice is not always given by a specialist renal dietitian. The committee noted that there is some variation in how long people have to wait for this assessment, and variation in ongoing management. The committee agreed that dietary advice is important for people with a transplant, particularly straight after the surgery. This was supported by the evidence. The committee noted the importance of the person giving dietary advice having specialist knowledge of dietary requirements in transplant patients. However, the evidence was too limited to recommend that dietary advice should routinely be from a specialist renal dietitian for this group given it would be a change in practice in many areas and could result in a substantial resource impact.
The committee agreed that following initial assessment further dietary assessment would be determined by specific circumstances or indicators and made a recommendation summarising what these would be. They highlighted that there is variation in the level of dietitian input available in renal centres, which may affect how quickly people can access services or the level of input following initial assessment. However, the evidence was not considered sufficient to make specific recommendations to address this.
The committee agreed that involving family members and carers in discussions was important for improving adherence to dietary management and fluid allowance. There was no evidence on the benefits or harms of a low protein diet so the committee was not able to make a recommendation on this. The committee agreed that dietary management and fluid assessment should not be a 'one-step' process and that people's needs should be reviewed when circumstances change (for example, when switching RRT modalities) or when biochemical measures indicate.
## How the recommendations might affect practice
The recommendations made reflect current practice and are not expected to result in a substantial resource impact to the NHS in England.
Full details of the evidence and the committee's discussion are in evidence review I: dietary management and fluid restriction.
Return to the recommendations
# Frequency of review
## Why the committee made the recommendation for research
No evidence was identified to support any particular strategy for timing of review for people on RRT or conservative management. Because of the lack of evidence, considerable variation in current practice and the likely resource implications of a practice recommendation, the committee made a recommendation for research to inform future guidance.
Full details of the evidence and the committee's discussion are in evidence review J: frequency of review.
# Information, education and support
## Why the committee made the recommendations
Recommendations 1.8.1 to 1.8.11
The committee used the evidence and their own experience to update the recommendations on information and support from NICE's 2011 guideline on peritoneal dialysis (CG125) and to extend these to cover other forms of RRT and conservative management. Key findings related to information being provided well in advance of decisions being needed, multiple formats of information being available, and full information on all modalities being provided. Information should also be provided on the psychological impact of starting RRT and the decision-making process.
## How the recommendations might affect practice
The recommendations broadly reflect current practice and therefore are unlikely to have a resource impact. They focus mainly on the principles of information and support rather than on specific interventions.
Full details of the evidence and the committee's discussion are in evidence review K: information, education and support.
Return to the recommendations
# Decision support interventions
## Why the committee made the recommendation for research
Limited evidence suggested a benefit of structured education programmes although results were inconsistent. The committee noted that decision aids are used in clinical practice but do not replace discussions between the patient, families and carers, and healthcare professionals when making decisions about RRT or conservative management. Education classes and peer support are also important to support decision-making. In the absence of evidence showing clinically important benefits, the committee were unable to recommend that decision aids should be used. They decided to make a recommendation for research to inform future practice.
Full details of the evidence and the committee's discussion are in evidence review L: decision support interventions.
# Coordinating care
Recommendations 1.9.1 to 1.9.3
## Why the committee made the recommendations
There was limited evidence on the coordination of care but the committee agreed that people should know who to contact with questions about their condition or treatment. This is particularly important when they start or change RRT modalities. The committee noted that people on RRT experience considerable treatment burden and that strategies should be adopted to reduce this. There was no evidence on care coordination by a keyworker so the committee recommended the healthcare professional responsible for renal care as a first point of contact. They made a recommendation for research on care coordination by a keyworker to inform future guidance.
## How the recommendations might affect practice
Current practice is variable in terms of when a person is given the details of the person responsible for care. This recommendation will ensure that this is done before starting treatment or when switching modalities or to conservative management. Similarly the recommendation on reducing treatment burden standardises and reinforces good practice. Some healthcare professionals may need to change their practice but this would not result in a substantial resource impact.
Full details of the evidence and the committee's discussion are in evidence review M: coordinating care.
Return to the recommendations# Context
People with chronic kidney disease (CKD) have an irreversible and progressive deterioration in kidney function. Renal replacement therapy (RRT) is a treatment option in people with CKD whose condition progresses to kidney failure. RRT essentially comprises either transplantation or dialysis (artificially removing waste products and excess water from the blood). Transplantation can be from living or deceased donors, and for some people it may involve the transplantation of more than one organ simultaneously (for example, combined pancreas and kidney transplantation for people with type I diabetes mellitus). In some cases, transplantation may be pre-emptive, occurring before dialysis would be needed. There are 2 main types of dialysis: haemodialysis (where the blood is filtered outside of the body using a dialysis machine) and peritoneal dialysis (where the person's abdominal lining is used to filter the blood). Some people choose not to receive RRT but continue to receive other supportive and symptomatic treatment for kidney failure – for example, treatment for their anaemia or dietary modification. This is usually called conservative management. People may also receive end of life care, and this may include both supportive and palliative care.
According to the 19th annual report by the UK Renal Registry (2016), on 31 December 2015 there were 61,256 adults in the UK receiving RRT. Of these, 53.1% had received a transplant, 41.0% were receiving haemodialysis (21.2% in satellite units, 17.8% in hospitals, 2.0% at home), 2.5% were receiving continuous ambulatory peritoneal dialysis and 3.4% were receiving automated peritoneal dialysis. In addition, 769 children and young people under the age of 16 years were receiving RRT. Most had received a transplant (41% live, 34% deceased), with 13% on haemodialysis and 12% on peritoneal dialysis. The median age of all people newly requiring RRT was 59.0 years; 22.7% of people were from minority ethnic groups. The reported 1-year risk of death for people on RRT aged 35 to 39 years was approximately 22.0 times higher than age- and sex-matched controls not on RRT. Survival rates for people with diabetes on maintenance haemodialysis are lower than those of people without diabetes. The number of people receiving conservative management varies between renal units and has been difficult to establish, but up to 40% of people over 70 choose this option. Most of these still receive their care and treatment through renal services.
Approximately 5,500 adults and children are currently on the national renal transplant (waiting) list (NHS Blood and Transplant), with about 3,000 renal transplants performed each year. The median time to transplantation for those on the list is around 1,000 days for adults and 300 days for children. There is considerable inequality across ethnic groups, with relatively fewer people from black, Asian and minority ethnic groups on the organ donor list. These groups have a higher incidence and prevalence of CKD needing RRT and tend to reach this stage at a younger age.
RRT is an expensive treatment. The total cost of CKD in England in 2009–10 was estimated at £1.45 billion; more than half of this sum was spent on RRT.
This guideline aims to improve the care of people with CKD who need RRT or conservative management. The guideline covers the choice, timing, preparation for and switching of RRT 'modalities' for children and adults, as well as symptom recognition, information, education and support, and coordination of care.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Indications for starting dialysis\n\nFollow the recommendations on referral criteria in NICE's guideline on chronic kidney disease.\n\nConsider starting dialysis when indicated by the impact of symptoms of uraemia on daily living, or biochemical measures or uncontrollable fluid overload, or at an estimated glomerular filtration rate (eGFR) of around 5 to 7\xa0ml/min/1.73\xa0m2 if there are no symptoms.\n\nEnsure the decision to start dialysis is made jointly by the person (or, where appropriate, their family members or carers) and their healthcare team.\n\nBefore starting dialysis in response to symptoms, be aware that some symptoms may be caused by non-renal conditions.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for starting renal replacement therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.\n\nLoading. Please wait.\n\n# Preparing for renal replacement therapy or conservative management\n\n## When to assess\n\nStart assessment for renal replacement therapy (RRT) or conservative management at least 1\xa0year before therapy is likely to be needed, including for those with a failing transplant.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on preparing for renal replacement therapy or conservative management – when to assess\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: when to assess for renal replacement therapy.\n\nLoading. Please wait.\n\n## How to assess\n\nInvolve the person and their family members or carers (as appropriate) in shared decision-making over the course of assessment to include:\n\nclinical preparation\n\npsychosocial evaluation, preparation and support\n\nthe person's individual preferences for type of RRT and when to start\n\nhow decisions are likely to affect daily life.\n\nConsider further assessment by a clinical psychologist or psychiatrist for:\n\nall children and young people being considered for a transplant, and\n\nadults being considered for a transplant if risk factors for poor outcomes have been identified; these may include:\n\n\n\nlack of social support\n\nneurocognitive issues\n\nnon-adherence (medicines, diet, hospital appointments)\n\npoor understanding of process and complexities of treatment\n\npoorly controlled mental health conditions or severe mental illness\n\nsubstance misuse or dependence.\n\n\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preparing for renal replacement therapy or conservative management – how to assess\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.\n\nLoading. Please wait.\n\n# Choosing modalities of renal replacement therapy or conservative management\n\nOffer a choice of RRT or conservative management to people who are likely to need RRT. Conservative management for children should only be considered within appropriate regulatory frameworks. See NICE's guideline on end of life care for children and young people with life-limiting conditions.\n\nEnsure that decisions about RRT modalities or conservative management are made jointly with the person (or with their family members or carers for children or adults lacking capacity) and healthcare team, taking into account:\n\npredicted quality of life\n\npredicted life expectancy\n\nthe person's preferences (see the recommendations on information, education and support)\n\nother factors such as co-existing conditions.\n\nOffer people (and their family members or carers, as appropriate) regular opportunities:\n\nto review the decision regarding RRT modalities or conservative management\n\nto discuss any concerns or changes in their preferences.\n\n## Transplantation\n\nDiscuss the individual factors that affect the risks and benefits of transplantation with all people who are likely to need RRT, and their family members or carers (as appropriate).\n\nInclude living donor transplantation in the full informed discussion of options for RRT.\n\nOffer a pre-emptive living donor transplant (when there is a suitable living donor) or pre-emptive listing for deceased donor transplantation to people considered eligible after a full assessment.\n\nDo not exclude people from receiving a kidney transplant based on BMI alone.\n\n## Choice of dialysis modalities\n\nOffer a choice of dialysis modalities at home or in centre ensuring that the decision is informed by clinical considerations and patient preferences (see recommendation 1.3.2).\n\nOffer all people who choose peritoneal dialysis a choice of continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD), if this is medically appropriate.\n\nConsider peritoneal dialysis as the first choice for children 2\xa0years or under.\n\nFor people who choose haemodialysis/haemodiafiltration (HD/HDF):\n\nConsider HDF rather than HD if in centre (hospital or satellite unit).\n\nConsider HDF or HD at home, taking into account the suitability of the space and facilities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on choosing modalities of renal replacement therapy or conservative management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: modalities of renal replacement therapy\xa0and evidence review C: sequencing modalities of renal replacement therapy.\n\nLoading. Please wait.\n\n# Planning dialysis access formation\n\nDiscuss with the person, their family members and carers (as appropriate) the risk and benefits of the different types of dialysis access, for example, fistula, graft, central venous or peritoneal dialysis catheter.\n\nWhen peritoneal dialysis is planned via a catheter placed by an open surgical technique, aim to create the access around 2\xa0weeks before the anticipated start of dialysis.\n\nWhen HDF or HD is planned via an arteriovenous fistula, aim to create the fistula around 6\xa0months before the anticipated start of dialysis to allow for maturation. When deciding on timing, take into account the possibility of the first fistula failing or needing further interventions before use.\n\nOffer ultrasound scanning to determine vascular access sites for creating arteriovenous fistulae for HDF or HD.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on planning dialysis access formation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: when to create access formation and/or list for transplantation and evidence review F: how to assess people for renal replacement therapy.\n\nLoading. Please wait.\n\n# Indications for switching or stopping renal replacement therapy\n\nOffer information on all medically appropriate treatment options when discussing switching RRT modality.\n\nConsider switching treatment modality or stopping RRT if medically indicated or if the person (or, where appropriate, their family members or carers) asks.\n\nPlan switching treatment modality or stopping RRT in advance wherever possible.\n\nDo not routinely switch people on peritoneal dialysis to a different treatment modality in anticipation of potential future complications such as encapsulating peritoneal sclerosis. However, monitor risk factors, such as loss of ultrafiltration.\n\nSeek specialist advice on the need for switching treatment modality when women become pregnant or wish to become pregnant.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for switching or stopping renal replacement therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: indicators for transferring or discontinuing renal replacement therapy.\n\nLoading. Please wait.\n\n# Recognising symptoms\n\nRecognise that people on RRT or receiving conservative management may have the symptoms in box\xa01 and that these may affect their day-to-day life.\n\n## Box 1 Possible symptoms in people on renal replacement therapy or conservative management\n\nGeneral symptoms:\n\nbreathlessness\n\nfatigue\n\ninsomnia\n\nitching\n\nlethargy\n\npain\n\npoor appetite\n\nswelling\n\ntaste changes\n\nthirst\n\nweakness\n\nweight loss/gain.\n\nGastro-intestinal/urological symptoms:\n\nabdominal cramps\n\nchange in bowel or urinary habits\n\nnausea.\n\nMusculoskeletal symptoms:\n\nmuscle cramps\n\nrestless legs.\n\nNeurological symptoms:\n\ncognitive impairment\n\ndizziness\n\nheadaches.\n\nPsychological/behavioural symptoms:\n\nanxiety\n\nbody image concerns\n\ndepression\n\nmood disturbances/fluctuations\n\nsexual dysfunction.\n\nThroughout the course of RRT and conservative management:\n\nAsk people about any symptoms they have.\n\nExplore whether symptoms are due to the renal condition, treatment or another cause.\n\nExplain the likely cause of the symptoms and how well treatment may be expected to control them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on recognising symptoms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: symptom recognition.\n\nLoading. Please wait.\n\n# Diet and fluids\n\nOffer a full dietary assessment by a specialist renal dietitian to people starting dialysis or conservative management. This should include:\n\nweight history\n\nfluid intake\n\nsodium\n\npotassium\n\nphosphate\n\nprotein\n\ncalories\n\nmicronutrients (vitamin and minerals).\n\nAfter transplantation, offer dietary advice from a healthcare professional with training and skills in this area.\n\nRe-assess dietary management and fluid allowance when:\n\na person's circumstances change (for example, when switching RRT modality), or\n\nbiochemical measures or body composition measures (for example, unintentional weight loss) indicate, or\n\nthe person (or, where appropriate, their family members or carers) asks.\n\nProvide individualised information, advice and ongoing support on dietary management and fluid allowance to the person and their family members or carers (as appropriate). The information should be in an accessible format and be sensitive to the person's cultural needs and beliefs.\n\nFollow the recommendations on dietary management and phosphate binders in NICE's guideline on chronic kidney disease.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and fluids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: dietary management and fluid restriction.\n\nLoading. Please wait.\n\n# Information, education and support\n\nTo enable people, and their families and carers (as appropriate), to make informed decisions, offer balanced and accurate information about:\n\nall treatments available to them (including RRT modalities and conservative management), and\n\nhow the treatments may affect their lives.See box\xa02 for more details.\n\n## Box 2 Information about treatments and how they may affect lifestyle\n\nInformation about treatments, including RRT, conservative management and dietary intervention:\n\nWhat they involve, for example, availability of assistance, time that treatment takes place, and number of sessions per day/week\n\nPotential benefits.\n\nThe benefits of adherence to treatment regimens and the potential consequences of non-adherence.\n\nPotential adverse effects, their severity and how they may be managed.\n\nThe likely prognosis on dialysis, after transplant or with conservative management.\n\nThe transplant listing process (when appropriate).\n\nSwitching the modality of RRT and the possible consequences (that is, the impact on the person's life or how this may affect future treatment or outcomes).\n\nReviewing treatment decisions.\n\nStopping treatment and planning end of life care.\n\nInformation about how treatments may affect lifestyle:\n\nThe person or carer's ability to carry out and adjust the treatment themselves.\n\nThe possible impact of dietary management and management of fluid allowance.\n\nHow treatment may fit in with daily activities such as work, school, hobbies, family commitments and travel for work or leisure.\n\nHow treatment may affect sexual function, fertility and family planning.\n\nOpportunities to maintain social interaction.\n\nHow treatment may affect body image.\n\nHow treatment may affect physical activity (for example, whether contact sports should be avoided after transplantation, whether swimming should be avoided with peritoneal dialysis).\n\nWhether a person's home will need to be modified to accommodate treatment.\n\nHow much time and travel treatment or training will involve.\n\nThe availability of transport.\n\nThe flexibility of the treatment regimen.\n\nWhether any additional support or services might be needed.\n\nRecognise the psychological impact of a person being offered RRT or conservative management and discuss what psychological support may be available to help with decision-making.\n\nDiscuss with people which treatment options are available to them and explain why any options may be inappropriate or not advised.\n\nOffer oral and written information and support early enough to allow time for people to fully understand their treatment options and make informed decisions. Information should be in an accessible format.\n\nDirect people to other sources of information and support (for example, online resources, pre-dialysis classes and peer support).\n\nRemember that some decisions must be made months before RRT is needed (for example, a fistula is created at least 6\xa0months before starting dialysis).\n\nBe prepared to discuss the information provided both before and after decisions are made, in line with the person's wishes.\n\nTake into account information the person has obtained from other sources (such as family members and carers) and how this information has influenced their decision.\n\nEnsure that healthcare professionals offering information have specialist knowledge about late stage chronic kidney disease and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage).\n\nOffer people who have presented late, or who started dialysis in an unplanned way, the same information as people who present at an earlier stage.\n\nFollow the recommendations on enabling patients to actively participate in their care in NICE's guideline on\xa0patient experience in adult NHS services\xa0and on information and education in NICE's guideline on\xa0chronic kidney disease. See also NICE's guideline on shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information, education and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: information, education and support.\n\nLoading. Please wait.\n\n# Coordinating care\n\nProvide the person with the contact details of the healthcare professional responsible for their overall renal care:\n\nbefore they start RRT or conservative management, and\n\nwhen they switch from one modality to another.\n\nCoordinate care to reduce its effect on day-to-day life and wellbeing (treatment burden). For example, take account of people's preferences and avoid scheduling appointments on non-dialysis days for people on hospital dialysis wherever possible.\n\nFollow the recommendations on:\n\ndelivering an approach to care that takes account of multimorbidity in NICE's guideline on multimorbidity, and\n\ncontinuity of care and relationships, and enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordinating care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review M: coordinating care.\n\nLoading. Please wait.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Cardiac assessment\n\nWhat is the clinical and cost effectiveness of cardiac assessment before transplantation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on preparing for renal replacement therapy or conservative management – how to assess\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.\n\nLoading. Please wait.\n\n## Timing of pre-emptive transplant\n\nWhat is the most clinical and cost-effective strategy for timing of pre-emptive transplantation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on indications for starting renal replacement therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.\n\nLoading. Please wait.\n\n## Acute haemodialysis versus acute peritoneal dialysis\n\nWhat is the clinical and cost effectiveness of initial haemodialysis versus initial peritoneal dialysis for people who start dialysis in an unplanned way?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on choosing modalities of renal replacement therapy or conservative management\xa0.\n\nFull details of the evidence and the committee's discussion are in\xa0evidence review B: modalities of renal replacement therapy\xa0and evidence review C: sequencing modalities of renal replacement therapy.\n\nLoading. Please wait.\n\n## Frequency of review\n\nWhat is the most clinical and cost-effective frequency of review for people on peritoneal dialysis, haemodiafiltration, haemodialysis or conservative management?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on frequency of review\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: frequency of review.\n\nLoading. Please wait.\n\n## Coordinating care\n\nWhat is the clinical and cost effectiveness of having keyworkers present in the context of renal replacement therapy (RRT)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on coordinating care\xa0.\n\nFull details of the evidence and the committee's discussion are in \xa0evidence review M: coordinating care.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\nWhat is the clinical and cost effectiveness of strategies for switching RRT modality?\n\nWhat is the clinical and cost effectiveness of using decision aids in the context of RRT?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on decision support interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: decision support interventions.\n\nLoading. Please wait.\n\nWhat is the optimum timing of laparoscopic and percutaneous peritoneal dialysis access creation?\n\nWhat is the clinical and cost effectiveness of conservative management versus dialysis in frail, older people?\n\nWhat is the clinical and cost effectiveness of home haemodiafiltration versus home haemodialysis, taking into account the impact of frequency?\n\nWhat is the clinical and cost effectiveness of haemodialysis/haemodiafiltration before peritoneal dialysis versus peritoneal dialysis before haemodialysis/haemodiafiltration?\n\nWhat is the optimum timing of listing for transplantation?", 'Rationale and impact': "# Indications for starting renal replacement therapy\n\nRecommendations 1.1.1 to 1.1.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that when to start dialysis is a complex decision that should take into account a number of factors (symptoms, patient preference, biochemistry, fluid overload and estimated glomerular filtration rate [eGFR]). Most people start dialysis due to symptoms, but evidence suggested that there was no overall harm or benefit of starting dialysis at an eGFR of around 5 to 7\xa0ml/min/1.73\xa0m2 in the absence of symptoms. However, there was evidence that starting dialysis when there are symptoms or the eGFR reaches 5 to 7 ml/min per 1.73\xa0m2 was cost saving compared with an earlier start. The committee noted that some people prefer to have an agreed starting point (eGFR), but may need dialysis before this because symptoms are affecting normal daily activities. Some people with slowly progressing chronic kidney disease may not recognise and report symptoms that indicate dialysis is needed. Taking all this information together, the committee acknowledged several indications for starting dialysis and agreed that these should be considered on an individual basis.\n\nThe committee agreed that it is important to establish whether symptoms (for example, fatigue and depression) are due to uraemia or not, and to discuss their impact on daily life.\n\nEvidence on the timing of pre-emptive transplant was limited and contradictory, with one study showing a clinically important benefit of transplanting at an eGFR of less than 10\xa0ml/min/1.73\xa0m2 but another showing no difference. The committee agreed to make a recommendation for research on this to guide future practice.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect common practice for adults and children, and so are not likely to involve a change of practice for most NHS providers or have a substantial resource impact for the NHS in England. If providers need to change from an earlier to a later initiation strategy, this is likely to be cost saving due to a reduction in time on dialysis.\n\nFull details of the evidence and the committee's discussion are in evidence review A: initiating renal replacement therapy.\n\nReturn to recommendations\n\n# Preparing for renal replacement therapy or conservative management – when to assess\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nSome evidence indicated that earlier referral to nephrology services improved survival on RRT at 90\xa0days. The committee were interested in the timing of referral for assessment for RRT and used their experience to recommend that this should be at least 1\xa0year before RRT is likely to be needed. They agreed that this would provide time for clinical and psychological preparation for dialysis or pre-emptive transplantation, and give the person, family members and carers enough time to think about the options. The committee acknowledged that there might be possible harms and costs for people who were referred but did not go on to need RRT, but they agreed that these were outweighed by the benefits of early referral for most people.\n\n## How the recommendation might affect practice\n\nThe recommendation generally reflects current practice so there should be no significant change in practice or substantial resource impact to the NHS in England.\n\nFull details of the evidence and the committee's discussion are in evidence review E: when to assess for renal replacement therapy.\n\nReturn to the recommendation\n\n# Preparing for renal replacement therapy or conservative management – how to assess\n\n## Why the committee made the recommendations\n\nRecommendations 1.2.2 to 1.2.3\n\nThe committee recognised that an assessment should involve preparing people for RRT, for example, by explaining the procedures to create vascular access and checking heart function and immunity. Psychosocial preparation is also important for reducing non-adherence and improving outcomes. They also highlighted the importance of discussing a person's preferences and understanding how decisions on RRT or conservative management are likely to affect a person's everyday life.\n\nNo evidence was identified on the psychological assessment of transplant recipients or donors. The committee agreed that there were likely benefits for identifying risk factors for non-adherence or morbidity after the operation. These could include substance misuse, current non-adherence or a previous or current mental health condition. Given the lack of evidence and potential resource impact, the committee agreed that assessment could be considered for specific high-risk groups.\n\nThere was no evidence on cardiac assessment before transplantation. The committee discussed current practice and agreed it is very variable. They therefore decided to make a recommendation for research to inform future practice.\n\n## How the recommendations might affect practice\n\nPsychological assessment in people at high risk of non-adherence or morbidity is current practice in many areas. The recommendation is likely to lead to better targeting of psychological assessment in other areas. The recommendation was not considered likely to have a substantial resource impact overall.\n\nFull details of the evidence and the committee's discussion are in evidence review F: how to assess people for renal replacement therapy.\n\nReturn to the recommendations\n\n# Choosing modalities of renal replacement therapy or conservative management\n\nRecommendations 1.3.1 to 1.3.11\n\n## Why the committee made the recommendations\n\nPeople who are likely to need RRT should be supported to make decisions about treatment options, including conservative management. There was no evidence of differential benefits or harms in any specific group of people and the committee agreed that the decision needs to be based on individual factors (such as frailty, cognitive impairment and multimorbidity) and patient preference.\n\nEvidence showed that if RRT is chosen, transplantation offers a clear advantage over dialysis in terms of extending life. This benefit was observed in each age group. In the committee's experience, quality of life and hospitalisation are also likely to be improved by transplantation. However, the individual factors that affect the risks and benefits of transplantation, for example, comorbidities, should be discussed. There was no evidence on cost effectiveness but the committee considered transplantation likely to have a lower cost over the long term due to the cost of avoiding dialysis. The committee agreed to recommend pre-emptive transplantation with a living donor or, if this is not an option, a transplant from a deceased donor.\n\nThe committee noted that the only available evidence suggested that people with a BMI greater than 30 benefited from transplant (as opposed to dialysis) to a similar degree as people with a BMI of 30 or under, in terms of mortality. The committee agreed to recommend that healthcare professionals do not exclude people from transplantation based on BMI alone.\n\nLimited evidence showed that if a transplant is not possible, peritoneal dialysis and haemodialysis (HD) offered similar benefits and equivalent harms. There was uncertainty about the differences in costs between peritoneal dialysis and HD due to uncertainty in current UK dialysis costs and transport costs. There was no evidence comparing haemodiafiltration (HDF) and peritoneal dialysis. The committee agreed that peritoneal dialysis and HD/HDF may have quite different effects on a person's life (for example, affecting their ability to travel and the need for self-care) so they agreed that a person should be able to choose the type of dialysis most suitable for them. Peritoneal dialysis should be considered for children under 2\xa0years due to difficulties with vascular access and extracorporeal blood volume.\n\nThere was no evidence to suggest clear differences between home and in-centre (hospital or satellite unit) HD/HDF. There is uncertainty in current UK dialysis costs but they may be lower at home. The committee acknowledged that these treatments can have very different effects on lifestyle and recommended patient choice.\n\nEvidence suggested that in-centre HDF was more effective than in-centre HD and was cost effective, so the committee agreed that HDF rather than HD should be recommended when dialysis was in centre. However, they were aware of an ongoing trial H4RT comparing high-volume HDF with high-flux HD and, following stakeholder consultation, changed the recommendation to consider HDF rather than HD for in-centre dialysis. The committee noted that HD may be done more frequently at home than in centre. The benefits of HDF are unknown in people who dialyse more frequently. There was no evidence on the efficacy of HDF at home. The committee was aware that some centres offer home HDF, although some people opt for transportable dialysis machines (which cannot do HDF currently) and these centres also provide home HD. Taking all of this information together the committee could not recommend one option over another for HD/HDF at home. They decided that either HD or HDF could be considered.\n\nThere was no evidence comparing HD/HDF and peritoneal dialysis as initial therapy for people who start dialysis in an unplanned way. The committee agreed to make a recommendation for research on this to inform future guidance.\n\nThere was no evidence to suggest clear differences between automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). Again the committee acknowledged that these treatments can have very different effects on lifestyle and recommended patient choice.\n\nThe committee agreed that people should have regular opportunities to review treatment options.\n\nThere was not enough evidence to recommend any particular sequence of RRT modalities. The committee agreed that decisions about sequence would mostly be guided by personal circumstances.\n\n## How the recommendations might affect practice\n\nCurrently there is a mix of HDF and HD provision in the NHS in England. The recommendation to consider HDF over HD for in-centre dialysis may affect resource use in areas where this is a change in practice. There are likely to be additional costs relating to consumables and water consumption with HDF compared with HD, but these may be partly offset by reduced use of erythropoietin-stimulating agent (ESA). There may be additional costs for machines where HDF-capable machines are not currently used. However, most centres already have some HDF-capable machines. This will enable them to accommodate any initial increased demand for HDF. Provision can be expanded if demand increases within the usual replacement cycles. These additional costs may result in a substantial resource impact to the NHS in England overall. However, this is uncertain as it is not possible to accurately predict how widely additional use of HDF will be considered.\n\nAlthough use of different RRT modalities and conservative management varies between areas, other recommendations reinforce current good practice to offer people a choice of modalities and settings, and conservative management, and so are not expected to have a substantial resource impact.\n\nThe committee agreed that people are often not offered regular opportunities to discuss the option of switching treatment modality or stopping RRT and so this may be a change in practice in many areas. However, these discussions could form part of current patient reviews and so would not mean a difference in resource use. More regular discussions may lead to more people switching or stopping RRT but this is not expected to result in a substantial resource impact overall.\n\nFull details of the evidence and the committee's discussion are in evidence review B: modalities of renal replacement therapy and evidence review C: sequencing modalities of renal replacement therapy.\n\nReturn to the recommendations\n\n# Planning dialysis access formation\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThe committee highlighted the importance of discussing with the person the different types of dialysis and their access and the impacts of these on everyday life.\n\nEvidence suggested that the best time for creating access for peritoneal dialysis by open surgery is around 2\xa0weeks before starting dialysis. There was no evidence on the best time for creating other types of peritoneal access so the committee decided to make a recommendation for research to inform future guidance.\n\nEvidence suggested that the best time for creating an arteriovenous fistula (AVF) for vascular access was 3 to 6\xa0months before starting HD or HDF. It suggested that earlier AVF creation may increase the rate of AVF success. The committee agreed that doing this early (around 6\xa0months) reduced the need for additional access procedures. However, when a fistula is created early, some people may never need it, for example, because they have a pre-emptive transplant. The committee agreed that the benefits of establishing a fistula around 6\xa0months before starting dialysis, including the cost savings associated with avoiding additional access procedures, were likely to outweigh the potential disadvantages and increased costs associated with unused fistulae. The committee noted that the precise timing will vary from person to person, depending on the likely success of fistula creation.\n\nEvidence showed a benefit of routine ultrasound scanning in terms of reduced failure of AVF. Cost calculations based on the clinical evidence suggested that routine scanning is likely to reduce overall costs because of fewer repeat interventions. The committee agreed to recommend routine ultrasound scanning to determine vascular access sites.\n\nThe committee noted that there was no evidence to guide the optimum timing of transplant listing and therefore made a recommendation for research in this area.\n\n## How the recommendations might affect practice\n\nCurrent practice for creating vascular access is variable. A minimum timing from creation to use of 6\xa0weeks has been suggested – however, the committee agreed that creation around 6 months reflected common practice. The recommendation is not expected to have a significant impact on practice, but should standardise some current variability. It is not expected to have a substantial resource impact to the NHS in England.\n\nCurrent practice for creating peritoneal dialysis access via open surgery is broadly in line with the recommendation (that is, 2\xa0weeks before use) and so this recommendation is not expected to have a substantial resource impact to the NHS in England.\n\nCurrent practice regarding ultrasound scanning to determine access sites is variable; some centres use routine ultrasound scanning but others offer a more selective approach. The recommendation would not involve a large change in practice and is likely to be cost saving because of the reduced need for repeat intervention. It is not expected to have a substantial resource impact to the NHS in England.\n\nFull details of the evidence and the committee's discussion are in evidence review D: when to create access formation and/or list for transplantation and evidence review F: how to assess people for renal replacement therapy.\n\nReturn to the recommendations\n\n# Indications for switching or stopping renal replacement therapy\n\nRecommendations 1.5.1 to 1.5.5\n\n## Why the committee made the recommendations\n\nThere was no evidence on indications for switching treatment and the committee agreed to make recommendations for research on possible indicators to inform future guidance. There was no evidence that people on peritoneal dialysis should switch modality in anticipation of future complications such as encapsulating peritoneal sclerosis and the committee agreed this should not be routine. They highlighted that healthcare professionals should monitor for risk factors predicting complications (for example, loss of ultrafiltration).\n\nThere was also no evidence to support a switch from peritoneal dialysis to HD/HDF for women who become or wish to become pregnant. The committee agreed that the need for a switch would depend on the adequacy of dialysis, the health of the fetus and the control of urea. They recommended that specialist advice should be sought before any decisions were made.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current good practice and are not expected to have a resource impact to the NHS in England.\n\nFull details of the evidence and the committee's discussion are in evidence review G: indicators for transferring or discontinuing renal replacement therapy.\n\nReturn to the recommendations\n\n# Recognising symptoms\n\nRecommendations 1.6.1 to 1.6.2\n\n## Why the committee made the recommendations\n\nEvidence identified symptoms that people approaching the need for RRT or receiving RRT or conservative management frequently report as affecting their lives. The committee also identified others (for example, change in urinary habits). People may feel uncomfortable talking about some symptoms (for example, sexual dysfunction) and may not associate them with their condition or its treatment. The committee agreed that healthcare professionals should ask people about symptoms and determine the likely cause. It is important that people understand which symptoms they may experience, which may need further management and if treatment will control them.\n\n## How the recommendations might affect practice\n\nCurrently, not all healthcare professionals ask people about all of the symptoms they are experiencing. They may only ask about specific symptoms and not explore all of them. Healthcare professionals should ascertain whether symptoms are due to the person's renal condition or not and explain this to them. This may be a change in practice for some, but is not expected to have a substantial resource impact to the NHS in England.\n\nFull details of the evidence and the committee's discussion are in evidence review H: symptom recognition.\n\nReturn to the recommendations\n\n# Diet and fluids\n\nRecommendations 1.7.1 to 1.7.5\n\n## Why the committee made the recommendations\n\nLimited evidence, including in people with a transplant, indicated that people receiving RRT or conservative management may benefit from dietary and/or fluid management. The committee agreed that current practice is for people receiving dialysis or conservative management to have an assessment by a specialist dietitian. NICE's guideline on managing hyperphosphataemia in chronic kidney disease recommends assessment by a specialist renal dietitian for those at risk of hyperphosphataemia, which would include these groups of people. They also considered it current practice for dietary advice to be given after transplantation, although this advice is not always given by a specialist renal dietitian. The committee noted that there is some variation in how long people have to wait for this assessment, and variation in ongoing management. The committee agreed that dietary advice is important for people with a transplant, particularly straight after the surgery. This was supported by the evidence. The committee noted the importance of the person giving dietary advice having specialist knowledge of dietary requirements in transplant patients. However, the evidence was too limited to recommend that dietary advice should routinely be from a specialist renal dietitian for this group given it would be a change in practice in many areas and could result in a substantial resource impact.\n\nThe committee agreed that following initial assessment further dietary assessment would be determined by specific circumstances or indicators and made a recommendation summarising what these would be. They highlighted that there is variation in the level of dietitian input available in renal centres, which may affect how quickly people can access services or the level of input following initial assessment. However, the evidence was not considered sufficient to make specific recommendations to address this.\n\nThe committee agreed that involving family members and carers in discussions was important for improving adherence to dietary management and fluid allowance. There was no evidence on the benefits or harms of a low protein diet so the committee was not able to make a recommendation on this. The committee agreed that dietary management and fluid assessment should not be a 'one-step' process and that people's needs should be reviewed when circumstances change (for example, when switching RRT modalities) or when biochemical measures indicate.\n\n## How the recommendations might affect practice\n\nThe recommendations made reflect current practice and are not expected to result in a substantial resource impact to the NHS in England.\n\nFull details of the evidence and the committee's discussion are in evidence review I: dietary management and fluid restriction.\n\nReturn to the recommendations\n\n# Frequency of review\n\n## Why the committee made the recommendation for research\n\nNo evidence was identified to support any particular strategy for timing of review for people on RRT or conservative management. Because of the lack of evidence, considerable variation in current practice and the likely resource implications of a practice recommendation, the committee made a recommendation for research to inform future guidance.\n\nFull details of the evidence and the committee's discussion are in evidence review J: frequency of review.\n\n# Information, education and support\n\n## Why the committee made the recommendations\n\nRecommendations 1.8.1 to 1.8.11\n\nThe committee used the evidence and their own experience to update the recommendations on information and support from NICE's 2011 guideline on peritoneal dialysis (CG125) and to extend these to cover other forms of RRT and conservative management. Key findings related to information being provided well in advance of decisions being needed, multiple formats of information being available, and full information on all modalities being provided. Information should also be provided on the psychological impact of starting RRT and the decision-making process.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current practice and therefore are unlikely to have a resource impact. They focus mainly on the principles of information and support rather than on specific interventions.\n\nFull details of the evidence and the committee's discussion are in evidence review K: information, education and support.\n\nReturn to the recommendations\n\n# Decision support interventions\n\n## Why the committee made the recommendation for research\n\nLimited evidence suggested a benefit of structured education programmes although results were inconsistent. The committee noted that decision aids are used in clinical practice but do not replace discussions between the patient, families and carers, and healthcare professionals when making decisions about RRT or conservative management. Education classes and peer support are also important to support decision-making. In the absence of evidence showing clinically important benefits, the committee were unable to recommend that decision aids should be used. They decided to make a recommendation for research to inform future practice.\n\nFull details of the evidence and the committee's discussion are in evidence review L: decision support interventions.\n\n# Coordinating care\n\nRecommendations 1.9.1 to 1.9.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on the coordination of care but the committee agreed that people should know who to contact with questions about their condition or treatment. This is particularly important when they start or change RRT modalities. The committee noted that people on RRT experience considerable treatment burden and that strategies should be adopted to reduce this. There was no evidence on care coordination by a keyworker so the committee recommended the healthcare professional responsible for renal care as a first point of contact. They made a recommendation for research on care coordination by a keyworker to inform future guidance.\n\n## How the recommendations might affect practice\n\nCurrent practice is variable in terms of when a person is given the details of the person responsible for care. This recommendation will ensure that this is done before starting treatment or when switching modalities or to conservative management. Similarly the recommendation on reducing treatment burden standardises and reinforces good practice. Some healthcare professionals may need to change their practice but this would not result in a substantial resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review M: coordinating care.\n\nReturn to the recommendations", 'Context': "People with chronic kidney disease (CKD) have an irreversible and progressive deterioration in kidney function. Renal replacement therapy (RRT) is a treatment option in people with CKD whose condition progresses to kidney failure. RRT essentially comprises either transplantation or dialysis (artificially removing waste products and excess water from the blood). Transplantation can be from living or deceased donors, and for some people it may involve the transplantation of more than one organ simultaneously (for example, combined pancreas and kidney transplantation for people with type I diabetes mellitus). In some cases, transplantation may be pre-emptive, occurring before dialysis would be needed. There are 2 main types of dialysis: haemodialysis (where the blood is filtered outside of the body using a dialysis machine) and peritoneal dialysis (where the person's abdominal lining is used to filter the blood). Some people choose not to receive RRT but continue to receive other supportive and symptomatic treatment for kidney failure – for example, treatment for their anaemia or dietary modification. This is usually called conservative management. People may also receive end of life care, and this may include both supportive and palliative care.\n\nAccording to the 19th annual report by the UK Renal Registry (2016), on 31 December 2015 there were 61,256 adults in the UK receiving RRT. Of these, 53.1% had received a transplant, 41.0% were receiving haemodialysis (21.2% in satellite units, 17.8% in hospitals, 2.0% at home), 2.5% were receiving continuous ambulatory peritoneal dialysis and 3.4% were receiving automated peritoneal dialysis. In addition, 769 children and young people under the age of 16\xa0years were receiving RRT. Most had received a transplant (41% live, 34% deceased), with 13% on haemodialysis and 12% on peritoneal dialysis. The median age of all people newly requiring RRT was 59.0\xa0years; 22.7% of people were from minority ethnic groups. The reported 1-year risk of death for people on RRT aged 35 to 39\xa0years was approximately 22.0 times higher than age- and sex-matched controls not on RRT. Survival rates for people with diabetes on maintenance haemodialysis are lower than those of people without diabetes. The number of people receiving conservative management varies between renal units and has been difficult to establish, but up to 40% of people over 70 choose this option. Most of these still receive their care and treatment through renal services.\n\nApproximately 5,500 adults and children are currently on the national renal transplant (waiting) list (NHS Blood and Transplant), with about 3,000 renal transplants performed each year. The median time to transplantation for those on the list is around 1,000\xa0days for adults and 300\xa0days for children. There is considerable inequality across ethnic groups, with relatively fewer people from black, Asian and minority ethnic groups on the organ donor list. These groups have a higher incidence and prevalence of CKD needing RRT and tend to reach this stage at a younger age.\n\nRRT is an expensive treatment. The total cost of CKD in England in 2009–10 was estimated at £1.45\xa0billion; more than half of this sum was spent on RRT.\n\nThis guideline aims to improve the care of people with CKD who need RRT or conservative management. The guideline covers the choice, timing, preparation for and switching of RRT 'modalities' for children and adults, as well as symptom recognition, information, education and support, and coordination of care."}
|
https://www.nice.org.uk/guidance/ng107
|
This guideline covers renal replacement therapy (dialysis and transplantation) and conservative management for people with chronic kidney disease stages 4 and 5. It aims to improve quality of life by making recommendations on planning, starting and switching treatments, and coordinating care.
|
10d21407db143f6403468e7f2dddc5f0ee06c438
|
nice
|
Cabozantinib for untreated advanced renal cell carcinoma
|
Cabozantinib for untreated advanced renal cell carcinoma
Evidence-based recommendations on cabozantinib (Cabometyx) for untreated advanced renal cell carcinoma in adults.
# Recommendations
Cabozantinib is recommended, within its marketing authorisation, for adults with untreated advanced renal cell carcinoma that is intermediate‑ or poor‑risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria. It is recommended only if the company provides cabozantinib according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for untreated advanced renal cell carcinoma is usually pazopanib or sunitinib.
Clinical trial evidence shows that cabozantinib extends the time until cancer progresses compared with current treatment. But the evidence on whether cabozantinib increases how long people live is less certain. It appears to be at least as effective as current treatment, but it's not clear how much extra benefit it offers.
Cost-effectiveness estimates for cabozantinib compared with current treatment are uncertain. This is because there is not much evidence available to estimate how long people live, and the costs and benefits of treatments after cabozantinib do not fully reflect those in the NHS. The cost‑effectiveness estimates are within the range that NICE usually considers a cost‑effective use of NHS resources, taking into account the uncertain estimates. Therefore, cabozantinib is recommended as an option for treating advanced renal cell carcinoma in the NHS.# Information about cabozantinib
Marketing authorisation indication
Cabozantinib (Cabometyx, Ipsen) is indicated for 'the treatment of advanced renal cell carcinoma in untreated adults with intermediate‑ or poor‑risk' as defined in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria'.
Dosage in the marketing authorisation
Cabozantinib is for oral use. The recommended dose is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefitting from therapy or until unacceptable toxicity occurs.
Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction. When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.
Price
£5,143 per pack of 30×60 mg tablets (excluding VAT; British National Formulary online, accessed August 2018).
The company has a commercial arrangement. This makes cabozantinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Ipsen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with untreated intermediate- or poor-risk renal cell carcinoma would welcome a new treatment option
The patient and clinical experts explained that tyrosine kinase inhibitors, such as sunitinib and pazopanib, are the current standard of care for people with untreated advanced renal cell carcinoma. They can cause adverse effects such as extreme fatigue, hand and foot syndrome, and chronic diarrhoea, which can affect quality of life. The committee concluded that people with intermediate- or poor‑risk advanced renal cell carcinoma would welcome a new treatment option.
# Clinical management
## Prognostic risk scores are not routinely used in UK clinical practice, but there are no barriers to using them
Cabozantinib is indicated for treating intermediate- and poor-risk advanced renal cell carcinoma. The clinical experts stated that prognostic scores to define intermediate‑ and poor‑risk groups are not used in clinical practice. They noted that the 2 best known risk scores are the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score and the Memorial Sloan-Kettering Cancer Center (MSKCC) risk score. The clinical experts considered that the 2 scores were similar, but would prefer to use the IMDC risk score because it was used in the clinical trial for cabozantinib. They stated that clinicians routinely collect all components of the risk scores, and would be able to start using the risk scores immediately.
# Comparators
## Sunitinib or pazopanib are appropriate comparators, and can be considered clinically equivalent
People with newly diagnosed untreated advanced renal cell carcinoma would be offered 1 of 3 tyrosine kinase inhibitors; recommended in NICE's technology appraisal guidance on pazopanib, sunitinib or tivozanib. Tivozanib was not included in the scope of this appraisal because it was not part of clinical practice at the start of the appraisal. The clinical experts and the Cancer Drugs Fund clinical lead confirmed that most people would be offered pazopanib and the rest sunitinib. The clinical experts stated that in practice, sunitinib and pazopanib are considered clinically equivalent. The committee recalled that in previous appraisals it considered sunitinib and pazopanib to be clinically equivalent, and there was no new evidence to change this conclusion. The committee concluded that pazopanib and sunitinib were the relevant comparators in this appraisal, and could be considered clinically equivalent.
# Clinical evidence
## The small number of people in the main clinical trial, CABOSUN, makes the results uncertain
The main evidence on the clinical effectiveness of cabozantinib came from CABOSUN. This was a phase 2 clinical trial comparing cabozantinib with sunitinib in 157 patients with untreated, intermediate- or poor-risk (IMDC criteria) advanced renal cell carcinoma. The primary outcome of the trial was progression‑free survival; overall survival was a secondary outcome. The company explained that CABOSUN was not designed to be a registration trial, but was submitted to the regulators because the results were 'encouraging'. The committee concluded that the small number of patients in the trial made the results uncertain.
## The results of CABOSUN are generalisable to clinical practice in England
CABOSUN was carried out in the US, where clinical practice and the characteristics of people who have renal cell carcinoma treatment are different to those in England. The clinical experts stated that the patients in the trial generally reflect people who are expected to have cabozantinib in NHS clinical practice. However, they noted that people recruited to clinical trials are sometimes younger, in better health and able to tolerate a short wait before treatment begins. The clinical experts therefore expected people in NHS clinical practice to have poorer health and a poorer prognosis than those in CABOSUN. The Cancer Drugs Fund clinical lead stated that the proportion of people with intermediate- and poor-risk disease who will have treatment in clinical practice was uncertain, but there was no evidence to suggest that the proportion was different to that in CABOSUN. Although the committee considered that it was possible that people in NHS clinical practice have poorer health and a poorer prognosis than the trial population, it had not seen robust evidence to support this. Therefore, it concluded that the results of CABOSUN are generalisable to clinical practice in England.
# Progression‑free survival
## Cabozantinib increases progression-free survival compared with sunitinib
Cabozantinib increased median progression‑free survival assessed by investigators (primary outcome), compared with sunitinib, from 5.4 months to 8.3 months (hazard ratio 0.56, 95% confidence interval 0.37 to 0.83, p=0.0042). The company retrospectively analysed progression‑free survival assessed by an independent review committee to support its regulatory submissions. This analysis used a 2‑sided test for significance rather than the 1‑sided test used in the investigator analysis. It also included additional censoring of patients who had non‑protocol systemic anticancer therapy or whose disease progressed after missing 2 or more assessments. The results of the retrospective analysis showed that cabozantinib increased median progression‑free survival compared with sunitinib, from 5.3 months to 8.6 months (HR 0.48, 95% CI 0.31 to 0.74, p=0.0008). The committee concluded that cabozantinib increased progression‑free survival compared with sunitinib.
# Overall survival
## There is no strong evidence that people taking cabozantinib live longer than people taking sunitinib
The results from the July 2017 data cut showed a median overall survival of 26.6 months with cabozantinib compared with 21.2 months with sunitinib (HR 0.80, 95% CI 0.53 to 1.21, p=0.29). The committee was aware that the trial was not powered to show a difference between treatments in overall survival, a secondary outcome. It noted that the Kaplan–Meier curves converged at around 14 months before separating again at around 21 months. The clinical experts advised that there was no clinical explanation for this, but that it may be explained by chance given the small numbers in the trial (157 patients). The committee concluded that there was no strong evidence to show that people who are offered cabozantinib live longer than those who are offered sunitinib.
## There is no robust evidence to show that the effectiveness of cabozantinib is different in the poor- and intermediate‑risk groups
The company provided data on overall survival in the poor- and intermediate‑risk groups in response to a clarification request from the ERG. The committee noted that these results were uncertain, particularly for the poor-risk group, because the patient numbers in each group were small: 127 patients in the intermediate‑risk group and 30 patients in the poor‑risk group. It concluded that no firm conclusion could be drawn about the effectiveness of cabozantinib in any 1 particular subgroup.
# Indirect treatment comparison
## An indirect treatment comparison is not needed because pazopanib and sunitinib are considered clinically equivalent
The company did an indirect treatment comparison to compare the clinical effectiveness of cabozantinib and pazopanib. The committee was aware that indirect comparisons are inherently uncertain, and more so in this appraisal. This was because the evidence on pazopanib came from the COMPARZ trial, which also included patients in the favourable-risk category who have a better prognosis than those with intermediate- or poor-risk disease. The committee recalled that pazopanib and sunitinib can be considered equally clinically effective (see section 3.3). Therefore, it concluded that an indirect treatment comparison was not needed, and did not consider it further.
# The company's economic model
## The structure of the company's model is appropriate for decision-making
The company used a partitioned‑survival economic model that included 3 states: pre-progression, post-progression and death. The committee concluded that the structure of the model was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma.
# Treatment effects in the economic model
## The model that includes the assumption that pazopanib is as effective as sunitinib is preferable
The company's original analysis modelled the treatment effectiveness of pazopanib based on an indirect treatment comparison. The ERG's base case did not include pazopanib separately, but assumed that it was equally effective to sunitinib, which the committee agreed was reasonable (see section 3.3). The committee concluded that it was more appropriate to include pazopanib in the analysis, and assume that it was clinically equivalent to sunitinib (as per the ERG's analyses), than to include an indirect treatment comparison (as per the company's analyses). The company used this approach in their revised analysis.
## Basing the modelling on independent review committee-assessed progression-free survival is acceptable
The company and ERG both based their modelling of progression‑free survival on the retrospective assessment by independent review committee. The committee generally prefers using the primary end point of the trial in the model, which for CABOSUN was investigator-assessed progression-free survival. However, it noted that the results using either assessment were similar, and unlikely to have had a large effect on cost effectiveness. The committee therefore accepted the approach used by the company and ERG.
## There is a high degree of uncertainty in the extrapolation of overall survival
The committee recognised that the immaturity of the data and the small size of the trial meant that projecting survival outcomes beyond the trial follow-up would be challenging and inherently uncertain. Also, because the Kaplan–Meier curves for overall survival crossed, no parametric curve fitted the data well. The committee considered whether piecewise modelling would be suitable (for example, using the Kaplan–Meier curves for the duration of follow-up and parametric extrapolation fitted to the end of the curve thereafter), but it agreed that such modelling needs larger patient numbers. The committee noted that both the company and the ERG preferred the exponential distribution, which the clinical experts advised produced plausible predictions of overall survival at 5 years and 10 years after starting treatment. The ERG assumed proportional hazards (despite the log‑cumulative hazard plots violating proportional hazards) because it considered that the Kaplan–Meier curves should not be 'over‑interpreted' given the small numbers of patients. The committee agreed that it was unclear whether proportional hazards holds. It concluded that the chosen distributions fitted the data poorly and that the curve was a source of uncertainty in the economic model.
## Scenario analyses of the choice of curve for overall survival extrapolation are appropriate to consider in decision-making
The company conducted scenario analyses to examine the sensitivity of the model to the choice of overall survival extrapolation. It provided analyses using Weibull and Gompertz distributions fitted separately (assuming the proportional hazards assumption did not hold) and jointly (assuming the proportional hazards assumption did hold). The ERG also included scenarios using alternative parametric distributions. The committee noted that the incremental cost‑effectiveness ratios (ICERs) generated by the scenario analyses varied by around £6,500 per quality‑adjusted life year (QALY) gained, depending on whether curves were fitted separately or jointly, and depending on which distribution was used. It concluded that it would take into account the uncertainty in the choice of curve for extrapolating overall survival in its decision-making.
## It is not appropriate to assume that cabozantinib has a relative survival benefit compared with sunitinib after 5 years
The company's original base case assumed that the relative effect of cabozantinib compared with sunitinib continued beyond the trial follow-up (that is, the hazard ratio remained below 1), even after the disease progressed or patients stopped treatment, but there was no evidence to support this. The clinical experts considered that it was not clear whether a survival benefit would continue after stopping treatment. The ERG's base case assumed that treatment benefit with cabozantinib compared with sunitinib did not persist after 5 years (that is, the hazard ratio became 1 after 5 years). The committee agreed that assuming the treatment benefit of cabozantinib compared with sunitinib continued for up to 20 years or even for 10 years, based on a trial with a median follow‑up of under 3 years, was not plausible. The committee agreed that the modelling should assume that there is no treatment effect beyond the observed survival data, which covered a duration of less than 4 years. It therefore concluded that the ERG's assumption was preferable and the company used this assumption in its revised base case.
# Utility values in the economic model
## The source of utility values used in the economic model is appropriate
Quality-of-life data were not collected in CABOSUN. Therefore, the company and ERG used utility values from NICE's technology appraisal guidance on tivozanib in their base cases. The committee concluded that this source of utility values was appropriate.
# Costs in the economic model
## The costs and benefits of subsequent therapies (treatments second line and beyond) are a key source of uncertainty in the cost-effectiveness model
Both the company's and ERG's base cases included a distribution of subsequent therapies (that is, therapies for renal cell cancer second line and beyond) based on CABOSUN for cabozantinib and sunitinib, and based on COMPARZ for pazopanib. The committee agreed that, given the assumption that pazopanib and sunitinib are equivalent (see sections 3.3 and 3.11), the same source of data for therapies after sunitinib and pazopanib should be used. It preferred using CABOSUN because CABOSUN is more recent than COMPARZ, so more closely reflects clinical practice. However, CABOSUN and COMPARZ included subsequent treatments that are not recommended in the NHS. The committee noted that both the company and the ERG presented scenario analyses of second‑line NHS drug use based on clinical expert opinion. Clinical experts indicated that the ERG's scenario analysis more closely reflected the expected second‑line therapy use in the NHS. However, the company modelled therapies by reflecting only their cost, but not their benefits, and the committee preferred including both costs and benefits of subsequent therapies. Therefore, the committee agreed that the base‑case assumptions using clinical trial data to depict subsequent treatment were acceptable, but should be based on CABOSUN for both pazopanib and sunitinib. In response to consultation, the company revised its analyses to assume the same subsequent therapies after pazopanib and sunitinib (see table 1). Because the ERG's scenario analysis more closely reflected the cost of subsequent therapies used in the NHS, the committee also considered this scenario when making its decision. The ERG's scenario increased the revised base-case ICER by around £10,500 per QALY gained. However, this difference would likely be smaller when adjusting the benefits as well as the costs of subsequent therapy to reflect NHS practice. Because of this, the committee concluded that the costs and benefits of subsequent therapies were a key source of uncertainty in the cost‑effectiveness model.
NHS recommended subsequent therapies
Revised company base case for cabozantinib (%)
Evidence review group (ERG) scenario for cabozantinib (%)
Revised company base case for sunitinib (%)
ERG scenario for sunitinib (%)
Axitinib
Cabozantinib
Everolimus
Nivolumab
Lenvatinib plus everolimus
Best supportive care
Other therapies
Total
# Cost-effectiveness estimates
## The company's revised base case reflects the committee's preferred assumptions
In response to the appraisal consultation document, the company updated its economic model to include the committee's preferred assumptions, which were:
including pazopanib in the analysis and assuming it is clinically equivalent to sunitinib (see sections 3.3 and 3.11)
basing overall survival extrapolation on the most recent data cut (see section 3.7)
including a duration of treatment benefit for cabozantinib compared with sunitinib persisting only up to 5 years (see section 3.15)
reflecting both costs and benefits of subsequent treatments (see section 3.17).The company also updated its model to incorporate an increase to the confidential patient access scheme discount. The committee concluded that the company's revised model reflected its preferred assumptions.
# Uncaptured benefits
## There are no health‑related benefits that are not captured in the analysis
The committee recalled the conclusion from NICE's technology appraisal guidance on cabozantinib for previously treated advanced renal cell carcinoma. This was that cabozantinib did not reflect a 'step-change' in treatment and no benefits were identified which were not otherwise accounted for in the modelling. The committee saw no evidence to change its conclusion for people with untreated advanced renal cell carcinoma. It therefore concluded that there were no additional health‑related quality-of-life benefits not already captured in the QALY calculations.
# End of life
## Life expectancy for people in the combined intermediate- and poor-risk group is likely to be more than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.
The median overall survival in the sunitinib arm in CABOSUN was 21.2 months.
Using the committee's preferred analysis, the model estimated a mean of more than 24.0 months in the sunitinib arm.The committee preferred mean estimates when considering the end-of-life criteria. It was aware that survival estimates were also available from the ongoing CheckMate 214 clinical trial of nivolumab with ipilimumab in the same population. The median overall survival in the sunitinib arm of CheckMate 214 was 25.9 months, but the mix of patients with intermediate‑ or poor‑risk disease differed from the CABOSUN trial. For the combined poor‑ and intermediate‑risk group, there was no robust evidence that average life expectancy was less than 24 months. Therefore, the committee concluded that cabozantinib did not meet the criterion for short life expectancy.
## Cabozantinib meets the criterion for extending life by more than 3 months compared with standard of care
The committee noted that CABOSUN trial did not show that cabozantinib extends life, but acknowledged that the trial was not powered to show a difference in overall survival (see section 3.7). The economic model estimated that cabozantinib extends life compared with sunitinib by around 6 months on average in the company's revised base case. The committee accepted that cabozantinib extends life by more than 3 months compared with established NHS practice in England for the purposes of the end‑of‑life considerations.
## The plausible ICERs are consistent with those usually considered a cost‑effective use of NHS resources
In incremental analyses using the company's revised base case, cabozantinib and sunitinib 'extendedly dominated' pazopanib (that is, pazopanib was more expensive and more costly than having the options of cabozantinib and sunitinib) leaving the relevant comparison between cabozantinib and sunitinib. The ICER reflecting the cost effectiveness of cabozantinib compared with sunitinib was less than £20,000 per QALY gained. Because the subsequent therapies included in the model were priced based on confidential patient access schemes, the estimated ICER taking these into account cannot be included here. In addition to the base case, the committee considered several scenarios exploring the key areas of uncertainty in the model, including:
The choice of curve used to estimate overall survival: the ICERs generated from these scenario analyses changed by about £6,500 per QALY gained (see section 3.14).
The costs and benefits of treatments second‑line and beyond: when considering the ERG's scenario reflecting the costs (but not benefits) of second-line treatment use in the NHS, the company's revised base‑case ICER compared with sunitinib increased by about £10,500 per QALY gained (see section 3.17). The committee agreed that the impact of this change on the most plausible ICER was likely to be lower when including the benefits of life-extending, second-line treatments used in the NHS.The committee concluded that, taking into account the degree of uncertainty associated with the evidence base, the estimated ICERs reflected a cost-effective use of NHS resources for people with untreated intermediate‑ and poor‑risk advanced renal cell carcinoma.
|
{'Recommendations': "Cabozantinib is recommended, within its marketing authorisation, for adults with untreated advanced renal cell carcinoma that is intermediate‑ or poor‑risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria. It is recommended only if the company provides cabozantinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for untreated advanced renal cell carcinoma is usually pazopanib or sunitinib.\n\nClinical trial evidence shows that cabozantinib extends the time until cancer progresses compared with current treatment. But the evidence on whether cabozantinib increases how long people live is less certain. It appears to be at least as effective as current treatment, but it's not clear how much extra benefit it offers.\n\nCost-effectiveness estimates for cabozantinib compared with current treatment are uncertain. This is because there is not much evidence available to estimate how long people live, and the costs and benefits of treatments after cabozantinib do not fully reflect those in the NHS. The cost‑effectiveness estimates are within the range that NICE usually considers a cost‑effective use of NHS resources, taking into account the uncertain estimates. Therefore, cabozantinib is recommended as an option for treating advanced renal cell carcinoma in the NHS.", 'Information about cabozantinib': "Marketing authorisation indication\n\nCabozantinib (Cabometyx, Ipsen) is indicated for 'the treatment of advanced renal cell carcinoma in untreated adults with intermediate‑ or poor‑risk' as defined in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria'.\n\nDosage in the marketing authorisation\n\nCabozantinib is for oral use. The recommended dose is 60\xa0mg once daily. Treatment should continue until the patient is no longer clinically benefitting from therapy or until unacceptable toxicity occurs.\n\nManagement of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction. When dose reduction is necessary, it is recommended to reduce to 40\xa0mg daily, and then to 20\xa0mg daily.\n\nPrice\n\n£5,143 per pack of 30×60\xa0mg tablets (excluding VAT; British National Formulary online, accessed August 2018).\n\nThe company has a commercial arrangement. This makes cabozantinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Ipsen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with untreated intermediate- or poor-risk renal cell carcinoma would welcome a new treatment option\n\nThe patient and clinical experts explained that tyrosine kinase inhibitors, such as sunitinib and pazopanib, are the current standard of care for people with untreated advanced renal cell carcinoma. They can cause adverse effects such as extreme fatigue, hand and foot syndrome, and chronic diarrhoea, which can affect quality of life. The committee concluded that people with intermediate- or poor‑risk advanced renal cell carcinoma would welcome a new treatment option.\n\n# Clinical management\n\n## Prognostic risk scores are not routinely used in UK clinical practice, but there are no barriers to using them\n\nCabozantinib is indicated for treating intermediate- and poor-risk advanced renal cell carcinoma. The clinical experts stated that prognostic scores to define intermediate‑ and poor‑risk groups are not used in clinical practice. They noted that the 2\xa0best known risk scores are the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score and the Memorial Sloan-Kettering Cancer Center (MSKCC) risk score. The clinical experts considered that the 2\xa0scores were similar, but would prefer to use the IMDC risk score because it was used in the clinical trial for cabozantinib. They stated that clinicians routinely collect all components of the risk scores, and would be able to start using the risk scores immediately.\n\n# Comparators\n\n## Sunitinib or pazopanib are appropriate comparators, and can be considered clinically equivalent\n\nPeople with newly diagnosed untreated advanced renal cell carcinoma would be offered 1\xa0of\xa03 tyrosine kinase inhibitors; recommended in NICE's technology appraisal guidance on pazopanib, sunitinib or tivozanib. Tivozanib was not included in the scope of this appraisal because it was not part of clinical practice at the start of the appraisal. The clinical experts and the Cancer Drugs Fund clinical lead confirmed that most people would be offered pazopanib and the rest sunitinib. The clinical experts stated that in practice, sunitinib and pazopanib are considered clinically equivalent. The committee recalled that in previous appraisals it considered sunitinib and pazopanib to be clinically equivalent, and there was no new evidence to change this conclusion. The committee concluded that pazopanib and sunitinib were the relevant comparators in this appraisal, and could be considered clinically equivalent.\n\n# Clinical evidence\n\n## The small number of people in the main clinical trial, CABOSUN, makes the results uncertain\n\nThe main evidence on the clinical effectiveness of cabozantinib came from CABOSUN. This was a phase\xa02 clinical trial comparing cabozantinib with sunitinib in 157\xa0patients with untreated, intermediate- or poor-risk (IMDC criteria) advanced renal cell carcinoma. The primary outcome of the trial was progression‑free survival; overall survival was a secondary outcome. The company explained that CABOSUN was not designed to be a registration trial, but was submitted to the regulators because the results were 'encouraging'. The committee concluded that the small number of patients in the trial made the results uncertain.\n\n## The results of CABOSUN are generalisable to clinical practice in England\n\nCABOSUN was carried out in the US, where clinical practice and the characteristics of people who have renal cell carcinoma treatment are different to those in England. The clinical experts stated that the patients in the trial generally reflect people who are expected to have cabozantinib in NHS clinical practice. However, they noted that people recruited to clinical trials are sometimes younger, in better health and able to tolerate a short wait before treatment begins. The clinical experts therefore expected people in NHS clinical practice to have poorer health and a poorer prognosis than those in CABOSUN. The Cancer Drugs Fund clinical lead stated that the proportion of people with intermediate- and poor-risk disease who will have treatment in clinical practice was uncertain, but there was no evidence to suggest that the proportion was different to that in CABOSUN. Although the committee considered that it was possible that people in NHS clinical practice have poorer health and a poorer prognosis than the trial population, it had not seen robust evidence to support this. Therefore, it concluded that the results of CABOSUN are generalisable to clinical practice in England.\n\n# Progression‑free survival\n\n## Cabozantinib increases progression-free survival compared with sunitinib\n\nCabozantinib increased median progression‑free survival assessed by investigators (primary outcome), compared with sunitinib, from 5.4\xa0months to 8.3\xa0months (hazard ratio [HR]\xa00.56, 95%\xa0confidence interval [CI] 0.37\xa0to\xa00.83, p=0.0042). The company retrospectively analysed progression‑free survival assessed by an independent review committee to support its regulatory submissions. This analysis used a 2‑sided test for significance rather than the 1‑sided test used in the investigator analysis. It also included additional censoring of patients who had non‑protocol systemic anticancer therapy or whose disease progressed after missing 2\xa0or more assessments. The results of the retrospective analysis showed that cabozantinib increased median progression‑free survival compared with sunitinib, from 5.3\xa0months to 8.6\xa0months (HR\xa00.48, 95%\xa0CI 0.31\xa0to\xa00.74, p=0.0008). The committee concluded that cabozantinib increased progression‑free survival compared with sunitinib.\n\n# Overall survival\n\n## There is no strong evidence that people taking cabozantinib live longer than people taking sunitinib\n\nThe results from the July 2017 data cut showed a median overall survival of 26.6\xa0months with cabozantinib compared with 21.2\xa0months with sunitinib (HR\xa00.80, 95%\xa0CI 0.53\xa0to\xa01.21, p=0.29). The committee was aware that the trial was not powered to show a difference between treatments in overall survival, a secondary outcome. It noted that the Kaplan–Meier curves converged at around 14\xa0months before separating again at around 21\xa0months. The clinical experts advised that there was no clinical explanation for this, but that it may be explained by chance given the small numbers in the trial (157\xa0patients). The committee concluded that there was no strong evidence to show that people who are offered cabozantinib live longer than those who are offered sunitinib.\n\n## There is no robust evidence to show that the effectiveness of cabozantinib is different in the poor- and intermediate‑risk groups\n\nThe company provided data on overall survival in the poor- and intermediate‑risk groups in response to a clarification request from the ERG. The committee noted that these results were uncertain, particularly for the poor-risk group, because the patient numbers in each group were small: 127\xa0patients in the intermediate‑risk group and 30\xa0patients in the poor‑risk group. It concluded that no firm conclusion could be drawn about the effectiveness of cabozantinib in any 1\xa0particular subgroup.\n\n# Indirect treatment comparison\n\n## An indirect treatment comparison is not needed because pazopanib and sunitinib are considered clinically equivalent\n\nThe company did an indirect treatment comparison to compare the clinical effectiveness of cabozantinib and pazopanib. The committee was aware that indirect comparisons are inherently uncertain, and more so in this appraisal. This was because the evidence on pazopanib came from the COMPARZ trial, which also included patients in the favourable-risk category who have a better prognosis than those with intermediate- or poor-risk disease. The committee recalled that pazopanib and sunitinib can be considered equally clinically effective (see section\xa03.3). Therefore, it concluded that an indirect treatment comparison was not needed, and did not consider it further.\n\n# The company's economic model\n\n## The structure of the company's model is appropriate for decision-making\n\nThe company used a partitioned‑survival economic model that included 3\xa0states: pre-progression, post-progression and death. The committee concluded that the structure of the model was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma.\n\n# Treatment effects in the economic model\n\n## The model that includes the assumption that pazopanib is as effective as sunitinib is preferable\n\nThe company's original analysis modelled the treatment effectiveness of pazopanib based on an indirect treatment comparison. The ERG's base case did not include pazopanib separately, but assumed that it was equally effective to sunitinib, which the committee agreed was reasonable (see section\xa03.3). The committee concluded that it was more appropriate to include pazopanib in the analysis, and assume that it was clinically equivalent to sunitinib (as per the ERG's analyses), than to include an indirect treatment comparison (as per the company's analyses). The company used this approach in their revised analysis.\n\n## Basing the modelling on independent review committee-assessed progression-free survival is acceptable\n\nThe company and ERG both based their modelling of progression‑free survival on the retrospective assessment by independent review committee. The committee generally prefers using the primary end point of the trial in the model, which for CABOSUN was investigator-assessed progression-free survival. However, it noted that the results using either assessment were similar, and unlikely to have had a large effect on cost effectiveness. The committee therefore accepted the approach used by the company and ERG.\n\n## There is a high degree of uncertainty in the extrapolation of overall survival\n\nThe committee recognised that the immaturity of the data and the small size of the trial meant that projecting survival outcomes beyond the trial follow-up would be challenging and inherently uncertain. Also, because the Kaplan–Meier curves for overall survival crossed, no parametric curve fitted the data well. The committee considered whether piecewise modelling would be suitable (for example, using the Kaplan–Meier curves for the duration of follow-up and parametric extrapolation fitted to the end of the curve thereafter), but it agreed that such modelling needs larger patient numbers. The committee noted that both the company and the ERG preferred the exponential distribution, which the clinical experts advised produced plausible predictions of overall survival at 5\xa0years and 10\xa0years after starting treatment. The ERG assumed proportional hazards (despite the log‑cumulative hazard plots violating proportional hazards) because it considered that the Kaplan–Meier curves should not be 'over‑interpreted' given the small numbers of patients. The committee agreed that it was unclear whether proportional hazards holds. It concluded that the chosen distributions fitted the data poorly and that the curve was a source of uncertainty in the economic model.\n\n## Scenario analyses of the choice of curve for overall survival extrapolation are appropriate to consider in decision-making\n\nThe company conducted scenario analyses to examine the sensitivity of the model to the choice of overall survival extrapolation. It provided analyses using Weibull and Gompertz distributions fitted separately (assuming the proportional hazards assumption did not hold) and jointly (assuming the proportional hazards assumption did hold). The ERG also included scenarios using alternative parametric distributions. The committee noted that the incremental cost‑effectiveness ratios (ICERs) generated by the scenario analyses varied by around £6,500 per quality‑adjusted life year (QALY) gained, depending on whether curves were fitted separately or jointly, and depending on which distribution was used. It concluded that it would take into account the uncertainty in the choice of curve for extrapolating overall survival in its decision-making.\n\n## It is not appropriate to assume that cabozantinib has a relative survival benefit compared with sunitinib after 5\xa0years\n\nThe company's original base case assumed that the relative effect of cabozantinib compared with sunitinib continued beyond the trial follow-up (that is, the hazard ratio remained below\xa01), even after the disease progressed or patients stopped treatment, but there was no evidence to support this. The clinical experts considered that it was not clear whether a survival benefit would continue after stopping treatment. The ERG's base case assumed that treatment benefit with cabozantinib compared with sunitinib did not persist after 5\xa0years (that is, the hazard ratio became\xa01 after 5\xa0years). The committee agreed that assuming the treatment benefit of cabozantinib compared with sunitinib continued for up to 20\xa0years or even for 10\xa0years, based on a trial with a median follow‑up of under 3\xa0years, was not plausible. The committee agreed that the modelling should assume that there is no treatment effect beyond the observed survival data, which covered a duration of less than 4\xa0years. It therefore concluded that the ERG's assumption was preferable and the company used this assumption in its revised base case.\n\n# Utility values in the economic model\n\n## The source of utility values used in the economic model is appropriate\n\nQuality-of-life data were not collected in CABOSUN. Therefore, the company and ERG used utility values from NICE's technology appraisal guidance on tivozanib in their base cases. The committee concluded that this source of utility values was appropriate.\n\n# Costs in the economic model\n\n## The costs and benefits of subsequent therapies (treatments second line and beyond) are a key source of uncertainty in the cost-effectiveness model\n\nBoth the company's and ERG's base cases included a distribution of subsequent therapies (that is, therapies for renal cell cancer second line and beyond) based on CABOSUN for cabozantinib and sunitinib, and based on COMPARZ for pazopanib. The committee agreed that, given the assumption that pazopanib and sunitinib are equivalent (see sections\xa03.3 and\xa03.11), the same source of data for therapies after sunitinib and pazopanib should be used. It preferred using CABOSUN because CABOSUN is more recent than COMPARZ, so more closely reflects clinical practice. However, CABOSUN and COMPARZ included subsequent treatments that are not recommended in the NHS. The committee noted that both the company and the ERG presented scenario analyses of second‑line NHS drug use based on clinical expert opinion. Clinical experts indicated that the ERG's scenario analysis more closely reflected the expected second‑line therapy use in the NHS. However, the company modelled therapies by reflecting only their cost, but not their benefits, and the committee preferred including both costs and benefits of subsequent therapies. Therefore, the committee agreed that the base‑case assumptions using clinical trial data to depict subsequent treatment were acceptable, but should be based on CABOSUN for both pazopanib and sunitinib. In response to consultation, the company revised its analyses to assume the same subsequent therapies after pazopanib and sunitinib (see table\xa01). Because the ERG's scenario analysis more closely reflected the cost of subsequent therapies used in the NHS, the committee also considered this scenario when making its decision. The ERG's scenario increased the revised base-case ICER by around £10,500 per QALY gained. However, this difference would likely be smaller when adjusting the benefits as well as the costs of subsequent therapy to reflect NHS practice. Because of this, the committee concluded that the costs and benefits of subsequent therapies were a key source of uncertainty in the cost‑effectiveness model.\n\nNHS recommended subsequent therapies\n\nRevised company base case for cabozantinib (%)\n\nEvidence review group (ERG) scenario for cabozantinib (%)\n\nRevised company base case for sunitinib (%)\n\nERG scenario for sunitinib (%)\n\nAxitinib\n\n\n\n\n\n\n\n\n\nCabozantinib\n\n\n\n\n\n\n\n\n\nEverolimus\n\n\n\n\n\n\n\n\n\nNivolumab\n\n\n\n\n\n\n\n\n\nLenvatinib plus everolimus\n\n\n\n\n\n\n\n\n\nBest supportive care\n\n\n\n\n\n\n\n\n\nOther therapies\n\n\n\n–\n\n\n\n–\n\nTotal\n\n%\n\n%\n\n%\n\n%\n\n# Cost-effectiveness estimates\n\n## The company's revised base case reflects the committee's preferred assumptions\n\nIn response to the appraisal consultation document, the company updated its economic model to include the committee's preferred assumptions, which were:\n\nincluding pazopanib in the analysis and assuming it is clinically equivalent to sunitinib (see sections\xa03.3 and\xa03.11)\n\nbasing overall survival extrapolation on the most recent data cut (see section\xa03.7)\n\nincluding a duration of treatment benefit for cabozantinib compared with sunitinib persisting only up to 5\xa0years (see section\xa03.15)\n\nreflecting both costs and benefits of subsequent treatments (see section\xa03.17).The company also updated its model to incorporate an increase to the confidential patient access scheme discount. The committee concluded that the company's revised model reflected its preferred assumptions.\n\n# Uncaptured benefits\n\n## There are no health‑related benefits that are not captured in the analysis\n\nThe committee recalled the conclusion from NICE's technology appraisal guidance on cabozantinib for previously treated advanced renal cell carcinoma. This was that cabozantinib did not reflect a 'step-change' in treatment and no benefits were identified which were not otherwise accounted for in the modelling. The committee saw no evidence to change its conclusion for people with untreated advanced renal cell carcinoma. It therefore concluded that there were no additional health‑related quality-of-life benefits not already captured in the QALY calculations.\n\n# End of life\n\n## Life expectancy for people in the combined intermediate- and poor-risk group is likely to be more than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.\n\nThe median overall survival in the sunitinib arm in CABOSUN was 21.2\xa0months.\n\nUsing the committee's preferred analysis, the model estimated a mean of more than 24.0\xa0months in the sunitinib arm.The committee preferred mean estimates when considering the end-of-life criteria. It was aware that survival estimates were also available from the ongoing CheckMate\xa0214 clinical trial of nivolumab with ipilimumab in the same population. The median overall survival in the sunitinib arm of CheckMate\xa0214 was 25.9\xa0months, but the mix of patients with intermediate‑ or poor‑risk disease differed from the CABOSUN trial. For the combined poor‑ and intermediate‑risk group, there was no robust evidence that average life expectancy was less than 24\xa0months. Therefore, the committee concluded that cabozantinib did not meet the criterion for short life expectancy.\n\n## Cabozantinib meets the criterion for extending life by more than 3\xa0months compared with standard of care\n\nThe committee noted that CABOSUN trial did not show that cabozantinib extends life, but acknowledged that the trial was not powered to show a difference in overall survival (see section\xa03.7). The economic model estimated that cabozantinib extends life compared with sunitinib by around 6\xa0months on average in the company's revised base case. The committee accepted that cabozantinib extends life by more than 3\xa0months compared with established NHS practice in England for the purposes of the end‑of‑life considerations.\n\n## The plausible ICERs are consistent with those usually considered a cost‑effective use of NHS resources\n\nIn incremental analyses using the company's revised base case, cabozantinib and sunitinib 'extendedly dominated' pazopanib (that is, pazopanib was more expensive and more costly than having the options of cabozantinib and sunitinib) leaving the relevant comparison between cabozantinib and sunitinib. The ICER reflecting the cost effectiveness of cabozantinib compared with sunitinib was less than £20,000 per QALY gained. Because the subsequent therapies included in the model were priced based on confidential patient access schemes, the estimated ICER taking these into account cannot be included here. In addition to the base case, the committee considered several scenarios exploring the key areas of uncertainty in the model, including:\n\nThe choice of curve used to estimate overall survival: the ICERs generated from these scenario analyses changed by about £6,500 per QALY gained (see section\xa03.14).\n\nThe costs and benefits of treatments second‑line and beyond: when considering the ERG's scenario reflecting the costs (but not benefits) of second-line treatment use in the NHS, the company's revised base‑case ICER compared with sunitinib increased by about £10,500 per QALY gained (see section\xa03.17). The committee agreed that the impact of this change on the most plausible ICER was likely to be lower when including the benefits of life-extending, second-line treatments used in the NHS.The committee concluded that, taking into account the degree of uncertainty associated with the evidence base, the estimated ICERs reflected a cost-effective use of NHS resources for people with untreated intermediate‑ and poor‑risk advanced renal cell carcinoma."}
|
https://www.nice.org.uk/guidance/ta542
|
Evidence-based recommendations on cabozantinib (Cabometyx) for untreated advanced renal cell carcinoma in adults.
|
31a2ee24cdd54c32c411d0e33ad698a60f688f25
|
nice
|
Tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs
|
Tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs
Evidence-based recommendations on tofacitinib (Xeljanz) for treating active psoriatic arthritis in adults after inadequate response to DMARDs.
# Recommendations
Tofacitinib, with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults, only if:
it is used as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or
the person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has not responded within the first 12 weeks or has stopped responding after 12 weeks or
TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Tofacitinib is only recommended if the company provides it according to the commercial arrangement.
Assess the response to tofacitinib after 12 weeks of treatment. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2 of the 4 Psoriatic Arthritis Response Criteria (PsARC), 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation 1.3).
When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
These recommendations are not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
NICE recommends several treatments for treating psoriatic arthritis. Tofacitinib is the first of a new class of drugs for treating psoriatic arthritis (Janus kinase inhibitors).
Clinical trial evidence shows that tofacitinib is more effective than placebo at treating joint and skin symptoms. An indirect comparison suggests that tofacitinib is likely to improve symptoms about as well as some of the current treatments used in the NHS for psoriatic arthritis.
Overall, the cost-effectiveness estimates of tofacitinib are within the range normally considered to be an acceptable use of NHS resources when it is used after 2 conventional disease-modifying anti-rheumatic drugs (DMARDs), or after treatment with a TNF‑alpha inhibitor after 2 conventional DMARDs. Therefore, it can be recommended.# Information about tofacitinib
Marketing authorisation indication
Tofacitinib (Xeljanz, Pfizer), in combination with methotrexate, is indicated 'for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying anti-rheumatic drug (DMARD) therapy'.
Dosage in the marketing authorisation
The recommended dose of tofacitinib is 5 mg taken orally twice daily.
No dose adjustment is needed when tofacitinib is used with methotrexate. Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Price
The list price of a 56‑tablet pack of 5 mg tofacitinib is £690.03 (excluding VAT; British national formulary online ).
The company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition
## Psoriatic arthritis can substantially decrease quality of life
The patient experts explained that psoriatic arthritis can affect people from a young age (peak onset is 30 to 50 years) and is a lifelong condition. Symptoms including joint stiffness, fatigue and pain can make day-to-day activities difficult and have a serious negative effect on people's quality of life. The patient experts also emphasised that, because psoriatic arthritis can develop at a young age, it often affects people's relationships and career aspirations. Most people develop joint symptoms a few years after skin psoriasis and adding a painful joint disease to the skin symptoms can have a substantial psychological impact. The committee concluded that psoriatic arthritis can substantially decrease quality of life.
# Treatment pathway and current management
## Tofacitinib will be used in people who have had at least 2 DMARDs
The marketing authorisation for tofacitinib (with methotrexate) indicates treatment for people whose disease has had an inadequate response or cannot tolerate 1 or more disease-modifying anti-rheumatic drugs (DMARDs). The company did not submit any clinical- or cost-effectiveness analyses for the population who have had 1 conventional DMARD because this is not in line with British Society for Rheumatology guidelines and previous NICE technology appraisal guidance. These recommend people have 2 conventional DMARDs before non-conventional DMARD therapies. In previous technology appraisals, clinical experts confirmed that in the NHS, people usually have 2 DMARDs before moving on to non-conventional DMARDs. The committee concluded that tofacitinib would be used in people who have had at least 2 DMARDs and that the company's positioning of tofacitinib in the treatment pathway was in line with clinical practice, and therefore appropriate.
## Patients and clinicians would welcome an additional effective treatment option
The clinical experts explained that choice of therapy would depend on the patient's symptoms and characteristics, their previous treatments and tolerability of the drug. They explained that tofacitinib has a different mechanism of action. It would be a useful treatment option because there are only a limited number of non-conventional therapies that are not tumour necrosis factor (TNF)‑alpha inhibitors. The clinical experts also highlighted that most non-conventional DMARDs are given subcutaneously, and that it is valuable to have other oral treatment options available. The patient experts explained that because the disease can stop responding to non-conventional DMARDs over time, and because psoriatic arthritis is a lifelong disease, all treatment options can be exhausted by some people. The patient expert also explained that each patient might have different symptoms of psoriatic arthritis and certain treatments can improve some symptoms more than others. The committee concluded that patients and clinicians would welcome an additional treatment option.
# Clinical trial evidence
## Tofacitinib reduces joint and skin symptoms compared with placebo
The main source of clinical-effectiveness evidence for tofacitinib came from 2 randomised, double-blinded, placebo-controlled trials. OPAL Broaden included patients who had had previous treatment with a conventional DMARD but had not had previous treatment with a TNF‑alpha inhibitor. It compared tofacitinib with placebo and adalimumab. OPAL Beyond included patients who had previously had a TNF‑alpha inhibitor but had stopped treatment because their disease had had an inadequate response or they could not tolerate treatment. OPAL Beyond compared tofacitinib with placebo. In both trials, a statistically significant proportion of people having tofacitinib had reductions in joint symptoms as assessed by the American College of Rheumatology (ACR) 20 at 3 months, compared with placebo. The results also showed higher rates of Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI) responses at 3 months with tofacitinib compared with placebo in both trials. Also, a statistically significantly higher proportion of people having tofacitinib also saw improvements in their ability to do daily activities compared with placebo, as assessed by the health assessment questionnaire disability index (HAQ‑DI). The committee was aware that there was limited evidence on radiographic progression for tofacitinib. However, the clinical experts stated that the symptoms of psoriatic arthritis gave an indication of disease progression, and that if treatment was able to control symptoms they would expect to see a delay in the progression of joint destruction. The clinical experts also commented that there were good data available for tofacitinib's effect on progression in people with rheumatoid arthritis. The committee recognised that the symptoms of psoriatic arthritis were the main outcomes relevant to the cost-effectiveness analysis. It concluded that tofacitinib improved joint and skin symptoms compared with placebo.
## The OPAL trials are generalisable to NHS clinical practice
The ERG considered that the OPAL trials were well conducted, and that the study design was similar to trials of other NICE recommended treatments for psoriatic arthritis. However, it did highlight that some patients in the trials had tofacitinib with conventional DMARDs other than methotrexate, and that this was outside the marketing authorisation for tofacitinib. The committee was aware that about 18% of OPAL Broaden and 24% of OPAL Beyond patients had other conventional DMARDs, but the clinical experts advised that this distribution reflects current NHS clinical practice. The patient experts commented that the mean age of patients in the trial was slightly higher than they would expect to see in clinical practice, but the clinical experts considered that this was unlikely to affect the generalisability of the trial results. The committee concluded that the results of the OPAL trials were generalisable to the NHS.
# Network meta-analysis
## It is appropriate to have separate network meta-analyses for people who have, and who have not, had previous biological DMARDs
The company presented 2 sets of network meta-analyses to give evidence of tofacitinib's effectiveness in people who had, and had not, previously had biological DMARDs. The network meta-analyses of trials including people who had not had a previous biological DMARD compared tofacitinib's effectiveness with placebo, adalimumab, apremilast, etanercept, infliximab, ustekinumab, golimumab, secukinumab and certolizumab pegol. Although ustekinumab is not recommended in the population with inadequate disease response to 2 previous conventional DMARDs, it was included in the network meta-analysis to provide evidence for the population in whom treatment with a TNF‑alpha inhibitor is contraindicated or not tolerated. The network meta-analyses of trials including people who had had a previous biological DMARD compared tofacitinib with placebo, ustekinumab and secukinumab. The network meta-analyses explored the effectiveness of treatments on PsARC response, PASI 75 response, and change in HAQ‑DI score dependant on PsARC response. The committee was aware that doing separate network meta-analyses for the no previous biological DMARD and previous biological DMARD populations was consistent with the approach used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs, and concluded that this approach was appropriate.
## The company's network meta-analysis for PsARC outcomes in patients who have not had previous biological DMARDs is acceptable
The company highlighted that the PsARC response rate for the placebo arm in the OPAL Broaden trial was the highest of all the trials included in the network meta-analysis (45%). Because of differences in placebo response rates between the trials, the company adjusted its network meta-analysis of PsARC response in the no previous biological DMARD population. The committee agreed that this approach was consistent with the assumptions used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs. The ERG highlighted that the company had incorrectly implemented its network meta-analysis and presented updated results based on the correct implementation, which the company accepted. In its preferred network meta-analysis model, the ERG also adjusted for placebo response rates. However, instead of assuming independent treatment effects, the ERG preferred to assume class effects between treatments because these models provided a better fit to the data. The committee noted that the choice between the company and ERG approach to the network meta-analysis only had a small effect on the cost-effectiveness results. The committee preferred to use assumptions that were consistent with NICE's technology appraisal guidance on certolizumab pegol and secukinumab, and concluded that the company's approach was acceptable (when correctly implemented).
## Tofacitinib has similar effectiveness to other non-conventional DMARDs
The results from the company's network meta-analysis in the no previous biological DMARD population show that tofacitinib was less effective at improving PsARC outcomes compared with biological DMARDs, but had similar effectiveness to apremilast. The exact results from the company's analysis are academic in confidence. The results also showed that tofacitinib was more effective at improving PASI and HAQ‑DI outcomes than improving PsARC response in the no previous biological DMARD population. The results from the network meta-analysis in the previous biological DMARD population show that tofacitinib 5 mg had similar effectiveness to ustekinumab in improving PsARC response. The clinical experts observed that, in this population, tofacitinib was less effective at improving PASI outcomes than ustekinumab and secukinumab. They also commented that their clinical experience of tofacitinib suggested it was not as effective at improving skin symptoms as TNF‑alpha inhibitors. However, based on the academic in confidence results, on balance, the committee concluded that tofacitinib had similar effectiveness to other NICE recommended non-conventional DMARDs.
## Tofacitinib has an acceptable safety profile
The clinical experts highlighted that people taking tofacitinib have an increased risk of herpes zoster infection, although the event rate is lower for psoriatic arthritis compared with rheumatoid arthritis. They explained that this adverse effect was specific to the class of Janus kinase inhibitors rather than tofacitinib alone. The clinical experts also highlighted that because tofacitinib is given with methotrexate, people who develop herpes zoster may experience more severe symptoms of the infection. However, the ERG considered that the adverse events profile of tofacitinib was similar to adalimumab, and that its tolerability was reflected in the low rate of withdrawals from adverse events in the OPAL trials. In the appraisal of tofacitinib for rheumatoid arthritis, clinical experts suggested that herpes zoster was a manageable infection. Therefore it concluded that tofacitinib has an acceptable safety profile that was similar to other non-conventional DMARDs.
# The company's economic model
## The comparators included in the model are appropriate
The company submitted cost-effectiveness analyses for 3 different subpopulations:
people whose disease did not adequately respond to at least 2 previous conventional DMARDs
people whose disease did not adequately respond to at least 2 previous conventional DMARDs and at least 1 TNF‑alpha inhibitor, and
people who cannot have TNF‑alpha inhibitors or they are not tolerated.The clinical evidence for the no previous biological DMARD population informed the modelling of people whose disease had an inadequate response to at least 2 previous conventional DMARDs. In this subpopulation, the company compared tofacitinib with etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, secukinumab, apremilast and best supportive care. The clinical evidence for the no previous biological DMARD population also informed the modelling of people who cannot have TNF‑alpha inhibitors or they are not tolerated. The clinical evidence for the previous biological DMARD population informed the modelling of people whose disease had an inadequate response to at least 1 TNF‑alpha inhibitor. In both these subpopulations, the company compared tofacitinib with ustekinumab, secukinumab and best supportive care. The committee concluded that the company's choice of comparators is appropriate.
## PsARC response should be assessed at 12 weeks
The committee noted that the economic analysis was based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 3 months (12 weeks) stop tofacitinib treatment. This matches the timing of the primary outcome assessment in the OPAL trials. The committee concluded that PsARC response should be assessed at 12 weeks to decide if tofacitinib treatment should continue.
## It is appropriate to model separate subgroups to reflect psoriasis severity
The economic model was based on the assessment group's model developed in NICE's technology appraisal guidance on certolizumab pegol and secukinumab. In this, the assessment group modelled the cost effectiveness of 3 psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, and with concomitant moderate to severe psoriasis). The company differed from the approach used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab and modelled a 'weighted average' of the severity level of psoriasis, rather than separate subgroups. The ERG explained that modelling severity of psoriasis as a weighted average would not adequately capture the costs and benefits of secukinumab, because the licensed dose of secukinumab depends on the severity of psoriasis. The committee concluded that it is appropriate to capture differences in severity of psoriasis using separate subgroups, in line with the technology appraisal guidance on certolizumab pegol and secukinumab.
## The company's modelling of disease progression is acceptable
After the 12‑week assessment of response, the company modelled psoriasis and arthritis progression separately. The company assumed that with best supportive care, the arthritis element of the disease would progress over time, but the level of psoriasis would stay stable. The company assumed that HAQ‑DI scores would stay constant while people were having tofacitinib or biological DMARDs, and would rebound and progress in line with best supportive care in people who stopped treatment. For people having apremilast, the company's model was in line with the committee preferred approach in NICE's technology appraisal guidance on apremilast for treating active psoriatic arthritis. The clinical experts explained that in practice, disease progression increases with age. The clinical experts suggested that, because people with psoriatic arthritis tend to be younger, the assumption of constant HAQ‑DI scores was reasonable. To explore the uncertainty in this area, the ERG presented scenario analyses for different rates of 'on‑treatment' disease progression for tofacitinib. The committee noted that the ERG's exploratory analyses showed that different assumptions about disease progression only had a small effect on the cost-effectiveness results. The committee understood that there was some evidence on radiographic progression from OPAL Broaden, but noted that the ERG did not consider the evidence strong. The committee recalled that it had accepted the same assumptions about disease progression in the NICE technology appraisal guidance on certolizumab pegol and secukinumab in this indication, without any radiographic evidence. The committee concluded that the company's modelling of disease progression was acceptable.
# Cost-effectiveness results
## Pairwise ICERs comparing treatment to best supportive care are appropriate for decision-making
For each population, the company presented fully incremental analyses and pairwise analyses comparing all treatments to best supportive care. The ERG explained that the total costs and quality-adjusted life years (QALYs) for all therapies included in the company's analysis were very similar. Because of this, the fully incremental analyses were very sensitive to small differences in the estimates of costs and QALYs. The ERG recommended that in this instance, pairwise incremental cost-effectiveness ratios (ICERs) would give a better reflection of the cost effectiveness of the technologies. The committee agreed that in this appraisal, pairwise comparisons with best supportive care were appropriate for decision-making.
## Tofacitinib is a cost-effective treatment option for people who have, and who have not, had a previous biological DMARD
The committee considered the ICERs presented by the company and the ERG. It took into account commercial arrangements for tofacitinib and its comparators. Some of the commercial arrangements are confidential, so the exact cost-effectiveness results cannot be reported. The committee noted that:
The company's base-case pairwise analysis showed that tofacitinib had the second lowest ICER for people who had not previously had a biological DMARD and the lowest ICER in for people who had had a previous biological DMARD, when compared with best supportive care.
In the ERG's exploration of subgroups based on psoriasis severity:
tofacitinib had the lowest ICER in people with psoriatic arthritis with moderate to severe psoriasis who had not had a previous biological DMARD compared with best supportive care
secukinumab had a higher ICER than tofacitinib in people with no psoriasis and mild to moderate psoriasis who had not had a previous biological DMARD compared with best supportive care. However, the committee recognised that the differences in costs and QALYs between tofacitinib and secukinumab were small.
Tofacitinib had the lowest ICER for most of the psoriasis subgroups in the previous biological DMARD populations.All the ICERs for tofacitinib were below £20,000 per QALY gained. The committee concluded that tofacitinib was a cost-effective treatment option for people who have had, and who have not had, a previous biological DMARD.
# Conclusion
## Tofacitinib is a cost-effective use of NHS resources
The committee concluded that tofacitinib (with methotrexate) was a cost-effective use of NHS resources when:
the criteria in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3 tender joints and at least 3 swollen joints, and the psoriatic arthritis has not responded adequately to trials of at least 2 conventional DMARDs, given either individually or together or
the person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12 weeks or had stopped responding after the 12 weeks or
TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).
# Other factors
## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed
The committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 3 months stop treatment with tofacitinib. The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for tofacitinib. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
## Fatigue symptoms may not have been fully captured in the QALY
The clinical experts suggested that tofacitinib might have additional benefits in treating fatigue, and that improvements in this domain might not be captured adequately by the HAQ‑DI assessment and therefore the QALY. The clinical experts explained that there is a lack of adequate measures of fatigue in the psoriatic arthritis disease area. The committee agreed that there may be some health benefits that had not been captured in the QALY calculation, but that there was uncertainty about the extent of these benefits and that this would apply similarly to other treatments for psoriatic arthritis. The committee concluded that tofacitinib's effect in improving fatigue symptoms may be a potential uncaptured benefit in the analysis, and took this into account.
|
{'Recommendations': "Tofacitinib, with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults, only if:\n\nit is used as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has not responded within the first 12\xa0weeks or has stopped responding after 12\xa0weeks or\n\nTNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Tofacitinib is only recommended if the company provides it according to the commercial arrangement.\n\nAssess the response to tofacitinib after 12\xa0weeks of treatment. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2\xa0of the 4\xa0Psoriatic Arthritis Response Criteria (PsARC), 1\xa0of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria. People whose disease has a Psoriasis Area and Severity Index (PASI)\xa075 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation\xa01.3).\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nNICE recommends several treatments for treating psoriatic arthritis. Tofacitinib is the first of a new class of drugs for treating psoriatic arthritis (Janus kinase inhibitors).\n\nClinical trial evidence shows that tofacitinib is more effective than placebo at treating joint and skin symptoms. An indirect comparison suggests that tofacitinib is likely to improve symptoms about as well as some of the current treatments used in the NHS for psoriatic arthritis.\n\nOverall, the cost-effectiveness estimates of tofacitinib are within the range normally considered to be an acceptable use of NHS resources when it is used after 2\xa0conventional disease-modifying anti-rheumatic drugs (DMARDs), or after treatment with a TNF‑alpha inhibitor after 2\xa0conventional DMARDs. Therefore, it can be recommended.", 'Information about tofacitinib': "Marketing authorisation indication\n\nTofacitinib (Xeljanz, Pfizer), in combination with methotrexate, is indicated 'for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying anti-rheumatic drug (DMARD) therapy'.\n\nDosage in the marketing authorisation\n\nThe recommended dose of tofacitinib is 5\xa0mg taken orally twice daily.\n\nNo dose adjustment is needed when tofacitinib is used with methotrexate. Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.\n\nPrice\n\nThe list price of a 56‑tablet pack of 5\xa0mg tofacitinib is £690.03 (excluding VAT; British national formulary [BNF] online [accessed July\xa02018]).\n\nThe company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition\n\n## Psoriatic arthritis can substantially decrease quality of life\n\nThe patient experts explained that psoriatic arthritis can affect people from a young age (peak onset is 30\xa0to 50\xa0years) and is a lifelong condition. Symptoms including joint stiffness, fatigue and pain can make day-to-day activities difficult and have a serious negative effect on people's quality of life. The patient experts also emphasised that, because psoriatic arthritis can develop at a young age, it often affects people's relationships and career aspirations. Most people develop joint symptoms a few years after skin psoriasis and adding a painful joint disease to the skin symptoms can have a substantial psychological impact. The committee concluded that psoriatic arthritis can substantially decrease quality of life.\n\n# Treatment pathway and current management\n\n## Tofacitinib will be used in people who have had at least 2\xa0DMARDs\n\nThe marketing authorisation for tofacitinib (with methotrexate) indicates treatment for people whose disease has had an inadequate response or cannot tolerate 1\xa0or more disease-modifying anti-rheumatic drugs (DMARDs). The company did not submit any clinical- or cost-effectiveness analyses for the population who have had 1\xa0conventional DMARD because this is not in line with British Society for Rheumatology guidelines and previous NICE technology appraisal guidance. These recommend people have 2\xa0conventional DMARDs before non-conventional DMARD therapies. In previous technology appraisals, clinical experts confirmed that in the NHS, people usually have 2\xa0DMARDs before moving on to non-conventional DMARDs. The committee concluded that tofacitinib would be used in people who have had at least 2\xa0DMARDs and that the company's positioning of tofacitinib in the treatment pathway was in line with clinical practice, and therefore appropriate.\n\n## Patients and clinicians would welcome an additional effective treatment option\n\nThe clinical experts explained that choice of therapy would depend on the patient's symptoms and characteristics, their previous treatments and tolerability of the drug. They explained that tofacitinib has a different mechanism of action. It would be a useful treatment option because there are only a limited number of non-conventional therapies that are not tumour necrosis factor (TNF)‑alpha inhibitors. The clinical experts also highlighted that most non-conventional DMARDs are given subcutaneously, and that it is valuable to have other oral treatment options available. The patient experts explained that because the disease can stop responding to non-conventional DMARDs over time, and because psoriatic arthritis is a lifelong disease, all treatment options can be exhausted by some people. The patient expert also explained that each patient might have different symptoms of psoriatic arthritis and certain treatments can improve some symptoms more than others. The committee concluded that patients and clinicians would welcome an additional treatment option.\n\n# Clinical trial evidence\n\n## Tofacitinib reduces joint and skin symptoms compared with placebo\n\nThe main source of clinical-effectiveness evidence for tofacitinib came from 2\xa0randomised, double-blinded, placebo-controlled trials. OPAL Broaden included patients who had had previous treatment with a conventional DMARD but had not had previous treatment with a TNF‑alpha inhibitor. It compared tofacitinib with placebo and adalimumab. OPAL Beyond included patients who had previously had a TNF‑alpha inhibitor but had stopped treatment because their disease had had an inadequate response or they could not tolerate treatment. OPAL Beyond compared tofacitinib with placebo. In both trials, a statistically significant proportion of people having tofacitinib had reductions in joint symptoms as assessed by the American College of Rheumatology (ACR)\xa020 at 3\xa0months, compared with placebo. The results also showed higher rates of Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI) responses at 3\xa0months with tofacitinib compared with placebo in both trials. Also, a statistically significantly higher proportion of people having tofacitinib also saw improvements in their ability to do daily activities compared with placebo, as assessed by the health assessment questionnaire disability index (HAQ‑DI). The committee was aware that there was limited evidence on radiographic progression for tofacitinib. However, the clinical experts stated that the symptoms of psoriatic arthritis gave an indication of disease progression, and that if treatment was able to control symptoms they would expect to see a delay in the progression of joint destruction. The clinical experts also commented that there were good data available for tofacitinib's effect on progression in people with rheumatoid arthritis. The committee recognised that the symptoms of psoriatic arthritis were the main outcomes relevant to the cost-effectiveness analysis. It concluded that tofacitinib improved joint and skin symptoms compared with placebo.\n\n## The OPAL trials are generalisable to NHS clinical practice\n\nThe ERG considered that the OPAL trials were well conducted, and that the study design was similar to trials of other NICE recommended treatments for psoriatic arthritis. However, it did highlight that some patients in the trials had tofacitinib with conventional DMARDs other than methotrexate, and that this was outside the marketing authorisation for tofacitinib. The committee was aware that about 18% of OPAL Broaden and 24% of OPAL Beyond patients had other conventional DMARDs, but the clinical experts advised that this distribution reflects current NHS clinical practice. The patient experts commented that the mean age of patients in the trial was slightly higher than they would expect to see in clinical practice, but the clinical experts considered that this was unlikely to affect the generalisability of the trial results. The committee concluded that the results of the OPAL trials were generalisable to the NHS.\n\n# Network meta-analysis\n\n## It is appropriate to have separate network meta-analyses for people who have, and who have not, had previous biological DMARDs\n\nThe company presented 2\xa0sets of network meta-analyses to give evidence of tofacitinib's effectiveness in people who had, and had not, previously had biological DMARDs. The network meta-analyses of trials including people who had not had a previous biological DMARD compared tofacitinib's effectiveness with placebo, adalimumab, apremilast, etanercept, infliximab, ustekinumab, golimumab, secukinumab and certolizumab pegol. Although ustekinumab is not recommended in the population with inadequate disease response to 2\xa0previous conventional DMARDs, it was included in the network meta-analysis to provide evidence for the population in whom treatment with a TNF‑alpha inhibitor is contraindicated or not tolerated. The network meta-analyses of trials including people who had had a previous biological DMARD compared tofacitinib with placebo, ustekinumab and secukinumab. The network meta-analyses explored the effectiveness of treatments on PsARC response, PASI\xa075 response, and change in HAQ‑DI score dependant on PsARC response. The committee was aware that doing separate network meta-analyses for the no previous biological DMARD and previous biological DMARD populations was consistent with the approach used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs, and concluded that this approach was appropriate.\n\n## The company's network meta-analysis for PsARC outcomes in patients who have not had previous biological DMARDs is acceptable\n\nThe company highlighted that the PsARC response rate for the placebo arm in the OPAL Broaden trial was the highest of all the trials included in the network meta-analysis (45%). Because of differences in placebo response rates between the trials, the company adjusted its network meta-analysis of PsARC response in the no previous biological DMARD population. The committee agreed that this approach was consistent with the assumptions used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs. The ERG highlighted that the company had incorrectly implemented its network meta-analysis and presented updated results based on the correct implementation, which the company accepted. In its preferred network meta-analysis model, the ERG also adjusted for placebo response rates. However, instead of assuming independent treatment effects, the ERG preferred to assume class effects between treatments because these models provided a better fit to the data. The committee noted that the choice between the company and ERG approach to the network meta-analysis only had a small effect on the cost-effectiveness results. The committee preferred to use assumptions that were consistent with NICE's technology appraisal guidance on certolizumab pegol and secukinumab, and concluded that the company's approach was acceptable (when correctly implemented).\n\n## Tofacitinib has similar effectiveness to other non-conventional DMARDs\n\nThe results from the company's network meta-analysis in the no previous biological DMARD population show that tofacitinib was less effective at improving PsARC outcomes compared with biological DMARDs, but had similar effectiveness to apremilast. The exact results from the company's analysis are academic in confidence. The results also showed that tofacitinib was more effective at improving PASI and HAQ‑DI outcomes than improving PsARC response in the no previous biological DMARD population. The results from the network meta-analysis in the previous biological DMARD population show that tofacitinib 5\xa0mg had similar effectiveness to ustekinumab in improving PsARC response. The clinical experts observed that, in this population, tofacitinib was less effective at improving PASI outcomes than ustekinumab and secukinumab. They also commented that their clinical experience of tofacitinib suggested it was not as effective at improving skin symptoms as TNF‑alpha inhibitors. However, based on the academic in confidence results, on balance, the committee concluded that tofacitinib had similar effectiveness to other NICE recommended non-conventional DMARDs.\n\n## Tofacitinib has an acceptable safety profile\n\nThe clinical experts highlighted that people taking tofacitinib have an increased risk of herpes zoster infection, although the event rate is lower for psoriatic arthritis compared with rheumatoid arthritis. They explained that this adverse effect was specific to the class of Janus kinase inhibitors rather than tofacitinib alone. The clinical experts also highlighted that because tofacitinib is given with methotrexate, people who develop herpes zoster may experience more severe symptoms of the infection. However, the ERG considered that the adverse events profile of tofacitinib was similar to adalimumab, and that its tolerability was reflected in the low rate of withdrawals from adverse events in the OPAL trials. In the appraisal of tofacitinib for rheumatoid arthritis, clinical experts suggested that herpes zoster was a manageable infection. Therefore it concluded that tofacitinib has an acceptable safety profile that was similar to other non-conventional DMARDs.\n\n# The company's economic model\n\n## The comparators included in the model are appropriate\n\nThe company submitted cost-effectiveness analyses for 3\xa0different subpopulations:\n\npeople whose disease did not adequately respond to at least 2\xa0previous conventional DMARDs\n\npeople whose disease did not adequately respond to at least 2\xa0previous conventional DMARDs and at least 1\xa0TNF‑alpha inhibitor, and\n\npeople who cannot have TNF‑alpha inhibitors or they are not tolerated.The clinical evidence for the no previous biological DMARD population informed the modelling of people whose disease had an inadequate response to at least 2\xa0previous conventional DMARDs. In this subpopulation, the company compared tofacitinib with etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, secukinumab, apremilast and best supportive care. The clinical evidence for the no previous biological DMARD population also informed the modelling of people who cannot have TNF‑alpha inhibitors or they are not tolerated. The clinical evidence for the previous biological DMARD population informed the modelling of people whose disease had an inadequate response to at least 1\xa0TNF‑alpha inhibitor. In both these subpopulations, the company compared tofacitinib with ustekinumab, secukinumab and best supportive care. The committee concluded that the company's choice of comparators is appropriate.\n\n## PsARC response should be assessed at 12\xa0weeks\n\nThe committee noted that the economic analysis was based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 3\xa0months (12\xa0weeks) stop tofacitinib treatment. This matches the timing of the primary outcome assessment in the OPAL trials. The committee concluded that PsARC response should be assessed at 12\xa0weeks to decide if tofacitinib treatment should continue.\n\n## It is appropriate to model separate subgroups to reflect psoriasis severity\n\nThe economic model was based on the assessment group's model developed in NICE's technology appraisal guidance on certolizumab pegol and secukinumab. In this, the assessment group modelled the cost effectiveness of 3\xa0psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, and with concomitant moderate to severe psoriasis). The company differed from the approach used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab and modelled a 'weighted average' of the severity level of psoriasis, rather than separate subgroups. The ERG explained that modelling severity of psoriasis as a weighted average would not adequately capture the costs and benefits of secukinumab, because the licensed dose of secukinumab depends on the severity of psoriasis. The committee concluded that it is appropriate to capture differences in severity of psoriasis using separate subgroups, in line with the technology appraisal guidance on certolizumab pegol and secukinumab.\n\n## The company's modelling of disease progression is acceptable\n\nAfter the 12‑week assessment of response, the company modelled psoriasis and arthritis progression separately. The company assumed that with best supportive care, the arthritis element of the disease would progress over time, but the level of psoriasis would stay stable. The company assumed that HAQ‑DI scores would stay constant while people were having tofacitinib or biological DMARDs, and would rebound and progress in line with best supportive care in people who stopped treatment. For people having apremilast, the company's model was in line with the committee preferred approach in NICE's technology appraisal guidance on apremilast for treating active psoriatic arthritis. The clinical experts explained that in practice, disease progression increases with age. The clinical experts suggested that, because people with psoriatic arthritis tend to be younger, the assumption of constant HAQ‑DI scores was reasonable. To explore the uncertainty in this area, the ERG presented scenario analyses for different rates of 'on‑treatment' disease progression for tofacitinib. The committee noted that the ERG's exploratory analyses showed that different assumptions about disease progression only had a small effect on the cost-effectiveness results. The committee understood that there was some evidence on radiographic progression from OPAL Broaden, but noted that the ERG did not consider the evidence strong. The committee recalled that it had accepted the same assumptions about disease progression in the NICE technology appraisal guidance on certolizumab pegol and secukinumab in this indication, without any radiographic evidence. The committee concluded that the company's modelling of disease progression was acceptable.\n\n# Cost-effectiveness results\n\n## Pairwise ICERs comparing treatment to best supportive care are appropriate for decision-making\n\nFor each population, the company presented fully incremental analyses and pairwise analyses comparing all treatments to best supportive care. The ERG explained that the total costs and quality-adjusted life years (QALYs) for all therapies included in the company's analysis were very similar. Because of this, the fully incremental analyses were very sensitive to small differences in the estimates of costs and QALYs. The ERG recommended that in this instance, pairwise incremental cost-effectiveness ratios (ICERs) would give a better reflection of the cost effectiveness of the technologies. The committee agreed that in this appraisal, pairwise comparisons with best supportive care were appropriate for decision-making.\n\n## Tofacitinib is a cost-effective treatment option for people who have, and who have not, had a previous biological DMARD\n\nThe committee considered the ICERs presented by the company and the ERG. It took into account commercial arrangements for tofacitinib and its comparators. Some of the commercial arrangements are confidential, so the exact cost-effectiveness results cannot be reported. The committee noted that:\n\nThe company's base-case pairwise analysis showed that tofacitinib had the second lowest ICER for people who had not previously had a biological DMARD and the lowest ICER in for people who had had a previous biological DMARD, when compared with best supportive care.\n\nIn the ERG's exploration of subgroups based on psoriasis severity:\n\n\n\ntofacitinib had the lowest ICER in people with psoriatic arthritis with moderate to severe psoriasis who had not had a previous biological DMARD compared with best supportive care\n\nsecukinumab had a higher ICER than tofacitinib in people with no psoriasis and mild to moderate psoriasis who had not had a previous biological DMARD compared with best supportive care. However, the committee recognised that the differences in costs and QALYs between tofacitinib and secukinumab were small.\n\n\n\nTofacitinib had the lowest ICER for most of the psoriasis subgroups in the previous biological DMARD populations.All the ICERs for tofacitinib were below £20,000 per QALY gained. The committee concluded that tofacitinib was a cost-effective treatment option for people who have had, and who have not had, a previous biological DMARD.\n\n# Conclusion\n\n## Tofacitinib is a cost-effective use of NHS resources\n\nThe committee concluded that tofacitinib (with methotrexate) was a cost-effective use of NHS resources when:\n\nthe criteria in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3\xa0tender joints and at least 3\xa0swollen joints, and the psoriatic arthritis has not responded adequately to trials of at least 2\xa0conventional DMARDs, given either individually or together or\n\nthe person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12\xa0weeks or had stopped responding after the 12\xa0weeks or\n\nTNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).\n\n# Other factors\n\n## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed\n\nThe committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 3\xa0months stop treatment with tofacitinib. The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for tofacitinib. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\n## Fatigue symptoms may not have been fully captured in the QALY\n\nThe clinical experts suggested that tofacitinib might have additional benefits in treating fatigue, and that improvements in this domain might not be captured adequately by the HAQ‑DI assessment and therefore the QALY. The clinical experts explained that there is a lack of adequate measures of fatigue in the psoriatic arthritis disease area. The committee agreed that there may be some health benefits that had not been captured in the QALY calculation, but that there was uncertainty about the extent of these benefits and that this would apply similarly to other treatments for psoriatic arthritis. The committee concluded that tofacitinib's effect in improving fatigue symptoms may be a potential uncaptured benefit in the analysis, and took this into account."}
|
https://www.nice.org.uk/guidance/ta543
|
Evidence-based recommendations on tofacitinib (Xeljanz) for treating active psoriatic arthritis in adults after inadequate response to DMARDs.
|
6c5307257c333175ccaadea8e50c59c20a0f447e
|
nice
|
E‑vita open plus for treating complex aneurysms and dissections of the thoracic aorta
|
E‑vita open plus for treating complex aneurysms and dissections of the thoracic aorta
Evidence-based recommendations on the E-vita open plus for treating complex aneurysms and dissections of the thoracic aorta.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the E‑vita open plus for treating complex aneurysms and dissections of the thoracic aorta, in a carefully selected group of people, is supported by the evidence.
Using the E‑vita open plus could remove the need for a second procedure and the associated risk of serious complications, and it should therefore be considered for people:
who would otherwise need a 2-stage repair procedure because their aortic disease extends into or beyond the distal part of their aortic arch (into the proximal descending aorta), but
who would not need additional intervention (such as stent grafting) in the descending aorta.
The E‑vita open plus is estimated to generate cost savings compared with current 2-stage repair from about 2 years after the procedure. The estimated cost saving per patient at 5 years after the procedure is around £13,334 when compared with 2‑stage repair involving open insertion of a vascular graft, £10,225 when compared with 2‑stage repair involving endovascular stent grafting and £12,536 when compared with open surgical debranching followed by endoluminal stent grafting. At 10 years after the procedure, the estimated cost savings range from around £22,704 to £29,210 across the 3 comparators. # The technology
# Description of the technology
The E‑vita open plus (JOTEC GmbH) is an endoluminal stent graft system designed for treating aneurysms and dissections of the thoracic aorta. The device is a 1-piece polyester fabric tube which combines a conventional vascular graft attached to an endovascular stent graft that allows treatment of the ascending aorta at the same time as the arch and descending aorta. The E‑vita open plus supersedes its immediate predecessor device, the E‑vita open. The 2 devices are similar in design and function but the E‑vita open plus is impermeable to blood, and fibrin glue is not needed to seal the stent graft.
The E‑vita open plus is a single-use device with a shelf life of 2 years. It is supplied sterile and pre-loaded in its delivery system. The device is available in a range of sizes with varying diameters and lengths. The delivery system consists of a release handle, nested catheters and a positioning aid. A luer connector is also incorporated to allow flushing of the inner guide catheter. A stiff guide wire is used to aid tracking of the device delivery. Radiopaque markers are integrated into the fabric of the graft for radiological imaging.
The E‑vita open plus received a CE mark in October 2008 for the repair or replacement of the thoracic aorta in cases of complex aneurysms or dissections that involve the ascending aorta, the aortic arch and the descending aorta.
The E‑vita open plus is used in a single-stage procedure known as a 'frozen elephant trunk'. The thoracic aorta is surgically opened with access through a median sternotomy approach. The distal stent graft portion of the device is self-expanding, containing nitinol springs, and is used to treat the upper part of the descending aorta. The vascular graft part of the device (for repair of the arch and ascending aorta) is invaginated in the distal stent graft portion. The stent graft, in its delivery system, is inserted into the descending aorta and deployed by retracting a retaining sheath. Once the stent graft is in place, the delivery system is removed and the proximal vascular graft component is drawn out a short distance (5–10 mm). The stent graft is then surgically anastomosed to the distal aorta. The vascular graft portion of the device is then drawn out fully and used to repair the ascending aorta and arch in a standard surgical fashion. The aortic branch vessels are attached to the vascular graft using a patch and the graft is anastomosed to the ascending aorta.
The cost of the E‑vita open plus stated in the sponsor's submission was £10,500 excluding VAT.
The claimed benefits of the E‑vita open plus in the case for adoption presented by the sponsor are:
repair of the ascending aorta, arch and descending aorta in a single-stage procedure
a reduction in pain and discomfort
elimination of the psychological distress associated with the anticipation of a second procedure
a reduction in treatment times and costs
a reduction in total end-organ ischaemia
a reduction in incisional complications and infections
a reduction in anaesthetic use and the elimination of the need for additional epidural pain management
a reduction in both total length of stay and intensive care unit length of stay
a reduction in rehabilitation time
an earlier return to normal activities and work.
# Current management
The management of thoracic aortic aneurysms and dissections is determined by the location, severity and rate of change of the disease, as well as the clinical circumstances. Thoracic aortic aneurysms result from a weakening of the aortic wall, leading to localised dilation. People with thoracic aneurysms are often observed with clinical and imaging surveillance. Invasive treatment may be offered depending upon the size and rate of enlargement of the aneurysm.
Aortic dissections result from a tear in the inner layer of the aorta. Blood flows through the tear, separating the layers of the wall. Acute aortic dissections are less than 2 weeks old, and chronic dissections have been present for longer than 2 weeks. Management of aortic dissections depends primarily on their location. Emergency surgery is usually offered for a Stanford type A aortic dissection, which affects the ascending thoracic aorta and often also the arch and descending aorta. Stanford type B dissections, typically involving the descending thoracic aorta, are often managed with conservative medical treatment. Elective surgical repair is sometimes undertaken, but endovascular repair with stent grafts is more commonly used.
There are 3 main current methods of surgically treating complex aneurysms and dissections of the thoracic aorta, 2 of which involve a 2-stage 'elephant trunk' procedure. Both approaches are similar in their first stage but use alternative repair techniques to complete the second stage. During the first stage, the ascending aorta and arch are repaired with a vascular graft through a median sternotomy. During this procedure a free-floating extension of the arch graft prosthesis (the 'elephant trunk') is left unattached in the descending aorta. Attaching it (and extending it as necessary) may be done by an endovascular procedure during which a stent graft is inserted into the descending aorta with access via the femoral artery (thoracic endovascular aortic repair – TEVAR). Alternatively the descending aorta may be repaired in a second surgical procedure some weeks or months later, by extending the 'elephant trunk' as necessary, through a lateral thoracotomy approach. The third method involves 'debranching' of the head and neck vessels from the aortic arch by creating a surgical anastomosis between the ascending aorta and the head and neck vessels using a vascular graft. This then allows an endoluminal stent graft to be inserted into the aortic arch and descending aorta either as a hybrid procedure (during the same operation) or at a second-stage operation.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.
The key clinical outcomes for the E‑vita open plus presented in the decision problem were:
completion and success of technical procedure(s)
mortality
major complications, for example stroke, paraplegia, renal failure, myocardial infarction and other events that may delay discharge
length of intensive care unit stay
total length of hospital stay
freedom from further interventions
long-term survival rates
incidence of junctional endoleak
device-related adverse events.
The sponsor identified 13 papers relevant to the E‑vita open plus. Most of these were derived from the International E‑vita Open Registry, which is reported to contain data on 70–80% of patients in 11 European centres who have received the E‑vita open or open plus devices to treat their complex aortic disease. The sponsor excluded 10 (of the 13) papers from further consideration, either because the data were already included in a more recent report on the entire register dataset at the time of publication (Jakob et al. 2011), or because they reported on small numbers of patients or on animal studies. The External Assessment Centre excluded a further 2 papers from its evaluation: a small study with limited follow-up, and a study using the same data as the paper by Jakob et al. (2011). The External Assessment Centre judged that the principal clinical evidence for the E‑vita open plus was presented in the observational study on the International E‑vita Open Registry by Jakob et al. (2011).
Jakob et al. (2011) reported observational data, gathered between January 2005 and December 2010, for 274 patients with complex aortic disease enrolled in the International E‑vita Open Registry from, at the time, 8 European centres. This comprised the entire dataset at the time of publication. Details of the 274 patients treated, in terms of condition and interventions, are shown in table 1. Outcomes were presented as proportions and survival analysis was carried out using the Kaplan–Meier technique. Stent-graft deployment and arch replacement were carried out under selective antegrade cerebral perfusion during a mean time of 75 minutes. Median length of hospital stay was 19 days (range 12–29). Adverse events are shown in table 2. For patients with dissections the false lumen was assessed postoperatively and at a median time of 59 months (range 28–99) after surgery. The false lumen thrombosed fully in 83% (62/75) of patients with acute aortic dissection, and 72% (68/94) of patients with chronic aortic dissection. After follow-up these figures rose to 93% and 92% respectively. For patients with aneurysms, complete exclusion of the aneurysm was achieved in 77% of cases (61/79). The overall 5‑year survival rate was 74%. Of the 233 patients surviving the procedure initially, secondary endovascular intervention was needed in 13% (29) and surgery downstream was needed in 3% (6) of cases.
Table 1 Conditions and interventions for patients enrolled in the International E‑vita Open Registry (Jakob et al. 2011)
Included patients (n=274)
Emergency surgery
Previous proximal repair
Presenting condition needing treatment
Acute aortic dissection
Chronic aortic dissection
Thoracic aortic aneurysm
Underlying condition
Marfan's syndrome
Interventions received during treatment with the E‑vita open plus
Arch replacement with E‑vita open plus
Arch replacement with other prosthesis
Additional coronary artery bypass graft
The sponsor presented limited evidence on clinical outcomes for 2-stage procedures to allow comparison with those for the E‑vita open plus. The External Assessment Centre therefore carried out a systematic review and meta-analysis of available data for the comparator procedures. The review identified 10 papers and the meta‑analysis provided pooled estimates of outcome rates with 95% confidence intervals forin-hospital and 30 day mortality, stroke, bleeding, paraplegia and renal failure, which were the main complications reported in the literature. The External Assessment Centre was unable to calculate single outcome estimates for the combined 2-stage procedures because of a lack of data. It judged that direct comparisons between the E‑vita open plus and the comparators would therefore be complex and that the figures did not take into account factors such as survival from stage 1 to 2 or the impact of the combined outcomes for each procedure. Long-term survival rates could not be included in the meta-analysis because no confidence intervals were reported and individual patient data were not available. The pooled estimate data for the comparators are shown in table 2.
Table 2 Adverse events for the E‑vita open plus, as reported in Jakob et al. (2011), and comparators
Stage
E‑vita open plus
(Jakob et al. 2011)
(n; %; 95% confidence interval)
-stage open surgical repair with vascular graft placement
(%; 95% confidence interval
-stage repair with endovascular stent graft placement
Open surgical 'debranching' with endoluminal stent graft placement (2-stage procedure)
In-hospital mortality
(15.0%: 11.0 to 19.7%)
% (6.4 to 11.1%)
% (3.4 to 21.4%)
% (4.5 to 28.8%)
% (5.6 to 11.2%)
% (4.4 to 19.8%)
% (0.1 to 19.0%)
day mortality
(12.0%: 8.4 to 16.5%)
% (5.4 to 10.5%)
% (1.6 to 19.0%)
% (0.08 to 16.7%)
Re-exploration for bleeding
(13.9%: 10.0 to 18.5%)
% (2.8 to 7.4%)
% (0.1 to 21.1%)
% (1.7 to 21.9%)
% (1.7 to 7.8%)
% (0.1 to 27.3%)
Stroke
(5.8%: 3.4 to 9.3%)
% (2.3 to 4.9%)
% (3.3 to 16.1%)
% (1.7 to 21.9%)
% (1.1 to 13.0%)
% (0.1 to 19.0%)
Paraplegia
(8.0%: 5.1 to 11.9%)
% (0.1 to 21.1%)
% (1.6 to 9.8%)
% (3.0 to 19.1%)
Renal failure (permanent)
(3.6%: 1.8 to 6.6%)
% (3.4 to 19.6%)
% (2.7 to 32.4%)
% (1.1 to 27.6%)
% confidence intervals were calculated by the External Assessment Centre, and pooled outcome estimates for the comparator technologies were taken from the External Assessment Centre's meta-analysis.
During consultation, an additional clinical report was identified that presented more recent data from the International E‑vita Open Registry (Jakob and Tsagakis, 2013). The paper reported outcomes for in-hospital mortality, stroke, paraplegia and 5-year survival rates for a total of 416 patients from 11 international centres. No outcomes were reported for 30-day mortality, bleeding or renal failure. Figures for 5-year survival rates were reported for 3 subgroups but no overall figure was reported or could be calculated from the data presented. The External Assessment Centre determined that, overall, there was insufficient information available, in terms of completeness or long-term follow-up, to provide additional reliable estimates of outcome rates beyond those derived from the Jakob et al. (2011) study (see section 3.4).
## Committee considerations
The Committee considered that the clinical evidence was limited because it was restricted to observational studies. However, it considered that the evidence was sufficient, when taken together with clinical expert advice, to conclude that the E‑vita open plus is effective for use in a selected group of people (see 3.10–3.11).
The Committee considered that the pooled estimates of outcomes for the comparators produced by the External Assessment Centre indicated that more bleeding would be likely to occur with the E‑vita open plus (13.9%) than with the comparators (ranging from 4.2% to 8.1% at stage 1, and from 3.7% to 5.6% at stage 2). The Committee was advised that bleeding was a complication experienced with both the E‑vita open plus and the comparators and that excess bleeding with the E‑vita open plus may have reflected incorrect choice of device size during early experiences of its use. It was mindful that bleeding is a complication which is normally controlled at the time of surgery, without patients experiencing long-lasting adverse consequences, in contrast to the other major adverse events (stroke, paraplegia and renal failure) which may have serious consequences for patients in the long term.
The Committee was advised that patient selection would be important in realising the claimed benefits of the E‑vita open plus. The Committee heard expert clinical advice that the E‑vita open plus is primarily suitable for people needing aortic arch repair and that the device enables repair to the arch to be completed more rapidly than by other techniques. Expert advice also confirmed that in people whose aortic disease extends less than 10 cm into the descending aorta (based on the size of the stent graft portion of the device), the E‑vita open plus would allow a complex repair in a single procedure.
The Committee concluded that in people with aneurysms or acute aortic dissections needing repair of the aortic arch and ascending aorta, if the disease extends less than 10 cm into the descending aorta, the E‑vita open plus would be a suitable treatment. The Committee recognised that the E‑vita open plus might be suitable for use in other people with more extensive disease in the descending aorta that would need multiple stent grafts. However, it decided that the potential benefits of the technology for these people were not clear, based on the evidence presented. The Committee therefore considered that making a recommendation for use of the technology in those with more extensive disease in the descending thoracic aorta was not possible.
The Committee was advised that many people for whom treatment with the E‑vita open plus would be suitable have progressive aortic disease that would need further interventions, regardless of whether the repair was carried out in a single or 2-stage procedure. It was advised that this is significantly more likely in people with connective tissue disorders such as Marfan's syndrome than in those with atherosclerotic disease.
The Committee judged that the main advantage of the E‑vita open plus is the avoidance of a second procedure with its associated serious risks, which include stroke, renal failure, paraplegia and bleeding. The Committee was advised by clinical experts that some people decide not to return for a second procedure because of negative experiences from the first operation. The Committee considered that the opportunity to repair the aorta in a single procedure would confer significant benefits to these people.
The Committee was advised by clinical experts that the estimate in the scope for the number of people in England (50–100 per year) eligible for treatment was reasonable.
The Committee considered the paper by Jakob and Tsagakis (2013), but judged that the outcomes it reported did not add to the evidence base for the E‑vita open plus: no data for 30-day mortality, bleeding or renal failure were reported. It considered that the included outcome data did not differ significantly from those reported by Jakob et al. (2011) and would not alter the outcomes from the External Assessment Centre's cost analysis.# NHS considerations
# System impact
The sponsor stated that using the E‑vita open plus could allow repair of the thoracic aorta in a single procedure, when a 2-stage procedure would otherwise be necessary. It claimed that this would consequently reduce overall length of stay in hospital and reduce the risk of complications needing hospital treatment. The clinical evidence consisted of the study by Jakob et al. (2011), which contained no comparative data about resource use during other aortic repair techniques. The review and meta-analysis carried out by the sponsor focused on clinical outcomes rather than resource implications.
## Committee considerations
The Committee was satisfied that a second repair procedure could be avoided by using the E‑vita open plus in a selected group of people and that this could reduce associated NHS resource use.
The Committee was advised that aortic repair using the E‑vita open plus is a highly specialised procedure, carried out in a small number of centres, in a small patient group. Despite these limitations, the Committee considered that the potential benefits of releasing operating theatre and clinical time by avoiding the need for a second procedure could be significant. It recognised that the resources needed for treating complications associated with a second procedure (some of which would be severe and would result in long-term disability) would also be released.# Cost considerations
# Cost evidence
Neither thesponsor nor the External Assessment Centre identified any relevant published economic evidence for the E‑vita open plus or for the comparator techniques.
The sponsor submitted a de novo analysis comparing the use of the E‑vita open plus against a 2-stage classical 'elephant trunk' procedure in terms of overall costs, in-hospital mortality and adoption rates. The population was a cohort of 3,500 people with aneurysms, dissections and other specified lesions of the thoracic aorta. The model consisted of 2 decision trees over a 1-year time horizon:
a current practice model using the classical 'elephant trunk' procedure
an intervention model comparing current practice against use of the E‑vita open plus at a 40% adoption rate.
The first stage of the current practice arm was divided into 2 options: woven graft or branched graft. For patients undergoing stage 2, the options were woven graft (open surgery) or endovascular stent graft. Following clarification from the sponsor, these options were further defined as follows:
Woven graft at stages 1 and 2 referred to 2-stage open surgical repair with vascular graft placement.
Woven graft followed by stent graft at stage 2 referred to 2-stage repair with open surgical graft placement in the ascending aorta and arch and endovascular stent graft placement in the descending aorta.
Branched graft followed by woven or stent graft at stage 2 referred to open surgical 'debranching' of the head and neck vessels with endoluminal stent graft placement in the aortic arch and either a vascular graft or endovascular stent graft in the descending aorta.
The sponsor carried out 1- and 2-way sensitivity analyses to include base-case, worst-case and best-case scenarios in its analysis.
The key assumptions used in the model were:
In-hospital and 30 day mortality was 15% for the E‑vita open plus, based on data from the paper by Jakob et al. (2011).
The remaining 85% of patients treated would not experience other complications.
Mortality rates were 20% for woven graft and 30% for branched graft at stage 2.
The number of inpatient days for the classical elephant trunk procedure was 10 at stage 1 and 15 at stage 2.
The number of inpatient days for the endovascular stent procedure was 10 at stage 1 and 8 at stage 2.
The number of inpatient days for the E‑vita open plus was 4 in the intensive care unit and 6 in a surgical ward.
Technology costs were provided by the sponsor. The cost of the E‑vita open plus was £10,500 and the comparator costs were £200 for a woven graft for stages 1 and 2, £1,000 for a branched graft, and £5,000 for an endovascular stent graft. Consumable costs (mainly for the guide wire, estimated to be £130) were not included because the sponsor considered these to be the same for the technology and comparators. Cost estimates for clinical time and resource use were sourced from published literature, the Personal Social Services Research Unit (PSSRU) unit costs of health and social care manual, and NHS reference costs.
The cost of a surgeon was estimated to be £399 per hour and the costs of a perfusionist and anaesthetist were each estimated to be £87 per hour (registrar rate). The cost for theatre time, including nursing and consumables, was estimated to be £24 per hour, and £30 per hour for corresponding intensive care unit costs. These were derived from the NHS tariff for admitted patient case and outpatient procedures but no codes were specified. The sponsor used a daily cost for an intensive care unit stay of £1,500, taken from a report in The Lancet. The cost of a surgical ward inpatient stay was taken to be £420 per day, based on 2 different tariff codes. The cost of death cited by the sponsor (£8,000) was taken from a cancer network publication.
The sponsor carried out 1-way sensitivity analyses varying the adoption rate from 20% to 100% (in the modelled population of 3,500 patients assumed to be eligible for the E‑vita open plus). The proportion of woven or branched grafts used at stage 1 was varied from 60% to 95% from a base-case estimate of 85%. The proportional suitability for a second stage operation was varied from a base case of 80% to 60% and 95%, and the proportion of patients having each stage 2 procedure was varied from a 50% base case to 40% and 100%. The sponsor also carried out a 2-way sensitivity analysis varying the in-hospital death rate at stage 1 of the classical elephant trunk procedure and for the E‑vita open plus.
The sponsor presented the results of its de novo analysis as an average cost per patient, assuming a 100% adoption level (rather than the 40% adoption level described in the model decision tree in section 5.2) for the E‑vita open plus compared with current practice. The cost for the E‑vita open plus was £25,689 and the overall cost presented for the comparators was £30,241, indicating a cost saving per patient of £4,553 if the E‑vita open plus was used. The cost per patient varied across the different comparators, ranging from £26,691 for woven graft (stage 1) with endovascular stent (stage 2) to £36,016 for branched graft (stage 1) with woven graft (stage 2).
The sponsor's sensitivity analysis showed little variation in the cost savings generated for the E‑vita open plus at different adoption levels, with an average cost saving of around £4,358. The sponsor reported that varying the parameters for second-stage suitability and in-hospital death had an impact on the cost savings, but that this was relatively small. Varying the suitability of a second stage operation produced higher cost savings per patient if the level of suitability was raised. The sponsor did not consider the subgroups defined in the scope in its de novo analysis because of a lack of available data on the comparators.
The External Assessment Centre considered that the sponsor's de novo cost model was flawed because it did not include the short- or long-term costs of complications and because some of the costs and clinical parameters were inaccurate or inappropriate. Specifically, the External Assessment Centre considered that a per-patient, rather than a cohort, approach would have been more useful and that the estimated cohort of 3,500 patients was too large.
The External Assessment Centre carried out additional modelling to address these issues, constructing short- and long-term models that included the costs of complications (stroke, paraplegia, renal failure and bleeding). Both models compared per-patient costs for the E‑vita open plus and the 3 comparators defined in the scope. A decision tree was constructed for each procedure in each model. In-hospital mortality was modelled at each stage of each procedure. The time horizon for the short-term model was 1 year, as the External Assessment Centre considered that stage 2 procedures were likely to be carried out within 6 months of stage 1. The long-term model had a 20 year time horizon, based on the UK life expectancy of the average age (65 years) of those receiving treatment described in published literature. Lifetime costs of complications were included in this model.
In the short-term model for each comparator, patients with no complications or bleeding at stage 1 were assumed to proceed to the second stage procedure, whereas it was assumed that those who had a stroke, renal failure or paraplegia would not. In the long-term model, the annual costs of care for stroke, paraplegia and renal failure were taken from published literature and discounted at 3.5%. The discounted annual cost was multiplied by a survival probability for 65–85 years and the weighted annual costs were summed to estimate the lifetime cost of the complications.
The External Assessment Centre estimated the probabilities of the outcomes at each stage from the register data for the E‑vita open plus and from its meta-analysis of the clinical evidence on the comparator procedures. The probability of paraplegia at stage 1 was assumed to be the same for 2-stage repair with vascular graft and 2-stage repair with endovascular stent graft. For open debranching, the probability of paraplegia and that of renal failure at stage 1 was taken from hybrid procedure estimates. Operating times and total lengths of stay for all the comparators were sourced from published literature. Operating time for the E‑vita open plus and details of the surgical team involved for each procedure were taken from the sponsor's model. The team included a consultant surgeon, consultant anaesthetist, associate specialist, perfusionist and 2 specialist nurses. A consultant radiologist was included for stage 2 procedures involving stent grafts.
The External Assessment Centre used technology and comparator costs from the sponsor's model but derived more precise estimates for staff and ward stay costs than those used by the sponsor (as described in section 5.7). Costs for each professional in the surgical team were taken from PSSRU 2012 unit costs. The costs for an intensive care unit and surgical ward stay were sourced from NHS reference costs at £1,410 per day and £383 per day respectively.
Complications were assumed to incur additional in-hospital management costs and a single cost figure was applied across all procedures (£2,155). The annual cost for stroke care was estimated to be £9,597 at 2012 prices, from atrial fibrillation (NICE clinical guideline 36). The annual cost of paraplegia was estimated to be £14,580, based on published literature and inflated to 2012 prices. The annual cost for renal failure used was £32,961, taken from peritoneal dialysis (NICE clinical guideline 125) and inflated to 2012 prices.
Costs for multiple stents were included in the analysis and sourced from the sponsor's submission. However, the External Assessment Centre was not able to model the probable outcomes from using multiple stents, citing a lack of available clinical evidence.
Results of the short-term model showed that treatment with the E‑vita open plus could generate a cost saving of £280 per patient when compared against 2-stage repair with vascular graft. The E‑vita open plus incurred costs when compared against 2-stage repair with endovascular stent graft (£4,760) and also when compared against open debranching with endoluminal stent graft (£7,663).
Results from the long-term model, which included the lifetime costs of complications, showed that treatment with the E‑vita open plus could generate significant cost savings when compared with all 3 comparator procedures. The estimated saving per patient 20 years after the procedure was £41,213 when compared against 2-stage repair with vascular graft, £39,392 when compared against 2-stage repair with endovascular stent graft and £51,778 when compared against open debranching with endoluminal stent graft.
The External Assessment Centre carried out a deterministic sensitivity analysis to investigate the impact of uncertainty on the likelihood and costs of complications. The probabilities of in-hospital mortality and paraplegia were varied separately based on their 95% confidence intervals from the External Assessment Centre's meta-analysis of the clinical evidence. The overall management costs and the annual costs of complications were varied separately using minimum and maximum ranges identified in the literature, if available. The proportion of days spent in an intensive care unit and the cost of an intensive care unit day were also varied to reflect uncertainty in the number of organs needing support. Results of the sensitivity analysis showed that varying the probability of in-hospital mortality and paraplegia for the E‑vita open plus, or the management or annual costs of complications, did not substantially change the expected cost savings in the base-case estimate. In the short-term model, varying the proportion of days spent in the intensive care unit did change the observed cost savings. At a 20% level, the E‑vita open plus incurred costs when compared with all 3 comparators. At a 60% level, there were cost savings for the E‑vita open plus compared against 2-stage repair with vascular graft. Varying the cost of intensive care unit stay affected the short-term model results in a similar way, but neither variable substantially altered the cost savings in the long term.
The External Assessment Centre acknowledged some limitations in its model. Complications were assumed to occur only in the short term, because data were not available about their occurrence in the longer term. However, clinical expert advice indicated that the majority of complications would occur during or shortly after the intervention. The External Assessment Centre recognised that a more complex model (such as Markov or discrete event simulation) might have facilitated a more refined analysis and noted that the sensitivity analysis did not account for the possibility of multiple complications occurring in individual patients.
The External Assessment Centre developed a profile of year-on-year costs for the long-term model from year 1 to year 20. The E‑vita open plus was estimated to be cost saving at and beyond 2 years after the procedure compared with all 3 comparator procedures. For example, when compared with 2-stage repair with vascular grafting, the base-case cost savings per person treated with the E‑vita open plus were £6,057 at 2 years after the procedure, £13,822 at 5 years, and £24,948 at 10 years. When compared with 2-stage repair with endovascular stent grafting, the cost savings were £1,471 at 2 years after the procedure, £9,847 at 5 years, and £21,847 at 10 years. When compared with open surgical debranching with endoluminal stent grafting, the cost savings were £726 at 2 years after the procedure, £12,003 at 5 years, and £28,158 at 10 years.
For the guidance review, the external assessment centre revised the model to reflect 2018 costs. The major changes in the update relate to acute care costs of adverse events and staff costs. In the original model, the acute care cost of adverse events was calculated as £2,155; in the revised model, the costs depend on the type of adverse event and range from £498 for bleeding to £11,663 for paraplegia. Staff costs in the revised model were taken from the Personal Social Services Research Unit (PPSRU) 2017 and were often cheaper. Base-case results for the 2018 revised model show that estimated cost savings per patient at 5 years after the procedure are:
£13,334 compared with 2-stage repair involving open insertion of a vascular graft.
£10,225 compared with 2-stage repair involving endovascular stent grafting.
£12,536 compared with open surgical debranching followed by endoluminal stent grafting.These saving increase across the 3 comparators in the longer term. Further details of the 2018 revised model are in the revised model summary.
## Committee considerations
The Committee recognised the difficulties of cost modelling based on the limited clinical evidence. It considered that the External Assessment Centre's critique of the sponsor's cost analysis was generally valid and judged its additional modelling to be sufficiently robust to provide a reasonable estimate of potential cost savings.
The Committee heard clinical expert advice that 10–20% of people treated with the E‑vita open plus might need a second procedure. It was advised that reintervention was likely for people with connective tissue disorders regardless of whether they had a 1- or 2‑stage procedure initially. The External Assessment Centre had been unable to include the possibility of reintervention in its model, citing a lack of data on which to base estimates. The External Assessment Centre advised the Committee that including the assumption that 10–20% of people would need reintervention would not substantially change the findings from the long-term model.
The Committee recognised that the E‑vita open plus could incur costs in the short term when compared with most methods of current practice. However, the opportunity to avoid a second stage procedure by using the E‑vita open plus would reduce resource use. The Committee accepted the External Assessment Centre's year-on-year costs profile and concluded that the E‑vita open plus was likely to have a cost advantage from year 2 onwards.# Conclusions
The Committee concluded that use of the E‑vita open plus would be likely to provide benefits compared with current practice for a small group of people with disease of the ascending aorta, aortic arch and the proximal descending aorta. Benefits would be conferred by eliminating the need for a second procedure and the associated risk of serious complications. Patients would need to be selected carefully based on the extent of their thoracic aortic disease.
The Committee recognised that some people for whom treatment with the E‑vita open plus would be suitable would have progressive aortic disease needing reintervention in the future, regardless of the method of repair used initially. This would be significantly more likely in people with connective tissue disorders such as Marfan's syndrome than in those with atherosclerotic conditions.
The Committee concluded that using the E‑vita open plus in the NHS was likely to save money compared with current standard practice in the longer term, from about 2 years after the intervention.Sir Andrew DillonChief ExecutiveDecember 2013# About this guidance
This guidance was developed using the NICE medical technologies guidance process.
We have produced a summary of this guidance for the public. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Related NICE guidance
For related NICE guidance, please see the NICE website.
ISBN: 978-1-4731-0391-7
|
{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the E‑vita open plus for treating complex aneurysms and dissections of the thoracic aorta, in a carefully selected group of people, is supported by the evidence.\n\nUsing the E‑vita open plus could remove the need for a second procedure and the associated risk of serious complications, and it should therefore be considered for people:\n\nwho would otherwise need a 2-stage repair procedure because their aortic disease extends into or beyond the distal part of their aortic arch (into the proximal descending aorta), but\n\nwho would not need additional intervention (such as stent grafting) in the descending aorta.\n\nThe E‑vita open plus is estimated to generate cost savings compared with current 2-stage repair from about 2\xa0years after the procedure. The estimated cost saving per patient at 5\xa0years after the procedure is around £13,334 when compared with 2‑stage repair involving open insertion of a vascular graft, £10,225 when compared with 2‑stage repair involving endovascular stent grafting and £12,536 when compared with open surgical debranching followed by endoluminal stent grafting. At 10\xa0years after the procedure, the estimated cost savings range from around £22,704 to £29,210 across the 3 comparators. [2018 – see section 5.23]", 'The technology': "# Description of the technology\n\nThe E‑vita open plus (JOTEC GmbH) is an endoluminal stent graft system designed for treating aneurysms and dissections of the thoracic aorta. The device is a 1-piece polyester fabric tube which combines a conventional vascular graft attached to an endovascular stent graft that allows treatment of the ascending aorta at the same time as the arch and descending aorta. The E‑vita open plus supersedes its immediate predecessor device, the E‑vita open. The 2\xa0devices are similar in design and function but the E‑vita open plus is impermeable to blood, and fibrin glue is not needed to seal the stent graft.\n\nThe E‑vita open plus is a single-use device with a shelf life of 2\xa0years. It is supplied sterile and pre-loaded in its delivery system. The device is available in a range of sizes with varying diameters and lengths. The delivery system consists of a release handle, nested catheters and a positioning aid. A luer connector is also incorporated to allow flushing of the inner guide catheter. A stiff guide wire is used to aid tracking of the device delivery. Radiopaque markers are integrated into the fabric of the graft for radiological imaging.\n\nThe E‑vita open plus received a CE mark in October 2008\xa0for the repair or replacement of the thoracic aorta in cases of complex aneurysms or dissections that involve the ascending aorta, the aortic arch and the descending aorta.\n\nThe E‑vita open plus is used in a single-stage procedure known as a 'frozen elephant trunk'. The thoracic aorta is surgically opened with access through a median sternotomy approach. The distal stent graft portion of the device is self-expanding, containing nitinol springs, and is used to treat the upper part of the descending aorta. The vascular graft part of the device (for repair of the arch and ascending aorta) is invaginated in the distal stent graft portion. The stent graft, in its delivery system, is inserted into the descending aorta and deployed by retracting a retaining sheath. Once the stent graft is in place, the delivery system is removed and the proximal vascular graft component is drawn out a short distance (5–10\xa0mm). The stent graft is then surgically anastomosed to the distal aorta. The vascular graft portion of the device is then drawn out fully and used to repair the ascending aorta and arch in a standard surgical fashion. The aortic branch vessels are attached to the vascular graft using a patch and the graft is anastomosed to the ascending aorta.\n\nThe cost of the E‑vita open plus stated in the sponsor's submission was £10,500\xa0excluding VAT.\n\nThe claimed benefits of the E‑vita open plus in the case for adoption presented by the sponsor are:\n\nrepair of the ascending aorta, arch and descending aorta in a single-stage procedure\n\na reduction in pain and discomfort\n\nelimination of the psychological distress associated with the anticipation of a second procedure\n\na reduction in treatment times and costs\n\na reduction in total end-organ ischaemia\n\na reduction in incisional complications and infections\n\na reduction in anaesthetic use and the elimination of the need for additional epidural pain management\n\na reduction in both total length of stay and intensive care unit length of stay\n\na reduction in rehabilitation time\n\nan earlier return to normal activities and work.\n\n# Current management\n\nThe management of thoracic aortic aneurysms and dissections is determined by the location, severity and rate of change of the disease, as well as the clinical circumstances. Thoracic aortic aneurysms result from a weakening of the aortic wall, leading to localised dilation. People with thoracic aneurysms are often observed with clinical and imaging surveillance. Invasive treatment may be offered depending upon the size and rate of enlargement of the aneurysm.\n\nAortic dissections result from a tear in the inner layer of the aorta. Blood flows through the tear, separating the layers of the wall. Acute aortic dissections are less than 2\xa0weeks old, and chronic dissections have been present for longer than 2\xa0weeks. Management of aortic dissections depends primarily on their location. Emergency surgery is usually offered for a Stanford type A aortic dissection, which affects the ascending thoracic aorta and often also the arch and descending aorta. Stanford type B dissections, typically involving the descending thoracic aorta, are often managed with conservative medical treatment. Elective surgical repair is sometimes undertaken, but endovascular repair with stent grafts is more commonly used.\n\nThere are 3\xa0main current methods of surgically treating complex aneurysms and dissections of the thoracic aorta, 2\xa0of which involve a 2-stage 'elephant trunk' procedure. Both approaches are similar in their first stage but use alternative repair techniques to complete the second stage. During the first stage, the ascending aorta and arch are repaired with a vascular graft through a median sternotomy. During this procedure a free-floating extension of the arch graft prosthesis (the 'elephant trunk') is left unattached in the descending aorta. Attaching it (and extending it as necessary) may be done by an endovascular procedure during which a stent graft is inserted into the descending aorta with access via the femoral artery (thoracic endovascular aortic repair – TEVAR). Alternatively the descending aorta may be repaired in a second surgical procedure some weeks or months later, by extending the 'elephant trunk' as necessary, through a lateral thoracotomy approach. The third method involves 'debranching' of the head and neck vessels from the aortic arch by creating a surgical anastomosis between the ascending aorta and the head and neck vessels using a vascular graft. This then allows an endoluminal stent graft to be inserted into the aortic arch and descending aorta either as a hybrid procedure (during the same operation) or at a second-stage operation.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview.\n\nThe key clinical outcomes for the E‑vita open plus presented in the decision problem were:\n\ncompletion and success of technical procedure(s)\n\nmortality\n\nmajor complications, for example stroke, paraplegia, renal failure, myocardial infarction and other events that may delay discharge\n\nlength of intensive care unit stay\n\ntotal length of hospital stay\n\nfreedom from further interventions\n\nlong-term survival rates\n\nincidence of junctional endoleak\n\ndevice-related adverse events.\n\nThe sponsor identified 13\xa0papers relevant to the E‑vita open plus. Most of these were derived from the International E‑vita Open Registry, which is reported to contain data on 70–80% of patients in 11\xa0European centres who have received the E‑vita open or open plus devices to treat their complex aortic disease. The sponsor excluded 10\xa0(of the 13) papers from further consideration, either because the data were already included in a more recent report on the entire register dataset at the time of publication (Jakob et al. 2011), or because they reported on small numbers of patients or on animal studies. The External Assessment Centre excluded a further 2\xa0papers from its evaluation: a small study with limited follow-up, and a study using the same data as the paper by Jakob et al. (2011). The External Assessment Centre judged that the principal clinical evidence for the E‑vita open plus was presented in the observational study on the International E‑vita Open Registry by Jakob et al. (2011).\n\nJakob et al. (2011) reported observational data, gathered between January 2005\xa0and December 2010, for 274\xa0patients with complex aortic disease enrolled in the International E‑vita Open Registry from, at the time, 8\xa0European centres. This comprised the entire dataset at the time of publication. Details of the 274\xa0patients treated, in terms of condition and interventions, are shown in table\xa01. Outcomes were presented as proportions and survival analysis was carried out using the Kaplan–Meier technique. Stent-graft deployment and arch replacement were carried out under selective antegrade cerebral perfusion during a mean time of 75\xa0minutes. Median length of hospital stay was 19\xa0days (range 12–29). Adverse events are shown in table 2. For patients with dissections the false lumen was assessed postoperatively and at a median time of 59\xa0months (range 28–99) after surgery. The false lumen thrombosed fully in 83% (62/75) of patients with acute aortic dissection, and 72% (68/94) of patients with chronic aortic dissection. After follow-up these figures rose to 93% and 92% respectively. For patients with aneurysms, complete exclusion of the aneurysm was achieved in 77% of cases (61/79). The overall 5‑year survival rate was 74%. Of the 233\xa0patients surviving the procedure initially, secondary endovascular intervention was needed in 13% (29) and surgery downstream was needed in 3% (6) of cases.\n\nTable 1 Conditions and interventions for patients enrolled in the International E‑vita Open Registry (Jakob et al. 2011)\n\n\n\n\n\nIncluded patients (n=274)\n\nEmergency surgery\n\nPrevious proximal repair\n\nPresenting condition needing treatment\n\nAcute aortic dissection\n\n(32%)\n\n(88%)\n\n-\n\nChronic aortic dissection\n\n(37%)\n\n-\n\n(70%)\n\nThoracic aortic aneurysm\n\n(31%)\n\n-\n\n-\n\nUnderlying condition\n\nMarfan's syndrome\n\n(5%)\n\n-\n\n-\n\nInterventions received during treatment with the E‑vita open plus\n\nArch replacement with E‑vita open plus\n\n(55%)\n\n-\n\n-\n\nArch replacement with other prosthesis\n\n(45%)\n\n-\n\n-\n\nAdditional coronary artery bypass graft\n\n(16%)\n\n-\n\n-\n\nThe sponsor presented limited evidence on clinical outcomes for 2-stage procedures to allow comparison with those for the E‑vita open plus. The External Assessment Centre therefore carried out a systematic review and meta-analysis of available data for the comparator procedures. The review identified 10\xa0papers and the meta‑analysis provided pooled estimates of outcome rates with 95% confidence intervals forin-hospital and 30\xa0day mortality, stroke, bleeding, paraplegia and renal failure, which were the main complications reported in the literature. The External Assessment Centre was unable to calculate single outcome estimates for the combined 2-stage procedures because of a lack of data. It judged that direct comparisons between the E‑vita open plus and the comparators would therefore be complex and that the figures did not take into account factors such as survival from stage\xa01\xa0to 2\xa0or the impact of the combined outcomes for each procedure. Long-term survival rates could not be included in the meta-analysis because no confidence intervals were reported and individual patient data were not available. The pooled estimate data for the comparators are shown in table 2.\n\nTable 2 Adverse events for the E‑vita open plus, as reported in Jakob et al. (2011), and comparators\n\n\n\nStage\n\nE‑vita open plus\n\n(Jakob et al. 2011)\n\n(n; %; 95% confidence interval)\n\n-stage open surgical repair with vascular graft placement\n\n(%; 95% confidence interval\n\n-stage repair with endovascular stent graft placement\n\nOpen surgical 'debranching' with endoluminal stent graft placement (2-stage procedure)\n\nIn-hospital mortality\n\n\n\n(15.0%: 11.0\xa0to 19.7%)\n\n% (6.4\xa0to 11.1%)\n\n% (3.4\xa0to 21.4%)\n\n% (4.5\xa0to 28.8%)\n\n\n\n-\n\n% (5.6\xa0to 11.2%)\n\n% (4.4\xa0to 19.8%)\n\n% (0.1\xa0to 19.0%)\n\nday mortality\n\n\n\n(12.0%: 8.4\xa0to 16.5%)\n\n% (5.4\xa0to 10.5%)\n\n-\n\n-\n\n\n\n-\n\n% (1.6\xa0to 19.0%)\n\n% (0.08\xa0to 16.7%)\n\n-\n\nRe-exploration for bleeding\n\n\n\n(13.9%: 10.0\xa0to 18.5%)\n\n% (2.8\xa0to 7.4%)\n\n% (0.1\xa0to 21.1%)\n\n% (1.7\xa0to 21.9%)\n\n\n\n-\n\n% (1.7\xa0to 7.8%)\n\n% (0.1\xa0to 27.3%)\n\n-\n\nStroke\n\n\n\n(5.8%: 3.4\xa0to 9.3%)\n\n% (2.3\xa0to 4.9%)\n\n% (3.3\xa0to 16.1%)\n\n% (1.7\xa0to 21.9%)\n\n\n\n-\n\n% (1.1\xa0to 13.0%)\n\n-\n\n% (0.1\xa0to 19.0%)\n\nParaplegia\n\n\n\n(8.0%: 5.1\xa0to 11.9%)\n\n-\n\n% (0.1\xa0to 21.1%)\n\n-\n\n\n\n-\n\n% (1.6\xa0to 9.8%)\n\n% (3.0\xa0to 19.1%)\n\n-\n\nRenal failure (permanent)\n\n\n\n(3.6%: 1.8\xa0to 6.6%)\n\n% (3.4\xa0to 19.6%)\n\n% (2.7\xa0to 32.4%)\n\n-\n\n\n\n-\n\n% (1.1\xa0to 27.6%)\n\n-\n\n-\n\n% confidence intervals were calculated by the External Assessment Centre, and pooled outcome estimates for the comparator technologies were taken from the External Assessment Centre's meta-analysis.\n\nDuring consultation, an additional clinical report was identified that presented more recent data from the International E‑vita Open Registry (Jakob and Tsagakis, 2013). The paper reported outcomes for in-hospital mortality, stroke, paraplegia and 5-year survival rates for a total of 416\xa0patients from 11\xa0international centres. No outcomes were reported for 30-day mortality, bleeding or renal failure. Figures for 5-year survival rates were reported for 3\xa0subgroups but no overall figure was reported or could be calculated from the data presented. The External Assessment Centre determined that, overall, there was insufficient information available, in terms of completeness or long-term follow-up, to provide additional reliable estimates of outcome rates beyond those derived from the Jakob et al. (2011) study (see section 3.4).\n\n## Committee considerations\n\nThe Committee considered that the clinical evidence was limited because it was restricted to observational studies. However, it considered that the evidence was sufficient, when taken together with clinical expert advice, to conclude that the E‑vita open plus is effective for use in a selected group of people (see 3.10–3.11).\n\nThe Committee considered that the pooled estimates of outcomes for the comparators produced by the External Assessment Centre indicated that more bleeding would be likely to occur with the E‑vita open plus (13.9%) than with the comparators (ranging from 4.2% to 8.1% at stage\xa01, and from 3.7% to 5.6% at stage\xa02). The Committee was advised that bleeding was a complication experienced with both the E‑vita open plus and the comparators and that excess bleeding with the E‑vita open plus may have reflected incorrect choice of device size during early experiences of its use. It was mindful that bleeding is a complication which is normally controlled at the time of surgery, without patients experiencing long-lasting adverse consequences, in contrast to the other major adverse events (stroke, paraplegia and renal failure) which may have serious consequences for patients in the long term.\n\nThe Committee was advised that patient selection would be important in realising the claimed benefits of the E‑vita open plus. The Committee heard expert clinical advice that the E‑vita open plus is primarily suitable for people needing aortic arch repair and that the device enables repair to the arch to be completed more rapidly than by other techniques. Expert advice also confirmed that in people whose aortic disease extends less than 10\xa0cm into the descending aorta (based on the size of the stent graft portion of the device), the E‑vita open plus would allow a complex repair in a single procedure.\n\nThe Committee concluded that in people with aneurysms or acute aortic dissections needing repair of the aortic arch and ascending aorta, if the disease extends less than 10\xa0cm into the descending aorta, the E‑vita open plus would be a suitable treatment. The Committee recognised that the E‑vita open plus might be suitable for use in other people with more extensive disease in the descending aorta that would need multiple stent grafts. However, it decided that the potential benefits of the technology for these people were not clear, based on the evidence presented. The Committee therefore considered that making a recommendation for use of the technology in those with more extensive disease in the descending thoracic aorta was not possible.\n\nThe Committee was advised that many people for whom treatment with the E‑vita open plus would be suitable have progressive aortic disease that would need further interventions, regardless of whether the repair was carried out in a single or 2-stage procedure. It was advised that this is significantly more likely in people with connective tissue disorders such as Marfan's syndrome than in those with atherosclerotic disease.\n\nThe Committee judged that the main advantage of the E‑vita open plus is the avoidance of a second procedure with its associated serious risks, which include stroke, renal failure, paraplegia and bleeding. The Committee was advised by clinical experts that some people decide not to return for a second procedure because of negative experiences from the first operation. The Committee considered that the opportunity to repair the aorta in a single procedure would confer significant benefits to these people.\n\nThe Committee was advised by clinical experts that the estimate in the scope for the number of people in England (50–100\xa0per year) eligible for treatment was reasonable.\n\nThe Committee considered the paper by Jakob and Tsagakis (2013), but judged that the outcomes it reported did not add to the evidence base for the E‑vita open plus: no data for 30-day mortality, bleeding or renal failure were reported. It considered that the included outcome data did not differ significantly from those reported by Jakob et al. (2011) and would not alter the outcomes from the External Assessment Centre's cost analysis.", 'NHS considerations': '# System impact\n\nThe sponsor stated that using the E‑vita open plus could allow repair of the thoracic aorta in a single procedure, when a 2-stage procedure would otherwise be necessary. It claimed that this would consequently reduce overall length of stay in hospital and reduce the risk of complications needing hospital treatment. The clinical evidence consisted of the study by Jakob et al. (2011), which contained no comparative data about resource use during other aortic repair techniques. The review and meta-analysis carried out by the sponsor focused on clinical outcomes rather than resource implications.\n\n## Committee considerations\n\nThe Committee was satisfied that a second repair procedure could be avoided by using the E‑vita open plus in a selected group of people and that this could reduce associated NHS resource use.\n\nThe Committee was advised that aortic repair using the E‑vita open plus is a highly specialised procedure, carried out in a small number of centres, in a small patient group. Despite these limitations, the Committee considered that the potential benefits of releasing operating theatre and clinical time by avoiding the need for a second procedure could be significant. It recognised that the resources needed for treating complications associated with a second procedure (some of which would be severe and would result in long-term disability) would also be released.', 'Cost considerations': "# Cost evidence\n\nNeither thesponsor nor the External Assessment Centre identified any relevant published economic evidence for the E‑vita open plus or for the comparator techniques.\n\nThe sponsor submitted a de\xa0novo analysis comparing the use of the E‑vita open plus against a 2-stage classical 'elephant trunk' procedure in terms of overall costs, in-hospital mortality and adoption rates. The population was a cohort of 3,500\xa0people with aneurysms, dissections and other specified lesions of the thoracic aorta. The model consisted of 2\xa0decision trees over a 1-year time horizon:\n\na current practice model using the classical 'elephant trunk' procedure\n\nan intervention model comparing current practice against use of the E‑vita open plus at a 40% adoption rate.\n\nThe first stage of the current practice arm was divided into 2\xa0options: woven graft or branched graft. For patients undergoing stage\xa02, the options were woven graft (open surgery) or endovascular stent graft. Following clarification from the sponsor, these options were further defined as follows:\n\nWoven graft at stages 1\xa0and 2\xa0referred to 2-stage open surgical repair with vascular graft placement.\n\nWoven graft followed by stent graft at stage\xa02\xa0referred to 2-stage repair with open surgical graft placement in the ascending aorta and arch and endovascular stent graft placement in the descending aorta.\n\nBranched graft followed by woven or stent graft at stage\xa02\xa0referred to open surgical 'debranching' of the head and neck vessels with endoluminal stent graft placement in the aortic arch and either a vascular graft or endovascular stent graft in the descending aorta.\n\nThe sponsor carried out 1- and 2-way sensitivity analyses to include base-case, worst-case and best-case scenarios in its analysis.\n\nThe key assumptions used in the model were:\n\nIn-hospital and 30\xa0day mortality was 15% for the E‑vita open plus, based on data from the paper by Jakob et al. (2011).\n\nThe remaining 85% of patients treated would not experience other complications.\n\nMortality rates were 20% for woven graft and 30% for branched graft at stage\xa02.\n\nThe number of inpatient days for the classical elephant trunk procedure was 10\xa0at stage\xa01\xa0and 15\xa0at stage\xa02.\n\nThe number of inpatient days for the endovascular stent procedure was 10\xa0at stage\xa01\xa0and 8\xa0at stage\xa02.\n\nThe number of inpatient days for the E‑vita open plus was 4\xa0in the intensive care unit and 6\xa0in a surgical ward.\n\nTechnology costs were provided by the sponsor. The cost of the E‑vita open plus was £10,500\xa0and the comparator costs were £200\xa0for a woven graft for stages 1\xa0and 2, £1,000\xa0for a branched graft, and £5,000\xa0for an endovascular stent graft. Consumable costs (mainly for the guide wire, estimated to be £130) were not included because the sponsor considered these to be the same for the technology and comparators. Cost estimates for clinical time and resource use were sourced from published literature, the Personal Social Services Research Unit (PSSRU) unit costs of health and social care manual, and NHS reference costs.\n\nThe cost of a surgeon was estimated to be £399\xa0per hour and the costs of a perfusionist and anaesthetist were each estimated to be £87\xa0per hour (registrar rate). The cost for theatre time, including nursing and consumables, was estimated to be £24\xa0per hour, and £30\xa0per hour for corresponding intensive care unit costs. These were derived from the NHS tariff for admitted patient case and outpatient procedures but no codes were specified. The sponsor used a daily cost for an intensive care unit stay of £1,500, taken from a report in The Lancet. The cost of a surgical ward inpatient stay was taken to be £420\xa0per day, based on 2\xa0different tariff codes. The cost of death cited by the sponsor (£8,000) was taken from a cancer network publication.\n\nThe sponsor carried out 1-way sensitivity analyses varying the adoption rate from 20% to 100% (in the modelled population of 3,500\xa0patients assumed to be eligible for the E‑vita open plus). The proportion of woven or branched grafts used at stage\xa01\xa0was varied from 60% to 95% from a base-case estimate of 85%. The proportional suitability for a second stage operation was varied from a base case of 80% to 60% and 95%, and the proportion of patients having each stage\xa02\xa0procedure was varied from a 50% base case to 40% and 100%. The sponsor also carried out a 2-way sensitivity analysis varying the in-hospital death rate at stage\xa01\xa0of the classical elephant trunk procedure and for the E‑vita open plus.\n\nThe sponsor presented the results of its de\xa0novo analysis as an average cost per patient, assuming a 100% adoption level (rather than the 40% adoption level described in the model decision tree in section 5.2) for the E‑vita open plus compared with current practice. The cost for the E‑vita open plus was £25,689\xa0and the overall cost presented for the comparators was £30,241, indicating a cost saving per patient of £4,553\xa0if the E‑vita open plus was used. The cost per patient varied across the different comparators, ranging from £26,691\xa0for woven graft (stage\xa01) with endovascular stent (stage\xa02) to £36,016\xa0for branched graft (stage\xa01) with woven graft (stage\xa02).\n\nThe sponsor's sensitivity analysis showed little variation in the cost savings generated for the E‑vita open plus at different adoption levels, with an average cost saving of around £4,358. The sponsor reported that varying the parameters for second-stage suitability and in-hospital death had an impact on the cost savings, but that this was relatively small. Varying the suitability of a second stage operation produced higher cost savings per patient if the level of suitability was raised. The sponsor did not consider the subgroups defined in the scope in its de\xa0novo analysis because of a lack of available data on the comparators.\n\nThe External Assessment Centre considered that the sponsor's de\xa0novo cost model was flawed because it did not include the short- or long-term costs of complications and because some of the costs and clinical parameters were inaccurate or inappropriate. Specifically, the External Assessment Centre considered that a per-patient, rather than a cohort, approach would have been more useful and that the estimated cohort of 3,500\xa0patients was too large.\n\nThe External Assessment Centre carried out additional modelling to address these issues, constructing short- and long-term models that included the costs of complications (stroke, paraplegia, renal failure and bleeding). Both models compared per-patient costs for the E‑vita open plus and the 3\xa0comparators defined in the scope. A decision tree was constructed for each procedure in each model. In-hospital mortality was modelled at each stage of each procedure. The time horizon for the short-term model was 1\xa0year, as the External Assessment Centre considered that stage\xa02\xa0procedures were likely to be carried out within 6\xa0months of stage\xa01. The long-term model had a 20\xa0year time horizon, based on the UK life expectancy of the average age (65\xa0years) of those receiving treatment described in published literature. Lifetime costs of complications were included in this model.\n\nIn the short-term model for each comparator, patients with no complications or bleeding at stage\xa01\xa0were assumed to proceed to the second stage procedure, whereas it was assumed that those who had a stroke, renal failure or paraplegia would not. In the long-term model, the annual costs of care for stroke, paraplegia and renal failure were taken from published literature and discounted at 3.5%. The discounted annual cost was multiplied by a survival probability for 65–85\xa0years and the weighted annual costs were summed to estimate the lifetime cost of the complications.\n\nThe External Assessment Centre estimated the probabilities of the outcomes at each stage from the register data for the E‑vita open plus and from its meta-analysis of the clinical evidence on the comparator procedures. The probability of paraplegia at stage\xa01\xa0was assumed to be the same for 2-stage repair with vascular graft and 2-stage repair with endovascular stent graft. For open debranching, the probability of paraplegia and that of renal failure at stage\xa01\xa0was taken from hybrid procedure estimates. Operating times and total lengths of stay for all the comparators were sourced from published literature. Operating time for the E‑vita open plus and details of the surgical team involved for each procedure were taken from the sponsor's model. The team included a consultant surgeon, consultant anaesthetist, associate specialist, perfusionist and 2\xa0specialist nurses. A consultant radiologist was included for stage\xa02\xa0procedures involving stent grafts.\n\nThe External Assessment Centre used technology and comparator costs from the sponsor's model but derived more precise estimates for staff and ward stay costs than those used by the sponsor (as described in section 5.7). Costs for each professional in the surgical team were taken from PSSRU 2012\xa0unit costs. The costs for an intensive care unit and surgical ward stay were sourced from NHS reference costs at £1,410\xa0per day and £383\xa0per day respectively.\n\nComplications were assumed to incur additional in-hospital management costs and a single cost figure was applied across all procedures (£2,155). The annual cost for stroke care was estimated to be £9,597\xa0at 2012\xa0prices, from atrial fibrillation (NICE clinical guideline 36). The annual cost of paraplegia was estimated to be £14,580, based on published literature and inflated to 2012\xa0prices. The annual cost for renal failure used was £32,961, taken from peritoneal dialysis (NICE clinical guideline 125) and inflated to 2012\xa0prices.\n\nCosts for multiple stents were included in the analysis and sourced from the sponsor's submission. However, the External Assessment Centre was not able to model the probable outcomes from using multiple stents, citing a lack of available clinical evidence.\n\nResults of the short-term model showed that treatment with the E‑vita open plus could generate a cost saving of £280\xa0per patient when compared against 2-stage repair with vascular graft. The E‑vita open plus incurred costs when compared against 2-stage repair with endovascular stent graft (£4,760) and also when compared against open debranching with endoluminal stent graft (£7,663).\n\nResults from the long-term model, which included the lifetime costs of complications, showed that treatment with the E‑vita open plus could generate significant cost savings when compared with all 3\xa0comparator procedures. The estimated saving per patient 20\xa0years after the procedure was £41,213\xa0when compared against 2-stage repair with vascular graft, £39,392\xa0when compared against 2-stage repair with endovascular stent graft and £51,778\xa0when compared against open debranching with endoluminal stent graft.\n\nThe External Assessment Centre carried out a deterministic sensitivity analysis to investigate the impact of uncertainty on the likelihood and costs of complications. The probabilities of in-hospital mortality and paraplegia were varied separately based on their 95% confidence intervals from the External Assessment Centre's meta-analysis of the clinical evidence. The overall management costs and the annual costs of complications were varied separately using minimum and maximum ranges identified in the literature, if available. The proportion of days spent in an intensive care unit and the cost of an intensive care unit day were also varied to reflect uncertainty in the number of organs needing support. Results of the sensitivity analysis showed that varying the probability of in-hospital mortality and paraplegia for the E‑vita open plus, or the management or annual costs of complications, did not substantially change the expected cost savings in the base-case estimate. In the short-term model, varying the proportion of days spent in the intensive care unit did change the observed cost savings. At a 20% level, the E‑vita open plus incurred costs when compared with all 3\xa0comparators. At a 60% level, there were cost savings for the E‑vita open plus compared against 2-stage repair with vascular graft. Varying the cost of intensive care unit stay affected the short-term model results in a similar way, but neither variable substantially altered the cost savings in the long term.\n\nThe External Assessment Centre acknowledged some limitations in its model. Complications were assumed to occur only in the short term, because data were not available about their occurrence in the longer term. However, clinical expert advice indicated that the majority of complications would occur during or shortly after the intervention. The External Assessment Centre recognised that a more complex model (such as Markov or discrete event simulation) might have facilitated a more refined analysis and noted that the sensitivity analysis did not account for the possibility of multiple complications occurring in individual patients.\n\nThe External Assessment Centre developed a profile of year-on-year costs for the long-term model from year 1\xa0to year 20. The E‑vita open plus was estimated to be cost saving at and beyond 2\xa0years after the procedure compared with all 3\xa0comparator procedures. For example, when compared with 2-stage repair with vascular grafting, the base-case cost savings per person treated with the E‑vita open plus were £6,057\xa0at 2\xa0years after the procedure, £13,822\xa0at 5\xa0years, and £24,948\xa0at 10\xa0years. When compared with 2-stage repair with endovascular stent grafting, the cost savings were £1,471\xa0at 2\xa0years after the procedure, £9,847\xa0at 5\xa0years, and £21,847\xa0at 10\xa0years. When compared with open surgical debranching with endoluminal stent grafting, the cost savings were £726\xa0at 2\xa0years after the procedure, £12,003\xa0at 5\xa0years, and £28,158\xa0at 10\xa0years.\n\nFor the guidance review, the external assessment centre revised the model to reflect 2018 costs. The major changes in the update relate to acute care costs of adverse events and staff costs. In the original model, the acute care cost of adverse events was calculated as £2,155; in the revised model, the costs depend on the type of adverse event and range from £498 for bleeding to £11,663 for paraplegia. Staff costs in the revised model were taken from the Personal Social Services Research Unit (PPSRU) 2017 and were often cheaper. Base-case results for the 2018 revised model show that estimated cost savings per patient at 5 years after the procedure are:\n\n£13,334 compared with 2-stage repair involving open insertion of a vascular graft.\n\n£10,225 compared with 2-stage repair involving endovascular stent grafting.\n\n£12,536 compared with open surgical debranching followed by endoluminal stent grafting.These saving increase across the 3 comparators in the longer term. Further details of the 2018 revised model are in the revised model summary. \n\n## Committee considerations\n\nThe Committee recognised the difficulties of cost modelling based on the limited clinical evidence. It considered that the External Assessment Centre's critique of the sponsor's cost analysis was generally valid and judged its additional modelling to be sufficiently robust to provide a reasonable estimate of potential cost savings.\n\nThe Committee heard clinical expert advice that 10–20% of people treated with the E‑vita open plus might need a second procedure. It was advised that reintervention was likely for people with connective tissue disorders regardless of whether they had a 1-\xa0or 2‑stage procedure initially. The External Assessment Centre had been unable to include the possibility of reintervention in its model, citing a lack of data on which to base estimates. The External Assessment Centre advised the Committee that including the assumption that 10–20% of people would need reintervention would not substantially change the findings from the long-term model.\n\nThe Committee recognised that the E‑vita open plus could incur costs in the short term when compared with most methods of current practice. However, the opportunity to avoid a second stage procedure by using the E‑vita open plus would reduce resource use. The Committee accepted the External Assessment Centre's year-on-year costs profile and concluded that the E‑vita open plus was likely to have a cost advantage from year 2\xa0onwards.", 'Conclusions': "The Committee concluded that use of the E‑vita open plus would be likely to provide benefits compared with current practice for a small group of people with disease of the ascending aorta, aortic arch and the proximal descending aorta. Benefits would be conferred by eliminating the need for a second procedure and the associated risk of serious complications. Patients would need to be selected carefully based on the extent of their thoracic aortic disease.\n\nThe Committee recognised that some people for whom treatment with the E‑vita open plus would be suitable would have progressive aortic disease needing reintervention in the future, regardless of the method of repair used initially. This would be significantly more likely in people with connective tissue disorders such as Marfan's syndrome than in those with atherosclerotic conditions.\n\nThe Committee concluded that using the E‑vita open plus in the NHS was likely to save money compared with current standard practice in the longer term, from about 2\xa0years after the intervention.Sir Andrew DillonChief ExecutiveDecember 2013", 'About this guidance ': 'This guidance was developed using the NICE medical technologies guidance process.\n\nWe have produced a summary of this guidance for the public. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nRelated NICE guidance\n\nFor related NICE guidance, please see the NICE website.\n\nISBN: 978-1-4731-0391-7'}
|
https://www.nice.org.uk/guidance/mtg16
|
Evidence-based recommendations on the E-vita open plus for treating complex aneurysms and dissections of the thoracic aorta.
|
b734ca1a08fa86b3da43c42a8c6d107d16604f1f
|
nice
|
Transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia
|
Transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia
Evidence-based recommendations on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves injecting a high-speed jet of water into the prostate to destroy some of the tissue.
# Recommendations
The evidence on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia raises no major safety concerns. The evidence on efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia is recommended.
Audit and review clinical outcomes of all patients having transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
The procedure should only be done by clinicians who have been trained in the technique.
NICE encourages further research into transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia and may update the guidance on publication of further evidence. Further research should report long-term follow‑up and include reintervention rates.# The condition, current treatments and procedure
# The condition
Benign prostatic hyperplasia is a common condition that affects older men. Stromal and epithelial cells increase in number, causing the prostate to get bigger. It often happens in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during urination, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.
# Current treatments
Mild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5‑alpha-reductase inhibitors. If other treatments have not worked, there are a range of surgical options that may be considered. These include transurethral resection of the prostate, transurethral vaporisation, holmium laser enucleation, insertion of prostatic urethral lift implants, prostate artery embolisation or prostatectomy (see NICE's clinical guideline on lower urinary tract symptoms in men). Potential complications of some of these procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction.
# The procedure
Transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia uses a specialised system that combines image guidance and robotics for the targeted heat-free removal of prostate tissue. The procedure is usually done with the patient under general or spinal anaesthesia. Transrectal ultrasound is used throughout the procedure. A handpiece with an integrated cystoscope and ablation probe is inserted through the urethra and into the bladder. Positioning is confirmed by using visual markers on a computer screen, and the surgeon is able to plan the depth and angle of resection using the system software. Once the surgical mapping is complete, a high-speed jet of saline is delivered to the prostate at various flow rates, according to the depth of penetration needed. The ablated tissue is aspirated through ports in the handpiece and can be used for histological analysis. Haemostasis can be achieved by cautery or by inflating a Foley balloon catheter inside the prostatic cavity. The average resection time is typically about 3 to 5 minutes. After the procedure, a 3‑way Foley catheter is placed under traction and continuous bladder irrigation is started. Traction is removed a few hours after the procedure and irrigation is progressively decreased. The catheter is removed before the patient is discharged from hospital, usually the day after the procedure.
The possible advantages of the procedure include a reduction in resection time compared with other endoscopic methods, and the potential to preserve sexual function. The procedure is heat-free, which removes the risk of complications arising from thermal injury.
|
{'Recommendations': "The evidence on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia raises no major safety concerns. The evidence on efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia is recommended.\n\nAudit and review clinical outcomes of all patients having transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nThe procedure should only be done by clinicians who have been trained in the technique.\n\nNICE encourages further research into transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia and may update the guidance on publication of further evidence. Further research should report long-term follow‑up and include reintervention rates.", 'The condition, current treatments and procedure': "# The condition\n\nBenign prostatic hyperplasia is a common condition that affects older men. Stromal and epithelial cells increase in number, causing the prostate to get bigger. It often happens in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during urination, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.\n\n# Current treatments\n\nMild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5‑alpha-reductase inhibitors. If other treatments have not worked, there are a range of surgical options that may be considered. These include transurethral resection of the prostate, transurethral vaporisation, holmium laser enucleation, insertion of prostatic urethral lift implants, prostate artery embolisation or prostatectomy (see NICE's clinical guideline on lower urinary tract symptoms in men). Potential complications of some of these procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction.\n\n# The procedure\n\nTransurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia uses a specialised system that combines image guidance and robotics for the targeted heat-free removal of prostate tissue. The procedure is usually done with the patient under general or spinal anaesthesia. Transrectal ultrasound is used throughout the procedure. A handpiece with an integrated cystoscope and ablation probe is inserted through the urethra and into the bladder. Positioning is confirmed by using visual markers on a computer screen, and the surgeon is able to plan the depth and angle of resection using the system software. Once the surgical mapping is complete, a high-speed jet of saline is delivered to the prostate at various flow rates, according to the depth of penetration needed. The ablated tissue is aspirated through ports in the handpiece and can be used for histological analysis. Haemostasis can be achieved by cautery or by inflating a Foley balloon catheter inside the prostatic cavity. The average resection time is typically about 3\xa0to 5\xa0minutes. After the procedure, a 3‑way Foley catheter is placed under traction and continuous bladder irrigation is started. Traction is removed a few hours after the procedure and irrigation is progressively decreased. The catheter is removed before the patient is discharged from hospital, usually the day after the procedure.\n\nThe possible advantages of the procedure include a reduction in resection time compared with other endoscopic methods, and the potential to preserve sexual function. The procedure is heat-free, which removes the risk of complications arising from thermal injury."}
|
https://www.nice.org.uk/guidance/ipg629
|
Evidence-based recommendations on transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves injecting a high-speed jet of water into the prostate to destroy some of the tissue.
|
1f0785bfb28e0027f11d8491d0fe68490b046392
|
nice
|
Intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer
|
Intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer
Evidence-based recommendations on intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer in adults. This involves using microwaves to improve the effect of the chemotherapy given directly into the bladder.
# Recommendations
The evidence on the safety of intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer shows there are well-recognised adverse events. Current evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, alternative treatments and provide them with clear written information. In addition, the use of NICE's information for the public on intravesical microwave hyperthermia and chemotherapy is recommended.
Audit and review clinical outcomes of all patients having intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Patient selection should be by a specialist bladder cancer multidisciplinary team. The procedure should only be done in specialist centres by clinicians who have had supervised training in the procedure.
NICE encourages further research into intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer. Research should include randomised controlled trials, which stratify patients by risk and give adequate follow-up. They should report frequency of adverse events, patient-reported outcome measures, overall and disease-free survival and quality of life.
NICE may review this procedure on publication of further evidence.# The condition, current treatments and procedure
# The condition
Transitional cell carcinoma is the most common form of bladder cancer. Non-muscle-invasive transitional cell carcinoma is classified as stage Ta when the tumour is confined to the uroepithelium with no spread into the bladder wall or beyond. It is classified as stage T1 when there is spread into the connective tissue layer between the urothelium and the muscle wall. Non-muscle-invasive transitional cell carcinomas can be graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Carcinoma in situ is a form of tumour consisting of aggressive cancer cells which spread within the surface lining of the bladder.
# Current treatments
Surgical interventions for non-muscle-invasive transitional cell carcinoma include transurethral resection, in which malignant tissue is removed with an electrocautery device during cystoscopy. Bacillus Calmette-Guérin (BCG) vaccine or chemotherapy drugs may be put directly into the bladder, either as a treatment in itself, or as adjuvant therapy after transurethral resection. Cystectomy may also be necessary in some patients.
# The procedure
Intravesical microwave hyperthermia and chemotherapy can be used as neoadjuvant therapy before transurethral resection, with the aim of eradicating tumours. Alternatively the procedure can be used after transurethral resection, as adjuvant therapy (sometimes referred to as prophylactic treatment), aiming to prevent recurrence. Hyperthermia is believed to have a direct and immune-mediated cytotoxic effect on tumour cells and to improve the efficacy of chemotherapy drugs.
The procedure can be done on an outpatient basis. Using local anaesthetic urethral gel, a balloon catheter (containing a radiofrequency antenna and several insulated thermocouples), is inserted through the urethra into the bladder. Ultrasound is sometimes used to assess the position of the device. The radiofrequency antenna gives off microwaves which heat the superficial layers of the bladder wall. The thermocouples are spread out from the catheter and pushed against the bladder lining. They monitor temperature to help prevent overheating. A solution of a cytostatic agent, usually mitomycin C, is instilled into the bladder, between the bladder wall and the balloon surface. The solution is continuously pumped out of the bladder, cooled, and recirculated to prevent overheating. Treatment sessions typically last between 40 minutes and 60 minutes and are usually repeated weekly for 4 to 8 weeks, or longer for adjuvant treatment.
|
{'Recommendations': "The evidence on the safety of intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer shows there are well-recognised adverse events. Current evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, alternative treatments and provide them with clear written information. In addition, the use of NICE's information for the public on intravesical microwave hyperthermia and chemotherapy is recommended.\n\nAudit and review clinical outcomes of all patients having intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nPatient selection should be by a specialist bladder cancer multidisciplinary team. The procedure should only be done in specialist centres by clinicians who have had supervised training in the procedure.\n\nNICE encourages further research into intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer. Research should include randomised controlled trials, which stratify patients by risk and give adequate follow-up. They should report frequency of adverse events, patient-reported outcome measures, overall and disease-free survival and quality of life.\n\nNICE may review this procedure on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nTransitional cell carcinoma is the most common form of bladder cancer. Non-muscle-invasive transitional cell carcinoma is classified as stage\xa0Ta when the tumour is confined to the uroepithelium with no spread into the bladder wall or beyond. It is classified as stage\xa0T1 when there is spread into the connective tissue layer between the urothelium and the muscle wall. Non-muscle-invasive transitional cell carcinomas can be graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Carcinoma in situ is a form of tumour consisting of aggressive cancer cells which spread within the surface lining of the bladder.\n\n# Current treatments\n\nSurgical interventions for non-muscle-invasive transitional cell carcinoma include transurethral resection, in which malignant tissue is removed with an electrocautery device during cystoscopy. Bacillus Calmette-Guérin (BCG) vaccine or chemotherapy drugs may be put directly into the bladder, either as a treatment in itself, or as adjuvant therapy after transurethral resection. Cystectomy may also be necessary in some patients.\n\n# The procedure\n\nIntravesical microwave hyperthermia and chemotherapy can be used as neoadjuvant therapy before transurethral resection, with the aim of eradicating tumours. Alternatively the procedure can be used after transurethral resection, as adjuvant therapy (sometimes referred to as prophylactic treatment), aiming to prevent recurrence. Hyperthermia is believed to have a direct and immune-mediated cytotoxic effect on tumour cells and to improve the efficacy of chemotherapy drugs.\n\nThe procedure can be done on an outpatient basis. Using local anaesthetic urethral gel, a balloon catheter (containing a radiofrequency antenna and several insulated thermocouples), is inserted through the urethra into the bladder. Ultrasound is sometimes used to assess the position of the device. The radiofrequency antenna gives off microwaves which heat the superficial layers of the bladder wall. The thermocouples are spread out from the catheter and pushed against the bladder lining. They monitor temperature to help prevent overheating. A solution of a cytostatic agent, usually mitomycin\xa0C, is instilled into the bladder, between the bladder wall and the balloon surface. The solution is continuously pumped out of the bladder, cooled, and recirculated to prevent overheating. Treatment sessions typically last between 40\xa0minutes and 60\xa0minutes and are usually repeated weekly for 4 to 8\xa0weeks, or longer for adjuvant treatment.'}
|
https://www.nice.org.uk/guidance/ipg628
|
Evidence-based recommendations on intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer in adults. This involves using microwaves to improve the effect of the chemotherapy given directly into the bladder.
|
51874f40a87914dfda192a5b48795b3f34f5a623
|
nice
|
Inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia
|
Inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia
Evidence-based recommendations on inotuzumab ozogamicin (Besponsa) for relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia in adults.
# Recommendations
Inotuzumab ozogamicin is recommended, within its marketing authorisation, as an option for treating relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia in adults. People with relapsed or refractory Philadelphia-chromosome-positive disease should have had at least 1 tyrosine kinase inhibitor.Inotuzumab ozogamicin is recommended only if the company provides it according to the commercial arrangement.
# Why the committee made these recommendations
Treatment for relapsed or refractory B-cell acute lymphoblastic leukaemia is usually fludarabine, cytarabine and granulocyte colony-stimulating factor based chemotherapy (FLAG) with idarubicin. People with Philadelphia-chromosome-positive disease can have FLAG-based therapy with tyrosine kinase inhibitors or tyrosine kinase inhibitors alone. Clinical trial evidence does not show an overall survival benefit for people having inotuzumab ozogamicin compared with those having FLAG, high-dose cytarabine or cytarabine with mitoxantrone-based chemotherapy. However, more people having inotuzumab ozogamicin are able to go on to have a stem cell transplant when compared with people having the other treatments. Inotuzumab ozogamicin also meets NICE's criteria to be a life-extending treatment at the end of life.
The most plausible cost-effectiveness estimates for inotuzumab ozogamicin compared with standard care are in the range NICE considers an acceptable use of NHS resources. Therefore it can be recommended for treating relapsed or refractory B-cell acute lymphoblastic leukaemia.# Information about inotuzumab ozogamicin
Marketing authorisation
Inotuzumab ozogamicin (Besponsa, Pfizer) is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). Adult patients with Philadelphia-chromosome-positive relapsed or refractory B-cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor.
Dosage in the marketing authorisation
Intravenously at a starting dose of 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15), in 3- to 4-week cycles. Cycle 1 lasts for 3 weeks, and each subsequent cycle lasts for 4 weeks. See the summary of product characteristics for further details.
Price
£8,048 per 1 mg vial of powder concentrate for solution for infusion (excluding VAT; BNF 2018). The company has a commercial arrangement. This makes inotuzumab ozogamicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## People with B-cell acute lymphoblastic leukaemia would welcome a new treatment option
The clinical and patient experts noted that people with relapsed or refractory B-cell acute lymphoblastic leukaemia have limited treatment options. The committee understood that current treatment can cause unpleasant side effects. The clinical expert explained that inotuzumab ozogamicin is innovative, reduces the need for hospitalisation, and has potential to have a substantial effect on health-related benefits. The committee understood that although inotuzumab ozogamicin can cause a serious side effect (veno-occlusive liver disease), it is generally well tolerated. The committee concluded that inotuzumab ozogamicin could be an important treatment option for people with relapsed or refractory B-cell acute lymphoblastic leukaemia.
## FLAG-based therapy is the most appropriate comparator
The committee considered the most appropriate comparators for inotuzumab ozogamicin and its likely position in the treatment pathway. The patient and clinical experts stated that people with relapsed or refractory acute B-cell lymphoblastic leukaemia have combination chemotherapy. For most people this would be fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) with idarubicin (FLAG-IDA), which involves prolonged hospitalisation for treatment and is associated with debilitating side effects. Also, patients with Philadelphia-chromosome-positive disease can have FLAG-based therapy with tyrosine kinase inhibitors (TKIs) or TKIs alone. Clofarabine is sometimes used instead of FLAG-based therapy, but the committee noted that its marketing authorisation is only for people aged 21 years or younger. The committee noted there was an ongoing appraisal of blinatumomab, but that this was not included in the scope because it is not established clinical practice in the NHS. It was also aware that in the main clinical trial (INO-VATE 1022), neither TKIs nor clofarabine were used and that most patients in the standard care arm had FLAG-based therapy without idarubicin. The clinical expert stated that in clinical practice in England, inotuzumab ozogamicin would be used for patients at first relapse before considering other salvage therapies, which are poorly tolerated. The committee concluded that FLAG-based therapy was the most appropriate comparator for this appraisal.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS practice
INO-VATE 1022 (n=326) is an open-label, phase III, randomised controlled trial comparing inotuzumab ozogamicin with 3 different standard care chemotherapy regimens (FLAG, high-dose cytarabine, and cytarabine with mitoxantrone). The trial population broadly represents patients in the NHS. INO-VATE 1022 included patients with relapsed or refractory acute lymphoblastic leukaemia having trial treatments as the first or second salvage therapy. Patients with Philadelphia-chromosome-positive disease had to have had at least 1 TKI. The trial only recruited adults fit for intensive treatments; a subgroup of inotuzumab ozogamicin's marketing authorisation population. Patients who would have best supportive care and patients expected to have 3 or more salvage therapies were not included in the trial. The committee was aware that high-dose cytarabine and cytarabine with mitoxantrone are currently not used in clinical practice in England and that most patients in the trial had FLAG-based therapy. The committee concluded that the trial populations broadly correspond to those that would be seen in NHS clinical practice, even though the marketing authorisation is wider.
# Clinical effectiveness
## Inotuzumab ozogamicin does not increase overall survival but increases the rate of stem cell transplant
The median overall survival in INO-VATE 1022 was 7.7 months for inotuzumab ozogamicin compared with 6.7 months for standard care in the intention-to-treat population. This difference was not statistically significant. The company's post-hoc restricted mean survival time analysis (cut short at 37.7 months) suggested a median overall survival of 13.9 and 9.9 months for inotuzumab ozogamicin and standard care respectively (p=0.0023). The ERG stated that the results of the restricted mean survival time analysis depended on when it was cut short and that the company results appeared to inflate overall survival. However, more patients had complete remission or complete remission with incomplete haematological recovery with inotuzumab ozogamicin than with standard care: 88 (80.7%) compared with 32 (29.4%) respectively (p<0.0001; based on the analysis of results for the first 218 patients enrolled in the trial). Similarly, more patients were able to have haematopoietic stem cell transplant (HSCT) directly after inotuzumab ozogamicin compared with standard care; 45 (41%) and 12 (11%) respectively (p<0.001; analysis of results for the first 218 patients). These results were confirmed by the intention-to-treat analyses (the results were submitted as academic in confidence and cannot be reported here). The company stated that in general, by increasing the rate of HSCT, inotuzumab ozogamicin could increase mean survival. The clinical expert and the ERG agreed that this is plausible. The committee noted that although inotuzumab ozogamicin's survival benefits are uncertain, it increased the response rate and the rate of HSCT. The committee therefore concluded that inotuzumab ozogamicin is clinically effective compared with FLAG-based chemotherapy.
# Adverse events
## Inotuzumab ozogamicin has an acceptable safety profile
Inotuzumab ozogamicin is associated with potentially life-threatening veno‑occlusive liver disease. The clinical expert noted that this mainly happens in people who have had conditioning alkylating treatments that are not used in the UK. Continued experience with inotuzumab ozogamicin could minimise the risk of veno‑occlusive disease. The committee acknowledged the risks associated with inotuzumab ozogamicin treatment and concluded that it has an acceptable safety profile.
# The company's original economic model
## The model structure is appropriate for decision-making
The company model consisted of 3 partitioned survival sub models, with sub states for progression-free disease, progressed disease and death:
no complete remission or complete remission with incomplete haematological recovery and no HSCT
complete remission or complete remission with incomplete haematological recovery and no HSCT
HSCT and post-HSCT (patients could enter this state regardless of remission status). The company's sensitivity analyses showed that the incremental cost-effectiveness ratio (ICER) was most sensitive to the cost of HSCT, the proportion of patients having blinatumomab and inotuzumab ozogamicin as subsequent induction treatments, and the utility of progressive disease. All clinical parameters in the model were derived from the safety population of INO-VATE 1022. The company explained that because some patients in the standard care arm were randomised but did not have treatment (and all patients randomised to inotuzumab ozogamicin had treatment), it considered the safety population to be more appropriate for modelling. This is because it excluded patients who did not have treatment; these patients would be classified as not having complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. The company considered that this approach was conservative. The ERG disagreed with the company, noting that there were other factors to be considered. The ERG stated that it was not clear whether using the safety population instead of the intention-to-treat population for the modelling would result in bias towards patients who had inotuzumab ozogamicin or standard care. The committee agreed that because it had not seen the intention-to-treat population's results it was not able to decide about the most appropriate population for modelling, but it concluded that the model structure was appropriate for decision-making.
# Overall survival extrapolation in the original economic model
## The company's extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making
In each sub-model population, the company applied parametric curves for overall and progression-free survival, using the same type of curve in each case. The ERG stated that the company used a non-standard way of fitting parametric curves to the HSCT and non-HSCT data, which resulted in wide separation of the 2 survival curves. The ERG also explained that splitting the INO-VATE 1022 population and fitting multiple parametric curves is a very complex approach. The company's approach resulted in populations that are small and no longer support randomised comparisons. Specifically, a very small number of patients remained in the HSCT and post-HSCT state after 2 years. The committee noted that after having HSCT, people could be considered to act as a single group. The committee understood that about 95% of the quality-adjusted life year (QALY) gain was in the HSCT and post-HSCT state after the trial follow-up period (after data extrapolation). The clinical expert noted that veno-occlusive liver disease happens after HSCT and causes some early mortality. The clinical expert further noted that the prognosis after HSCT depends on the pre-HSCT conditioning treatments and that fitter and younger patients would have a better prognosis. The committee was not persuaded that the use of treatment-specific overall survival curves in the HSCT and post-HSCT state was justified. The committee did not agree with the company's overall survival extrapolation in the HSCT and post-HSCT state and therefore concluded that it was not appropriate for decision-making.
# ERG's exploratory analyses
## Pooled overall survival analysis with minimal residual disease status as a covariate in the HSCT and post-HSCT state is appropriate for decision-making
The ERG presented 2 alternative analyses for survival extrapolation in the HSCT and post-HSCT state. The first scenario was a non-parametric approach to survival analysis using the observed INO-VATE 1022 data with Kaplan–Meier data pooled across treatment groups. The second scenario was a fully parametric model (including treatment, age group, duration of first remission at randomisation, Philadelphia-chromosome category, previous HSCT and region as covariates) with pooled overall survival in the HSCT and post-HSCT state, using minimal residual disease status as a separate covariate. This resulted in overall survival for patients having inotuzumab ozogamicin and standard care based on the proportions in each treatment group with negative minimal residual disease status. The clinical expert stated that minimal residual disease status is a known predictive biomarker and can be measured with great precision, but has not been shown to be a prognostic indicator for overall survival. However, the clinical expert noted that no minimal residual disease is associated with better outcomes after HSCT. The committee previously agreed that the company's overall survival extrapolation in the HSCT and post-HSCT state was not suitable for decision-making (see section 3.7). It further agreed that the ERG's exploratory analyses have limitations, but considered the second scenario (pooled overall survival with minimal residual disease status as a covariate in the HSCT and post-HSCT states) to be clinically plausible and the most suitable analysis of those presented. The committee concluded that the parametric model with pooled overall survival with minimal residual disease status as a covariate fitted to the HSCT and post-HSCT state is appropriate for decision-making.
# Long-term survival in the original economic model
## A 4-fold increase in mortality 3 years after stem cell transplant is the preferred assumption
In the HSCT and post-HSCT state, the company model assumed that patients are cured after HSCT if they are still alive after 3 years. It assumed general population mortality estimates from 3 years after HSCT. The company's sensitivity analyses suggested that the ICERs were not sensitive to a different cure point. Similarly, the ERG's sensitivity analyses applied to its parametric preferred analysis were relatively insensitive to the variation in cure point. However, the ERG disagreed with the company's assumption and stated that post-HSCT patients would continue to have increased mortality compared with the general population. The clinical expert's view was the same as the ERG's. The ERG stated that although mortality improves 5 years after HSCT, it remains 4 to 9 times higher for at least 25 years after that (Martin et al. 2010). The committee was aware that the Martin et al. mortality estimates were based on a cohort of 2,574 patients in the US between 1970 and 2002 who survived without their original disease recurring for at least 5 years after HSCT. The committee noted that it is difficult to determine the best time point in the model to assume a change in derivation of mortality post-HSCT. It agreed that the company's time point of 3 years is plausible for decision-making but that other time points may be also suitable. The committee also agreed with the ERG and the clinical expert that mortality remains increased after HSCT. The committee noted that assuming a 4‑fold increase in mortality for patients from 3 years after HSCT is at the lower end of the Martin et al. 2010 range and concluded that this is its' preferred assumption.
# Health-related quality of life in the original economic model
## Age-adjusted utilities and INO-VATE 1022 utilities pooled across treatment groups are preferred
The company's model used:
INO-VATE 1022-based utilities for the no complete remission or complete remission with incomplete haematological recovery and no HSCT state and the complete remission or complete remission with incomplete haematological recovery and no HSCT state
utilities based on Kurosawa et al. 2016 (time dependent) for the HSCT and post-HSCT state and
a utility for progressed disease from Aristides et al. 2015.The ERG stated that the utilities used in the model were not age adjusted (and could exceed the utility in the general population) and that the utility value for progressed disease had a large effect on the estimated QALY gains. INO-VATE 1022 was an open-label trial and to minimise bias, the ERG suggested averaging utilities across the treatment groups for each (pre-progression) state. The clinical expert and committee agreed with the ERG that utility values decline with age and that utilities should be age adjusted. The committee noted that the pooled utilities across the trial did not differentiate between adverse events from inotuzumab ozogamicin or standard care. It acknowledged that using pooled utilities had only a marginal effect on the company's base-case ICER. The committee agreed that because of the possibility of bias for subjective end points, although conservative, the analysis with pooled utilities is more suitable for decision-making. The committee concluded that age-adjusted utilities and pooled INO-VATE 1022 utilities are its preferred assumptions.
# Cost of comparators in the original economic model
## Basing the cost of the comparators on the actual therapy taken in INO-VATE 1022 is preferred
INO-VATE 1022 compared inotuzumab ozogamicin with the investigator's choice of standard care (FLAG, high-dose cytarabine or cytarabine with mitoxantrone). The company's model included the cost of FLAG and added the cost of idarubicin, and imatinib for patients with Philadelphia-chromosome-positive disease, assuming no changes to the clinical effectiveness of the treatments. The ERG stated that including the costs of therapies when treatment benefits are excluded is inappropriate. The clinical expert and ERG both noted that ponatinib, rather than imatinib, is more likely to be used for Philadelphia-chromosome-positive disease. The ERG's exploratory analysis matched the costs to the actual therapy taken in INO-VATE 1022 (FLAG, high-dose cytarabine or cytarabine with mitoxantrone). The committee agreed that the additional cost of idarubicin and imatinib should not be included in the model because the benefits are not accounted for. The committee concluded that the ERG's exploratory analysis with the cost of comparators based on the actual therapy taken in INO-VATE 1022 is its preferred assumption.
# Cost of subsequent therapy in the original economic model
## The company's calculation of subsequent treatment costs is highly uncertain
The company's model based the cost of subsequent therapies on the INO-VATE 1022 intention-to-treat population. It was not clear why the safety population had not been used when all other clinical data were based on the safety population. The ERG mentioned the possibility of positive bias towards inotuzumab ozogamicin when the intention-to-treat population is used to calculate the cost of subsequent therapies because more expensive subsequent treatments were given to patients having standard care. Also, it was unclear whether the benefits from post-induction therapies were adequately reflected in the safety population used to inform the economic model. The committee was aware that the company's sensitivity analyses showed that the ICER was sensitive to the proportion of patients having blinatumomab or inotuzumab ozogamicin as subsequent induction treatment (see section 3.6). Given the uncertainty around which patients were included in the model and the uncertainty in the cost of the subsequent therapies, the ERG's exploratory analysis replaced the cost of blinatumomab and inotuzumab ozogamicin as second-line induction therapies with the cost of chemotherapy. The committee recalled that no other results from the intention-to-treat population were presented (see section 3.6). It concluded that because of the uncertainty in the way the company calculated subsequent treatment costs, the ERG's exploratory analysis replacing the costs of blinatumomab and inotuzumab ozogamicin with the cost of chemotherapy is its preferred analysis.
# Administration costs and inpatient days in the original economic model
## Administration costs based on INO-VATE 1022 and 9.5 inpatient days in both arms are preferred
The company's model assumed that administering inotuzumab ozogamicin would need 3 outpatient visits and no inpatient days per cycle, compared with no outpatient visits and 6.2 inpatient days for standard care (based on the summary of product characteristics). The ERG stated that the company's assumptions underestimated the cost of administering inotuzumab ozogamicin because no inpatient days were included. The clinical expert agreed with the ERG and also highlighted that patients having standard care often need an extended stay in hospital. The ERG's exploratory analysis based the administration cost of inotuzumab ozogamicin on INO-VATE 1022 (including both inpatient and outpatient costs as recorded in the trial) and used a weighted average NHS reference cost for regimens used in the standard care arm, resulting in an average length of stay of 9.5 days for both inotuzumab ozogamicin and standard care. The committee concluded that it preferred the ERG's analysis with the administration cost of inotuzumab ozogamicin based on INO-VATE 1022 and an average length of stay of 9.5 days in both arms.
# Costs and benefits discount rate in the original economic model
## The standard 3.5% discount rate for costs and benefits is more appropriate than 1.5%
The company applied a 1.5% discount rate to costs and QALYs based on assuming that HSCT restores normal life expectancy for patients. Results with a 3.5% discount rate were presented as a sensitivity analysis. The ERG did not agree with the company's 1.5% discount rate because mortality rates remain increased after HSCT. The committee discussed NICE's guide to the methods of technology appraisal 2013 and precedents for using non-reference case discount rates. It did not consider these relevant to the data or outcomes for the proposed use of inotuzumab ozogamicin. The committee recalled the median and mean survival rates from the INO-VATE 1022 clinical trial and its conclusion that a 4-fold increase in mortality for patients 3 years after HSCT and beyond is preferred (see section 3.9). It concluded that a 3.5% discount rate for costs and QALYs was appropriate for this appraisal.
# The company's original economic analysis
## The probabilistic ICERs are appropriate for decision-making
The company's deterministic ICERs were £40,013 and £55,869 per QALY gained using the 1.5% and 3.5% discount rates respectively for inotuzumab ozogamicin compared with standard care. The probabilistic ICERs were £48,459 and £67,575 per QALY gained using the 1.5% and 3.5% discount rates respectively for inotuzumab ozogamicin compared with standard care. The ERG stated that the large difference between the probabilistic and deterministic results suggested that the company's model is non-linear. The ERG highlighted that when a model is non-linear, the deterministic ICER can be biased and that the probabilistic ICER is the more appropriate estimate. The committee concluded that the probabilistic ICERs are appropriate for decision-making.
# The committee's preferred economic analysis
## The committee's preferred analysis results in a deterministic ICER of over £100,000 per QALY gained
The committee considered the ERG's parametric model with pooled overall survival and minimal residual disease status as a covariate fitted to the HSCT and post-HSCT state (see section 3.8) to be appropriate for decision-making, with the following assumptions (as preferred by the committee):
a 4‑fold increase in mortality compared with the general population for patients 3 years post‑HSCT and beyond (see section 3.9)
age-adjusted utilities, and pooled INO-VATE 1022 utilities (see section 3.10)
basing the cost of comparators on the actual therapy taken in INO-VATE 1022 (see section 3.11)
replacing the costs of the subsequent therapies, blinatumomab and inotuzumab ozogamicin, with the cost of chemotherapy (see section 3.12)
basing the administration cost of inotuzumab ozogamicin on INO-VATE 1022 and 9.5 inpatient days for both arms (see section 3.13)
a discount rate of 3.5% for costs and QALYs (see section 3.14).Including all the committee's preferred assumptions, the analysis resulted in a deterministic ICER for inotuzumab ozogamicin compared with standard care of £114,078 per QALY gained.
# First appraisal consultation comments
## Differences between the NICE appraisals of inotuzumab ozogamicin and blinatumomab are because of differences in the available evidence
The consultees and commentators noted that NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia, recommending blinatumomab as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia, was published in June 2017. Comments received during consultation drew a comparison between the blinatumomab and inotuzumab ozogamicin appraisals and suggested inconsistencies in modelling between the 2, namely survival between transplantation and the cure point, longer-term survival post-cure point, and health-related quality of life post-cure point. The committee was aware that blinatumomab was not a comparator in this appraisal, but also noted that it was not bound by the modelling and interpretation of a separate appraisal. Furthermore, the committee noted that the marketing authorisations for the 2 drugs are different: blinatumomab has a marketing authorisation for Philadelphia-chromosome-negative acute lymphoblastic leukaemia, but inotuzumab ozogamicin has a marketing authorisation for Philadelphia-chromosome-positive and -negative acute lymphoblastic leukaemia. The ERG stated that there are differences in the mechanism of action between the 2 drugs. The ERG also highlighted that although the survival benefit with inotuzumab ozogamicin was uncertain (see section 3.4), blinatumomab showed a statistically significant benefit in survival compared with standard care in the TOWER trial. The ERG further noted that the company did not include blinatumomab in any of its analyses for inotuzumab ozogamicin. The committee understood that the populations considered in both appraisals were similar, but it concluded that because the evidence available for each appraisal is different, differences in modelling are unavoidable.
# New evidence from the company before the appeal
## The company submitted a new model including a patient access scheme and new assumptions
The company submitted a new analysis which included:
a patient access scheme
a discount rate of 3.5% for costs and QALYs
age-adjusted utilities and pooled INO-VATE 1022 utilities
basing the cost of comparators on the actual therapies used in INO-VATE 1022.The company's new analysis did not include the following assumptions preferred by the committee (see section 3.16):
modelling of overall survival in the HSCT and post-HSCT state
‑fold increase in mortality compared with the general population for patients 3 years post-HSCT and beyond
replacing the costs of the subsequent therapies, blinatumomab and inotuzumab ozogamicin, with the cost of chemotherapy
using 9.5 inpatient days for both arms.It also used general population utilities for patients without progressed disease 3 years post-HSCT and beyond.The company's new analysis resulted in a deterministic ICER of £37,734 per QALY gained and a probabilistic ICER of £46,152 per QALY gained. In comparison, the analysis using all committee's preferred assumptions and including the patient access scheme resulted in an ICER lower than the original committee preferred ICER of more than £100,000 per QALY gained (see section 3.16), but still substantially higher than £50,000 per QALY gained (the results were submitted as commercial in confidence and cannot be reported here).
# Overall survival in the company's economic analysis before the appeal
## The company's extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making
The company reverted to its original method of modelling overall survival in the HSCT and post-HSCT state (fitting separate parametric curves to Kaplan–Meyer data; see section 3.7). Also, a new scenario analysis was introduced which, similar to the committee's preferred overall survival modelling, pooled data post-HSCT with a minimal residual disease status as a covariate. However, all other covariates were removed from the company's scenario analysis and were not adjusted for. The committee recalled its earlier conclusion that the company's overall survival extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making (see section 3.7). The ERG stated that all analyses based on the HSCT and post-HSCT state subpopulation are highly uncertain, but an analysis that adjusts for more observed confounders is preferable to one that adjusts only for rates of minimal residual disease negativity. The committee concluded that the ERG's modelling of overall survival with a minimal residual disease status as a covariate (including all other covariates) as accepted earlier (see section 3.7) is its preferred method of modelling overall survival.
# Long-term survival in the company's new economic analysis before the appeal
## A 4‑fold increase in mortality and the original base-case utilities 3 years after stem cell transplant are the preferred assumptions
The company estimated mortality post-cure using cumulative survival at 2 years post-HSCT from Karanes et al. 2008 and an event-free survival hazard ratio for minimal residual disease-negative patients (compared with minimal residual disease-positive patients) after induction therapy from Berry et al. 2017. The company applied a 3‑fold increase in mortality for minimal residual disease-positive patients and a 1.6‑fold increase in mortality for minimal residual disease-negative patients compared with the general population. Also, the company applied a general population utility (0.88) for disease-free patients post-cure. The ERG did not agree with the company's estimation of mortality risk or with the use of general population utilities. The ERG noted that the utility values used in the company's original base case post-cure (0.74 and 0.76) were based on a relevant published study (Kurosawa et al. 2016) and are preferable to the new assumption, which is not supported by evidence. The ERG explained that cumulative survival probabilities do not suggest hazard of death compared with the general population. It further noted that in the company's model (and also in the committee's preferred way of modelling overall survival), survival for patients at 2 years post-HSCT was modelled using parametric curves from INO-VATE 1022. The ERG also stated that incorporation of an additional treatment effect on survival by differentiating the risk of mortality after the cure point according to rates of minimal residual disease negativity is not supported by any evidence. The committee agreed with the ERG and recalled that assuming a 4‑fold increase in mortality for patients from 3 years after HSCT is at the lower end of the range in Martin et al. 2010 (see section 3.9). The committee concluded that a 4‑fold increase in mortality for patients from 3 years post-HSCT and utilities from Kurosawa et al. 2016 for disease-free patients are its preferred assumptions.
# Subsequent therapy costs in the company's new analysis before the appeal
## The committee accepted the cost of subsequent therapy based on the safety population but list prices were not appropriate
The company's original model based the cost of subsequent therapies on the INO-VATE 1022 intention-to-treat population, but its revised model used the safety population (the company deemed the safety population to be more appropriate for modelling; see section 3.6 and section 3.12). The ERG stated that, although it is questionable to include inotuzumab ozogamicin in the cost of subsequent therapies in the standard care arm, it is methodically acceptable to include the costs of subsequent therapies as seen in the trial. However, the ERG also noted that the company used list prices to calculate the cost of subsequent therapy, which would underestimate the resulting ICER. The committee's preferred base case including the company's revised cost of subsequent therapies and the patient access scheme resulted in a deterministic ICER that was more than £50,000 per QALY gained, but lower than the committee's preferred base-case ICER with the patient access scheme (the results were submitted as commercial in confidence and cannot be reported here, see section 3.18). The committee agreed with the ERG that the cost of subsequent therapy based on the safety population could be included, but it is not appropriate to use the list prices for the calculation of the cost. The committee therefore concluded that including the cost of subsequent therapy from the safety population in the company's revised model leads to the ICER being underestimated.
# Inpatient days in the company's new analysis before the appeal
## There is a difference in the number of inpatient days for inotuzumab ozogamicin and standard care patients
The company increased the number of inpatient days from its original base case (see section 3.13) to 1 inpatient day for inotuzumab ozogamicin and 14 days for standard care. The committee noted that the company did not base the calculation of inpatient days on INO-VATE 1022, which it would have preferred. The ERG stated that no new evidence was presented and the reason for changing the number of inpatient days was not explained. The committee's preferred base case, including the company's new number of inpatient days and the patient access scheme, resulted in a deterministic ICER that was more than £50,000 per QALY gained (the results were submitted as commercial in confidence and cannot be reported here). The committee discussed the need for hospitalisation for patients having inotuzumab ozogamicin and standard care. The committee agreed that 1 inpatient day for inotuzumab ozogamicin is too low, and that it is likely that there is a difference in the number of inpatient days for inotuzumab ozogamicin and standard care, but that the ratio is likely to be larger than the ratio used in the company's analysis (1/14). The committee therefore concluded that the number of inpatient days in the company's revised model leads to the ICER being underestimated.
# The cost-effectiveness estimate before the appeal
## The most plausible cost-effectiveness estimate is above what is normally considered a cost-effective use of NHS resources
The committee recalled its preferred assumptions (see section 3.16). After consultation the committee accepted that the cost of subsequent therapy should be based on the safety population (excluding the list prices; see section 3.21), and that there would be a difference in the number of inpatient days for patients having inotuzumab ozogamicin and standard care (see section 3.22). The committee further recalled its earlier conclusion that probabilistic ICERs are more appropriate for decision-making in this appraisal (see section 3.15). The committee was aware that the ERG's analysis had fewer issues with non-linearity than the company's base case and that the ERG's probabilistic ICER would be about £2,000 per QALY gained more than the deterministic ICER. Taking into consideration the deterministic and probabilistic ICERs, the committee concluded that the most plausible ICER including the patient access scheme for inotuzumab ozogamicin compared with standard care was substantially higher than £50,000 per QALY gained.
# After the appeal
At the third appraisal committee meeting, the committee considered the appeal panel decision to uphold 3 appeal points and to refer these back to the appraisal committee for further consideration. These were:
The committee need to clearly explain its decision to reject utilities proposed by the company in response to the first appraisal consultation document (see section 3.25).
The committee need to consider and explain the differences in assumptions post-cure point made in this appraisal explicitly compared to previously published guidance on blinatumomab (see section 3.26).
The committee should reconsider inotuzumab ozogamicin treatment administration in the context of UK clinical practice (usually 2 cycles plus a third if needed). Also, a costing model based on appropriate stopping rules may be considered (see section 3.27).Also, at the third appraisal committee meeting the company requested permission to submit new evidence after the appeal, which was accepted by NICE. The committee considered the company's updated model including a revised patient access scheme and new assumptions which included:
assuming general population mortality from 3 years post-HSCT
assuming general population utility values from 3 years post-HSCT
capping the number of cycles of inotuzumab ozogamicin at 3, with no adjustment to the trial efficacy data
including the cost of subsequent therapies using the price of generic imatinib and assuming a simple patient access scheme discount for blinatumomab
assuming 3 days of administration-related inpatient days with inotuzumab ozogamicin and 14 days with FLAG.
## Utility values in the post-transplant state are between Kurosawa et al. 2016 and those of the general population
The committee considered the first upheld appeal point (see section 3.24). It discussed the most appropriate utility values to use in the post-transplant state. Previously, the company and the committee had preferred the published values from Kurosawa et al. 2016 which were 0.74 for 3 to 5 years post-transplant and 0.76 for 5 years post-transplant (see section 3.10). After the first appraisal consultation document was released (see section 3.20), the company submitted an economic model using general population post-transplant utility values (0.88). The company noted that these were the same values used in the post-transplant state in NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia. At the third committee meeting, the clinical experts explained that although many people who have had a transplant and who did not experience complications such as graft versus host disease or relapse should be expected to return to full health, a substantial number of patients have longer-term health problems related to the transplant. They suggested that the actual utility values 5 years post-transplant are likely to be between those presented in Kurosawa et al. 2016 (0.76) and the value for the general population (0.88). The committee therefore concluded that the most appropriate post-transplant utility values are between the values from Kurosawa et al. 2016 and general population post-transplant utility (0.76 and 0.88).
## A 4‑fold increase in mortality from 3 years after stem cell transplant is the preferred assumption
The committee considered the second upheld appeal point (see section 3.24). It discussed the differences in post-HSCT assumptions between this appraisal and NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia, specifically the increase in mortality after the cure point. The committee recalled its earlier conclusions (see section 3.17) that the populations considered in both appraisals were similar, but because the evidence available for each appraisal is different, differences in modelling are inevitable. It was aware that the company had assumed general population mortality from 3 years post-HSCT in its original submission and that in NICE's technology appraisal guidance on blinatumomab, the mortality post-HSCT was the general population mortality risk added to the risk derived from the extrapolated parametric curve for overall survival. The committee had previously concluded that a 4-fold increase in mortality for patients from 3 years post-HSCT based on the lowest values reported in Martin et al. 2010 was appropriate (see section 3.20). At the third committee meeting, the clinical experts noted that the Martin et al. 2010 study was well designed and included a large sample size but transplant care had improved substantially since the study was published meaning a 4-fold increase in mortality could be too high. The clinical experts suggested that any increase in mortality from 3 years post-HSCT is likely to be between the risk of the general population and the value in Martin et al. 2010. The committee accepted that transplant care had improved but it had not been presented with any new evidence to suggest that mortality from 3 years post-HSCT was lower than that presented in Martin et al. 2010. The committee noted that other smaller studies identified by the ERG had shown much larger increases in mortality (see section 3.20) and the 4-fold increase in mortality was at the bottom end of the range in Martin et al. 2010. The committee therefore concluded that a 4-fold increase in mortality from 3 years post-HSCT is preferred.
## The number of treatment cycles in the economic model should reflect the number of cycles administered in INO-VATE 1022
The committee considered the third upheld appeal point (see section 3.24). It discussed the appropriate number of inotuzumab ozogamicin treatment cycles to include in the model in the context of NHS clinical practice. The summary of product characteristics for inotuzumab ozogamicin states that:
for patients proceeding to HSCT, the recommended duration of treatment is 2 cycles. A third cycle may be considered for those patients whose leukaemia does not achieve complete remission or complete remission with incomplete haematological recovery and minimal residual disease negativity after 2 cycles.
for patients not proceeding to HSCT, additional cycles of treatment (up to a maximum of 6 cycles), may be given. Patients whose disease does not achieve complete remission or complete remission with incomplete haematological recovery within 3 cycles should stop treatment.The committee was aware that the company had used the number of inotuzumab ozogamicin cycles (up to 6) informed by the INO-VATE 1022 trial in its base-case analysis. It noted that the company had included a scenario analysis which capped treatment at 3 cycles. At the third committee meeting, the clinical experts explained that patients in the UK who go on to have a HSCT would not have more than 3 cycles of treatment and would often only have 2, the intention being to move to allogeneic stem cell transplant if the disease was controlled. They explained that because inotuzumab ozogamicin is associated with high rates of hepatotoxicity and veno-occlusive liver disease, treatment would be stopped if there was no evidence of complete remission or complete remission with incomplete haematological recovery after 3 cycles, regardless of HSCT eligibility. The concern about veno-occlusive disease with longer duration of therapy had increased since the original trial leading to greater reluctance to proceed beyond 3 cycles. The committee considered the company's post-appeal scenario analyses which capped inotuzumab ozogamicin treatment at 3 cycles. The first scenario, which was the company's preferred scenario, capped the costs of treatment at 3 cycles but retained the efficacy data for inotuzumab ozogamicin from INNO-VATE 1022. The company noted that complete remission or complete remission with incomplete haematological recovery was achieved in the INO-VATE 1022 trial within the first 3 cycles. The company further explained that this is a prerequisite for HSCT and it considered it plausible to assume that the same HSCT rate would be seen when treatment is stopped at 3 cycles. The second company scenario removed data on patients in the inotuzumab ozogamicin arm of INO-VATE 1022 who did not proceed to transplant. The ERG stated that the company's second scenario would result in the breaking of trial randomisation. The committee agreed and did not consider this scenario further. The committee understood that most patients in the UK would have no more than 3 cycles of treatment. However, the INO-VATE 1022 trial (on which the clinical efficacy of inotuzumab ozogamicin is based) included up to 6 cycles of treatment. The committee agreed that the sources of efficacy and cost data in the model should be consistent and that benefit and cost should not be uncoupled. The committee concluded that the number of inotuzumab ozogamicin cycles in the economic modelling should reflect the number given in the INO-VATE 1022 trial (up to 6 cycles).
## Subsequent therapy costs are appropriate
The committee had previously accepted the inclusion of subsequent therapy costs based on the safety population (see section 3.21). The committee was aware that the company had included the cost of generic imatinib in its post-appeal analyses. It was aware that company's deterministic ICERs did not include the correct price of blinatumomab because there is a confidential patient access scheme. In line with NICE processes, the ERG updated the company's post-appeal analyses with the correct price of blinatumomab however, the results cannot be reported here since they are commercial in confidence.
## There is a difference in the average number of inpatient days for treatment with inotuzumab ozogamicin compared with standard care
At the third appraisal committee meeting the committee considered the average length of inpatient days for treatment with inotuzumab ozogamicin compared with standard care. Originally, the committee's most plausible ICER (see section 3.23) had been based on the ERG's exploratory analyses. These used a weighted average from NHS reference cost for regimens used in the standard care arm. This resulted in an average of 9.5 inpatient days for both inotuzumab ozogamicin and standard care (which is often FLAG-IDA). The committee was aware that the economic model was highly sensitive to the average number of inpatient days. At the third appraisal committee meeting, after the appeal, the clinical experts noted that an average of 9.5 inpatient days for standard care is not clinically plausible and patients having FLAG-IDA are usually in hospital for longer periods. After a second appraisal consultation, the clinical experts submitted unpublished observational data on the average number of inpatient days with inotuzumab ozogamicin and FLAG-IDA from a compassionate use programme at 2 specialist centres in England (the results of which were provided as academic in confidence and therefore cannot be reported here). The committee noted the limitations with the study including its small sample size but accepted that the results were representative of clinical practice in England. The committee concluded that there is a substantial difference in the average number of inpatient days for treatment with inotuzumab ozogamicin compared with FLAG-IDA.
# Company's post-appeal new evidence and updated model assumptions.
# End of life
## Inotuzumab ozogamicin meets NICE's end-of-life criteria
The committee discussed whether life expectancy without inotuzumab ozogamicin would be less than 24 months. It noted that median overall survival was 6.7 months with standard care in INO-VATE 1022 and concluded that the short life expectancy criterion was met. The committee discussed whether a survival benefit of over 3 months can be expected for inotuzumab ozogamicin compared with standard care. It recalled its earlier conclusion about survival benefit with inotuzumab ozogamicin (see section 3.4) and agreed that although the survival benefits of inotuzumab ozogamicin are highly uncertain, it is likely that by increasing the rate of HSCT, inotuzumab ozogamicin would increase mean survival for people with relapsed or refractory B-cell acute lymphoblastic leukaemia by more than 3 months. The committee concluded that the extension-to-life criterion was met. The committee concluded that inotuzumab ozogamicin met the life expectancy and life extension criteria to be considered a life-extending, end-of-life treatment.
## Inotuzumab ozogamicin's benefits are captured in the cost-effectiveness analysis
The patient and clinical experts explained that there is considerable unmet need for people with relapsed or refractory acute lymphoblastic leukaemia because of the ineffective and toxic chemotherapy regimens currently being used. The committee noted that the company considered inotuzumab ozogamicin to be innovative, reducing the need for hospitalisation and leading to a major change in treating a rare illness. The committee concluded that inotuzumab ozogamicin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# The cost-effectiveness estimates after the appeal
## The company's updated model with the committee's preferred assumptions is suitable for decision-making
Following the appeal and a second appraisal consultation the company updated its cost model to incorporate the committee's preferred assumptions (see sections 3.25 to 3.29). The updated model comparing inotuzumab ozogamicin with standard care included:
utility values for all patients 5 years post-HSCT between Kurasowa et al 2016 and the general population
-fold increase in mortality compared with the general population for patients 3 years post-HSCT and beyond
the same number of treatment cycles for inotuzumab ozogamicin as administered in INNO-VATE 1022 (up to 6 cycles)
the cost of subsequent therapy from the safety population using the generic price for imatinib and the list price for blinatumomab (results using the price of blinatumomab with a commercial arrangement were updated by the ERG)
using observational data from the inotuzumab ozogamicin compassionate use programme to inform the average number of inpatient days for inotuzumab ozogamicin and FLAG-IDA.
## Inotuzumab ozogamicin is recommended for treating relapsed or refractory B-cell acute lymphoblastic leukaemia
The company's new analysis, using the committee's preferred assumptions (see sections 3.25 to 3.29) resulted in a deterministic ICER between £37,497 per QALY gained when using utility values from Kurasowa et al 2016 (0.76) and £33,749 per QALY gained when using utility values from the general population (0.88). The committee recalled that inotuzumab ozogamicin met NICE's end-of-life criteria compared with standard care (see section 3.30). The committee noted that when the confidential discount for blinatumomab was incorporated by the ERG the ICER was still within the range normally considered a cost-effective use of NHS resources (these ICERs are commercial in confidence and cannot be reported here). The committee therefore recommended inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia.
# Other factors
No equality issues were identified.
|
{'Recommendations': "Inotuzumab ozogamicin is recommended, within its marketing authorisation, as an option for treating relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia in adults. People with relapsed or refractory Philadelphia-chromosome-positive disease should have had at least 1 tyrosine kinase inhibitor.Inotuzumab ozogamicin is recommended only if the company provides it according to the commercial arrangement.\n\n# Why the committee made these recommendations\n\nTreatment for relapsed or refractory B-cell acute lymphoblastic leukaemia is usually fludarabine, cytarabine and granulocyte colony-stimulating factor based chemotherapy (FLAG) with idarubicin. People with Philadelphia-chromosome-positive disease can have FLAG-based therapy with tyrosine kinase inhibitors or tyrosine kinase inhibitors alone. Clinical trial evidence does not show an overall survival benefit for people having inotuzumab ozogamicin compared with those having FLAG, high-dose cytarabine or cytarabine with mitoxantrone-based chemotherapy. However, more people having inotuzumab ozogamicin are able to go on to have a stem cell transplant when compared with people having the other treatments. Inotuzumab ozogamicin also meets NICE's criteria to be a life-extending treatment at the end of life.\n\nThe most plausible cost-effectiveness estimates for inotuzumab ozogamicin compared with standard care are in the range NICE considers an acceptable use of NHS resources. Therefore it can be recommended for treating relapsed or refractory B-cell acute lymphoblastic leukaemia.", 'Information about inotuzumab ozogamicin': "Marketing authorisation\n\nInotuzumab ozogamicin (Besponsa, Pfizer) is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). Adult patients with Philadelphia-chromosome-positive relapsed or refractory B-cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor.\n\nDosage in the marketing authorisation\n\nIntravenously at a starting dose of 1.8\xa0mg/m2 per cycle (0.8\xa0mg/m2 on day\xa01 and 0.5\xa0mg/m2 on days\xa08 and 15), in 3- to 4-week cycles. Cycle\xa01 lasts for 3\xa0weeks, and each subsequent cycle lasts for 4 weeks. See the summary of product characteristics for further details.\n\nPrice\n\n£8,048 per 1\xa0mg vial of powder concentrate for solution for infusion (excluding VAT; BNF 2018). The company has a commercial arrangement. This makes inotuzumab ozogamicin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## People with B-cell acute lymphoblastic leukaemia would welcome a new treatment option\n\nThe clinical and patient experts noted that people with relapsed or refractory B-cell acute lymphoblastic leukaemia have limited treatment options. The committee understood that current treatment can cause unpleasant side effects. The clinical expert explained that inotuzumab ozogamicin is innovative, reduces the need for hospitalisation, and has potential to have a substantial effect on health-related benefits. The committee understood that although inotuzumab ozogamicin can cause a serious side effect (veno-occlusive liver disease), it is generally well tolerated. The committee concluded that inotuzumab ozogamicin could be an important treatment option for people with relapsed or refractory B-cell acute lymphoblastic leukaemia.\n\n## FLAG-based therapy is the most appropriate comparator\n\nThe committee considered the most appropriate comparators for inotuzumab ozogamicin and its likely position in the treatment pathway. The patient and clinical experts stated that people with relapsed or refractory acute B-cell lymphoblastic leukaemia have combination chemotherapy. For most people this would be fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) with idarubicin (FLAG-IDA), which involves prolonged hospitalisation for treatment and is associated with debilitating side effects. Also, patients with Philadelphia-chromosome-positive disease can have FLAG-based therapy with tyrosine kinase inhibitors (TKIs) or TKIs alone. Clofarabine is sometimes used instead of FLAG-based therapy, but the committee noted that its marketing authorisation is only for people aged 21\xa0years or younger. The committee noted there was an ongoing appraisal of blinatumomab, but that this was not included in the scope because it is not established clinical practice in the NHS. It was also aware that in the main clinical trial (INO-VATE\xa01022), neither TKIs nor clofarabine were used and that most patients in the standard care arm had FLAG-based therapy without idarubicin. The clinical expert stated that in clinical practice in England, inotuzumab ozogamicin would be used for patients at first relapse before considering other salvage therapies, which are poorly tolerated. The committee concluded that FLAG-based therapy was the most appropriate comparator for this appraisal.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS practice\n\nINO-VATE\xa01022 (n=326) is an open-label, phase\xa0III, randomised controlled trial comparing inotuzumab ozogamicin with 3\xa0different standard care chemotherapy regimens (FLAG, high-dose cytarabine, and cytarabine with mitoxantrone). The trial population broadly represents patients in the NHS. INO-VATE\xa01022 included patients with relapsed or refractory acute lymphoblastic leukaemia having trial treatments as the first or second salvage therapy. Patients with Philadelphia-chromosome-positive disease had to have had at least 1\xa0TKI. The trial only recruited adults fit for intensive treatments; a subgroup of inotuzumab ozogamicin's marketing authorisation population. Patients who would have best supportive care and patients expected to have 3 or more salvage therapies were not included in the trial. The committee was aware that high-dose cytarabine and cytarabine with mitoxantrone are currently not used in clinical practice in England and that most patients in the trial had FLAG-based therapy. The committee concluded that the trial populations broadly correspond to those that would be seen in NHS clinical practice, even though the marketing authorisation is wider.\n\n# Clinical effectiveness\n\n## Inotuzumab ozogamicin does not increase overall survival but increases the rate of stem cell transplant\n\nThe median overall survival in INO-VATE\xa01022 was 7.7\xa0months for inotuzumab ozogamicin compared with 6.7\xa0months for standard care in the intention-to-treat population. This difference was not statistically significant. The company's post-hoc restricted mean survival time analysis (cut short at 37.7\xa0months) suggested a median overall survival of 13.9 and 9.9\xa0months for inotuzumab ozogamicin and standard care respectively (p=0.0023). The ERG stated that the results of the restricted mean survival time analysis depended on when it was cut short and that the company results appeared to inflate overall survival. However, more patients had complete remission or complete remission with incomplete haematological recovery with inotuzumab ozogamicin than with standard care: 88 (80.7%) compared with 32 (29.4%) respectively (p<0.0001; based on the analysis of results for the first 218\xa0patients enrolled in the trial). Similarly, more patients were able to have haematopoietic stem cell transplant (HSCT) directly after inotuzumab ozogamicin compared with standard care; 45 (41%) and 12 (11%) respectively (p<0.001; analysis of results for the first 218\xa0patients). These results were confirmed by the intention-to-treat analyses (the results were submitted as academic in confidence and cannot be reported here). The company stated that in general, by increasing the rate of HSCT, inotuzumab ozogamicin could increase mean survival. The clinical expert and the ERG agreed that this is plausible. The committee noted that although inotuzumab ozogamicin's survival benefits are uncertain, it increased the response rate and the rate of HSCT. The committee therefore concluded that inotuzumab ozogamicin is clinically effective compared with FLAG-based chemotherapy.\n\n# Adverse events\n\n## Inotuzumab ozogamicin has an acceptable safety profile\n\nInotuzumab ozogamicin is associated with potentially life-threatening veno‑occlusive liver disease. The clinical expert noted that this mainly happens in people who have had conditioning alkylating treatments that are not used in the UK. Continued experience with inotuzumab ozogamicin could minimise the risk of veno‑occlusive disease. The committee acknowledged the risks associated with inotuzumab ozogamicin treatment and concluded that it has an acceptable safety profile.\n\n# The company's original economic model\n\n## The model structure is appropriate for decision-making\n\nThe company model consisted of 3\xa0partitioned survival sub\xa0models, with sub\xa0states for progression-free disease, progressed disease and death:\n\nno complete remission or complete remission with incomplete haematological recovery and no HSCT\n\ncomplete remission or complete remission with incomplete haematological recovery and no HSCT\n\nHSCT and post-HSCT (patients could enter this state regardless of remission status). The company's sensitivity analyses showed that the incremental cost-effectiveness ratio (ICER) was most sensitive to the cost of HSCT, the proportion of patients having blinatumomab and inotuzumab ozogamicin as subsequent induction treatments, and the utility of progressive disease. All clinical parameters in the model were derived from the safety population of INO-VATE\xa01022. The company explained that because some patients in the standard care arm were randomised but did not have treatment (and all patients randomised to inotuzumab ozogamicin had treatment), it considered the safety population to be more appropriate for modelling. This is because it excluded patients who did not have treatment; these patients would be classified as not having complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. The company considered that this approach was conservative. The ERG disagreed with the company, noting that there were other factors to be considered. The ERG stated that it was not clear whether using the safety population instead of the intention-to-treat population for the modelling would result in bias towards patients who had inotuzumab ozogamicin or standard care. The committee agreed that because it had not seen the intention-to-treat population's results it was not able to decide about the most appropriate population for modelling, but it concluded that the model structure was appropriate for decision-making.\n\n# Overall survival extrapolation in the original economic model\n\n## The company's extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making\n\nIn each sub-model population, the company applied parametric curves for overall and progression-free survival, using the same type of curve in each case. The ERG stated that the company used a non-standard way of fitting parametric curves to the HSCT and non-HSCT data, which resulted in wide separation of the 2 survival curves. The ERG also explained that splitting the INO-VATE\xa01022 population and fitting multiple parametric curves is a very complex approach. The company's approach resulted in populations that are small and no longer support randomised comparisons. Specifically, a very small number of patients remained in the HSCT and post-HSCT state after 2\xa0years. The committee noted that after having HSCT, people could be considered to act as a single group. The committee understood that about 95% of the quality-adjusted life year (QALY) gain was in the HSCT and post-HSCT state after the trial follow-up period (after data extrapolation). The clinical expert noted that veno-occlusive liver disease happens after HSCT and causes some early mortality. The clinical expert further noted that the prognosis after HSCT depends on the pre-HSCT conditioning treatments and that fitter and younger patients would have a better prognosis. The committee was not persuaded that the use of treatment-specific overall survival curves in the HSCT and post-HSCT state was justified. The committee did not agree with the company's overall survival extrapolation in the HSCT and post-HSCT state and therefore concluded that it was not appropriate for decision-making.\n\n# ERG's exploratory analyses\n\n## Pooled overall survival analysis with minimal residual disease status as a covariate in the HSCT and post-HSCT state is appropriate for decision-making\n\nThe ERG presented 2\xa0alternative analyses for survival extrapolation in the HSCT and post-HSCT state. The first scenario was a non-parametric approach to survival analysis using the observed INO-VATE\xa01022 data with Kaplan–Meier data pooled across treatment groups. The second scenario was a fully parametric model (including treatment, age group, duration of first remission at randomisation, Philadelphia-chromosome category, previous HSCT and region as covariates) with pooled overall survival in the HSCT and post-HSCT state, using minimal residual disease status as a separate covariate. This resulted in overall survival for patients having inotuzumab ozogamicin and standard care based on the proportions in each treatment group with negative minimal residual disease status. The clinical expert stated that minimal residual disease status is a known predictive biomarker and can be measured with great precision, but has not been shown to be a prognostic indicator for overall survival. However, the clinical expert noted that no minimal residual disease is associated with better outcomes after HSCT. The committee previously agreed that the company's overall survival extrapolation in the HSCT and post-HSCT state was not suitable for decision-making (see section\xa03.7). It further agreed that the ERG's exploratory analyses have limitations, but considered the second scenario (pooled overall survival with minimal residual disease status as a covariate in the HSCT and post-HSCT states) to be clinically plausible and the most suitable analysis of those presented. The committee concluded that the parametric model with pooled overall survival with minimal residual disease status as a covariate fitted to the HSCT and post-HSCT state is appropriate for decision-making.\n\n# Long-term survival in the original economic model\n\n## A 4-fold increase in mortality 3\xa0years after stem cell transplant is the preferred assumption\n\nIn the HSCT and post-HSCT state, the company model assumed that patients are cured after HSCT if they are still alive after 3\xa0years. It assumed general population mortality estimates from 3\xa0years after HSCT. The company's sensitivity analyses suggested that the ICERs were not sensitive to a different cure point. Similarly, the ERG's sensitivity analyses applied to its parametric preferred analysis were relatively insensitive to the variation in cure point. However, the ERG disagreed with the company's assumption and stated that post-HSCT patients would continue to have increased mortality compared with the general population. The clinical expert's view was the same as the ERG's. The ERG stated that although mortality improves 5\xa0years after HSCT, it remains 4 to 9\xa0times higher for at least 25\xa0years after that (Martin et al. 2010). The committee was aware that the Martin et al. mortality estimates were based on a cohort of 2,574\xa0patients in the US between 1970 and 2002 who survived without their original disease recurring for at least 5\xa0years after HSCT. The committee noted that it is difficult to determine the best time point in the model to assume a change in derivation of mortality post-HSCT. It agreed that the company's time point of 3\xa0years is plausible for decision-making but that other time points may be also suitable. The committee also agreed with the ERG and the clinical expert that mortality remains increased after HSCT. The committee noted that assuming a 4‑fold increase in mortality for patients from 3\xa0years after HSCT is at the lower end of the Martin et al. 2010 range and concluded that this is its' preferred assumption.\n\n# Health-related quality of life in the original economic model\n\n## Age-adjusted utilities and INO-VATE\xa01022 utilities pooled across treatment groups are preferred\n\nThe company's model used:\n\nINO-VATE\xa01022-based utilities for the no complete remission or complete remission with incomplete haematological recovery and no HSCT state and the complete remission or complete remission with incomplete haematological recovery and no HSCT state\n\nutilities based on Kurosawa et al. 2016 (time dependent) for the HSCT and post-HSCT state and\n\na utility for progressed disease from Aristides et al. 2015.The ERG stated that the utilities used in the model were not age adjusted (and could exceed the utility in the general population) and that the utility value for progressed disease had a large effect on the estimated QALY gains. INO-VATE\xa01022 was an open-label trial and to minimise bias, the ERG suggested averaging utilities across the treatment groups for each (pre-progression) state. The clinical expert and committee agreed with the ERG that utility values decline with age and that utilities should be age adjusted. The committee noted that the pooled utilities across the trial did not differentiate between adverse events from inotuzumab ozogamicin or standard care. It acknowledged that using pooled utilities had only a marginal effect on the company's base-case ICER. The committee agreed that because of the possibility of bias for subjective end points, although conservative, the analysis with pooled utilities is more suitable for decision-making. The committee concluded that age-adjusted utilities and pooled INO-VATE\xa01022 utilities are its preferred assumptions.\n\n# Cost of comparators in the original economic model\n\n## Basing the cost of the comparators on the actual therapy taken in INO-VATE\xa01022 is preferred\n\nINO-VATE\xa01022 compared inotuzumab ozogamicin with the investigator's choice of standard care (FLAG, high-dose cytarabine or cytarabine with mitoxantrone). The company's model included the cost of FLAG and added the cost of idarubicin, and imatinib for patients with Philadelphia-chromosome-positive disease, assuming no changes to the clinical effectiveness of the treatments. The ERG stated that including the costs of therapies when treatment benefits are excluded is inappropriate. The clinical expert and ERG both noted that ponatinib, rather than imatinib, is more likely to be used for Philadelphia-chromosome-positive disease. The ERG's exploratory analysis matched the costs to the actual therapy taken in INO-VATE\xa01022 (FLAG, high-dose cytarabine or cytarabine with mitoxantrone). The committee agreed that the additional cost of idarubicin and imatinib should not be included in the model because the benefits are not accounted for. The committee concluded that the ERG's exploratory analysis with the cost of comparators based on the actual therapy taken in INO-VATE\xa01022 is its preferred assumption.\n\n# Cost of subsequent therapy in the original economic model\n\n## The company's calculation of subsequent treatment costs is highly uncertain\n\nThe company's model based the cost of subsequent therapies on the INO-VATE\xa01022 intention-to-treat population. It was not clear why the safety population had not been used when all other clinical data were based on the safety population. The ERG mentioned the possibility of positive bias towards inotuzumab ozogamicin when the intention-to-treat population is used to calculate the cost of subsequent therapies because more expensive subsequent treatments were given to patients having standard care. Also, it was unclear whether the benefits from post-induction therapies were adequately reflected in the safety population used to inform the economic model. The committee was aware that the company's sensitivity analyses showed that the ICER was sensitive to the proportion of patients having blinatumomab or inotuzumab ozogamicin as subsequent induction treatment (see section\xa03.6). Given the uncertainty around which patients were included in the model and the uncertainty in the cost of the subsequent therapies, the ERG's exploratory analysis replaced the cost of blinatumomab and inotuzumab ozogamicin as second-line induction therapies with the cost of chemotherapy. The committee recalled that no other results from the intention-to-treat population were presented (see section\xa03.6). It concluded that because of the uncertainty in the way the company calculated subsequent treatment costs, the ERG's exploratory analysis replacing the costs of blinatumomab and inotuzumab ozogamicin with the cost of chemotherapy is its preferred analysis.\n\n# Administration costs and inpatient days in the original economic model\n\n## Administration costs based on INO-VATE\xa01022 and 9.5\xa0inpatient days in both arms are preferred\n\nThe company's model assumed that administering inotuzumab ozogamicin would need 3\xa0outpatient visits and no inpatient days per cycle, compared with no outpatient visits and 6.2\xa0inpatient days for standard care (based on the summary of product characteristics). The ERG stated that the company's assumptions underestimated the cost of administering inotuzumab ozogamicin because no inpatient days were included. The clinical expert agreed with the ERG and also highlighted that patients having standard care often need an extended stay in hospital. The ERG's exploratory analysis based the administration cost of inotuzumab ozogamicin on INO-VATE\xa01022 (including both inpatient and outpatient costs as recorded in the trial) and used a weighted average NHS reference cost for regimens used in the standard care arm, resulting in an average length of stay of 9.5\xa0days for both inotuzumab ozogamicin and standard care. The committee concluded that it preferred the ERG's analysis with the administration cost of inotuzumab ozogamicin based on INO-VATE\xa01022 and an average length of stay of 9.5\xa0days in both arms.\n\n# Costs and benefits discount rate in the original economic model\n\n## The standard 3.5% discount rate for costs and benefits is more appropriate than 1.5%\n\nThe company applied a 1.5% discount rate to costs and QALYs based on assuming that HSCT restores normal life expectancy for patients. Results with a 3.5% discount rate were presented as a sensitivity analysis. The ERG did not agree with the company's 1.5% discount rate because mortality rates remain increased after HSCT. The committee discussed NICE's guide to the methods of technology appraisal 2013 and precedents for using non-reference case discount rates. It did not consider these relevant to the data or outcomes for the proposed use of inotuzumab ozogamicin. The committee recalled the median and mean survival rates from the INO-VATE\xa01022 clinical trial and its conclusion that a 4-fold increase in mortality for patients 3\xa0years after HSCT and beyond is preferred (see section\xa03.9). It concluded that a 3.5% discount rate for costs and QALYs was appropriate for this appraisal.\n\n# The company's original economic analysis\n\n## The probabilistic ICERs are appropriate for decision-making\n\nThe company's deterministic ICERs were £40,013 and £55,869 per QALY gained using the 1.5% and 3.5% discount rates respectively for inotuzumab ozogamicin compared with standard care. The probabilistic ICERs were £48,459 and £67,575 per QALY gained using the 1.5% and 3.5% discount rates respectively for inotuzumab ozogamicin compared with standard care. The ERG stated that the large difference between the probabilistic and deterministic results suggested that the company's model is non-linear. The ERG highlighted that when a model is non-linear, the deterministic ICER can be biased and that the probabilistic ICER is the more appropriate estimate. The committee concluded that the probabilistic ICERs are appropriate for decision-making.\n\n# The committee's preferred economic analysis\n\n## The committee's preferred analysis results in a deterministic ICER of over £100,000 per QALY gained\n\nThe committee considered the ERG's parametric model with pooled overall survival and minimal residual disease status as a covariate fitted to the HSCT and post-HSCT state (see section\xa03.8) to be appropriate for decision-making, with the following assumptions (as preferred by the committee):\n\na 4‑fold increase in mortality compared with the general population for patients 3\xa0years post‑HSCT and beyond (see section\xa03.9)\n\nage-adjusted utilities, and pooled INO-VATE\xa01022 utilities (see section\xa03.10)\n\nbasing the cost of comparators on the actual therapy taken in INO-VATE\xa01022 (see section\xa03.11)\n\nreplacing the costs of the subsequent therapies, blinatumomab and inotuzumab ozogamicin, with the cost of chemotherapy (see section\xa03.12)\n\nbasing the administration cost of inotuzumab ozogamicin on INO-VATE\xa01022 and 9.5\xa0inpatient days for both arms (see section\xa03.13)\n\na discount rate of 3.5% for costs and QALYs (see section\xa03.14).Including all the committee's preferred assumptions, the analysis resulted in a deterministic ICER for inotuzumab ozogamicin compared with standard care of £114,078 per QALY gained.\n\n# First appraisal consultation comments\n\n## Differences between the NICE appraisals of inotuzumab ozogamicin and blinatumomab are because of differences in the available evidence\n\nThe consultees and commentators noted that NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia, recommending blinatumomab as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia, was published in June 2017. Comments received during consultation drew a comparison between the blinatumomab and inotuzumab ozogamicin appraisals and suggested inconsistencies in modelling between the 2, namely survival between transplantation and the cure point, longer-term survival post-cure point, and health-related quality of life post-cure point. The committee was aware that blinatumomab was not a comparator in this appraisal, but also noted that it was not bound by the modelling and interpretation of a separate appraisal. Furthermore, the committee noted that the marketing authorisations for the 2 drugs are different: blinatumomab has a marketing authorisation for Philadelphia-chromosome-negative acute lymphoblastic leukaemia, but inotuzumab ozogamicin has a marketing authorisation for Philadelphia-chromosome-positive and -negative acute lymphoblastic leukaemia. The ERG stated that there are differences in the mechanism of action between the 2 drugs. The ERG also highlighted that although the survival benefit with inotuzumab ozogamicin was uncertain (see section\xa03.4), blinatumomab showed a statistically significant benefit in survival compared with standard care in the TOWER trial. The ERG further noted that the company did not include blinatumomab in any of its analyses for inotuzumab ozogamicin. The committee understood that the populations considered in both appraisals were similar, but it concluded that because the evidence available for each appraisal is different, differences in modelling are unavoidable.\n\n# New evidence from the company before the appeal\n\n## The company submitted a new model including a patient access scheme and new assumptions\n\nThe company submitted a new analysis which included:\n\na patient access scheme\n\na discount rate of 3.5% for costs and QALYs\n\nage-adjusted utilities and pooled INO-VATE\xa01022 utilities\n\nbasing the cost of comparators on the actual therapies used in INO-VATE\xa01022.The company's new analysis did not include the following assumptions preferred by the committee (see section\xa03.16):\n\nmodelling of overall survival in the HSCT and post-HSCT state\n\n‑fold increase in mortality compared with the general population for patients 3\xa0years post-HSCT and beyond\n\nreplacing the costs of the subsequent therapies, blinatumomab and inotuzumab ozogamicin, with the cost of chemotherapy\n\nusing 9.5\xa0inpatient days for both arms.It also used general population utilities for patients without progressed disease 3\xa0years post-HSCT and beyond.The company's new analysis resulted in a deterministic ICER of £37,734 per QALY gained and a probabilistic ICER of £46,152 per QALY gained. In comparison, the analysis using all committee's preferred assumptions and including the patient access scheme resulted in an ICER lower than the original committee preferred ICER of more than £100,000 per QALY gained (see section\xa03.16), but still substantially higher than £50,000 per QALY gained (the results were submitted as commercial in confidence and cannot be reported here).\n\n# Overall survival in the company's economic analysis before the appeal\n\n## The company's extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making\n\nThe company reverted to its original method of modelling overall survival in the HSCT and post-HSCT state (fitting separate parametric curves to Kaplan–Meyer data; see section\xa03.7). Also, a new scenario analysis was introduced which, similar to the committee's preferred overall survival modelling, pooled data post-HSCT with a minimal residual disease status as a covariate. However, all other covariates were removed from the company's scenario analysis and were not adjusted for. The committee recalled its earlier conclusion that the company's overall survival extrapolation in the HSCT and post-HSCT state is not appropriate for decision-making (see section\xa03.7). The ERG stated that all analyses based on the HSCT and post-HSCT state subpopulation are highly uncertain, but an analysis that adjusts for more observed confounders is preferable to one that adjusts only for rates of minimal residual disease negativity. The committee concluded that the ERG's modelling of overall survival with a minimal residual disease status as a covariate (including all other covariates) as accepted earlier (see section\xa03.7) is its preferred method of modelling overall survival.\n\n# Long-term survival in the company's new economic analysis before the appeal\n\n## A 4‑fold increase in mortality and the original base-case utilities 3\xa0years after stem cell transplant are the preferred assumptions\n\nThe company estimated mortality post-cure using cumulative survival at 2\xa0years post-HSCT from Karanes et al. 2008 and an event-free survival hazard ratio for minimal residual disease-negative patients (compared with minimal residual disease-positive patients) after induction therapy from Berry et al. 2017. The company applied a 3‑fold increase in mortality for minimal residual disease-positive patients and a 1.6‑fold increase in mortality for minimal residual disease-negative patients compared with the general population. Also, the company applied a general population utility (0.88) for disease-free patients post-cure. The ERG did not agree with the company's estimation of mortality risk or with the use of general population utilities. The ERG noted that the utility values used in the company's original base case post-cure (0.74 and 0.76) were based on a relevant published study (Kurosawa et al. 2016) and are preferable to the new assumption, which is not supported by evidence. The ERG explained that cumulative survival probabilities do not suggest hazard of death compared with the general population. It further noted that in the company's model (and also in the committee's preferred way of modelling overall survival), survival for patients at 2\xa0years post-HSCT was modelled using parametric curves from INO-VATE\xa01022. The ERG also stated that incorporation of an additional treatment effect on survival by differentiating the risk of mortality after the cure point according to rates of minimal residual disease negativity is not supported by any evidence. The committee agreed with the ERG and recalled that assuming a 4‑fold increase in mortality for patients from 3\xa0years after HSCT is at the lower end of the range in Martin et al. 2010 (see section\xa03.9). The committee concluded that a 4‑fold increase in mortality for patients from 3\xa0years post-HSCT and utilities from Kurosawa et al. 2016 for disease-free patients are its preferred assumptions.\n\n# Subsequent therapy costs in the company's new analysis before the appeal\n\n## The committee accepted the cost of subsequent therapy based on the safety population but list prices were not appropriate\n\nThe company's original model based the cost of subsequent therapies on the INO-VATE\xa01022 intention-to-treat population, but its revised model used the safety population (the company deemed the safety population to be more appropriate for modelling; see section\xa03.6 and\xa0section 3.12). The ERG stated that, although it is questionable to include inotuzumab ozogamicin in the cost of subsequent therapies in the standard care arm, it is methodically acceptable to include the costs of subsequent therapies as seen in the trial. However, the ERG also noted that the company used list prices to calculate the cost of subsequent therapy, which would underestimate the resulting ICER. The committee's preferred base case including the company's revised cost of subsequent therapies and the patient access scheme resulted in a deterministic ICER that was more than £50,000 per QALY gained, but lower than the committee's preferred base-case ICER with the patient access scheme (the results were submitted as commercial in confidence and cannot be reported here, see section\xa03.18). The committee agreed with the ERG that the cost of subsequent therapy based on the safety population could be included, but it is not appropriate to use the list prices for the calculation of the cost. The committee therefore concluded that including the cost of subsequent therapy from the safety population in the company's revised model leads to the ICER being underestimated.\n\n# Inpatient days in the company's new analysis before the appeal\n\n## There is a difference in the number of inpatient days for inotuzumab ozogamicin and standard care patients\n\nThe company increased the number of inpatient days from its original base case (see section\xa03.13) to 1 inpatient day for inotuzumab ozogamicin and 14 days for standard care. The committee noted that the company did not base the calculation of inpatient days on INO-VATE 1022, which it would have preferred. The ERG stated that no new evidence was presented and the reason for changing the number of inpatient days was not explained. The committee's preferred base case, including the company's new number of inpatient days and the patient access scheme, resulted in a deterministic ICER that was more than £50,000 per QALY gained (the results were submitted as commercial in confidence and cannot be reported here). The committee discussed the need for hospitalisation for patients having inotuzumab ozogamicin and standard care. The committee agreed that 1 inpatient day for inotuzumab ozogamicin is too low, and that it is likely that there is a difference in the number of inpatient days for inotuzumab ozogamicin and standard care, but that the ratio is likely to be larger than the ratio used in the company's analysis (1/14). The committee therefore concluded that the number of inpatient days in the company's revised model leads to the ICER being underestimated.\n\n# The cost-effectiveness estimate before the appeal\n\n## The most plausible cost-effectiveness estimate is above what is normally considered a cost-effective use of NHS resources\n\nThe committee recalled its preferred assumptions (see section\xa03.16). After consultation the committee accepted that the cost of subsequent therapy should be based on the safety population (excluding the list prices; see section\xa03.21), and that there would be a difference in the number of inpatient days for patients having inotuzumab ozogamicin and standard care (see section 3.22). The committee further recalled its earlier conclusion that probabilistic ICERs are more appropriate for decision-making in this appraisal (see section\xa03.15). The committee was aware that the ERG's analysis had fewer issues with non-linearity than the company's base case and that the ERG's probabilistic ICER would be about £2,000 per QALY gained more than the deterministic ICER. Taking into consideration the deterministic and probabilistic ICERs, the committee concluded that the most plausible ICER including the patient access scheme for inotuzumab ozogamicin compared with standard care was substantially higher than £50,000 per QALY gained.\n\n# After the appeal\n\nAt the third appraisal committee meeting, the committee considered the appeal panel decision to uphold 3 appeal points and to refer these back to the appraisal committee for further consideration. These were:\n\nThe committee need to clearly explain its decision to reject utilities proposed by the company in response to the first appraisal consultation document (see section\xa03.25).\n\nThe committee need to consider and explain the differences in assumptions post-cure point made in this appraisal explicitly compared to previously published guidance on blinatumomab (see section\xa03.26).\n\nThe committee should reconsider inotuzumab ozogamicin treatment administration in the context of UK clinical practice (usually 2\xa0cycles plus a third if needed). Also, a costing model based on appropriate stopping rules may be considered (see section\xa03.27).Also, at the third appraisal committee meeting the company requested permission to submit new evidence after the appeal, which was accepted by NICE. The committee considered the company's updated model including a revised patient access scheme and new assumptions which included:\n\nassuming general population mortality from 3\xa0years post-HSCT\n\nassuming general population utility values from 3\xa0years post-HSCT\n\ncapping the number of cycles of inotuzumab ozogamicin at 3, with no adjustment to the trial efficacy data\n\nincluding the cost of subsequent therapies using the price of generic imatinib and assuming a simple patient access scheme discount for blinatumomab\n\nassuming 3\xa0days of administration-related inpatient days with inotuzumab ozogamicin and 14\xa0days with FLAG.\n\n## Utility values in the post-transplant state are between Kurosawa et al. 2016 and those of the general population\n\nThe committee considered the first upheld appeal point (see section\xa03.24). It discussed the most appropriate utility values to use in the post-transplant state. Previously, the company and the committee had preferred the published values from Kurosawa et al. 2016 which were 0.74 for 3 to 5\xa0years post-transplant and 0.76 for 5\xa0years post-transplant (see section\xa03.10). After the first appraisal consultation document was released (see section\xa03.20), the company submitted an economic model using general population post-transplant utility values (0.88). The company noted that these were the same values used in the post-transplant state in NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia. At the third committee meeting, the clinical experts explained that although many people who have had a transplant and who did not experience complications such as graft versus host disease or relapse should be expected to return to full health, a substantial number of patients have longer-term health problems related to the transplant. They suggested that the actual utility values 5\xa0years post-transplant are likely to be between those presented in Kurosawa et al. 2016 (0.76) and the value for the general population (0.88). The committee therefore concluded that the most appropriate post-transplant utility values are between the values from Kurosawa et al. 2016 and general population post-transplant utility (0.76 and 0.88).\n\n## A 4‑fold increase in mortality from 3\xa0years after stem cell transplant is the preferred assumption\n\nThe committee considered the second upheld appeal point (see section\xa03.24). It discussed the differences in post-HSCT assumptions between this appraisal and NICE's technology appraisal guidance on blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia, specifically the increase in mortality after the cure point. The committee recalled its earlier conclusions (see section\xa03.17) that the populations considered in both appraisals were similar, but because the evidence available for each appraisal is different, differences in modelling are inevitable. It was aware that the company had assumed general population mortality from 3\xa0years post-HSCT in its original submission and that in NICE's technology appraisal guidance on blinatumomab, the mortality post-HSCT was the general population mortality risk added to the risk derived from the extrapolated parametric curve for overall survival. The committee had previously concluded that a 4-fold increase in mortality for patients from 3\xa0years post-HSCT based on the lowest values reported in Martin et al. 2010 was appropriate (see section\xa03.20). At the third committee meeting, the clinical experts noted that the Martin et al. 2010 study was well designed and included a large sample size but transplant care had improved substantially since the study was published meaning a 4-fold increase in mortality could be too high. The clinical experts suggested that any increase in mortality from 3\xa0years post-HSCT is likely to be between the risk of the general population and the value in Martin et al. 2010. The committee accepted that transplant care had improved but it had not been presented with any new evidence to suggest that mortality from 3\xa0years post-HSCT was lower than that presented in Martin et al. 2010. The committee noted that other smaller studies identified by the ERG had shown much larger increases in mortality (see section\xa03.20) and the 4-fold increase in mortality was at the bottom end of the range in Martin et al. 2010. The committee therefore concluded that a 4-fold increase in mortality from 3\xa0years post-HSCT is preferred.\n\n## The number of treatment cycles in the economic model should reflect the number of cycles administered in INO-VATE\xa01022\n\nThe committee considered the third upheld appeal point (see section\xa03.24). It discussed the appropriate number of inotuzumab ozogamicin treatment cycles to include in the model in the context of NHS clinical practice. The summary of product characteristics for inotuzumab ozogamicin states that:\n\nfor patients proceeding to HSCT, the recommended duration of treatment is 2\xa0cycles. A third cycle may be considered for those patients whose leukaemia does not achieve complete remission or complete remission with incomplete haematological recovery and minimal residual disease negativity after 2\xa0cycles.\n\nfor patients not proceeding to HSCT, additional cycles of treatment (up to a maximum of 6\xa0cycles), may be given. Patients whose disease does not achieve complete remission or complete remission with incomplete haematological recovery within 3\xa0cycles should stop treatment.The committee was aware that the company had used the number of inotuzumab ozogamicin cycles (up to 6) informed by the INO-VATE\xa01022 trial in its base-case analysis. It noted that the company had included a scenario analysis which capped treatment at 3\xa0cycles. At the third committee meeting, the clinical experts explained that patients in the UK who go on to have a HSCT would not have more than 3\xa0cycles of treatment and would often only have 2, the intention being to move to allogeneic stem cell transplant if the disease was controlled. They explained that because inotuzumab ozogamicin is associated with high rates of hepatotoxicity and veno-occlusive liver disease, treatment would be stopped if there was no evidence of complete remission or complete remission with incomplete haematological recovery after 3\xa0cycles, regardless of HSCT eligibility. The concern about veno-occlusive disease with longer duration of therapy had increased since the original trial leading to greater reluctance to proceed beyond 3 cycles. The committee considered the company's post-appeal scenario analyses which capped inotuzumab ozogamicin treatment at 3\xa0cycles. The first scenario, which was the company's preferred scenario, capped the costs of treatment at 3\xa0cycles but retained the efficacy data for inotuzumab ozogamicin from INNO-VATE\xa01022. The company noted that complete remission or complete remission with incomplete haematological recovery was achieved in the INO-VATE\xa01022 trial within the first 3\xa0cycles. The company further explained that this is a prerequisite for HSCT and it considered it plausible to assume that the same HSCT rate would be seen when treatment is stopped at 3\xa0cycles. The second company scenario removed data on patients in the inotuzumab ozogamicin arm of INO-VATE\xa01022 who did not proceed to transplant. The ERG stated that the company's second scenario would result in the breaking of trial randomisation. The committee agreed and did not consider this scenario further. The committee understood that most patients in the UK would have no more than 3\xa0cycles of treatment. However, the INO-VATE\xa01022 trial (on which the clinical efficacy of inotuzumab ozogamicin is based) included up to 6\xa0cycles of treatment. The committee agreed that the sources of efficacy and cost data in the model should be consistent and that benefit and cost should not be uncoupled. The committee concluded that the number of inotuzumab ozogamicin cycles in the economic modelling should reflect the number given in the INO-VATE\xa01022 trial (up to 6\xa0cycles).\n\n## Subsequent therapy costs are appropriate\n\nThe committee had previously accepted the inclusion of subsequent therapy costs based on the safety population (see section\xa03.21). The committee was aware that the company had included the cost of generic imatinib in its post-appeal analyses. It was aware that company's deterministic ICERs did not include the correct price of blinatumomab because there is a confidential patient access scheme. In line with NICE processes, the ERG updated the company's post-appeal analyses with the correct price of blinatumomab however, the results cannot be reported here since they are commercial in confidence.\n\n## There is a difference in the average number of inpatient days for treatment with inotuzumab ozogamicin compared with standard care\n\nAt the third appraisal committee meeting the committee considered the average length of inpatient days for treatment with inotuzumab ozogamicin compared with standard care. Originally, the committee's most plausible ICER (see section\xa03.23) had been based on the ERG's exploratory analyses. These used a weighted average from NHS reference cost for regimens used in the standard care arm. This resulted in an average of 9.5 inpatient\xa0days for both inotuzumab ozogamicin and standard care (which is often FLAG-IDA). The committee was aware that the economic model was highly sensitive to the average number of inpatient days. At the third appraisal committee meeting, after the appeal, the clinical experts noted that an average of 9.5\xa0inpatient days for standard care is not clinically plausible and patients having FLAG-IDA are usually in hospital for longer periods. After a second appraisal consultation, the clinical experts submitted unpublished observational data on the average number of inpatient days with inotuzumab ozogamicin and FLAG-IDA from a compassionate use programme at 2 specialist centres in England (the results of which were provided as academic in confidence and therefore cannot be reported here). The committee noted the limitations with the study including its small sample size but accepted that the results were representative of clinical practice in England. The committee concluded that there is a substantial difference in the average number of inpatient days for treatment with inotuzumab ozogamicin compared with FLAG-IDA.\n\n# Company's post-appeal new evidence and updated model assumptions.\n\n# End of life\n\n## Inotuzumab ozogamicin meets NICE's end-of-life criteria\n\nThe committee discussed whether life expectancy without inotuzumab ozogamicin would be less than 24\xa0months. It noted that median overall survival was 6.7\xa0months with standard care in INO-VATE\xa01022 and concluded that the short life expectancy criterion was met. The committee discussed whether a survival benefit of over 3\xa0months can be expected for inotuzumab ozogamicin compared with standard care. It recalled its earlier conclusion about survival benefit with inotuzumab ozogamicin (see section\xa03.4) and agreed that although the survival benefits of inotuzumab ozogamicin are highly uncertain, it is likely that by increasing the rate of HSCT, inotuzumab ozogamicin would increase mean survival for people with relapsed or refractory B-cell acute lymphoblastic leukaemia by more than 3\xa0months. The committee concluded that the extension-to-life criterion was met. The committee concluded that inotuzumab ozogamicin met the life expectancy and life extension criteria to be considered a life-extending, end-of-life treatment.\n\n## Inotuzumab ozogamicin's benefits are captured in the cost-effectiveness analysis\n\nThe patient and clinical experts explained that there is considerable unmet need for people with relapsed or refractory acute lymphoblastic leukaemia because of the ineffective and toxic chemotherapy regimens currently being used. The committee noted that the company considered inotuzumab ozogamicin to be innovative, reducing the need for hospitalisation and leading to a major change in treating a rare illness. The committee concluded that inotuzumab ozogamicin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# The cost-effectiveness estimates after the appeal\n\n## The company's updated model with the committee's preferred assumptions is suitable for decision-making\n\nFollowing the appeal and a second appraisal consultation the company updated its cost model to incorporate the committee's preferred assumptions (see sections\xa03.25 to 3.29). The updated model comparing inotuzumab ozogamicin with standard care included:\n\nutility values for all patients 5\xa0years post-HSCT between Kurasowa et al 2016 and the general population\n\n-fold increase in mortality compared with the general population for patients 3\xa0years post-HSCT and beyond\n\nthe same number of treatment cycles for inotuzumab ozogamicin as administered in INNO-VATE\xa01022 (up to 6\xa0cycles)\n\nthe cost of subsequent therapy from the safety population using the generic price for imatinib and the list price for blinatumomab (results using the price of blinatumomab with a commercial arrangement were updated by the ERG)\n\nusing observational data from the inotuzumab ozogamicin compassionate use programme to inform the average number of inpatient days for inotuzumab ozogamicin and FLAG-IDA.\n\n## Inotuzumab ozogamicin is recommended for treating relapsed or refractory B-cell acute lymphoblastic leukaemia\n\nThe company's new analysis, using the committee's preferred assumptions (see sections\xa03.25 to 3.29) resulted in a deterministic ICER between £37,497 per QALY gained when using utility values from Kurasowa et al 2016 (0.76) and £33,749 per QALY gained when using utility values from the general population (0.88). The committee recalled that inotuzumab ozogamicin met NICE's end-of-life criteria compared with standard care (see section\xa03.30). The committee noted that when the confidential discount for blinatumomab was incorporated by the ERG the ICER was still within the range normally considered a cost-effective use of NHS resources (these ICERs are commercial in confidence and cannot be reported here). The committee therefore recommended inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia.\n\n# Other factors\n\nNo equality issues were identified."}
|
https://www.nice.org.uk/guidance/ta541
|
Evidence-based recommendations on inotuzumab ozogamicin (Besponsa) for relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia in adults.
|
a14a945674ef5ffc9079b7f0b2cfdf524ffbb279
|
nice
|
Chronic heart failure in adults: diagnosis and management
|
Chronic heart failure in adults: diagnosis and management
This guideline covers diagnosing and managing chronic heart failure in people aged 18 and over. It aims to improve diagnosis and treatment to increase the length and quality of life for people with heart failure.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Team working in the management of heart failure
The core specialist heart failure multidisciplinary team (MDT) should work in collaboration with the primary care team, and should include:
a lead physician with subspecialty training in heart failure (usually a consultant cardiologist) who is responsible for making the clinical diagnosis
a specialist heart failure nurse
a healthcare professional with expertise in specialist prescribing for heart failure.
The specialist heart failure MDT should:
diagnose heart failure
give information to people newly diagnosed with heart failure (see the section on giving information to people with heart failure)
manage newly diagnosed, recently decompensated or advanced heart failure (NYHA class III to IV)
-ptimise treatment
start new medicines that need specialist supervision
continue to manage heart failure after an interventional procedure such as implantation of a cardioverter defibrillator or cardiac resynchronisation device
manage heart failure that is not responding to treatment.
The specialist heart failure MDT should directly involve, or refer people to, other services, including rehabilitation, services for older people and palliative care services, as needed.
The primary care team should carry out the following for people with heart failure at all times, including periods when the person is also receiving specialist heart failure care from the MDT:
ensure effective communication links between different care settings and clinical services involved in the person's care
lead a full review of the person's heart failure care, which may form part of a long-term conditions review
recall the person at least every 6 months and update the clinical record
ensure that changes to the clinical record are understood and agreed by the person with heart failure and shared with the specialist heart failure MDT
arrange access to specialist heart failure services if needed.
## Care after an acute event
For recommendations on the diagnosis and management of acute heart failure, see the NICE guideline on acute heart failure.
People with heart failure should generally be discharged from hospital only when their clinical condition is stable and the management plan is optimised. Timing of discharge should take into account the wishes of the person and their family or carer, and the level of care and support that can be provided in the community.
The primary care team should take over routine management of heart failure as soon as it has been stabilised and its management optimised.
## Writing a care plan
The specialist heart failure MDT should write a summary for each person with heart failure that includes:
diagnosis and aetiology
medicines prescribed, monitoring of medicines, when medicines should be reviewed and any support the person needs to take the medicines
functional abilities and any social care needs
social circumstances, including carers' needs.
The summary should form the basis of a care plan for each person, which should include:
plans for managing the person's heart failure, including follow-up care, rehabilitation and access to social care
symptoms to look out for in case of deterioration
a process for any subsequent access to the specialist heart failure MDT if needed
contact details for
a named healthcare coordinator (usually a specialist heart failure nurse)
alternative local heart failure specialist care providers, for urgent care or review.
additional sources of information for people with heart failure.
Give a copy of the care plan to the person with heart failure, their family or carer if appropriate, and all health and social care professionals involved in their care.
# Diagnosing heart failure
## Symptoms, signs and investigations
Take a careful and detailed history, and perform a clinical examination and tests to confirm the presence of heart failure.
Measure N-terminal pro-B-type natriuretic peptide (NT‑proBNP) in people with suspected heart failure.
Because very high levels of NT‑proBNP carry a poor prognosis, refer people with suspected heart failure and an NT‑proBNP level above 2,000 ng/litre (236 pmol/litre) urgently, to have specialist assessment and transthoracic echocardiography within 2 weeks.
Refer people with suspected heart failure and an NT‑proBNP level between 400 and 2,000 ng/litre (47 to 236 pmol/litre) to have specialist assessment and transthoracic echocardiography within 6 weeks.
Be aware that:
an NT‑proBNP level less than 400 ng/litre (47 pmol/litre) in an untreated person makes a diagnosis of heart failure less likely
the level of serum natriuretic peptide does not differentiate between heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
Review alternative causes for symptoms of heart failure in people with NT-proBNP levels below 400 ng/litre. If there is still concern that the symptoms might be related to heart failure, discuss with a physician with subspeciality training in heart failure.
Be aware that:
-besity, African or African–Caribbean family background, or treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta‑blockers, angiotensin II receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs) can reduce levels of serum natriuretic peptides
high levels of serum natriuretic peptides can have causes other than heart failure (for example, age over 70 years, left ventricular hypertrophy, ischaemia, tachycardia, right ventricular overload, hypoxaemia , renal dysfunction , sepsis, chronic obstructive pulmonary disease, diabetes, or cirrhosis of the liver).
Perform transthoracic echocardiography to exclude important valve disease, assess the systolic (and diastolic) function of the (left) ventricle, and detect intracardiac shunts. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease.
Transthoracic echocardiography should be performed on high‑resolution equipment by experienced operators trained to the relevant professional standards. Need and demand for these studies should not compromise quality.
Ensure that those reporting echocardiography are experienced in doing so.
Consider alternative methods of imaging the heart (for example, radionuclide angiography , cardiac MRI or transoesophageal echocardiography) if a poor image is produced by transthoracic echocardiography.
Perform an ECG and consider the following tests to evaluate possible aggravating factors and/or alternative diagnoses:
chest X-ray
blood tests:
renal function profile
thyroid function profile
liver function profile
lipid profile
glycosylated haemoglobin (HbA1c)
full blood count
urinalysis
peak flow or spirometry.
Try to exclude other disorders that may present in a similar manner.
When a diagnosis of heart failure has been made, assess severity, aetiology, precipitating factors, type of cardiac dysfunction and correctable causes.
## Heart failure caused by valve disease
Refer people with heart failure caused by valve disease for specialist assessment and advice regarding follow-up. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease.
## Reviewing existing diagnoses
Review the basis for a historical diagnosis of heart failure, and manage care in accordance with this guideline only if the diagnosis is confirmed.
If the diagnosis of heart failure is still suspected, but confirmation of the underlying cardiac abnormality has not occurred, then the person should have appropriate further investigation.
# Giving information to people with heart failure
When giving information to people with heart failure, follow the recommendations in the NICE guideline on patient experience in adult NHS services.
Discuss the person's prognosis in a sensitive, open and honest manner. Be frank about the uncertainty in predicting the course of their heart failure. Revisit this discussion as the person's condition evolves.
Provide information whenever needed throughout the person's care.
Consider training in advanced communication skills for all healthcare professionals working with people who have heart failure.
## First consultations for people newly diagnosed with heart failure
The specialist heart failure MDT should offer people newly diagnosed with heart failure an extended first consultation, followed by a second consultation to take place within 2 weeks if possible. At each consultation:
discuss the person's diagnosis and prognosis
explain heart failure terminology
discuss treatments
address the risk of sudden death, including any misconceptions about that risk
encourage the person and their family or carers to ask any questions they have.
# Treating heart failure with reduced ejection fraction
See the section on managing all types of heart failure for general recommendations on managing all types of heart failure.
See NICE's technology appraisal guidance on dapagliflozin and empagliflozin for treating chronic heart failure with reduced ejection fraction.
When managing pharmacological treatment, follow the recommendations in the NICE guidelines on medicines adherence and medicines optimisation.
## First-line treatment
Offer an angiotensin-converting enzyme (ACE) inhibitor and a beta‑blocker licensed for heart failure to people who have heart failure with reduced ejection fraction. Use clinical judgement when deciding which drug to start first.
Do not offer ACE inhibitor therapy if there is a clinical suspicion of haemodynamically significant valve disease until the valve disease has been assessed by a specialist. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease.
Start ACE inhibitor therapy at a low dose and titrate upwards at short intervals (for example, every 2 weeks) until the target or maximum tolerated dose is reached.
Measure serum sodium and potassium, and assess renal function, before and 1 to 2 weeks after starting an ACE inhibitor, and after each dose increment.
Measure blood pressure before and after each dose increment of an ACE inhibitor. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults.
Once the target or maximum tolerated dose of an ACE inhibitor is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell.
Consider an ARB licensed for heart failure as an alternative to an ACE inhibitor for people who have heart failure with reduced ejection fraction and intolerable side effects with ACE inhibitors.
Measure serum sodium and potassium, and assess renal function, before and after starting an ARB and after each dose increment.
Measure blood pressure after each dose increment of an ARB. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults.
Once the target or maximum tolerated dose of an ARB is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell.
If neither ACE inhibitors nor ARBs are tolerated, seek specialist advice and consider hydralazine in combination with nitrate for people who have heart failure with reduced ejection fraction.
Do not withhold treatment with a beta-blocker solely because of age or the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease.
Introduce beta-blockers in a 'start low, go slow' manner. Assess heart rate and clinical status after each titration. Measure blood pressure before and after each dose increment of a beta‑blocker.
Switch people whose condition is stable and who are already taking a beta-blocker for a comorbidity (for example, angina or hypertension), and who develop heart failure with reduced ejection fraction, to a beta-blocker licensed for heart failure.
Offer an mineralocorticoid receptor antagonists (MRA), in addition to an ACE inhibitor (or ARB) and beta-blocker, to people who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure.
Measure serum sodium and potassium, and assess renal function, before and after starting an MRA and after each dose increment.
Measure blood pressure before and after after each dose increment of an MRA. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults.
Once the target, or maximum tolerated, dose of an MRA is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell.
## Specialist treatment
These recommendations are from the NICE technology appraisal guidance on ivabradine for treating chronic heart failure.
Ivabradine is recommended as an option for treating chronic heart failure for people:
with New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction and
who are in sinus rhythm with a heart rate of 75 beats per minute (bpm) or more and
who are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta‑blocker therapy is contraindicated or not tolerated and
with a left ventricular ejection fraction of 35% or less.
Ivabradine should only be initiated after a stabilisation period of 4 weeks on optimised standard therapy with ACE inhibitors, beta‑blockers and aldosterone antagonists.
Ivabradine should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be carried out by a heart failure specialist, or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse.
These recommendations are from the NICE technology appraisal guidance on sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction.
Sacubitril valsartan is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people:
with New York Heart Association (NYHA) class II to IV symptoms and
with a left ventricular ejection fraction of 35% or less and
who are already taking a stable dose of angiotensin‑converting enzyme (ACE) inhibitors or ARBs.
Treatment with sacubitril valsartan should be started by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be performed by the most appropriate team member (see the section on team working in the management of heart failure).
This guidance is not intended to affect the position of patients whose treatment with sacubitril valsartan was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
Seek specialist advice and consider offering hydralazine in combination with nitrate (especially if the person is of African or Caribbean family origin and has moderate to severe heart failure with reduced ejection fraction).
For recommendations on digoxin for people with atrial fibrillation see the section on rate and rhythm control in the NICE guideline on atrial fibrillation.
Digoxin is recommended for worsening or severe heart failure with reduced ejection fraction despite first-line treatment for heart failure. Seek specialist advice before initiating.
Routine monitoring of serum digoxin concentrations is not recommended. A digoxin concentration measured within 8 to 12 hours of the last dose may be useful to confirm a clinical impression of toxicity or non‑adherence.
The serum digoxin concentration should be interpreted in the clinical context as toxicity may occur even when the concentration is within the 'therapeutic range'.
# Treating heart failure with reduced ejection fraction in people with chronic kidney disease
For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR of 30 ml/min/1.73 m2 or above:
-ffer the treatment outlined in the section on treating heart failure with reduced ejection fraction and
if the person's eGFR is 45 ml/min/1.73 m2 or below, consider lower doses and/or slower titration of dose of ACE inhibitors or ARBs, MRAs and digoxin.
For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR below 30 ml/min/1.73 m2, the specialist heart failure MDT should consider liaising with a renal physician.
Monitor the response to titration of medicines closely in people who have heart failure with reduced ejection fraction and chronic kidney disease, taking into account the increased risk of hyperkalaemia.
# Managing all types of heart failure
When managing pharmacological treatment, follow the recommendations in the NICE guidelines on medicines adherence and medicines optimisation.
## Pharmacological treatment
Diuretics should be routinely used for the relief of congestive symptoms and fluid retention in people with heart failure, and titrated (up and down) according to need following the initiation of subsequent heart failure therapies.
People who have heart failure with preserved ejection fraction should usually be offered a low to medium dose of loop diuretics (for example, less than 80 mg furosemide per day). People whose heart failure does not respond to this treatment will need further specialist advice.
Avoid verapamil, diltiazem and short-acting dihydropyridine agents in people who have heart failure with reduced ejection fraction.
Make the decision to prescribe amiodarone in consultation with a specialist.
Review the need to continue the amiodarone prescription at the 6‑monthly clinical review.
Offer people taking amiodarone liver and thyroid function tests, and a review of side effects, as part of their routine 6‑monthly clinical review.
For people who have heart failure and atrial fibrillation, follow the recommendations on anticoagulation in the NICE guideline on atrial fibrillation. Be aware of the effects of impaired renal and liver function on anticoagulant therapies.
In people with heart failure in sinus rhythm, anticoagulation should be considered for those with a history of thromboembolism, left ventricular aneurysm or intracardiac thrombus.
## Vaccinations
Offer people with heart failure an annual vaccination against influenza.
Offer people with heart failure vaccination against pneumococcal disease (only required once).
## Contraception and pregnancy
In women of childbearing potential who have heart failure, contraception and pregnancy should be discussed. If pregnancy is being considered or occurs, specialist advice should be sought. Subsequently, specialist care should be shared between the cardiologist and obstetrician.
## Depression
See NICE's guideline on depression in adults with a chronic physical health problem.
## Lifestyle advice
Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows:
restricting fluids for people with dilutional hyponatraemia
reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid.
Advise people with heart failure to avoid salt substitutes that contain potassium.
See NICE's guidance on smoking and tobacco and alcohol.
Air travel will be possible for the majority of people with heart failure, depending on their clinical condition at the time of travel.
Large Goods Vehicle and Passenger Carrying Vehicle licence: physicians should be up to date with the latest Driver and Vehicle Licensing Agency (DVLA) guidelines. Check the DVLA website for regular updates.
# Monitoring treatment for all types of heart failure
See the section on treating heart failure with reduced ejection fraction for specific recommendations on monitoring treatment for heart failure with reduced ejection fraction.
## Clinical review
All people with chronic heart failure need monitoring. This monitoring should include:
a clinical assessment of functional capacity, fluid status, cardiac rhythm (minimum of examining the pulse), cognitive status and nutritional status
a review of medication, including need for changes and possible side effects
an assessment of renal function. Note: This is a minimum. People with comorbidities or co-prescribed medications will need further monitoring. Monitoring serum potassium is particularly important if a person is taking digoxin or an MRA.
More detailed monitoring will be needed if the person has significant comorbidity or if their condition has deteriorated since the previous review.
The frequency of monitoring should depend on the clinical status and stability of the person. The monitoring interval should be short (days to 2 weeks) if the clinical condition or medication has changed, but is needed at least 6-monthly for stable people with proven heart failure.
People with heart failure who wish to be involved in monitoring of their condition should be provided with sufficient education and support from their healthcare professional to do this, with clear guidelines as to what to do in the event of deterioration.
## Measuring NT-proBNP
Consider measuring NT-proBNP (N-terminal pro-B-type natriuretic peptide) as part of a treatment optimisation protocol only in a specialist care setting for people aged under 75 who have heart failure with reduced ejection fraction and an eGFR above 60 ml/min/1.73 m2.
# Interventional procedures
## Coronary revascularisation
Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease.
## Cardiac transplantation
Specialist referral for transplantation should be considered for people with severe refractory symptoms or refractory cardiogenic shock.
## Implantable cardioverter defibrillators and cardiac resynchronisation therapy
See NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.
When discussing implantation of a cardioverter defibrillator:
explain the risks, benefits and consequences of cardioverter defibrillator implantation, following the principles on shared decision making in the NICE guideline on patient experience in adult NHS services
ensure the person knows that the defibrillator function can be deactivated without affecting any cardiac resynchronisation or pacing, and reactivated later
explain the circumstances in which deactivation might be offered
discuss and dispel common misconceptions about the function of the device and the consequences of deactivation
provide the person and, if they wish, their family or carers with written information covering the information discussed.
Review the benefits and potential harms of a cardioverter defibrillator remaining active in a person with heart failure:
at each 6‑monthly review of their heart failure care
whenever their care goals change
as part of advance care planning if it is thought they are nearing the end of life.
# Cardiac rehabilitation
Offer people with heart failure a personalised, exercise-based cardiac rehabilitation programme, unless their condition is unstable. The programme:
should be preceded by an assessment to ensure that it is suitable for the person
should be provided in a format and setting (at home, in the community or in the hospital) that is easily accessible for the person
should include a psychological and educational component
may be incorporated within an existing cardiac rehabilitation programme
should be accompanied by information about support available from healthcare professionals when the person is doing the programme.
# Palliative care
Do not offer long-term home oxygen therapy for advanced heart failure. Be aware that long-term home oxygen therapy may be offered for comorbidities, such as for some people with chronic obstructive pulmonary disease (see the section on oxygen in the NICE guideline on chronic obstructive pulmonary disease in over 16s).
Do not use prognostic risk tools to determine whether to refer a person with heart failure to palliative care services.
If the symptoms of a person with heart failure are worsening despite optimal specialist treatment, discuss their palliative care needs with the specialist heart failure multidisciplinary team and consider a needs assessment for palliative care.
People with heart failure and their families or carers should have access to professionals with palliative care skills within the heart failure team.
If it is thought that a person may be entering the last 2 to 3 days of life, follow the NICE guideline on care of dying adults in the last days of life.
# Terms used in this guideline
## Heart failure with preserved ejection fraction
This is usually associated with impaired left ventricular relaxation, rather than left ventricular contraction, and is characterised by normal or preserved left ventricular ejection fraction with evidence of diastolic dysfunction .
## Heart failure with reduced ejection fraction
Heart failure with an ejection fraction below 40%.
## Mineralocorticoid receptor antagonist
A drug that antagonises the action of aldosterone at mineralocorticoid receptors.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Heart failure is a complex clinical syndrome of symptoms and signs that suggest the efficiency of the heart as a pump is impaired. It is caused by structural or functional abnormalities of the heart. Around 920,000 people in the UK today have been diagnosed with heart failure. Both the incidence and prevalence of heart failure increase steeply with age, and the average age at diagnosis is 77. Improvements in care have increased survival for people with ischaemic heart disease, and treatments for heart failure have become more effective. But the overall prevalence of heart failure is rising because of population ageing and increasing rates of obesity.
Uptake of NICE's 2010 guidance on chronic heart failure appears to be good. However, the Department of Health and Social Care's policy paper on improving cardiovascular disease outcomes: strategy noted that prescribing of ACE inhibitors, beta-blockers and aldosterone antagonists remains suboptimal, and that improved use of these drugs has the potential to reduce hospitalisations and deaths caused by heart failure. This update reviewed evidence on the clinical and cost effectiveness of these therapies.
Interdisciplinary working has contributed to better outcomes in heart failure but there is further room to improve the provision of multidisciplinary teams (MDTs) and integrate them more fully into healthcare processes. This update highlights and further expands on the roles of the MDT and collaboration between the MDT and the primary care team.
The Department of Health and Social Care's policy paper on improving cardiovascular disease outcomes: strategy also noted that the proportion of people with heart failure who have cardiac rehabilitation was around 4%, and that increasing this proportion would reduce mortality and hospitalisation. This update recommends that all people with heart failure are offered an easily accessible, exercise-based cardiac rehabilitation programme, if this is suitable for them.# Recommendations for research
The guideline committee has made the following key recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Diuretic therapy for managing fluid overload in people with advanced heart failure in the community
In people with advanced heart failure and significant peripheral fluid overload, what is the clinical and cost effectiveness of oral, subcutaneous and intravenous diuretic therapy in the community?
## Why this is important
This research is critical to inform practice of how best to manage people with advanced heart failure in the community if they develop significant peripheral fluid overload. These people are more likely to have multiple admissions that, together with fluid overload, have a negative impact on their quality of life. Management in the community can minimise disruption for the person and reduce costs from hospital admissions. Knowledge of the most clinically and cost-effective routes of administration for diuretic therapy will dictate the level of resource needed to provide the service. Intravenous and subcutaneous diuretics usually need to be administered by nursing or healthcare staff. although a pump for self-administration of subcutaneous diuretics has recently been developed. Oral formulations can be self‑administered.
# Cardiac MRI versus other imaging techniques for diagnosing heart failure
What is the optimal imaging technique for the diagnosis of heart failure?
## Why this is important
The role of cardiac MRI in the detection and characterisation of several structural and functional cardiac abnormalities has become well established over the past 25 years. In people with heart failure, cardiac MRI provides reliable and reproducible assessments of the left ventricular (and to a degree the right ventricular) shapes, volumes and ejection fractions. It also provides spatial assessments of the congenital and acquired structural abnormalities of the heart and their interrelationships with the remainder of the heart, as well as functional and haemodynamic assessments of these abnormalities on the heart's performance. Finally, cardiac MRI provides valuable information about the myocardial structure and metabolism, including the presence of inflammation, scarring, fibrosis and infiltration. Cardiac MRI is an expensive form of imaging, and much of this diagnostic information could be provided by less costly non-invasive imaging techniques, chiefly echocardiography. This question aims to find the most clinically and cost-effective imaging technique for the clinical diagnosis of heart failure.
# The impact of atrial fibrillation on the natriuretic peptide threshold for diagnosing heart failure
What is the optimal NT‑proBNP threshold for the diagnosis of heart failure in people with atrial fibrillation?
## Why this is important
Atrial fibrillation is a common arrhythmia in the general population, and occurs in 30 to 40% of people with heart failure. Atrial fibrillation can raise the level of serum natriuretic peptides, including NT‑proBNP, even in the absence of heart failure. This is complicated further in heart failure with preserved ejection fraction, in which 2 echocardiographic diagnostic criteria become unreliable (the left atrial volume and the tissue doppler imaging assessment of diastolic function). These factors contribute to the complexity of the diagnosis and have a potential impact on the usual thresholds for NT‑proBNP in people who have atrial fibrillation. This has been recognised in several ongoing randomised controlled trials of heart failure, which are using higher NT‑proBNP thresholds for the diagnosis of heart failure in people with atrial fibrillation.
# The impact of advanced kidney disease on the natriuretic peptide threshold for diagnosing heart failure
What are the optimal NT‑proBNP thresholds for diagnosing heart failure in people with stage IIIb, IV or V chronic kidney disease?
## Why this is important
Heart failure incidence and prevalence increase with age, with the rise starting at age 65 and peaking between 75 and 85. Both advancing age and heart failure are associated with a gradual and progressive decline in renal function. In addition, the progression of heart failure and some treatments for heart failure lead to progressive deterioration of renal function. A decline in renal function is associated with increased fluid retention and a rise in the level of the serum natriuretic peptides, including NT‑proBNP, even in the absence of heart failure. There is some evidence that the use of higher NT‑proBNP thresholds would improve diagnostic accuracy for heart failure in people with significant deterioration of creatinine clearance.
# Risk tools for predicting non-sudden death in heart failure
What is the most accurate prognostic risk tool in predicting 1‑year mortality from heart failure at specific clinically relevant thresholds (for example, sensitivity, specificity, negative predictive value and positive predictive value at a threshold of 50% risk of mortality at 1 year)?
## Why this is important
There are a number of validated prognostic risk tools for heart failure but most do not report sensitivity and specificity at clinically relevant thresholds. This information is crucial to enable accurate prediction of a person's risk of mortality. The ability to accurately predict a person's prognosis would allow clearer communication and timely referral to other services such as palliative care. Inaccurate prediction has the potential to lead to significant psychological harm and increased morbidity.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Team working in the management of heart failure\n\nThe core specialist heart failure multidisciplinary team (MDT) should work in collaboration with the primary care team, and should include:\n\na lead physician with subspecialty training in heart failure (usually a consultant cardiologist) who is responsible for making the clinical diagnosis\n\na specialist heart failure nurse\n\na healthcare professional with expertise in specialist prescribing for heart failure. \n\nThe specialist heart failure MDT should:\n\ndiagnose heart failure\n\ngive information to people newly diagnosed with heart failure (see the section on giving information to people with heart failure)\n\nmanage newly diagnosed, recently decompensated or advanced heart failure (NYHA [New York Heart Association] class III to IV)\n\noptimise treatment\n\nstart new medicines that need specialist supervision\n\ncontinue to manage heart failure after an interventional procedure such as implantation of a cardioverter defibrillator or cardiac resynchronisation device\n\nmanage heart failure that is not responding to treatment. \n\nThe specialist heart failure MDT should directly involve, or refer people to, other services, including rehabilitation, services for older people and palliative care services, as needed. \n\nThe primary care team should carry out the following for people with heart failure at all times, including periods when the person is also receiving specialist heart failure care from the MDT:\n\nensure effective communication links between different care settings and clinical services involved in the person's care\n\nlead a full review of the person's heart failure care, which may form part of a long-term conditions review\n\nrecall the person at least every 6\xa0months and update the clinical record\n\nensure that changes to the clinical record are understood and agreed by the person with heart failure and shared with the specialist heart failure MDT\n\narrange access to specialist heart failure services if needed. \n\n## Care after an acute event\n\nFor recommendations on the diagnosis and management of acute heart failure, see the NICE guideline on acute heart failure.\n\nPeople with heart failure should generally be discharged from hospital only when their clinical condition is stable and the management plan is optimised. Timing of discharge should take into account the wishes of the person and their family or carer, and the level of care and support that can be provided in the community. \n\nThe primary care team should take over routine management of heart failure as soon as it has been stabilised and its management optimised. \n\n## Writing a care plan\n\nThe specialist heart failure MDT should write a summary for each person with heart failure that includes:\n\ndiagnosis and aetiology\n\nmedicines prescribed, monitoring of medicines, when medicines should be reviewed and any support the person needs to take the medicines\n\nfunctional abilities and any social care needs\n\nsocial circumstances, including carers' needs. \n\nThe summary should form the basis of a care plan for each person, which should include:\n\nplans for managing the person's heart failure, including follow-up care, rehabilitation and access to social care\n\nsymptoms to look out for in case of deterioration\n\na process for any subsequent access to the specialist heart failure MDT if needed\n\ncontact details for\n\n\n\na named healthcare coordinator (usually a specialist heart failure nurse)\n\nalternative local heart failure specialist care providers, for urgent care or review.\n\n\n\nadditional sources of information for people with heart failure. \n\nGive a copy of the care plan to the person with heart failure, their family or carer if appropriate, and all health and social care professionals involved in their care. \n\n# Diagnosing heart failure\n\n## Symptoms, signs and investigations\n\nTake a careful and detailed history, and perform a clinical examination and tests to confirm the presence of heart failure. \n\nMeasure N-terminal pro-B-type natriuretic peptide (NT‑proBNP) in people with suspected heart failure. \n\nBecause very high levels of NT‑proBNP carry a poor prognosis, refer people with suspected heart failure and an NT‑proBNP level above 2,000\xa0ng/litre (236\xa0pmol/litre) urgently, to have specialist assessment and transthoracic echocardiography within 2\xa0weeks. \n\nRefer people with suspected heart failure and an NT‑proBNP level between 400 and 2,000\xa0ng/litre (47 to 236\xa0pmol/litre) to have specialist assessment and transthoracic echocardiography within 6\xa0weeks. \n\nBe aware that:\n\nan NT‑proBNP level less than 400\xa0ng/litre (47\xa0pmol/litre) in an untreated person makes a diagnosis of heart failure less likely\n\nthe level of serum natriuretic peptide does not differentiate between heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. \n\nReview alternative causes for symptoms of heart failure in people with NT-proBNP levels below 400\xa0ng/litre. If there is still concern that the symptoms might be related to heart failure, discuss with a physician with subspeciality training in heart failure. \n\nBe aware that:\n\nobesity, African or African–Caribbean family background, or treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta‑blockers, angiotensin\xa0II receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs) can reduce levels of serum natriuretic peptides\n\nhigh levels of serum natriuretic peptides can have causes other than heart failure (for example, age over 70\xa0years, left ventricular hypertrophy, ischaemia, tachycardia, right ventricular overload, hypoxaemia [including pulmonary embolism], renal dysfunction [eGFR less than 60\xa0ml/minute/1.73\xa0m2], sepsis, chronic obstructive pulmonary disease, diabetes, or cirrhosis of the liver). [2010, amended 2018]\n\nPerform transthoracic echocardiography to exclude important valve disease, assess the systolic (and diastolic) function of the (left) ventricle, and detect intracardiac shunts. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease. [2003, amended 2018]\n\nTransthoracic echocardiography should be performed on high‑resolution equipment by experienced operators trained to the relevant professional standards. Need and demand for these studies should not compromise quality. [2003, amended 2018]\n\nEnsure that those reporting echocardiography are experienced in doing so. \n\nConsider alternative methods of imaging the heart (for example, radionuclide angiography [multigated acquisition scanning], cardiac MRI or transoesophageal echocardiography) if a poor image is produced by transthoracic echocardiography. [2003, amended 2018]\n\nPerform an ECG and consider the following tests to evaluate possible aggravating factors and/or alternative diagnoses:\n\nchest X-ray\n\nblood tests:\n\n\n\nrenal function profile\n\nthyroid function profile\n\nliver function profile\n\nlipid profile\n\nglycosylated haemoglobin (HbA1c)\n\nfull blood count\n\n\n\nurinalysis\n\npeak flow or spirometry. [2010, amended 2018]\n\nTry to exclude other disorders that may present in a similar manner. \n\nWhen a diagnosis of heart failure has been made, assess severity, aetiology, precipitating factors, type of cardiac dysfunction and correctable causes. \n\n## Heart failure caused by valve disease\n\nRefer people with heart failure caused by valve disease for specialist assessment and advice regarding follow-up. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease. \n\n## Reviewing existing diagnoses\n\nReview the basis for a historical diagnosis of heart failure, and manage care in accordance with this guideline only if the diagnosis is confirmed. \n\nIf the diagnosis of heart failure is still suspected, but confirmation of the underlying cardiac abnormality has not occurred, then the person should have appropriate further investigation. \n\n# Giving information to people with heart failure\n\nWhen giving information to people with heart failure, follow the recommendations in the NICE guideline on patient experience in adult NHS services. \n\nDiscuss the person's prognosis in a sensitive, open and honest manner. Be frank about the uncertainty in predicting the course of their heart failure. Revisit this discussion as the person's condition evolves. \n\nProvide information whenever needed throughout the person's care. \n\nConsider training in advanced communication skills for all healthcare professionals working with people who have heart failure. \n\n## First consultations for people newly diagnosed with heart failure\n\nThe specialist heart failure MDT should offer people newly diagnosed with heart failure an extended first consultation, followed by a second consultation to take place within 2\xa0weeks if possible. At each consultation:\n\ndiscuss the person's diagnosis and prognosis\n\nexplain heart failure terminology\n\ndiscuss treatments\n\naddress the risk of sudden death, including any misconceptions about that risk\n\nencourage the person and their family or carers to ask any questions they have. \n\n# Treating heart failure with reduced ejection fraction\n\nSee the section on managing all types of heart failure for general recommendations on managing all types of heart failure.\n\nSee NICE's technology appraisal guidance on dapagliflozin and empagliflozin for treating chronic heart failure with reduced ejection fraction.\n\nWhen managing pharmacological treatment, follow the recommendations in the NICE guidelines on medicines adherence and medicines optimisation.\n\n## First-line treatment\n\nOffer an angiotensin-converting enzyme (ACE) inhibitor and a beta‑blocker licensed for heart failure to people who have heart failure with reduced ejection fraction. Use clinical judgement when deciding which drug to start first. \n\nDo not offer ACE inhibitor therapy if there is a clinical suspicion of haemodynamically significant valve disease until the valve disease has been assessed by a specialist. See the section on referral for echocardiography and specialist assessment in the NICE guideline on heart valve disease. \n\nStart ACE inhibitor therapy at a low dose and titrate upwards at short intervals (for example, every 2\xa0weeks) until the target or maximum tolerated dose is reached. \n\nMeasure serum sodium and potassium, and assess renal function, before and 1 to 2\xa0weeks after starting an ACE inhibitor, and after each dose increment. [2010, amended 2018]\n\nMeasure blood pressure before and after each dose increment of an ACE inhibitor. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults. \n\nOnce the target or maximum tolerated dose of an ACE inhibitor is reached, monitor treatment monthly for 3\xa0months and then at least every 6\xa0months, and at any time the person becomes acutely unwell. [2010, amended 2018]\n\nConsider an ARB licensed for heart failure as an alternative to an ACE inhibitor for people who have heart failure with reduced ejection fraction and intolerable side effects with ACE inhibitors. \n\nMeasure serum sodium and potassium, and assess renal function, before and after starting an ARB and after each dose increment. [2010, amended 2018]\n\nMeasure blood pressure after each dose increment of an ARB. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults. \n\nOnce the target or maximum tolerated dose of an ARB is reached, monitor treatment monthly for 3\xa0months and then at least every 6\xa0months, and at any time the person becomes acutely unwell. [2010, amended 2018]\n\nIf neither ACE inhibitors nor ARBs are tolerated, seek specialist advice and consider hydralazine in combination with nitrate for people who have heart failure with reduced ejection fraction. \n\nDo not withhold treatment with a beta-blocker solely because of age or the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease. \n\nIntroduce beta-blockers in a 'start low, go slow' manner. Assess heart rate and clinical status after each titration. Measure blood pressure before and after each dose increment of a beta‑blocker. [2010,amended 2018]\n\nSwitch people whose condition is stable and who are already taking a beta-blocker for a comorbidity (for example, angina or hypertension), and who develop heart failure with reduced ejection fraction, to a beta-blocker licensed for heart failure. \n\nOffer an mineralocorticoid receptor antagonists (MRA), in addition to an ACE inhibitor (or ARB) and beta-blocker, to people who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure. \n\nMeasure serum sodium and potassium, and assess renal function, before and after starting an MRA and after each dose increment. \n\nMeasure blood pressure before and after after each dose increment of an MRA. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults. \n\nOnce the target, or maximum tolerated, dose of an MRA is reached, monitor treatment monthly for 3\xa0months and then at least every 6\xa0months, and at any time the person becomes acutely unwell. \n\n## Specialist treatment\n\nThese recommendations are from the NICE technology appraisal guidance on ivabradine for treating chronic heart failure.\n\nIvabradine is recommended as an option for treating chronic heart failure for people:\n\nwith New York Heart Association (NYHA) class\xa0II to IV stable chronic heart failure with systolic dysfunction and\n\nwho are in sinus rhythm with a heart rate of 75\xa0beats per minute (bpm) or more and\n\nwho are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta‑blocker therapy is contraindicated or not tolerated and\n\nwith a left ventricular ejection fraction of 35% or less. \n\nIvabradine should only be initiated after a stabilisation period of 4\xa0weeks on optimised standard therapy with ACE inhibitors, beta‑blockers and aldosterone antagonists. \n\nIvabradine should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be carried out by a heart failure specialist, or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse. \n\nThese recommendations are from the NICE technology appraisal guidance on sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction.\n\nSacubitril valsartan is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people:\n\nwith New York Heart Association (NYHA) class\xa0II to IV symptoms and\n\nwith a left ventricular ejection fraction of 35% or less and\n\nwho are already taking a stable dose of angiotensin‑converting enzyme (ACE) inhibitors or ARBs. \n\nTreatment with sacubitril valsartan should be started by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be performed by the most appropriate team member (see the section on team working in the management of heart failure). \n\nThis guidance is not intended to affect the position of patients whose treatment with sacubitril valsartan was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. \n\nSeek specialist advice and consider offering hydralazine in combination with nitrate (especially if the person is of African or Caribbean family origin and has moderate to severe heart failure [NYHA class III/IV] with reduced ejection fraction). \n\nFor recommendations on digoxin for people with atrial fibrillation see the section on rate and rhythm control in the NICE guideline on atrial fibrillation.\n\nDigoxin is recommended for worsening or severe heart failure with reduced ejection fraction despite first-line treatment for heart failure. Seek specialist advice before initiating. [2010, amended 2018]\n\nRoutine monitoring of serum digoxin concentrations is not recommended. A digoxin concentration measured within 8 to 12\xa0hours of the last dose may be useful to confirm a clinical impression of toxicity or non‑adherence. \n\nThe serum digoxin concentration should be interpreted in the clinical context as toxicity may occur even when the concentration is within the 'therapeutic range'. \n\n# Treating heart failure with reduced ejection fraction in people with chronic kidney disease\n\nFor people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR\xa0of 30\xa0ml/min/1.73\xa0m2 or above:\n\noffer the treatment outlined in the section on treating heart failure with reduced ejection fraction and\n\nif the person's eGFR is 45\xa0ml/min/1.73\xa0m2 or below, consider lower doses and/or slower titration of dose of ACE inhibitors or ARBs, MRAs and digoxin. \n\nFor people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR below 30\xa0ml/min/1.73\xa0m2, the specialist heart failure MDT should consider liaising with a renal physician. \n\nMonitor the response to titration of medicines closely in people who have heart failure with reduced ejection fraction and chronic kidney disease, taking into account the increased risk of hyperkalaemia. \n\n# Managing all types of heart failure\n\nWhen managing pharmacological treatment, follow the recommendations in the NICE guidelines on medicines adherence and medicines optimisation.\n\n## Pharmacological treatment\n\nDiuretics should be routinely used for the relief of congestive symptoms and fluid retention in people with heart failure, and titrated (up and down) according to need following the initiation of subsequent heart failure therapies. \n\nPeople who have heart failure with preserved ejection fraction should usually be offered a low to medium dose of loop diuretics (for example, less than 80\xa0mg furosemide per day). People whose heart failure does not respond to this treatment will need further specialist advice. [2003, amended 2018]\n\nAvoid verapamil, diltiazem and short-acting dihydropyridine agents in people who have heart failure with reduced ejection fraction. [2003, amended 2018]\n\nMake the decision to prescribe amiodarone in consultation with a specialist. \n\nReview the need to continue the amiodarone prescription at the 6‑monthly clinical review. [2003, amended 2018]\n\nOffer people taking amiodarone liver and thyroid function tests, and a review of side effects, as part of their routine 6‑monthly clinical review. [2003, amended 2018]\n\nFor people who have heart failure and atrial fibrillation, follow the recommendations on anticoagulation in the NICE guideline on atrial fibrillation. Be aware of the effects of impaired renal and liver function on anticoagulant therapies. \n\nIn people with heart failure in sinus rhythm, anticoagulation should be considered for those with a history of thromboembolism, left ventricular aneurysm or intracardiac thrombus. \n\n## Vaccinations\n\nOffer people with heart failure an annual vaccination against influenza. \n\nOffer people with heart failure vaccination against pneumococcal disease (only required once). \n\n## Contraception and pregnancy\n\nIn women of childbearing potential who have heart failure, contraception and pregnancy should be discussed. If pregnancy is being considered or occurs, specialist advice should be sought. Subsequently, specialist care should be shared between the cardiologist and obstetrician. \n\n## Depression\n\nSee NICE's guideline on depression in adults with a chronic physical health problem.\n\n## Lifestyle advice\n\nDo not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows:\n\nrestricting fluids for people with dilutional hyponatraemia\n\nreducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. \n\nAdvise people with heart failure to avoid salt substitutes that contain potassium. \n\nSee NICE's guidance on smoking and tobacco and alcohol.\n\nAir travel will be possible for the majority of people with heart failure, depending on their clinical condition at the time of travel. \n\nLarge Goods Vehicle and Passenger Carrying Vehicle licence: physicians should be up to date with the latest Driver and Vehicle Licensing Agency (DVLA) guidelines. Check the DVLA website for regular updates. \n\n# Monitoring treatment for all types of heart failure\n\nSee the section on treating heart failure with reduced ejection fraction for specific recommendations on monitoring treatment for heart failure with reduced ejection fraction.\n\n## Clinical review\n\nAll people with chronic heart failure need monitoring. This monitoring should include:\n\na clinical assessment of functional capacity, fluid status, cardiac rhythm (minimum of examining the pulse), cognitive status and nutritional status\n\na review of medication, including need for changes and possible side effects\n\nan assessment of renal function. Note: This is a minimum. People with comorbidities or co-prescribed medications will need further monitoring. Monitoring serum potassium is particularly important if a person is taking digoxin or an MRA. [2010, amended 2018]\n\nMore detailed monitoring will be needed if the person has significant comorbidity or if their condition has deteriorated since the previous review. \n\nThe frequency of monitoring should depend on the clinical status and stability of the person. The monitoring interval should be short (days to 2\xa0weeks) if the clinical condition or medication has changed, but is needed at least 6-monthly for stable people with proven heart failure. \n\nPeople with heart failure who wish to be involved in monitoring of their condition should be provided with sufficient education and support from their healthcare professional to do this, with clear guidelines as to what to do in the event of deterioration. \n\n## Measuring NT-proBNP\n\nConsider measuring NT-proBNP (N-terminal pro-B-type natriuretic peptide) as part of a treatment optimisation protocol only in a specialist care setting for people aged under 75 who have heart failure with reduced ejection fraction and an eGFR above 60\xa0ml/min/1.73\xa0m2. \n\n# Interventional procedures\n\n## Coronary revascularisation\n\nDo not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. \n\n## Cardiac transplantation\n\nSpecialist referral for transplantation should be considered for people with severe refractory symptoms or refractory cardiogenic shock. \n\n## Implantable cardioverter defibrillators and cardiac resynchronisation therapy\n\nSee NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.\n\nWhen discussing implantation of a cardioverter defibrillator:\n\nexplain the risks, benefits and consequences of cardioverter defibrillator implantation, following the principles on shared decision making in the NICE guideline on patient experience in adult NHS services\n\nensure the person knows that the defibrillator function can be deactivated without affecting any cardiac resynchronisation or pacing, and reactivated later\n\nexplain the circumstances in which deactivation might be offered\n\ndiscuss and dispel common misconceptions about the function of the device and the consequences of deactivation\n\nprovide the person and, if they wish, their family or carers with written information covering the information discussed. \n\nReview the benefits and potential harms of a cardioverter defibrillator remaining active in a person with heart failure:\n\nat each 6‑monthly review of their heart failure care\n\nwhenever their care goals change\n\nas part of advance care planning if it is thought they are nearing the end of life. \n\n# Cardiac rehabilitation\n\nOffer people with heart failure a personalised, exercise-based cardiac rehabilitation programme, unless their condition is unstable. The programme:\n\nshould be preceded by an assessment to ensure that it is suitable for the person\n\nshould be provided in a format and setting (at home, in the community or in the hospital) that is easily accessible for the person\n\nshould include a psychological and educational component\n\nmay be incorporated within an existing cardiac rehabilitation programme\n\nshould be accompanied by information about support available from healthcare professionals when the person is doing the programme. \n\n# Palliative care\n\nDo not offer long-term home oxygen therapy for advanced heart failure. Be aware that long-term home oxygen therapy may be offered for comorbidities, such as for some people with chronic obstructive pulmonary disease (see the section on oxygen in the NICE guideline on chronic obstructive pulmonary disease in over 16s). \n\nDo not use prognostic risk tools to determine whether to refer a person with heart failure to palliative care services. \n\nIf the symptoms of a person with heart failure are worsening despite optimal specialist treatment, discuss their palliative care needs with the specialist heart failure multidisciplinary team and consider a needs assessment for palliative care. \n\nPeople with heart failure and their families or carers should have access to professionals with palliative care skills within the heart failure team. \n\nIf it is thought that a person may be entering the last 2 to 3\xa0days of life, follow the NICE guideline on care of dying adults in the last days of life. \n\n# Terms used in this guideline\n\n## Heart failure with preserved ejection fraction\n\nThis is usually associated with impaired left ventricular relaxation, rather than left ventricular contraction, and is characterised by normal or preserved left ventricular ejection fraction with evidence of diastolic dysfunction .\n\n## Heart failure with reduced ejection fraction\n\nHeart failure with an ejection fraction below 40%.\n\n## Mineralocorticoid receptor antagonist\n\nA drug that antagonises the action of aldosterone at mineralocorticoid receptors.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "Heart failure is a complex clinical syndrome of symptoms and signs that suggest the efficiency of the heart as a pump is impaired. It is caused by structural or functional abnormalities of the heart. Around 920,000\xa0people in the UK today have been diagnosed with heart failure. Both the incidence and prevalence of heart failure increase steeply with age, and the average age at diagnosis is 77. Improvements in care have increased survival for people with ischaemic heart disease, and treatments for heart failure have become more effective. But the overall prevalence of heart failure is rising because of population ageing and increasing rates of obesity.\n\nUptake of NICE's 2010 guidance on chronic heart failure appears to be good. However, the Department of Health and Social Care's policy paper on improving cardiovascular disease outcomes: strategy noted that prescribing of ACE inhibitors, beta-blockers and aldosterone antagonists remains suboptimal, and that improved use of these drugs has the potential to reduce hospitalisations and deaths caused by heart failure. This update reviewed evidence on the clinical and cost effectiveness of these therapies.\n\nInterdisciplinary working has contributed to better outcomes in heart failure but there is further room to improve the provision of multidisciplinary teams (MDTs) and integrate them more fully into healthcare processes. This update highlights and further expands on the roles of the MDT and collaboration between the MDT and the primary care team.\n\nThe Department of Health and Social Care's policy paper on improving cardiovascular disease outcomes: strategy also noted that the proportion of people with heart failure who have cardiac rehabilitation was around 4%, and that increasing this proportion would reduce mortality and hospitalisation. This update recommends that all people with heart failure are offered an easily accessible, exercise-based cardiac rehabilitation programme, if this is suitable for them.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Diuretic therapy for managing fluid overload in people with advanced heart failure in the community\n\nIn people with advanced heart failure and significant peripheral fluid overload, what is the clinical and cost effectiveness of oral, subcutaneous and intravenous diuretic therapy in the community?\n\n## Why this is important\n\nThis research is critical to inform practice of how best to manage people with advanced heart failure in the community if they develop significant peripheral fluid overload. These people are more likely to have multiple admissions that, together with fluid overload, have a negative impact on their quality of life. Management in the community can minimise disruption for the person and reduce costs from hospital admissions. Knowledge of the most clinically and cost-effective routes of administration for diuretic therapy will dictate the level of resource needed to provide the service. Intravenous and subcutaneous diuretics usually need to be administered by nursing or healthcare staff. although a pump for self-administration of subcutaneous diuretics has recently been developed. Oral formulations can be self‑administered.\n\n# Cardiac MRI versus other imaging techniques for diagnosing heart failure\n\nWhat is the optimal imaging technique for the diagnosis of heart failure?\n\n## Why this is important\n\nThe role of cardiac MRI in the detection and characterisation of several structural and functional cardiac abnormalities has become well established over the past 25\xa0years. In people with heart failure, cardiac MRI provides reliable and reproducible assessments of the left ventricular (and to a degree the right ventricular) shapes, volumes and ejection fractions. It also provides spatial assessments of the congenital and acquired structural abnormalities of the heart and their interrelationships with the remainder of the heart, as well as functional and haemodynamic assessments of these abnormalities on the heart's performance. Finally, cardiac MRI provides valuable information about the myocardial structure and metabolism, including the presence of inflammation, scarring, fibrosis and infiltration. Cardiac MRI is an expensive form of imaging, and much of this diagnostic information could be provided by less costly non-invasive imaging techniques, chiefly echocardiography. This question aims to find the most clinically and cost-effective imaging technique for the clinical diagnosis of heart failure.\n\n# The impact of atrial fibrillation on the natriuretic peptide threshold for diagnosing heart failure\n\nWhat is the optimal NT‑proBNP threshold for the diagnosis of heart failure in people with atrial fibrillation?\n\n## Why this is important\n\nAtrial fibrillation is a common arrhythmia in the general population, and occurs in 30 to 40% of people with heart failure. Atrial fibrillation can raise the level of serum natriuretic peptides, including NT‑proBNP, even in the absence of heart failure. This is complicated further in heart failure with preserved ejection fraction, in which 2 echocardiographic diagnostic criteria become unreliable (the left atrial volume and the tissue doppler imaging assessment of diastolic function). These factors contribute to the complexity of the diagnosis and have a potential impact on the usual thresholds for NT‑proBNP in people who have atrial fibrillation. This has been recognised in several ongoing randomised controlled trials of heart failure, which are using higher NT‑proBNP thresholds for the diagnosis of heart failure in people with atrial fibrillation.\n\n# The impact of advanced kidney disease on the natriuretic peptide threshold for diagnosing heart failure\n\nWhat are the optimal NT‑proBNP thresholds for diagnosing heart failure in people with stage IIIb, IV or V chronic kidney disease?\n\n## Why this is important\n\nHeart failure incidence and prevalence increase with age, with the rise starting at age\xa065 and peaking between 75 and 85. Both advancing age and heart failure are associated with a gradual and progressive decline in renal function. In addition, the progression of heart failure and some treatments for heart failure lead to progressive deterioration of renal function. A decline in renal function is associated with increased fluid retention and a rise in the level of the serum natriuretic peptides, including NT‑proBNP, even in the absence of heart failure. There is some evidence that the use of higher NT‑proBNP thresholds would improve diagnostic accuracy for heart failure in people with significant deterioration of creatinine clearance.\n\n# Risk tools for predicting non-sudden death in heart failure\n\nWhat is the most accurate prognostic risk tool in predicting 1‑year mortality from heart failure at specific clinically relevant thresholds (for example, sensitivity, specificity, negative predictive value and positive predictive value at a threshold of 50% risk of mortality at 1\xa0year)?\n\n## Why this is important\n\nThere are a number of validated prognostic risk tools for heart failure but most do not report sensitivity and specificity at clinically relevant thresholds. This information is crucial to enable accurate prediction of a person's risk of mortality. The ability to accurately predict a person's prognosis would allow clearer communication and timely referral to other services such as palliative care. Inaccurate prediction has the potential to lead to significant psychological harm and increased morbidity."}
|
https://www.nice.org.uk/guidance/ng106
|
This guideline covers diagnosing and managing chronic heart failure in people aged 18 and over. It aims to improve diagnosis and treatment to increase the length and quality of life for people with heart failure.
|
2b7be971bfe557febad7d46cb81625c205a4db16
|
nice
|
Preventing suicide in community and custodial settings
|
Preventing suicide in community and custodial settings
This guideline covers ways to reduce suicide and help people bereaved or affected by suicides. It aims to:
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline should be read in conjunction with Public Health England's Local suicide prevention planning: a practice resource.
# Suicide prevention partnerships
Local authorities should work with local organisations to:
Set up a multi-agency partnership for suicide prevention. This could consist of a core group and a wider network of representatives.
Identify clear leadership for the partnership.
Ensure the partnership has clear terms of reference, based on a shared understanding that suicide can be prevented.
Ensure the partnership has clear governance and accountability structures. Include oversight from local health and care planning groups, for example health and wellbeing boards.
## Multi-agency partnerships in the community
Include representatives from the following in the partnership's core group:
clinical commissioning groups
local public health services
healthcare providers
social care services
voluntary and other third-sector organisations, including those used by people in high-risk groups
emergency services
criminal justice services
police and custody suites
people with personal experience of a suicide attempt, suicidal thoughts and feelings, or a suicide bereavement.
## Multi-agency partnerships in residential custodial and detention settings
Set up a multi-agency partnership for suicide prevention in residential custodial and detention settings. This could consist of a core group and a wider network of representatives. Ensure the partnership has:
clear leadership
clear terms of reference, based on a shared understanding that suicide can be prevented
clear governance and accountability structures.
Include representatives from the following in the partnership's core group:
governors or directors in residential custodial and detention settings
healthcare staff in residential custodial and detention settings
staff in residential custodial and detention settings
pastoral support services
voluntary and other third-sector organisations
escort custody services
liaison and diversion services
emergency services
-ffender management and resettlement services
people with personal experience of a suicide attempt, suicidal thoughts and feelings, or a suicide bereavement, to be selected according to local protocols.
Link the partnership with other relevant multi-agency partnerships in the community.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 1: multi-agency partnerships
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Suicide prevention strategies
Develop a multi-agency strategy based on the principles of the Department of Health and Social Care's suicide prevention strategy for England and other relevant strategies. It should emphasise that suicide is preventable, and it is safe to talk about it.
Identify clear leadership for the multi-agency strategy.
Consider how to measure activities to prevent suicide. Include the introduction of constructive, meaningful preventive activities (for example, education and physical activity) rather than focusing on suicide numbers alone.
Review local and national data on suicide and self-harm to ensure the strategy is as effective as possible (see recommendation 1.4.2).
Assess whether initiatives successfully adopted elsewhere are appropriate locally or can be adapted to local needs, or whether previously successful initiatives can be reintroduced.
Oversee provision and delivery of training and evaluate effectiveness.
## Multi-agency partnerships in the community
Consider collaborating with neighbouring local authorities to deliver a single strategy.
Consider advising local institutions and organisations on what to include in their contingency plans for responding to a suicide. This includes: schools, universities, further and higher education institutions, and workplaces.
## Multi-agency partnerships in residential custodial and detention settings
Identify and manage risk factors and behaviours that make suicide more likely.
Consider collaborating with neighbouring residential custodial and detention organisations to deliver a single strategy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention strategies .
Full details of the evidence and the committee's discussion are in evidence review 1: multi-agency partnerships.
Loading. Please wait.
# Suicide prevention action plans
Develop and implement a plan for suicide prevention and for after a suspected suicide. Ensure the approach can be adapted according to which agencies are likely to spot emerging suicide clusters:
Identify clear leadership for the action plan.
Interpret data to determine local patterns of suicide and self-harm, particularly among groups at high suicide risk.
Compare local patterns with national trends.
Prioritise actions based on the joint strategic needs assessment and other local data to ensure the plan is tailored to local needs.
Map stakeholders and their suicide prevention activities (including support services for groups at high risk).
Share experience and knowledge between stakeholders. Also share data, subject to local information sharing agreements.
Keep up to date with suicide prevention activities by organisations in neighbouring settings.
Oversee local suicide prevention activities, including awareness raising and crisis planning.
Review the action plan at a time agreed at the outset by the multi-agency partnership.
## Multi-agency partnerships in the community
In addition to recommendation 1.3.1, set out how to:
Promote evidence-based best practice with rail, tram and underground train companies.
Work with planners who have responsibility for designing bridges, multi-storey car parks and other structures that could potentially pose a suicide risk.
Collaborate with coroners to provide a context for local suicide data and help interpret inquest conclusions.
Build relationships with the media (including social media, broadcasting and newspapers) to promote best practice when reporting suicides or suspected suicides.
## Multi-agency partnerships in residential custodial and detention settings
In addition to recommendation 1.3.1, set out how to:
Work with the Prison and Probation Ombudsman and coroners to ensure recommendations from investigations and inquests are implemented.
Implement recommendations from internal investigations of instances of self-harm.
Assess suicide and self-harm prevention procedures (for example, HM Prison and Probation Service's Assessment Care in Custody and Teamwork and Assessment care-planning system, and the Home Office's Assessment Care in Detention and Teamwork case management systems).
Interpret and act on the findings.
Ensure systems for identifying risk, information sharing and multidisciplinary working put the emphasis on 'early days' and transitions between estates or into the community.
Monitor the impact of restricted regimes on suicide risk.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention action plans .
Full details of the evidence and the committee's discussion are in:
evidence review 2: local suicide plans
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Gathering and analysing suicide-related information
Use routinely collected data from sources such as Public Health England's Fingertips tool (public health profiles) or HM Prisons and Probation Service.
Collect and analyse local data on suicide and self-harm. This could include data on: method, location, timing, details of individual and local circumstances, demographics, occupation and characteristics protected under the Equality Act 2010. Sources could include reports from:
the local ombudsman
the Parliamentary and Health Service Ombudsman
coroners
the Prison and Probation Ombudsman
the voluntary sector.
For community settings, also use rapid intelligence gathering (continuous and timely collection of data) to identify suspected suicides, emerging methods and potential suicide clusters. This intelligence could also be used to identify people who need support after such events (see recommendation 1.8.1 and recommendation 1.9.1). Collect this local data from a range of sources including:
police and transport police
prisons
immigration removal centres (IRCs)
coroners.
For residential custodial and detention settings, also collect data on:
sentencing or placement patterns
sentence type
-ffence
length of detention
transition periods (for example, 'early days' and transitions between estates or into the community).
Assess the quality of data from each local source to ensure data collection is robust and consistent.
Ensure staff gathering and analysing this information are given resilience training and other support as needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on gathering and analysing suicide-related information .
Full details of the evidence and the committee's discussion are in:
evidence review 1: multi-agency partnerships
evidence review 2: local suicide plans
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Awareness raising by suicide prevention partnerships
Consider local activities to:
raise community awareness of the scale and impact of suicide and self-harm
reduce the stigma around suicide and self-harm
address common misconceptions by emphasising that:
suicide is not inevitable and can be prevented
asking someone about suicidal thoughts does not increase risk
make people aware of the support available nationally and locally
encourage help-seeking behaviours
encourage communities to recognise and respond to a suicide risk.
For residential custodial and detention settings, also consider raising awareness of:
the risk associated with 'early days' and transitions between estates or into the community
the value of peer support, for example the Samaritans' Listener scheme
the need for institutional support, such as safer custody teams (see HM Prisons and Probation Service and the Ministry of Justice's Prison Service Instructions 2011 on the management of prisoners at risk of harm to self, to others and from others).
Take into account socioeconomic deprivation, disability, physical and mental health status, and cultural, religious and social norms about suicide and help-seeking behaviour, particularly among groups at high suicide risk.
Ensure the language and content of any awareness-raising materials is:
appropriate for the target group
sensitive and compliant with media reporting guidelines, such as the Samaritans' media guidelines for the reporting of suicide.
Coordinate local activities and ensure they are consistent, and coordinated, with national initiatives.
Consider encouraging employers to develop policies to raise suicide awareness and provide support after a suspected suicide. For example, see Public Health England and Business in the Community's toolkits.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on awareness raising by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 8: suicide awareness campaigns
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Reducing access to methods of suicide
Use local data including audit, Office for National Statistics and NHS data, as well as rapid intelligence gathering to:
identify emerging trends in suicide methods and locations
understand local characteristics that may influence the methods used
determine when to take action to reduce access to the means of suicide.
Ensure local compliance with national guidance to reduce access to methods of suicide:
In custodial settings, for example, provide safer cells (see the Ministry of Justice's Quick-time learning bulletin on safer cells).
In the community, for example, restrict access to painkillers (see NHS England's Items which should not be routinely prescribed in primary care: guidance for CCGs, the Medicines and Healthcare products Regulatory Agency's Best practice guidance on the sale of medicines for pain relief (appendix 4 in the Blue guide), and the Faculty of Pain Medicine's Opioids Aware resource).
Reduce the opportunity for suicide in locations where suicide is more likely, for example, by erecting physical barriers. Also see Public Health England's Preventing suicide in public places: a practice resource.
Consider other measures to reduce the opportunity for suicide. For example, at locations where suicide is more likely, consider:
providing information about how and where people can get help when they feel unable to cope
using CCTV or other surveillance to allow staff to monitor when someone may need help
increasing the number and visibility of staff, or times when staff are available.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on how suicide prevention partnerships can reduce access to methods of suicide .
Full details of the evidence and the committee's discussion are in:
evidence review 6: reducing access to means
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Training by suicide prevention partnerships
Ensure training is available for:
those in contact with people or groups at high suicide risk
people working at locations where suicide is more likely
gatekeepers
people who provide peer support in residential custodial and detention settings
people leading suicide prevention partnerships
people supporting those bereaved by suicide.
Offer training to organisations employing, working with or representing groups at high suicide risk.
Provide generic and specialist training as needed for specialists and non-specialists.
Ensure suicide awareness and prevention training helps people to:
understand local suicide incidence and its impact, and know what support services are available
encourage others to talk openly about suicidal thoughts and to seek help (this includes providing details of where they can get this help)
take into account socioeconomic deprivation, disability, physical and mental health status, and cultural, religious and social norms about suicide and help-seeking behaviour, particularly among groups at high suicide risk.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on training by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 4: information, advice, education and training
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Supporting people bereaved or affected by a suspected suicide
Use rapid intelligence gathering and data from other sources, such as coroners to identify anyone who may be affected by a suspected suicide or may benefit from bereavement support. Those affected may include relatives, friends, classmates, colleagues, other prisoners or detainees, as well as first responders and other professionals who provided support.
Offer those who are bereaved or affected by a suspected suicide practical information expressed in a sensitive way, such as Public Health England's Help is at hand guide (this also signposts to other services). Ask them if they need more help and, if so, offer them tailored support.
Consider:
providing support from trained peers who have been bereaved or affected by a suicide or suspected suicide
whether any adjustments are needed to working patterns or the regime in residential custodial and detention settings.See also the National Suicide Prevention Alliance's resources on support after a suicide.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on how suicide prevention partnerships can support people bereaved or affected by a suspected suicide .
Full details of the evidence and the committee's discussion are in:
evidence review 5: interventions to support people bereaved or affected by a suspected suicide
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Preventing and responding to suicide clusters
Use information from the action plan and rapid intelligence gathering to identify and prevent potential suicide clusters (see recommendation 1.3.1).
After a suspected suicide in residential custodial and detention settings, undertake a serious incident review as soon as possible in partnership with the health providers. Identify how:
to improve the suicide prevention action plan
to help identify emerging clusters
-thers have responded to clusters.
Develop a coordinated approach to reduce the risk of additional suicides.
Develop a standard procedure for reducing, or 'stepping down', responses to any suspected suicide cluster.
Provide ongoing support for those involved, including people directly bereaved or affected and those who are responding to the situation.See Public Health England's identifying and responding to suicide clusters and contagion: a practice resource.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on preventing and responding to suicide clusters .
Full details of the evidence and the committee's discussion are in:
evidence review 3: local approaches to suicide clusters
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Reducing the potential harmful effects of media reporting of a suspected suicide
Develop a clear plan for liaising with the media. Identify someone in the multi-agency partnership as the lead.
For community settings, promote guidance on best practice for media reporting of suicide (including providers of social media platforms). Highlight the need to:
use sensitive language that is not stigmatising or in any other way distressing to people who have been affected
reduce speculative reporting
avoid presenting detail on methods. See: the World Health Organization's preventing suicide: a resource for media professionals, the Samaritans' media guidelines for reporting suicide, OFCOM's Broadcasting code and the Independent Press Standards Organisation (IPSO).
For residential custodial and detention settings, where a suspected suicide would be reported via the Ministry of Justice, ensure Ministry of Justice press officers follow good practice in suicide reporting.
Monitor media coverage of suspected suicides locally. If necessary, provide feedback to the journalist or editor in relation to their reporting (see the Samaritans' media guidelines for reporting suicide).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on reducing the potential harmful effects of media reporting of a suspected suicide .
Full details of the evidence and the committee's discussion are in evidence review 7: local media reporting of suicides.
Loading. Please wait.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.
## Gatekeepers
People in groups that have contact, because of their paid or voluntary work, with people at risk of suicide. People in these groups may be trained to identify people at risk of suicide and refer them to treatment or supporting services as appropriate.
They may include: health and social care practitioners, criminal justice and detention settings staff, police and emergency services, people who provide a paid or voluntary service for the public, faith leaders, railway and underground station staff, and staff in educational institutions.
## High suicide risk
High suicide risk means that the rate of suicide in a group or setting is higher than the expected rate based on the general population in England. Groups at high risk can include: young and middle-aged men, people who self-harm, people in care of mental health services, family and friends of those who have died by suicide, people who misuse drugs or alcohol, people with a physical illness, particularly older adults, people in the LGBT community, people with autism, people in contact with the criminal justice system, particularly those in prisons, people in detention settings, including immigration detention settings, and specific occupation groups (see the Office for National Statistics' suicide by occupation, England: 2011 to 2015).
## Locations where suicide is more likely
These include high buildings such as multi-storey car parks, railways and bridges and places where other means of suicide are accessible, such as medical, veterinary or agricultural settings where human or animal drugs may be readily available. See Public Health England's preventing suicides in public places: a practice resource.
## Restricted regimes
Reduced access to time out of cell and purposeful activity, usually as a result of short staffing or serious incidents.
## Suicide clusters
A series of 3 or more closely grouped deaths linked by space or social relationships. In the absence of transparent social connectedness, evidence of space and time linkages are needed to define a cluster. In the presence of a strong demonstrated social connection, only temporal significance is needed. (Adapted from Public Health England's identifying and responding to suicide clusters and contagion: a practice resource.)# Recommendations for research
The guideline committee has made the following recommendations for research.
# Non-clinical interventions
How effective and cost effective are non-clinical interventions to reduce suicidal behaviours?
For a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 8: suicide awareness campaigns
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Supporting people bereaved or affected by a suicide
How effective and cost effective are interventions to support people in the community who are bereaved or affected by a suicide?
For a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 5: interventions to support people bereaved or affected by a suspected suicide
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
For a short explanation of why the committee made this recommendation for research, see the rationale section on how suicide prevention in custodial and detention settings .
Full details of the evidence and the committee's discussion are in:
evidence review 5: interventions to support people bereaved or affected by a suspected suicide
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Suicide prevention in custodial and detention settings
What interventions are effective and cost effective in reducing suicide rates in custodial and residential settings?
For a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 8: suicide awareness campaigns
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.
# Training
How effective and cost effective is gatekeeper training in preventing suicides?
For a short explanation of why the committee made this recommendation for research, see the rationale section on training by suicide prevention partnerships .
Full details of the evidence and the committee's discussion are in:
evidence review 4: information, advice, education and training
evidence review 9: preventing suicides in residential custodial and detention settings.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Suicide prevention partnerships
Recommendations 1.1.1 to 1.1.6
## Why the committee made the recommendations
Approximately 6,000 people take their own life each year in the UK. The risk of suicide in the UK prison population is considerably higher than among the general population. The number of people dying by suicide in custodial or other detention settings such as prisons, immigration detention centres, young offender institutions and police custody has increased over the past decade.
Many local agencies can be involved in preventing suicide in the community. Although the evidence was limited, the committee felt strongly that these agencies need to work together to focus on the most effective and cost-effective interventions. By combining expertise and resources, partnerships can cover a much wider area more effectively and implement a range of activities.
Likewise, different services within residential custodial and detention settings can be more effective if they work together in a local multi-agency partnership and with similar partnerships in the community.
## How the recommendations might affect practice
Improved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.
But multi-agency partnership working is already enshrined in the Department of Health and Social Care's suicide prevention strategy for England, updated in the Department of Health and Social Care's suicide prevention: third annual report. As a result, multi-agency suicide prevention partnerships have been set up in most community and residential custodial and detention settings, so no additional costs are expected.
Return to recommendations
# Suicide prevention strategies
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
Some evidence and expert opinion showed that having a strategy for how to connect local organisations can help prevent suicide in community and residential custodial and detention settings. For general reasons why we have made the recommendations, see the rationale section on suicide prevention partnerships.
If the strategy has clear leadership and is based on what is currently happening in the area or setting, it is likely to be effective. This involves gathering data on suicide rates and sharing best practice. A strategy may also help to ensure organisations are prepared to respond to a suicide.
Expert opinion showed that when partnerships share knowledge and experience, this is of greater benefit than working individually. It may include collaborating with neighbouring organisations in the same setting to develop a shared strategy.
## How the recommendations might affect practice
Improved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.
But the Department of Health and Social Care's suicide prevention strategy for England advocates multi-agency partnerships, and suicide prevention strategies have been set up in most community and residential custodial and detention settings. So no additional costs are expected.
Return to recommendations
# Suicide prevention action plans
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
Having a detailed action plan based on local knowledge and clear leadership can help prevent suicide in the community and in residential custodial or detention settings. The plan will be effective if it is based on knowledge of what is happening in the area or setting, involves stakeholders and is adaptable. (For general reasons why we have made the recommendations, see the rationale section on suicide prevention partnerships.)
## How the recommendations might affect practice
Multi-agency suicide prevention action plans have been set up in most community and residential custodial and detention settings, so no additional costs are expected. For example, Public Health England's Suicide Prevention Profile shows which local authorities have suicide prevention plans.
Return to recommendations
# Gathering and analysing suicide-related information
Recommendations 1.4.1 to 1.4.6
## Why the committee made the recommendations
Good information is essential for planning, monitoring success and improving the strategy and plan for all settings. The committee agreed that the information should come from different sources to get a clear picture of what is happening. But they also agreed that it is important to make sure the local data collected is as reliable as possible, so that the strategy and plan is as effective as possible.
Although the evidence was limited, the committee agreed with an expert that more rapid and frequent information gathering (rapid intelligence gathering) is important, for example for early detection of suicide clusters.
The committee also agreed that because analysing information on suicides may expose staff to some distressing material, training and support is essential to help them cope.
## How the recommendations might affect practice
Gathering and analysing data may involve some additional resources. But most multi-agency suicide prevention partnerships have some work already in place. So we do not expect this will have a significant resource impact.
Return to recommendations
# Awareness raising by suicide prevention partnerships
Recommendations 1.5.1 to 1.5.6
## Why the committee made the recommendations
Many people who take their own lives are not in contact with mental health services and may not necessarily be in contact with a GP, so opportunities for clinical interventions can be limited. Non-clinical interventions, such as telephone or text helplines or volunteer-run face-to-face talking are important to support people with suicidal thoughts and keep them safe.
There is increasing demand for non-clinical interventions but little evidence on the benefits. Research is needed to evaluate how effective they are (see the recommendation for research on non-clinical interventions).
The committee agreed that awareness-raising activities and messages, tailored to people's needs and circumstances, can help get rid of common misconceptions about suicide and self-harm and let people know where they can go for help. They also agreed that increasing local awareness of suicide and the support available is likely to encourage people to seek help. But there can be a fine line between helpful and potentially harmful messages (see the recommendation for research on supporting people bereaved or affected by a suicide).
In residential custodial and detention settings, they agreed that extra support during particularly vulnerable times, such as 'early days', might reduce the risk of suicide. Peer support, along with measures such as the provision of 'safer cells', might also help to act as deterrents. But there is a lack of evidence and more research is needed to evaluate the effectiveness of different interventions in a range of custodial settings (see the recommendation for research on suicide prevention in custodial and detention settings).
## How the recommendations might affect practice
Increasing local awareness of suicide and the support available could encourage more people to seek help and so increase health and social care costs.
Return to recommendations
# How suicide prevention partnerships can reduce access to methods of suicide
Recommendations 1.6.1 to 1.6.4
## Why the committee made the recommendations
The committee agreed that it is important to identify local suicide trends, including common methods and locations where suicide is more likely, such as bridges and railway stations. That way action can be taken to reduce people's access to both the methods and places.
Physical barriers like fences and netting could reduce the number of suicide deaths in places where suicide is more likely because it makes it more difficult for people to put themselves in danger. Evidence showed that if a barrier stops a person from taking their life in one place, they will not automatically go somewhere else and try again.
Similarly, compliance with national guidance, for example on safer cells in custodial settings (see the Ministry of Justice's Quick-time learning bulletin on safer cells) and restrictions on painkiller sales in the community can act as an effective deterrent.
The committee agreed that, despite the lack of evidence, it may be worth thinking about implementing these measures because they can sometimes give people time to stop and think – and so may prevent deaths. The presence of staff at high-risk locations may also give people a chance to reconsider, as well as being a source of timely support.
## How the recommendations might affect practice
Where physical barriers or other measures are needed this may have a resource impact in terms of staff time and construction and maintenance costs. NICE has an implementation tool to help determine the cost effectiveness of different interventions.
Return to recommendations
# Training by suicide prevention partnerships
Recommendations 1.7.1 to 1.7.4
## Why the committee made the recommendations
Some evidence showed that training improves people's knowledge about suicide, the risks and how to prevent it. The committee agreed that it may be effective to train a range of people involved with both the public and with occupational groups known to be at high risk of suicide. That way they can help spread general prevention messages and encourage people at risk to talk and seek help.
But UK evidence on the effectiveness of gatekeeper training is limited and there are only a few specific training programmes available. Training for all gatekeepers is important because it may help to identify more people at risk of suicide. But research is needed to evaluate how effective it is (see the recommendation for research on training).
## How the recommendations might affect practice
Training can be costly. But it is expected to be made available through existing continuous professional development programmes, so the costs for professionals and organisations could be minimised. For example, Health Education England has developed generic and specialist competencies for people working with adults and children with suicidal behaviour or ideas, and for non-specialists working in community settings.
Return to recommendations
# How suicide prevention partnerships can support people bereaved or affected by a suspected suicide
Recommendations 1.8.1 to 1.8.3
## Why the committee made the recommendations
The committee agreed that people affected by a suspected suicide may, as a result, be at risk of harming themselves. This includes family members and friends of people who have died, as well as first responders.
The committee heard that bereavement support can reduce this risk, especially when tailored to the person's needs. People who had bereavement support were also likely to experience lower levels of depression and anxiety. Some of these benefits were based on personal accounts because the evidence was limited.
Some services have been developed locally to provide this type of support. But because there is very little evidence on the benefits, local authorities are reluctant to commission such services. Research is needed to build an evidence base on these interventions for people in the community so that effective and cost-effective statutory and voluntary services can be developed (see the recommendation for research on supporting people bereaved or affected by a suicide).
## How the recommendations might affect practice
The committee recognised that providing support for people affected by suicide may be cost effective from a societal perspective, when the costs of productivity losses are taken into account. However, because of the lack of evidence this supposition needs to be treated with caution.
Return to recommendations
# Preventing and responding to suicide clusters
Recommendations 1.9.1 to 1.9.5
## Why the committee made the recommendations
Suicide clusters can emerge quickly and unexpectedly. But an expert told the committee that if the right systems are in place, then it is possible to reduce the likelihood of further deaths.
This was supported by the committee's own experience. An expert also explained to the committee that the police and the coroner's office need to notify agencies as soon as possible when a suspected suicide is being investigated. That is because an inquest to confirm cause of death is usually only held 6 to 12 months after the event. This is too late to prevent new suicide deaths if a cluster is developing. Residential custodial and detention settings have a duty to undertake and learn from reviews of incidents of self-harm to prevent future occurrences and make custody safer.
Based on this information and their own experience, the committee agreed that rapid intelligence sharing is important.
## How the recommendations might affect practice
Improved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.
Return to recommendations
# Reducing the potential harmful effects of media reporting of a suspected suicide
Recommendations 1.10.1 to 1.10.4
## Why the committee made the recommendations
Irresponsible reporting of suicide may have harmful effects, including potentially increasing the risk of suicide.
Reports of the method used in a suspected suicide seems to increase the risk of other people copying the suicide – so‑called copycat suicides. And inaccurate media reporting upsets people bereaved by suicide. So steps to encourage responsible reporting could prevent further suicide deaths.
Although there was little evidence on the personal effect of suicide or suicidal behaviour being shared through social media, the committee agreed that the guidance given to the media should also apply to social media.
To combat the harmful effects of irresponsible reporting, the committee agreed that it is important to promote best practice and also monitor media coverage.
## How the recommendations might affect practice
Providing training for journalists may have cost implications. But better reporting generally has beneficial outcomes.
Return to recommendations# Context
The UK suicide rate was 10.4 deaths per 100,000 population in 2016 (see the Office for National Statistics suicides in the UK: 2016 registrations). Suicide is more than 3 times as common in men as in women. People aged 40 to 44 had the highest suicide rate at 15.3 per 100,000. This age group also had the highest rate among men, at 24.1 per 100,000. For women, 50- to 54‑year‑olds had the highest rate of 8.3 per 100,000.
Overall, the financial cost of someone of working age dying by suicide in the UK is more than £1.6 million (Evaluation of the first phase of Choose Life: the national strategy and action plan to prevent suicide in Scotland Scottish Executive Social Research).
The risk of suicide in the UK prison population is considerably higher than among the general population. The 3-year average rate of self-inflicted deaths by people in prison in England was 69 per 100,000 between 2009 and 2011; approximately 80% received a suicide or open verdict at inquest. There were 62 'apparent suicides following police custody' during 2013/14 in England and 119 deaths by suicide in prison in England and Wales in 2016.
Suicide and self-harm are major public health problems, with someone who self-harms being at increased risk of suicide (see the Department of Health and Social Care's Chief Medical Officer annual report 2013: public mental health priorities). Approximately three-quarters of people who die by suicide have not had recent contact with mental health services at the time of their death. However, many may have seen their GP in the year before they died and others may have been seen in A&E or another setting.
People at risk of dying by suicide may come into contact with a wide range of professionals and others. The Department of Health and Social Care's suicide prevention strategy for England and the House of Commons report on the government's suicide prevention strategy highlight the potential role of the community in preventing suicide. For example, people can make contact with suicide prevention services through helplines and support groups (offered by charities such as Samaritans), or they can speak to a GP.
This guideline covers people of all ages but focuses particularly on groups with high suicide risk.
It also looks at interventions for people who are, or have been in custodial settings, and those in contact with any branch of the criminal justice system.
Suicide prevention in mental health settings is not covered by this guideline. For further information on preventing suicide in mental health services see the reports from the University of Manchester's National Confidential Inquiry into Suicide and Safety in Mental Health.# Finding more information and resources
To find NICE guidance on related topics, including guidance in development, see the NICE topic pages on depression, self-harm, alcohol-use disorders, drug misuse and prisons and other secure settings.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
ISBN: 978-1-4731-3086-9
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read in conjunction with Public Health England's\xa0Local suicide prevention planning: a practice resource.\n\n# Suicide prevention partnerships\n\nLocal authorities should work with local organisations to:\n\nSet up a multi-agency partnership for suicide prevention. This could consist of a core group and a wider network of representatives.\n\nIdentify clear leadership for the partnership.\n\nEnsure the partnership has clear terms of reference, based on a shared understanding that suicide can be prevented.\n\nEnsure the partnership has clear governance and accountability structures. Include oversight from local health and care planning groups, for example health and wellbeing boards.\n\n## Multi-agency partnerships in the community\n\nInclude representatives from the following in the partnership's core group:\n\nclinical commissioning groups\n\nlocal public health services\n\nhealthcare providers\n\nsocial care services\n\nvoluntary and other third-sector organisations, including those used by people in high-risk groups\n\nemergency services\n\ncriminal justice services\n\npolice and custody suites\n\npeople with personal experience of a suicide attempt, suicidal thoughts and feelings, or a suicide bereavement.\n\n## Multi-agency partnerships in residential custodial and detention settings\n\nSet up a multi-agency partnership for suicide prevention in residential custodial and detention settings. This could consist of a core group and a wider network of representatives. Ensure the partnership has:\n\nclear leadership\n\nclear terms of reference, based on a shared understanding that suicide can be prevented\n\nclear governance and accountability structures.\n\nInclude representatives from the following in the partnership's core group:\n\ngovernors or directors in residential custodial and detention settings\n\nhealthcare staff in residential custodial and detention settings\n\nstaff in residential custodial and detention settings\n\npastoral support services\n\nvoluntary and other third-sector organisations\n\nescort custody services\n\nliaison and diversion services\n\nemergency services\n\noffender management and resettlement services\n\npeople with personal experience of a suicide attempt, suicidal thoughts and feelings, or a suicide bereavement, to be selected according to local protocols.\n\nLink the partnership with other relevant multi-agency partnerships in the community.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: multi-agency partnerships\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Suicide prevention strategies\n\nDevelop a multi-agency strategy based on the principles of the Department of Health and Social Care's suicide prevention strategy for England and other relevant strategies. It should emphasise that suicide is preventable, and it is safe to talk about it.\n\nIdentify clear leadership for the multi-agency strategy.\n\nConsider how to measure activities to prevent suicide. Include the introduction of constructive, meaningful preventive activities (for example, education and physical activity) rather than focusing on suicide numbers alone.\n\nReview local and national data on suicide and self-harm to ensure the strategy is as effective as possible (see recommendation 1.4.2).\n\nAssess whether initiatives successfully adopted elsewhere are appropriate locally or can be adapted to local needs, or whether previously successful initiatives can be reintroduced.\n\nOversee provision and delivery of training and evaluate effectiveness.\n\n## Multi-agency partnerships in the community\n\nConsider collaborating with neighbouring local authorities to deliver a single strategy.\n\nConsider advising local institutions and organisations on what to include in their contingency plans for responding to a suicide. This includes: schools, universities, further and higher education institutions, and workplaces.\n\n## Multi-agency partnerships in residential custodial and detention settings\n\nIdentify and manage risk factors and behaviours that make suicide more likely.\n\nConsider collaborating with neighbouring residential custodial and detention organisations to deliver a single strategy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention strategies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review 1: multi-agency partnerships.\n\nLoading. Please wait.\n\n# Suicide prevention action plans\n\nDevelop and implement a plan for suicide prevention and for after a suspected suicide. Ensure the approach can be adapted according to which agencies are likely to spot emerging suicide clusters:\n\nIdentify clear leadership for the action plan.\n\nInterpret data to determine local patterns of suicide and self-harm, particularly among groups at high suicide risk.\n\nCompare local patterns with national trends.\n\nPrioritise actions based on the joint strategic needs assessment and other local data to ensure the plan is tailored to local needs.\n\nMap stakeholders and their suicide prevention activities (including support services for groups at high risk).\n\nShare experience and knowledge between stakeholders. Also share data, subject to local information sharing agreements.\n\nKeep up to date with suicide prevention activities by organisations in neighbouring settings.\n\nOversee local suicide prevention activities, including awareness raising and crisis planning.\n\nReview the action plan at a time agreed at the outset by the multi-agency partnership.\n\n## Multi-agency partnerships in the community\n\nIn addition to recommendation\xa01.3.1, set out how to:\n\nPromote evidence-based best practice with rail, tram and underground train companies.\n\nWork with planners who have responsibility for designing bridges, multi-storey car parks and other structures that could potentially pose a suicide risk.\n\nCollaborate with coroners to provide a context for local suicide data and help interpret inquest conclusions.\n\nBuild relationships with the media (including social media, broadcasting and newspapers) to promote best practice when reporting suicides or suspected suicides.\n\n## Multi-agency partnerships in residential custodial and detention settings\n\nIn addition to recommendation\xa01.3.1, set out how to:\n\nWork with the Prison and Probation Ombudsman and coroners to ensure recommendations from investigations and inquests are implemented.\n\nImplement recommendations from internal investigations of instances of self-harm.\n\nAssess suicide and self-harm prevention procedures (for example, HM Prison and Probation Service's Assessment Care in Custody and Teamwork and Assessment care-planning system, and the Home Office's Assessment Care in Detention and Teamwork case management systems).\n\nInterpret and act on the findings.\n\nEnsure systems for identifying risk, information sharing and multidisciplinary working put the emphasis on 'early days' and transitions between estates or into the community.\n\nMonitor the impact of restricted regimes on suicide risk.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on suicide prevention action plans\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 2: local suicide plans\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Gathering and analysing suicide-related information\n\nUse routinely collected data from sources such as Public Health England's Fingertips tool (public health profiles) or HM Prisons and Probation Service.\n\nCollect and analyse local data on suicide and self-harm. This could include data on: method, location, timing, details of individual and local circumstances, demographics, occupation and characteristics protected under the Equality Act 2010. Sources could include reports from:\n\nthe local ombudsman\n\nthe Parliamentary and Health Service Ombudsman\n\ncoroners\n\nthe Prison and Probation Ombudsman\n\nthe voluntary sector.\n\nFor community settings, also use rapid intelligence gathering (continuous and timely collection of data) to identify suspected suicides, emerging methods and potential suicide clusters. This intelligence could also be used to identify people who need support after such events (see recommendation\xa01.8.1 and recommendation 1.9.1). Collect this local data from a range of sources including:\n\npolice and transport police\n\nprisons\n\nimmigration removal centres (IRCs)\n\ncoroners.\n\nFor residential custodial and detention settings, also collect data on:\n\nsentencing or placement patterns\n\nsentence type\n\noffence\n\nlength of detention\n\ntransition periods (for example, 'early days' and transitions between estates or into the community).\n\nAssess the quality of data from each local source to ensure data collection is robust and consistent.\n\nEnsure staff gathering and analysing this information are given resilience training and other support as needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on gathering and analysing suicide-related information\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: multi-agency partnerships\n\nevidence review 2: local suicide plans\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Awareness raising by suicide prevention partnerships\n\nConsider local activities to:\n\nraise community awareness of the scale and impact of suicide and self-harm\n\nreduce the stigma around suicide and self-harm\n\naddress common misconceptions by emphasising that:\n\n\n\nsuicide is not inevitable and can be prevented\n\nasking someone about suicidal thoughts does not increase risk\n\n\n\nmake people aware of the support available nationally and locally\n\nencourage help-seeking behaviours\n\nencourage communities to recognise and respond to a suicide risk.\n\nFor residential custodial and detention settings, also consider raising awareness of:\n\nthe risk associated with 'early days' and transitions between estates or into the community\n\nthe value of peer support, for example the Samaritans' Listener scheme\n\nthe need for institutional support, such as safer custody teams (see HM Prisons and Probation Service and the Ministry of Justice's Prison Service Instructions 2011 on the management of prisoners at risk of harm to self, to others and from others).\n\nTake into account socioeconomic deprivation, disability, physical and mental health status, and cultural, religious and social norms about suicide and help-seeking behaviour, particularly among groups at high suicide risk.\n\nEnsure the language and content of any awareness-raising materials is:\n\nappropriate for the target group\n\nsensitive and compliant with media reporting guidelines, such as the Samaritans' media guidelines for the reporting of suicide.\n\nCoordinate local activities and ensure they are consistent, and coordinated, with national initiatives.\n\nConsider encouraging employers to develop policies to raise suicide awareness and provide support after a suspected suicide. For example, see Public Health England and Business in the Community's toolkits.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on awareness raising by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 8: suicide awareness campaigns\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Reducing access to methods of suicide\n\nUse local data including audit, Office for National Statistics and NHS data, as well as rapid intelligence gathering to:\n\nidentify emerging trends in suicide methods and locations\n\nunderstand local characteristics that may influence the methods used\n\ndetermine when to take action to reduce access to the means of suicide.\n\nEnsure local compliance with national guidance to reduce access to methods of suicide:\n\nIn custodial settings, for example, provide safer cells (see the Ministry of Justice's Quick-time learning bulletin on safer cells).\n\nIn the community, for example, restrict access to painkillers (see NHS England's Items which should not be routinely prescribed in primary care: guidance for CCGs, the Medicines and Healthcare products Regulatory Agency's Best practice guidance on the sale of medicines for pain relief (appendix\xa04 in the Blue guide), and the Faculty of Pain Medicine's Opioids Aware resource).\n\nReduce the opportunity for suicide in locations where suicide is more likely, for example, by erecting physical barriers. Also see Public Health England's Preventing suicide in public places: a practice resource.\n\nConsider other measures to reduce the opportunity for suicide. For example, at locations where suicide is more likely, consider:\n\nproviding information about how and where people can get help when they feel unable to cope\n\nusing CCTV or other surveillance to allow staff to monitor when someone may need help\n\nincreasing the number and visibility of staff, or times when staff are available.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on how suicide prevention partnerships can reduce access to methods of suicide\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 6: reducing access to means\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Training by suicide prevention partnerships\n\nEnsure training is available for:\n\nthose in contact with people or groups at high suicide risk\n\npeople working at locations where suicide is more likely\n\ngatekeepers\n\npeople who provide peer support in residential custodial and detention settings\n\npeople leading suicide prevention partnerships\n\npeople supporting those bereaved by suicide.\n\nOffer training to organisations employing, working with or representing groups at high suicide risk.\n\nProvide generic and specialist training as needed for specialists and non-specialists.\n\nEnsure suicide awareness and prevention training helps people to:\n\nunderstand local suicide incidence and its impact, and know what support services are available\n\nencourage others to talk openly about suicidal thoughts and to seek help (this includes providing details of where they can get this help)\n\ntake into account socioeconomic deprivation, disability, physical and mental health status, and cultural, religious and social norms about suicide and help-seeking behaviour, particularly among groups at high suicide risk.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on training by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 4: information, advice, education and training\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Supporting people bereaved or affected by a suspected suicide\n\nUse rapid intelligence gathering and data from other sources, such as coroners to identify anyone who may be affected by a suspected suicide or may benefit from bereavement support. Those affected may include relatives, friends, classmates, colleagues, other prisoners or detainees, as well as first responders and other professionals who provided support.\n\nOffer those who are bereaved or affected by a suspected suicide practical information expressed in a sensitive way, such as Public Health England's Help is at hand guide (this also signposts to other services). Ask them if they need more help and, if so, offer them tailored support.\n\nConsider:\n\nproviding support from trained peers who have been bereaved or affected by a suicide or suspected suicide\n\nwhether any adjustments are needed to working patterns or the regime in residential custodial and detention settings.See also the National Suicide Prevention Alliance's resources on support after a suicide.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on how suicide prevention partnerships can support people bereaved or affected by a suspected suicide\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 5: interventions to support people bereaved or affected by a suspected suicide\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Preventing and responding to suicide clusters\n\nUse information from the action plan and rapid intelligence gathering to identify and prevent potential suicide clusters (see recommendation\xa01.3.1).\n\nAfter a suspected suicide in residential custodial and detention settings, undertake a serious incident review as soon as possible in partnership with the health providers. Identify how:\n\nto improve the suicide prevention action plan\n\nto help identify emerging clusters\n\nothers have responded to clusters.\n\nDevelop a coordinated approach to reduce the risk of additional suicides.\n\nDevelop a standard procedure for reducing, or 'stepping down', responses to any suspected suicide cluster.\n\nProvide ongoing support for those involved, including people directly bereaved or affected and those who are responding to the situation.See Public Health England's identifying and responding to suicide clusters and contagion: a practice resource.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on preventing and responding to suicide clusters\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 3: local approaches to suicide clusters\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Reducing the potential harmful effects of media reporting of a suspected suicide\n\nDevelop a clear plan for liaising with the media. Identify someone in the multi-agency partnership as the lead.\n\nFor community settings, promote guidance on best practice for media reporting of suicide (including providers of social media platforms). Highlight the need to:\n\nuse sensitive language that is not stigmatising or in any other way distressing to people who have been affected\n\nreduce speculative reporting\n\navoid presenting detail on methods. See: the World Health Organization's preventing suicide: a resource for media professionals, the Samaritans' media guidelines for reporting suicide, OFCOM's Broadcasting code and the Independent Press Standards Organisation (IPSO).\n\nFor residential custodial and detention settings, where a suspected suicide would be reported via the Ministry of Justice, ensure Ministry of Justice press officers follow good practice in suicide reporting.\n\nMonitor media coverage of suspected suicides locally. If necessary, provide feedback to the journalist or editor in relation to their reporting (see the Samaritans' media guidelines for reporting suicide).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact on reducing the potential harmful effects of media reporting of a suspected suicide\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review 7: local media reporting of suicides.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Gatekeepers\n\nPeople in groups that have contact, because of their paid or voluntary work, with people at risk of suicide. People in these groups may be trained to identify people at risk of suicide and refer them to treatment or supporting services as appropriate.\n\nThey may include: health and social care practitioners, criminal justice and detention settings staff, police and emergency services, people who provide a paid or voluntary service for the public, faith leaders, railway and underground station staff, and staff in educational institutions.\n\n## High suicide risk\n\nHigh suicide risk means that the rate of suicide in a group or setting is higher than the expected rate based on the general population in England. Groups at high risk can include: young and middle-aged men, people who self-harm, people in care of mental health services, family and friends of those who have died by suicide, people who misuse drugs or alcohol, people with a physical illness, particularly older adults, people in the LGBT community, people with autism, people in contact with the criminal justice system, particularly those in prisons, people in detention settings, including immigration detention settings, and specific occupation groups (see the Office for National Statistics' suicide by occupation, England: 2011 to 2015).\n\n## Locations where suicide is more likely\n\nThese include high buildings such as multi-storey car parks, railways and bridges and places where other means of suicide are accessible, such as medical, veterinary or agricultural settings where human or animal drugs may be readily available. See Public Health England's preventing suicides in public places: a practice resource.\n\n## Restricted regimes\n\nReduced access to time out of cell and purposeful activity, usually as a result of short staffing or serious incidents.\n\n## Suicide clusters\n\nA series of 3\xa0or more closely grouped deaths linked by space or social relationships. In the absence of transparent social connectedness, evidence of space and time linkages are needed to define a cluster. In the presence of a strong demonstrated social connection, only temporal significance is needed. (Adapted from Public Health England's identifying and responding to suicide clusters and contagion: a practice resource.)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Non-clinical interventions\n\nHow effective and cost effective are non-clinical interventions to reduce suicidal behaviours?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 8: suicide awareness campaigns\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Supporting people bereaved or affected by a suicide\n\nHow effective and cost effective are interventions to support people in the community who are bereaved or affected by a suicide?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 5: interventions to support people bereaved or affected by a suspected suicide\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on how suicide prevention in custodial and detention settings\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 5: interventions to support people bereaved or affected by a suspected suicide\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Suicide prevention in custodial and detention settings\n\nWhat interventions are effective and cost effective in reducing suicide rates in custodial and residential settings?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on awareness raising by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 8: suicide awareness campaigns\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.\n\n# Training\n\nHow effective and cost effective is gatekeeper training in preventing suicides?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on training by suicide prevention partnerships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 4: information, advice, education and training\n\nevidence review 9: preventing suicides in residential custodial and detention settings.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Suicide prevention partnerships\n\nRecommendations 1.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nApproximately 6,000\xa0people take their own life each year in the UK. The risk of suicide in the UK prison population is considerably higher than among the general population. The number of people dying by suicide in custodial or other detention settings such as prisons, immigration detention centres, young offender institutions and police custody has increased over the past decade.\n\nMany local agencies can be involved in preventing suicide in the community. Although the evidence was limited, the committee felt strongly that these agencies need to work together to focus on the most effective and cost-effective interventions. By combining expertise and resources, partnerships can cover a much wider area more effectively and implement a range of activities.\n\nLikewise, different services within residential custodial and detention settings can be more effective if they work together in a local multi-agency partnership and with similar partnerships in the community.\n\n## How the recommendations might affect practice\n\nImproved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.\n\nBut multi-agency partnership working is already enshrined in the Department of Health and Social Care's suicide prevention strategy for England, updated in the Department of Health and Social Care's suicide prevention: third annual report. As a result, multi-agency suicide prevention partnerships have been set up in most community and residential custodial and detention settings, so no additional costs are expected.\n\nReturn to recommendations\n\n# Suicide prevention strategies\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nSome evidence and expert opinion showed that having a strategy for how to connect local organisations can help prevent suicide in community and residential custodial and detention settings. For general reasons why we have made the recommendations, see the rationale section on suicide prevention partnerships.\n\nIf the strategy has clear leadership and is based on what is currently happening in the area or setting, it is likely to be effective. This involves gathering data on suicide rates and sharing best practice. A strategy may also help to ensure organisations are prepared to respond to a suicide.\n\nExpert opinion showed that when partnerships share knowledge and experience, this is of greater benefit than working individually. It may include collaborating with neighbouring organisations in the same setting to develop a shared strategy.\n\n## How the recommendations might affect practice\n\nImproved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.\n\nBut the Department of Health and Social Care's suicide prevention strategy for England advocates multi-agency partnerships, and suicide prevention strategies have been set up in most community and residential custodial and detention settings. So no additional costs are expected.\n\nReturn to recommendations\n\n# Suicide prevention action plans\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nHaving a detailed action plan based on local knowledge and clear leadership can help prevent suicide in the community and in residential custodial or detention settings. The plan will be effective if it is based on knowledge of what is happening in the area or setting, involves stakeholders and is adaptable. (For general reasons why we have made the recommendations, see the rationale section on suicide prevention partnerships.)\n\n## How the recommendations might affect practice\n\nMulti-agency suicide prevention action plans have been set up in most community and residential custodial and detention settings, so no additional costs are expected. For example, Public Health England's Suicide Prevention Profile shows which local authorities have suicide prevention plans.\n\nReturn to recommendations\n\n# Gathering and analysing suicide-related information\n\nRecommendations 1.4.1 to 1.4.6\n\n## Why the committee made the recommendations\n\nGood information is essential for planning, monitoring success and improving the strategy and plan for all settings. The committee agreed that the information should come from different sources to get a clear picture of what is happening. But they also agreed that it is important to make sure the local data collected is as reliable as possible, so that the strategy and plan is as effective as possible.\n\nAlthough the evidence was limited, the committee agreed with an expert that more rapid and frequent information gathering (rapid intelligence gathering) is important, for example for early detection of suicide clusters.\n\nThe committee also agreed that because analysing information on suicides may expose staff to some distressing material, training and support is essential to help them cope.\n\n## How the recommendations might affect practice\n\nGathering and analysing data may involve some additional resources. But most multi-agency suicide prevention partnerships have some work already in place. So we do not expect this will have a significant resource impact.\n\nReturn to recommendations\n\n# Awareness raising by suicide prevention partnerships\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nMany people who take their own lives are not in contact with mental health services and may not necessarily be in contact with a GP, so opportunities for clinical interventions can be limited. Non-clinical interventions, such as telephone or text helplines or volunteer-run face-to-face talking are important to support people with suicidal thoughts and keep them safe.\n\nThere is increasing demand for non-clinical interventions but little evidence on the benefits. Research is needed to evaluate how effective they are (see the recommendation\xa0for research on non-clinical interventions).\n\nThe committee agreed that awareness-raising activities and messages, tailored to people's needs and circumstances, can help get rid of common misconceptions about suicide and self-harm and let people know where they can go for help. They also agreed that increasing local awareness of suicide and the support available is likely to encourage people to seek help. But there can be a fine line between helpful and potentially harmful messages (see the recommendation for research on supporting people bereaved or affected by a suicide).\n\nIn residential custodial and detention settings, they agreed that extra support during particularly vulnerable times, such as 'early days', might reduce the risk of suicide. Peer support, along with measures such as the provision of 'safer cells', might also help to act as deterrents. But there is a lack of evidence and more research is needed to evaluate the effectiveness of different interventions in a range of custodial settings (see the recommendation\xa0for research on suicide prevention in custodial and detention settings).\n\n## How the recommendations might affect practice\n\nIncreasing local awareness of suicide and the support available could encourage more people to seek help and so increase health and social care costs.\n\nReturn to recommendations\n\n# How suicide prevention partnerships can reduce access to methods of suicide\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that it is important to identify local suicide trends, including common methods and locations where suicide is more likely, such as bridges and railway stations. That way action can be taken to reduce people's access to both the methods and places.\n\nPhysical barriers like fences and netting could reduce the number of suicide deaths in places where suicide is more likely because it makes it more difficult for people to put themselves in danger. Evidence showed that if a barrier stops a person from taking their life in one place, they will not automatically go somewhere else and try again.\n\nSimilarly, compliance with national guidance, for example on safer cells in custodial settings (see the Ministry of Justice's Quick-time learning bulletin on safer cells) and restrictions on painkiller sales in the community can act as an effective deterrent.\n\nThe committee agreed that, despite the lack of evidence, it may be worth thinking about implementing these measures because they can sometimes give people time to stop and think – and so may prevent deaths. The presence of staff at high-risk locations may also give people a chance to reconsider, as well as being a source of timely support.\n\n## How the recommendations might affect practice\n\nWhere physical barriers or other measures are needed this may have a resource impact in terms of staff time and construction and maintenance costs. NICE has an implementation tool to help determine the cost effectiveness of different interventions.\n\nReturn to recommendations\n\n# Training by suicide prevention partnerships\n\nRecommendations 1.7.1 to 1.7.4\n\n## Why the committee made the recommendations\n\nSome evidence showed that training improves people's knowledge about suicide, the risks and how to prevent it. The committee agreed that it may be effective to train a range of people involved with both the public and with occupational groups known to be at high risk of suicide. That way they can help spread general prevention messages and encourage people at risk to talk and seek help.\n\nBut UK evidence on the effectiveness of gatekeeper training is limited and there are only a few specific training programmes available. Training for all gatekeepers is important because it may help to identify more people at risk of suicide. But research is needed to evaluate how effective it is (see the recommendation\xa0for research on training).\n\n## How the recommendations might affect practice\n\nTraining can be costly. But it is expected to be made available through existing continuous professional development programmes, so the costs for professionals and organisations could be minimised. For example, Health Education England has developed generic and specialist competencies for people working with adults and children with suicidal behaviour or ideas, and for non-specialists working in community settings.\n\nReturn to recommendations\n\n# How suicide prevention partnerships can support people bereaved or affected by a suspected suicide\n\nRecommendations 1.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nThe committee agreed that people affected by a suspected suicide may, as a result, be at risk of harming themselves. This includes family members and friends of people who have died, as well as first responders.\n\nThe committee heard that bereavement support can reduce this risk, especially when tailored to the person's needs. People who had bereavement support were also likely to experience lower levels of depression and anxiety. Some of these benefits were based on personal accounts because the evidence was limited.\n\nSome services have been developed locally to provide this type of support. But because there is very little evidence on the benefits, local authorities are reluctant to commission such services. Research is needed to build an evidence base on these interventions for people in the community so that effective and cost-effective statutory and voluntary services can be developed (see the recommendation\xa0for research on supporting people bereaved or affected by a suicide).\n\n## How the recommendations might affect practice\n\nThe committee recognised that providing support for people affected by suicide may be cost effective from a societal perspective, when the costs of productivity losses are taken into account. However, because of the lack of evidence this supposition needs to be treated with caution.\n\nReturn to recommendations\n\n# Preventing and responding to suicide clusters\n\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\n\nSuicide clusters can emerge quickly and unexpectedly. But an expert told the committee that if the right systems are in place, then it is possible to reduce the likelihood of further deaths.\n\nThis was supported by the committee's own experience. An expert also explained to the committee that the police and the coroner's office need to notify agencies as soon as possible when a suspected suicide is being investigated. That is because an inquest to confirm cause of death is usually only held 6\xa0to 12\xa0months after the event. This is too late to prevent new suicide deaths if a cluster is developing. Residential custodial and detention settings have a duty to undertake and learn from reviews of incidents of self-harm to prevent future occurrences and make custody safer.\n\nBased on this information and their own experience, the committee agreed that rapid intelligence sharing is important.\n\n## How the recommendations might affect practice\n\nImproved communication and information sharing between statutory agencies and community organisations may have resource implications. For example, the costs of staff time, communication, interventions and the meetings associated with multi-agency teams.\n\nReturn to recommendations\n\n# Reducing the potential harmful effects of media reporting of a suspected suicide\n\nRecommendations 1.10.1 to 1.10.4\n\n## Why the committee made the recommendations\n\nIrresponsible reporting of suicide may have harmful effects, including potentially increasing the risk of suicide.\n\nReports of the method used in a suspected suicide seems to increase the risk of other people copying the suicide – so‑called copycat suicides. And inaccurate media reporting upsets people bereaved by suicide. So steps to encourage responsible reporting could prevent further suicide deaths.\n\nAlthough there was little evidence on the personal effect of suicide or suicidal behaviour being shared through social media, the committee agreed that the guidance given to the media should also apply to social media.\n\nTo combat the harmful effects of irresponsible reporting, the committee agreed that it is important to promote best practice and also monitor media coverage.\n\n## How the recommendations might affect practice\n\nProviding training for journalists may have cost implications. But better reporting generally has beneficial outcomes.\n\nReturn to recommendations", 'Context': "The UK suicide rate was 10.4\xa0deaths per 100,000\xa0population in 2016 (see the Office for National Statistics suicides in the UK: 2016 registrations). Suicide is more than 3\xa0times as common in men as in women. People aged 40\xa0to\xa044 had the highest suicide rate at 15.3 per 100,000. This age group also had the highest rate among men, at 24.1 per 100,000. For women, 50- to 54‑year‑olds had the highest rate of 8.3 per 100,000.\n\nOverall, the financial cost of someone of working age dying by suicide in the UK is more than £1.6\xa0million (Evaluation of the first phase of Choose Life: the national strategy and action plan to prevent suicide in Scotland Scottish Executive Social Research).\n\nThe risk of suicide in the UK prison population is considerably higher than among the general population. The 3-year average rate of self-inflicted deaths by people in prison in England was 69 per 100,000 between 2009 and 2011; approximately 80% received a suicide or open verdict at inquest. There were 62\xa0'apparent suicides following police custody' during 2013/14 in England and 119\xa0deaths by suicide in prison in England and Wales in 2016.\n\nSuicide and self-harm are major public health problems, with someone who self-harms being at increased risk of suicide (see the Department of Health and Social Care's Chief Medical Officer annual report 2013: public mental health priorities). Approximately three-quarters of people who die by suicide have not had recent contact with mental health services at the time of their death. However, many may have seen their GP in the year before they died and others may have been seen in A&E or another setting.\n\nPeople at risk of dying by suicide may come into contact with a wide range of professionals and others. The Department of Health and Social Care's suicide prevention strategy for England and the House of Commons report on the government's suicide prevention strategy highlight the potential role of the community in preventing suicide. For example, people can make contact with suicide prevention services through helplines and support groups (offered by charities such as Samaritans), or they can speak to a GP.\n\nThis guideline covers people of all ages but focuses particularly on groups with high suicide risk.\n\nIt also looks at interventions for people who are, or have been in custodial settings, and those in contact with any branch of the criminal justice system.\n\nSuicide prevention in mental health settings is not covered by this guideline. For further information on preventing suicide in mental health services see the reports from the University of Manchester's National Confidential Inquiry into Suicide and Safety in Mental Health.", 'Finding more information and resources': "To find NICE guidance on related topics, including guidance in development, see the NICE topic pages on depression, self-harm, alcohol-use disorders, drug misuse and prisons and other secure settings.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.\n\nISBN: 978-1-4731-3086-9"}
|
https://www.nice.org.uk/guidance/ng105
|
This guideline covers ways to reduce suicide and help people bereaved or affected by suicides. It aims to:
|
37fc4ab3dcb126f2008fbb438688d930e41ca768
|
nice
|
Pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma
|
Pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma
Evidence-based recommendations on pembrolizumab (Keytruda) for treating relapsed or refractory classical Hodgkin lymphoma in adults.
# Recommendations
Pembrolizumab is not recommended for treating relapsed or refractory classical Hodgkin lymphoma in adults who have had autologous stem cell transplant and brentuximab vedotin.
Pembrolizumab is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults who have had brentuximab vedotin and cannot have autologous stem cell transplant, only if:
pembrolizumab is stopped after 2 years of treatment or earlier if the person has a stem cell transplant or the disease progresses and
the conditions in the managed access agreement for pembrolizumab are followed.
These recommendations are not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
The marketing authorisation for pembrolizumab includes 2 subpopulations of people with relapsed or refractory classical Hodgkin lymphoma: people who have had brentuximab vedotin and autologous stem cell transplant and those who have had brentuximab vedotin but cannot have autologous stem cell transplant.
There is no evidence directly comparing pembrolizumab with current standard care in either of the subpopulations. Indirect analyses suggest that having pembrolizumab after brentuximab vedotin may lead to longer progression-free survival than current treatment. This would increase the number of people who can have curative allogeneic stem cell transplant. It is uncertain how many people having pembrolizumab will be able to have allogeneic stem cell transplant and their long-term outcomes compared with those having standard care and this is a key driver of cost effectiveness.
NICE recommends nivolumab for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and brentuximab vedotin. The committee heard from clinical experts that the clinical effectiveness of pembrolizumab and nivolumab are likely to be similar in this population. The company did not provide a cost-comparison between pembrolizumab and nivolumab and so the committee based its decision on the cost effectiveness of pembrolizumab compared with standard care before the introduction of nivolumab.
Pembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life.
Because of uncertainties in the clinical effectiveness and the modelling, the cost-effectiveness estimates are uncertain. Because of this, pembrolizumab cannot be recommended for routine use in the NHS.
There is an unmet treatment need for people who have had brentuximab vedotin and cannot have autologous stem cell transplant. There are no licensed immunotherapies for this subpopulation. Pembrolizumab has plausible potential to be cost effective for people who cannot have autologous stem cell transplant. Further data collection may reduce the uncertainty about the cost effectiveness. Therefore, pembrolizumab is recommended for use in the Cancer Drugs Fund for people who have classical Hodgkin lymphoma that has relapsed after, or not responded to, brentuximab vedotin and who cannot have autologous stem cell transplant.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation as monotherapy 'for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV'.
# Dosage in the marketing authorisation
Pembrolizumab (200 mg) is given every 3 weeks by intravenous infusion, until disease progression or unacceptable toxicity.
# Price
£2,630 per 100‑mg vial (excluding VAT; company submission). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck, Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Pembrolizumab is a potentially important treatment option
The marketing authorisation for pembrolizumab includes 2 subpopulations of people with relapsed or refractory classical Hodgkin lymphoma: people who have had brentuximab vedotin and autologous stem cell transplant (population 1), and those who have had brentuximab vedotin but cannot have autologous stem cell transplant (population 2). These subpopulations have different treatment options available to them. For population 1, NICE technology appraisal guidance recommends nivolumab for treating relapsed or refractory classical Hodgkin lymphoma. The clinical expert stated that the use of nivolumab has increased since the publication of this guidance. For population 2 the clinical expert explained that there is considerable need for effective treatment for disease that relapses after, or doesn't respond to, brentuximab vedotin and that the aim is to achieve sufficient disease response to enable allogeneic stem cell transplant to be done (which may cure the disease). Comments received during consultation from patients and clinicians also highlighted an unmet need for treatment in this population. The committee concluded that pembrolizumab is a potentially important treatment option for people with relapsed or refractory classical Hodgkin lymphoma after treatment with brentuximab vedotin, particularly if they cannot have autologous stem cell transplant.
# Clinical evidence
## Pembrolizumab is clinically effective based on response rates but the effect on overall survival is unknown
Clinical-effectiveness data for pembrolizumab came from the most recent data-cut from KEYNOTE‑087, an ongoing single-arm, open-label trial. This included people with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin (population 1), or after salvage chemotherapy and brentuximab vedotin but no autologous stem cell transplant (population 2). The committee considered objective response rates and progression-free survival assessed by blinded, independent central review from the most recent data-cut (March 2017) from KEYNOTE‑087 (table 1). It noted that overall survival data from the trial are not mature.
Clinical data measure
KEYNOTE-087 population 1
KEYNOTE-087 population 2
Number of patients
Progression-free survival, median (95% confidence interval )
months (11.2 to not reached)
months (7.6 to 13.7)
Best overall response – complete remission (CR; 95% CI)
% (17.5 to 39.6)
% (15.8 to 35.5)
Best overall response – partial remission (PR; 95% CI)
% (35.6 to 60.2)
% (31.1 to 53.5)
Best overall response – objective response (CR plus PR)
(63.5 to 84.9)
% (55.3 to 76.8)
The committee concluded that pembrolizumab is clinically effective based on response rates and progression-free survival data but the effect on overall survival is not known.
# Comparator data
## Cheah et al. (2016) was the best available data for standard care at the time of the company's submission, particularly for population 1, but UK data are now available for standard care in population 2
No data providing direct evidence for the clinical effectiveness of pembrolizumab compared with current standard care are available. The company used Cheah et al. (2016), a retrospective observational study done in the US that reported data from a mixture of chemotherapy regimens, as a source of data for standard care. However, the company did not include any comparisons with best supportive care because there were insufficient data available. The committee heard from a clinical expert that the study was done in a single specialist centre and included patients with relatively good health (performance status). Around 70% of the total study population had had autologous stem cell transplant (population 1), and 30% had not (population 2). The committee noted that the Cheah study was used to provide comparator data in NICE's technology appraisal guidance on nivolumab for treating relapsed or refractory classical Hodgkin lymphoma (TA462). It heard from the ERG that although the study was not a particularly good match for population 2, it was not aware of a more appropriate source of data for standard care at the time of reviewing the company submission. However, it heard from the clinical expert that a recent UK study (Eyre et al. 2017) might be a useful source of additional comparator data, because it provides data for standard care in a UK population rather than in the US (as in Cheah et al.). The company highlighted concerns about the use of data from the Eyre study. This included differences in the population, which was more heavily pre-treated in KEYNOTE‑087 than in Eyre. The company also highlighted the small sample size in the Eyre study and the need to use estimates from digitised published survival curves. The company considered Cheah et al. to represent the most comparable population to the whole KEYNOTE‑087 population, but it provided results of naive-indirect comparisons between Eyre et al. and KEYNOTE‑087 (population 2) data for both overall and progression-free survival for the first 24 weeks after starting treatment. The company commented that the hazard ratio for overall survival produced from this comparison (which is academic in confidence) is similar to the hazard ratio of 13.13 derived from a comparison of KEYNOTE‑087 (whole population) and Cheah et al. data, which was used in the updated 24‑week model (see section 3.7). However, the ERG cautioned against using this exploratory analysis to validate the use of this hazard ratio in the company's model. The committee concluded that the Cheah study was the best available evidence for standard care at the time of the company's submission, particularly for population 1, but may not fully represent UK clinical practice. The committee welcomed the exploratory analyses based on Eyre et al. that the company provided for the third committee meeting, but noted that the company and ERG had concerns about using this study as a source of evidence for standard care.
# Indirect treatment comparisons
## Pembrolizumab increases progression-free survival and objective response rate, but the size of the benefit and long-term outcomes are uncertain
To provide estimates of relative treatment effectiveness, the company separately compared population 1 and population 2 from KEYNOTE‑087 with standard care (using the whole population from Cheah et al. 2016). Both a naive-indirect comparison and matched-adjusted indirect comparisons were used. The company plans to publish these data and therefore considers the results to be academic in confidence, so they are not reported here. The committee noted that these comparisons showed a beneficial effect for pembrolizumab for both of the outcomes included in the company's analysis (progression-free survival and objective response rate). It also noted that these beneficial effects were generally higher in the matched-adjusted indirect comparison than in the naive-indirect comparison. It heard from the ERG that it considers neither method to be robust, but that on balance the naive comparison is more appropriate because it provides a more conservative estimate. The committee noted that the indirect comparisons may have underestimated the effect of pembrolizumab in population 2, because they compared the KEYNOTE‑087 populations with the total population in the Cheah study. The Cheah study was predominantly population 1, who are likely to have a better prognosis than people in population 2. The committee heard from the company that it had not been possible to provide separate comparisons for each population, because it did not have access to the individual patient data from the Cheah study. The committee concluded that the indirect comparisons suggest that pembrolizumab has a beneficial effect on progression-free survival and objective response rate, but there is considerable uncertainty over the size of the effect and long-term outcomes.
# The company's 'week 12' economic models
## The assumption about timing of allogeneic stem cell transplants in the company's original model is not appropriate
The company's original model included a structural assumption that all allogeneic stem cell transplants would be done 12 weeks after starting treatment. This was modelled as a decision tree at week 12 when patients with partial or complete response, or stable disease, had the option of allogeneic stem cell transplant. The committee heard from the company that this was based on the mean number of administrations of pembrolizumab before allogeneic stem cell transplant in KEYNOTE‑087, and on responses to a clinician survey. The committee heard from a clinical expert that a decision about whether to go ahead with allogeneic stem cell transplant will typically be made around 2.5 to 3 months after starting treatment. However, the arrangements for the transplant, such as establishing donor availability and arranging an inpatient stay for the procedure, usually cause some delay. The committee considered that a 12‑week transplant model structure could potentially favour pembrolizumab because more people treated with pembrolizumab will have allogeneic stem cell transplant compared with standard care, and earlier transplant allows them to benefit from an earlier point in time. The ERG highlighted that this uncertainty could not be explored in the original model because the fixed time point of 12 weeks could not be adjusted. The committee concluded that the 12‑week timing for allogeneic transplant in the model is not appropriate. However, it noted that the company subsequently provided models that assume all transplants happen at 24 weeks, to allow it to explore this uncertainty.
## The omission of a progressed-disease state after allogeneic transplant in the company's original model is not clinically plausible
The company's original 12‑week model for the post-allogeneic stem cell transplant population included only 2 states (alive or dead) and did not consider that disease could progress. The committee heard from the ERG that this lacks external validity because data from Lafferty et al. (2017) reported a progression-free survival of 54% at 1 year after allogeneic stem cell transplant. A clinical expert confirmed that not all allogeneic stem cell transplants are curative and that disease may return and progress. The committee concluded that the company's approach was not appropriate and that the omission of a progressed-disease state after allogeneic transplant is not clinically plausible. An updated 12‑week model submitted by the company included a progressed-disease state after allogeneic stem cell transplant, and the committee agreed that this was more clinically appropriate. It noted that the inclusion of the progressed-disease state increased the incremental cost-effectiveness ratios (ICERs) by around £2,000 per quality-adjusted life year (QALY) gained.
# The company's 'week‑24' economic model
## The difference in overall survival between pembrolizumab and standard care is likely to be overestimated at week 24 using results from the naive-indirect comparison of data from Cheah and KEYNOTE-087
The committee considered a revised model provided by the company, which assumed that all allogeneic stem cell transplants were done 24 weeks after starting treatment. It noted that several parameters and assumptions had been updated in the company's model when changing the time at which allogeneic stem cell transplant occurs from week 12 to week 24. Unlike the 12‑week models, the updated 24‑week model did not assume equivalent overall survival for pembrolizumab and standard care in the period before allogeneic stem cell transplant (that is, a hazard ratio of 1) for populations 1 and 2. Instead, a hazard ratio of 13.13 (95% confidence interval 3.07 to 56.04) was used in the base case, and the impact of assuming no difference was explored in a scenario analysis. The company explained that this value was produced from a naive comparison between an earlier data-cut of KEYNOTE‑087, which pooled data from both subpopulations, and the Cheah study. However, the company did not provide information to allow the ERG to confirm this estimate. The committee noted that at week 24 in the Cheah study, 88% of the standard-care population were alive. Using a hazard ratio of 13.13 estimated that only 78% (population 1) or 72% (population 2) of the standard-care population were alive, and using a hazard ratio of 1 estimated a value of 98%. Further analysis provided by the company used alternative hazard ratios for overall survival in weeks 0 to 24, which were calibrated to match observed survival data for standard care from Cheah et al. (hazard ratios of 8.01 for population 1 and 5.18 for population 2). The ERG had concerns about the use of a methodology that matched overall survival estimates to those at a single point, because this does not follow conventional curve-fitting methodology and may result in the curve being a poor fit to the data at other time points. However, because data were not provided to validate the use of the 13.13 hazard ratio and a hazard ratio of 1.0 lacked face validity, the ERG had a slight preference for using the alternative hazard ratios in the week‑24 economic model. The ERG commented that because of uncertainty about the most appropriate value to use, the results of the week‑24 model should be interpreted with caution, and should only be considered as a scenario analysis. The committee concluded that the difference in overall survival at week 24 is subject to uncertainty, but is likely to have been overestimated in the model using a naive-indirect comparison between Cheah and KEYNOTE‑087.
## There is uncertainty about the parametric overall and progression-free survival curves used to model the pre-allogeneic transplant period
The ERG commented that the choice of parametric model for overall and progression-free survival in the period before allogeneic stem cell transplant can affect the results of the model. The committee heard that different parametric models for progression-free survival in the pre-allogeneic stem cell transplant period had been used in the 24‑week model, compared with the 12‑week models, and some of these had poor statistical fit with the Kaplan–Meier curve from KEYNOTE‑087. A subsequently updated 24‑week model used the same parametric models for progression-free survival as the 12‑week model. The committee questioned why parametric models had been used for modelling when observed survival data are available for both the 12‑week and 24‑week time points. The committee concluded that the choices made by the company to model progression-free and overall survival in the 24‑week model pre-allogeneic stem cell transplant period introduced considerable uncertainty, which had not been fully investigated. The committee considered that the use of observed survival data in the pre-allogeneic stem cell transplant period in the model would have been preferable.
# Rate of allogeneic stem cell transplants
## The uptake rate of allogeneic stem cell transplant is uncertain
To estimate the uptake of allogeneic stem cell transplant, the company combined results from 2 surveys of clinicians. Data from KEYNOTE‑087 were not used by the company, because uptake of allogeneic stem cell transplant was low in the study and they did not consider it to be representative of UK practice. The committee considered that survey results provide suboptimal evidence to inform parameter estimates and heard from the ERG that the same clinicians could have been included in both surveys, potentially resulting in double-counting in the combined results. The ERG also stated that the results represented expected, rather than observed, transplant rates. The committee noted that the sample size of the survey was small and heard from a clinical expert that this was to be expected because only a small number of clinicians treat this disease in the UK. Combining the 2 surveys resulted in a higher predicted rate of allogeneic stem cell transplants than in the single survey carried out by the company. The committee heard from a clinical expert that in their opinion the number of people with a complete or partial response to treatment who would have an allogeneic stem cell transplant is higher than the estimates from the company's survey alone (which were 57% for complete response and 44% for partial response), and closer to the combined overall mean (values are academic in confidence and cannot be reported here). The committee concluded that there is considerable uncertainty about whether the rates of allogeneic stem cell transplant used in the models are an accurate reflection of transplant rates in UK clinical practice. The committee concluded that combining the results of the 2 surveys did increase the number of responses, although the combined number of responses was still small. However, there remained uncertainty about the validity and reliability of clinical predictions, as well as the potential duplication of clinicians in the combined survey.
## It is appropriate to assume that people with progressed disease would not have allogeneic stem cell transplant
The company's models assume that patients with progressed disease do not have allogeneic stem cell transplant. The committee heard from the ERG that some clinicians included in the company survey had suggested that some patients with progressed disease may go on to have a transplant. A clinical expert stated that this was not done in current practice, and noted that guidelines from the British Committee for Standards in Haematology advise against transplants for people with progressive disease. The committee concluded that it is appropriate to assume that patients with progressed disease do not have allogeneic stem cell transplants.
# Stopping rule
## It is appropriate to assume that people will have pembrolizumab for up to 24 months
The company's models assume that treatment with pembrolizumab continues for up to 24 months as in the trial protocol for KEYNOTE‑087, unless unacceptable toxicity occurs. The committee was aware that a 24‑month stopping rule is not included in the summary of product characteristics and it questioned how long pembrolizumab treatment would be continued in clinical practice, particularly for people unable to have allogeneic stem cell transplant. It noted a submission received from NHS England, which stated that an assumption of discontinuation at 24 months is appropriate and is supported by the current evidence base. The committee therefore concluded that stopping treatment with pembrolizumab at a maximum of 24 months in the models is appropriate.
# Utility values in the economic models
## There is considerable uncertainty about the utility value for progressed disease
The committee considered the utility values used in the company's and the ERG's base-case analyses. The company aims to publish utility data from KEYNOTE‑087 and therefore considers the results to be academic in confidence, so they cannot be reported here. The committee noted that the company used utility data from KEYNOTE‑087 from week 12 only, and that they had estimated the utility for progressed disease by applying a decrement from Swinburn et al. (2015). It heard from the company that this was because EQ-5D data were only collected in KEYNOTE‑087 for up to 30 days post-progression, and any longer-term effects of progression will therefore not have been captured. The committee noted that the company's utility values decreased substantially when disease progressed and it considered that the size of the decrease, relative to the other health states in the model, is implausible. In its base-case analysis of the company's original model, the ERG had used utility values from KEYNOTE‑087 alone. It preferred to use a mixed-effects model provided by the company, incorporating all available EQ-5D data from KEYNOTE‑087, rather than using only the 12‑week data. The committee noted that this results in a far smaller decrease in utility when disease progresses than estimated by the company. The committee heard from a clinical expert that symptoms caused by progressed disease will not immediately appear, but are expected to worsen over time, although receiving the diagnosis of disease progression alone could have a substantial effect on the patient. Consequently, it is plausible that the utility for progressive disease was too high in the ERG's base case, but it is unlikely to be as low as the value proposed by the company. The committee therefore concluded that there is considerable uncertainty about the utility decrease that occurs when disease progresses, and that the actual value is likely to be between the company's and the ERG's base-case values.
# Cost-effectiveness estimates
## There is uncertainty about the time to allogeneic stem cell transplant, which is a key driver of the cost-effectiveness estimates
The committee noted that how allogeneic stem cell transplant is incorporated in the models is a major driver of incremental QALYs for pembrolizumab compared with standard care. The company's submission stated that the average time to transplant is likely to be between 12 and 24 weeks after starting treatment. The committee noted its previous consideration that it is unrealistic to assume that all allogeneic stem cell transplants would have occurred by week 12 (see section 3.5). It considered that, in practice, allogeneic stem cell transplants are likely to occur between weeks 12 and 24. It also heard from a clinical expert that all allogeneic stem cell transplants are likely to have occurred by week 24. The most plausible ICER is therefore likely to fall between the values predicted by models using a fixed time of transplant of 12 and 24 weeks.
## The cost effectiveness of pembrolizumab relative to standard care in population 1 is highly uncertain
After the committee concluded at its second meeting that a plausible ICER for population 1 could not be accurately estimated using the company's 12‑week or 24‑week model, the company provided updated 12‑week and 24‑week analyses for the third appraisal committee meeting. These included an updated commercial access agreement and changes to the parametric distributions used for progression-free and overall survival in the models. The company also presented further scenario analyses to explore some of the uncertainties the committee had highlighted in the consultation document. For population 1, the updated base-case ICERs were £42,123 (24‑week model) and £49,058 (12‑week model) per QALY gained. The ERG implemented their preferred assumptions in the updated models and produced ICERs of £45,829 (24‑week model) and £54,325 (12‑week model) per QALY gained. The ERG commented that there is still substantial uncertainty associated with the model results, particularly for the 24‑week model (see section 3.7 and section 3.8). The committee recalled its conclusion that the most plausible ICER is likely to fall between the values predicted by models using a fixed time of transplant of 12 and 24 weeks (section 3.13). It noted that the range of ICERs produced by the company's and ERG's 24‑week and 12‑week models are between £42,100 and £54,300 per QALY gained, but that these results are highly uncertain because of the total life-years predicted by the model (see section 3.17), the uncertainties associated with the 24‑week model, uptake rate and timing of allogenic stem cell transplant (see section 3.9 and section 3.13). The committee concluded that because of the substantial uncertainty associated with the model results, the ICERs for population 1 remain highly uncertain.
## A requested cost-comparison with nivolumab for population 1 was not provided
The committee noted that NICE technology appraisal guidance recommends nivolumab for use in population 1 (TA462), and that the committee in that appraisal concluded that the most plausible ICER is likely to be around £30,000 per QALY gained. The ERG commented that the committee's and ERG's preferred analyses in TA462 used the same cost of allogenic stem cell transplant (from Radford et al. 2017) as used in the current appraisal. The committee noted that, despite using the same study to provide comparator data for standard care (Cheah et al. 2016), the total QALYs and costs generated by modelling standard care for population 1 in the company's models for the current appraisal of pembrolizumab are higher than those generated for standard care in TA462. It noted a statement from NHS England that, compared with nivolumab, pembrolizumab may have clinical and cost benefits because it is administered less frequently. The committee further noted that nivolumab's marketing authorisation had recently changed to fixed-dosing, rather than dosing based on body weight. A clinical expert commented that the clinical effectiveness of pembrolizumab and nivolumab in this population is likely to be similar. The committee therefore concluded that because of the uncertainties in the company's modelling for this population, and the substantial differences in its results compared with the nivolumab model, a cost-comparison between the 2 technologies may address these uncertainties for the NHS. It requested that this should be provided by the company. The company did not provide a cost-comparison for the third committee meeting. The committee heard from the company that based on a naive comparison, results from single-arm trials are more favourable for pembrolizumab and that there are insufficient comparative data to confirm that the clinical effectiveness of the 2 drugs is similar. The company also commented that the 2 drugs differ in chemical structure. The committee noted that the company had not provided evidence to demonstrate different clinical efficacy between nivolumab and pembrolizumab, or provided a convincing explanation as to why the treatment effects would be likely to differ. The committee concluded that, in the absence of a cost-comparison with nivolumab, it can only base its estimate of cost effectiveness for pembrolizumab in population 1 on the analyses comparing it with standard of care and that the results of these analyses are highly uncertain.
## The most plausible ICER for pembrolizumab in population 2 is highly uncertain
The committee noted its conclusions from the first and second appraisal meetings; that the cost effectiveness of pembrolizumab in population 2 is highly uncertain, and that a plausible ICER could not be accurately estimated using the company's 12‑week or 24‑week models. The committee noted that the company had provided updated 12‑week and 24‑week scenario analyses for the third appraisal committee meeting (see section 3.14). For population 2, the updated base-case ICERs are £36,950 (24‑week model) and £55,628 (12‑week model) per QALY gained. The ERG implemented their preferred assumptions in the updated models provided for the third committee meeting, which produced ICERs of £42,501 (24‑week model) and £62,527 (12‑week model) per QALY gained. The ERG commented that there is still substantial uncertainty associated with the model results, particularly for the 24‑week model (see section 3.7 and section 3.8). The committee concluded that because of the substantial uncertainty associated with the model results, including the total life-years generated by the model (see section 3.14 and section 3.17) it is unable to predict the most plausible ICER for population 2, but the extreme values from the company's and ERG's 24‑week and 12‑week models (that is, between £37,000 and £62,500 per QALY gained) reflected a plausible range in which the true ICER may fall. The committee concluded that the estimates of cost effectiveness are too uncertain to recommend pembrolizumab for routine use.
## There is a lack of face validity between the modelled survival estimates for standard care and the clinical evidence, and the company's assertion that end-of-life criteria are met
The committee was concerned that there was a lack of face validity between the modelled survival for standard care and the clinical evidence, and for the company's assertion that end-of-life criteria are met, because more than 2 life-years were estimated for standard care in the company's base-case models. The company explained that it used aggregated data from the Cheah study in the model, because it did not have access to individual patient data from the study. Survival estimates for people who could not have allogeneic stem cell transplant are therefore likely to have been influenced by data from people who did have stem cell transplant. The committee heard from a clinical expert that they would expect overall survival, particularly for population 2, to be closer to that reported in the literature (median overall survival of between 17.1 and 19 months), as presented in the company's submission. The company highlighted that Eyre et al. reported a median overall survival of 12.2 months (95% CI 8.1 to 18.3) for people who were transplant naive and were unable to have a stem cell transplant after treatment with brentuximab vedotin, in a UK population. The committee concluded that there is lack of face validity between the modelled survival estimates for standard care and the clinical evidence, and company's assertion that end-of-life criteria are met, which further adds to the uncertainty about the results produced by the models.
# Innovation
## Pembrolizumab's benefits are captured in the measurement of QALYs
The company considered pembrolizumab to be an innovative treatment. A clinical expert explained that there is an unmet need for treatment to allow people with disease that has not responded or relapsed after brentuximab vedotin, and who cannot have autologous stem cell transplant, to have allogeneic stem cell transplant, which is potentially curative. The committee concluded that pembrolizumab would be beneficial for patients, but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# End of life
## The committee agreed that, on balance, pembrolizumab meets the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company made the case that pembrolizumab meets the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months) based on available literature estimates of median overall survival for people with relapsed or refractory classical Hodgkin lymphoma. The committee noted that more than 2 life-years were estimated for standard care in the company's models, which is inconsistent with the company's claim and the published literature. However, the committee noted the company's explanation for the higher number of life-years produced by the models (see section 3.17). It also noted the conclusion of the NICE technology appraisal committee for nivolumab (TA462), in which models using Cheah data for standard care predicted overall survival of more than 24 months for the comparator treatment arm. The committee concluded that while pembrolizumab did not unequivocally meet the criterion for short life expectancy, it is plausible that the criterion could apply. The committee concluded that on balance, pembrolizumab meets the criterion for short life expectancy.
## Pembrolizumab offers an extension to life of at least 3 months
The committee considered that based on survival data from KEYNOTE‑087 and model results, there is sufficient evidence to indicate that pembrolizumab offers an extension to life of at least 3 months.
# Cancer Drugs Fund
## The committee considered pembrolizumab as an option for use in the Cancer Drugs Fund
Having concluded that pembrolizumab could not be recommended for routine use (see section 3.16) the committee considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum).
## The company proposed pembrolizumab for the Cancer Drugs Fund for population 2
The company commented that it has no further plans to collect data on pembrolizumab for treating relapsed or refractory Hodgkin lymphoma in population 2. It requested that the committee consider pembrolizumab for inclusion in the Cancer Drugs Fund for this population to allow further data collection, which may reduce the uncertainty.
It suggested data that could be feasible for collection in the Cancer Drugs Fund:
proportion of people who have an allogeneic stem cell transplant
timing of allogenic stem cell transplant
duration of pembrolizumab treatment before allogeneic stem cell transplant.The company noted that data collection should include long-term follow-up of all people having pembrolizumab, regardless of whether they subsequently have allogeneic stem cell transplant. The committee noted the considerable unmet need for treatment in population 2 (see section 3.1) and that there is considerable uncertainty about the most plausible ICER for this population, which is likely to be between £37,000 and £62,500 per QALY gained (see section 3.16). It noted that time to allogeneic stem cell transplant is a key driver of the cost-effectiveness estimates and there is considerable uncertainty about the true value (see section 3.13). There is also uncertainty about whether the rates of allogeneic stem cell transplant used in the models (which are based on clinician surveys) are an accurate reflection of transplant rates in UK clinical practice (see section 3.9). The committee concluded that these are appropriate outcomes to collect data on, and this would reduce uncertainty in the cost-effectiveness estimate for population 2. It considered that overall survival for people having pembrolizumab would be a useful long-term outcome to measure.
## Pembrolizumab is recommended as an option for use in the Cancer Drugs Fund for population 2
The committee concluded that pembrolizumab meets the criteria to be considered for inclusion in the Cancer Drugs Fund for population 2. It therefore recommended pembrolizumab for use within the Cancer Drugs Fund as an option for adults with relapsed or refractory classical Hodgkin lymphoma who have had brentuximab vedotin and cannot have autologous stem cell transplant, if the conditions in the managed access agreement are followed.
## Pembrolizumab is not recommended as an option for use in the Cancer Drugs Fund for population 1
The committee considered pembrolizumab for inclusion in the Cancer Drugs Fund for population 1. It noted that the company had not requested that this population should be considered in the Cancer Drugs Fund. It further noted that nivolumab is in routine use for this population, therefore people in this population already have access to immunotherapy. The committee was unable to resolve its uncertainties about the relative cost effectiveness of pembrolizumab and nivolumab because a requested cost-comparison was not provided. The committee did not recommend pembrolizumab for use within the Cancer Drugs Fund for population 1.
# Conclusions
## Pembrolizumab is not recommended as an option for population 1
Pembrolizumab is a clinically effective treatment, compared with standard care, for relapsed or refractory classical Hodgkin lymphoma, although there is uncertainty about the size of the effect (see section 3.4). Despite considerable uncertainty in the results of the model provided by the company for this appraisal (see section 3.14 and section 3.15), the model results had to be used for decision making because a requested cost-comparison with nivolumab for this population was not provided. The committee noted that the estimated ICERs in the current appraisal are substantially higher than the most plausible ICER in TA462. The committee took into account the case for pembrolizumab meeting the end-of-life criteria (see section 3.19 and section 3.20). However, because of the considerable uncertainty associated with the model results there is insufficient justification for recommending pembrolizumab as a cost-effective use of NHS resources in population 1.
## Pembrolizumab is recommended for use in the Cancer Drugs Fund for population 2
The committee noted that because there is no licensed immunotherapy for population 2 (that is, people who have had brentuximab vedotin and who cannot have allogeneic stem cell transplant) there is a high unmet need for treatment (see section 3.1). The most plausible ICER for pembrolizumab in population 2 is highly uncertain (see section 3.16) and therefore it cannot be recommended for use in routine commissioning. However, it is plausible that pembrolizumab could be cost effective in this population, and therefore it is recommended for use within the Cancer Drugs Fund. Further data collection through inclusion in the Cancer Drugs Fund will allow a more accurate estimate of the cost effectiveness of pembrolizumab in this population (see section 5).# Recommendations for data collection
Proposals for further data collection in the Cancer Drugs Fund include:
proportion of people having pembrolizumab who have an allogenic stem cell transplant
time to allogenic stem cell transplant
duration of treatment with pembrolizumab before allogenic stem cell transplant
long-term follow-up of people having pembrolizumab with or without subsequent allogenic stem cell transplant (in particular, collection of data on overall survival).
|
{'Recommendations': "Pembrolizumab is not recommended for treating relapsed or refractory classical Hodgkin lymphoma in adults who have had autologous stem cell transplant and brentuximab vedotin.\n\nPembrolizumab is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults who have had brentuximab vedotin and cannot have autologous stem cell transplant, only if:\n\npembrolizumab is stopped after 2\xa0years of treatment or earlier if the person has a stem cell transplant or the disease progresses and\n\nthe conditions in the managed access agreement for pembrolizumab are followed.\n\nThese recommendations are not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe marketing authorisation for pembrolizumab includes 2\xa0subpopulations of people with relapsed or refractory classical Hodgkin lymphoma: people who have had brentuximab vedotin and autologous stem cell transplant and those who have had brentuximab vedotin but cannot have autologous stem cell transplant.\n\nThere is no evidence directly comparing pembrolizumab with current standard care in either of the subpopulations. Indirect analyses suggest that having pembrolizumab after brentuximab vedotin may lead to longer progression-free survival than current treatment. This would increase the number of people who can have curative allogeneic stem cell transplant. It is uncertain how many people having pembrolizumab will be able to have allogeneic stem cell transplant and their long-term outcomes compared with those having standard care and this is a key driver of cost effectiveness.\n\nNICE recommends nivolumab for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and brentuximab vedotin. The committee heard from clinical experts that the clinical effectiveness of pembrolizumab and nivolumab are likely to be similar in this population. The company did not provide a cost-comparison between pembrolizumab and nivolumab and so the committee based its decision on the cost effectiveness of pembrolizumab compared with standard care before the introduction of nivolumab.\n\nPembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life.\n\nBecause of uncertainties in the clinical effectiveness and the modelling, the cost-effectiveness estimates are uncertain. Because of this, pembrolizumab cannot be recommended for routine use in the NHS.\n\nThere is an unmet treatment need for people who have had brentuximab vedotin and cannot have autologous stem cell transplant. There are no licensed immunotherapies for this subpopulation. Pembrolizumab has plausible potential to be cost effective for people who cannot have autologous stem cell transplant. Further data collection may reduce the uncertainty about the cost effectiveness. Therefore, pembrolizumab is recommended for use in the Cancer Drugs Fund for people who have classical Hodgkin lymphoma that has relapsed after, or not responded to, brentuximab vedotin and who cannot have autologous stem cell transplant.", 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation as monotherapy 'for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV'.\n\n# Dosage in the marketing authorisation\n\nPembrolizumab (200\xa0mg) is given every 3\xa0weeks by intravenous infusion, until disease progression or unacceptable toxicity.\n\n# Price\n\n£2,630 per 100‑mg vial (excluding VAT; company submission). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck, Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Pembrolizumab is a potentially important treatment option\n\nThe marketing authorisation for pembrolizumab includes 2\xa0subpopulations of people with relapsed or refractory classical Hodgkin lymphoma: people who have had brentuximab vedotin and autologous stem cell transplant (population\xa01), and those who have had brentuximab vedotin but cannot have autologous stem cell transplant (population\xa02). These subpopulations have different treatment options available to them. For population\xa01, NICE technology appraisal guidance recommends nivolumab for treating relapsed or refractory classical Hodgkin lymphoma. The clinical expert stated that the use of nivolumab has increased since the publication of this guidance. For population\xa02 the clinical expert explained that there is considerable need for effective treatment for disease that relapses after, or doesn't respond to, brentuximab vedotin and that the aim is to achieve sufficient disease response to enable allogeneic stem cell transplant to be done (which may cure the disease). Comments received during consultation from patients and clinicians also highlighted an unmet need for treatment in this population. The committee concluded that pembrolizumab is a potentially important treatment option for people with relapsed or refractory classical Hodgkin lymphoma after treatment with brentuximab vedotin, particularly if they cannot have autologous stem cell transplant.\n\n# Clinical evidence\n\n## Pembrolizumab is clinically effective based on response rates but the effect on overall survival is unknown\n\nClinical-effectiveness data for pembrolizumab came from the most recent data-cut from KEYNOTE‑087, an ongoing single-arm, open-label trial. This included people with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin (population\xa01), or after salvage chemotherapy and brentuximab vedotin but no autologous stem cell transplant (population\xa02). The committee considered objective response rates and progression-free survival assessed by blinded, independent central review from the most recent data-cut (March 2017) from KEYNOTE‑087 (table\xa01). It noted that overall survival data from the trial are not mature.\n\nClinical data measure\n\nKEYNOTE-087 population\xa01\n\nKEYNOTE-087 population\xa02\n\nNumber of patients\n\n\n\n\n\nProgression-free survival, median (95% confidence interval [CI])\n\nmonths (11.2 to not reached)\n\nmonths (7.6 to 13.7)\n\nBest overall response – complete remission (CR; 95% CI)\n\n% (17.5 to 39.6)\n\n% (15.8 to 35.5)\n\nBest overall response – partial remission (PR; 95% CI)\n\n% (35.6 to 60.2)\n\n% (31.1 to 53.5)\n\nBest overall response – objective response (CR plus PR)\n\n(63.5 to 84.9)\n\n% (55.3 to 76.8)\n\nThe committee concluded that pembrolizumab is clinically effective based on response rates and progression-free survival data but the effect on overall survival is not known.\n\n# Comparator data\n\n## Cheah et al. (2016) was the best available data for standard care at the time of the company's submission, particularly for population\xa01, but UK data are now available for standard care in population\xa02\n\nNo data providing direct evidence for the clinical effectiveness of pembrolizumab compared with current standard care are available. The company used Cheah et al. (2016), a retrospective observational study done in the US that reported data from a mixture of chemotherapy regimens, as a source of data for standard care. However, the company did not include any comparisons with best supportive care because there were insufficient data available. The committee heard from a clinical expert that the study was done in a single specialist centre and included patients with relatively good health (performance status). Around 70% of the total study population had had autologous stem cell transplant (population\xa01), and 30% had not (population\xa02). The committee noted that the Cheah study was used to provide comparator data in NICE's technology appraisal guidance on nivolumab for treating relapsed or refractory classical Hodgkin lymphoma (TA462). It heard from the ERG that although the study was not a particularly good match for population\xa02, it was not aware of a more appropriate source of data for standard care at the time of reviewing the company submission. However, it heard from the clinical expert that a recent UK study (Eyre et al. 2017) might be a useful source of additional comparator data, because it provides data for standard care in a UK population rather than in the US (as in Cheah et al.). The company highlighted concerns about the use of data from the Eyre study. This included differences in the population, which was more heavily pre-treated in KEYNOTE‑087 than in Eyre. The company also highlighted the small sample size in the Eyre study and the need to use estimates from digitised published survival curves. The company considered Cheah et al. to represent the most comparable population to the whole KEYNOTE‑087 population, but it provided results of naive-indirect comparisons between Eyre et al. and KEYNOTE‑087 (population\xa02) data for both overall and progression-free survival for the first 24\xa0weeks after starting treatment. The company commented that the hazard ratio for overall survival produced from this comparison (which is academic in confidence) is similar to the hazard ratio of 13.13 derived from a comparison of KEYNOTE‑087 (whole population) and Cheah et al. data, which was used in the updated 24‑week model (see section\xa03.7). However, the ERG cautioned against using this exploratory analysis to validate the use of this hazard ratio in the company's model. The committee concluded that the Cheah study was the best available evidence for standard care at the time of the company's submission, particularly for population\xa01, but may not fully represent UK clinical practice. The committee welcomed the exploratory analyses based on Eyre et al. that the company provided for the third committee meeting, but noted that the company and ERG had concerns about using this study as a source of evidence for standard care.\n\n# Indirect treatment comparisons\n\n## Pembrolizumab increases progression-free survival and objective response rate, but the size of the benefit and long-term outcomes are uncertain\n\nTo provide estimates of relative treatment effectiveness, the company separately compared population\xa01 and population\xa02 from KEYNOTE‑087 with standard care (using the whole population from Cheah et al. 2016). Both a naive-indirect comparison and matched-adjusted indirect comparisons were used. The company plans to publish these data and therefore considers the results to be academic in confidence, so they are not reported here. The committee noted that these comparisons showed a beneficial effect for pembrolizumab for both of the outcomes included in the company's analysis (progression-free survival and objective response rate). It also noted that these beneficial effects were generally higher in the matched-adjusted indirect comparison than in the naive-indirect comparison. It heard from the ERG that it considers neither method to be robust, but that on balance the naive comparison is more appropriate because it provides a more conservative estimate. The committee noted that the indirect comparisons may have underestimated the effect of pembrolizumab in population\xa02, because they compared the KEYNOTE‑087 populations with the total population in the Cheah study. The Cheah study was predominantly population\xa01, who are likely to have a better prognosis than people in population\xa02. The committee heard from the company that it had not been possible to provide separate comparisons for each population, because it did not have access to the individual patient data from the Cheah study. The committee concluded that the indirect comparisons suggest that pembrolizumab has a beneficial effect on progression-free survival and objective response rate, but there is considerable uncertainty over the size of the effect and long-term outcomes.\n\n# The company's 'week 12' economic models\n\n## The assumption about timing of allogeneic stem cell transplants in the company's original model is not appropriate\n\nThe company's original model included a structural assumption that all allogeneic stem cell transplants would be done 12\xa0weeks after starting treatment. This was modelled as a decision tree at week\xa012 when patients with partial or complete response, or stable disease, had the option of allogeneic stem cell transplant. The committee heard from the company that this was based on the mean number of administrations of pembrolizumab before allogeneic stem cell transplant in KEYNOTE‑087, and on responses to a clinician survey. The committee heard from a clinical expert that a decision about whether to go ahead with allogeneic stem cell transplant will typically be made around 2.5\xa0to 3\xa0months after starting treatment. However, the arrangements for the transplant, such as establishing donor availability and arranging an inpatient stay for the procedure, usually cause some delay. The committee considered that a 12‑week transplant model structure could potentially favour pembrolizumab because more people treated with pembrolizumab will have allogeneic stem cell transplant compared with standard care, and earlier transplant allows them to benefit from an earlier point in time. The ERG highlighted that this uncertainty could not be explored in the original model because the fixed time point of 12\xa0weeks could not be adjusted. The committee concluded that the 12‑week timing for allogeneic transplant in the model is not appropriate. However, it noted that the company subsequently provided models that assume all transplants happen at 24\xa0weeks, to allow it to explore this uncertainty.\n\n## The omission of a progressed-disease state after allogeneic transplant in the company's original model is not clinically plausible\n\nThe company's original 12‑week model for the post-allogeneic stem cell transplant population included only 2\xa0states (alive or dead) and did not consider that disease could progress. The committee heard from the ERG that this lacks external validity because data from Lafferty et al. (2017) reported a progression-free survival of 54% at 1\xa0year after allogeneic stem cell transplant. A clinical expert confirmed that not all allogeneic stem cell transplants are curative and that disease may return and progress. The committee concluded that the company's approach was not appropriate and that the omission of a progressed-disease state after allogeneic transplant is not clinically plausible. An updated 12‑week model submitted by the company included a progressed-disease state after allogeneic stem cell transplant, and the committee agreed that this was more clinically appropriate. It noted that the inclusion of the progressed-disease state increased the incremental cost-effectiveness ratios (ICERs) by around £2,000 per quality-adjusted life year (QALY) gained.\n\n# The company's 'week‑24' economic model\n\n## The difference in overall survival between pembrolizumab and standard care is likely to be overestimated at week 24 using results from the naive-indirect comparison of data from Cheah and KEYNOTE-087\n\nThe committee considered a revised model provided by the company, which assumed that all allogeneic stem cell transplants were done 24\xa0weeks after starting treatment. It noted that several parameters and assumptions had been updated in the company's model when changing the time at which allogeneic stem cell transplant occurs from week\xa012 to week\xa024. Unlike the 12‑week models, the updated 24‑week model did not assume equivalent overall survival for pembrolizumab and standard care in the period before allogeneic stem cell transplant (that is, a hazard ratio of 1) for populations 1\xa0and\xa02. Instead, a hazard ratio of 13.13 (95% confidence interval [CI] 3.07 to 56.04) was used in the base case, and the impact of assuming no difference was explored in a scenario analysis. The company explained that this value was produced from a naive comparison between an earlier data-cut of KEYNOTE‑087, which pooled data from both subpopulations, and the Cheah study. However, the company did not provide information to allow the ERG to confirm this estimate. The committee noted that at week\xa024 in the Cheah study, 88% of the standard-care population were alive. Using a hazard ratio of 13.13 estimated that only 78% (population 1) or 72% (population 2) of the standard-care population were alive, and using a hazard ratio of 1 estimated a value of 98%. Further analysis provided by the company used alternative hazard ratios for overall survival in weeks 0\xa0to\xa024, which were calibrated to match observed survival data for standard care from Cheah et al. (hazard ratios of 8.01 for population\xa01 and 5.18 for population\xa02). The ERG had concerns about the use of a methodology that matched overall survival estimates to those at a single point, because this does not follow conventional curve-fitting methodology and may result in the curve being a poor fit to the data at other time points. However, because data were not provided to validate the use of the 13.13 hazard ratio and a hazard ratio of 1.0 lacked face validity, the ERG had a slight preference for using the alternative hazard ratios in the week‑24 economic model. The ERG commented that because of uncertainty about the most appropriate value to use, the results of the week‑24 model should be interpreted with caution, and should only be considered as a scenario analysis. The committee concluded that the difference in overall survival at week\xa024 is subject to uncertainty, but is likely to have been overestimated in the model using a naive-indirect comparison between Cheah and KEYNOTE‑087.\n\n## There is uncertainty about the parametric overall and progression-free survival curves used to model the pre-allogeneic transplant period\n\nThe ERG commented that the choice of parametric model for overall and progression-free survival in the period before allogeneic stem cell transplant can affect the results of the model. The committee heard that different parametric models for progression-free survival in the pre-allogeneic stem cell transplant period had been used in the 24‑week model, compared with the 12‑week models, and some of these had poor statistical fit with the Kaplan–Meier curve from KEYNOTE‑087. A subsequently updated 24‑week model used the same parametric models for progression-free survival as the 12‑week model. The committee questioned why parametric models had been used for modelling when observed survival data are available for both the 12‑week and 24‑week time points. The committee concluded that the choices made by the company to model progression-free and overall survival in the 24‑week model pre-allogeneic stem cell transplant period introduced considerable uncertainty, which had not been fully investigated. The committee considered that the use of observed survival data in the pre-allogeneic stem cell transplant period in the model would have been preferable.\n\n# Rate of allogeneic stem cell transplants\n\n## The uptake rate of allogeneic stem cell transplant is uncertain\n\nTo estimate the uptake of allogeneic stem cell transplant, the company combined results from 2\xa0surveys of clinicians. Data from KEYNOTE‑087 were not used by the company, because uptake of allogeneic stem cell transplant was low in the study and they did not consider it to be representative of UK practice. The committee considered that survey results provide suboptimal evidence to inform parameter estimates and heard from the ERG that the same clinicians could have been included in both surveys, potentially resulting in double-counting in the combined results. The ERG also stated that the results represented expected, rather than observed, transplant rates. The committee noted that the sample size of the survey was small and heard from a clinical expert that this was to be expected because only a small number of clinicians treat this disease in the UK. Combining the 2\xa0surveys resulted in a higher predicted rate of allogeneic stem cell transplants than in the single survey carried out by the company. The committee heard from a clinical expert that in their opinion the number of people with a complete or partial response to treatment who would have an allogeneic stem cell transplant is higher than the estimates from the company's survey alone (which were 57% for complete response and 44% for partial response), and closer to the combined overall mean (values are academic in confidence and cannot be reported here). The committee concluded that there is considerable uncertainty about whether the rates of allogeneic stem cell transplant used in the models are an accurate reflection of transplant rates in UK clinical practice. The committee concluded that combining the results of the 2\xa0surveys did increase the number of responses, although the combined number of responses was still small. However, there remained uncertainty about the validity and reliability of clinical predictions, as well as the potential duplication of clinicians in the combined survey.\n\n## It is appropriate to assume that people with progressed disease would not have allogeneic stem cell transplant\n\nThe company's models assume that patients with progressed disease do not have allogeneic stem cell transplant. The committee heard from the ERG that some clinicians included in the company survey had suggested that some patients with progressed disease may go on to have a transplant. A clinical expert stated that this was not done in current practice, and noted that guidelines from the British Committee for Standards in Haematology advise against transplants for people with progressive disease. The committee concluded that it is appropriate to assume that patients with progressed disease do not have allogeneic stem cell transplants.\n\n# Stopping rule\n\n## It is appropriate to assume that people will have pembrolizumab for up to 24\xa0months\n\nThe company's models assume that treatment with pembrolizumab continues for up to 24\xa0months as in the trial protocol for KEYNOTE‑087, unless unacceptable toxicity occurs. The committee was aware that a 24‑month stopping rule is not included in the summary of product characteristics and it questioned how long pembrolizumab treatment would be continued in clinical practice, particularly for people unable to have allogeneic stem cell transplant. It noted a submission received from NHS England, which stated that an assumption of discontinuation at 24\xa0months is appropriate and is supported by the current evidence base. The committee therefore concluded that stopping treatment with pembrolizumab at a maximum of 24\xa0months in the models is appropriate.\n\n# Utility values in the economic models\n\n## There is considerable uncertainty about the utility value for progressed disease\n\nThe committee considered the utility values used in the company's and the ERG's base-case analyses. The company aims to publish utility data from KEYNOTE‑087 and therefore considers the results to be academic in confidence, so they cannot be reported here. The committee noted that the company used utility data from KEYNOTE‑087 from week\xa012 only, and that they had estimated the utility for progressed disease by applying a decrement from Swinburn et al. (2015). It heard from the company that this was because EQ-5D data were only collected in KEYNOTE‑087 for up to 30\xa0days post-progression, and any longer-term effects of progression will therefore not have been captured. The committee noted that the company's utility values decreased substantially when disease progressed and it considered that the size of the decrease, relative to the other health states in the model, is implausible. In its base-case analysis of the company's original model, the ERG had used utility values from KEYNOTE‑087 alone. It preferred to use a mixed-effects model provided by the company, incorporating all available EQ-5D data from KEYNOTE‑087, rather than using only the 12‑week data. The committee noted that this results in a far smaller decrease in utility when disease progresses than estimated by the company. The committee heard from a clinical expert that symptoms caused by progressed disease will not immediately appear, but are expected to worsen over time, although receiving the diagnosis of disease progression alone could have a substantial effect on the patient. Consequently, it is plausible that the utility for progressive disease was too high in the ERG's base case, but it is unlikely to be as low as the value proposed by the company. The committee therefore concluded that there is considerable uncertainty about the utility decrease that occurs when disease progresses, and that the actual value is likely to be between the company's and the ERG's base-case values.\n\n# Cost-effectiveness estimates\n\n## There is uncertainty about the time to allogeneic stem cell transplant, which is a key driver of the cost-effectiveness estimates\n\nThe committee noted that how allogeneic stem cell transplant is incorporated in the models is a major driver of incremental QALYs for pembrolizumab compared with standard care. The company's submission stated that the average time to transplant is likely to be between 12\xa0and\xa024\xa0weeks after starting treatment. The committee noted its previous consideration that it is unrealistic to assume that all allogeneic stem cell transplants would have occurred by week\xa012 (see section\xa03.5). It considered that, in practice, allogeneic stem cell transplants are likely to occur between weeks 12\xa0and\xa024. It also heard from a clinical expert that all allogeneic stem cell transplants are likely to have occurred by week\xa024. The most plausible ICER is therefore likely to fall between the values predicted by models using a fixed time of transplant of 12\xa0and 24\xa0weeks.\n\n## The cost effectiveness of pembrolizumab relative to standard care in population\xa01 is highly uncertain\n\nAfter the committee concluded at its second meeting that a plausible ICER for population\xa01 could not be accurately estimated using the company's 12‑week or 24‑week model, the company provided updated 12‑week and 24‑week analyses for the third appraisal committee meeting. These included an updated commercial access agreement and changes to the parametric distributions used for progression-free and overall survival in the models. The company also presented further scenario analyses to explore some of the uncertainties the committee had highlighted in the consultation document. For population\xa01, the updated base-case ICERs were £42,123 (24‑week model) and £49,058 (12‑week model) per QALY gained. The ERG implemented their preferred assumptions in the updated models and produced ICERs of £45,829 (24‑week model) and £54,325 (12‑week model) per QALY gained. The ERG commented that there is still substantial uncertainty associated with the model results, particularly for the 24‑week model (see section\xa03.7 and section\xa03.8). The committee recalled its conclusion that the most plausible ICER is likely to fall between the values predicted by models using a fixed time of transplant of 12\xa0and 24\xa0weeks (section\xa03.13). It noted that the range of ICERs produced by the company's and ERG's 24‑week and 12‑week models are between £42,100 and £54,300 per QALY gained, but that these results are highly uncertain because of the total life-years predicted by the model (see section\xa03.17), the uncertainties associated with the 24‑week model, uptake rate and timing of allogenic stem cell transplant (see section\xa03.9 and section\xa03.13). The committee concluded that because of the substantial uncertainty associated with the model results, the ICERs for population\xa01 remain highly uncertain.\n\n## A requested cost-comparison with nivolumab for population\xa01 was not provided\n\nThe committee noted that NICE technology appraisal guidance recommends nivolumab for use in population\xa01 (TA462), and that the committee in that appraisal concluded that the most plausible ICER is likely to be around £30,000 per QALY gained. The ERG commented that the committee's and ERG's preferred analyses in TA462 used the same cost of allogenic stem cell transplant (from Radford et al. 2017) as used in the current appraisal. The committee noted that, despite using the same study to provide comparator data for standard care (Cheah et al. 2016), the total QALYs and costs generated by modelling standard care for population\xa01 in the company's models for the current appraisal of pembrolizumab are higher than those generated for standard care in TA462. It noted a statement from NHS England that, compared with nivolumab, pembrolizumab may have clinical and cost benefits because it is administered less frequently. The committee further noted that nivolumab's marketing authorisation had recently changed to fixed-dosing, rather than dosing based on body weight. A clinical expert commented that the clinical effectiveness of pembrolizumab and nivolumab in this population is likely to be similar. The committee therefore concluded that because of the uncertainties in the company's modelling for this population, and the substantial differences in its results compared with the nivolumab model, a cost-comparison between the 2\xa0technologies may address these uncertainties for the NHS. It requested that this should be provided by the company. The company did not provide a cost-comparison for the third committee meeting. The committee heard from the company that based on a naive comparison, results from single-arm trials are more favourable for pembrolizumab and that there are insufficient comparative data to confirm that the clinical effectiveness of the 2\xa0drugs is similar. The company also commented that the 2\xa0drugs differ in chemical structure. The committee noted that the company had not provided evidence to demonstrate different clinical efficacy between nivolumab and pembrolizumab, or provided a convincing explanation as to why the treatment effects would be likely to differ. The committee concluded that, in the absence of a cost-comparison with nivolumab, it can only base its estimate of cost effectiveness for pembrolizumab in population\xa01 on the analyses comparing it with standard of care and that the results of these analyses are highly uncertain.\n\n## The most plausible ICER for pembrolizumab in population 2 is highly uncertain\n\nThe committee noted its conclusions from the first and second appraisal meetings; that the cost effectiveness of pembrolizumab in population\xa02 is highly uncertain, and that a plausible ICER could not be accurately estimated using the company's 12‑week or 24‑week models. The committee noted that the company had provided updated 12‑week and 24‑week scenario analyses for the third appraisal committee meeting (see section\xa03.14). For population\xa02, the updated base-case ICERs are £36,950 (24‑week model) and £55,628 (12‑week model) per QALY gained. The ERG implemented their preferred assumptions in the updated models provided for the third committee meeting, which produced ICERs of £42,501 (24‑week model) and £62,527 (12‑week model) per QALY gained. The ERG commented that there is still substantial uncertainty associated with the model results, particularly for the 24‑week model (see section\xa03.7 and section\xa03.8). The committee concluded that because of the substantial uncertainty associated with the model results, including the total life-years generated by the model (see section\xa03.14 and section\xa03.17) it is unable to predict the most plausible ICER for population\xa02, but the extreme values from the company's and ERG's 24‑week and 12‑week models (that is, between £37,000 and £62,500 per QALY gained) reflected a plausible range in which the true ICER may fall. The committee concluded that the estimates of cost effectiveness are too uncertain to recommend pembrolizumab for routine use.\n\n## There is a lack of face validity between the modelled survival estimates for standard care and the clinical evidence, and the company's assertion that end-of-life criteria are met\n\nThe committee was concerned that there was a lack of face validity between the modelled survival for standard care and the clinical evidence, and for the company's assertion that end-of-life criteria are met, because more than 2\xa0life-years were estimated for standard care in the company's base-case models. The company explained that it used aggregated data from the Cheah study in the model, because it did not have access to individual patient data from the study. Survival estimates for people who could not have allogeneic stem cell transplant are therefore likely to have been influenced by data from people who did have stem cell transplant. The committee heard from a clinical expert that they would expect overall survival, particularly for population\xa02, to be closer to that reported in the literature (median overall survival of between 17.1\xa0and 19\xa0months), as presented in the company's submission. The company highlighted that Eyre et al. reported a median overall survival of 12.2\xa0months (95% CI 8.1 to 18.3) for people who were transplant naive and were unable to have a stem cell transplant after treatment with brentuximab vedotin, in a UK population. The committee concluded that there is lack of face validity between the modelled survival estimates for standard care and the clinical evidence, and company's assertion that end-of-life criteria are met, which further adds to the uncertainty about the results produced by the models.\n\n# Innovation\n\n## Pembrolizumab's benefits are captured in the measurement of QALYs\n\nThe company considered pembrolizumab to be an innovative treatment. A clinical expert explained that there is an unmet need for treatment to allow people with disease that has not responded or relapsed after brentuximab vedotin, and who cannot have autologous stem cell transplant, to have allogeneic stem cell transplant, which is potentially curative. The committee concluded that pembrolizumab would be beneficial for patients, but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# End of life\n\n## The committee agreed that, on balance, pembrolizumab meets the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company made the case that pembrolizumab meets the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months) based on available literature estimates of median overall survival for people with relapsed or refractory classical Hodgkin lymphoma. The committee noted that more than 2\xa0life-years were estimated for standard care in the company's models, which is inconsistent with the company's claim and the published literature. However, the committee noted the company's explanation for the higher number of life-years produced by the models (see section\xa03.17). It also noted the conclusion of the NICE technology appraisal committee for nivolumab (TA462), in which models using Cheah data for standard care predicted overall survival of more than 24\xa0months for the comparator treatment arm. The committee concluded that while pembrolizumab did not unequivocally meet the criterion for short life expectancy, it is plausible that the criterion could apply. The committee concluded that on balance, pembrolizumab meets the criterion for short life expectancy.\n\n## Pembrolizumab offers an extension to life of at least 3\xa0months\n\nThe committee considered that based on survival data from KEYNOTE‑087 and model results, there is sufficient evidence to indicate that pembrolizumab offers an extension to life of at least 3\xa0months.\n\n# Cancer Drugs Fund\n\n## The committee considered pembrolizumab as an option for use in the Cancer Drugs Fund\n\nHaving concluded that pembrolizumab could not be recommended for routine use (see section\xa03.16) the committee considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum).\n\n## The company proposed pembrolizumab for the Cancer Drugs Fund for population\xa02\n\nThe company commented that it has no further plans to collect data on pembrolizumab for treating relapsed or refractory Hodgkin lymphoma in population\xa02. It requested that the committee consider pembrolizumab for inclusion in the Cancer Drugs Fund for this population to allow further data collection, which may reduce the uncertainty.\n\nIt suggested data that could be feasible for collection in the Cancer Drugs Fund:\n\nproportion of people who have an allogeneic stem cell transplant\n\ntiming of allogenic stem cell transplant\n\nduration of pembrolizumab treatment before allogeneic stem cell transplant.The company noted that data collection should include long-term follow-up of all people having pembrolizumab, regardless of whether they subsequently have allogeneic stem cell transplant. The committee noted the considerable unmet need for treatment in population\xa02 (see section\xa03.1) and that there is considerable uncertainty about the most plausible ICER for this population, which is likely to be between £37,000 and £62,500 per QALY gained (see section\xa03.16). It noted that time to allogeneic stem cell transplant is a key driver of the cost-effectiveness estimates and there is considerable uncertainty about the true value (see section\xa03.13). There is also uncertainty about whether the rates of allogeneic stem cell transplant used in the models (which are based on clinician surveys) are an accurate reflection of transplant rates in UK clinical practice (see section\xa03.9). The committee concluded that these are appropriate outcomes to collect data on, and this would reduce uncertainty in the cost-effectiveness estimate for population\xa02. It considered that overall survival for people having pembrolizumab would be a useful long-term outcome to measure.\n\n## Pembrolizumab is recommended as an option for use in the Cancer Drugs Fund for population\xa02\n\nThe committee concluded that pembrolizumab meets the criteria to be considered for inclusion in the Cancer Drugs Fund for population\xa02. It therefore recommended pembrolizumab for use within the Cancer Drugs Fund as an option for adults with relapsed or refractory classical Hodgkin lymphoma who have had brentuximab vedotin and cannot have autologous stem cell transplant, if the conditions in the managed access agreement are followed.\n\n## Pembrolizumab is not recommended as an option for use in the Cancer Drugs Fund for population\xa01\n\nThe committee considered pembrolizumab for inclusion in the Cancer Drugs Fund for population\xa01. It noted that the company had not requested that this population should be considered in the Cancer Drugs Fund. It further noted that nivolumab is in routine use for this population, therefore people in this population already have access to immunotherapy. The committee was unable to resolve its uncertainties about the relative cost effectiveness of pembrolizumab and nivolumab because a requested cost-comparison was not provided. The committee did not recommend pembrolizumab for use within the Cancer Drugs Fund for population\xa01.\n\n# Conclusions\n\n## Pembrolizumab is not recommended as an option for population\xa01\n\nPembrolizumab is a clinically effective treatment, compared with standard care, for relapsed or refractory classical Hodgkin lymphoma, although there is uncertainty about the size of the effect (see section\xa03.4). Despite considerable uncertainty in the results of the model provided by the company for this appraisal (see section\xa03.14 and section\xa03.15), the model results had to be used for decision making because a requested cost-comparison with nivolumab for this population was not provided. The committee noted that the estimated ICERs in the current appraisal are substantially higher than the most plausible ICER in TA462. The committee took into account the case for pembrolizumab meeting the end-of-life criteria (see section\xa03.19 and section\xa03.20). However, because of the considerable uncertainty associated with the model results there is insufficient justification for recommending pembrolizumab as a cost-effective use of NHS resources in population\xa01.\n\n## Pembrolizumab is recommended for use in the Cancer Drugs Fund for population\xa02\n\nThe committee noted that because there is no licensed immunotherapy for population\xa02 (that is, people who have had brentuximab vedotin and who cannot have allogeneic stem cell transplant) there is a high unmet need for treatment (see section\xa03.1). The most plausible ICER for pembrolizumab in population\xa02 is highly uncertain (see section\xa03.16) and therefore it cannot be recommended for use in routine commissioning. However, it is plausible that pembrolizumab could be cost effective in this population, and therefore it is recommended for use within the Cancer Drugs Fund. Further data collection through inclusion in the Cancer Drugs Fund will allow a more accurate estimate of the cost effectiveness of pembrolizumab in this population (see section\xa05).", 'Recommendations for data collection': 'Proposals for further data collection in the Cancer Drugs Fund include:\n\nproportion of people having pembrolizumab who have an allogenic stem cell transplant\n\ntime to allogenic stem cell transplant\n\nduration of treatment with pembrolizumab before allogenic stem cell transplant\n\nlong-term follow-up of people having pembrolizumab with or without subsequent allogenic stem cell transplant (in particular, collection of data on overall survival).'}
|
https://www.nice.org.uk/guidance/ta540
|
Evidence-based recommendations on pembrolizumab (Keytruda) for treating relapsed or refractory classical Hodgkin lymphoma in adults.
|
4912ae31993fcaf146c5672096b43768c9c013b2
|
nice
|
Superior rectal artery embolisation for haemorrhoids
|
Superior rectal artery embolisation for haemorrhoids
Evidence-based recommendations on superior rectal artery embolisation for haemorrhoids in adults. This involves blocking the blood vessels supplying the haemorrhoids with tiny plastic particles or metal coils.
# Recommendations
Current evidence on the safety and efficacy of superior rectal artery embolisation for haemorrhoids is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should report details of patient selection, and follow‑up efficacy (including symptom relief), need for subsequent treatments, quality of life and safety outcomes for at least 1 year.# The condition, current treatments and procedure
# The condition
Haemorrhoids occur when the vascular anal cushions become enlarged. Some patients may be asymptomatic but others have symptoms of bleeding, itching or discomfort. Goligher's classification is commonly used to grade haemorrhoids from I to IV. Small symptomatic haemorrhoids are classified as grade I and they do not prolapse. Larger haemorrhoids may prolapse out of the anus. Prolapsed haemorrhoids may reduce spontaneously after defaecation (grade II), may need to be reduced digitally (grade III), or they may not be reducible and remain prolapsed (grade IV).
# Current treatments
Grade I and II haemorrhoids may be managed by changes in diet or using laxatives, or treated by topical applications (such as corticosteroid creams or local anaesthetics). Established interventional treatments include rubber band ligation, sclerosant injections, infrared coagulation or electrocoagulation.
Established treatments for symptomatic grade III and IV haemorrhoids include haemorrhoidectomy, stapled haemorrhoidopexy, haemorrhoidal artery ligation and electrocoagulation.
# The procedure
Superior rectal artery embolisation for haemorrhoids is done under local anaesthesia. A catheter is passed into the inferior mesenteric artery through an introducer sheath in a large artery (usually the femoral artery). A microcatheter is then passed into the superior rectal arteries using X‑ray fluoroscopy to confirm correct placement and to identify the branches of the superior rectal artery. Small coils (about 2 mm to 3 mm in diameter) or particles are placed into the most distal branches of the superior rectal arteries, to occlude the blood supply to the haemorrhoids.
The aim is to occlude permanently the branches that feed the haemorrhoidal plexuses and relieve the symptoms associated with haemorrhoids, such as pain and bleeding.
|
{'Recommendations': 'Current evidence on the safety and efficacy of superior rectal artery embolisation for haemorrhoids is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report details of patient selection, and follow‑up efficacy (including symptom relief), need for subsequent treatments, quality of life and safety outcomes for at least 1\xa0year.', 'The condition, current treatments and procedure': "# The condition\n\nHaemorrhoids occur when the vascular anal cushions become enlarged. Some patients may be asymptomatic but others have symptoms of bleeding, itching or discomfort. Goligher's classification is commonly used to grade haemorrhoids from I\xa0to\xa0IV. Small symptomatic haemorrhoids are classified as grade\xa0I and they do not prolapse. Larger haemorrhoids may prolapse out of the anus. Prolapsed haemorrhoids may reduce spontaneously after defaecation (grade\xa0II), may need to be reduced digitally (grade\xa0III), or they may not be reducible and remain prolapsed (grade\xa0IV).\n\n# Current treatments\n\nGrade\xa0I and\xa0II haemorrhoids may be managed by changes in diet or using laxatives, or treated by topical applications (such as corticosteroid creams or local anaesthetics). Established interventional treatments include rubber band ligation, sclerosant injections, infrared coagulation or electrocoagulation.\n\nEstablished treatments for symptomatic grade\xa0III and\xa0IV haemorrhoids include haemorrhoidectomy, stapled haemorrhoidopexy, haemorrhoidal artery ligation and electrocoagulation.\n\n# The procedure\n\nSuperior rectal artery embolisation for haemorrhoids is done under local anaesthesia. A catheter is passed into the inferior mesenteric artery through an introducer sheath in a large artery (usually the femoral artery). A microcatheter is then passed into the superior rectal arteries using X‑ray fluoroscopy to confirm correct placement and to identify the branches of the superior rectal artery. Small coils (about 2\xa0mm to 3\xa0mm in diameter) or particles are placed into the most distal branches of the superior rectal arteries, to occlude the blood supply to the haemorrhoids.\n\nThe aim is to occlude permanently the branches that feed the haemorrhoidal plexuses and relieve the symptoms associated with haemorrhoids, such as pain and bleeding."}
|
https://www.nice.org.uk/guidance/ipg627
|
Evidence-based recommendations on superior rectal artery embolisation for haemorrhoids in adults. This involves blocking the blood vessels supplying the haemorrhoids with tiny plastic particles or metal coils.
|
22a199355b713c7b1c3de15d5367c25e705594ec
|
nice
|
Leadless cardiac pacemaker implantation for bradyarrhythmias
|
Leadless cardiac pacemaker implantation for bradyarrhythmias
Evidence-based recommendations on leadless cardiac pacemaker implantation for bradyarrhythmias in adults. This involves inserting a device into the heart that helps it beat at a normal rate.
# Recommendations
Evidence on the safety of leadless cardiac pacemaker implantation for bradyarrhythmias shows that there are serious but well-recognised complications. The evidence on efficacy is inadequate in quantity and quality:
For people who can have conventional cardiac pacemaker implantation, leadless pacemakers should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
For people in whom a conventional cardiac pacemaker implantation is contraindicated following a careful risk assessment by a multidisciplinary team, leadless cardiac pacemakers should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do leadless cardiac pacemaker implantation for bradyarrhythmias in people who cannot have conventional cardiac pacemaker implantation should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy compared with conventional pacemaker implantation, and provide them with clear written information. In addition, the use of NICE's information for the public on leadless cardiac pacemaker implantation for bradyarrhythmias is recommended.
Further research in people who could have conventional cardiac pacemaker implantation should report the patient selection criteria and compare leadless pacemakers with conventional pacemakers. Follow‑up should be for at least 5 years and outcomes should include adverse events, symptom relief, quality of life and device durability in the long‑term.
Clinicians should enter details about all patients having leadless cardiac pacemaker implantation for bradyarrhythmias onto the National Institute for Cardiovascular Outcomes Research database and review local clinical outcomes.
The procedure should only be done in specialist centres by clinicians with specific training on, and supervised experience in, inserting the device. Centres where this procedure is done should have both cardiac and vascular surgical support for emergency treatment of complications.
NICE advises clinicians to follow the Medicines and Healthcare products Regulatory Agency's (MHRA) Expert Advisory Group recommendations on leadless cardiac pacemaker therapy.
NICE may review this procedure on publication of further evidence.# The condition, current treatments and procedure
# The condition
Bradyarrhythmias are abnormal heart rhythms that can result in a slow heart rate (bradycardia), usually defined as less than 60 beats per minute. There are a range of causes including diseases such as sick sinus syndrome or atrioventricular block. The most common causes are the natural ageing process, ischaemic heart disease, heart valve disorders and heart failure. If untreated, bradycardia may lead to fatigue, fainting, palpitations, dizziness, heart failure and an increased risk of death.
# Current treatments
Bradyarrhythmias are managed with pacemakers, as described in NICE technology appraisal guidance on dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block and dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block. Dual-chamber pacing is recommended for symptomatic bradycardia caused by sick sinus syndrome, atrioventricular block, or a combination of sick sinus syndrome and/or atrioventricular block, and also for sick sinus syndrome in people without atrioventricular block. Single-chamber ventricular pacemakers may be used for atrioventricular block alone or with sick sinus syndrome in people with continuous atrial fibrillation, or people who have specific factors such as frailty or comorbidities that influence the balance of risks and benefits in favour of single-chamber pacing.
# The procedure
The aim of implanting a leadless cardiac pacemaker is to detect cardiac bradyarrhythmias and deliver electric pulses to the heart to increase the heart rate. The leadless pacemaker has a built‑in pulse generator, battery and electrodes. The procedure is done under local anaesthesia, with or without sedation, in a cardiac catheterisation laboratory. Under fluoroscopic guidance, the proximal end of the pacemaker is attached to a deflectable bespoke delivery catheter system and inserted percutaneously through the femoral vein using a dedicated introducer sheath. It is then advanced into the right atrium through the tricuspid valve, into the right ventricle and positioned near the apex or lower septum. Contrast may be injected into the right ventricle to visualise the desired location. Once positioned, the pacemaker is deployed and securely implanted into the endocardial wall using a fixation mechanism (a screw‑in helix or nitinol tines). An electrode at the distal end of the pacemaker delivers electrical impulses that pace the heart. Electrical measurements are taken and, if satisfactory, the pacemaker is released from the catheter and the catheter is removed. If the position is suboptimal, the pacemaker can be detached from the endocardium and repositioned prior to final release of the delivery catheter.
The pacemaker is programmed using an external programmer that transmits signals to it. The pacemaker can be retrieved using a catheter retrieval system, if device dislodgement is discovered at follow‑up.
The device can only detect and pace the right ventricle (single chamber) in contrast to some conventional pacemakers that can provide dual-chamber (right atrium and right ventricle) detection and pacing. It is therefore suitable for people who only need single-chamber ventricular pacing.
|
{'Recommendations': "Evidence on the safety of leadless cardiac pacemaker implantation for bradyarrhythmias shows that there are serious but well-recognised complications. The evidence on efficacy is inadequate in quantity and quality:\n\nFor people who can have conventional cardiac pacemaker implantation, leadless pacemakers should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFor people in whom a conventional cardiac pacemaker implantation is contraindicated following a careful risk assessment by a multidisciplinary team, leadless cardiac pacemakers should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do leadless cardiac pacemaker implantation for bradyarrhythmias in people who cannot have conventional cardiac pacemaker implantation should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy compared with conventional pacemaker implantation, and provide them with clear written information. In addition, the use of NICE's information for the public on leadless cardiac pacemaker implantation for bradyarrhythmias is recommended.\n\nFurther research in people who could have conventional cardiac pacemaker implantation should report the patient selection criteria and compare leadless pacemakers with conventional pacemakers. Follow‑up should be for at least 5\xa0years and outcomes should include adverse events, symptom relief, quality of life and device durability in the long‑term.\n\nClinicians should enter details about all patients having leadless cardiac pacemaker implantation for bradyarrhythmias onto the National Institute for Cardiovascular Outcomes Research database and review local clinical outcomes.\n\nThe procedure should only be done in specialist centres by clinicians with specific training on, and supervised experience in, inserting the device. Centres where this procedure is done should have both cardiac and vascular surgical support for emergency treatment of complications.\n\nNICE advises clinicians to follow the Medicines and Healthcare products Regulatory Agency's (MHRA) Expert Advisory Group recommendations on leadless cardiac pacemaker therapy.\n\nNICE may review this procedure on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nBradyarrhythmias are abnormal heart rhythms that can result in a slow heart rate (bradycardia), usually defined as less than 60\xa0beats per minute. There are a range of causes including diseases such as sick sinus syndrome or atrioventricular block. The most common causes are the natural ageing process, ischaemic heart disease, heart valve disorders and heart failure. If untreated, bradycardia may lead to fatigue, fainting, palpitations, dizziness, heart failure and an increased risk of death.\n\n# Current treatments\n\nBradyarrhythmias are managed with pacemakers, as described in NICE technology appraisal guidance on dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block and dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block. Dual-chamber pacing is recommended for symptomatic bradycardia caused by sick sinus syndrome, atrioventricular block, or a combination of sick sinus syndrome and/or atrioventricular block, and also for sick sinus syndrome in people without atrioventricular block. Single-chamber ventricular pacemakers may be used for atrioventricular block alone or with sick sinus syndrome in people with continuous atrial fibrillation, or people who have specific factors such as frailty or comorbidities that influence the balance of risks and benefits in favour of single-chamber pacing.\n\n# The procedure\n\nThe aim of implanting a leadless cardiac pacemaker is to detect cardiac bradyarrhythmias and deliver electric pulses to the heart to increase the heart rate. The leadless pacemaker has a built‑in pulse generator, battery and electrodes. The procedure is done under local anaesthesia, with or without sedation, in a cardiac catheterisation laboratory. Under fluoroscopic guidance, the proximal end of the pacemaker is attached to a deflectable bespoke delivery catheter system and inserted percutaneously through the femoral vein using a dedicated introducer sheath. It is then advanced into the right atrium through the tricuspid valve, into the right ventricle and positioned near the apex or lower septum. Contrast may be injected into the right ventricle to visualise the desired location. Once positioned, the pacemaker is deployed and securely implanted into the endocardial wall using a fixation mechanism (a screw‑in helix or nitinol tines). An electrode at the distal end of the pacemaker delivers electrical impulses that pace the heart. Electrical measurements are taken and, if satisfactory, the pacemaker is released from the catheter and the catheter is removed. If the position is suboptimal, the pacemaker can be detached from the endocardium and repositioned prior to final release of the delivery catheter.\n\nThe pacemaker is programmed using an external programmer that transmits signals to it. The pacemaker can be retrieved using a catheter retrieval system, if device dislodgement is discovered at follow‑up.\n\nThe device can only detect and pace the right ventricle (single chamber) in contrast to some conventional pacemakers that can provide dual-chamber (right atrium and right ventricle) detection and pacing. It is therefore suitable for people who only need single-chamber ventricular pacing.'}
|
https://www.nice.org.uk/guidance/ipg626
|
Evidence-based recommendations on leadless cardiac pacemaker implantation for bradyarrhythmias in adults. This involves inserting a device into the heart that helps it beat at a normal rate.
|
77d37ed15302009348701039c1b6665a83755ca1
|
nice
|
Lutetium (177Lu) oxodotreotide for treating unresectable or metastatic neuroendocrine tumours
|
Lutetium (177Lu) oxodotreotide for treating unresectable or metastatic neuroendocrine tumours
Evidence-based recommendations on lutetium (177Lu) oxodotreotide (Lutathera) for treating unresectable or metastatic neuroendocrine tumours in adults.
# Recommendations
Lutetium (177Lu) oxodotreotide is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
NETs can affect the pancreas and gastrointestinal tissue and are difficult to diagnose and treat. Current treatment options include everolimus, sunitinib and best supportive care.
Clinical trial evidence shows that lutetium (177Lu) oxodotreotide (referred to as lutetium) is effective for treating somatostatin receptor-positive gastrointestinal and pancreatic NETs. Indirect comparison with everolimus, sunitinib and best supportive care suggests lutetium is effective for treating gastrointestinal and pancreatic NETs in people with progressive disease.
For treating pancreatic NETs, lutetium meets NICE's end-of-life criteria. Compared with everolimus, sunitinib and best supportive care, the cost-effectiveness estimates are within the range NICE normally considers acceptable. So lutetium can be recommended for treating pancreatic NETs.
For treating gastrointestinal NETs, lutetium does not meet the end-of-life criteria because life expectancy for this form of the disease is between 5 and 6 years. But it can be recommended because the most plausible cost-effectiveness estimate is within what NICE normally considers acceptable and treatment options for gastrointestinal NETs are limited.# Information about lutetium (177Lu) oxodotreotide
Marketing authorisation indication
Lutetium (177Lu) oxodotreotide (Lutathera, AAA, referred to as lutetium) is indicated for 'unresectable or metastatic, progressive, well-differentiated (G1 and G2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults'.
Dosage in the marketing authorisation
Lutetium is administered as an intravenous infusion. A single cycle consists of 4 infusions of 7.4 gigabecquerels (GBq). The recommended interval between infusions is 8 weeks.
Price
£71,500.00 for 4 administrations of 7.4 GBq (excluding VAT; company submission).
The company has a commercial arrangement. This makes lutetium available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Clinical need and current practice
## People with NETs will welcome new treatment options because of high unmet need
The committee understood that neuroendocrine tumours (NETs) can affect the pancreas and gastrointestinal tissue. They are difficult to diagnose and treat, can significantly affect emotional health and often mean that people are unable to work. The patient expert explained that lutetium (177Lu) oxodotreotide (referred to as lutetium) is a very effective treatment with tolerable side effects, which allowed people to live a relatively normal life. The committee concluded that there is a recognised need for treatment for NETs at different sites.
## Everolimus, sunitinib and best supportive care are appropriate comparators for lutetium for pancreatic NETs
The clinical experts explained that managing NETs in the NHS follows the European Neuroendocrine Tumor Society's (ENETs) guidelines. For treating pancreatic NETs causing symptoms (functional NETs) in people with progressive disease, options include everolimus and lutetium. For non-functional pancreatic NETs, the guidelines suggest lutetium or chemotherapy for progressive disease after offering everolimus or sunitinib. The clinical experts stated that although most centres would use lutetium after everolimus or sunitinib, there is no evidence to show that this is more effective than using it instead of everolimus or sunitinib. They further explained that chemotherapy is sometimes used if people have symptoms because of the bulk of their disease (mainly people with high disease burden with a Ki-67 proliferative index of around 20% or more, that is, grade 3 tumours). The committee agreed that chemotherapy was not a relevant comparator because lutetium is indicated for grade 1 and 2 tumours. The committee concluded that everolimus, sunitinib and best supportive care were appropriate comparators.
## Everolimus and best supportive care are appropriate comparators for lutetium for gastrointestinal NETs
For treating functional and non-functional advanced gastrointestinal NETs in people with progressive disease, the ENETs guidelines suggest lutetium as an option with everolimus, and interferons. The committee agreed that everolimus may be a relevant comparator for lutetium but noted that its marketing authorisation is for non-functional gastrointestinal NETs only. The clinical experts explained that although interferons may be considered in people with progressive disease, they are not routinely used in England because of their toxicity. The committee agreed that interferons were not relevant comparators for lutetium. It therefore concluded that the relevant comparators for lutetium for gastrointestinal NETs were everolimus (non-functional disease only) and best supportive care.
# Clinical trial evidence (ERASMUS)
## Lutetium is effective for treating gastroenteropancreatic NETs
ERASMUS is a phase 1 and 2 single-arm study, which evaluated the efficacy of lutetium in people with different somatostatin receptor-positive tumour types, including pancreatic, foregut, midgut, hindgut and bronchial NETs. However, because bronchial NETs are not covered by the marketing authorisation for lutetium, these results were not considered by the committee. The committee was concerned that ERASMUS was a single-arm open-label study but acknowledged that it was the largest study of NETs currently available. It noted that the company only presented results for the Dutch population (n=360) in the trial (see table 1). This was because of the high percentage of non-Dutch patients lost to follow-up, which resulted in a substantial amount of missing data.
Type of neuroendocrine tumours (NETs)
Median progression-free survival in months (95% confidence interval)
Median overall survival in months (95% confidence interval)
Gastroenteropancreatic (n=360, includes bronchial NETs)
(24.8 to 31.4)
(54.8 to 67.4)
Pancreatic (n=133)
(24.3 to 36.3)
(57.2 to 80.9)
Midgut (n=183)
(23.9 to 33.3)
(47.5 to 63.2)
Foregut (n=12)
(10.9 to not reached)
Not reached
Hindgut (n=13)
(18.9 to 35.0)
Not reached
The committee concluded that lutetium was clinically effective for people with gastroenteropancreatic NETs.
# Clinical trial evidence (NETTER-1)
## Lutetium is effective for treating midgut gastrointestinal NETs
NETTER‑1 is a phase 3, open-label, randomised controlled trial, which recruited people with inoperable, progressive, somatostatin receptor-positive, midgut gastrointestinal NETs. The trial compared lutetium plus long-acting release octreotide 30 mg (n=116) with long-acting release octreotide 60 mg (n=113). The results from the June 2016 data-cut were:
Progression-free survival: hazard ratio (HR) 0.21 (95% confidence interval 0.14 to 0.33).
Overall survival: HR 0.54 (95% CI 0.33 to 0.86), median overall survival not reached in the lutetium arm.
Overall survival, adjusted for crossover from octreotide 60 mg to lutetium: HR 0.49 (95% CI 0.30 to 0.80).The committee considered whether these results were relevant to clinical practice in England given that the dose of the comparator, octreotide 60 mg, is higher than the licensed dose of 30 mg. The clinical experts confirmed that the results were relevant because some centres would increase the dose of octreotide for progressive disease. The clinical experts explained that octreotide 60 mg was actually more effective than best supportive care, therefore underestimating the results for lutetium. Although NETTER‑1 only recruited people with midgut gastrointestinal NETs, the clinical experts explained that they would not expect much difference in the efficacy of lutetium across the different tumour sites. The committee considered that the results were relevant and supported the conclusions from ERASMUS. It concluded that lutetium was clinically effective for people with midgut gastrointestinal NETs compared with octreotide 60 mg.
# Indirect and mixed treatment comparisons
## The company's matched adjusted indirect treatment comparisons are very uncertain
The company did matched adjusted indirect treatment comparisons (MAICs) for pancreatic NETs and gastrointestinal NETs using lutetium data from ERASMUS. Data for the comparators were taken from 3 randomised controlled trials (A6181111, RADIANT‑3 and RADIANT‑4). For pancreatic NETs, lutetium was compared with sunitinib from A6181111 and with everolimus and best supportive care from RADIANT‑3. For gastrointestinal NETs, lutetium was compared with everolimus and best supportive care from RADIANT‑4. The assessment group highlighted several limitations in the company's MAICs:
The company only included the Dutch population from the ERASMUS study, which resulted in very small sample sizes after the selected baseline covariates were matched.
The approach to selecting baseline covariates for matching meant that the most important prognostic factors and treatment effect modifiers, such as tumour functionality and grade and stage of disease, were excluded.
Relative treatment effects were modelled after assuming proportional hazards, without any statistical testing for that assumption.
For the pancreatic NETs MAIC, the company could not carry out a closed network because individual patient data from A6181111 and RADIANT‑3 were not available to them. Also, the single-arm ERASMUS trial was being compared with 2 randomised controlled trials (A6181111 and RADIANT‑3) and the inclusion criteria (such as tumour functionality, grade and stage of disease, presence of somatostatin receptors) among the 3 trials differed.
For gastrointestinal NETs, the company was only able to do a MAIC for progression-free survival because overall survival data from RADIANT‑4 were not available to them.The committee acknowledged these limitations. Therefore it concluded that the results of the company's MAICs for pancreatic NETs and gastrointestinal NETs were associated with uncertainty, which needed to be accounted for in its decision-making.
## The company's network meta-analysis for gastrointestinal NETs is inappropriate for decision-making
The committee noted that the company also did a network meta-analysis for gastrointestinal NETs comparing lutetium with everolimus and best supportive care, using data from NETTER‑1 and RADIANT‑4. However, it noted that there were important differences between the 2 trials:
The control arm of RADIANT‑4 (placebo plus best supportive care) was assumed to be equivalent to the control arm of NETTER‑1 (octreotide 60 mg).
The population from RADIANT‑4 (non-functional gastrointestinal and lung NETs) was assumed to be equivalent to the population from NETTER‑1 (functional and non-functional somatostatin receptor-positive midgut-only NETs).The committee concluded that because of these differences, the trials may not be fully comparable and results from any indirect comparison would not be robust. It therefore agreed that it would not consider the network meta-analysis further.
## The assessment group's MAICs are preferred for decision-making
Having established that the company's MAICs for the pancreatic and gastrointestinal NETs populations were limited, the committee considered the assessment group's revisions to the analyses. It noted that the assessment group had done 3 MAICs based on the NETs location (using ERASMUS), which included revisions to the company's preferred assumptions:
Including additional baseline covariates for matching.
Including both the Dutch and non-Dutch populations from ERASMUS to increase the sample size for matching.
Building a complete network for the pancreatic NETs population; the sunitinib arm by Bucher indirect comparison and the ERASMUS arm by MAIC were matched to RADIANT‑3 as a whole.
Doing a MAIC for overall survival for the gastrointestinal NETs population based on additional data from Novartis (for everolimus).
Doing a MAIC of midgut-only NETs by matching the midgut-only NETs population from ERASMUS to the whole gastrointestinal NETs population in RADIANT‑4.
Estimating relative treatment effects by fitting separate curves to each arm using proportional hazards and accelerated failure time functions.The committee acknowledged that the assessment group's analyses addressed most of the limitations highlighted in the company's MAICs (see section 3.6). It therefore accepted the assessment group's MAICs as the preferred analyses for decision-making. But because the MAIC analysis for midgut-only NETs used the whole gastrointestinal NETs population in RADIANT‑4, the committee considered it inappropriate to consider the midgut NETs population separately. It therefore concluded that it would consider only the MAIC analyses for pancreatic and gastrointestinal NETs for decision-making.
## Lutetium improves progression-free survival and overall survival for people with pancreatic and gastrointestinal NETs
The results of the assessment group's MAICs and Bucher indirect comparisons showed that lutetium was statistically significantly more effective in improving progression-free survival than current treatment (everolimus, sunitinib and best supportive care for pancreatic NETs and everolimus and best supportive care for gastrointestinal NETs). For pancreatic NETs, lutetium was statistically significantly more effective in prolonging overall survival than everolimus (HR 0.54; 95% CI 0.33 to 0.88) and best supportive care (HR 0.22; 95% CI 0.10 to 0.50) but not sunitinib (HR 0.65; 95% CI 0.16 to 2.54). For gastrointestinal NETs, a statistically significant improvement in overall survival was seen only when lutetium was compared with best supportive care (HR 0.34; 95% CI 0.16 to 0.69). The difference in overall survival between lutetium and everolimus was not statistically significant (HR 0.55; 95% CI 0.27 to 1.11), but the committee considered it reasonable to assume that both drugs have similar effectiveness in prolonging survival. The committee concluded that lutetium was effective for people with pancreatic and gastrointestinal NETs compared with current treatment.
# Economic models
## The assessment group's economic model is the most appropriate for decision-making
The company and the assessment group's models were partitioned survival models with health states corresponding to pre-progression, post-progression and death. Both models included data for lutetium and the comparators (everolimus, sunitinib and best supportive care) from the MAIC analyses. The company also included separate analyses comparing lutetium with best supportive care (octreotide 60 mg) using data from NETTER‑1 and analyses using the network meta-analysis of lutetium and everolimus for gastrointestinal NETs. Given the concerns with the population in NETTER‑1 (see section 3.5) and the concerns with the company's indirect treatment comparisons (see section 3.6 and section 3.7), the committee concluded that the assessment group's economic model was the most appropriate for decision-making.
## Applying background mortality in the gastrointestinal NETs analyses is appropriate
The committee noted that in the assessment group's base-case analysis for gastrointestinal NETs, an adjustment in the survival analysis for background mortality was made. It understood that this was applied because of the short follow-up period in the indirect comparison of progression and mortality. It agreed that this approach was appropriate to minimise the effect of death from other causes on relative health benefit.
# Health-related quality of life
## The assessment group's estimates are acceptable for decision-making
For pancreatic NETs, the assessment group used EQ-5D valuations from A6181111 and assumed that the utilities for lutetium, everolimus and sunitinib were equal. The committee had previously accepted this assumption in NICE's technology appraisal guidance on everolimus and sunitinib for treating unresectable or metastatic neuroendocrine tumours in people with progressive disease following the comment from clinical experts that it was reasonable to assume that health-related quality of life would be similar. For gastrointestinal NETs, the assessment group used values estimated from RADIANT‑4 for everolimus, best supportive care and lutetium (progressed disease only) and from ERASMUS for lutetium (stable disease). The committee noted that using alternative sources reduced the incremental cost-effectiveness ratios (ICERs) slightly, more so for pancreatic NETs than for gastrointestinal NETs. The company used values from ERASMUS in its base case for pancreatic and gastrointestinal NETs. The committee understood that new data from NETTER‑1, which showed statistically significant improvement in quality of life for lutetium compared with octreotide, had become available. The company stated that it did not use these data because the model is primarily based on effectiveness data from ERASMUS. Based on the data presented to it, the committee concluded that the assessment group's estimates were acceptable for decision-making.
# Resource use and costs
## None of the analyses reflect the use of somatostatin receptor agonists in clinical practice
The company's definition of best supportive care was based on the design of NETTER‑1, in which all patients had a high dose of octreotide (60 mg) before progression and a lower dose (30 mg) after progression. The committee noted that the company's estimates of somatostatin receptor agonist use were substantially different to the assessment group's estimates, which were based on the observed rates in RADIANT‑3 (pancreatic NETs) and RADIANT‑4 (gastrointestinal NETs). However, the clinical experts explained that the assessment group's estimates were lower than would be seen in clinical practice, particularly for gastrointestinal NETs. The clinical experts stated that for progressive disease, most people with pancreatic or gastrointestinal NETs (approximately 85% and 95%, respectively) would continue having a somatostatin receptor agonist. On further progression, about 10% would stop treatment or reduce their dose. The committee noted the comment from 1 of the experts that about 20% of people would have a somatostatin receptor agonist at a higher dose. The assessment group also presented 3 separate best supportive care scenario analyses:
Scenario 1: octreotide 60 mg in 40% of people in the progression-free health state, best supportive care arm only.
Scenario 2: octreotide 60 mg in 100% of people in the progression-free health state, best supportive care arm only.
Scenario 3: octreotide 30 mg in 90% of people in the progression-free health state, regardless of the treatment arm of the model, reducing to 85% after progression (based on expert opinion).The clinical experts explained that concomitant use of somatostatin receptor agonists with targeted treatments varied in clinical practice. The company emphasised that the marketing authorisation for lutetium is for monotherapy and that only about half of the patients in ERASMUS had octreotide with lutetium. The committee noted that none of the analyses presented completely reflected the views of the clinical experts. However, it agreed that the most reasonable estimate for its decision-making would lie between the assessment group's best supportive care scenarios 2 and 3.
## The dose intensity estimate for lutetium should be based on ERASMUS
The committee noted that the dose intensity estimate for lutetium in the company's model was based on NETTER‑1 instead of ERASMUS, which is the source trial for the lutetium effectiveness data used in the indirect comparisons for pancreatic and gastrointestinal NETs. The assessment group explained that this potentially overestimated the cost effectiveness of lutetium because the dose intensity increased from 86.4% to between 94.4% and 97.8%. However, it stated that when the figures from ERASMUS were implemented in the model, the dose intensity reduced to about 86% to 88%. The committee agreed that the dose intensity should be based on the source trial and concluded that relative dose intensity based on ERASMUS was more appropriate.
## Retreatment with lutetium is not considered
The assessment group included retreatment with lutetium in a sensitivity analysis at the time of the first appraisal committee meeting. In response to consultation on the assessment report, the company stated that retreatment with lutetium was not recommended clinical practice. The committee noted that there was no mention of retreatment after disease progression in the lutetium summary of product characteristics or any evidence supporting retreatment from the clinical trials that underpinned the marketing authorisation. It also noted that previous treatment with peptide receptor radionuclide therapy at any time before randomisation was an exclusion criterion in NETTER‑1. Also, none of the company's analyses or the assessment group's revised analyses included lutetium retreatment. The committee concluded that it was not appropriate to include retreatment with lutetium after disease progression in its consideration of the clinical and cost effectiveness of lutetium.
## All relevant administration costs for lutetium are included in the assessment group's model
The committee questioned whether there would be additional costs for administering lutetium because it is a radionuclide. The clinical experts explained that the initial scans needed to identify somatostatin receptor-positive tumours are part of standard care. They also stated that although most people having lutetium usually stay overnight in hospital (over 90%), some are discharged the same day. The assessment group's base case assumed that 90% of patients stay overnight. It also used the national average cost of an elective inpatient excess bed day instead of the national average cost of a non-elective inpatient short stay to reduce potential double counting of resources. In a scenario analysis, the assessment group explored lutetium being administered in a day-case setting in 65% of patients. The effect of this assumption on the assessment group's base-case ICERs was minimal. The clinical experts agreed with the company that although a nuclear medicines consultant needs to be present on site, they do not necessarily administer the treatment. Also, the committee noted that the expert evidence submissions stated that no additional resources would be needed for lutetium because several centres in England have been providing it for some time. The committee was satisfied that all relevant costs associated with lutetium had been captured in the assessment group's model.
# Cost-effectiveness results
## There are confidential patient access scheme discounts for lutetium and everolimus
The assessment group's base-case results, which were used in the committee's decision-making, included the confidential patient access scheme discounts for lutetium and everolimus. So the exact cost-effectiveness results cannot be reported here.
## The ICERs for lutetium for pancreatic NETs are less than £30,000 per QALY gained
The committee considered the cost effectiveness of lutetium compared with everolimus, sunitinib and best supportive care for pancreatic NETs. All the deterministic and probabilistic ICERs were below £30,000 per quality-adjusted life year (QALY) gained.
## The ICER for lutetium for gastrointestinal NETs is less than £30,000 per QALY gained
The committee considered the cost effectiveness of lutetium compared with everolimus and best supportive care for gastrointestinal NETs. It recalled that everolimus was only licensed for non-functional NETs, therefore it agreed that best supportive care was the most appropriate comparator. The most plausible ICER for lutetium using the committee's preferred somatostatin receptor agonist scenarios (see section 3.13) was below £30,000 per QALY gained when compared with best supportive care.
# Innovation
## All significant health-related benefits are captured in the analyses
The patient and clinical experts explained that lutetium is an important new treatment option that represents a major change in managing NETs. The company commented that lutetium addresses a significant unmet need for people with inoperable NETs whose disease has progressed on somatostatin analogues. However, the committee concluded that there were no additional health benefits that had not been captured in the QALY calculations.
# End of life
## Lutetium meets NICE's end-of-life criteria for pancreatic NETs
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. For pancreatic NETs, the committee noted that the extrapolated survival for best supportive care was 41.6 months. However, the clinical experts stated that they would expect people with pancreatic NETs to have a life expectancy of less than 24 months (the first end-of-life criterion). The committee recalled that in NICE's technology appraisal guidance on everolimus and sunitinib, these drugs met the short life expectancy criterion based on the clinical experts' views that life expectancy for people with pancreatic NETs was closer to 20.5 months (from A6181111) than to 41.6 months (from RADIANT‑3). It also understood from the assessment group that the choice of parametric extrapolation could be the reason for the different results, so the estimates were very uncertain. Based on the clinical experts' views and previous conclusions from the guidance on everolimus and sunitinib, the committee accepted that life expectancy for people with pancreatic NETs was less than 24 months. The committee noted that the extrapolated survival benefit for lutetium compared with best supportive care, everolimus and sunitinib was over 3 months (64.2, 49.5 and 29.1 months, respectively), meaning that the second end-of-life criterion, of extending life by at least 3 months, was met. The committee therefore concluded that lutetium met the end-of-life criteria for somatostatin receptor-positive pancreatic NETs in people with progressive disease.
## Lutetium does not meet NICE's end-of-life criteria for gastrointestinal NETs
The clinical experts explained that the average life expectancy for people with advanced gastrointestinal NETs was around 5 to 6 years. Survival of less than 24 months, as would be necessary to meet NICE's first end-of-life criterion, was not seen in practice. The committee noted that the extrapolated survival was 58.8 months for best supportive care, meaning that the criterion for short life expectancy of 24 months was not met. For the second criterion, of extension to life of at least 3 months, the difference in extrapolated survival for lutetium compared with best supportive care was 36.1 months. The committee considered that the second criterion was met. However, because the criterion for short life expectancy was not met, the committee concluded that lutetium did not meet the end-of-life criteria for somatostatin receptor-positive gastrointestinal NETs in people with progressive disease.
# Recommendations
## Lutetium is recommended for treating pancreatic NETs
For pancreatic NETs, lutetium met the end-of-life criteria (see section 3.21) and all the ICERs were below £30,000 per QALY gained (see section 3.18). Therefore, the committee concluded that it could be recommended as a cost-effective use of NHS resources for treating somatostatin receptor-positive pancreatic NETs in people with progressive disease.
## Lutetium is recommended for treating gastrointestinal NETs
The committee had concluded that lutetium did not meet the end-of-life criteria for gastrointestinal NETs (see section 3.22). However, it noted that the most plausible ICER was below £30,000 per QALY gained (see section 3.19). The committee understood that the treatment options for this group of people were limited, particularly for people with functional NETs. Based on the ICER estimate and the limited treatment options available, the committee concluded that it could recommend lutetium as a cost-effective use of NHS resources for treating somatostatin receptor-positive gastrointestinal NETs in people with progressive disease.
|
{'Recommendations': "Lutetium (177Lu) oxodotreotide is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic, progressive, well-differentiated (grade\xa01 or grade\xa02), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nNETs can affect the pancreas and gastrointestinal tissue and are difficult to diagnose and treat. Current treatment options include everolimus, sunitinib and best supportive care.\n\nClinical trial evidence shows that lutetium (177Lu) oxodotreotide (referred to as lutetium) is effective for treating somatostatin receptor-positive gastrointestinal and pancreatic NETs. Indirect comparison with everolimus, sunitinib and best supportive care suggests lutetium is effective for treating gastrointestinal and pancreatic NETs in people with progressive disease.\n\nFor treating pancreatic NETs, lutetium meets NICE's end-of-life criteria. Compared with everolimus, sunitinib and best supportive care, the cost-effectiveness estimates are within the range NICE normally considers acceptable. So lutetium can be recommended for treating pancreatic NETs.\n\nFor treating gastrointestinal NETs, lutetium does not meet the end-of-life criteria because life expectancy for this form of the disease is between 5 and 6\xa0years. But it can be recommended because the most plausible cost-effectiveness estimate is within what NICE normally considers acceptable and treatment options for gastrointestinal NETs are limited.", 'Information about lutetium (177Lu) oxodotreotide': "Marketing authorisation indication\n\nLutetium (177Lu) oxodotreotide (Lutathera, AAA, referred to as lutetium) is indicated for 'unresectable or metastatic, progressive, well-differentiated (G1 and G2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults'.\n\nDosage in the marketing authorisation\n\nLutetium is administered as an intravenous infusion. A single cycle consists of 4\xa0infusions of 7.4\xa0gigabecquerels (GBq). The recommended interval between\xa0infusions is 8\xa0weeks.\n\nPrice\n\n£71,500.00 for 4\xa0administrations of 7.4\xa0GBq (excluding VAT; company submission).\n\nThe company has a commercial arrangement. This makes lutetium available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Clinical need and current practice\n\n## People with NETs will welcome new treatment options because of high unmet need\n\nThe committee understood that neuroendocrine tumours (NETs) can affect the pancreas and gastrointestinal tissue. They are difficult to diagnose and treat, can significantly affect emotional health and often mean that people are unable to work. The patient expert explained that lutetium (177Lu) oxodotreotide (referred to as lutetium) is a very effective treatment with tolerable side effects, which allowed people to live a relatively normal life. The committee concluded that there is a recognised need for treatment for NETs at different sites.\n\n## Everolimus, sunitinib and best supportive care are appropriate comparators for lutetium for pancreatic NETs\n\nThe clinical experts explained that managing NETs in the NHS follows the European Neuroendocrine Tumor Society's (ENETs) guidelines. For treating pancreatic NETs causing symptoms (functional NETs) in people with progressive disease, options include everolimus and lutetium. For non-functional pancreatic NETs, the guidelines suggest lutetium or chemotherapy for progressive disease after offering everolimus or sunitinib. The clinical experts stated that although most centres would use lutetium after everolimus or sunitinib, there is no evidence to show that this is more effective than using it instead of everolimus or sunitinib. They further explained that chemotherapy is sometimes used if people have symptoms because of the bulk of their disease (mainly people with high disease burden with a Ki-67 proliferative index of around 20% or more, that is, grade\xa03 tumours). The committee agreed that chemotherapy was not a relevant comparator because lutetium is indicated for grade\xa01 and 2 tumours. The committee concluded that everolimus, sunitinib and best supportive care were appropriate comparators.\n\n## Everolimus and best supportive care are appropriate comparators for lutetium for gastrointestinal NETs\n\nFor treating functional and non-functional advanced gastrointestinal NETs in people with progressive disease, the ENETs guidelines suggest lutetium as an option with everolimus, and interferons. The committee agreed that everolimus may be a relevant comparator for lutetium but noted that its marketing authorisation is for non-functional gastrointestinal NETs only. The clinical experts explained that although interferons may be considered in people with progressive disease, they are not routinely used in England because of their toxicity. The committee agreed that interferons were not relevant comparators for lutetium. It therefore concluded that the relevant comparators for lutetium for gastrointestinal NETs were everolimus (non-functional disease only) and best supportive care.\n\n# Clinical trial evidence (ERASMUS)\n\n## Lutetium is effective for treating gastroenteropancreatic NETs\n\nERASMUS is a phase\xa01 and 2 single-arm study, which evaluated the efficacy of lutetium in people with different somatostatin receptor-positive tumour types, including pancreatic, foregut, midgut, hindgut and bronchial NETs. However, because bronchial NETs are not covered by the marketing authorisation for lutetium, these results were not considered by the committee. The committee was concerned that ERASMUS was a single-arm open-label study but acknowledged that it was the largest study of NETs currently available. It noted that the company only presented results for the Dutch population (n=360) in the trial (see table\xa01). This was because of the high percentage of non-Dutch patients lost to follow-up, which resulted in a substantial amount of missing data.\n\nType of neuroendocrine tumours (NETs)\n\nMedian progression-free survival in months (95% confidence interval)\n\nMedian overall survival in months (95% confidence interval)\n\nGastroenteropancreatic (n=360, includes bronchial NETs)\n\n(24.8 to 31.4)\n\n(54.8 to 67.4)\n\nPancreatic (n=133)\n\n(24.3 to 36.3)\n\n(57.2 to 80.9)\n\nMidgut (n=183)\n\n(23.9 to 33.3)\n\n(47.5 to 63.2)\n\nForegut (n=12)\n\n(10.9 to not reached)\n\nNot reached\n\nHindgut (n=13)\n\n(18.9 to 35.0)\n\nNot reached\n\nThe committee concluded that lutetium was clinically effective for people with gastroenteropancreatic NETs.\n\n# Clinical trial evidence (NETTER-1)\n\n## Lutetium is effective for treating midgut gastrointestinal NETs\n\nNETTER‑1 is a phase\xa03, open-label, randomised controlled trial, which recruited people with inoperable, progressive, somatostatin receptor-positive, midgut gastrointestinal NETs. The trial compared lutetium plus long-acting release octreotide 30\xa0mg (n=116) with long-acting release octreotide 60\xa0mg (n=113). The results from the June 2016 data-cut were:\n\nProgression-free survival: hazard ratio (HR) 0.21 (95% confidence interval [CI] 0.14 to 0.33).\n\nOverall survival: HR 0.54 (95% CI 0.33 to 0.86), median overall survival not reached in the lutetium arm.\n\nOverall survival, adjusted for crossover from octreotide 60\xa0mg to lutetium: HR 0.49 (95% CI 0.30 to 0.80).The committee considered whether these results were relevant to clinical practice in England given that the dose of the comparator, octreotide 60\xa0mg, is higher than the licensed dose of 30\xa0mg. The clinical experts confirmed that the results were relevant because some centres would increase the dose of octreotide for progressive disease. The clinical experts explained that octreotide 60\xa0mg was actually more effective than best supportive care, therefore underestimating the results for lutetium. Although NETTER‑1 only recruited people with midgut gastrointestinal NETs, the clinical experts explained that they would not expect much difference in the efficacy of lutetium across the different tumour sites. The committee considered that the results were relevant and supported the conclusions from ERASMUS. It concluded that lutetium was clinically effective for people with midgut gastrointestinal NETs compared with octreotide 60\xa0mg.\n\n# Indirect and mixed treatment comparisons\n\n## The company's matched adjusted indirect treatment comparisons are very uncertain\n\nThe company did matched adjusted indirect treatment comparisons (MAICs) for pancreatic NETs and gastrointestinal NETs using lutetium data from ERASMUS. Data for the comparators were taken from\xa03 randomised controlled trials (A6181111, RADIANT‑3 and RADIANT‑4). For pancreatic NETs, lutetium was compared with sunitinib from A6181111 and with everolimus and best supportive care from RADIANT‑3. For gastrointestinal NETs, lutetium was compared with everolimus and best supportive care from RADIANT‑4. The assessment group highlighted several limitations in the company's MAICs:\n\nThe company only included the Dutch population from the ERASMUS study, which resulted in very small sample sizes after the selected baseline covariates were matched.\n\nThe approach to selecting baseline covariates for matching meant that the most important prognostic factors and treatment effect modifiers, such as tumour functionality and grade and stage of disease, were excluded.\n\nRelative treatment effects were modelled after assuming proportional hazards, without any statistical testing for that assumption.\n\nFor the pancreatic NETs MAIC, the company could not carry out a closed network because individual patient data from A6181111 and RADIANT‑3 were not available to them. Also, the single-arm ERASMUS trial was being compared with 2\xa0randomised controlled trials (A6181111 and RADIANT‑3) and the inclusion criteria (such as tumour functionality, grade and stage of disease, presence of somatostatin receptors) among the 3\xa0trials differed.\n\nFor gastrointestinal NETs, the company was only able to do a MAIC for progression-free survival because overall survival data from RADIANT‑4 were not available to them.The committee acknowledged these limitations. Therefore it concluded that the results of the company's MAICs for pancreatic NETs and gastrointestinal NETs were associated with uncertainty, which needed to be accounted for in its decision-making.\n\n## The company's network meta-analysis for gastrointestinal NETs is inappropriate for decision-making\n\nThe committee noted that the company also did a network meta-analysis for gastrointestinal NETs comparing lutetium with everolimus and best supportive care, using data from NETTER‑1 and RADIANT‑4. However, it noted that there were important differences between the 2\xa0trials:\n\nThe control arm of RADIANT‑4 (placebo plus best supportive care) was assumed to be equivalent to the control arm of NETTER‑1 (octreotide 60\xa0mg).\n\nThe population from RADIANT‑4 (non-functional gastrointestinal and lung NETs) was assumed to be equivalent to the population from NETTER‑1 (functional and non-functional somatostatin receptor-positive midgut-only NETs).The committee concluded that because of these differences, the trials may not be fully comparable and results from any indirect comparison would not be robust. It therefore agreed that it would not consider the network meta-analysis further.\n\n## The assessment group's MAICs are preferred for decision-making\n\nHaving established that the company's MAICs for the pancreatic and gastrointestinal NETs populations were limited, the committee considered the assessment group's revisions to the analyses. It noted that the assessment group had done 3\xa0MAICs based on the NETs location (using ERASMUS), which included revisions to the company's preferred assumptions:\n\nIncluding additional baseline covariates for matching.\n\nIncluding both the Dutch and non-Dutch populations from ERASMUS to increase the sample size for matching.\n\nBuilding a complete network for the pancreatic NETs population; the sunitinib arm by Bucher indirect comparison and the ERASMUS arm by MAIC were matched to RADIANT‑3 as a whole.\n\nDoing a MAIC for overall survival for the gastrointestinal NETs population based on additional data from Novartis (for everolimus).\n\nDoing a MAIC of midgut-only NETs by matching the midgut-only NETs population from ERASMUS to the whole gastrointestinal NETs population in RADIANT‑4.\n\nEstimating relative treatment effects by fitting separate curves to each arm using proportional hazards and accelerated failure time functions.The committee acknowledged that the assessment group's analyses addressed most of the limitations highlighted in the company's MAICs (see section\xa03.6). It therefore accepted the assessment group's MAICs as the preferred analyses for decision-making. But because the MAIC analysis for midgut-only NETs used the whole gastrointestinal NETs population in RADIANT‑4, the committee considered it inappropriate to consider the midgut NETs population separately. It therefore concluded that it would consider only the MAIC analyses for pancreatic and gastrointestinal NETs for decision-making.\n\n## Lutetium improves progression-free survival and overall survival for people with pancreatic and gastrointestinal NETs\n\nThe results of the assessment group's MAICs and Bucher indirect comparisons showed that lutetium was statistically significantly more effective in improving progression-free survival than current treatment (everolimus, sunitinib and best supportive care for pancreatic NETs and everolimus and best supportive care for gastrointestinal NETs). For pancreatic NETs, lutetium was statistically significantly more effective in prolonging overall survival than everolimus (HR 0.54; 95% CI 0.33 to 0.88) and best supportive care (HR 0.22; 95% CI 0.10 to 0.50) but not sunitinib (HR 0.65; 95% CI 0.16 to 2.54). For gastrointestinal NETs, a statistically significant improvement in overall survival was seen only when lutetium was compared with best supportive care (HR 0.34; 95% CI 0.16 to 0.69). The difference in overall survival between lutetium and everolimus was not statistically significant (HR 0.55; 95% CI 0.27 to 1.11), but the committee considered it reasonable to assume that both drugs have similar effectiveness in prolonging survival. The committee concluded that lutetium was effective for people with pancreatic and gastrointestinal NETs compared with current treatment.\n\n# Economic models\n\n## The assessment group's economic model is the most appropriate for decision-making\n\nThe company and the assessment group's models were partitioned survival models with health states corresponding to pre-progression, post-progression and death. Both models included data for lutetium and the comparators (everolimus, sunitinib and best supportive care) from the MAIC analyses. The company also included separate analyses comparing lutetium with best supportive care (octreotide 60\xa0mg) using data from NETTER‑1 and analyses using the network meta-analysis of lutetium and everolimus for gastrointestinal NETs. Given the concerns with the population in NETTER‑1 (see section\xa03.5) and the concerns with the company's indirect treatment comparisons (see section\xa03.6 and section\xa03.7), the committee concluded that the assessment group's economic model was the most appropriate for decision-making.\n\n## Applying background mortality in the gastrointestinal NETs analyses is appropriate\n\nThe committee noted that in the assessment group's base-case analysis for gastrointestinal NETs, an adjustment in the survival analysis for background mortality was made. It understood that this was applied because of the short follow-up period in the indirect comparison of progression and mortality. It agreed that this approach was appropriate to minimise the effect of death from other causes on relative health benefit.\n\n# Health-related quality of life\n\n## The assessment group's estimates are acceptable for decision-making\n\nFor pancreatic NETs, the assessment group used EQ-5D valuations from A6181111 and assumed that the utilities for lutetium, everolimus and sunitinib were equal. The committee had previously accepted this assumption in NICE's technology appraisal guidance on everolimus and sunitinib for treating unresectable or metastatic neuroendocrine tumours in people with progressive disease following the comment from clinical experts that it was reasonable to assume that health-related quality of life would be similar. For gastrointestinal NETs, the assessment group used values estimated from RADIANT‑4 for everolimus, best supportive care and lutetium (progressed disease only) and from ERASMUS for lutetium (stable disease). The committee noted that using alternative sources reduced the incremental cost-effectiveness ratios (ICERs) slightly, more so for pancreatic NETs than for gastrointestinal NETs. The company used values from ERASMUS in its base case for pancreatic and gastrointestinal NETs. The committee understood that new data from NETTER‑1, which showed statistically significant improvement in quality of life for lutetium compared with octreotide, had become available. The company stated that it did not use these data because the model is primarily based on effectiveness data from ERASMUS. Based on the data presented to it, the committee concluded that the assessment group's estimates were acceptable for decision-making.\n\n# Resource use and costs\n\n## None of the analyses reflect the use of somatostatin receptor agonists in clinical practice\n\nThe company's definition of best supportive care was based on the design of NETTER‑1, in which all patients had a high dose of octreotide (60\xa0mg) before progression and a lower dose (30\xa0mg) after progression. The committee noted that the company's estimates of somatostatin receptor agonist use were substantially different to the assessment group's estimates, which were based on the observed rates in RADIANT‑3 (pancreatic NETs) and RADIANT‑4 (gastrointestinal NETs). However, the clinical experts explained that the assessment group's estimates were lower than would be seen in clinical practice, particularly for gastrointestinal NETs. The clinical experts stated that for progressive disease, most people with pancreatic or gastrointestinal NETs (approximately 85% and 95%, respectively) would continue having a somatostatin receptor agonist. On further progression, about 10% would stop treatment or reduce their dose. The committee noted the comment from\xa01 of the experts that about 20% of people would have a somatostatin receptor agonist at a higher dose. The assessment group also presented 3\xa0separate best supportive care scenario analyses:\n\nScenario 1: octreotide 60\xa0mg in 40% of people in the progression-free health state, best supportive care arm only.\n\nScenario 2: octreotide 60\xa0mg in 100% of people in the progression-free health state, best supportive care arm only.\n\nScenario 3: octreotide 30\xa0mg in 90% of people in the progression-free health state, regardless of the treatment arm of the model, reducing to 85% after progression (based on expert opinion).The clinical experts explained that concomitant use of somatostatin receptor agonists with targeted treatments varied in clinical practice. The company emphasised that the marketing authorisation for lutetium is for monotherapy and that only about half of the patients in ERASMUS had octreotide with lutetium. The committee noted that none of the analyses presented completely reflected the views of the clinical experts. However, it agreed that the most reasonable estimate for its decision-making would lie between the assessment group's best supportive care scenarios 2\xa0and\xa03.\n\n## The dose intensity estimate for lutetium should be based on ERASMUS\n\nThe committee noted that the dose intensity estimate for lutetium in the company's model was based on NETTER‑1 instead of ERASMUS, which is the source trial for the lutetium effectiveness data used in the indirect comparisons for pancreatic and gastrointestinal NETs. The assessment group explained that this potentially overestimated the cost effectiveness of lutetium because the dose intensity increased from 86.4% to between 94.4% and 97.8%. However, it stated that when the figures from ERASMUS were implemented in the model, the dose intensity reduced to about 86% to 88%. The committee agreed that the dose intensity should be based on the source trial and concluded that relative dose intensity based on ERASMUS was more appropriate.\n\n## Retreatment with lutetium is not considered\n\nThe assessment group included retreatment with lutetium in a sensitivity analysis at the time of the first appraisal committee meeting. In response to consultation on the assessment report, the company stated that retreatment with lutetium was not recommended clinical practice. The committee noted that there was no mention of retreatment after disease progression in the lutetium summary of product characteristics or any evidence supporting retreatment from the clinical trials that underpinned the marketing authorisation. It also noted that previous treatment with peptide receptor radionuclide therapy at any time before randomisation was an exclusion criterion in NETTER‑1. Also, none of the company's analyses or the assessment group's revised analyses included lutetium retreatment. The committee concluded that it was not appropriate to include retreatment with lutetium after disease progression in its consideration of the clinical and cost effectiveness of lutetium.\n\n## All relevant administration costs for lutetium are included in the assessment group's model\n\nThe committee questioned whether there would be additional costs for administering lutetium because it is a radionuclide. The clinical experts explained that the initial scans needed to identify somatostatin receptor-positive tumours are part of standard care. They also stated that although most people having lutetium usually stay overnight in hospital (over 90%), some are discharged the same day. The assessment group's base case assumed that 90% of patients stay overnight. It also used the national average cost of an elective inpatient excess bed day instead of the national average cost of a non-elective inpatient short stay to reduce potential double counting of resources. In a scenario analysis, the assessment group explored lutetium being administered in a day-case setting in 65% of patients. The effect of this assumption on the assessment group's base-case ICERs was minimal. The clinical experts agreed with the company that although a nuclear medicines consultant needs to be present on site, they do not necessarily administer the treatment. Also, the committee noted that the expert evidence submissions stated that no additional resources would be needed for lutetium because several centres in England have been providing it for some time. The committee was satisfied that all relevant costs associated with lutetium had been captured in the assessment group's model.\n\n# Cost-effectiveness results\n\n## There are confidential patient access scheme discounts for lutetium and everolimus\n\nThe assessment group's base-case results, which were used in the committee's decision-making, included the confidential patient access scheme discounts for lutetium and everolimus. So the exact cost-effectiveness results cannot be reported here.\n\n## The ICERs for lutetium for pancreatic NETs are less than £30,000 per QALY gained\n\nThe committee considered the cost effectiveness of lutetium compared with everolimus, sunitinib and best supportive care for pancreatic NETs. All the deterministic and probabilistic ICERs were below £30,000 per quality-adjusted life year (QALY) gained.\n\n## The ICER for lutetium for gastrointestinal NETs is less than £30,000 per QALY gained\n\nThe committee considered the cost effectiveness of lutetium compared with everolimus and best supportive care for gastrointestinal NETs. It recalled that everolimus was only licensed for non-functional NETs, therefore it agreed that best supportive care was the most appropriate comparator. The most plausible ICER for lutetium using the committee's preferred somatostatin receptor agonist scenarios (see section\xa03.13) was below £30,000 per QALY gained when compared with best supportive care.\n\n# Innovation\n\n## All significant health-related benefits are captured in the analyses\n\nThe patient and clinical experts explained that lutetium is an important new treatment option that represents a major change in managing NETs. The company commented that lutetium addresses a significant unmet need for people with inoperable NETs whose disease has progressed on somatostatin analogues. However, the committee concluded that there were no additional health benefits that had not been captured in the QALY calculations.\n\n# End of life\n\n## Lutetium meets NICE's end-of-life criteria for pancreatic NETs\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. For pancreatic NETs, the committee noted that the extrapolated survival for best supportive care was 41.6\xa0months. However, the clinical experts stated that they would expect people with pancreatic NETs to have a life expectancy of less than 24\xa0months (the first end-of-life criterion). The committee recalled that in NICE's technology appraisal guidance on everolimus and sunitinib, these drugs met the short life expectancy criterion based on the clinical experts' views that life expectancy for people with pancreatic NETs was closer to 20.5\xa0months (from A6181111) than to 41.6\xa0months (from RADIANT‑3). It also understood from the assessment group that the choice of parametric extrapolation could be the reason for the different results, so the estimates were very uncertain. Based on the clinical experts' views and previous conclusions from the guidance on everolimus and sunitinib, the committee accepted that life expectancy for people with pancreatic NETs was less than 24\xa0months. The committee noted that the extrapolated survival benefit for lutetium compared with best supportive care, everolimus and sunitinib was over 3\xa0months (64.2, 49.5 and 29.1\xa0months, respectively), meaning that the second end-of-life criterion, of extending life by at least 3\xa0months, was met. The committee therefore concluded that lutetium met the end-of-life criteria for somatostatin receptor-positive pancreatic NETs in people with progressive disease.\n\n## Lutetium does not meet NICE's end-of-life criteria for gastrointestinal NETs\n\nThe clinical experts explained that the average life expectancy for people with advanced gastrointestinal NETs was around 5 to 6\xa0years. Survival of less than 24\xa0months, as would be necessary to meet NICE's first end-of-life criterion, was not seen in practice. The committee noted that the extrapolated survival was 58.8\xa0months for best supportive care, meaning that the criterion for short life expectancy of 24\xa0months was not met. For the second criterion, of extension to life of at least 3\xa0months, the difference in extrapolated survival for lutetium compared with best supportive care was 36.1\xa0months. The committee considered that the second criterion was met. However, because the criterion for short life expectancy was not met, the committee concluded that lutetium did not meet the end-of-life criteria for somatostatin receptor-positive gastrointestinal NETs in people with progressive disease.\n\n# Recommendations\n\n## Lutetium is recommended for treating pancreatic NETs\n\nFor pancreatic NETs, lutetium met the end-of-life criteria (see section\xa03.21) and all the ICERs were below £30,000 per QALY gained (see section\xa03.18). Therefore, the committee concluded that it could be recommended as a cost-effective use of NHS resources for treating somatostatin receptor-positive pancreatic NETs in people with progressive disease.\n\n## Lutetium is recommended for treating gastrointestinal NETs\n\nThe committee had concluded that lutetium did not meet the end-of-life criteria for gastrointestinal NETs (see section\xa03.22). However, it noted that the most plausible ICER was below £30,000 per QALY gained (see section\xa03.19). The committee understood that the treatment options for this group of people were limited, particularly for people with functional NETs. Based on the ICER estimate and the limited treatment options available, the committee concluded that it could recommend lutetium as a cost-effective use of NHS resources for treating somatostatin receptor-positive gastrointestinal NETs in people with progressive disease."}
|
https://www.nice.org.uk/guidance/ta539
|
Evidence-based recommendations on lutetium (177Lu) oxodotreotide (Lutathera) for treating unresectable or metastatic neuroendocrine tumours in adults.
|
816647a8caac005a72aa6e1a8c09365ae76dc74f
|
nice
|
Sutureless aortic valve replacement for aortic stenosis
|
Sutureless aortic valve replacement for aortic stenosis
Evidence-based recommendations on sutureless aortic valve replacement for aortic stenosis in adults. This involves removing the narrowed aortic valve and replacing it with an artificial valve that holds itself in place.
# Recommendations
Current evidence on the safety and efficacy of sutureless aortic valve replacement for aortic stenosis is adequate to support the use of this procedure, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team, including cardiologists and cardiac surgeons.
Specific training is important for this procedure and surgeons should do their initial procedures with an experienced mentor.
Clinicians should enter details about all patients having sutureless aortic valve replacement for aortic stenosis onto the UK National Institute for Cardiovascular Outcomes Research database.# The condition, current treatments and procedure
# The condition
Aortic stenosis causes impaired blood flow out of the heart and is usually progressive. The increased cardiac workload leads to left ventricular hypertrophy, arrhythmias, and may lead to life‑threatening heart failure. Symptoms of aortic stenosis typically include shortness of breath and chest pain on exertion.
# Current treatments
Conventional treatment for patients with severe symptomatic aortic stenosis is surgical aortic valve replacement. Surgical aortic valve replacement may not be suitable for some patients because of medical comorbidities or technical considerations, such as a calcified aorta or scarring from previous cardiac surgery. Continued medical care may be the only option for some patients. Transcatheter aortic valve implantation (TAVI) for aortic stenosis is an alternative for patients for whom surgery is unsuitable, but it does not allow for concomitant coronary artery bypass grafting.
# The procedure
Sutureless aortic valve replacement (SUAVR) for aortic stenosis is an alternative to conventional surgical aortic valve replacement. The potential benefits of the procedure are that the diseased valve is removed, combined pathologies of the aortic valve and the coronary arteries can be treated, as they can in conventional surgical aortic valve replacement. Also, the procedure may be quicker because the valve does not need to be sewn in, which reduces cardiopulmonary and aortic cross‑clamp times.
With the patient under general anaesthesia, access to the heart is usually made through a full- or mini‑sternotomy, or right anterior thoracotomy. Once cardiopulmonary bypass and cardioplegia are established, the diseased aortic valve is accessed and removed through a cut in the aorta. Bulky calcifications around the native aortic annulus are removed to achieve a smooth round annulus for valve implantation. The valve prosthesis with self‑expanding or balloon expanding frame, loaded into a special delivery device, is deployed into the native annulus. Once in position the valve is released. The exact deployment method varies between the different devices available for this procedure and with some devices; one or more temporary guiding or securing sutures may be used. Balloon dilatation of the new valve may be used to maximise the area of contact between the prosthesis and the aortic annulus. Once the valve is deployed, the delivery system is removed and the aortotomy is closed. All of the devices used in this procedure contain material derived from animal sources.
This procedure is sometimes described as sutureless aortic valve replacement and sometimes as rapid deployment aortic valve replacement.
|
{'Recommendations': 'Current evidence on the safety and efficacy of sutureless aortic valve replacement for aortic stenosis is adequate to support the use of this procedure, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team, including cardiologists and cardiac surgeons.\n\nSpecific training is important for this procedure and surgeons should do their initial procedures with an experienced mentor.\n\nClinicians should enter details about all patients having sutureless aortic valve replacement for aortic stenosis onto the UK National Institute for Cardiovascular Outcomes Research database.', 'The condition, current treatments and procedure': '# The condition\n\nAortic stenosis causes impaired blood flow out of the heart and is usually progressive. The increased cardiac workload leads to left ventricular hypertrophy, arrhythmias, and may lead to life‑threatening heart failure. Symptoms of aortic stenosis typically include shortness of breath and chest pain on exertion.\n\n# Current treatments\n\nConventional treatment for patients with severe symptomatic aortic stenosis is surgical aortic valve replacement. Surgical aortic valve replacement may not be suitable for some patients because of medical comorbidities or technical considerations, such as a calcified aorta or scarring from previous cardiac surgery. Continued medical care may be the only option for some patients. Transcatheter aortic valve implantation (TAVI) for aortic stenosis is an alternative for patients for whom surgery is unsuitable, but it does not allow for concomitant coronary artery bypass grafting.\n\n# The procedure\n\nSutureless aortic valve replacement (SUAVR) for aortic stenosis is an alternative to conventional surgical aortic valve replacement. The potential benefits of the procedure are that the diseased valve is removed, combined pathologies of the aortic valve and the coronary arteries can be treated, as they can in conventional surgical aortic valve replacement. Also, the procedure may be quicker because the valve does not need to be sewn in, which reduces cardiopulmonary and aortic cross‑clamp times.\n\nWith the patient under general anaesthesia, access to the heart is usually made through a full- or mini‑sternotomy, or right anterior thoracotomy. Once cardiopulmonary bypass and cardioplegia are established, the diseased aortic valve is accessed and removed through a cut in the aorta. Bulky calcifications around the native aortic annulus are removed to achieve a smooth round annulus for valve implantation. The valve prosthesis with self‑expanding or balloon expanding frame, loaded into a special delivery device, is deployed into the native annulus. Once in position the valve is released. The exact deployment method varies between the different devices available for this procedure and with some devices; one or more temporary guiding or securing sutures may be used. Balloon dilatation of the new valve may be used to maximise the area of contact between the prosthesis and the aortic annulus. Once the valve is deployed, the delivery system is removed and the aortotomy is closed. All of the devices used in this procedure contain material derived from animal sources.\n\nThis procedure is sometimes described as sutureless aortic valve replacement and sometimes as rapid deployment aortic valve replacement.'}
|
https://www.nice.org.uk/guidance/ipg624
|
Evidence-based recommendations on sutureless aortic valve replacement for aortic stenosis in adults. This involves removing the narrowed aortic valve and replacing it with an artificial valve that holds itself in place.
|
40437334bb6ad04bc236e49d4a27dced84af49a8
|
nice
|
Flu vaccination: increasing uptake
|
Flu vaccination: increasing uptake
This guideline covers how to increase uptake of the free flu vaccination among people who are eligible. It describes ways to increase awareness and how to use all opportunities in primary and secondary care to identify people who should be encouraged to have the vaccination.
# Recommendations
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use) professional guidelines standards and laws (including on consent and mental capacity) and safeguarding.
The recommendations in this guideline should be read together with the NICE guideline on vaccine uptake in the general population.
# A multicomponent approach
Use a multicomponent approach to develop and deliver programmes to increase flu vaccination uptake. Combine interventions recommended in this guideline to influence both demand and supply.
Providers of flu vaccination should work together with other agencies (including intervention developers, commissioners and local stakeholders) to develop programmes to increase vaccination uptake. This could include assigning within organisations a lead team or flu vaccination champion to manage the programmes and be responsible for working across organisations.
See how the committee made recommendations 1.1.1 and 1.1.2.
# Raising awareness
## Raising awareness in health and social care staff
These recommendations are for educators, line managers and organisational leads.
Educate health and social care staff, particularly those in contact with eligible groups, about flu vaccination. These could include:
Staff working in GP surgeries and community pharmacies.
Secondary care staff, for example in clinics for children with chronic conditions or wards such as oncology or antenatal.
Social care staff who may have contact with carers and other eligible groups, such as people with learning disabilities. This may include during home visits, individual needs assessments and carers' assessments.
Provide information on the following as part of an education programme on flu vaccination for health and social care staff, particularly those in contact with eligible groups:
Who is eligible for free flu vaccination, and where to get it.
Benefits of vaccination for people at high risk from flu and its complications. For example, those with immunosuppression, chronic liver disease or neurological disease.
Benefits of flu vaccination for health and social care staff.
How flu is transmitted.
Relevant guidelines and definitions of eligible groups as outlined in chapter 19 of the UK Health Security Agency's immunisation against infectious disease (known as the 'Green Book').
How the flu vaccine is given to children and adults.
Evidence supporting the safety and effectiveness of flu vaccination.
Explain to health and social care staff how they can:
Identify people who are eligible, for example by using GP records or medicines dispensing records (including how to identify carers who might be eligible; see the section on flu vaccination in carers).
Make the most of opportunities to raise awareness about and offer flu vaccination to eligible groups. This could include discussing it with:
pregnant women during antenatal appointments
eligible people booking GP or other clinical appointments
eligible people visiting community pharmacies to seek health advice, collect prescriptions or buy over-the-counter medicines.
Health and social care staff who are in direct contact with eligible groups (for example, practice nurses, health visitors, community pharmacists, midwives, specialist nurses and domiciliary care workers) should:
Include training on flu and flu vaccination as part of their continuing professional development plan (see Public Health England's national minimum standards and core curriculum for immunisation training for registered healthcare practitioners).
Be able to provide tailored information on the risks and benefits of flu vaccination, and be able to offer and administer it (see the NICE guideline on patient group directions).
## Raising awareness in eligible groups
These recommendations are for providers of flu vaccination.
Raise awareness of free flu vaccination among people who are eligible, as listed in the Green Book and the annual flu letter. Do this at the earliest opportunity before the flu vaccination season starts in September, and ideally by the end of December.
Consider working with statutory and voluntary organisations, including those representing people with relevant medical conditions, to increase awareness of flu vaccination among eligible groups (and their parents or carers, if relevant).
Give people who are eligible (or their parents or carers, if relevant) face-to-face brief advice or a brief intervention on the importance of flu vaccination. Tell them that they can have a free flu vaccination and explain why they are being offered it, using language they can understand and taking into account cultural sensitivities. This includes explaining:
How people get flu.
How serious flu and its complications can be (make it clear it is not just a bad cold).
That flu can affect anyone, but if a person has a long-term health condition the effects of flu can make it worse, even if the condition is well managed and they normally feel well.
That flu vaccination is safe.
That having a flu vaccination is the single best way of helping to protect against catching or spreading flu.
That they should get the vaccination as soon as it becomes available to maximise their protection throughout the flu season.
Any myths about flu vaccination: dispel these myths, including the belief that it can give you flu.
The need to have a flu vaccination every year.
Explain to parents or carers that the nasal spray (not injection) is recommended for eligible children from the age of 2 years. Explain that the injection will be offered instead of the nasal spray only if:
the child is in a clinical risk group and
the child cannot have the nasal spray for medical reasons (for example, if it is contraindicated because they or a close family member is severely immunocompromised), or they choose not to because of their religious beliefs; see NHS Choices for more information.
Give people information about the location and opening hours of relevant flu vaccination services, including out-of-hours services and community pharmacies.
Include information on flu vaccination with other health-related messages and existing health-promotion or vaccination programmes for people in eligible groups.
See how the committee made recommendations 1.2.1 to 1.2.10.
# Offering vaccination
These recommendations are for providers of flu vaccination services.
Use every opportunity throughout the flu vaccination season to identify people in eligible groups and offer them the flu vaccination. This could include when:
People register in general practice.
Women have a newly confirmed pregnancy.
People are newly diagnosed with a condition that may place them in a clinical risk group, or have a BMI of 40 or over.
People attend outpatient and antenatal clinics or drug and alcohol services.
People (including children aged 6 months to 17 years) who are in a clinical risk group attend routine GP or outpatient clinic appointments, or for other vaccination services.
People visit community pharmacies for health advice, a New Medicine Service, or to collect prescriptions (check whether the person taking the medicine or their carer is eligible, while taking into account confidentiality).
People in clinical risk groups are staying in hospital.
People who are eligible are having home visits for healthcare.
Establish and use links with statutory and voluntary organisations that work with carers, looked-after children and young people or other groups, to identify eligible people who have not been vaccinated. These could include drug and alcohol services, and organisations working with Traveller communities or people who are homeless.
Provide multiple opportunities and routes for eligible people to have their flu vaccination at a time and location convenient to them. This could include at community pharmacies, GP surgeries or clinics they attend regularly for a chronic condition.
Consider outreach opportunities for underserved groups in line with local practice and patient group directions arrangements (see the NICE guideline on patient group directions).
Consider providing evening and weekend services in primary care, including community pharmacy, to deliver flu vaccination to people who may find it difficult to attend at other times.
Use clinical systems to identify eligible groups and work out supply requirements, planning for a higher uptake than the previous year. Ensure enough flu vaccine is available to meet local needs.
See how the committee made recommendations 1.3.1 to 1.3.6.
# Increasing uptake among eligible groups in primary and secondary care
## Primary care
Inform and invite children and adults in eligible groups for flu vaccination during face-to-face interactions, whenever the opportunity arises.
Advise parents of all children aged 2 and 3 years who are covered by the universal vaccination programme, and children aged 6 months and over who are in a clinical risk group, about the benefits of flu vaccination. Do this whenever the opportunity arises, for example when they attend routine appointments or for other vaccination programmes.At the time of publication (August 2018), the universal vaccination programme is available for children aged 2 to 9 years (up to school year 5). Preschool children (aged 2 and 3 years) should be given the nasal flu vaccine in general practice. Older children (from reception age) are usually given the nasal vaccine by local healthcare teams working with schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.
When inviting people for flu vaccination:
Ensure the invitation comes from a healthcare practitioner that they know, such as a practice nurse, midwife, doctor, pharmacist or health visitor.
Tailor it to the person's situation, for example link it to their pregnancy or clinical risk factors.
Include information about the risks of not being vaccinated.
Include educational messages to help overcome barriers to accepting the offer of a vaccination (see the section on raising awareness).
Use written reminders (including text messages, letters and email), phone calls from staff or an auto dialler, social media, or a combination of methods, to contact people in eligible groups whose immunisations are due ('call') or overdue ('recall').
For invitations and reminders using digital media:
link to further information on trusted websites (see NHS Choices) and enable the person to ask for further information
provide a prompt (for example, a hyperlink) so the person can make an appointment online
encourage people to find out more during face-to-face interactions, such as with their health visitor or pharmacist.
Consider using peer-led approaches for inviting people in underserved groups who are eligible for flu vaccination.
## Secondary care
Consider providing flu vaccination during routine appointments in specialist clinics to people who are at high risk from flu and its complications. For example, people with immunosuppression, chronic liver or neurological disease, and pregnant women.
When the opportunity arises, for example when people attend routine hospital appointments, identify anyone in a clinical risk group who has not been vaccinated and offer them a flu vaccination. Ensure this is in line with any local patient group directions or enhanced service arrangements that have been agreed with commissioners (see the NICE guideline on patient group directions).
When offering people the flu vaccination:
Make the offer face-to-face, if possible.
Use positive messages to encourage people to have the vaccination. For example, for a pregnant woman the message could be that the flu vaccination gives 'two for one' protection to both her and her baby before and after the birth.
Tailor information to the person's situation, for example their pregnancy or clinical risk factors. Include the risks of not being vaccinated.
Ensure information is simple, easy to read (if written) and provides a consistent message about flu and flu vaccination.
Ensure a healthcare practitioner they know (for example, a midwife or a consultant from an outpatient clinic they attend) offers the vaccination.
Make it easy for the person to get the vaccination, for example by offering and administering it during the same visit.
## Patient records
Include prompts about people's eligibility for flu vaccination in electronic patient records or in medical notes (for example, by putting reminder stickers in antenatal notes).
See how the committee made recommendations 1.4.1 to 1.4.10.
# Audit, monitoring and feedback
Healthcare providers should keep patient records up to date and accurate to help identify people who have not been vaccinated and are eligible for flu vaccination that season.
Providers of flu vaccination should record uptake rates. For example, keep records of the following:
reason for eligibility
numbers of people called and recalled
vaccination setting (for example GP, community pharmacy, antenatal clinic, outpatient clinic)
people who declined vaccination and why, by eligible group.
Commissioners and providers should agree approaches for sharing information with general practices about flu vaccination given outside a person's own GP surgery (for example, by a school nurse or in a diabetes outpatient clinic). Aim for timely, accurate and consistent recording of vaccination status in health records to ensure all vaccinations are included in uptake data, and to avoid wasting resources by inviting people to attend appointments unnecessarily or duplicating vaccination.
Use audit and monitoring systems to give providers of flu vaccination regular feedback on organisational progress towards targets throughout the immunisation season. Also use them to review past activity and impact on uptake to help plan and prioritise for the next season.
## Organisational incentives
Commissioners should raise awareness among healthcare staff and providers of flu vaccination about enhanced services payments and provider payments linked to flu vaccination. Also keep them informed and up to date about other financial incentives linked to flu vaccination. This includes those offered in the general practice Quality and Outcomes Framework (QOF), or the Commissioning for Quality and Innovation (CQUIN) system in secondary care.
Commissioners should ensure that providers of flu vaccination know that submission of information on flu vaccination directly affects any linked organisational incentive payments.
Commissioners should highlight the need for audit, monitoring and feedback of flu vaccinations given as part of an incentives programme. Link agreed Read codes or CQUIN indicators to incentives and include the required code or indicator.
Organisations responsible for agreeing quality indicators in incentives programmes (such as QOF) should be aware that revising target conditions may encourage providers to meet targets for flu vaccination across all clinical risk groups.
See how the committee made recommendations 1.5.1 to 1.5.8.
# Flu vaccination in carers
When considering increasing flu vaccination uptake in carers who are not otherwise eligible, use clinical judgement. Base decisions to offer vaccination on whether the carer looks after someone whose wellbeing may be at risk, needing hospital or other formal care, if the carer had flu.
Providers of flu vaccination, including primary care staff and nurses working in the community (such as district nurses, specialist nurses and those working in rehabilitation) could consider:
Identifying and offering eligible carers a flu vaccination as the opportunity arises. For example, this could be offered during a home visit when the person they look after is being vaccinated.
Informing the carer about other local vaccination services if a patient group direction or enhanced service arrangement has not been agreed with primary care commissioners (see the NICE guideline on patient group directions).
See how the committee made recommendations 1.6.1 and 1.6.2.
# Employers of health and social care staff
Employers of health and social care staff are responsible for providing occupational flu vaccinations. This includes: NHS organisations, independent contractors, local authorities, and private and voluntary sector employers of social care staff. Immunisation should be provided by occupational health services, infection prevention and control teams, or using arrangements with private healthcare providers.
Provide flu vaccination to all front-line health and social care staff who have direct contact with patients or clients. This includes employees who provide community-based care services to people in their own homes, or who care for people in residential care homes or other long-stay care facilities (see the Green Book).
Use audit and monitoring systems to review previous strategies and flu vaccination uptake rates among eligible staff and to plan what methods to use to increase uptake and manage the supply for the next flu season. Start planning each year when the annual flu letter for the forthcoming season is published.
Consider the following as part of a multicomponent approach to increasing uptake of flu vaccination among front-line health and social care staff:
A full participation vaccination strategy, with nationally agreed opt out criteria (A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.)
Assigning dedicated staff (for example, a flu vaccination champion or a team with responsibility for implementing a communication strategy) to increase awareness and uptake.
Using local broadcast media and social media.
Getting and publicising support from high-profile organisational leaders or staff representatives.
Providing information about the effectiveness and safety of the flu vaccine.
Using staff incentives that fit with the organisation's culture and the values of its employees.
Training peers to vaccinate their co‑workers, or to encourage uptake and challenge barriers, such as myths that the flu vaccine can give you flu.
Using prompts and reminders in various printed and digital formats. Include information about on- or off‑site vaccination locations and times.
Using systems linked to named staff records to monitor uptake and to target prompts and reminders.
Consider promoting flu vaccination to front-line health and social care staff as a way to:
protect the people they care for
protect themselves and their families
protect their co‑workers
meet professional expectations such as the General Medical Council's guidance on good medical practice and the Royal College of Nursing's duty of care statement.
Consider:
Extending on‑site vaccination clinic hours to fit in with staff work patterns.
Using outreach or mobile services to offer flu vaccination in areas and at times where large numbers of staff congregate, such as staff canteens or during shift changeovers.
Publicising information about mobile flu vaccination services.
Offering opportunities for off‑site and out-of-hours access, for example, by providing vouchers for flu vaccination at a community pharmacy.
Publicise flu vaccine uptake rates and the comparative performance of individual departments or sites within the organisation or locality. This could be done within the context of national targets such as the Commissioning for Quality and Innovation (CQUIN).
Develop the flu vaccination strategy in conjunction with staff representatives. Consider an anonymous survey of reasons for opting out, which could be used to inform future flu vaccination programmes.
Agree approaches for information sharing if off‑site access to flu vaccination is offered to allow timely, accurate and consistent recording of people's vaccination status.
See how the committee made recommendations 1.7.1 to 1.7.8.
# Terms used in this guideline
This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.
## Carers
People who receive a carer's allowance or who are the informal 'main carer' of an older or disabled person whose welfare may be at risk if the carer falls ill. This definition is in line with the Green Book, which recommends offering the flu vaccination on the basis of clinical judgement, regardless of whether the person receives a carer's allowance.
## Clinical risk groups
People who have a medical condition that means they are more likely to develop potentially serious complications from flu. People in these groups are eligible for free flu vaccination and are specified in the Green Book and the annual flu letter. At the time of publication of this guideline, the groups are:
chronic respiratory disease, such as asthma (requiring use of inhaled or systemic steroids, or with previous exacerbations needing hospital admission), chronic obstructive pulmonary disease, or bronchiectasis
chronic heart disease
chronic kidney disease (stage 3 or above)
chronic liver disease
chronic neurological disease such as Parkinson's disease, motor neurone disease, or a learning disability
diabetes
a weakened immune system caused by disease (such as HIV/AIDS) or treatment (such as chemotherapy or high-dose corticosteroids)
asplenia or conditions that can lead to dysfunction of the spleen, such as sickle cell disease or coeliac disease
morbid obesity (adults with a BMI of 40 or over).
## Eligible groups
People who are eligible for free flu vaccination in the NHS, as outlined in the Green Book. For the purpose of this guideline, the specific eligible groups considered were:
children and adults aged 6 months to 64 years in a clinical risk group (as listed in the annual flu letter)
pregnant women
people in receipt of a carer's allowance
people who are the main informal carer of an elderly or disabled person whose welfare may be at risk if the carer falls ill.
In addition, flu vaccination with live attenuated intranasal vaccine (LAIV) is recommended for all children aged 2 to 17 years who are not in a clinical risk group. This programme is being implemented in a phased roll-out, starting with the youngest first. At the time of publication (August 2018), the universal vaccination programme is available for children aged 2 to 9 years (up to school year 5). Preschool children (aged 2 and 3 years) should be vaccinated in general practice. Older children (from reception age) are being vaccinated by local healthcare teams working with schools. Once the programme has been rolled out to all primary-school-aged children, it will be reviewed to assess whether to continue the extension into secondary schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.
## Full participation vaccination strategy
A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front‑line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.
## Multicomponent approach
A set of multiple interventions implemented together to increase flu vaccination uptake. These target both demand (for example, increasing awareness of eligibility and the reasons why vaccination is beneficial) and supply (for example, creating more opportunities for vaccination, such as increasing the offer by professionals).
## Peer-led approaches
Approaches to reach underserved groups in which people with lived experience (for example, people who have been homeless, or who are from particular cultural backgrounds) work alongside health and social care professionals to provide information that is accessible and appropriate to the target group, acting as local 'flu champions' to promote awareness and uptake among their peers.
## Providers of flu vaccination
Staff who are allowed to administer the flu vaccination, or affiliated staff (for example general practice staff who log patient demographics and could therefore see who satisfies Green Book criteria).
## Statutory organisations
Organisations with legal responsibility at a national or local level for the provision, commissioning, regulation or improvement and oversight of government-funded health and care services.
## Underserved groups
This term is used in this guideline to mean adults and children from any background who are 'underserved' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to:
recognise they are eligible for flu vaccination (for example, they have an undiagnosed clinical condition)
access health services
attend healthcare appointments.
The groups classified as underserved in this guideline are:
people who are homeless or sleep rough
people who misuse substances
asylum seekers
Gypsy, Traveller and Roma people
people with learning disabilities
young people leaving long-term care.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Education of health and social care staff and support workers – there are national minimum standards for these groups (see national minimum standards and core curriculum for immunisation training for registered healthcare practitioners, the Royal College of Nursing's immunisation knowledge and skills competence assessment tool, and Public Health England's immunisation training of healthcare support workers: national minimum standards and core curriculum). Also see Health Education England's flu immunisation eLearning programme and Public Health England's national flu programme training slide set. The Royal Pharmaceutical Society's seasonal influenza hub has information and educational resources for members. These resources could be used in implementing this guideline.
Support from national bodies, professional groups and royal colleges – organisations such as the British Medical Association (BMA), Royal College of Nursing and the Royal Pharmaceutical Society encourage their members and others to accept the flu vaccination. This includes advice that the BMA provides for occupational health providers. See also: the General Medical Council's guidance on good medical practice, the Nursing and Midwifery Council Code, advice from the General Pharmaceutical Council, the Health and Care Professions Council's standards of conduct and the Royal College of Nursing's guidance and resources on flu vaccination. This support and drive to increase flu vaccination could provide a useful lever for action in implementing this guideline.
Existing national targets – there are a number of national targets including public health outcomes frameworks (3.03, 4.03, 4.07, 4.08) relating to population flu vaccination uptake. These targets could be used to establish the case when seeking to commission, develop and implement interventions recommended in this guideline.
Existing incentive-based payment mechanisms to organisations to increase uptake – there are a number of incentives in primary and secondary care to increase flu vaccination, including Quality and Outcomes Framework, or QOF (secondary prevention of coronary heart disease ; diabetes mellitus ; chronic obstructive pulmonary disease ; and stroke and transient ischaemic attack ) and Commissioning for Quality and Innovation or CQUIN (improving the uptake of flu vaccinations for front-line clinical staff ). Framing proposals to increase flu vaccination in terms of the achievement of indicator criteria, as well as stating the impact on mortality and morbidity, may positively influence development and implementation of interventions recommended in this guideline.
Existing examples of best practice guidance for increasing flu vaccination uptake – GPs have Flu vaccine for children: best practice guide for GPs and for healthcare workers, NHS Employers have good practice guides and case studies from former flu fighter award winners as well as planning, communications and reviewing campaign guides.
Existing resources to support targeting, tailoring and information provision for eligible groups, including template letters, posters and Easy Read leaflets, can be found at the Stay Well This Winter campaign, and in the government's annual flu letter.# Context
Each winter hundreds of thousands of people see their GP and tens of thousands are hospitalised because of flu. Deaths attributable to flu are estimated to range from around 4,000 to 14,000 per year, with an average of around 8,000 per year (Public Health England and the NHS prepare for unpredictable flu season).
Flu vaccination has been recommended in the UK since the late 1960s. Everyone aged 65 and over, those who are the main carer of an older adult or person with a disability, anyone aged 6 months to 64 years in a clinical risk group that puts them at a higher than average risk of illness and death linked to flu, and all pregnant women are offered free vaccination as part of the Public Health England and NHS England national programme. In addition, the Joint Committee on Vaccination and Immunisation has recommended extending flu vaccination to children to reduce transmission in the community and reduce the number of cases of flu-related illness and death among older adults.
At the time of publication (August 2018), the universal flu vaccination programme is available for children aged 2 to 9 years (up to school year 5). Preschool children (aged 2 and 3 years) should be vaccinated in general practice. Older children (from reception age) are being vaccinated by local healthcare teams working with schools. Once the programme has been rolled out to all primary-school-aged children, it will be reviewed to assess whether to continue the extension into secondary schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.
In addition to the groups already mentioned, the Health and Safety at Work Act (1974) makes employers responsible for offering the flu vaccination to health and social care staff who have direct care responsibilities.
Among people aged 65 or over, annual uptake of free NHS flu vaccination is relatively high and consistent, at around 70 to 75%. For this reason, this group was not included as a target population for increasing uptake in the scope for this guideline.
Among people under 65 who are in clinical risk groups, uptake is lower and more variable: 49% overall in 2017/18, ranging from 39% in patients with morbid obesity (with a BMI of 40 or over) and 41% in patients without a spleen or with splenic dysfunction, to 65% in patients who have diabetes. Uptake is particularly low among babies and infants (aged 6 months to under 2 years) who are in a clinical risk group: the vaccination rate in 2017/18 was only 21%. Uptake increased among preschool children in a clinical risk group (52% of those aged 2 to under 5 years), but then dropped off again among those of school age (44%). Among children not in a clinical risk group, uptake of the universal flu vaccination programme was 43% for 2‑year‑olds and 44% for 3‑year‑olds. Among pregnant women, flu vaccination uptake was 47% in 2017/18, whereas for people under 65 years who are registered as a carer by their GP, uptake was 40% (Public Health England's seasonal flu vaccine uptake in GP patients in England: winter 2017/18).
In England, among children and adults aged 6 months to 64 years who are in a clinical risk group, the average age‑adjusted risk of flu‑related death is 11 times greater than for those not in a clinical risk group. However, this masks considerable variation between the different target groups. A much higher relative risk (RR) of flu‑related death is associated, for example, with chronic liver disease (RR=48.2), immunosuppression (RR=47.3) and chronic neurological disease (RR=40.4). For other clinical groups, the age‑adjusted relative mortality risks are: chronic renal disease, RR=18.5; chronic heart disease, RR=10.7; chronic respiratory disease, RR=7.4; diabetes, RR=5.8; and pregnant women RR=7.0.
In England 69% of healthcare workers in NHS trusts and area teams with direct patient contact were vaccinated in 2017/18, an increase from 63% the previous year (Public Health England's seasonal flu vaccine uptake in healthcare workers in England: winter 2017/18).
This guideline considers interventions to increase flu vaccination uptake in children aged 2 to 17 years (to take account of any future roll-out of the current children's universal vaccination programme); children and adults aged between 6 months and 64 years who are in clinical risk groups (see the Green Book), or adults who are morbidly obese (with a BMI of 40 or over); pregnant women, carers, and front-line health and social care staff, in line with the national flu immunisation programme plan 2022 to 2023.
See the guideline scope for more details.# The committee's discussion
Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details.
# Current practice
The committee noted that general practice is where most vaccination of eligible groups (other than front-line health and social care staff) currently takes place and should therefore be considered the primary route by which flu vaccination is offered. Provision in general practice is driven by a national enhanced service specification. This requires all eligible patients to be called (invited); records to be kept up to date; vaccination status (or reason for declining a flu vaccine) to be recorded accurately; appropriate skills and training for those administering flu vaccine; consideration of accessibility to ensure that service users' needs are met; and regular monitoring and reporting of vaccination activity. However, current delivery of flu vaccination in primary care is variable. Results of a cross-sectional survey suggest that well-organised general practices that implement multiple strategies for promoting uptake tend to have highest rates of flu vaccination, particularly among over 65s but also among people from clinical risk groups (Strategies to increase influenza vaccination rates: outcomes of a nationwide cross-sectional survey of UK general practice, Dexter et al. 2012).
In addition to general practice provision, community pharmacies can choose to offer flu vaccination to adults aged 18 years or over who are in eligible groups, as detailed in an advanced service specification included as part of the NHS Community Pharmacy Contractual Framework. Some areas also have other local arrangements in place, such as commissioning vaccination provision in secondary care clinics or wards.
Vaccination of health and social care staff is delivered as part of employer occupational health responsibilities. This is driven by decision-making at the level of individual organisations, and rates of vaccination uptake are variable.
# Economic modelling
To support committee decision-making, economic modelling was done to estimate the cost effectiveness of increasing flu vaccination uptake within each of the 4 populations (children, people in clinical risk groups, carers, and health and social care staff).
Public Health England developed an economic model to inform the recommendations of the Joint Committee on Vaccinations and Immunisations on vaccinating children and people in clinical risk groups. We updated it to use the most recent and appropriate clinical and economic data.
We developed new economic models for carers and for health and social care staff because there were no existing models for these populations.
We considered interventions to be cost effective if they cost up to £20,000 per quality-adjusted life year (QALY). We conducted scenario analyses to determine the intervention cost that would be cost effective for a given increase in uptake.
# A multicomponent approach
The discussion below explains how the committee made recommendations 1.1.1 and 1.1.2.
## Rationale and impact
Flu-related illness places a strain on NHS resources every winter because many of the people whose health is most at risk from flu – as well as the staff who come into contact with them – are not vaccinated. Evidence showed that the most effective way to encourage people to have a flu vaccination every year is to use a combination of interventions. The committee agreed there is no single intervention that can improve both how likely vaccination is to be offered and also the likelihood that people will accept vaccination. Based on their knowledge of practice in the UK, the committee agreed with experts who said that organisations need to work closely together to achieve this, an approach that was supported by evidence on collaborative multi-agency working and leadership.
The recommendations will help to reduce current variation in practice. For example, vaccination uptake among eligible groups in general practice can range from 15 to 100%. The greatest resource impact is therefore likely to be for those practices that are less active in promoting flu vaccination uptake. But the cost impact should be relatively small compared with the reduction in mortality and morbidity associated with flu. In addition, there are opportunities to gain incentive payments by results, which may offset organisational costs.
## Evidence discussion
Uptake of flu vaccination by people in eligible groups, and its acceptability to them.
Little research evidence was identified that met the review protocol criteria on carers as a target population for flu vaccination .
For children not in any clinical risk groups , evidence for the effectiveness of both single interventions and multicomponent approaches to increasing flu vaccination uptake was of variable quality, ranging from moderate to very low. Most downgrading was due to risk of bias and imprecision of effect estimates. There was also some 'indirectness' downgrading for studies that included children outside the age range specified in the review protocol (2 to 17 years). The committee noted that all but 1 of the included studies was conducted in the USA, and that they covered a range of primary care, school-based and secondary care settings.
Overall, the evidence suggested single interventions were not effective in increasing flu vaccination uptake among children by a clinically important amount (that is, 5% or more above control group or baseline uptake levels). There was some evidence to support educational interventions aimed at parents , and provider prompts , but effects were inconsistent across studies. For multicomponent approaches, 1 large cluster-randomised controlled trial showed a clinically important increase in vaccination uptake, and a resulting decrease in missed opportunities to vaccinate . Another large randomised controlled trial also showed an increase in uptake, but with greater uncertainty in the effect . The committee noted that both studies were conducted in primary care and that there was moderate certainty in the evidence in both cases. They also noted that the studies involved an organisational lead or vaccination champion to coordinate delivery of the multicomponent programme.
For adults and children in clinical risk groups , the quantitative evidence relating to single interventions and to multicomponent approaches was again of variable quality, with most rated low or very low. Downgrading was largely due to risk of bias issues and imprecision of effect estimates, or small sample sizes.
In pooled analyses there was evidence of serious or very serious heterogeneity. The committee agreed this would be expected, given differences between study populations in terms of clinical risk factors and the lack of standardisation of interventions and comparators across studies. Again the majority of studies were conducted in non-UK settings and covered a range of health and social care settings.
There was evidence that some single interventions were effective in increasing vaccination uptake among adults and children in clinical risk groups , but effects were inconsistent across different interventions. The committee noted that in 6 out of 10 evidence statements in which a clinically important increase was found, the population in question was children in clinical risk groups. Parents of children in clinical risk groups may be more risk-averse and likely to accept the protective health benefits of vaccination than adults in clinical risk groups.
For people in clinical risk groups, 9 of 14 evidence statements relating to multicomponent approaches showed an increase in flu vaccination uptake; in 7 cases the effect was clinically important (5% or more relative increase) . These covered a range of paediatric and adult populations and different clinical risk groups. The committee noted that within the same study, effects differed depending on the particular clinical risk group or, in a study of immunocompromised children, depending on the type of cancer . The committee concluded that information needs, perceptions of individual risk and other health beliefs that influence decision-making about flu vaccination are not the same for people in different clinical risk groups. This should be considered when planning and delivering interventions.
For health and social care staff the effectiveness evidence for single and multicomponent interventions for increasing flu vaccination uptake was mostly rated very low quality. Downgrading was largely due to risk of bias issues and imprecision of effect estimates. In pooled analyses there was evidence of serious or very serious heterogeneity, which the committee agreed would be expected, given differences in the types of health and social care staff involved and the lack of standardisation of interventions and comparators across different studies. The majority of evidence was from a non-UK context and covered a range of health and social care settings.
There was inconsistent evidence that educational interventions alone increase uptake of flu vaccination among health and social care staff. However, staff education and awareness raising was included in almost all multicomponent approaches to increasing vaccination uptake, combined with interventions to increase staff access through more flexible workplace delivery. A clinically important increase in vaccination uptake among health and social care staff (of 5% or more) was reported in 19 out of 20 evidence statements relating to multicomponent programmes .
To improve uptake, the committee noted the importance of both increasing demand for flu vaccination among target groups (for example, through awareness raising, using education to overcome informational barriers or sending reminders), and addressing 'supply' factors (for example, prompts to providers to increase offers of vaccination). Accessibility and convenience of vaccination provision were consistent themes highlighted in reviews of the qualitative evidence and expert testimonies . A key advantage of a multicomponent approach is that it can address demand and supply factors simultaneously.
The committee acknowledged that it may be difficult to identify what specific interventions within a multicomponent approach are more or less effective in promoting uptake. This may affect the ability of programme leaders to modify and improve the approach to increase uptake of flu vaccination over successive vaccination seasons.
No studies were identified that assessed the comparative cost effectiveness of multicomponent and single interventions for increasing uptake of flu vaccination.
Depending on the level of cost of the chosen mix of interventions needed to increase opportunities, they could be cost effective as described below. The committee's opinion was that although a multicomponent approach is likely to be more time- and resource-intensive than a single intervention, it will have greater impact on uptake because it targets multiple drivers affecting both demand and supply. Different approaches are likely to affect people differently and thus will have a greater impact at a population level. Experts emphasised the need for careful planning and coordination, which the committee agreed was best undertaken by an assigned organisational lead or team . This may incur an opportunity cost to organisations if the seasonal nature of the task means that staff need to be redeployed from other important duties. However, these costs are likely to be offset by financial remuneration from enhanced services payments and from achieving incentive-based targets in the QOF and CQUIN pay-for-performance schemes.
Overall, the committee felt that because many organisations are already implementing strategies to promote flu vaccination uptake (many of which take a multicomponent approach), the recommendations should not represent a significant impact on resources. The impact of implementing the recommendations will be largely determined by the current intensity and variety of activity undertaken by an organisation. The committee agreed that the recommended interventions are in line with the current service specification for flu vaccination delivery and that they are all generally likely to have a relatively low cost.
The committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations that are the focus of this guideline, interventions were considered cost effective if:
For adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.
For pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.
For children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.
For health and social care staff, they cost up to £2.15 per targeted person and increased vaccination uptake by at least 5%.
The committee felt that the costs per targeted person of multicomponent approaches were likely to be below the maximum costs, and achieve the necessary level of vaccination.
They also noted that wider, more consistent use of a multicomponent approach will potentially reduce current variability in rates of uptake around the country. They believe this will in turn reduce levels of circulating flu and the associated healthcare and societal costs.
The committee recognised the lack of peer-reviewed evidence about carers and limited evidence about children who are not in clinical risk groups. They also acknowledged the non-UK context of the majority of evidence in the reviews. However, on the basis of expert testimony relating to carers , people in clinical risk groups and health and social care staff , combined with their own experience of vaccination for multiple groups, the committee believed that evidence supporting the effectiveness of multicomponent approaches could be extrapolated to all eligible groups in UK settings. They noted that vaccination incurs a financial cost to the person in many of the settings the evidence relates to, whereas it is provided free to people in eligible groups in the UK. Effect sizes may therefore be greater in the UK where there are fewer financial barriers (although there may still be costs to the person, such as from taking time off work, or transport).
The committee noted that there was some evidence to indicate that the initial benefits of a multicomponent approach are sustainable, but that the same approach may not increase uptake year on year . Expert testimony supported the need to be flexible and innovative in order to extend the reach of a multicomponent approach over successive years .
The committee concluded that, overall, the evidence reviewed showed a more positive and consistent effect favouring multicomponent approaches over single interventions to increase uptake of flu vaccination in the populations of interest. They felt that multicomponent approaches offer opportunities to reach more groups, therefore representing a better long-term return on investment by increasing vaccination rates and so reducing the health impact and societal costs associated with flu infection.
Multicomponent approaches are complex interventions and the committee was not able, on the basis of the evidence, to recommend a specific configuration. There may be a synergistic effect of combining interventions and certain components may be more or less effective in differing target groups.
The recommendations in sections 1.2 to 1.7 present options that a commissioner or provider could use to develop an approach based on local intelligence, allowing them to apply what is most relevant to their needs.
## The evidence
The committee looked at evidence in:
Evidence review 2 on increasing flu vaccination uptake in children: ES123.1, ES123.2, ES123.3, ES123.4; Q-ES 1.4, Q-ES 1.5
Evidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES123.1, ES123.2, ES123.3, ES123.4, ES123.5; SR ES123.1, SR ES123.2, SR ES123.3, SR ES123.4, SR ES123.5, SR ES123.6, SR ES123.7, SR ES123.8, SR ES123.9; Q-ES 2.3
Evidence review 4 on increasing flu vaccination uptake in health and social care staff: ES 45.1, ES 45.2, ES 45.3, ES 45.4, ES 45.5, ES 45.6, ES 45.7, ES 45.8, ES 45.9, ES 45.10, ES 45.11; SR-ES 45.1, SR-ES 45.2, SR-ES 45.3, SR-ES 45.4, SR-ES 45.5, SR-ES 45.6, SR-ES 45.7, SR-ES 45.8, SR-ES 45.9
Expert testimony on increasing vaccination uptake among carers: Expert paper 1 (EP1)
Expert testimony on increasing vaccination uptake among people with chronic liver disease: Expert paper 2 (EP2)
Expert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: Expert paper 3 (EP3)
Expert testimony on increasing vaccination uptake among healthcare workers: Expert paper 4 (EP4) and Expert paper 5 (EP5)
Expert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)
# Raising awareness
The discussion below explains how the committee made recommendations 1.2.1 to 1.2.10.
## Rationale and impact
Not all health and social care staff know who is at greatest risk from flu, so they are not offering it to everyone who is eligible. There is evidence that training and educating health and social care staff improves vaccination rates. The evidence also showed that people in eligible groups who understand why flu vaccination is particularly important for them are more likely to be vaccinated. Professionals need to explain the benefits of vaccination and address people's misconceptions about it. The committee also agreed that it is important to make sure people know that flu vaccination is free if they are eligible.
There was some evidence that working with statutory and voluntary organisations might be effective in raising awareness about vaccination and its benefits, although there is currently a lack of empirical evidence in this area.
Current practice is variable in GP surgeries where most flu vaccination is given. Practices with high vaccination uptake are likely to be delivering services in line with these recommendations already; those practices with lower levels of vaccination uptake will be able to make a big impact by putting these recommendations into practice.
## Evidence discussion
Uptake of flu vaccination by people in eligible groups, and its acceptability to them.
There was some quantitative evidence supporting the effectiveness of provider education as part of a multicomponent approach to improving uptake of flu vaccination among eligible groups. There were 10 evidence statements relating to largely non-UK-based studies in which provider education explicitly formed part of the intervention being evaluated. The study populations included children not in clinical risk groups , pregnant women, and children and adults in clinical risk groups , and covered a range of healthcare settings. Certainty in the evidence was variable; most was rated low or very low quality. Reasons for downgrading included risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates in smaller studies. In 9 of the 10 evidence statements there was a reported increase in flu vaccination uptake; in 6 cases this was a clinically important increase (5% or more relative to control group or pre-intervention uptake) .
There was more available evidence on the effectiveness of education or awareness-raising interventions aimed at eligible people (or their parents, in the case of children) rather than healthcare providers. In this context, education was often combined with other interventions such as written or text message reminders. Various interventions were outlined and in many cases there was a lack of specific detail (the term 'educational materials' was frequently used).
Eighteen evidence statements generated across evidence review 2 and evidence review 3 , again relating to largely non-UK-based studies and covering a range of healthcare settings and populations, included an educational element targeted at the person eligible for flu vaccination. Eleven of the 18 statements reported an increase in vaccination uptake that, in 8 cases was clinically important . There was generally low or very low certainty in the evidence, with downgrading due to risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates.
Qualitative evidence highlighted that access to information was essential to parents making vaccination decisions on behalf of their children, and for people with chronic health conditions . People's perceptions of personal risk differ, and these need to be ascertained and addressed by healthcare providers, along with concerns about flu vaccine safety and effectiveness and misconceptions, for example that vaccination can give people flu .
Qualitative evidence also suggested that providers may themselves have differing risk–benefit perceptions depending on their own clinical or personal experience . Other studies highlighted that people deciding whether to have a flu vaccination place importance on the perceived strength of their healthcare provider's endorsement of the flu vaccine , and that they want to trust that the advice they are given is credible and delivered for their own health benefit without any conflict of interest (for example, to get incentive payments) . Providers and people in eligible groups may be aware that flu vaccine effectiveness varies, and this may work as a barrier to uptake. Although it is not possible to predict before a flu season how well the available vaccine and circulating strains of the virus will be matched, the committee were keen to note that the flu vaccine has generally been a good match and continues to provide the best protection for those at greatest risk from flu and its complications.
The evidence reviewed reinforced the committee's decision to recommend raising and sustaining awareness not only in eligible groups, but also in those who commission and deliver vaccination programmes. Encouraging use of professional minimum standards vaccination training will help to reduce variation in professional attitudes and ensure consistency of message delivery.
The committee was satisfied that the majority of evidence favoured using information and education to raise and sustain awareness of flu vaccination as a means of increasing uptake. They agreed it was important to target both healthcare providers and people in clinical risk groups. Based on their knowledge of this kind of approach in the UK and the generally positive direction of effect across studies in the evidence reviews, the committee felt the evidence could be extrapolated to all eligible groups specified in the Green Book and across health and social care settings, provided that individual needs underpin any information given as part of an intervention.
Raising and sustaining awareness – both among those with responsibility for providing and administering flu vaccination and those eligible for vaccination – should reduce barriers to offering, providing and accepting it.
Using opportunistic approaches, including brief interventions or brief advice, is in line with the principles of Making Every Contact Count and the NHS Five Year Forward View and should result in increased efficiency of service provision and access.
Raising awareness as a means of encouraging more people to be vaccinated needs to be coupled with interventions to ensure there are adequate supplies of flu vaccine to meet increased demand, and that appropriate and convenient access arrangements are in place. Otherwise there is a risk of deterring people from further engaging with vaccination services.
Educational interventions for people in eligible groups are generally low cost with relatively low resource implications, particularly if delivered opportunistically in the form of brief interventions or brief advice by knowledgeable healthcare staff they come into contact with, in line with Making Every Contact Count. Evidence from expert testimony suggested that efficiency savings can be made if information on flu vaccination is delivered at the same time as other health-promotion messages and preventive health interventions for eligible groups .
Education and awareness-raising interventions aimed at health and social care staff are likely to incur greater costs. However, there are national minimum standards and a core curriculum for staff involved in administering vaccines. These have free training resources for local use. Some areas provide bespoke training for designated flu champions, who may not be required to meet full national standards for immunisation training if flu vaccine is the only vaccine they administer in their professional role. This training is likely to have lower overall resource costs. For staff whose role includes delivering vaccination-related activities, in particular awareness raising and educational messages, training and educational interventions should be considered an integral part of their continuing professional development to ensure that they use safe practice and give up-to-date advice.
The committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:
For adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.
For pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.
For children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.
The committee felt that educational interventions were likely to be cost effective, and would help to achieve national targets and aspirations for flu vaccination.
The committee noted the lack of detail in some studies about intervention content and how they could be potentially combined, but agreed that the evidence was consistent on the importance of increasing and sustaining awareness in professionals and in parents, children and people in clinical risk groups. The committee discussed the potential for healthcare professionals to use face-to-face interactions to identify and opportunistically engage with those eligible for flu vaccination, but agreed that this raises equity issues, because people not in contact with healthcare services may be missed. They agreed with the testimonies of experts that providers should consider partnership working with local organisations (for example, drug and alcohol services) and voluntary sector groups working with underserved populations (such as carers or people who are homeless) to identify those who might be eligible for flu vaccination and give them information about how to access services .
Educating health and social care staff and eligible groups about flu vaccination in the context of protecting others was also seen by the committee as a way to increase uptake. The committee recognised the lack of UK-based studies generally and the lack of peer-reviewed evidence about carers specifically, but it considered expert testimony and was able to make recommendations about carers .
The committee noted that the flu vaccine is administered differently in children and adults. Children over the age of 2 who are eligible for annual flu vaccination are given live attenuated influenza vaccine (LAIV) in the form of a nasal spray (see recommendation 1.2.8 in the section on raising awareness in eligible groups). Eligible adults (aged 18 and over) should be given the inactivated flu vaccine by injection. Only in exceptional circumstances, alternative options for administering flu vaccine to adults who become seriously distressed by needles may be agreed (see Public Health England's information for healthcare practitioners on administering LAIV to patients with a needle phobia, pages 23 and 24).
## The evidence
The committee looked at evidence in:
Evidence review 2 on increasing flu vaccination uptake in children: ES123.3; Q-ES1.3
Evidence review 3 on increasing flu vaccination uptake in clinical risk groups: SR-ES 1.1; ES 123.2, ES123.3, ES123.5; SR-ES123.5, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES 2.1, Q-ES 2.2, Q-ES 2.4, Q-ES 2.5
Evidence review 2 on increasing flu vaccination uptake in children: ES1.1, ES1.2, ES3.2; Q-ES1.1, Q-ES1.2
Evidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES1.1, ES1.2; SR-ES1.1, SR -ES1.2; ES3.1, ES3.2, ES3.3; SR-ES3.8; ES123.3, ES123.4; SR-ES123.3, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES2.1, Q-ES2.2, Q-ES2.4
Expert testimony on increasing vaccination uptake among carers: expert paper 1 (EP1)
Expert testimony on increasing vaccination uptake among people with chronic liver disease: expert paper 2 (EP2)
Expert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: expert paper 3 (EP3)
Expert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: expert paper 6 (EP6)
# Offering vaccination
The discussion below explains how the committee made recommendations 1.3.1 to 1.3.6.
## Rationale and impact
Many potential opportunities are being missed to offer eligible people a free flu vaccination during contacts with health, social care and other statutory and voluntary services. There is evidence that using existing systems to offer flu vaccination and extending the way services are provided can encourage more people to be vaccinated. An expert told the committee that all organisations that can reach eligible people need to work together to ensure this happens.
The committee also agreed that being flexible with the hours when GP surgeries or other providers offer flu vaccination would enable people to come for vaccination at a time convenient for them. There was limited evidence that this improves vaccination rates but it was also supported by expert testimony.
There is evidence that flu vaccine supply can also affect uptake. People who request the vaccination may not return if it is not available immediately.
Using every opportunity to offer and provide flu vaccination will increase uptake among people who need it because they are particularly vulnerable to the complications of flu. Although this may increase costs in the short term, the committee agreed that it is likely to be cost effective.
## Evidence discussion
Uptake of flu vaccination by people in eligible groups, and its acceptability to them.
In relation to increasing offers of flu vaccination, the committee considered ways in which people who are eligible can be identified ('case-finding'), and interventions to ensure that vaccination services are accessible to those who are offered them.
Case-finding can be done opportunistically or systematically. The published evidence related mainly to systematic approaches using provider prompts embedded in healthcare records. This evidence is considered separately in the section on patient records.
Expert testimony highlighted the importance of using both opportunistic and systematic approaches to case-finding as a means of increasing opportunities to offer flu vaccination. Face-to-face interactions in primary care (including community pharmacy) provide opportunities to identify and offer vaccination to eligible people. Periodic searches of computer records can be undertaken in general practice to identify unvaccinated new patients or people who have recently become eligible (for example, people who are recently diagnosed with a condition that places them in a clinical risk group, or women with a newly confirmed pregnancy) .
Other strategies for case-finding should be considered for eligible people who may not be identifiable using existing general practice systems. The committee noted that carers are a difficult group to identify because their carer status may not be routinely recorded in GP records . Other expert testimony highlighted that chronic liver disease is associated with the highest risk of flu-related mortality but lowest rates of vaccination uptake across all clinical risk groups specified in the Green Book. Prevalence of chronic liver disease is high among people who abuse drugs and alcohol, who may be in more regular contact with specialist services and pharmacies than with GPs . People sleeping rough have a high prevalence of chronic respiratory illness and are usually not in regular contact with statutory healthcare services . The committee was keen to promote links between vaccination providers and other local organisations, such as those assessing and supporting carers, specialist drug and alcohol services, community pharmacies and voluntary groups working with carers or people who are homeless to identify eligible people and offer (or signpost them to) vaccination services.
Qualitative evidence highlighted that perceived availability and accessibility are significant barriers to or facilitators of uptake among eligible groups who are offered a flu vaccination .
Fourteen evidence statements related to effectiveness studies in which access had been improved for target populations by providing vaccination services more frequently or at more convenient times or locations. The published evidence ranged from moderate to very low quality, with the majority being of very low certainty and from non-UK settings. Reasons for downgrading included risk of bias, high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates. Eight of these evidence statements reported an increase in vaccination uptake, which was clinically important in 6 cases, among populations that included children not in clinical risk groups as well as adults and children with clinical risk factors and pregnant women . The majority of studies lacked specific detail about how access to vaccination services had been improved by the intervention, which made it difficult for the committee to make recommendations. One study that reported an increase in uptake compared year-round flu vaccination for children with asthma with appointments offered only during the flu season, which the committee agreed was not applicable to the UK . The committee discussed another before-and-after study that reported no clear improvement in uptake when 2 additional Saturday clinics were offered to children with asthma at the start of the flu vaccination season . The committee felt this relatively small US-based study did not support the qualitative evidence or their own experience of the importance of out-of-hours access, particularly for people in work or education. Expert testimony confirmed that GP practices offering weekend access have been able to achieve vaccination of hundreds of patients in 1 day. This had the added benefit that it was outside usual practice hours, so reducing impact on the winter pressure for GP appointments .
In England, community pharmacies are able to provide flu vaccinations to eligible adults. Studies in which community pharmacies were part of extended access arrangements did not show increased uptake among target populations . However, the committee noted that people of working age in clinical risk groups who are relatively well but need regular prescription medication, and carers in particular, may be more likely to use community pharmacies as a convenient alternative to GP vaccination services. This was confirmed by expert testimony relating to carers .
The committee concluded that increasing identification of eligible people and providing sufficient routes of access to meet the needs of different groups (including out-of-hours opportunities for people with work commitments) are key to increasing vaccination uptake, as is ensuring that supplies are sufficient to meet demand. The empirical evidence linking extended hours to increased uptake was inconsistent, but the committee felt it important to provide convenient access to as many eligible people as possible.
Organisations are encouraged to use clinical systems to systematically identify people who are eligible for free flu vaccination and record uptake. Flu vaccination providers should plan to exceed the previous year's uptake when ordering supplies.
Opportunistic approaches are in line with the principles of Making Every Contact Count and the Five Year Forward View. But it is not easy to ensure consistency of delivery.
Systematic case-finding needs procedures to be in place, including staff routinely checking for people who are newly eligible. However, implementation of such procedures is likely to be consistent and effective. Establishing links with local statutory and voluntary organisations to promote case-finding is dependent on what resources are available locally. Using outreach to offer flu vaccination to eligible people who are not in touch with services needs careful planning to ensure that the vaccine cold chain is maintained and staff have the capacity to recognise and treat any adverse reactions.
Increasing identification of eligible people and offers of flu vaccination should be coupled with appropriate interventions to ensure adequate availability and ease of access.
One cost–utility study and 1 cost effectiveness study (both low quality) were included in the review of interventions for increasing vaccination uptake in clinical risk groups . One study suggested that opportunistically identifying, offering and administering flu vaccination may be cost saving . The other study indicated that targeting pregnant women with a comorbidity was also likely to be cost saving. The evidence focused on pregnant women during routine practice visits and children from clinical risk groups in a hospital setting. The committee agreed that the principle of increasing the opportunistic offer and administration of the vaccination without increasing the need for additional visits would be cost effective across all eligible populations.
The committee noted that using computerised systems for case-finding could incur higher costs than opportunistic approaches but will be more consistent and may therefore be a more effective lever for increasing uptake, with greater long-term efficiency savings. Extending access to vaccination services will incur higher outlay in terms of staff costs and overheads. Using outreach 'find and treat' methods to vaccinate eligible people who are not in regular touch with services will incur costs, but the committee were keen to recognise the health benefits of vaccinating those who will not get vaccinated elsewhere. Off‑site provision offered through collaborative working (for example with community pharmacies and secondary care) needs to be negotiated by commissioners because there is potential loss of income for general practices.
The committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:
For adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.
For pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.
For children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.
The committee felt that the costs per targeted person of increasing opportunities to offer flu vaccination were likely to achieve the necessary level of vaccination to be cost effective.
Overall the committee agreed that increasing opportunities to reach more groups is a good use of resources given the morbidity and mortality associated with flu. In turn, this may reduce some of the winter pressures on the health service associated with flu infection. Opportunistic approaches are not likely to significantly impact resources because they specifically aim to reduce the likelihood of needing additional appointments and are targeted. This is in agreement with the cost effectiveness evidence showing the approach is likely to be cost saving.
## The evidence
The committee looked at evidence in:
Evidence review 1 on increasing flu vaccination uptake in carers: ES2.1
Evidence review 2 on increasing flu vaccination uptake in children: ES123.1/4, ES123.2, ES123.3; Q-ES1.4; Q-ES1.5
Evidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES2.1, ES2.2; SR-ES2.1, SR-ES2.2, ES123.1, SR-ES123.1, SR-ES123.3, SR-ES123.4, SR-ES123.5, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES2.3; CE-ES2.1, CE-ES2.3
Expert testimony on increasing vaccination uptake among carers: expert paper 1 (EP1)
Expert testimony on increasing vaccination uptake among people with chronic liver disease: expert paper 2 (EP2)
Expert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: expert paper 3 (EP3)
Expert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: expert paper 6 (EP6)
# Increasing uptake among eligible groups in primary and secondary care
The discussion below explains how the committee made recommendations 1.4.1 to 1.4.10.
## Rationale and impact
The committee agreed that most people who are particularly vulnerable to the complications of flu, or who are eligible for other reasons, are likely to be in regular contact with their GP surgery or local community pharmacy and know the staff. These routine contacts provide ideal opportunities to speak to people about flu vaccination. The evidence showed that making sure invitations to eligible people are personalised to their circumstances also helps to increase vaccination uptake. If eligible people are not in regular contact with primary care services, or have particular concerns about flu vaccination, using peers as local 'flu champions' providing information that is accessible and appropriate to the target group may help promote uptake.
Some people at high risk from flu and its complications visit hospital outpatients or other secondary care clinics more regularly than their GP. Existing hospital systems could be used to identify them, raise awareness and encourage them to have a free flu vaccination while they are there if this is a locally agreed route for offering vaccinations. There is evidence that this is most effective when the vaccination offer is tailored to their condition and made by a healthcare practitioner they know.
In both primary and secondary care, incorporating prompts in electronic health records helps to remind health and social care staff to offer flu vaccination to people who are eligible when they attend for appointments. Using already available systems to set these reminders helps the care provider raise awareness of and offer vaccination.
General practices that have signed up to the service specification for flu vaccination are required to proactively call and recall eligible patients. Computerised systems are already in place to do this; however, the way it is carried out is variable. GP surgeries will need to ensure that they personalise and tailor their invitations for vaccination.
A key element of the recommendations is to make the most of face-to-face interactions to offer and deliver vaccination. This may need additional time and resources initially. However, a personalised approach tailored to the person's situation is more likely to engage them with the flu vaccination programme. Embedding prompts in these eligible patients' healthcare records to remind providers to invite them for vaccination each flu season could avoid additional appointments and save costs in the longer term.
The lack of a national service specification for secondary care means that some areas don't have local enhanced services agreements to deliver vaccination and will need to set these up. Procedures for recognising and treating adverse reactions, the purchase and appropriate cold-chain storage of flu vaccine supplies, and ensuring that the setting used to administer vaccinations is appropriate are all issues that need to be taken into account when setting up these agreements with secondary care providers.
## Evidence discussion
Uptake of flu vaccination to people in eligible groups and its acceptability to them.
Call ('vaccination due') and recall ('vaccination overdue') interventions delivered using various formats are frequently used in UK primary care to remind people of their eligibility for free flu vaccination. The committee reviewed the published evidence on the effectiveness of such interventions, which was mostly from non‑UK studies and ranged from high to very low quality, with the majority being of low quality. Reasons for downgrading included risk of bias, high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates.
As a single intervention strategy, there was no evidence that reminders delivered as text messages (with or without an educational element) increased flu vaccination uptake among eligible groups by a clinically important amount (5% or more, compared with control or pre-intervention uptake rates) . However, call and recall methods using more personalised approaches (such as letters, postcards or personal telephone calls) appear to be more effective. There were 7 evidence statements relating to the use of such approaches among people from clinical risk groups, of which 5 reported an important increase in flu vaccination uptake . The committee noted that in 3 of the 5 cases the target population was children, suggesting that parents may be more amenable to personalised messages about the protective health benefits of vaccination when their children are in clinical risk groups than are adults who themselves have clinical risk factors. When reminders formed part of a multicomponent approach, an important increase in vaccination uptake was reported , although 1 UK-based study that targeted children aged 2 to 4 years who were not in a clinical risk group found no increase in uptake when practices incorporated text messaging into a multicomponent approach . The committee noted qualitative evidence that for parents of preschool children, a personal invitation from a healthcare professional is important for making a decision about vaccination . Other qualitative evidence further highlighted that people are more likely to trust advice and offers of vaccination that come from healthcare professionals they know, and that it is important for messages to be delivered with conviction .
The committee believed strongly that reminders should be proactive. Not everyone who is eligible for free flu vaccination will visit their GP surgery regularly, so it is not sufficient to rely on posters in waiting rooms to remind them. The committee discussed the equivocal evidence on the effectiveness of text messaging to call and recall people for flu vaccination, which they felt may be perceived by the recipient as too impersonal or lacking conviction. They agreed that, if possible, reminders to eligible people should be personalised and come from a healthcare professional they know, either in person or in writing. The committee acknowledged that digital formats may be more acceptable to some population groups than others but were keen to recommend that if they are used, they should include links to additional useful information, including options for seeking further face-to-face advice and for booking an appointment to have their flu vaccination.
The committee also considered expert testimony that supported the use of peers to inform and invite people who are not in contact with primary care services for vaccination, such as people who are homeless . They discussed that this approach could be extended to engage people who may have concerns about flu vaccination for religious reasons, as highlighted in another expert's testimony . For example, some parents of children eligible for flu vaccination may be reluctant for their child to take up the offer because the nasal spray that is used to vaccinate children contains a gelatine additive derived from pork, so may be considered 'forbidden' in certain faiths. In such situations, it may be worth trying to engage peers or community leaders to work with local healthcare providers to provide information and support that people feel able to trust, in a language that is accessible and appropriate to them.
The majority of published evidence considered by the committee was from the USA, where there is no distinction between primary care and secondary care that equates to the UK healthcare context. However, the committee noted there was low-quality evidence from studies in which interventions implemented in specialist healthcare settings had successfully improved vaccination uptake among children having treatment for different forms of cancer and, although with greater uncertainty in the effect, among people with end-stage renal disease who were having treatment in dialysis centres .
In relation to UK secondary care, the committee reviewed expert testimony about people with chronic liver disease. This highlighted that these people are at high risk of flu-related morbidity and mortality but currently have the lowest rates of vaccination uptake in primary care; also that they may be more likely to have regular contact with specialist hospital clinics or other services (such as drug and alcohol services) . The committee agreed this may also apply to other eligible groups, including those with chronic neurological or kidney disease, people who are immunocompromised due to a medical condition or ongoing treatment, and pregnant women attending hospital antenatal appointments. This offers opportunities to provide flu vaccination in secondary care to people who may otherwise not access vaccination through primary care. Existing hospital systems could be used to identify and prompt offers of vaccination to anyone attending a routine appointment during the flu season who remains unvaccinated. However, the committee were keen to underline that vaccination in secondary care needs to be done in line with local commissioning agreements. Also, arrangements should be in place to ensure that anyone who is opportunistically offered vaccination in secondary care can access it easily, because qualitative evidence suggests people are put off if they have to arrange a further appointment or go to another location to get the flu vaccine .
The committee drew on evidence from qualitative studies with pregnant women highlighting the importance of a personalised invitation from a known professional involved with their antenatal care . They discounted evidence from a number of small, low-quality studies that found no difference in vaccination decision-making among pregnant women when messages about flu vaccination were framed either 'negatively' (in terms of risks of remaining unvaccinated) or 'positively' (in terms of the benefits both to mother and baby of protection against flu both during pregnancy and after birth). There was contradictory evidence from other qualitative studies suggesting that pregnant women respond more readily to offers of vaccination when the benefits to their baby are clearly communicated . The committee felt this corresponded with other evidence already outlined suggesting that parents of children in clinical risk groups respond well to personalised interventions encouraging vaccination of their children. Given that flu vaccination rates are currently very low in young children, particularly babies and infants with clinical risk factors that put them at highest risk from flu, the committee felt it is important that providers help parents make decisions about flu vaccination by not only outlining the potential risks of not vaccinating but also the benefits – appealing to the parental instinct to nurture and protect their child's health.
The committee reviewed evidence for provider prompts embedded in patient medical records as an intervention to increase uptake of flu vaccination. There were 8 evidence statements relating to use of provider prompts – either as a single intervention or, more usually, combined with other approaches to increasing vaccination uptake . Seven of these statements reported an increase in vaccination uptake. This was clinically important (an increased uptake of 5% or more, compared with the control or pre‑intervention level), in 6 of the 7 evidence statements. The evidence was of variable quality with most rated of low or very low certainty. Reasons for downgrading included risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses and imprecision of effect estimates. The settings included primary and secondary care. Populations included children not in clinical risk groups , as well as adults and children with clinical risk factors and pregnant women . One study suggested that timing of prompts may be important, with a greater increase in uptake when provider prompts were activated later in the flu season (January to February) compared with earlier (October to December).
Primary care is the main setting in which flu vaccinations are given in the UK. Most people who are eligible for free flu vaccination are already registered with a GP, so it is relatively easy to use the systems already in place in primary care to implement interventions to increase uptake, such as case-finding and using provider prompts. Sending reminders to eligible people that they are due or overdue (call/recall) their flu vaccination is a useful means of sustaining awareness across successive flu seasons. However, this needs contact information to be kept up to date in patient records.
Face-to-face interactions are an opportunity to raise awareness and encourage uptake. However, some people who are eligible for flu vaccination may not be in regular contact with primary care and may remain unvaccinated, which is why the committee were keen to also include recommendations for increasing uptake in secondary care. Systems are in place to enable the identification of people receiving specialist treatment for health conditions that make them eligible for free flu vaccination so that the vaccine could be offered. However, vaccination needs to be available and easily accessible on‑site, and to be organised in line with local patient group directions or enhanced services arrangements that have been agreed with commissioners.
Embedding provider prompts in health records is likely to be a more consistent and efficient method of identifying eligible people and increasing offers of flu vaccination than opportunistic approaches to case-finding. It is relatively easy to implement because systems are already in place. For example, prompts for flu vaccination could be established through coding from previous hospital admissions or primary care records and automatically generated in electronic case records. However, a disadvantage of prompts is that they are often used for many aspects of healthcare delivery, and run the risk of practitioners getting 'prompt fatigue'.
One cost–utility study and 1 cost-effectiveness study (both low quality) were included in the review of interventions for increasing vaccination uptake in clinical risk groups . The studies suggest that opportunistically identifying, offering and administering flu vaccination may be cost effective. . The evidence focused on pregnant women during routine practice visits and children from clinical risk groups in a hospital setting, but the committee agreed that the principle of increasing opportunities would be cost effective across all eligible populations and both primary and secondary care settings.
The recommendations support using existing primary care systems in a more structured and consistent way to send personalised reminders inviting eligible people to get vaccinated. This may need some training but would be relatively low cost overall.
Economic modelling for children and adults in eligible groups was conducted by adapting a dynamic model which was developed by Public Health England and was used to inform recommendations from the Joint Committee on Vaccinations and Immunisations. The model considers the entire population of England from Office for National Statistics (ONS) 2016 data, stratified into age and risk groups. The age- and risk-stratified model uses a set of equations to model the interaction between groups and the transmission of flu. Baseline coverage, by age and risk group status, is informed by Public Health England's vaccine uptake guidance reports for winter 2015/16 seasons. Disease transmission parameters and flu vaccine efficacy are the same as those in the original Joint Committee on Vaccinations and Immunisations analysis.
The cost of a flu vaccine was calculated from the British National Formulary and Prescription Cost Analysis. For adults receiving an injection, the cost was £5.96. 90% of children were assumed to receive the nasal spray costing £18, and 10% to receive the injection.
The model includes flu vaccine side effects from injection and nasal spray, which have associated costs and QALY losses.
People who contract flu have an increased mortality risk (modelled as a lifetime QALY loss, depending on their age), a QALY loss of 0.008 for flu-like illness, 0.00101 for acute respiratory infection and 0.018 for hospitalisation. Hospitalisation was associated with a cost of £1,029, from NHS reference costs. The expected number of GP consultations were calculated using the same data as the original Joint Committee on Vaccinations and Immunisations analysis, with an updated cost per consultation of £31 for surgery visit, or £98 for home visit from the Unit Costs of Health and Social Care.
The perspective of the model is NHS and personal social services, and the time horizon is 1 year because each person must be vaccinated annually.
The model showed that increasing vaccination uptake in children decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations and hospitalisations, in both adults and children. At baseline, 13,067,472 children are vaccinated. Increasing this by 10% to 13,973,271 averts 872,015 cases of flu; 122 deaths; 55,634 GP consultations and 956 hospitalisations. The cost for the additional number of vaccinations is £10,945,753 and flu vaccine side effects costs an additional £688,942. There are cost savings from reduced GP consultations (£1,985,574) and hospitalisations (£983,879), leading to a total cost to the NHS of £8,655,242. Flu vaccine side effects lead to an additional QALY loss of 33.34 QALYs, but the reduction in flu cases avoids a QALY loss of 3,243. The incremental cost effectiveness ratio is therefore £2,645 per QALY. This is below £20,000 per QALY and therefore implies it would be cost effective to spend money to increase the uptake of the flu vaccination. Calculating the monetary net benefit, it would be cost effective to spend up to £5.50 per targeted child to increase uptake by 10%. Similar calculations find that it would be cost effective to spend up to £11.48 per targeted child to increase uptake by 25%. The maximum that an intervention could cost and be cost effective at £20,000 per QALY depends on the baseline coverage level. Interventions with a higher cost would be cost effective where uptake levels are lower.
The model showed that increasing vaccination uptake for adults in clinical risk groups, pregnant women and children in clinical risk groups decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations and hospitalisations, primarily within the group targeted. Increasing the number of vaccinations and flu vaccine side effects increased costs, but there were some cost offsets from avoiding cases of flu, hospitalisation and GP consultations. There were small QALY losses from the additional side effects, but large QALY gains from avoiding cases of flu and mortality. The net monetary benefit for increasing vaccination by 5% for adults in clinical risk groups is £4.00 per targeted person, for pregnant women is £4.50 per targeted person, and for children in clinical risks groups is £2.40 per targeted person. The maximum that an intervention could cost and be cost effective at £20,000 per QALY does not vary with baseline coverage.
The committee considered that opportunistic advice and identification, using existing systems to generate invitations and reminders, and embedding provider prompts embedded health records are effective interventions that could be delivered in primary and secondary care at a relatively low cost per targeted person. They believed that such interventions would help to achieve the necessary level of vaccination and are therefore likely to be cost effective.
The majority of the evidence was from non-UK settings, but the committee used expert testimony and their knowledge of the UK healthcare context to develop these recommendations. They concluded that encouraging the implementation of interventions in both primary and secondary care should result in increased identification, offer and delivery of flu vaccination to eligible people, as well as increasing the efficiency of these processes.
## The evidence
The committee looked at evidence in:
Evidence review 2 on increasing flu vaccination uptake in children: ES3.1, ES3.2, ES3.3, ES3.4, ES123.2; Q-ES1.9
Evidence review 3 on increasing flu vaccination uptake in people in clinical risk groups: ES3.2, ES3.3, ES3.4a; SR-ES3.1, SR-ES3.2, SR-ES3.3, SR-ES3.4, SR‑ES3.5, SR-ES3.7, SR-ES3.8, SR-ES3.9, SR-ES123.1, SR-ES123.3, SR-ES123.7, SR-ES123.9; ES123.3, ES123.5; Q-ES2.3, Q-ES2.4, Q-ES2.6; CE-ES2.1, CS‑ES2.2
Expert testimony on increasing vaccination increasing uptake among people with chronic liver disease: Expert paper 2 (EP2)
Expert testimony on increasing vaccination increasing uptake among people who are homeless or rough sleepers: Expert paper 3 (EP3)
Expert testimony on increasing vaccination increasing uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)
# Audit, monitoring and feedback
The discussion below explains how the committee made recommendations 1.5.1 to 1.5.8.
## Rationale and impact
Providers and employers need to know whether they are reaching their vaccination targets or whether they need to change the way they are delivering their flu vaccination programme to better protect their patients or vaccinate their staff. According to both evidence and expert testimony, audit, monitoring and feedback help providers and employers to plan for and offer flu vaccination to meet their targets, including for payment by results.
The committee also agreed that if different providers across the system are offering vaccination, it is important for services to share information with each other and keep accurate records of who has been vaccinated. This will ensure general practice uptake figures are accurate and avoid them wasting resources by inviting people for vaccination unnecessarily (leading to missed appointments) or duplicating vaccinations.
There is inconsistency among GP surgeries in how they record and use data to monitor their progress with flu vaccination during the season. To implement these recommendations some practices will need to improve their record-keeping using clinical software systems so they can monitor whether they are successfully targeting eligible people. Similarly, employers may need to improve their systems for recording and monitoring the vaccination status of staff, because some eligible health and social care staff may not be getting a free vaccination offer from their employer. This may be a particular issue in the social care sector, which has a large number of providers and currently no central requirement to submit data on the uptake of flu vaccination among front-line staff.
Monitoring uptake among eligible groups when vaccination is provided outside general practices in settings that do not have direct access to information technology (IT), or where different IT systems are used, may be a challenge. Mechanisms for sharing information need careful planning and oversight to minimise data loss.
## Evidence discussion
Uptake of flu vaccination by people in eligible groups, and its acceptability to them.
Qualitative evidence highlighted that providers need to feel that they can trust in the accuracy of computerised prompts and patient records, which should be maintained and updated in a consistent and timely fashion . The committee agreed that this is an important issue given the inclusion of recommendations in this guideline to extend vaccination provision to other settings to increase uptake, including schools (as part of the universal programme for vaccinating children), community pharmacies, secondary care and social care settings.
The committee reviewed very low- to moderate-quality evidence showing that audit and feedback interventions are associated with increases in flu vaccination when delivered individually or as part of a multicomponent strategy to increase uptake in clinical risk groups. The committee agreed there was some uncertainty in the size of effect because of study quality, or because it was difficult to be sure how much of the effect in multicomponent approaches was due specifically to audit, monitoring and feedback activities. However, the consistent direction of effect for the majority of patients enabled the committee to make recommendations.
The committee also heard expert testimony from a practice nurse who leads on increasing uptake in a general practice and also supports flu vaccination campaigns across her region for the clinical commissioning group. She stated that using audit and monitoring enabled them to improve their targeting of particular clinical groups in which uptake was low. It also helped her to spot any other general practices in her region that may need advice or support.
Published evidence on audit and feedback and the impact of QOF on increasing uptake is mixed. One study showed that practice audits increased uptake in some clinical risk groups but not others , although the committee agreed that the difference in impact between clinical risk groups may be due to relatively low numbers of post-splenectomy patients (in whom no significant effect was found) compared with other groups studied (coronary heart disease and diabetes).
In 2 studies looking at the impact of QOF, 1 showed that pay-for-performance targets increased flu vaccination rates in a target clinical risk group of people with coronary heart disease compared with control conditions of chronic obstructive pulmonary disease, diabetes and stroke . The other showed that removing pay-for-performance targets (in a condition previously incentivised) did not result in the uptake rate decaying over the 8‑year study period, with uptake rate being maintained at over 75%, which is above the national target. In 2 multicomponent studies that included audit and feedback, a cluster-randomised controlled trial indicated education plus audit increased vaccination in clinical risk groups . This was supported by a retrospective cohort of 6 years' repeated measures after the intervention showing provider feedback combined with education and nurse standing orders (PGD) increased and maintained uptake compared with baseline . The committee acknowledged the overall quality of the evidence was very low to moderate, but felt this was to be expected given the evidence is driven by the quality improvement cycle. They agreed that the consistency and in some cases durability of effect over time, in real-world circumstances, reduced any uncertainty resulting from study quality.
Expert testimony on increasing uptake in healthcare workers also highlighted the importance of monitoring and feedback because it encouraged staff to accept the vaccination and helped to show senior managers that the campaign was working. Evidence on feedback as an intervention to increase uptake in health and social care staff is mixed. One study showed it was a component in a successful approach on hospital wards and in outpatient clinics to increase uptake . However, this was not the case in a before-and-after study in which director-level feedback was a component in a multicomponent approach . The committee considered the inconsistency in the evidence, including the small numbers in the study that showed no effect and the fact that uptake had been corroborated with lab-confirmed cases of flu in the other study. Based on this, along with the expert testimony, the committee considered feedback to be a key component that should be recommended as an important approach to support increasing uptake. Additionally, the recent introduction of a CQUIN to increase uptake meant that monitoring and using feedback to improve programmes was likely to become increasingly important to meet targets, and to show that these targets have been met.
Overall, the committee agreed that healthcare records can be used effectively to identify and increase offers of flu vaccination to eligible groups. However, it is important that patient records are accurate and up to date to ensure all vaccinations are included in uptake data and that people are not inadvertently vaccinated more than once in a season. The committee confirmed that, although not in itself likely to be harmful to the person, over-vaccination will incur unnecessary costs and increase the burden of any associated short-term side effects such as pain, swelling or redness at the injection site.
If eligible people are vaccinated in settings other than their own GP surgery, poor information transfer may waste time and resources if practices invite and remind people unnecessarily, or booked flu clinic appointments go unused. Mechanisms for sharing information across providers need careful planning and oversight to minimise data loss.
Audit, monitoring and feedback activities are useful for needs assessment, enabling a practice to determine where extra effort or resources may be needed to increase uptake among particular groups. Monitoring uptake will also help in planning activities as well as in ordering and maintaining stock; this will have a knock-on effect of reducing inefficiency by reducing potential waste and allowing effort to be focused on targeting the most needed groups.
Recording why people decline vaccination helps to identify barriers and adapt interventions to address and overcome those issues in future activities or campaigns. However, this needs to be done accurately and consistently to support a better understanding of barriers to vaccination.
Payments will offset the resource impact of campaigns to increase vaccination uptake in some organisations, such as GP surgeries, community pharmacies and NHS trusts. This may motivate organisations to increase uptake and encourage staff to succeed, which in turn may improve job satisfaction if incentive targets are reached.
The social care sector and some NHS organisations may be disadvantaged by a current lack of systems to collect flu vaccination data and by the lack of payment by results incentivisation to increase uptake among staff. Resource impact from implementing the recommendations may therefore be greater in the social care sector in particular.
The committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:
For adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.
For pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.
For children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.
For health and social care staff, they cost up to £2.15 per targeted person and increased vaccination uptake by at least 5%.
The committee felt that the costs per targeted person of audit, monitoring and feedback were likely to be below the maximum intervention costs and achieve the necessary level of vaccination.
## The evidence
The committee looked at evidence in:
Evidence review 2 on increasing flu vaccination uptake in children: ES3.4; Q‑ES1.6
Evidence review 3 on increasing flu vaccination uptake in people in clinical risk groups: ES 3.4b, ES3.5, ES3.6, ES123.2, ES123.6
Evidence review 4 on increasing flu vaccination uptake among health and social care staff: ES45.9, ES45.10
Expert testimony on increasing vaccination uptake among healthcare staff: Expert paper 4 (EP4) and Expert paper 5 (EP5)
Expert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)
# Flu vaccination in carers
The discussion below explains how the committee made recommendations 1.6.1 and 1.6.2.
## Rationale and impact
If a carer has flu, the welfare of the person they care for may be at risk. There was a lack of evidence on interventions specifically for carers, and health economic modelling showed that increasing uptake among all carers would not be cost effective. The committee agreed that efforts to increase vaccination uptake should target carers who look after people who are particularly vulnerable and who would be at risk of needing hospital or other care if their carer was unwell with flu. Primary care staff and healthcare professionals working in the community (for example district or specialist nurses or those working in rehabilitation) could be a useful route to identify and offer vaccination to this group, for example during a home visit, if appropriate local agreements were in place.
Increasing uptake of flu vaccination among eligible carers is not likely to involve a major change to current practice, but the key is for providers to prioritise those carers who look after someone whose health or wellbeing would be at risk if the carer fell ill with flu. This needs clinical judgement and may mean community nurses using home visits to identify and offer vaccination to these particular carers.
## Evidence discussion
Uptake of flu vaccination by people in eligible groups, and its acceptability to them.
There was a lack of published effectiveness evidence relating to interventions to increase uptake among carers. Very-low-quality evidence from 1 non‑UK observational study suggested that a recommendation from a respected person may positively affect carers' uptake of flu vaccination . Other very-low-quality evidence from the UK suggested that extending access by offering vaccination services in community pharmacies does not increase uptake among carers, although they may be more likely than other eligible populations to opt to use pharmacies as a convenient out-of-hours alternative to GP vaccination services . This was confirmed by expert testimony relating to carers .
The committee also noted issues raised by the expert relating to carer identification, because carer status is not routinely recorded in GP records and many informal carers do not recognise themselves as such. They agreed that community and primary care staff, such as community nurses, may be well placed to identify informal carers and assess their eligibility for flu vaccination – for example, during home visits to the person they are caring for. If a patient group direction or enhanced service arrangement has been agreed with local commissioners, nurses could offer vaccination to eligible carers. Alternatively, nurses could signpost carers to local primary care vaccination services, including any community pharmacies participating in the flu vaccination scheme.
The committee discussed at length evidence from economic modelling (outlined in more detail in the section below on cost effectiveness and resource use) and concluded that it is not cost effective to increase uptake of flu vaccination in all carers. It is important to target people who care for someone who may need to be admitted to hospital, or need alternative statutory care arrangements, if the carer falls ill with flu and is unable to look after them, or if risk of transmission for those who can't or won't be vaccinated is high, or for people for whom the flu vaccine is less efficacious, such as those who are immunocompromised.
Carers are in close contact with people who are potentially at greater risk from flu. Carers have an important role; if they fall ill it can be detrimental to those they care for. In addition, they may pass the virus on to the person they care for. If the person being cared for has a weakened immune system they are still susceptible to the flu virus even if they have had the flu vaccine, because it works less well in this group. Increasing flu vaccination in carers can help sustain continuity of care and reduce the chances of onward transmission. However, the provider needs sufficient information to exercise clinical judgement on an individual carer's eligibility for flu vaccination, which should be based on the vulnerability of the person they look after.
The economic model for carers who are not in a clinical risk group uses a decision-tree structure. A proportion of carers are vaccinated, and the remainder are unvaccinated. At baseline, 37.4% are vaccinated (taken from Public Health Engand's influenza immunisation intervention for England for winter 2015/16). A proportion of vaccinated people experience side effects, which have associated costs and QALY losses.
Costs are considered from the perspective of the NHS and personal social services.
The probability of getting the flu virus is higher for the unvaccinated population than the vaccinated population, so there are more cases of flu. A proportion of the cases of the flu virus are flu-like illness or acute respiratory illness, which are associated with QALY losses of 0.008 and 0.00101. A proportion of cases of each need hospitalisation (costing £1,029, from NHS reference costs, and losing 0.018 QALYs) or a GP consultation (costing £31 for a surgery visit or £98 per home visit, from the Unit Costs of Health and Social Care). There is a mortality risk from flu, which has an associated QALY loss depending on the person's age.
If a carer gets flu, they may be unable to look after the person they care for. In most cases it is assumed that another family member or friend will temporarily provide care. However, the model assumes that in 1% of cases the person cared for would need emergency hospital admission, costing £4,995 (NHS reference costs) to the NHS.
If a carer gets flu, there is a risk that they may transmit flu to the person they care for. The model assumes that there are 0.19 secondary cases for each case of flu, each costing £343, based on a cost for high-risk cases, and with an associated QALY loss.
The model showed that increasing vaccination uptake in carers decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations, hospitalisations and secondary cases of flu-like illness. At baseline, 219,295 carers are vaccinated. Increasing this by 10% to 277,930 averts 6,755 cases of flu; 293 GP consultations; 55 hospitalisations and 207 secondary cases of flu-like illness. The cost for the additional number of vaccinations is £924,305 and flu vaccine side effects cost an additional £36,354. There are cost savings from reduced GP consultations (£10,470); hospitalisations (£56,663); and secondary cases (£71,132) and replacement care (£77,602), leading to a total cost to the NHS of £744,792. Flu vaccine side effects lead to an additional QALY loss of 2 QALYs, but the reduction in flu cases avoids a QALY loss of 13. The incremental cost-effectiveness ratio from the NHS and personal social services perspective is therefore £57,547/QALY. This is above £20,000 per QALY and therefore it is not cost effective to increase the uptake of vaccination in carers. Sensitivity analysis was undertaken to determine whether changing 1 of the inputs could make it cost effective to increase the uptake of vaccination in carers. This found that if the proportion needing emergency care when their carer has flu increases, or the cost of that emergency care increases, increasing the uptake of vaccination in carers could be cost effective. In the base case the average cost of care was £50 (1% of £4,995). If this is increased to £500 (for example 1% of £50,000 or 10% of £4,995), increasing the uptake of flu vaccination could be cost effective. The committee considered that there may be people at increased risk of needing expensive emergency care if their carer gets flu. In these cases, it is cost effective to increase the uptake of flu vaccination. Therefore the committee recommended that flu vaccination should be offered to carers who care for someone who is immunocompromised, disabled or vulnerable.
For carers, increasing the uptake of flu vaccination was not cost effective at £20,000 per QALY, even when onward transmission was considered. It could only be cost effective if there were potentially substantial costs associated with a carer getting flu, for example, if the person they care for needed expensive emergency care in their carer's absence.
The committee were of the opinion that there are various opportunities to identify carers and that these would not need significant resources because the systems were mostly in place but should be used more effectively. The only potential cost or resource implication identified was education and training to use or adapt existing systems to identify carers, and the subsequent resources associated with the increases in education of carers, and offers and delivery of vaccination.
Evidence for mandatory vaccination as part of a multicomponent intervention demonstrated some effect in care home settings and with care workers but the studies did not clarify whether this was relevant to unpaid carers in the UK context. The committee did not make recommendations about mandatory vaccination. They considered the limited published evidence in conjunction with the health economic modelling, expert testimony and their own experiences. They concluded that mandatory flu vaccination of carers – even in situations in which it is likely to be cost effective − should not be recommended, for ethical reasons. Unpaid carers provide a valuable service on a voluntary basis and the committee considered it unethical to undermine this by enforcing mandatory vaccination. Qualitative studies of mandatory flu vaccination schemes in paid health and social care employees report a negative impact on morale, leaving people feeling disempowered, lacking autonomy and resentful . The committee agreed that it was preferable to encourage vaccination among eligible carers by promoting it as a way of protecting the vulnerable person they care for.
## The evidence
The committee looked at evidence in:
Evidence review 1 on increasing flu vaccination uptake in carers: ES1.1, ES2.1
Evidence review 4 on increasing flu vaccination uptake in health and social care staff: Q-ES3.8, Q-ES3.9
Expert testimony on increasing flu vaccination in carers: Expert paper 1 (EP1)
# Employers of health and social care staff
The discussion below explains how the committee made recommendations 1.7.1 to 1.7.8.
## Rationale and impact
Health and social care staff are in daily contact with people who are susceptible to infection, and they could transmit flu to vulnerable people at risk of serious complications. Staff may not know they are eligible for a free vaccination through occupational health, or may not realise it may help protect their patients, family and co‑workers. Evidence suggests that actions to encourage staff to be vaccinated do work. Programmes involving a combination of actions, such as awareness raising, education and flexible services were effective and acceptable. Although the evidence was uncertain in some cases, the committee recommended a range of interventions so that organisations can tailor their approach to local needs, targeting demand (by increasing awareness, education and incentives) and supply (for example using mobile vaccination carts and off-site or out-of-hours access).
Implementing the recommendations will have a bigger impact in some organisations than others. Current variation in practice is partly because different incentives operate across the health and social care sectors. It may also be easier to provide vaccination for staff in some organisations than others. For example, a GP surgery already has access to flu vaccine supply and the skills to deliver the vaccination to staff. A social care provider may need to contract an occupational healthcare provider to carry out vaccination, or set up a scheme to help employees access community pharmacy flu vaccination.
## Evidence discussion
Uptake of flu vaccination by health and social care staff, and its acceptability to them.
The quantitative evidence relating to interventions to increase flu vaccination uptake among health and social care staff was of variable quality, with most rated low or very low. Downgrading was largely due to risk of bias and imprecision of effect estimates. In pooled analyses there was evidence of serious or very serious heterogeneity, which the committee agreed would be expected given the differences between study populations in the types of staff and the lack of standardisation of interventions and comparators across studies. The majority of studies were conducted outside the UK and covered a range of health and social care settings.
The committee noted that most studies included in the review examined combinations of interventions or their additive effects rather than a single approach, with staff education or awareness raising, and the provision of more flexible access (including off‑site or out-of-hours access) forming almost universal components. There was a clinically important increase in vaccination uptake (of 5% or more compared with the control or pre-intervention rate) in 19 out of 20 evidence statements in which a multicomponent approach was evaluated .
There was conflicting evidence from subgroup analyses on the effect of interventions among staff with direct or indirect patient contact , with different professional roles , or working in different care settings . The committee noted that the Green Book recommends vaccination of all health and social care staff who have direct involvement with patient or client care, and that responsibility for providing occupational flu vaccination rests with employers.
There was evidence that mandatory vaccination (with or without mask-wearing policies for those declining a flu vaccine) is the most effective lever of uptake among health and social care staff . However, the committee expressed concerns about the challenges that mandatory vaccination of staff would have, including qualitative evidence indicating that such policies can negatively affect staff morale and undermine autonomy .
The committee acknowledged the concerns of policy makers and senior managers to reduce staff absenteeism. They believed that these concerns can be met by evidence that non-mandatory multicomponent interventions are also effective. This in turn will reduce transmission of flu in health and social care premises. This was confirmed by a study that found a significant decrease in the proportion of laboratory-confirmed flu cases among health and social care staff after implementation of a multicomponent vaccination programme .
Very low‑ to low-quality evidence indicated that declination policies were an effective approach . A declination policy requires employees to submit a mandatory written statement stating that they have refused an offer of flu vaccination and citing their reasons why. A systematic review and meta-regression found that declination policies had an independent effect on flu vaccination uptake that was greater, on the whole, than all other types of intervention except mandatory vaccination . Although the quality of the evidence was limited, the quantity and overall consistency of effect suggested that declination policies could work well. However, qualitative evidence indicated that employees have mixed feelings about declination policies, and stakeholder consultation on the draft version of this guideline revealed some resistance to the idea. The committee reconsidered the evidence in light of stakeholder feedback, noting that the studies included in the meta-regression analysis evaluating declination statements were all conducted in a US or Japanese setting, where organisational culture and employment relations are likely to differ markedly from the UK.
The committee also reconsidered evidence from a randomised controlled trial comparing an 'opt‑in' with an 'opt‑out' flu vaccination strategy for healthcare workers, conducted in 1 tertiary care provider in the Netherlands . Participants in the opt‑out group were emailed with a pre-scheduled appointment for flu vaccination, which could be changed or cancelled by following a web link. In the opt‑in condition, participants received an email explaining that they had to book an appointment if they wanted to get vaccinated. The investigators failed to detect a statistically significant effect of either strategy on vaccination uptake, but because there were only 61 participants in each group it is likely the study was underpowered to detect a significant difference. However, healthcare workers in the opt‑out group were more likely than those in the opt‑in group to have an appointment for flu vaccination, which in turn increased the probability of them getting vaccinated (RR 1.70; 95% CI 0.85 to 3.41).
The committee concluded that an opt‑out strategy better respects individuals' autonomy, specifically the right to choose whether or not to accept a medical intervention, and may therefore be considered more acceptable than a declination policy for encouraging flu vaccination among front-line health and social care staff. The committee discussed the importance of involving staff representatives in developing a flu vaccination policy to minimise any negative impact on morale. The committee also agreed that it would not be appropriate to ask employees in an identifiable way to state their reasons for opting out of voluntary flu vaccination. However, it would usefully inform future flu vaccination campaigns if organisations could survey staff anonymously about their vaccination decision-making.
Expert testimony on increasing uptake in healthcare workers further supported the approaches recommended by the committee based on the evidence. The experts considered audit and monitoring systems to be particularly important to help them plan their activities effectively and understand how they were progressing and whether changes were needed. The experts also stated that a multicomponent approach was important to ensure they were targeting the breadth of the workforce, because different members might be reached more effectively by different approaches. They indicated that assigning a lead and flu champions, involving media and other publicity activities along with keeping staff abreast of progress via feedback were all useful and important aspects. The experts also noted that staff incentives proved popular. Another key factor was to ensure that access to vaccination was carefully considered. One expert described taking the vaccination service to eligible staff as a useful strategy. Using mobile vaccination carts and making them available in high footfall areas such as the staff canteen, and around shift switchover times on wards, all made it more convenient for eligible staff to take up the offer of vaccination . This testimony aligned with the qualitative and quantitative evidence considered by the committee. The committee highlighted that the recently introduced CQUIN would act as a significant lever for increasing vaccination rates among hospital-based staff for the foreseeable future.
The committee acknowledged that although the recommendation outlines a selection of interventions, it is difficult to specify what configuration would maximise any effect. They were satisfied that the recommendations outline an effective approach that can be tailored to local needs.
Increasing vaccination uptake in health and social care staff will reduce the risk of transmission and offer protection to those they come into contact with who may be more susceptible to infection. It also has the potential to reduce sickness absence and increase the continuity of care that they provide.
Raising awareness in healthcare staff about eligibility for flu vaccination and its efficacy should increase the identification of eligible groups and their subsequent vaccination, thus reducing transmission and associated mortality and morbidity.
The committee has not made recommendations about mandatory flu vaccination policies. They have recommended the adoption of a full participation vaccination strategy, with nationally agreed opt‑out criteria. Nationally agreed opt‑out criteria are needed to ensure consistency of approach. The committee believes they should be developed with the involvement of staff representatives. A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.
An opt‑out strategy is potentially more acceptable for employment relations. But it offers less opportunity than a declination policy to engage with health and social care staff who decline vaccination in order to target support and education to overcome barriers, such as needle phobia, or misinformation about the flu vaccine's safety and effectiveness.
The economic model for health and social care staff uses a decision-tree structure. A proportion of health and social care staff are vaccinated, and the remainder are unvaccinated. At baseline, 50.6% are vaccinated, taken from a Public Health England survey of the seasonal flu vaccine uptake among front-line health and social care workers 2015/16. A proportion of vaccinated people experience side effects, which have associated costs and QALY losses.
Costs are considered from the perspective of the NHS and personal social services. The time horizon is 1 year.
The probability of getting the flu virus is higher for the unvaccinated population than the vaccinated population, so there are more cases of flu. A proportion of the cases of the flu virus are flu-like illness or acute respiratory illness, which are associated with QALY losses of 0.008 and 0.00101. A proportion of cases of each need hospitalisation (costing £1,029, from NHS reference costs, and losing 0.018 QALYs) or a GP consultation (costing £31 for a surgery visit or £98 per home visit, from the Unit Costs of Health and Social Care). There is a mortality risk from flu, which has an associated QALY loss depending on the person's age.
If a health and social care worker gets flu, they may not be working. There will therefore be a cost to their employer of providing replacement staff. The average absence from work for a case of flu is 2.5 days from Public Health England's Flu Survey, and health and social care staff are assumed to work 7.5 hours per day, at an average cost of £26 per hour from Unit Costs of Health and Social Care.
If a health and social care worker gets flu, there is a risk that they may transmit flu to the people they care for. The model assumes that there are 0.7 secondary cases for each case of flu, each costing £289, based on a cost for high-risk cases, and with an associated QALY loss.
The model showed that increasing vaccination uptake in health and social care staff decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations, hospitalisations and secondary cases of flu-like illness. At baseline, 1,081,577 health and social care staff are vaccinated. Increasing this by 10% to 1,295,327 averts 24,624 cases of flu, 1,069 GP consultations, 201 hospitalisations and 16,920 secondary cases of flu-like illness. The cost for the additional number of vaccinations is £552,230, and flu vaccine side effects cost an additional £132,525. There are cost savings from reduced GP consultations (£38,166), hospitalisations (£206,560), secondary cases (£4,895,560) and replacement staff (£1,208,470) – leading to a total cost saving to the NHS of £5,664,002. Flu vaccine side effects lead to a loss of 6 QALYs, but the reduction in flu cases avoids a QALY loss of 171.5. Increasing the uptake of flu vaccination saves money and improves outcomes, and thus is 'dominant'. This is cost effective at £20,000 per QALY, and the net monetary benefit demonstrates that an intervention would be cost effective if it cost up to £4.30 per targeted person to increase uptake of the flu vaccination by 10%.
Considering only the costs of vaccination and the costs of replacement staff, increasing the uptake of flu vaccination is cost saving. Therefore it is cost saving for non-NHS employers to vaccinate health and social care staff. The committee felt that a range of interventions could be delivered by employers of health and social care staff at a sufficiently low cost to be cost effective.
Increasing access to vaccination on and off site may incur initial set‑up costs, which could include the need for additional employees and facilities. The committee were of the opinion that despite these initial costs, the benefits of reducing transmission and protecting health and social care staff from flu infection (with a potential reduction in sickness absence) outweigh these costs. Once the various systems and interventions to facilitate access have been established these services will be cost saving in the medium to longer term.
Expert testimony from a trust where large-scale changes have occurred over a number of years indicated that although the initial investment (resource impact) was quite high, it became considerably less intensive while maintaining and further increasing uptake, as it became part of the embedded culture.
## The evidence
The committee looked at evidence in:
Evidence review 4 on increasing flu vaccination uptake in health and social care staff: ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.7, ES4.8, ES45.1, ES45.2, ES45.3, ES45.4, ES45.5, ES45.6, ES45.7, ES45.8, ES45.9, ES45.10, ES45.11; SR-ES4.1, SR-ES4.2, SR-ES4.3, SR-ES4.4, SR-ES4.5, SR-ES4.6, SR-ES4.7, SR-ES4.8, SR-ES5.1, SR-ES45.1, SR-ES45.2, SR-ES45.3, SR-ES45.4, SR-ES45.5, SR-ES45.6, SR-ES45.7, SR-ES45.8, SR-ES45.9; Q-ES3.1, Q-ES3.2, Q-ES3.3, Q-ES3.4, Q-ES3.5, Q-ES3.6, Q-ES3.7, Q-ES3.8, Q-ES3.9, Q-ES3.10
Expert testimony on increasing vaccination uptake among healthcare workers: Expert paper 4 (EP4) and Expert paper 5 (EP5)
# Gaps in the evidence
The committee's assessment of the evidence on increasing uptake of flu vaccination identified a number of gaps. These gaps are set out below.
. Effective and cost-effective interventions for increasing flu vaccination uptake in carers.
(Source: Evidence review 1)
. Effectiveness and cost effectiveness of different configurations of multicomponent interventions in different eligible populations and across settings:
a) Differential impact by intensity.
b) Differential impact by who delivers the interventions.
c) Differential impact by where the intervention is started or delivered.
(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review 4)
. Effectiveness and cost effectiveness of electronic and online approaches to increasing flu vaccination uptake.
(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review 4)
. Evidence of what is effective and cost effective in increasing flu vaccination uptake in underserved groups who would be eligible for flu vaccination.
a) What is the effectiveness of recommended interventions in underserved groups?
b) What is the cost effectiveness of recommended interventions in underserved groups?
(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review 4)
. Barriers and facilitators to mandatory flu vaccination in UK settings.
(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review 4)
. Cost-effectiveness evidence on recommended interventions.
a) Evidence from the peer-reviewed literature on the cost effectiveness of recommended interventions.
(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review 4)# Recommendations for research
The guideline committee has made the following recommendations for research.
# People in eligible groups
What are the important messages and how should they be tailored and delivered to encourage and sustain flu vaccination uptake in eligible groups?
## Why this is important
There is limited qualitative, effectiveness and cost-effectiveness evidence about what is effective in increasing flu vaccination in most eligible groups. In particular, we need to know how to tailor and deliver messages, for example, to minority ethnic communities, who may have lower vaccination uptake and also be disproportionately affected by some chronic conditions that put them at greater clinical risk from flu. A key to this is understanding how to engage people, including children and young people, and how they want to be involved in decision-making. This might include carers and other decision-makers. Interventions may need to be specifically targeted for different groups, so there is a need to understand individual and cultural health beliefs underpinning decisions about vaccination. Evidence indicates that beliefs about flu vaccination (such as effectiveness and side effects) are a persistent barrier. Understanding the key messages and the best format to deliver them in (for example, using social media or other forms of electronic communication) to reach different groups will help to overcome these barriers. This will increase the precision with which commissioners and intervention developers can engage eligible groups and increase rates of flu vaccination.
# Underserved groups
What are the most effective and cost-effective ways of reaching underserved groups and removing barriers to access in order to increase their uptake of flu vaccination?
## Why this is important
The evidence reviewed did not provide specific details about the needs of people in underserved groups. Particularly important are those people who may be disproportionately affected by chronic conditions that increase their risk of complications from flu and who may have unique barriers to accessing flu vaccination (for example, they may have an undiagnosed clinical condition and not recognise that they are eligible for free flu vaccination, or they may not be registered with a general practice). They may also be difficult to identify. Research is needed into the specific needs, barriers and facilitators of eligible people in underserved groups. This should include how and what is effective in improving access, raising awareness, and offering and delivering vaccination. This will enable commissioners and those with responsibility for flu vaccination delivery to develop interventions to reach these groups.
# Carers
In what context is it cost effective to increase uptake of flu vaccination among carers?
## Why this is important
There is a lack of peer-reviewed evidence on what is effective and cost effective in increasing flu vaccination in carers. This key target group can be difficult to identify, and people who provide care may not always identify themselves as carers. The limited evidence suggests it is not cost effective to increase uptake of vaccination in all carers. Better understanding is needed about the effect of increasing vaccination in carers on rates of flu transmission, and the wider social and economic benefits to the health and social care system. Research is needed on the need for targeting, how this should be done and which cared-for groups are most important. Evidence about the effect on uptake of increasing the identification and offer of vaccination to carers through opportunistic engagement in all settings would enable more specific recommendations to be made. It would also allow further assessment of the economic benefits. Evidence about why a carer would choose not to be vaccinated will also improve understanding and inform recommendations and intervention development.
# Opt-out strategies for front-line health and social care staff
Are opt-out strategies effective and cost effective at increasing uptake of flu vaccination among front-line health and social care staff?
## Why this is important
The evidence indicated that mandatory flu vaccination and the use of declination policies, either as a single intervention or part of a multicomponent approach, had a large and consistent effect in increasing vaccination uptake among health and social care staff in non-UK settings. However there are potential barriers to this in the UK; in particular, the possible negative impact on employee morale, which has also been seen in qualitative studies from other countries. The committee felt that similar increases in flu vaccination may be achievable using an opt‑out strategy. But to clarify the potential of this intervention, empirical evidence is needed on whether it is more effective and cost effective than other successful approaches for promoting uptake of flu vaccination among front-line health and social care staff in different UK settings, and what barriers and facilitators there are to its implementation from the perspective of providers and recipients; in particular, attitudes to the feasibility and acceptability of an 'opt‑out' flu vaccination strategy.
# Community-based models of flu vaccination
What models of community-based flu vaccination provision (for example, community pharmacies, community nursing and midwifery teams and outreach services) are effective and cost-effective for increasing uptake in eligible groups?
## Why this is important
There is high variability across England in rates of flu vaccination uptake in eligible groups. Little is known about the effectiveness and cost effectiveness of extending community-based provision to include, for example, community pharmacies, community nursing and midwifery teams and outreach services into a variety of settings. Expert testimony suggested that community outreach interventions are effective for underserved groups such as people who are homeless, but empirical evidence for the effectiveness and cost effectiveness of such interventions is lacking. Limited evidence to date suggests that community pharmacy provision of NHS flu vaccinations has displaced rather than increased overall vaccination activity, because community pharmacies may be more convenient for some people in eligible groups. As new services become better publicised and embedded, there is a need to know if they are good value for money and whether (and why) they increase uptake. More research is needed on alternative models of community-based provision to inform future interventions and recommendations, particularly if it reaches groups who are currently underserved, and who may not use traditional routes such as GP services.# Glossary
For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.
# Brief intervention
A brief intervention involves oral discussion, negotiation or encouragement, with or without written or other support or follow-up. It may also involve a referral for further interventions, directing people to other options, or more intensive support. Brief interventions can be delivered by anyone who is trained in the necessary skills and knowledge. These interventions are often carried out when the opportunity arises, typically taking no more than a few minutes for basic advice.
# Care home
This covers 24‑hour accommodation with either non-nursing care (for example, a residential home) or nursing care.
# Carer's assessment
People who care informally on an unpaid basis for a family member or friend have the right to discuss with their local council what their own needs are, separate to the needs of the person they care for. The assessment covers anything the carer thinks would help them with their own health or with managing other aspects of their life. The council will use the information to decide what help it can offer.
# Full participation vaccination strategy
A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.
# Primary care
The day-to-day healthcare given by a healthcare provider. Typically this provider acts as the first contact and principal point of continuing care for patients within a healthcare system, and coordinates other specialist care that the patient may need. In the UK, people access primary care services through local general practice, community pharmacy, optometrist, dental surgery and community hearing care providers.
# Secondary care
Secondary care is often acute healthcare (elective care or emergency care) provided by medical specialists in a hospital or other secondary care setting. Patients are usually referred by a primary care professional such as a GP.
|
{'Recommendations': "Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use) professional guidelines standards and laws (including on consent and mental capacity) and safeguarding.\n\nThe recommendations in this guideline should be read together with the NICE guideline on vaccine uptake in the general population.\n\n# A multicomponent approach\n\nUse a multicomponent approach to develop and deliver programmes to increase flu vaccination uptake. Combine interventions recommended in this guideline to influence both demand and supply.\n\nProviders of flu vaccination should work together with other agencies (including intervention developers, commissioners and local stakeholders) to develop programmes to increase vaccination uptake. This could include assigning within organisations a lead team or flu vaccination champion to manage the programmes and be responsible for working across organisations.\n\nSee how the committee made recommendations\xa01.1.1 and\xa01.1.2.\n\n# Raising awareness\n\n## Raising awareness in health and social care staff\n\nThese recommendations are for educators, line managers and organisational leads.\n\nEducate health and social care staff, particularly those in contact with eligible groups, about flu vaccination. These could include:\n\nStaff working in GP surgeries and community pharmacies.\n\nSecondary care staff, for example in clinics for children with chronic conditions or wards such as oncology or antenatal.\n\nSocial care staff who may have contact with carers and other eligible groups, such as people with learning disabilities. This may include during home visits, individual needs assessments and carers' assessments.\n\nProvide information on the following as part of an education programme on flu vaccination for health and social care staff, particularly those in contact with eligible groups:\n\nWho is eligible for free flu vaccination, and where to get it.\n\nBenefits of vaccination for people at high risk from flu and its complications. For example, those with immunosuppression, chronic liver disease or neurological disease.\n\nBenefits of flu vaccination for health and social care staff.\n\nHow flu is transmitted.\n\nRelevant guidelines and definitions of eligible groups as outlined in chapter 19 of the UK Health Security Agency's immunisation against infectious disease (known as the 'Green Book').\n\nHow the flu vaccine is given to children and adults.\n\nEvidence supporting the safety and effectiveness of flu vaccination.\n\nExplain to health and social care staff how they can:\n\nIdentify people who are eligible, for example by using GP records or medicines dispensing records (including how to identify carers who might be eligible; see the section on flu vaccination in carers).\n\nMake the most of opportunities to raise awareness about and offer flu vaccination to eligible groups. This could include discussing it with:\n\n\n\npregnant women during antenatal appointments\n\neligible people booking GP or other clinical appointments\n\neligible people visiting community pharmacies to seek health advice, collect prescriptions or buy over-the-counter medicines.\n\n\n\nHealth and social care staff who are in direct contact with eligible groups (for example, practice nurses, health visitors, community pharmacists, midwives, specialist nurses and domiciliary care workers) should:\n\nInclude training on flu and flu vaccination as part of their continuing professional development plan (see Public Health England's national minimum standards and core curriculum for immunisation training for registered healthcare practitioners).\n\nBe able to provide tailored information on the risks and benefits of flu vaccination, and be able to offer and administer it (see the NICE guideline on patient group directions).\n\n## Raising awareness in eligible groups\n\nThese recommendations are for providers of flu vaccination.\n\nRaise awareness of free flu vaccination among people who are eligible, as listed in the Green Book and the annual flu letter. Do this at the earliest opportunity before the flu vaccination season starts in September, and ideally by the end of December.\n\nConsider working with statutory and voluntary organisations, including those representing people with relevant medical conditions, to increase awareness of flu vaccination among eligible groups (and their parents or carers, if relevant).\n\nGive people who are eligible (or their parents or carers, if relevant) face-to-face brief advice or a brief intervention on the importance of flu vaccination. Tell them that they can have a free flu vaccination and explain why they are being offered it, using language they can understand and taking into account cultural sensitivities. This includes explaining:\n\nHow people get flu.\n\nHow serious flu and its complications can be (make it clear it is not just a bad cold).\n\nThat flu can affect anyone, but if a person has a long-term health condition the effects of flu can make it worse, even if the condition is well managed and they normally feel well.\n\nThat flu vaccination is safe.\n\nThat having a flu vaccination is the single best way of helping to protect against catching or spreading flu.\n\nThat they should get the vaccination as soon as it becomes available to maximise their protection throughout the flu season.\n\nAny myths about flu vaccination: dispel these myths, including the belief that it can give you flu.\n\nThe need to have a flu vaccination every year.\n\nExplain to parents or carers that the nasal spray (not injection) is recommended for eligible children from the age of 2\xa0years. Explain that the injection will be offered instead of the nasal spray only if:\n\nthe child is in a clinical risk group and\n\nthe child cannot have the nasal spray for medical reasons (for example, if it is contraindicated because they or a close family member is severely immunocompromised), or they choose not to because of their religious beliefs; see NHS Choices for more information.\n\nGive people information about the location and opening hours of relevant flu vaccination services, including out-of-hours services and community pharmacies.\n\nInclude information on flu vaccination with other health-related messages and existing health-promotion or vaccination programmes for people in eligible groups.\n\nSee how the committee made recommendations\xa01.2.1 to\xa01.2.10.\n\n# Offering vaccination\n\nThese recommendations are for providers of flu vaccination services.\n\nUse every opportunity throughout the flu vaccination season to identify people in eligible groups and offer them the flu vaccination. This could include when:\n\nPeople register in general practice.\n\nWomen have a newly confirmed pregnancy.\n\nPeople are newly diagnosed with a condition that may place them in a clinical risk group, or have a BMI of 40\xa0or over.\n\nPeople attend outpatient and antenatal clinics or drug and alcohol services.\n\nPeople (including children aged 6\xa0months to 17\xa0years) who are in a clinical risk group attend routine GP or outpatient clinic appointments, or for other vaccination services.\n\nPeople visit community pharmacies for health advice, a New Medicine Service, or to collect prescriptions (check whether the person taking the medicine or their carer is eligible, while taking into account confidentiality).\n\nPeople in clinical risk groups are staying in hospital.\n\nPeople who are eligible are having home visits for healthcare.\n\nEstablish and use links with statutory and voluntary organisations that work with carers, looked-after children and young people or other groups, to identify eligible people who have not been vaccinated. These could include drug and alcohol services, and organisations working with Traveller communities or people who are homeless.\n\nProvide multiple opportunities and routes for eligible people to have their flu vaccination at a time and location convenient to them. This could include at community pharmacies, GP surgeries or clinics they attend regularly for a chronic condition.\n\nConsider outreach opportunities for underserved groups in line with local practice and patient group directions arrangements (see the NICE guideline on patient group directions).\n\nConsider providing evening and weekend services in primary care, including community pharmacy, to deliver flu vaccination to people who may find it difficult to attend at other times.\n\nUse clinical systems to identify eligible groups and work out supply requirements, planning for a higher uptake than the previous year. Ensure enough flu vaccine is available to meet local needs.\n\nSee how the committee made recommendations\xa01.3.1 to\xa01.3.6.\n\n# Increasing uptake among eligible groups in primary and secondary care\n\n## Primary care\n\nInform and invite children and adults in eligible groups for flu vaccination during face-to-face interactions, whenever the opportunity arises.\n\nAdvise parents of all children aged 2\xa0and 3\xa0years who are covered by the universal vaccination programme, and children aged 6\xa0months and over who are in a clinical risk group, about the benefits of flu vaccination. Do this whenever the opportunity arises, for example when they attend routine appointments or for other vaccination programmes.At the time of publication (August 2018), the universal vaccination programme is available for children aged 2\xa0to 9\xa0years (up to school year\xa05). Preschool children (aged 2\xa0and 3\xa0years) should be given the nasal flu vaccine in general practice. Older children (from reception age) are usually given the nasal vaccine by local healthcare teams working with schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.\n\nWhen inviting people for flu vaccination:\n\nEnsure the invitation comes from a healthcare practitioner that they know, such as a practice nurse, midwife, doctor, pharmacist or health visitor.\n\nTailor it to the person's situation, for example link it to their pregnancy or clinical risk factors.\n\nInclude information about the risks of not being vaccinated.\n\nInclude educational messages to help overcome barriers to accepting the offer of a vaccination (see the section on raising awareness).\n\nUse written reminders (including text messages, letters and email), phone calls from staff or an auto dialler, social media, or a combination of methods, to contact people in eligible groups whose immunisations are due ('call') or overdue ('recall').\n\nFor invitations and reminders using digital media:\n\nlink to further information on trusted websites (see NHS Choices) and enable the person to ask for further information\n\nprovide a prompt (for example, a hyperlink) so the person can make an appointment online\n\nencourage people to find out more during face-to-face interactions, such as with their health visitor or pharmacist.\n\nConsider using peer-led approaches for inviting people in underserved groups who are eligible for flu vaccination.\n\n## Secondary care\n\nConsider providing flu vaccination during routine appointments in specialist clinics to people who are at high risk from flu and its complications. For example, people with immunosuppression, chronic liver or neurological disease, and pregnant women.\n\nWhen the opportunity arises, for example when people attend routine hospital appointments, identify anyone in a clinical risk group who has not been vaccinated and offer them a flu vaccination. Ensure this is in line with any local patient group directions or enhanced service arrangements that have been agreed with commissioners (see the NICE guideline on patient group directions).\n\nWhen offering people the flu vaccination:\n\nMake the offer face-to-face, if possible.\n\nUse positive messages to encourage people to have the vaccination. For example, for a pregnant woman the message could be that the flu vaccination gives 'two for one' protection to both her and her baby before and after the birth.\n\nTailor information to the person's situation, for example their pregnancy or clinical risk factors. Include the risks of not being vaccinated.\n\nEnsure information is simple, easy to read (if written) and provides a consistent message about flu and flu vaccination.\n\nEnsure a healthcare practitioner they know (for example, a midwife or a consultant from an outpatient clinic they attend) offers the vaccination.\n\nMake it easy for the person to get the vaccination, for example by offering and administering it during the same visit.\n\n## Patient records\n\nInclude prompts about people's eligibility for flu vaccination in electronic patient records or in medical notes (for example, by putting reminder stickers in antenatal notes).\n\nSee how the committee made recommendations\xa01.4.1 to\xa01.4.10.\n\n# Audit, monitoring and feedback\n\nHealthcare providers should keep patient records up to date and accurate to help identify people who have not been vaccinated and are eligible for flu vaccination that season.\n\nProviders of flu vaccination should record uptake rates. For example, keep records of the following:\n\nreason for eligibility\n\nnumbers of people called and recalled\n\nvaccination setting (for example GP, community pharmacy, antenatal clinic, outpatient clinic)\n\npeople who declined vaccination and why, by eligible group.\n\nCommissioners and providers should agree approaches for sharing information with general practices about flu vaccination given outside a person's own GP surgery (for example, by a school nurse or in a diabetes outpatient clinic). Aim for timely, accurate and consistent recording of vaccination status in health records to ensure all vaccinations are included in uptake data, and to avoid wasting resources by inviting people to attend appointments unnecessarily or duplicating vaccination.\n\nUse audit and monitoring systems to give providers of flu vaccination regular feedback on organisational progress towards targets throughout the immunisation season. Also use them to review past activity and impact on uptake to help plan and prioritise for the next season.\n\n## Organisational incentives\n\nCommissioners should raise awareness among healthcare staff and providers of flu vaccination about enhanced services payments and provider payments linked to flu vaccination. Also keep them informed and up to date about other financial incentives linked to flu vaccination. This includes those offered in the general practice Quality and Outcomes Framework (QOF), or the Commissioning for Quality and Innovation (CQUIN) system in secondary care.\n\nCommissioners should ensure that providers of flu vaccination know that submission of information on flu vaccination directly affects any linked organisational incentive payments.\n\nCommissioners should highlight the need for audit, monitoring and feedback of flu vaccinations given as part of an incentives programme. Link agreed Read codes or CQUIN indicators to incentives and include the required code or indicator.\n\nOrganisations responsible for agreeing quality indicators in incentives programmes (such as QOF) should be aware that revising target conditions may encourage providers to meet targets for flu vaccination across all clinical risk groups.\n\nSee how the committee made recommendations\xa01.5.1 to\xa01.5.8.\n\n# Flu vaccination in carers\n\nWhen considering increasing flu vaccination uptake in carers who are not otherwise eligible, use clinical judgement. Base decisions to offer vaccination on whether the carer looks after someone whose wellbeing may be at risk, needing hospital or other formal care, if the carer had flu.\n\nProviders of flu vaccination, including primary care staff and nurses working in the community (such as district nurses, specialist nurses and those working in rehabilitation) could consider:\n\nIdentifying and offering eligible carers a flu vaccination as the opportunity arises. For example, this could be offered during a home visit when the person they look after is being vaccinated.\n\nInforming the carer about other local vaccination services if a patient group direction or enhanced service arrangement has not been agreed with primary care commissioners (see the NICE guideline on patient group directions).\n\nSee how the committee made recommendations\xa01.6.1 and\xa01.6.2.\n\n# Employers of health and social care staff\n\nEmployers of health and social care staff are responsible for providing occupational flu vaccinations. This includes: NHS organisations, independent contractors, local authorities, and private and voluntary sector employers of social care staff. Immunisation should be provided by occupational health services, infection prevention and control teams, or using arrangements with private healthcare providers.\n\nProvide flu vaccination to all front-line health and social care staff who have direct contact with patients or clients. This includes employees who provide community-based care services to people in their own homes, or who care for people in residential care homes or other long-stay care facilities (see the Green Book).\n\nUse audit and monitoring systems to review previous strategies and flu vaccination uptake rates among eligible staff and to plan what methods to use to increase uptake and manage the supply for the next flu season. Start planning each year when the annual flu letter for the forthcoming season is published.\n\nConsider the following as part of a multicomponent approach to increasing uptake of flu vaccination among front-line health and social care staff:\n\nA full participation vaccination strategy, with nationally agreed opt out criteria (A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.)\n\nAssigning dedicated staff (for example, a flu vaccination champion or a team with responsibility for implementing a communication strategy) to increase awareness and uptake.\n\nUsing local broadcast media and social media.\n\nGetting and publicising support from high-profile organisational leaders or staff representatives.\n\nProviding information about the effectiveness and safety of the flu vaccine.\n\nUsing staff incentives that fit with the organisation's culture and the values of its employees.\n\nTraining peers to vaccinate their co‑workers, or to encourage uptake and challenge barriers, such as myths that the flu vaccine can give you flu.\n\nUsing prompts and reminders in various printed and digital formats. Include information about on- or off‑site vaccination locations and times.\n\nUsing systems linked to named staff records to monitor uptake and to target prompts and reminders.\n\nConsider promoting flu vaccination to front-line health and social care staff as a way to:\n\nprotect the people they care for\n\nprotect themselves and their families\n\nprotect their co‑workers\n\nmeet professional expectations such as the General Medical Council's guidance on good medical practice and the Royal College of Nursing's duty of care statement.\n\nConsider:\n\nExtending on‑site vaccination clinic hours to fit in with staff work patterns.\n\nUsing outreach or mobile services to offer flu vaccination in areas and at times where large numbers of staff congregate, such as staff canteens or during shift changeovers.\n\nPublicising information about mobile flu vaccination services.\n\nOffering opportunities for off‑site and out-of-hours access, for example, by providing vouchers for flu vaccination at a community pharmacy.\n\nPublicise flu vaccine uptake rates and the comparative performance of individual departments or sites within the organisation or locality. This could be done within the context of national targets such as the Commissioning for Quality and Innovation (CQUIN).\n\nDevelop the flu vaccination strategy in conjunction with staff representatives. Consider an anonymous survey of reasons for opting out, which could be used to inform future flu vaccination programmes.\n\nAgree approaches for information sharing if off‑site access to flu vaccination is offered to allow timely, accurate and consistent recording of people's vaccination status.\n\nSee how the committee made recommendations\xa01.7.1 to\xa01.7.8.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Carers\n\nPeople who receive a carer's allowance or who are the informal 'main carer' of an older or disabled person whose welfare may be at risk if the carer falls ill. This definition is in line with the Green Book, which recommends offering the flu vaccination on the basis of clinical judgement, regardless of whether the person receives a carer's allowance.\n\n## Clinical risk groups\n\nPeople who have a medical condition that means they are more likely to develop potentially serious complications from flu. People in these groups are eligible for free flu vaccination and are specified in the Green Book and the annual flu letter. At the time of publication of this guideline, the groups are:\n\nchronic respiratory disease, such as asthma (requiring use of inhaled or systemic steroids, or with previous exacerbations needing hospital admission), chronic obstructive pulmonary disease, or bronchiectasis\n\nchronic heart disease\n\nchronic kidney disease (stage\xa03 or above)\n\nchronic liver disease\n\nchronic neurological disease such as Parkinson's disease, motor neurone disease, or a learning disability\n\ndiabetes\n\na weakened immune system caused by disease (such as HIV/AIDS) or treatment (such as chemotherapy or high-dose corticosteroids)\n\nasplenia or conditions that can lead to dysfunction of the spleen, such as sickle cell disease or coeliac disease\n\nmorbid obesity (adults with a BMI of 40\xa0or over).\n\n## Eligible groups\n\nPeople who are eligible for free flu vaccination in the NHS, as outlined in the Green Book. For the purpose of this guideline, the specific eligible groups considered were:\n\nchildren and adults aged 6\xa0months to 64\xa0years in a clinical risk group (as listed in the annual flu letter)\n\npregnant women\n\npeople in receipt of a carer's allowance\n\npeople who are the main informal carer of an elderly or disabled person whose welfare may be at risk if the carer falls ill.\n\nIn addition, flu vaccination with live attenuated intranasal vaccine (LAIV) is recommended for all children aged 2\xa0to 17\xa0years who are not in a clinical risk group. This programme is being implemented in a phased roll-out, starting with the youngest first. At the time of publication (August 2018), the universal vaccination programme is available for children aged 2\xa0to 9\xa0years (up to school year\xa05). Preschool children (aged 2\xa0and 3\xa0years) should be vaccinated in general practice. Older children (from reception age) are being vaccinated by local healthcare teams working with schools. Once the programme has been rolled out to all primary-school-aged children, it will be reviewed to assess whether to continue the extension into secondary schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.\n\n## Full participation vaccination strategy\n\nA full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front‑line staff should be vaccinated.\xa0The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.\n\n## Multicomponent approach\n\nA set of multiple interventions implemented together to increase flu vaccination uptake. These target both demand (for example, increasing awareness of eligibility and the reasons why vaccination is beneficial) and supply (for example, creating more opportunities for vaccination, such as increasing the offer by professionals).\n\n## Peer-led approaches\n\nApproaches to reach underserved groups in which people with lived experience (for example, people who have been homeless, or who are from particular cultural backgrounds) work alongside health and social care professionals to provide information that is accessible and appropriate to the target group, acting as local 'flu champions' to promote awareness and uptake among their peers.\n\n## Providers of flu vaccination\n\nStaff who are allowed to administer the flu vaccination, or affiliated staff (for example general practice staff who log patient demographics and could therefore see who satisfies Green Book criteria).\n\n## Statutory organisations\n\nOrganisations with legal responsibility at a national or local level for the provision, commissioning, regulation or improvement and oversight of government-funded health and care services.\n\n## Underserved groups\n\nThis term is used in this guideline to mean adults and children from any background who are 'underserved' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to:\n\nrecognise they are eligible for flu vaccination (for example, they have an undiagnosed clinical condition)\n\naccess health services\n\nattend healthcare appointments.\n\nThe groups classified as underserved in this guideline are:\n\npeople who are homeless or sleep rough\n\npeople who misuse substances\n\nasylum seekers\n\nGypsy, Traveller and Roma people\n\npeople with learning disabilities\n\nyoung people leaving long-term care.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nEducation of health and social care staff and support workers – there are national minimum standards for these groups (see national minimum standards and core curriculum for immunisation training for registered healthcare practitioners, the Royal College of Nursing's immunisation knowledge and skills competence assessment tool, and Public Health England's immunisation training of healthcare support workers: national minimum standards and core curriculum). Also see Health Education England's flu immunisation eLearning programme and Public Health England's national flu programme training slide set. The Royal Pharmaceutical Society's seasonal influenza hub has information and educational resources for members. These resources could be used in implementing this guideline.\n\nSupport from national bodies, professional groups and royal colleges – organisations such as the British Medical Association (BMA), Royal College of Nursing and the Royal Pharmaceutical Society encourage their members and others to accept the flu vaccination. This includes advice that the BMA provides for occupational health providers. See also: the General Medical Council's guidance on good medical practice, the Nursing and Midwifery Council Code, advice from the General Pharmaceutical Council, the Health and Care Professions Council's standards of conduct and the Royal College of Nursing's guidance and resources on flu vaccination. This support and drive to increase flu vaccination could provide a useful lever for action in implementing this guideline.\n\nExisting national targets – there are a number of national targets including public health outcomes frameworks (3.03, 4.03, 4.07, 4.08) relating to population flu vaccination uptake. These targets could be used to establish the case when seeking to commission, develop and implement interventions recommended in this guideline.\n\nExisting incentive-based payment mechanisms to organisations to increase uptake – there are a number of incentives in primary and secondary care to increase flu vaccination, including Quality and Outcomes Framework, or QOF (secondary prevention of coronary heart disease [CHD007]; diabetes mellitus [DM018]; chronic obstructive pulmonary disease [COPD007]; and stroke and transient ischaemic attack [STIA009]) and Commissioning for Quality and Innovation or CQUIN (improving the uptake of flu vaccinations for front-line clinical staff [CQUIN 1c]). Framing proposals to increase flu vaccination in terms of the achievement of indicator criteria, as well as stating the impact on mortality and morbidity, may positively influence development and implementation of interventions recommended in this guideline.\n\nExisting examples of best practice guidance for increasing flu vaccination uptake – GPs have Flu vaccine for children: best practice guide for GPs and for healthcare workers, NHS Employers have good practice guides and case studies from former flu fighter award winners as well as planning, communications and reviewing campaign guides.\n\nExisting resources to support targeting, tailoring and information provision for eligible groups, including template letters, posters and Easy Read leaflets, can be found at the Stay Well This Winter campaign, and in the government's annual flu letter.", 'Context': "Each winter hundreds of thousands of people see their GP and tens of thousands are hospitalised because of flu. Deaths attributable to flu are estimated to range from around 4,000 to 14,000 per year, with an average of around 8,000 per year (Public Health England and the NHS prepare for unpredictable flu season).\n\nFlu vaccination has been recommended in the UK since the late 1960s. Everyone aged 65\xa0and over, those who are the main carer of an older adult or person with a disability, anyone aged 6\xa0months to 64\xa0years in a clinical risk group that puts them at a higher than average risk of illness and death linked to flu, and all pregnant women are offered free vaccination as part of the Public Health England and NHS England national programme. In addition, the Joint Committee on Vaccination and Immunisation has recommended extending flu vaccination to children to reduce transmission in the community and reduce the number of cases of flu-related illness and death among older adults.\n\nAt the time of publication (August 2018), the universal flu vaccination programme is available for children aged 2\xa0to 9\xa0years (up to school year\xa05). Preschool children (aged 2\xa0and 3\xa0years) should be vaccinated in general practice. Older children (from reception age) are being vaccinated by local healthcare teams working with schools. Once the programme has been rolled out to all primary-school-aged children, it will be reviewed to assess whether to continue the extension into secondary schools. Decisions about further roll-out to include older year groups will be notified in the annual flu letter.\n\nIn addition to the groups already mentioned, the Health and Safety at Work Act (1974) makes employers responsible for offering the flu vaccination to health and social care staff who have direct care responsibilities.\n\nAmong people aged 65\xa0or over, annual uptake of free NHS flu vaccination is relatively high and consistent, at around 70\xa0to\xa075%. For this reason, this group was not included as a target population for increasing uptake in the scope for this guideline.\n\nAmong people under\xa065 who are in clinical risk groups, uptake is lower and more variable: 49% overall in 2017/18, ranging from 39% in patients with morbid obesity (with a BMI of 40\xa0or over) and 41% in patients without a spleen or with splenic dysfunction, to 65% in patients who have diabetes. Uptake is particularly low among babies and infants (aged 6\xa0months to under 2\xa0years) who are in a clinical risk group: the vaccination rate in 2017/18 was only 21%. Uptake increased among preschool children in a clinical risk group (52% of those aged 2 to under 5\xa0years), but then dropped off again among those of school age (44%). Among children not in a clinical risk group, uptake of the universal flu vaccination programme was 43% for 2‑year‑olds and 44% for 3‑year‑olds. Among pregnant women, flu vaccination uptake was 47% in 2017/18, whereas for people under 65\xa0years who are registered as a carer by their GP, uptake was 40% (Public Health England's seasonal flu vaccine uptake in GP patients in England: winter 2017/18).\n\nIn England, among children and adults aged 6\xa0months to 64\xa0years who are in a clinical risk group, the average age‑adjusted risk of flu‑related death is 11\xa0times greater than for those not in a clinical risk group. However, this masks considerable variation between the different target groups. A much higher relative risk (RR) of flu‑related death is associated, for example, with chronic liver disease (RR=48.2), immunosuppression (RR=47.3) and chronic neurological disease (RR=40.4). For other clinical groups, the age‑adjusted relative mortality risks are: chronic renal disease, RR=18.5; chronic heart disease, RR=10.7; chronic respiratory disease, RR=7.4; diabetes, RR=5.8; and pregnant women RR=7.0.\n\nIn England 69% of healthcare workers in NHS trusts and area teams with direct patient contact were vaccinated in 2017/18, an increase from 63% the previous year (Public Health England's seasonal flu vaccine uptake in healthcare workers in England: winter 2017/18).\n\nThis guideline considers interventions to increase flu vaccination uptake in children aged 2\xa0to 17\xa0years (to take account of any future roll-out of the current children's universal vaccination programme); children and adults aged between 6\xa0months and 64\xa0years who are in clinical risk groups (see the Green Book), or adults who are morbidly obese (with a BMI of 40\xa0or over); pregnant women, carers, and front-line health and social care staff, in line with the national flu immunisation programme plan 2022 to 2023.\n\nSee the guideline scope for more details.", "The committee's discussion": "Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details.\n\n# Current practice\n\nThe committee noted that general practice is where most vaccination of eligible groups (other than front-line health and social care staff) currently takes place and should therefore be considered the primary route by which flu vaccination is offered. Provision in general practice is driven by a national enhanced service specification. This requires all eligible patients to be called (invited); records to be kept up to date; vaccination status (or reason for declining a flu vaccine) to be recorded accurately; appropriate skills and training for those administering flu vaccine; consideration of accessibility to ensure that service users' needs are met; and regular monitoring and reporting of vaccination activity. However, current delivery of flu vaccination in primary care is variable. Results of a cross-sectional survey suggest that well-organised general practices that implement multiple strategies for promoting uptake tend to have highest rates of flu vaccination, particularly among over\xa065s but also among people from clinical risk groups (Strategies to increase influenza vaccination rates: outcomes of a nationwide cross-sectional survey of UK general practice, Dexter et al.\xa02012).\n\nIn addition to general practice provision, community pharmacies can choose to offer flu vaccination to adults aged 18\xa0years or over who are in eligible groups, as detailed in an advanced service specification included as part of the NHS Community Pharmacy Contractual Framework. Some areas also have other local arrangements in place, such as commissioning vaccination provision in secondary care clinics or wards.\n\nVaccination of health and social care staff is delivered as part of employer occupational health responsibilities. This is driven by decision-making at the level of individual organisations, and rates of vaccination uptake are variable.\n\n# Economic modelling\n\nTo support committee decision-making, economic modelling was done to estimate the cost effectiveness of increasing flu vaccination uptake within each of the 4\xa0populations (children, people in clinical risk groups, carers, and health and social care staff).\n\nPublic Health England developed an economic model to inform the recommendations of the Joint Committee on Vaccinations and Immunisations on vaccinating children and people in clinical risk groups. We updated it to use the most recent and appropriate clinical and economic data.\n\nWe developed new economic models for carers and for health and social care staff because there were no existing models for these populations.\n\nWe considered interventions to be cost effective if they cost up to £20,000 per quality-adjusted life year (QALY). We conducted scenario analyses to determine the intervention cost that would be cost effective for a given increase in uptake.\n\n# A multicomponent approach\n\nThe discussion below explains how the committee made recommendations\xa01.1.1 and\xa01.1.2.\n\n## Rationale and impact\n\nFlu-related illness places a strain on NHS resources every winter because many of the people whose health is most at risk from flu – as well as the staff who come into contact with them – are not vaccinated. Evidence showed that the most effective way to encourage people to have a flu vaccination every year is to use a combination of interventions. The committee agreed there is no single intervention that can improve both how likely vaccination is to be offered and also the likelihood that people will accept vaccination. Based on their knowledge of practice in the UK, the committee agreed with experts who said that organisations need to work closely together to achieve this, an approach that was supported by evidence on collaborative multi-agency working and leadership.\n\nThe recommendations will help to reduce current variation in practice. For example, vaccination uptake among eligible groups in general practice can range from 15\xa0to\xa0100%. The greatest resource impact is therefore likely to be for those practices that are less active in promoting flu vaccination uptake. But the cost impact should be relatively small compared with the reduction in mortality and morbidity associated with flu. In addition, there are opportunities to gain incentive payments by results, which may offset organisational costs.\n\n## Evidence discussion\n\nUptake of flu vaccination by people in eligible groups, and its acceptability to them.\n\nLittle research evidence was identified that met the review protocol criteria on carers as a target population for flu vaccination [Evidence review 1].\n\nFor children not in any clinical risk groups [Evidence review 2], evidence for the effectiveness of both single interventions and multicomponent approaches to increasing flu vaccination uptake was of variable quality, ranging from moderate to very low. Most downgrading was due to risk of bias and imprecision of effect estimates. There was also some 'indirectness' downgrading for studies that included children outside the age range specified in the review protocol (2\xa0to\xa017\xa0years). The committee noted that all but 1\xa0of the included studies was conducted in the USA, and that they covered a range of primary care, school-based and secondary care settings.\n\nOverall, the evidence suggested single interventions were not effective in increasing flu vaccination uptake among children by a clinically important amount (that is, 5% or more above control group or baseline uptake levels). There was some evidence to support educational interventions aimed at parents [Evidence review 2: ES1.1], and provider prompts [Evidence review 2: ES3.4], but effects were inconsistent across studies. For multicomponent approaches, 1\xa0large cluster-randomised controlled trial showed a clinically important increase in vaccination uptake, and a resulting decrease in missed opportunities to vaccinate [Evidence review 2: ES123.1, ES123.4]. Another large randomised controlled trial also showed an increase in uptake, but with greater uncertainty in the effect [Evidence review 2: ES123.3]. The committee noted that both studies were conducted in primary care and that there was moderate certainty in the evidence in both cases. They also noted that the studies involved an organisational lead or vaccination champion to coordinate delivery of the multicomponent programme.\n\nFor adults and children in clinical risk groups [Evidence review 3], the quantitative evidence relating to single interventions and to multicomponent approaches was again of variable quality, with most rated low or very low. Downgrading was largely due to risk of bias issues and imprecision of effect estimates, or small sample sizes.\n\nIn pooled analyses there was evidence of serious or very serious heterogeneity. The committee agreed this would be expected, given differences between study populations in terms of clinical risk factors and the lack of standardisation of interventions and comparators across studies. Again the majority of studies were conducted in non-UK settings and covered a range of health and social care settings.\n\nThere was evidence that some single interventions were effective in increasing vaccination uptake among adults and children in clinical risk groups [Evidence review 3: ES3.2, ES3.4b; SR-ES1.1, SR-ES1.2, SR-ES2.2, SR-ES3.1, SR-ES3.2, SR-ES3.3, SR-ES3.4, SR-ES3.5], but effects were inconsistent across different interventions. The committee noted that in 6\xa0out of 10\xa0evidence statements in which a clinically important increase was found, the population in question was children in clinical risk groups. Parents of children in clinical risk groups may be more risk-averse and likely to accept the protective health benefits of vaccination than adults in clinical risk groups.\n\nFor people in clinical risk groups, 9\xa0of 14\xa0evidence statements relating to multicomponent approaches showed an increase in flu vaccination uptake; in 7\xa0cases the effect was clinically important (5% or more relative increase) [Evidence review 3: ES123.2, ES123.3; SR-ES123.1, SR-ES123.3, SR-ES123.5, SR-ES123.9]. These covered a range of paediatric and adult populations and different clinical risk groups. The committee noted that within the same study, effects differed depending on the particular clinical risk group [Evidence review 3: ES123.2] or, in a study of immunocompromised children, depending on the type of cancer [Evidence review 3: ES123.3]. The committee concluded that information needs, perceptions of individual risk and other health beliefs that influence decision-making about flu vaccination are not the same for people in different clinical risk groups. This should be considered when planning and delivering interventions.\n\nFor health and social care staff [Evidence review 4] the effectiveness evidence for single and multicomponent interventions for increasing flu vaccination uptake was mostly rated very low quality. Downgrading was largely due to risk of bias issues and imprecision of effect estimates. In pooled analyses there was evidence of serious or very serious heterogeneity, which the committee agreed would be expected, given differences in the types of health and social care staff involved and the lack of standardisation of interventions and comparators across different studies. The majority of evidence was from a non-UK context and covered a range of health and social care settings.\n\nThere was inconsistent evidence that educational interventions alone increase uptake of flu vaccination among health and social care staff. However, staff education and awareness raising was included in almost all multicomponent approaches to increasing vaccination uptake, combined with interventions to increase staff access through more flexible workplace delivery. A clinically important increase in vaccination uptake among health and social care staff (of 5% or more) was reported in 19\xa0out of 20\xa0evidence statements relating to multicomponent programmes [Evidence review 4: ES45.1, ES45.2, ES45.3, ES45.4, ES45.5, ES45.6, ES45.7, ES45.8, ES45.9, ES45.10, ES45.11; SR-ES45.1, SR-ES45.2, SR-ES45.3, SR-ES45.4, SR-ES45.5, SR-ES45.6, SR-ES45.7, SR-ES45.8].\n\nTo improve uptake, the committee noted the importance of both increasing demand for flu vaccination among target groups (for example, through awareness raising, using education to overcome informational barriers or sending reminders), and addressing 'supply' factors (for example, prompts to providers to increase offers of vaccination). Accessibility and convenience of vaccination provision were consistent themes highlighted in reviews of the qualitative evidence and expert testimonies [Evidence review 2: Q-ES1.4, Q-ES1.5. Evidence review 3: Q-ES 2.3. Evidence review 4: Q-ES3.6. EP1, EP2, EP3, EP4, EP5, EP6]. A key advantage of a multicomponent approach is that it can address demand and supply factors simultaneously.\n\nThe committee acknowledged that it may be difficult to identify what specific interventions within a multicomponent approach are more or less effective in promoting uptake. This may affect the ability of programme leaders to modify and improve the approach to increase uptake of flu vaccination over successive vaccination seasons.\n\nNo studies were identified that assessed the comparative cost effectiveness of multicomponent and single interventions for increasing uptake of flu vaccination.\n\nDepending on the level of cost of the chosen mix of interventions needed to increase opportunities, they could be cost effective as described below. The committee's opinion was that although a multicomponent approach is likely to be more time- and resource-intensive than a single intervention, it will have greater impact on uptake because it targets multiple drivers affecting both demand and supply. Different approaches are likely to affect people differently and thus will have a greater impact at a population level. Experts emphasised the need for careful planning and coordination, which the committee agreed was best undertaken by an assigned organisational lead or team [Evidence review 2: ES123.1, ES 123.3. Evidence review 4: SR-ES45.6. EP4, EP5, EP6]. This may incur an opportunity cost to organisations if the seasonal nature of the task means that staff need to be redeployed from other important duties. However, these costs are likely to be offset by financial remuneration from enhanced services payments and from achieving incentive-based targets in the QOF and CQUIN pay-for-performance schemes.\n\nOverall, the committee felt that because many organisations are already implementing strategies to promote flu vaccination uptake (many of which take a multicomponent approach), the recommendations should not represent a significant impact on resources. The impact of implementing the recommendations will be largely determined by the current intensity and variety of activity undertaken by an organisation. The committee agreed that the recommended interventions are in line with the current service specification for flu vaccination delivery and that they are all generally likely to have a relatively low cost.\n\nThe committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations that are the focus of this guideline, interventions were considered cost effective if:\n\nFor adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.\n\nFor pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.\n\nFor children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.\n\nFor health and social care staff, they cost up to £2.15 per targeted person and increased vaccination uptake by at least 5%.\n\nThe committee felt that the costs per targeted person of multicomponent approaches were likely to be below the maximum costs, and achieve the necessary level of vaccination.\n\nThey also noted that wider, more consistent use of a multicomponent approach will potentially reduce current variability in rates of uptake around the country. They believe this will in turn reduce levels of circulating flu and the associated healthcare and societal costs.\n\nThe committee recognised the lack of peer-reviewed evidence about carers and limited evidence about children who are not in clinical risk groups. They also acknowledged the non-UK context of the majority of evidence in the reviews. However, on the basis of expert testimony relating to carers [EP1], people in clinical risk groups [EP2, EP3, EP6] and health and social care staff [EP4, EP5], combined with their own experience of vaccination for multiple groups, the committee believed that evidence supporting the effectiveness of multicomponent approaches could be extrapolated to all eligible groups in UK settings. They noted that vaccination incurs a financial cost to the person in many of the settings the evidence relates to, whereas it is provided free to people in eligible groups in the UK. Effect sizes may therefore be greater in the UK where there are fewer financial barriers (although there may still be costs to the person, such as from taking time off work, or transport).\n\nThe committee noted that there was some evidence to indicate that the initial benefits of a multicomponent approach are sustainable, but that the same approach may not increase uptake year on year [Evidence review 3: SR-ES123.5, SR-ES123.6. Evidence review 4: ES45.1, ES45.3, ES45.11]. Expert testimony supported the need to be flexible and innovative in order to extend the reach of a multicomponent approach over successive years [EP4, EP5, EP6].\n\nThe committee concluded that, overall, the evidence reviewed showed a more positive and consistent effect favouring multicomponent approaches over single interventions to increase uptake of flu vaccination in the populations of interest. They felt that multicomponent approaches offer opportunities to reach more groups, therefore representing a better long-term return on investment by increasing vaccination rates and so reducing the health impact and societal costs associated with flu infection.\n\nMulticomponent approaches are complex interventions and the committee was not able, on the basis of the evidence, to recommend a specific configuration. There may be a synergistic effect of combining interventions and certain components may be more or less effective in differing target groups.\n\nThe recommendations in sections\xa01.2 to\xa01.7 present options that a commissioner or provider could use to develop an approach based on local intelligence, allowing them to apply what is most relevant to their needs.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES123.1, ES123.2, ES123.3, ES123.4; Q-ES 1.4, Q-ES 1.5\n\nEvidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES123.1, ES123.2, ES123.3, ES123.4, ES123.5; SR\xa0ES123.1, SR\xa0ES123.2, SR\xa0ES123.3, SR\xa0ES123.4, SR\xa0ES123.5, SR\xa0ES123.6, SR\xa0ES123.7, SR\xa0ES123.8, SR\xa0ES123.9; Q-ES 2.3\n\nEvidence review 4 on increasing flu vaccination uptake in health and social care staff: ES 45.1, ES 45.2, ES 45.3, ES 45.4, ES 45.5, ES 45.6, ES 45.7, ES 45.8, ES 45.9, ES 45.10, ES 45.11; SR-ES 45.1, SR-ES 45.2, SR-ES 45.3, SR-ES 45.4, SR-ES 45.5, SR-ES 45.6, SR-ES 45.7, SR-ES 45.8, SR-ES 45.9\n\nExpert testimony on increasing vaccination uptake among carers: Expert paper 1 (EP1)\n\nExpert testimony on increasing vaccination uptake among people with chronic liver disease: Expert paper 2 (EP2)\n\nExpert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: Expert paper 3 (EP3)\n\nExpert testimony on increasing vaccination uptake among healthcare workers: Expert paper 4 (EP4) and Expert paper 5 (EP5)\n\nExpert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)\n\n# Raising awareness\n\nThe discussion below explains how the committee made recommendations\xa01.2.1 to\xa01.2.10.\n\n## Rationale and impact\n\nNot all health and social care staff know who is at greatest risk from flu, so they are not offering it to everyone who is eligible. There is evidence that training and educating health and social care staff improves vaccination rates. The evidence also showed that people in eligible groups who understand why flu vaccination is particularly important for them are more likely to be vaccinated. Professionals need to explain the benefits of vaccination and address people's misconceptions about it. The committee also agreed that it is important to make sure people know that flu vaccination is free if they are eligible.\n\nThere was some evidence that working with statutory and voluntary organisations might be effective in raising awareness about vaccination and its benefits, although there is currently a lack of empirical evidence in this area.\n\nCurrent practice is variable in GP surgeries where most flu vaccination is given. Practices with high vaccination uptake are likely to be delivering services in line with these recommendations already; those practices with lower levels of vaccination uptake will be able to make a big impact by putting these recommendations into practice.\n\n## Evidence discussion\n\nUptake of flu vaccination by people in eligible groups, and its acceptability to them.\n\nThere was some quantitative evidence supporting the effectiveness of provider education as part of a multicomponent approach to improving uptake of flu vaccination among eligible groups. There were 10\xa0evidence statements relating to largely non-UK-based studies in which provider education explicitly formed part of the intervention being evaluated. The study populations included children not in clinical risk groups [Evidence review 2: ES123.3], pregnant women, and children and adults in clinical risk groups [Evidence review 3: SR-ES1.1; ES123.2, ES123.3, ES123.5; SR-ES123.5, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9], and covered a range of healthcare settings. Certainty in the evidence was variable; most was rated low or very low quality. Reasons for downgrading included risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates in smaller studies. In 9\xa0of the 10\xa0evidence statements there was a reported increase in flu vaccination uptake; in 6\xa0cases this was a clinically important increase (5% or more relative to control group or pre-intervention uptake) [Evidence review 3: SR-ES1.1; ES123.2, ES123.3; SR-ES123.5, SR-ES123.6, SR-ES123.9].\n\nThere was more available evidence on the effectiveness of education or awareness-raising interventions aimed at eligible people (or their parents, in the case of children) rather than healthcare providers. In this context, education was often combined with other interventions such as written or text message reminders. Various interventions were outlined and in many cases there was a lack of specific detail (the term 'educational materials' was frequently used).\n\nEighteen evidence statements generated across evidence review 2 [ES1.1/4, ES1.2, ES3.2] and evidence review 3 [ES1.1, ES1.2, ES3.1, ES3.2, ES3.3, ES123.3, ES123.4; SR-ES1.1, SR-ES1.2, SR-ES3.8, SR-ES123.3, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9], again relating to largely non-UK-based studies and covering a range of healthcare settings and populations, included an educational element targeted at the person eligible for flu vaccination. Eleven of the 18\xa0statements reported an increase in vaccination uptake that, in 8\xa0cases was clinically important [Evidence review 2: ES1.1/4. Evidence review 3: ES3.2, ES123.3; SR-ES1.1, SR-ES1.2, SR-ES123.3, SR-ES123.6, SR-ES123.9]. There was generally low or very low certainty in the evidence, with downgrading due to risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates.\n\nQualitative evidence highlighted that access to information was essential to parents making vaccination decisions on behalf of their children, and for people with chronic health conditions [Evidence review 2: Q-ES1.1. Evidence review 3: Q-ES2.2]. People's perceptions of personal risk differ, and these need to be ascertained and addressed by healthcare providers, along with concerns about flu vaccine safety and effectiveness and misconceptions, for example that vaccination can give people flu [Evidence review 2: Q-ES1.1, Q-ES1.2. Evidence review 3: Q-ES2.1, Q-ES2.2].\n\nQualitative evidence also suggested that providers may themselves have differing risk–benefit perceptions depending on their own clinical or personal experience [Evidence review 3: Q-ES2.1, Q-ES2.2, Q-ES2.5]. Other studies highlighted that people deciding whether to have a flu vaccination place importance on the perceived strength of their healthcare provider's endorsement of the flu vaccine [Evidence review 3: Q-ES2.4], and that they want to trust that the advice they are given is credible and delivered for their own health benefit without any conflict of interest (for example, to get incentive payments) [Evidence review 2: Q-ES1.3]. Providers and people in eligible groups may be aware that flu vaccine effectiveness varies, and this may work as a barrier to uptake. Although it is not possible to predict before a flu season how well the available vaccine and circulating strains of the virus will be matched, the committee were keen to note that the flu vaccine has generally been a good match and continues to provide the best protection for those at greatest risk from flu and its complications.\n\nThe evidence reviewed reinforced the committee's decision to recommend raising and sustaining awareness not only in eligible groups, but also in those who commission and deliver vaccination programmes. Encouraging use of professional minimum standards vaccination training will help to reduce variation in professional attitudes and ensure consistency of message delivery.\n\nThe committee was satisfied that the majority of evidence favoured using information and education to raise and sustain awareness of flu vaccination as a means of increasing uptake. They agreed it was important to target both healthcare providers and people in clinical risk groups. Based on their knowledge of this kind of approach in the UK and the generally positive direction of effect across studies in the evidence reviews, the committee felt the evidence could be extrapolated to all eligible groups specified in the Green Book and across health and social care settings, provided that individual needs underpin any information given as part of an intervention.\n\nRaising and sustaining awareness – both among those with responsibility for providing and administering flu vaccination and those eligible for vaccination – should reduce barriers to offering, providing and accepting it.\n\nUsing opportunistic approaches, including brief interventions or brief advice, is in line with the principles of Making Every Contact Count and the NHS Five Year Forward View and should result in increased efficiency of service provision and access.\n\nRaising awareness as a means of encouraging more people to be vaccinated needs to be coupled with interventions to ensure there are adequate supplies of flu vaccine to meet increased demand, and that appropriate and convenient access arrangements are in place. Otherwise there is a risk of deterring people from further engaging with vaccination services.\n\nEducational interventions for people in eligible groups are generally low cost with relatively low resource implications, particularly if delivered opportunistically in the form of brief interventions or brief advice by knowledgeable healthcare staff they come into contact with, in line with Making Every Contact Count. Evidence from expert testimony suggested that efficiency savings can be made if information on flu vaccination is delivered at the same time as other health-promotion messages and preventive health interventions for eligible groups [EP3, EP6].\n\nEducation and awareness-raising interventions aimed at health and social care staff are likely to incur greater costs. However, there are national minimum standards and a core curriculum for staff involved in administering vaccines. These have free training resources for local use. Some areas provide bespoke training for designated flu champions, who may not be required to meet full national standards for immunisation training if flu vaccine is the only vaccine they administer in their professional role. This training is likely to have lower overall resource costs. For staff whose role includes delivering vaccination-related activities, in particular awareness raising and educational messages, training and educational interventions should be considered an integral part of their continuing professional development to ensure that they use safe practice and give up-to-date advice.\n\nThe committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:\n\nFor adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.\n\nFor pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.\n\nFor children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.\n\nThe committee felt that educational interventions were likely to be cost effective, and would help to achieve national targets and aspirations for flu vaccination.\n\nThe committee noted the lack of detail in some studies about intervention content and how they could be potentially combined, but agreed that the evidence was consistent on the importance of increasing and sustaining awareness in professionals and in parents, children and people in clinical risk groups. The committee discussed the potential for healthcare professionals to use face-to-face interactions to identify and opportunistically engage with those eligible for flu vaccination, but agreed that this raises equity issues, because people not in contact with healthcare services may be missed. They agreed with the testimonies of experts that providers should consider partnership working with local organisations (for example, drug and alcohol services) and voluntary sector groups working with underserved populations (such as carers or people who are homeless) to identify those who might be eligible for flu vaccination and give them information about how to access services [EP1, EP2, EP3].\n\nEducating health and social care staff and eligible groups about flu vaccination in the context of protecting others was also seen by the committee as a way to increase uptake. The committee recognised the lack of UK-based studies generally and the lack of peer-reviewed evidence about carers specifically, but it considered expert testimony and was able to make recommendations about carers [EP1].\n\nThe committee noted that the flu vaccine is administered differently in children and adults. Children over the age of\xa02 who are eligible for annual flu vaccination are given live attenuated influenza vaccine (LAIV) in the form of a nasal spray (see recommendation\xa01.2.8 in the section on raising awareness in eligible groups). Eligible adults (aged 18\xa0and over) should be given the inactivated flu vaccine by injection. Only in exceptional circumstances, alternative options for administering flu vaccine to adults who become seriously distressed by needles may be agreed (see Public Health England's information for healthcare practitioners on administering LAIV to patients with a needle phobia, pages\xa023 and\xa024).\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES123.3; Q-ES1.3\n\nEvidence review 3 on increasing flu vaccination uptake in clinical risk groups: SR-ES 1.1; ES 123.2, ES123.3, ES123.5; SR-ES123.5, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES 2.1, Q-ES 2.2, Q-ES 2.4, Q-ES 2.5\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES1.1, ES1.2, ES3.2; Q-ES1.1, Q-ES1.2\n\nEvidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES1.1, ES1.2; SR-ES1.1, SR -ES1.2; ES3.1, ES3.2, ES3.3; SR-ES3.8; ES123.3, ES123.4; SR-ES123.3, SR-ES123.6, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES2.1, Q-ES2.2, Q-ES2.4\n\nExpert testimony on increasing vaccination uptake among carers: expert paper 1 (EP1)\n\nExpert testimony on increasing vaccination uptake among people with chronic liver disease: expert paper 2 (EP2)\n\nExpert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: expert paper 3 (EP3)\n\nExpert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: expert paper 6 (EP6)\n\n# Offering vaccination\n\nThe discussion below explains how the committee made recommendations\xa01.3.1 to\xa01.3.6.\n\n## Rationale and impact\n\nMany potential opportunities are being missed to offer eligible people a free flu vaccination during contacts with health, social care and other statutory and voluntary services. There is evidence that using existing systems to offer flu vaccination and extending the way services are provided can encourage more people to be vaccinated. An expert told the committee that all organisations that can reach eligible people need to work together to ensure this happens.\n\nThe committee also agreed that being flexible with the hours when GP surgeries or other providers offer flu vaccination would enable people to come for vaccination at a time convenient for them. There was limited evidence that this improves vaccination rates but it was also supported by expert testimony.\n\nThere is evidence that flu vaccine supply can also affect uptake. People who request the vaccination may not return if it is not available immediately.\n\nUsing every opportunity to offer and provide flu vaccination will increase uptake among people who need it because they are particularly vulnerable to the complications of flu. Although this may increase costs in the short term, the committee agreed that it is likely to be cost effective.\n\n## Evidence discussion\n\nUptake of flu vaccination by people in eligible groups, and its acceptability to them.\n\nIn relation to increasing offers of flu vaccination, the committee considered ways in which people who are eligible can be identified ('case-finding'), and interventions to ensure that vaccination services are accessible to those who are offered them.\n\nCase-finding can be done opportunistically or systematically. The published evidence related mainly to systematic approaches using provider prompts embedded in healthcare records. This evidence is considered separately in the section on patient records.\n\nExpert testimony highlighted the importance of using both opportunistic and systematic approaches to case-finding as a means of increasing opportunities to offer flu vaccination. Face-to-face interactions in primary care (including community pharmacy) provide opportunities to identify and offer vaccination to eligible people. Periodic searches of computer records can be undertaken in general practice to identify unvaccinated new patients or people who have recently become eligible (for example, people who are recently diagnosed with a condition that places them in a clinical risk group, or women with a newly confirmed pregnancy) [EP6].\n\nOther strategies for case-finding should be considered for eligible people who may not be identifiable using existing general practice systems. The committee noted that carers are a difficult group to identify because their carer status may not be routinely recorded in GP records [EP1]. Other expert testimony highlighted that chronic liver disease is associated with the highest risk of flu-related mortality but lowest rates of vaccination uptake across all clinical risk groups specified in the Green Book. Prevalence of chronic liver disease is high among people who abuse drugs and alcohol, who may be in more regular contact with specialist services and pharmacies than with GPs [EP2]. People sleeping rough have a high prevalence of chronic respiratory illness and are usually not in regular contact with statutory healthcare services [EP3]. The committee was keen to promote links between vaccination providers and other local organisations, such as those assessing and supporting carers, specialist drug and alcohol services, community pharmacies and voluntary groups working with carers or people who are homeless to identify eligible people and offer (or signpost them to) vaccination services.\n\nQualitative evidence highlighted that perceived availability and accessibility are significant barriers to or facilitators of uptake among eligible groups who are offered a flu vaccination [Evidence review 2: Q-ES1.4, Q-ES1.5. Evidence review 3: Q‑ES2.3].\n\nFourteen evidence statements related to effectiveness studies in which access had been improved for target populations by providing vaccination services more frequently or at more convenient times or locations. The published evidence ranged from moderate to very low quality, with the majority being of very low certainty and from non-UK settings. Reasons for downgrading included risk of bias, high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates. Eight of these evidence statements reported an increase in vaccination uptake, which was clinically important in 6\xa0cases, among populations that included children not in clinical risk groups [Evidence review 2: ES123.1/4] as well as adults and children with clinical risk factors and pregnant women [Evidence review 3: SR-ES2.2, SR‑ES123.1, SR-ES123.3, SR-ES123.5, SR-ES123.9]. The majority of studies lacked specific detail about how access to vaccination services had been improved by the intervention, which made it difficult for the committee to make recommendations. One study that reported an increase in uptake compared year-round flu vaccination for children with asthma with appointments offered only during the flu season, which the committee agreed was not applicable to the UK [Evidence review 3: SR-ES2.2]. The committee discussed another before-and-after study that reported no clear improvement in uptake when 2\xa0additional Saturday clinics were offered to children with asthma at the start of the flu vaccination season [Evidence review 3: SR-ES 2.1]. The committee felt this relatively small US-based study did not support the qualitative evidence or their own experience of the importance of out-of-hours access, particularly for people in work or education. Expert testimony confirmed that GP practices offering weekend access have been able to achieve vaccination of hundreds of patients in 1\xa0day. This had the added benefit that it was outside usual practice hours, so reducing impact on the winter pressure for GP appointments [EP6].\n\nIn England, community pharmacies are able to provide flu vaccinations to eligible adults. Studies in which community pharmacies were part of extended access arrangements did not show increased uptake among target populations [Evidence review 1: ES2.1. Evidence review 3: ES2.1, ES2.2, ES123.1]. However, the committee noted that people of working age in clinical risk groups who are relatively well but need regular prescription medication, and carers in particular, may be more likely to use community pharmacies as a convenient alternative to GP vaccination services. This was confirmed by expert testimony relating to carers [EP1].\n\nThe committee concluded that increasing identification of eligible people and providing sufficient routes of access to meet the needs of different groups (including out-of-hours opportunities for people with work commitments) are key to increasing vaccination uptake, as is ensuring that supplies are sufficient to meet demand. The empirical evidence linking extended hours to increased uptake was inconsistent, but the committee felt it important to provide convenient access to as many eligible people as possible.\n\nOrganisations are encouraged to use clinical systems to systematically identify people who are eligible for free flu vaccination and record uptake. Flu vaccination providers should plan to exceed the previous year's uptake when ordering supplies.\n\nOpportunistic approaches are in line with the principles of Making Every Contact Count and the Five Year Forward View. But it is not easy to ensure consistency of delivery.\n\nSystematic case-finding needs procedures to be in place, including staff routinely checking for people who are newly eligible. However, implementation of such procedures is likely to be consistent and effective. Establishing links with local statutory and voluntary organisations to promote case-finding is dependent on what resources are available locally. Using outreach to offer flu vaccination to eligible people who are not in touch with services needs careful planning to ensure that the vaccine cold chain is maintained and staff have the capacity to recognise and treat any adverse reactions.\n\nIncreasing identification of eligible people and offers of flu vaccination should be coupled with appropriate interventions to ensure adequate availability and ease of access.\n\nOne cost–utility study and 1\xa0cost effectiveness study (both low quality) were included in the review of interventions for increasing vaccination uptake in clinical risk groups [Evidence review 3]. One study suggested that opportunistically identifying, offering and administering flu vaccination may be cost saving [Evidence review 3: CE-ES 2.2]. The other study indicated that targeting pregnant women with a comorbidity [Evidence review 3: CE-ES2.1] was also likely to be cost saving. The evidence focused on pregnant women during routine practice visits and children from clinical risk groups in a hospital setting. The committee agreed that the principle of increasing the opportunistic offer and administration of the vaccination without increasing the need for additional visits would be cost effective across all eligible populations.\n\nThe committee noted that using computerised systems for case-finding could incur higher costs than opportunistic approaches but will be more consistent and may therefore be a more effective lever for increasing uptake, with greater long-term efficiency savings. Extending access to vaccination services will incur higher outlay in terms of staff costs and overheads. Using outreach 'find and treat' methods to vaccinate eligible people who are not in regular touch with services will incur costs, but the committee were keen to recognise the health benefits of vaccinating those who will not get vaccinated elsewhere. Off‑site provision offered through collaborative working (for example with community pharmacies and secondary care) needs to be negotiated by commissioners because there is potential loss of income for general practices.\n\nThe committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:\n\nFor adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.\n\nFor pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.\n\nFor children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.\n\nThe committee felt that the costs per targeted person of increasing opportunities to offer flu vaccination were likely to achieve the necessary level of vaccination to be cost effective.\n\nOverall the committee agreed that increasing opportunities to reach more groups is a good use of resources given the morbidity and mortality associated with flu. In turn, this may reduce some of the winter pressures on the health service associated with flu infection. Opportunistic approaches are not likely to significantly impact resources because they specifically aim to reduce the likelihood of needing additional appointments and are targeted. This is in agreement with the cost effectiveness evidence showing the approach is likely to be cost saving.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 1 on increasing flu vaccination uptake in carers: ES2.1\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES123.1/4, ES123.2, ES123.3; Q-ES1.4; Q-ES1.5\n\nEvidence review 3 on increasing flu vaccination uptake in clinical risk groups: ES2.1, ES2.2; SR-ES2.1, SR-ES2.2, ES123.1, SR-ES123.1, SR-ES123.3, SR-ES123.4, SR-ES123.5, SR-ES123.7, SR-ES123.8, SR-ES123.9; Q-ES2.3; CE-ES2.1, CE-ES2.3\n\nExpert testimony on increasing vaccination uptake among carers: expert paper 1 (EP1)\n\nExpert testimony on increasing vaccination uptake among people with chronic liver disease: expert paper 2 (EP2)\n\nExpert testimony on increasing vaccination uptake among people who are homeless or rough sleepers: expert paper 3 (EP3)\n\nExpert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: expert paper 6 (EP6)\n\n# Increasing uptake among eligible groups in primary and secondary care\n\nThe discussion below explains how the committee made recommendations\xa01.4.1 to\xa01.4.10.\n\n## Rationale and impact\n\nThe committee agreed that most people who are particularly vulnerable to the complications of flu, or who are eligible for other reasons, are likely to be in regular contact with their GP surgery or local community pharmacy and know the staff. These routine contacts provide ideal opportunities to speak to people about flu vaccination. The evidence showed that making sure invitations to eligible people are personalised to their circumstances also helps to increase vaccination uptake. If eligible people are not in regular contact with primary care services, or have particular concerns about flu vaccination, using peers as local 'flu champions' providing information that is accessible and appropriate to the target group may help promote uptake.\n\nSome people at high risk from flu and its complications visit hospital outpatients or other secondary care clinics more regularly than their GP. Existing hospital systems could be used to identify them, raise awareness and encourage them to have a free flu vaccination while they are there if this is a locally agreed route for offering vaccinations. There is evidence that this is most effective when the vaccination offer is tailored to their condition and made by a healthcare practitioner they know.\n\nIn both primary and secondary care, incorporating prompts in electronic health records helps to remind health and social care staff to offer flu vaccination to people who are eligible when they attend for appointments. Using already available systems to set these reminders helps the care provider raise awareness of and offer vaccination.\n\nGeneral practices that have signed up to the service specification for flu vaccination are required to proactively call and recall eligible patients. Computerised systems are already in place to do this; however, the way it is carried out is variable. GP surgeries will need to ensure that they personalise and tailor their invitations for vaccination.\n\nA key element of the recommendations is to make the most of face-to-face interactions to offer and deliver vaccination. This may need additional time and resources initially. However, a personalised approach tailored to the person's situation is more likely to engage them with the flu vaccination programme. Embedding prompts in these eligible patients' healthcare records to remind providers to invite them for vaccination each flu season could avoid additional appointments and save costs in the longer term.\n\nThe lack of a national service specification for secondary care means that some areas don't have local enhanced services agreements to deliver vaccination and will need to set these up. Procedures for recognising and treating adverse reactions, the purchase and appropriate cold-chain storage of flu vaccine supplies, and ensuring that the setting used to administer vaccinations is appropriate are all issues that need to be taken into account when setting up these agreements with secondary care providers.\n\n## Evidence discussion\n\nUptake of flu vaccination to people in eligible groups and its acceptability to them.\n\nCall ('vaccination due') and recall ('vaccination overdue') interventions delivered using various formats are frequently used in UK primary care to remind people of their eligibility for free flu vaccination. The committee reviewed the published evidence on the effectiveness of such interventions, which was mostly from non‑UK studies and ranged from high to very low quality, with the majority being of low quality. Reasons for downgrading included risk of bias, high levels of heterogeneity in pooled analyses of data, and imprecision of effect estimates.\n\nAs a single intervention strategy, there was no evidence that reminders delivered as text messages (with or without an educational element) increased flu vaccination uptake among eligible groups by a clinically important amount (5% or more, compared with control or pre-intervention uptake rates) [Evidence review 2: ES3.1, ES3.2, ES3.3. Evidence review 3: ES3.3, ES3.4a; SR-ES3.8]. However, call and recall methods using more personalised approaches (such as letters, postcards or personal telephone calls) appear to be more effective. There were 7\xa0evidence statements relating to the use of such approaches among people from clinical risk groups, of which 5\xa0reported an important increase in flu vaccination uptake [Evidence review 3: ES3.2; SR-ES3.1, SR-ES3.2, SR-ES3.3, SR-ES3.5]. The committee noted that in 3\xa0of the 5\xa0cases the target population was children, suggesting that parents may be more amenable to personalised messages about the protective health benefits of vaccination when their children are in clinical risk groups than are adults who themselves have clinical risk factors. When reminders formed part of a multicomponent approach, an important increase in vaccination uptake was reported [Evidence review 3: SR-ES123.1, SR-ES123.3, SR-ES123.9], although 1\xa0UK-based study that targeted children aged 2\xa0to 4\xa0years who were not in a clinical risk group found no increase in uptake when practices incorporated text messaging into a multicomponent approach [Evidence review 2: ES123.2]. The committee noted qualitative evidence that for parents of preschool children, a personal invitation from a healthcare professional is important for making a decision about vaccination [Evidence review 2: Q-ES1.9]. Other qualitative evidence further highlighted that people are more likely to trust advice and offers of vaccination that come from healthcare professionals they know, and that it is important for messages to be delivered with conviction [Evidence review 3: Q-ES2.4].\n\nThe committee believed strongly that reminders should be proactive. Not everyone who is eligible for free flu vaccination will visit their GP surgery regularly, so it is not sufficient to rely on posters in waiting rooms to remind them. The committee discussed the equivocal evidence on the effectiveness of text messaging to call and recall people for flu vaccination, which they felt may be perceived by the recipient as too impersonal or lacking conviction. They agreed that, if possible, reminders to eligible people should be personalised and come from a healthcare professional they know, either in person or in writing. The committee acknowledged that digital formats may be more acceptable to some population groups than others but were keen to recommend that if they are used, they should include links to additional useful information, including options for seeking further face-to-face advice and for booking an appointment to have their flu vaccination.\n\nThe committee also considered expert testimony that supported the use of peers to inform and invite people who are not in contact with primary care services for vaccination, such as people who are homeless [EP3]. They discussed that this approach could be extended to engage people who may have concerns about flu vaccination for religious reasons, as highlighted in another expert's testimony [EP6]. For example, some parents of children eligible for flu vaccination may be reluctant for their child to take up the offer because the nasal spray that is used to vaccinate children contains a gelatine additive derived from pork, so may be considered 'forbidden' in certain faiths. In such situations, it may be worth trying to engage peers or community leaders to work with local healthcare providers to provide information and support that people feel able to trust, in a language that is accessible and appropriate to them.\n\nThe majority of published evidence considered by the committee was from the USA, where there is no distinction between primary care and secondary care that equates to the UK healthcare context. However, the committee noted there was low-quality evidence from studies in which interventions implemented in specialist healthcare settings had successfully improved vaccination uptake among children having treatment for different forms of cancer [Evidence review 3: ES123.3] and, although with greater uncertainty in the effect, among people with end-stage renal disease who were having treatment in dialysis centres [Evidence review 3: ES123.5].\n\nIn relation to UK secondary care, the committee reviewed expert testimony about people with chronic liver disease. This highlighted that these people are at high risk of flu-related morbidity and mortality but currently have the lowest rates of vaccination uptake in primary care; also that they may be more likely to have regular contact with specialist hospital clinics or other services (such as drug and alcohol services) [EP2]. The committee agreed this may also apply to other eligible groups, including those with chronic neurological or kidney disease, people who are immunocompromised due to a medical condition or ongoing treatment, and pregnant women attending hospital antenatal appointments. This offers opportunities to provide flu vaccination in secondary care to people who may otherwise not access vaccination through primary care. Existing hospital systems could be used to identify and prompt offers of vaccination to anyone attending a routine appointment during the flu season who remains unvaccinated. However, the committee were keen to underline that vaccination in secondary care needs to be done in line with local commissioning agreements. Also, arrangements should be in place to ensure that anyone who is opportunistically offered vaccination in secondary care can access it easily, because qualitative evidence suggests people are put off if they have to arrange a further appointment or go to another location to get the flu vaccine [Evidence review 3: Q-ES2.3].\n\nThe committee drew on evidence from qualitative studies with pregnant women highlighting the importance of a personalised invitation from a known professional involved with their antenatal care [Evidence review 3: Q-ES2.4]. They discounted evidence from a number of small, low-quality studies that found no difference in vaccination decision-making among pregnant women when messages about flu vaccination were framed either 'negatively' (in terms of risks of remaining unvaccinated) or 'positively' (in terms of the benefits both to mother and baby of protection against flu both during pregnancy and after birth). There was contradictory evidence from other qualitative studies suggesting that pregnant women respond more readily to offers of vaccination when the benefits to their baby are clearly communicated [Evidence review 3: Q-ES2.6]. The committee felt this corresponded with other evidence already outlined suggesting that parents of children in clinical risk groups respond well to personalised interventions encouraging vaccination of their children. Given that flu vaccination rates are currently very low in young children, particularly babies and infants with clinical risk factors that put them at highest risk from flu, the committee felt it is important that providers help parents make decisions about flu vaccination by not only outlining the potential risks of not vaccinating but also the benefits – appealing to the parental instinct to nurture and protect their child's health.\n\nThe committee reviewed evidence for provider prompts embedded in patient medical records as an intervention to increase uptake of flu vaccination. There were 8\xa0evidence statements relating to use of provider prompts – either as a single intervention or, more usually, combined with other approaches to increasing vaccination uptake [Evidence review 2: ES3.4. Evidence review 3: SR-ES3.4, SR‑ES3.7, SR-ES3.9, ES123.3, SR-ES123.1, SR-ES123.7, SR-ES123.9]. Seven of these statements reported an increase in vaccination uptake. This was clinically important (an increased uptake of 5% or more, compared with the control or pre‑intervention level), in 6\xa0of the 7\xa0evidence statements. The evidence was of variable quality with most rated of low or very low certainty. Reasons for downgrading included risk of bias (mostly observational studies), high levels of heterogeneity in pooled analyses and imprecision of effect estimates. The settings included primary and secondary care. Populations included children not in clinical risk groups [Evidence review 2: ES3.4], as well as adults and children with clinical risk factors and pregnant women [Evidence review 3: SR-ES3.4, SR-ES3.7; ES123.3; SR-ES123.1, SR-ES123.9]. One study suggested that timing of prompts may be important, with a greater increase in uptake when provider prompts were activated later in the flu season (January to February) compared with earlier (October to December).\n\nPrimary care is the main setting in which flu vaccinations are given in the UK. Most people who are eligible for free flu vaccination are already registered with a GP, so it is relatively easy to use the systems already in place in primary care to implement interventions to increase uptake, such as case-finding and using provider prompts. Sending reminders to eligible people that they are due or overdue (call/recall) their flu vaccination is a useful means of sustaining awareness across successive flu seasons. However, this needs contact information to be kept up to date in patient records.\n\nFace-to-face interactions are an opportunity to raise awareness and encourage uptake. However, some people who are eligible for flu vaccination may not be in regular contact with primary care and may remain unvaccinated, which is why the committee were keen to also include recommendations for increasing uptake in secondary care. Systems are in place to enable the identification of people receiving specialist treatment for health conditions that make them eligible for free flu vaccination so that the vaccine could be offered. However, vaccination needs to be available and easily accessible on‑site, and to be organised in line with local patient group directions or enhanced services arrangements that have been agreed with commissioners.\n\nEmbedding provider prompts in health records is likely to be a more consistent and efficient method of identifying eligible people and increasing offers of flu vaccination than opportunistic approaches to case-finding. It is relatively easy to implement because systems are already in place. For example, prompts for flu vaccination could be established through coding from previous hospital admissions or primary care records and automatically generated in electronic case records. However, a disadvantage of prompts is that they are often used for many aspects of healthcare delivery, and run the risk of practitioners getting 'prompt fatigue'.\n\nOne cost–utility study and 1\xa0cost-effectiveness study (both low quality) were included in the review of interventions for increasing vaccination uptake in clinical risk groups [Evidence review 3]. The studies suggest that opportunistically identifying, offering and administering flu vaccination may be cost effective. [Evidence review 3: CE-ES2.1, CE-ES2.2]. The evidence focused on pregnant women during routine practice visits and children from clinical risk groups in a hospital setting, but the committee agreed that the principle of increasing opportunities would be cost effective across all eligible populations and both primary and secondary care settings.\n\nThe recommendations support using existing primary care systems in a more structured and consistent way to send personalised reminders inviting eligible people to get vaccinated. This may need some training but would be relatively low cost overall.\n\nEconomic modelling for children and adults in eligible groups was conducted by adapting a dynamic model which was developed by Public Health England and was used to inform recommendations from the Joint Committee on Vaccinations and Immunisations. The model considers the entire population of England from Office for National Statistics (ONS) 2016\xa0data, stratified into age and risk groups. The age- and risk-stratified model uses a set of equations to model the interaction between groups and the transmission of flu. Baseline coverage, by age and risk group status, is informed by Public Health England's vaccine uptake guidance reports for winter 2015/16 seasons. Disease transmission parameters and flu vaccine efficacy are the same as those in the original Joint Committee on Vaccinations and Immunisations analysis.\n\nThe cost of a flu vaccine was calculated from the British National Formulary and Prescription Cost Analysis. For adults receiving an injection, the cost was £5.96. 90% of children were assumed to receive the nasal spray costing £18, and 10% to receive the injection.\n\nThe model includes flu vaccine side effects from injection and nasal spray, which have associated costs and QALY losses.\n\nPeople who contract flu have an increased mortality risk (modelled as a lifetime QALY loss, depending on their age), a QALY loss of 0.008 for flu-like illness, 0.00101 for acute respiratory infection and 0.018 for hospitalisation. Hospitalisation was associated with a cost of £1,029, from NHS reference costs. The expected number of GP consultations were calculated using the same data as the original Joint Committee on Vaccinations and Immunisations analysis, with an updated cost per consultation of £31 for surgery visit, or £98 for home visit from the Unit Costs of Health and Social Care.\n\nThe perspective of the model is NHS and personal social services, and the time horizon is 1\xa0year because each person must be vaccinated annually.\n\nThe model showed that increasing vaccination uptake in children decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations and hospitalisations, in both adults and children. At baseline, 13,067,472\xa0children are vaccinated. Increasing this by 10% to\xa013,973,271 averts 872,015\xa0cases of flu; 122\xa0deaths; 55,634\xa0GP consultations and 956\xa0hospitalisations. The cost for the additional number of vaccinations is £10,945,753 and flu vaccine side effects costs an additional £688,942. There are cost savings from reduced GP consultations (£1,985,574) and hospitalisations (£983,879), leading to a total cost to the NHS of £8,655,242. Flu vaccine side effects lead to an additional QALY loss of 33.34\xa0QALYs, but the reduction in flu cases avoids a QALY loss of\xa03,243. The incremental cost effectiveness ratio is therefore £2,645 per QALY. This is below £20,000 per QALY and therefore implies it would be cost effective to spend money to increase the uptake of the flu vaccination. Calculating the monetary net benefit, it would be cost effective to spend up to £5.50 per targeted child to increase uptake by 10%. Similar calculations find that it would be cost effective to spend up to £11.48 per targeted child to increase uptake by 25%. The maximum that an intervention could cost and be cost effective at £20,000 per QALY depends on the baseline coverage level. Interventions with a higher cost would be cost effective where uptake levels are lower.\n\nThe model showed that increasing vaccination uptake for adults in clinical risk groups, pregnant women and children in clinical risk groups decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations and hospitalisations, primarily within the group targeted. Increasing the number of vaccinations and flu vaccine side effects increased costs, but there were some cost offsets from avoiding cases of flu, hospitalisation and GP consultations. There were small QALY losses from the additional side effects, but large QALY gains from avoiding cases of flu and mortality. The net monetary benefit for increasing vaccination by 5% for adults in clinical risk groups is £4.00 per targeted person, for pregnant women is £4.50 per targeted person, and for children in clinical risks groups is £2.40 per targeted person. The maximum that an intervention could cost and be cost effective at £20,000 per QALY does not vary with baseline coverage.\n\nThe committee considered that opportunistic advice and identification, using existing systems to generate invitations and reminders, and embedding provider prompts embedded health records are effective interventions that could be delivered in primary and secondary care at a relatively low cost per targeted person. They believed that such interventions would help to achieve the necessary level of vaccination and are therefore likely to be cost effective.\n\nThe majority of the evidence was from non-UK settings, but the committee used expert testimony and their knowledge of the UK healthcare context to develop these recommendations. They concluded that encouraging the implementation of interventions in both primary and secondary care should result in increased identification, offer and delivery of flu vaccination to eligible people, as well as increasing the efficiency of these processes.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES3.1, ES3.2, ES3.3, ES3.4, ES123.2; Q-ES1.9\n\nEvidence review 3 on increasing flu vaccination uptake in people in clinical risk groups: ES3.2, ES3.3, ES3.4a; SR-ES3.1, SR-ES3.2, SR-ES3.3, SR-ES3.4, SR‑ES3.5, SR-ES3.7, SR-ES3.8, SR-ES3.9, SR-ES123.1, SR-ES123.3, SR-ES123.7, SR-ES123.9; ES123.3, ES123.5; Q-ES2.3, Q-ES2.4, Q-ES2.6; CE-ES2.1, CS‑ES2.2\n\nExpert testimony on increasing vaccination increasing uptake among people with chronic liver disease: Expert paper 2 (EP2)\n\nExpert testimony on increasing vaccination increasing uptake among people who are homeless or rough sleepers: Expert paper 3 (EP3)\n\nExpert testimony on increasing vaccination increasing uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)\n\n# Audit, monitoring and feedback\n\nThe discussion below explains how the committee made recommendations\xa01.5.1 to\xa01.5.8.\n\n## Rationale and impact\n\nProviders and employers need to know whether they are reaching their vaccination targets or whether they need to change the way they are delivering their flu vaccination programme to better protect their patients or vaccinate their staff. According to both evidence and expert testimony, audit, monitoring and feedback help providers and employers to plan for and offer flu vaccination to meet their targets, including for payment by results.\n\nThe committee also agreed that if different providers across the system are offering vaccination, it is important for services to share information with each other and keep accurate records of who has been vaccinated. This will ensure general practice uptake figures are accurate and avoid them wasting resources by inviting people for vaccination unnecessarily (leading to missed appointments) or duplicating vaccinations.\n\nThere is inconsistency among GP surgeries in how they record and use data to monitor their progress with flu vaccination during the season. To implement these recommendations some practices will need to improve their record-keeping using clinical software systems so they can monitor whether they are successfully targeting eligible people. Similarly, employers may need to improve their systems for recording and monitoring the vaccination status of staff, because some eligible health and social care staff may not be getting a free vaccination offer from their employer. This may be a particular issue in the social care sector, which has a large number of providers and currently no central requirement to submit data on the uptake of flu vaccination among front-line staff.\n\nMonitoring uptake among eligible groups when vaccination is provided outside general practices in settings that do not have direct access to information technology (IT), or where different IT systems are used, may be a challenge. Mechanisms for sharing information need careful planning and oversight to minimise data loss.\n\n## Evidence discussion\n\nUptake of flu vaccination by people in eligible groups, and its acceptability to them.\n\nQualitative evidence highlighted that providers need to feel that they can trust in the accuracy of computerised prompts and patient records, which should be maintained and updated in a consistent and timely fashion [Evidence review 2: Q-ES1.6]. The committee agreed that this is an important issue given the inclusion of recommendations in this guideline to extend vaccination provision to other settings to increase uptake, including schools (as part of the universal programme for vaccinating children), community pharmacies, secondary care and social care settings.\n\nThe committee reviewed very low- to moderate-quality evidence showing that audit and feedback interventions are associated with increases in flu vaccination when delivered individually or as part of a multicomponent strategy to increase uptake in clinical risk groups. The committee agreed there was some uncertainty in the size of effect because of study quality, or because it was difficult to be sure how much of the effect in multicomponent approaches was due specifically to audit, monitoring and feedback activities. However, the consistent direction of effect for the majority of patients enabled the committee to make recommendations.\n\nThe committee also heard expert testimony from a practice nurse [EP6] who leads on increasing uptake in a general practice and also supports flu vaccination campaigns across her region for the clinical commissioning group. She stated that using audit and monitoring enabled them to improve their targeting of particular clinical groups in which uptake was low. It also helped her to spot any other general practices in her region that may need advice or support.\n\nPublished evidence on audit and feedback and the impact of QOF on increasing uptake is mixed. One study showed that practice audits increased uptake in some clinical risk groups but not others [Evidence review 3: ES3.4b], although the committee agreed that the difference in impact between clinical risk groups may be due to relatively low numbers of post-splenectomy patients (in whom no significant effect was found) compared with other groups studied (coronary heart disease and diabetes).\n\nIn 2\xa0studies looking at the impact of QOF, 1\xa0showed that pay-for-performance targets increased flu vaccination rates in a target clinical risk group of people with coronary heart disease compared with control conditions of chronic obstructive pulmonary disease, diabetes and stroke [Evidence review 3: ES3.5]. The other showed that removing pay-for-performance targets (in a condition previously incentivised) did not result in the uptake rate decaying over the 8‑year study period, with uptake rate being maintained at over 75%, which is above the national target. In 2\xa0multicomponent studies that included audit and feedback, a cluster-randomised controlled trial indicated education plus audit increased vaccination in clinical risk groups [Evidence review 3: ES123.2]. This was supported by a retrospective cohort of 6\xa0years' repeated measures after the intervention showing provider feedback combined with education and nurse standing orders (PGD) increased and maintained uptake compared with baseline [Evidence review 3: SR-ES123.6]. The committee acknowledged the overall quality of the evidence was very low to moderate, but felt this was to be expected given the evidence is driven by the quality improvement cycle. They agreed that the consistency and in some cases durability of effect over time, in real-world circumstances, reduced any uncertainty resulting from study quality.\n\nExpert testimony on increasing uptake in healthcare workers also highlighted the importance of monitoring and feedback because it encouraged staff to accept the vaccination and helped to show senior managers that the campaign was working. Evidence on feedback as an intervention to increase uptake in health and social care staff is mixed. One study showed it was a component in a successful approach on hospital wards and in outpatient clinics to increase uptake [Evidence review 4: ES45.10]. However, this was not the case in a before-and-after study in which director-level feedback was a component in a multicomponent approach [Evidence review 4: ES45.9]. The committee considered the inconsistency in the evidence, including the small numbers in the study that showed no effect and the fact that uptake had been corroborated with lab-confirmed cases of flu in the other study. Based on this, along with the expert testimony, the committee considered feedback to be a key component that should be recommended as an important approach to support increasing uptake. Additionally, the recent introduction of a CQUIN to increase uptake meant that monitoring and using feedback to improve programmes was likely to become increasingly important to meet targets, and to show that these targets have been met.\n\nOverall, the committee agreed that healthcare records can be used effectively to identify and increase offers of flu vaccination to eligible groups. However, it is important that patient records are accurate and up to date to ensure all vaccinations are included in uptake data and that people are not inadvertently vaccinated more than once in a season. The committee confirmed that, although not in itself likely to be harmful to the person, over-vaccination will incur unnecessary costs and increase the burden of any associated short-term side effects such as pain, swelling or redness at the injection site.\n\nIf eligible people are vaccinated in settings other than their own GP surgery, poor information transfer may waste time and resources if practices invite and remind people unnecessarily, or booked flu clinic appointments go unused. Mechanisms for sharing information across providers need careful planning and oversight to minimise data loss.\n\nAudit, monitoring and feedback activities are useful for needs assessment, enabling a practice to determine where extra effort or resources may be needed to increase uptake among particular groups. Monitoring uptake will also help in planning activities as well as in ordering and maintaining stock; this will have a knock-on effect of reducing inefficiency by reducing potential waste and allowing effort to be focused on targeting the most needed groups.\n\nRecording why people decline vaccination helps to identify barriers and adapt interventions to address and overcome those issues in future activities or campaigns. However, this needs to be done accurately and consistently to support a better understanding of barriers to vaccination.\n\nPayments will offset the resource impact of campaigns to increase vaccination uptake in some organisations, such as GP surgeries, community pharmacies and NHS trusts. This may motivate organisations to increase uptake and encourage staff to succeed, which in turn may improve job satisfaction if incentive targets are reached.\n\nThe social care sector and some NHS organisations may be disadvantaged by a current lack of systems to collect flu vaccination data and by the lack of payment by results incentivisation to increase uptake among staff. Resource impact from implementing the recommendations may therefore be greater in the social care sector in particular.\n\nThe committee noted the results from the economic modelling. For children, interventions would be cost effective if they increased vaccination uptake from the current average at a cost of up to £3.00 per targeted person for an increase of at least 5%, £5.50 for 10% and £11.50 for 25%. Increasing uptake at lower coverage rates is more cost effective than at higher coverage rates (for the same intervention cost and increase in uptake). For the other populations, interventions were considered cost effective if:\n\nFor adults in clinical risk groups, they cost up to £4.00 per targeted person and increased vaccination uptake by at least 5%.\n\nFor pregnant women, they cost up to £4.50 per targeted person and increased vaccination uptake by at least 5%.\n\nFor children in clinical risk groups, they cost up to £2.40 per targeted person and increased vaccination uptake by at least 5%.\n\nFor health and social care staff, they cost up to £2.15 per targeted person and increased vaccination uptake by at least 5%.\n\nThe committee felt that the costs per targeted person of audit, monitoring and feedback were likely to be below the maximum intervention costs and achieve the necessary level of vaccination.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 2 on increasing flu vaccination uptake in children: ES3.4; Q‑ES1.6\n\nEvidence review 3 on increasing flu vaccination uptake in people in clinical risk groups: ES 3.4b, ES3.5, ES3.6, ES123.2, ES123.6\n\nEvidence review 4 on increasing flu vaccination uptake among health and social care staff: ES45.9, ES45.10\n\nExpert testimony on increasing vaccination uptake among healthcare staff: Expert paper 4 (EP4) and Expert paper 5 (EP5)\n\nExpert testimony on increasing vaccination uptake among children and people in clinical risk groups in primary care: Expert paper 6 (EP6)\n\n# Flu vaccination in carers\n\nThe discussion below explains how the committee made recommendations\xa01.6.1 and\xa01.6.2.\n\n## Rationale and impact\n\nIf a carer has flu, the welfare of the person they care for may be at risk. There was a lack of evidence on interventions specifically for carers, and health economic modelling showed that increasing uptake among all carers would not be cost effective. The committee agreed that efforts to increase vaccination uptake should target carers who look after people who are particularly vulnerable and who would be at risk of needing hospital or other care if their carer was unwell with flu. Primary care staff and healthcare professionals working in the community (for example district or specialist nurses or those working in rehabilitation) could be a useful route to identify and offer vaccination to this group, for example during a home visit, if appropriate local agreements were in place.\n\nIncreasing uptake of flu vaccination among eligible carers is not likely to involve a major change to current practice, but the key is for providers to prioritise those carers who look after someone whose health or wellbeing would be at risk if the carer fell ill with flu. This needs clinical judgement and may mean community nurses using home visits to identify and offer vaccination to these particular carers.\n\n## Evidence discussion\n\nUptake of flu vaccination by people in eligible groups, and its acceptability to them.\n\nThere was a lack of published effectiveness evidence relating to interventions to increase uptake among carers. Very-low-quality evidence from 1\xa0non‑UK observational study suggested that a recommendation from a respected person may positively affect carers' uptake of flu vaccination [Evidence review 1: ES1.1]. Other very-low-quality evidence from the UK suggested that extending access by offering vaccination services in community pharmacies does not increase uptake among carers, although they may be more likely than other eligible populations to opt to use pharmacies as a convenient out-of-hours alternative to GP vaccination services [Evidence review 1: ES2.1]. This was confirmed by expert testimony relating to carers [EP1].\n\nThe committee also noted issues raised by the expert relating to carer identification, because carer status is not routinely recorded in GP records and many informal carers do not recognise themselves as such. They agreed that community and primary care staff, such as community nurses, may be well placed to identify informal carers and assess their eligibility for flu vaccination – for example, during home visits to the person they are caring for. If a patient group direction or enhanced service arrangement has been agreed with local commissioners, nurses could offer vaccination to eligible carers. Alternatively, nurses could signpost carers to local primary care vaccination services, including any community pharmacies participating in the flu vaccination scheme.\n\nThe committee discussed at length evidence from economic modelling (outlined in more detail in the section below on cost effectiveness and resource use) and concluded that it is not cost effective to increase uptake of flu vaccination in all carers. It is important to target people who care for someone who may need to be admitted to hospital, or need alternative statutory care arrangements, if the carer falls ill with flu and is unable to look after them, or if risk of transmission for those who can't or won't be vaccinated is high, or for people for whom the flu vaccine is less efficacious, such as those who are immunocompromised.\n\nCarers are in close contact with people who are potentially at greater risk from flu. Carers have an important role; if they fall ill it can be detrimental to those they care for. In addition, they may pass the virus on to the person they care for. If the person being cared for has a weakened immune system they are still susceptible to the flu virus even if they have had the flu vaccine, because it works less well in this group. Increasing flu vaccination in carers can help sustain continuity of care and reduce the chances of onward transmission. However, the provider needs sufficient information to exercise clinical judgement on an individual carer's eligibility for flu vaccination, which should be based on the vulnerability of the person they look after.\n\nThe economic model for carers who are not in a clinical risk group uses a decision-tree structure. A proportion of carers are vaccinated, and the remainder are unvaccinated. At baseline, 37.4% are vaccinated (taken from Public Health Engand's influenza immunisation intervention for England for winter 2015/16). A proportion of vaccinated people experience side effects, which have associated costs and QALY losses.\n\nCosts are considered from the perspective of the NHS and personal social services.\n\nThe probability of getting the flu virus is higher for the unvaccinated population than the vaccinated population, so there are more cases of flu. A proportion of the cases of the flu virus are flu-like illness or acute respiratory illness, which are associated with QALY losses of 0.008 and 0.00101. A proportion of cases of each need hospitalisation (costing £1,029, from NHS reference costs, and losing 0.018\xa0QALYs) or a GP consultation (costing £31 for a surgery visit or £98 per home visit, from the Unit Costs of Health and Social Care). There is a mortality risk from flu, which has an associated QALY loss depending on the person's age.\n\nIf a carer gets flu, they may be unable to look after the person they care for. In most cases it is assumed that another family member or friend will temporarily provide care. However, the model assumes that in 1% of cases the person cared for would need emergency hospital admission, costing £4,995 (NHS reference costs) to the NHS.\n\nIf a carer gets flu, there is a risk that they may transmit flu to the person they care for. The model assumes that there are 0.19\xa0secondary cases for each case of flu, each costing £343, based on a cost for high-risk cases, and with an associated QALY loss.\n\nThe model showed that increasing vaccination uptake in carers decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations, hospitalisations and secondary cases of flu-like illness. At baseline, 219,295\xa0carers are vaccinated. Increasing this by 10% to\xa0277,930 averts 6,755\xa0cases of flu; 293\xa0GP consultations; 55\xa0hospitalisations and 207\xa0secondary cases of flu-like illness. The cost for the additional number of vaccinations is £924,305 and flu vaccine side effects cost an additional £36,354. There are cost savings from reduced GP consultations (£10,470); hospitalisations (£56,663); and secondary cases (£71,132) and replacement care (£77,602), leading to a total cost to the NHS of £744,792. Flu vaccine side effects lead to an additional QALY loss of 2\xa0QALYs, but the reduction in flu cases avoids a QALY loss of\xa013. The incremental cost-effectiveness ratio from the NHS and personal social services perspective is therefore £57,547/QALY. This is above £20,000 per QALY and therefore it is not cost effective to increase the uptake of vaccination in carers. Sensitivity analysis was undertaken to determine whether changing 1\xa0of the inputs could make it cost effective to increase the uptake of vaccination in carers. This found that if the proportion needing emergency care when their carer has flu increases, or the cost of that emergency care increases, increasing the uptake of vaccination in carers could be cost effective. In the base case the average cost of care was £50 (1% of £4,995). If this is increased to £500 (for example 1% of £50,000 or 10% of £4,995), increasing the uptake of flu vaccination could be cost effective. The committee considered that there may be people at increased risk of needing expensive emergency care if their carer gets flu. In these cases, it is cost effective to increase the uptake of flu vaccination. Therefore the committee recommended that flu vaccination should be offered to carers who care for someone who is immunocompromised, disabled or vulnerable.\n\nFor carers, increasing the uptake of flu vaccination was not cost effective at £20,000 per QALY, even when onward transmission was considered. It could only be cost effective if there were potentially substantial costs associated with a carer getting flu, for example, if the person they care for needed expensive emergency care in their carer's absence.\n\nThe committee were of the opinion that there are various opportunities to identify carers and that these would not need significant resources because the systems were mostly in place but should be used more effectively. The only potential cost or resource implication identified was education and training to use or adapt existing systems to identify carers, and the subsequent resources associated with the increases in education of carers, and offers and delivery of vaccination.\n\nEvidence for mandatory vaccination as part of a multicomponent intervention demonstrated some effect in care home settings and with care workers but the studies did not clarify whether this was relevant to unpaid carers in the UK context. The committee did not make recommendations about mandatory vaccination. They considered the limited published evidence in conjunction with the health economic modelling, expert testimony and their own experiences. They concluded that mandatory flu vaccination of carers – even in situations in which it is likely to be cost effective − should not be recommended, for ethical reasons. Unpaid carers provide a valuable service on a voluntary basis and the committee considered it unethical to undermine this by enforcing mandatory vaccination. Qualitative studies of mandatory flu vaccination schemes in paid health and social care employees report a negative impact on morale, leaving people feeling disempowered, lacking autonomy and resentful [Evidence review 4: Q-ES3.8, Q-ES3.9]. The committee agreed that it was preferable to encourage vaccination among eligible carers by promoting it as a way of protecting the vulnerable person they care for.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 1 on increasing flu vaccination uptake in carers: ES1.1, ES2.1\n\nEvidence review 4 on increasing flu vaccination uptake in health and social care staff: Q-ES3.8, Q-ES3.9\n\nExpert testimony on increasing flu vaccination in carers: Expert paper 1 (EP1)\n\n# Employers of health and social care staff\n\nThe discussion below explains how the committee made recommendations\xa01.7.1 to\xa01.7.8.\n\n## Rationale and impact\n\nHealth and social care staff are in daily contact with people who are susceptible to infection, and they could transmit flu to vulnerable people at risk of serious complications. Staff may not know they are eligible for a free vaccination through occupational health, or may not realise it may help protect their patients, family and co‑workers. Evidence suggests that actions to encourage staff to be vaccinated do work. Programmes involving a combination of actions, such as awareness raising, education and flexible services were effective and acceptable. Although the evidence was uncertain in some cases, the committee recommended a range of interventions so that organisations can tailor their approach to local needs, targeting demand (by increasing awareness, education and incentives) and supply (for example using mobile vaccination carts and off-site or out-of-hours access).\n\nImplementing the recommendations will have a bigger impact in some organisations than others. Current variation in practice is partly because different incentives operate across the health and social care sectors. It may also be easier to provide vaccination for staff in some organisations than others. For example, a GP surgery already has access to flu vaccine supply and the skills to deliver the vaccination to staff. A social care provider may need to contract an occupational healthcare provider to carry out vaccination, or set up a scheme to help employees access community pharmacy flu vaccination.\n\n## Evidence discussion\n\nUptake of flu vaccination by health and social care staff, and its acceptability to them.\n\nThe quantitative evidence relating to interventions to increase flu vaccination uptake among health and social care staff was of variable quality, with most rated low or very low. Downgrading was largely due to risk of bias and imprecision of effect estimates. In pooled analyses there was evidence of serious or very serious heterogeneity, which the committee agreed would be expected given the differences between study populations in the types of staff and the lack of standardisation of interventions and comparators across studies. The majority of studies were conducted outside the UK and covered a range of health and social care settings.\n\nThe committee noted that most studies included in the review examined combinations of interventions or their additive effects rather than a single approach, with staff education or awareness raising, and the provision of more flexible access (including off‑site or out-of-hours access) forming almost universal components. There was a clinically important increase in vaccination uptake (of 5% or more compared with the control or pre-intervention rate) in 19\xa0out of 20\xa0evidence statements in which a multicomponent approach was evaluated [Evidence review\xa04: ES45.1, ES45.2, ES45.3, ES45.4, ES45.5, ES45.6, ES 45.7, ES45.8, ES45.9, ES45.10, ES45.11; SR-ES45.1, SR-ES45.2, SR-ES45.3, SR-ES45.4, SR-ES45.5, SR-ES45.6, SR-ES45.7, SR-ES45.8].\n\nThere was conflicting evidence from subgroup analyses on the effect of interventions among staff with direct or indirect patient contact [Evidence review 4: SR-ES4.6, SR-ES45.7; ES45.7; SR-ES45.8], with different professional roles [Evidence review 4: ES45.7], or working in different care settings [Evidence review 4: SR-ES4.5]. The committee noted that the Green Book recommends vaccination of all health and social care staff who have direct involvement with patient or client care, and that responsibility for providing occupational flu vaccination rests with employers.\n\nThere was evidence that mandatory vaccination (with or without mask-wearing policies for those declining a flu vaccine) is the most effective lever of uptake among health and social care staff [Evidence review 4: ES4.6, ES4.7; SR-ES4.7, SR-ES4.8]. However, the committee expressed concerns about the challenges that mandatory vaccination of staff would have, including qualitative evidence indicating that such policies can negatively affect staff morale and undermine autonomy [Evidence review 4: Q-ES3.8, Q-ES3.9].\n\nThe committee acknowledged the concerns of policy makers and senior managers to reduce staff absenteeism. They believed that these concerns can be met by evidence that non-mandatory multicomponent interventions are also effective. This in turn will reduce transmission of flu in health and social care premises. This was confirmed by a study that found a significant decrease in the proportion of laboratory-confirmed flu cases among health and social care staff after implementation of a multicomponent vaccination programme [Evidence review 4: ES45.10].\n\nVery low‑ to low-quality evidence indicated that declination policies were an effective approach [Evidence review 4: SR-ES4.4, SR-ES4.8, SR-ES 45.5, SR-ES 45.8; ES45.3, ES45.4, ES45.5, ES45.6, ES45.11]. A declination policy requires employees to submit a mandatory written statement stating that they have refused an offer of flu vaccination and citing their reasons why. A systematic review and meta-regression found that declination policies had an independent effect on flu vaccination uptake that was greater, on the whole, than all other types of intervention except mandatory vaccination [Evidence review 4: SR-ES 4.8]. Although the quality of the evidence was limited, the quantity and overall consistency of effect suggested that declination policies could work well. However, qualitative evidence indicated that employees have mixed feelings about declination policies, and stakeholder consultation on the draft version of this guideline revealed some resistance to the idea. The committee reconsidered the evidence in light of stakeholder feedback, noting that the studies included in the meta-regression analysis evaluating declination statements were all conducted in a US or Japanese setting, where organisational culture and employment relations are likely to differ markedly from the UK.\n\nThe committee also reconsidered evidence from a randomised controlled trial comparing an 'opt‑in' with an 'opt‑out' flu vaccination strategy for healthcare workers, conducted in 1\xa0tertiary care provider in the Netherlands [Evidence review 4: ES4.8]. Participants in the opt‑out group were emailed with a pre-scheduled appointment for flu vaccination, which could be changed or cancelled by following a web link. In the opt‑in condition, participants received an email explaining that they had to book an appointment if they wanted to get vaccinated. The investigators failed to detect a statistically significant effect of either strategy on vaccination uptake, but because there were only 61\xa0participants in each group it is likely the study was underpowered to detect a significant difference. However, healthcare workers in the opt‑out group were more likely than those in the opt‑in group to have an appointment for flu vaccination, which in turn increased the probability of them getting vaccinated (RR\xa01.70; 95% CI 0.85 to\xa03.41).\n\nThe committee concluded that an opt‑out strategy better respects individuals' autonomy, specifically the right to choose whether or not to accept a medical intervention, and may therefore be considered more acceptable than a declination policy for encouraging flu vaccination among front-line health and social care staff. The committee discussed the importance of involving staff representatives in developing a flu vaccination policy to minimise any negative impact on morale. The committee also agreed that it would not be appropriate to ask employees in an identifiable way to state their reasons for opting out of voluntary flu vaccination. However, it would usefully inform future flu vaccination campaigns if organisations could survey staff anonymously about their vaccination decision-making.\n\nExpert testimony on increasing uptake in healthcare workers [EP4, EP5] further supported the approaches recommended by the committee based on the evidence. The experts considered audit and monitoring systems to be particularly important to help them plan their activities effectively and understand how they were progressing and whether changes were needed. The experts also stated that a multicomponent approach was important to ensure they were targeting the breadth of the workforce, because different members might be reached more effectively by different approaches. They indicated that assigning a lead and flu champions, involving media and other publicity activities along with keeping staff abreast of progress via feedback were all useful and important aspects. The experts also noted that staff incentives proved popular. Another key factor was to ensure that access to vaccination was carefully considered. One expert described taking the vaccination service to eligible staff as a useful strategy. Using mobile vaccination carts and making them available in high footfall areas such as the staff canteen, and around shift switchover times on wards, all made it more convenient for eligible staff to take up the offer of vaccination [EP5]. This testimony aligned with the qualitative and quantitative evidence considered by the committee. The committee highlighted that the recently introduced CQUIN would act as a significant lever for increasing vaccination rates among hospital-based staff for the foreseeable future.\n\nThe committee acknowledged that although the recommendation outlines a selection of interventions, it is difficult to specify what configuration would maximise any effect. They were satisfied that the recommendations outline an effective approach that can be tailored to local needs.\n\nIncreasing vaccination uptake in health and social care staff will reduce the risk of transmission and offer protection to those they come into contact with who may be more susceptible to infection. It also has the potential to reduce sickness absence and increase the continuity of care that they provide.\n\nRaising awareness in healthcare staff about eligibility for flu vaccination and its efficacy should increase the identification of eligible groups and their subsequent vaccination, thus reducing transmission and associated mortality and morbidity.\n\nThe committee has not made recommendations about mandatory flu vaccination policies. They have recommended the adoption of a full participation vaccination strategy, with nationally agreed opt‑out criteria. Nationally agreed opt‑out criteria are needed to ensure consistency of approach. The committee believes they should be developed with the involvement of staff representatives. A full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.\n\nAn opt‑out strategy is potentially more acceptable for employment relations. But it offers less opportunity than a declination policy to engage with health and social care staff who decline vaccination in order to target support and education to overcome barriers, such as needle phobia, or misinformation about the flu vaccine's safety and effectiveness.\n\nThe economic model for health and social care staff uses a decision-tree structure. A proportion of health and social care staff are vaccinated, and the remainder are unvaccinated. At baseline, 50.6% are vaccinated, taken from a Public Health England survey of the seasonal flu vaccine uptake among front-line health and social care workers 2015/16. A proportion of vaccinated people experience side effects, which have associated costs and QALY losses.\n\nCosts are considered from the perspective of the NHS and personal social services. The time horizon is 1\xa0year.\n\nThe probability of getting the flu virus is higher for the unvaccinated population than the vaccinated population, so there are more cases of flu. A proportion of the cases of the flu virus are flu-like illness or acute respiratory illness, which are associated with QALY losses of 0.008 and 0.00101. A proportion of cases of each need hospitalisation (costing £1,029, from NHS reference costs, and losing 0.018\xa0QALYs) or a GP consultation (costing £31 for a surgery visit or £98 per home visit, from the Unit Costs of Health and Social Care). There is a mortality risk from flu, which has an associated QALY loss depending on the person's age.\n\nIf a health and social care worker gets flu, they may not be working. There will therefore be a cost to their employer of providing replacement staff. The average absence from work for a case of flu is 2.5\xa0days from Public Health England's Flu Survey, and health and social care staff are assumed to work 7.5\xa0hours per day, at an average cost of £26 per hour from Unit Costs of Health and Social Care.\n\nIf a health and social care worker gets flu, there is a risk that they may transmit flu to the people they care for. The model assumes that there are 0.7\xa0secondary cases for each case of flu, each costing £289, based on a cost for high-risk cases, and with an associated QALY loss.\n\nThe model showed that increasing vaccination uptake in health and social care staff decreased the number of cases of flu, flu-like illness, acute respiratory infection, deaths, GP consultations, hospitalisations and secondary cases of flu-like illness. At baseline, 1,081,577\xa0health and social care staff are vaccinated. Increasing this by 10% to 1,295,327 averts 24,624\xa0cases of flu, 1,069\xa0GP consultations, 201\xa0hospitalisations and 16,920\xa0secondary cases of flu-like illness. The cost for the additional number of vaccinations is £552,230, and flu vaccine side effects cost an additional £132,525. There are cost savings from reduced GP consultations (£38,166), hospitalisations (£206,560), secondary cases (£4,895,560) and replacement staff (£1,208,470) – leading to a total cost saving to the NHS of £5,664,002. Flu vaccine side effects lead to a loss of 6\xa0QALYs, but the reduction in flu cases avoids a QALY loss of 171.5. Increasing the uptake of flu vaccination saves money and improves outcomes, and thus is 'dominant'. This is cost effective at £20,000 per QALY, and the net monetary benefit demonstrates that an intervention would be cost effective if it cost up to £4.30 per targeted person to increase uptake of the flu vaccination by 10%.\n\nConsidering only the costs of vaccination and the costs of replacement staff, increasing the uptake of flu vaccination is cost saving. Therefore it is cost saving for non-NHS employers to vaccinate health and social care staff. The committee felt that a range of interventions could be delivered by employers of health and social care staff at a sufficiently low cost to be cost effective.\n\nIncreasing access to vaccination on and off site may incur initial set‑up costs, which could include the need for additional employees and facilities. The committee were of the opinion that despite these initial costs, the benefits of reducing transmission and protecting health and social care staff from flu infection (with a potential reduction in sickness absence) outweigh these costs. Once the various systems and interventions to facilitate access have been established these services will be cost saving in the medium to longer term.\n\nExpert testimony [EP5] from a trust where large-scale changes have occurred over a number of years indicated that although the initial investment (resource impact) was quite high, it became considerably less intensive while maintaining and further increasing uptake, as it became part of the embedded culture.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 4 on increasing flu vaccination uptake in health and social care staff: ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.7, ES4.8, ES45.1, ES45.2, ES45.3, ES45.4, ES45.5, ES45.6, ES45.7, ES45.8, ES45.9, ES45.10, ES45.11; SR-ES4.1, SR-ES4.2, SR-ES4.3, SR-ES4.4, SR-ES4.5, SR-ES4.6, SR-ES4.7, SR-ES4.8, SR-ES5.1, SR-ES45.1, SR-ES45.2, SR-ES45.3, SR-ES45.4, SR-ES45.5, SR-ES45.6, SR-ES45.7, SR-ES45.8, SR-ES45.9; Q-ES3.1, Q-ES3.2, Q-ES3.3, Q-ES3.4, Q-ES3.5, Q-ES3.6, Q-ES3.7, Q-ES3.8, Q-ES3.9, Q-ES3.10\n\nExpert testimony on increasing vaccination uptake among healthcare workers: Expert paper 4 (EP4) and Expert paper 5 (EP5)\n\n# Gaps in the evidence\n\nThe committee's assessment of the evidence on increasing uptake of flu vaccination identified a number of gaps. These gaps are set out below.\n\n. Effective and cost-effective interventions for increasing flu vaccination uptake in carers.\n\n(Source: Evidence review 1)\n\n. Effectiveness and cost effectiveness of different configurations of multicomponent interventions in different eligible populations and across settings:\n\na) Differential impact by intensity.\n\nb) Differential impact by who delivers the interventions.\n\nc) Differential impact by where the intervention is started or delivered.\n\n(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review\xa04)\n\n. Effectiveness and cost effectiveness of electronic and online approaches to increasing flu vaccination uptake.\n\n(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review\xa04)\n\n. Evidence of what is effective and cost effective in increasing flu vaccination uptake in underserved groups who would be eligible for flu vaccination.\n\na) What is the effectiveness of recommended interventions in underserved groups?\n\nb) What is the cost effectiveness of recommended interventions in underserved groups?\n\n(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review\xa04)\n\n. Barriers and facilitators to mandatory flu vaccination in UK settings.\n\n(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review\xa04)\n\n. Cost-effectiveness evidence on recommended interventions.\n\na) Evidence from the peer-reviewed literature on the cost effectiveness of recommended interventions.\n\n(Source: Evidence review 1; Evidence review 2; Evidence review 3; Evidence review\xa04)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# People in eligible groups\n\nWhat are the important messages and how should they be tailored and delivered to encourage and sustain flu vaccination uptake in eligible groups?\n\n## Why this is important\n\nThere is limited qualitative, effectiveness and cost-effectiveness evidence about what is effective in increasing flu vaccination in most eligible groups. In particular, we need to know how to tailor and deliver messages, for example, to minority ethnic communities, who may have lower vaccination uptake and also be disproportionately affected by some chronic conditions that put them at greater clinical risk from flu. A key to this is understanding how to engage people, including children and young people, and how they want to be involved in decision-making. This might include carers and other decision-makers. Interventions may need to be specifically targeted for different groups, so there is a need to understand individual and cultural health beliefs underpinning decisions about vaccination. Evidence indicates that beliefs about flu vaccination (such as effectiveness and side effects) are a persistent barrier. Understanding the key messages and the best format to deliver them in (for example, using social media or other forms of electronic communication) to reach different groups will help to overcome these barriers. This will increase the precision with which commissioners and intervention developers can engage eligible groups and increase rates of flu vaccination.\n\n# Underserved groups\n\nWhat are the most effective and cost-effective ways of reaching underserved groups and removing barriers to access in order to increase their uptake of flu vaccination?\n\n## Why this is important\n\nThe evidence reviewed did not provide specific details about the needs of people in underserved groups. Particularly important are those people who may be disproportionately affected by chronic conditions that increase their risk of complications from flu and who may have unique barriers to accessing flu vaccination (for example, they may have an undiagnosed clinical condition and not recognise that they are eligible for free flu vaccination, or they may not be registered with a general practice). They may also be difficult to identify. Research is needed into the specific needs, barriers and facilitators of eligible people in underserved groups. This should include how and what is effective in improving access, raising awareness, and offering and delivering vaccination. This will enable commissioners and those with responsibility for flu vaccination delivery to develop interventions to reach these groups.\n\n# Carers\n\nIn what context is it cost effective to increase uptake of flu vaccination among carers?\n\n## Why this is important\n\nThere is a lack of peer-reviewed evidence on what is effective and cost effective in increasing flu vaccination in carers. This key target group can be difficult to identify, and people who provide care may not always identify themselves as carers. The limited evidence suggests it is not cost effective to increase uptake of vaccination in all carers. Better understanding is needed about the effect of increasing vaccination in carers on rates of flu transmission, and the wider social and economic benefits to the health and social care system. Research is needed on the need for targeting, how this should be done and which cared-for groups are most important. Evidence about the effect on uptake of increasing the identification and offer of vaccination to carers through opportunistic engagement in all settings would enable more specific recommendations to be made. It would also allow further assessment of the economic benefits. Evidence about why a carer would choose not to be vaccinated will also improve understanding and inform recommendations and intervention development.\n\n# Opt-out strategies for front-line health and social care staff\n\nAre opt-out strategies effective and cost effective at increasing uptake of flu vaccination among front-line health and social care staff?\n\n## Why this is important\n\nThe evidence indicated that mandatory flu vaccination and the use of declination policies, either as a single intervention or part of a multicomponent approach, had a large and consistent effect in increasing vaccination uptake among health and social care staff in non-UK settings. However there are potential barriers to this in the UK; in particular, the possible negative impact on employee morale, which has also been seen in qualitative studies from other countries. The committee felt that similar increases in flu vaccination may be achievable using an opt‑out strategy. But to clarify the potential of this intervention, empirical evidence is needed on whether it is more effective and cost effective than other successful approaches for promoting uptake of flu vaccination among front-line health and social care staff in different UK settings, and what barriers and facilitators there are to its implementation from the perspective of providers and recipients; in particular, attitudes to the feasibility and acceptability of an 'opt‑out' flu vaccination strategy.\n\n# Community-based models of flu vaccination\n\nWhat models of community-based flu vaccination provision (for example, community pharmacies, community nursing and midwifery teams and outreach services) are effective and cost-effective for increasing uptake in eligible groups?\n\n## Why this is important\n\nThere is high variability across England in rates of flu vaccination uptake in eligible groups. Little is known about the effectiveness and cost effectiveness of extending community-based provision to include, for example, community pharmacies, community nursing and midwifery teams and outreach services into a variety of settings. Expert testimony suggested that community outreach interventions are effective for underserved groups such as people who are homeless, but empirical evidence for the effectiveness and cost effectiveness of such interventions is lacking. Limited evidence to date suggests that community pharmacy provision of NHS flu vaccinations has displaced rather than increased overall vaccination activity, because community pharmacies may be more convenient for some people in eligible groups. As new services become better publicised and embedded, there is a need to know if they are good value for money and whether (and why) they increase uptake. More research is needed on alternative models of community-based provision to inform future interventions and recommendations, particularly if it reaches groups who are currently underserved, and who may not use traditional routes such as GP services.", 'Glossary': "For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.\n\n# Brief intervention\n\nA brief intervention involves oral discussion, negotiation or encouragement, with or without written or other support or follow-up. It may also involve a referral for further interventions, directing people to other options, or more intensive support. Brief interventions can be delivered by anyone who is trained in the necessary skills and knowledge. These interventions are often carried out when the opportunity arises, typically taking no more than a few minutes for basic advice.\n\n# Care home\n\nThis covers 24‑hour accommodation with either non-nursing care (for example, a residential home) or nursing care.\n\n# Carer's assessment\n\nPeople who care informally on an unpaid basis for a family member or friend have the right to discuss with their local council what their own needs are, separate to the needs of the person they care for. The assessment covers anything the carer thinks would help them with their own health or with managing other aspects of their life. The council will use the information to decide what help it can offer.\n\n# Full participation vaccination strategy\n\nA full participation strategy is one in which a range of approaches are used to maximise uptake and in which the expectation is that all front-line staff should be vaccinated. The full participation approach includes agreed mechanisms enabling staff to opt out if they wish.\n\n# Primary care\n\nThe day-to-day healthcare given by a healthcare provider. Typically this provider acts as the first contact and principal point of continuing care for patients within a healthcare system, and coordinates other specialist care that the patient may need. In the UK, people access primary care services through local general practice, community pharmacy, optometrist, dental surgery and community hearing care providers.\n\n# Secondary care\n\nSecondary care is often acute healthcare (elective care or emergency care) provided by medical specialists in a hospital or other secondary care setting. Patients are usually referred by a primary care professional such as a GP."}
|
https://www.nice.org.uk/guidance/ng103
|
This guideline covers how to increase uptake of the free flu vaccination among people who are eligible. It describes ways to increase awareness and how to use all opportunities in primary and secondary care to identify people who should be encouraged to have the vaccination.
|
4e0af226287e769bcd74a6bb29fa5fb642d70c70
|
nice
|
Dinutuximab beta for treating neuroblastoma
|
Dinutuximab beta for treating neuroblastoma
Evidence-based recommendations on dinutuximab beta (Qarziba) for high-risk neuroblastoma in people aged 12 months and over.
# Recommendations
Dinutuximab beta is recommended as an option for treating high-risk neuroblastoma in people aged 12 months and over whose disease has at least partially responded to induction chemotherapy, followed by myeloablative therapy and stem cell transplant, only if:
they have not already had anti-GD2 immunotherapy and
the company provides dinutuximab beta according to the commercial arrangement.
This recommendation is not intended to affect treatment with dinutuximab beta that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For a child or young person, this decision should be made jointly by them or their parents or carers and their clinician.
Why the committee made these recommendations
Neuroblastoma mainly affects children and young people. Treatments for high-risk neuroblastoma include chemotherapy, radiotherapy, stem cell transplant, surgery and isotretinoin. Dinutuximab beta is an important, potentially curative option for maintenance treatment of the disease.
An indirect comparison with isotretinoin suggests that dinutuximab beta increases survival and the length of time before the disease progresses, compared with current treatment.
Dinutuximab beta does not meet NICE's criteria for a life-extending treatment at the end of life. Also, the range of cost-effectiveness estimates presented is higher than what NICE usually considers a cost-effective use of NHS resources. But taking into account the uncaptured health-related benefits, the rarity and severity of the disease and the potential lifetime benefit for children with neuroblastoma, dinutuximab beta can be recommended for high-risk neuroblastoma.
Dinutuximab beta also has a marketing authorisation to treat relapsed or refractory disease. This indication was not considered in this appraisal because it is not relevant to current NHS practice; most people with relapsed or refractory disease have already had dinutuximab beta.# Information about dinutuximab beta
Marketing authorisation indication
Dinutuximab beta (Qarziba, EUSA Pharma) has a marketing authorisation 'for the treatment of high-risk neuroblastoma in patients aged 12 months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with a history of relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures.
In patients with a history of relapsed or refractory disease and in patients who have not achieved a complete response after first line therapy, dinutuximab beta should be combined with interleukin-2 (IL-2).'
The marketing authorisation was granted under 'exceptional circumstances'. This happens when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the drug for which authorisation is being sought, because of the rarity of the condition it is intended for, limited scientific knowledge in the area concerned, or ethical considerations involved in the collection of such data.
Dosage in the marketing authorisation
There are 2 modes of administration:
continuous intravenous infusion over the first 10 days of each course at a daily dose of 10 mg/m2 or
daily infusions of 20 mg/m2 administered over 8 hours, on the first 5 days of each course.
When IL-2 is combined with dinutuximab beta, it should be administered as subcutaneous injections of 6×106 IU/m2/day, for 2 periods of 5 consecutive days, resulting in an overall dose of 60×106 IU/m2 per course. The first 5-day course should start 7 days before the first infusion of dinutuximab beta and the second 5-day course should start at the same time as dinutuximab beta infusion (days 1 to 5 of each dinutuximab beta course).
The individual dose is determined based on the body surface area and should be a total of 100 mg/m2 per course.
Based on the severity of adverse drug reactions to dinutuximab beta, patients may have a dose reduction of 50% or a temporary interruption of the infusion. As a result, either the infusion period is prolonged or, if tolerated, the infusion rate may be increased up to 3 ml/hour (continuous infusion), in order to administer the total dose.
Price
The dinutuximab beta list price is £7,610 per vial (excluding VAT; company submission).
The average cost of a course of treatment (body surface area of 0.63 m2 and age 3) is £152,200.
The company has a commercial arrangement. This makes dinutuximab beta available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by EUSA Pharma and a review of this submission by the evidence review group (ERG). It also considered additional company analyses and a review of these by the NICE decision support unit (DSU). See the committee papers for full details of the evidence.
# The condition
## Dinutuximab beta is an important potential option for high-risk and relapsed or refractory neuroblastoma
Neuroblastoma mainly affects children and young people. The patient experts stated that high-risk and relapsed or refractory neuroblastoma has a significant effect on children and young people and their families and carers. Children and young people with the condition have anxiety about their illness and treatment as well as discomfort and pain from the disease. The existing treatments and procedures for neuroblastoma are painful and debilitating, with severe and long-lasting side effects (including hearing loss, organ dysfunction, sterility, lack of growth, early onset of puberty, permanent disability, and secondary malignancies). The clinical and patient experts stated that a child's death has a significant effect on family members. The committee noted that treatment can involve many hospital visits and stays causing disruption to school, work and family life. It understood that parents and carers also have anxiety, emotional distress and disruption to their working life and income as well as strain on their relationships. The committee recognised that high-risk and relapsed or refractory neuroblastoma places a significant burden on patients, their families and carers. It concluded that new, effective treatment options would be welcomed.
# Current treatments
## Isotretinoin is the relevant comparator for decision-making for the maintenance treatment of high-risk neuroblastoma
The clinical and patient experts explained that the main aim of treatment is to extend event-free survival, but that ultimately a cure is needed. The committee acknowledged that since 2009 almost all patients with high-risk neuroblastoma in England, whose disease has at least partially responded to induction chemotherapy followed by myeloablative therapy and stem cell transplant, were enrolled in the immunotherapy phase of the HR-NBL-1 trial (APN311-302; comparing dinutuximab beta plus isotretinoin with dinutuximab beta plus isotretinoin plus interleukin-2). The committee agreed that dinutuximab beta cannot be considered established NHS practice because it has only been used in research as part of a clinical trial and is not routinely commissioned. The committee understood that before dinutuximab beta was available in the trial, maintenance therapy with isotretinoin was considered standard care in the NHS for high-risk neuroblastoma. It concluded that isotretinoin is the relevant comparator for the maintenance treatment of high-risk neuroblastoma that has at least partially responded to induction chemotherapy, followed by myeloablative therapy and stem cell transplant.
## Most patients with relapsed or refractory neuroblastoma have already had dinutuximab beta in the clinical trial
The clinical experts explained that there is no defined treatment pathway for relapsed or refractory neuroblastoma, but treatment is usually chemotherapy, radiotherapy and surgery. They also explained that patients with relapsed or refractory neuroblastoma have a poor long-term prognosis, especially if they have relapsed after treatment for high-risk disease. The clinical experts explained that since 2009 in England almost all patients with relapsed or refractory neuroblastoma have had first-line maintenance treatment with dinutuximab beta in the APN311-302 trial (see section 3.2). A small number of patients with relapsed or refractory neuroblastoma may not have already had dinutuximab beta if they were initially diagnosed as having low or intermediate-risk disease. However, if their disease relapsed or became refractory to treatment, these patients would be considered as having high-risk neuroblastoma. The committee concluded that almost all patients with relapsed or refractory neuroblastoma in clinical practice have already had dinutuximab beta in APN311-302.
# Clinical trial evidence
## APN311-302 is the best available evidence, but does not address dinutuximab beta's relative effectiveness compared with isotretinoin
The clinical evidence for the population with high-risk neuroblastoma came from APN311-302, an open-label phase 3 trial comparing dinutuximab beta plus isotretinoin (n=189) with dinutuximab beta plus isotretinoin plus interleukin-2 (n=190). The primary outcome in the trial was event-free survival at 3 years, with overall survival, overall response, incidence of relapsed or refractory disease and safety as secondary outcomes. The committee acknowledged that 55.4% of people randomised to dinutuximab beta and isotretinoin without interleukin-2 had not had an event at 3 years compared with 61.2% in the group having interleukin-2. This difference was not statistically significant (p=0.3202). For overall survival, 64.1% of people randomised to dinutuximab beta and isotretinoin without interleukin-2 were still alive at 3 years compared with 69.1% in the group having interleukin-2. This difference was not statistically significant (p=0.6114). The committee noted that median event-free and overall survival could not be estimated for either group because the data were immature. The ERG stated that no formal primary cut-off date for the analysis or time period for follow-up was specified for APN311-302. It also noted that because the trial was open label there could be performance bias in the assessment of event-free survival and overall response, but this was unlikely to affect overall survival. The committee acknowledged that the trial results showed that concomitant interleukin-2 did not improve event-free or overall survival, and that despite its limitations, APN311-302 was the best available evidence for dinutuximab beta. The committee concluded that because all patients in the trial had dinutuximab beta, the evidence did not inform the decision problem on the relative effectiveness of dinutuximab beta compared with isotretinoin.
## The clinical effectiveness evidence for the population with relapsed or refractory disease is not relevant to NHS clinical practice
The evidence for this population came from 2 observational studies of dinutuximab beta with isotretinoin and interleukin-2 in patients with relapsed or refractory disease after initial therapy: APN311-202 and APN311-303. The clinical experts explained that people in the NHS with high-risk neuroblastoma who have relapsed disease are likely to have had dinutuximab beta as part of their first-line maintenance therapy in the clinical trial (see section 3.3). The committee noted that none of the patients in APN311-202 and APN311-303 had already had dinutuximab beta. The company explained that it did not support retreatment with dinutuximab beta in the relapsed or refractory population. The clinical experts also explained that the small number of people with low or intermediate-risk disease who may not have already had dinutuximab beta would be considered as having high-risk neuroblastoma if the disease relapsed or became refractory to treatment (and in line with the recommendations in section 1.1 would be eligible for treatment). The committee recognised that the marketing authorisation included patients with relapsed or refractory disease, which could include a very small number of people with low or intermediate-risk disease that has relapsed but is not then considered high-risk. However, it had not seen any evidence for this small subgroup because the evidence for the relapsed and refractory population was not presented by category of initial risk. The committee agreed that the populations in APN311-202 and APN311-303 did not represent the population with relapsed or refractory disease in NHS clinical practice. This was because in England, these patients would be either considered high-risk and have already had dinutuximab beta or would be considered high-risk if their disease had relapsed or become refractory to treatment. It acknowledged that a potential small subgroup of patients with relapsed or refractory disease that was not considered high-risk was not the focus of the appraisal because no cost-effectiveness evidence was presented for this group. Therefore, the committee concluded, with agreement from the company and the experts, that the relapsed or refractory population would not be considered further in this appraisal.
# Concomitant interleukin-2
## Standard NHS practice does not include concomitant interleukin-2
The committee discussed whether interleukin-2 would be used in NHS practice in line with the dinutuximab beta marketing authorisation. This states that dinutuximab beta should be combined with interleukin-2 when induction therapy does not achieve a complete response. Clinical experts explained that adding interleukin-2 increases toxicity but does not appear to improve efficacy. The patient experts stated that a less toxic treatment allows patients to leave hospital sooner, which is important. The clinical experts explained that standard practice since APN311-302 finished recruiting is not to offer interleukin-2, even when there is residual disease. This is supported by the International Collaboration for Neuroblastoma Research and the UK Children's Cancer and Leukaemia Group and followed by paediatric oncologists in the NHS. In practice further lines of chemotherapy are often used to reduce the need for interleukin-2. The committee noted that this is not in line with the marketing authorisation for dinutuximab beta. But it concluded that standard NHS practice does not include concomitant interleukin-2 in most patients.
# Adverse effects
## Severe adverse effects occur with dinutuximab beta, but happen more frequently in patients also having interleukin-2
In APN311-302 severe adverse effects occurred more frequently in people having interleukin-2 (46% with interleukin-2 compared with 27% without interleukin-2). This is in line with clinical expert comments that concomitant interleukin-2 increases toxicity (see section 3.6). Of the 238 infections reported, 132 were in people having interleukin-2 and 106 were in people not having interleukin-2. There were more infections of grade 3 and 4 severity in the group having interleukin-2 than in the group who were not (exact figures are considered academic-in-confidence by the company). The committee concluded that dinutuximab beta was associated with severe adverse effects but these occurred more frequently in patients also having interleukin-2.
# Indirect treatment comparison
## A matched-adjusted indirect comparison shows that dinutuximab beta improves event-free and overall survival compared with isotretinoin
There was no direct evidence comparing dinutuximab beta with isotretinoin. This was because the European Neuroblastoma Research Group considered it unethical to include a control arm in APN311-302 after benefit was shown with dinutuximab alpha in ANBL0032 (a trial of dinutuximab alpha compared with isotretinoin; Yu et al. 2010). In response to the committee's request, the company provided a matched-adjusted indirect comparison using data from ANBL0032. For the dinutuximab beta arm of the analysis, the company pooled data from both arms of APN311-302 because all these patients had dinutuximab beta and there was no statistically significant difference in the event-free or overall survival results (see section 3.4). The matched-adjusted Kaplan–Meier curves for event-free and overall survival in the dinutuximab beta arm were similar to the observed trial data. The results of the analysis for dinutuximab beta compared with isotretinoin were:
event-free survival at 70 months: hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.62 to 0.8
-verall survival at 70 months: HR 0.63; 95% CI 0.54 to 0.86. The committee concluded that dinutuximab beta improved event-free and overall survival compared with isotretinoin.
## The most recent data from ANBL0032 are the best available comparator data
The DSU explained that the results of the matched-adjusted indirect comparison should be interpreted with caution because the hazard ratios had been generated assuming the data follows an exponential distribution. It considered this unlikely because the estimates of the hazard ratios would vary according to the time interval chosen. It also noted that it was not possible to adjust the analysis to account for previous consolidation therapy. This differed between the 2 trials and was a potential prognostic factor, and therefore may bias the results (although the direction or size of the potential bias was not known). The committee acknowledged consultation comments suggesting that an alternative comparison with an earlier phase of the HR-NBL-1 trial would help address this problem. However, the company did not have access to these data and the clinical experts considered that an alternative indirect treatment comparison would not resolve uncertainty and would be unlikely to produce different results. The DSU further noted that longer-term data were available from ANBL0032 in Yu et al. (2014), which it considered more appropriate to use in the analysis. It reproduced the analysis using the 2014 data. Because the patient population was the same as in the 2010 data, this did not affect the results of the company's analysis (see section 3.8). The committee agreed that the most recent data from ANBL0032 were the most appropriate to use in the indirect comparison and were the best available source of comparator data.
# The company's economic model
## The structure of the model is appropriate
The committee noted that the structure of the company's model was appropriate, but that the ERG had carried out a number of corrections. A partitioned survival method was used to model treatment effectiveness, which used the event-free and overall survival data from the matched-adjusted indirect comparison of dinutuximab beta and isotretinoin to determine mortality and disease progression for each cycle. The committee accepted the structure of the company's economic model and the ERG's corrections.
# Modelling clinical effectiveness of isotretinoin
## The most recent data for isotretinoin are the most appropriate to use in the model
In its original model the company used Kaplan–Meier data from APN311-302 and from ANBL0032 (as reported by Yu et al. 2010) up to 70 months and then extrapolated event-free and overall survival over a 10-year period. However, the DSU noted that the longer-term data from ANBL0032 (Yu et al. 2014) included 12 years of isotretinoin data. The DSU considered it more appropriate to use the Kaplan–Meier data from the 2014 analysis for the full 10 years because this would reduce the uncertainty that arises from extrapolating data. In its revised analysis after consultation, the company used the Yu et al. (2014) data. However, the company was concerned that the 2014 data could be confounded because of crossover. The committee was aware that only 4 of the 113 patients had switched treatment and that the direction of any potential bias would be unknown. Given the small proportion of patients switching treatment it considered that any potential confounding was likely to be negligible. The committee recalled its preference for using the latest and most mature data from the in development NICE technology appraisal on dinutuximab alpha, noting that patient and clinical experts had agreed with this approach. It was aware that the 2014 analysis was not published but that the overall survival data had been considered by the European Medicines Agency in its regulatory assessment of dinutuximab alpha. It concluded that the 2014 data for isotretinoin were the most appropriate to use in the model.
# Modelling clinical effectiveness of dinutuximab beta
## Long-term benefit is the main source of uncertainty so a range of extrapolations are considered
The company extrapolated event-free and overall survival for the dinutuximab beta arm from 70 months to 10 years using a Gompertz parametric curve. The committee noted that the company assumed proportional hazards between dinutuximab beta and isotretinoin, which implied that the relative treatment effect is maintained over the lifetime of the model. The committee recalled that in the in development NICE technology appraisal on dinutuximab alpha the data were more mature and after 5 years the event-free and overall survival curves began to converge, with the initial separation of the time-to-event curves diminishing. Given that dinutuximab alpha and dinutuximab beta are derived from the same antibodies, it was possible that a similar effect may be seen in the dinutuximab beta trial after longer follow-up. The DSU explored other extrapolations that enabled modelling of more complex hazard functions, allowing for the relative treatment effect to vary over time. The committee recognised that the long-term benefit of dinutuximab beta was the main source of uncertainty in the appraisal. It therefore considered a range of plausible extrapolations.
## Gompertz or spline models are the most plausible for overall survival, but all extrapolations are uncertain
The committee considered that the spline models fitted the overall survival data better at the early part of the curve than the parametric models. The clinical experts explained that most relapses occurred between 1 and 3 years, with relapses after 5 years being rare, and noted that none of the extrapolation curves for the dinutuximab beta arm fully captured this plateau from 5 years onwards. The committee recalled that in the 2014 analysis of ANBL0032, events did occur in the dinutuximab alpha arm after 5 years. But it was also aware that a plateau from about 7 years onwards was seen in the isotretinoin arm. The committee also noted that the point at which the plateau occurred in the extrapolated curves for the dinutuximab beta arm was at a lower survival rate than the Kaplan–Meier data showed. The DSU explained that this was because it was not possible for the models to fit to the exact shape of the curve, but the effect of different assumptions about long-term overall survival with dinutuximab beta was reflected in the scenario analyses exploring the effect of different cure thresholds. The scenario assuming a 5-year cure threshold for example would be equivalent to assuming that no further events occurred after 5 years, and therefore the plateau in this scenario would occur at a point closer to the actual Kaplan–Meier data. The committee noted that the DSU's Gompertz extrapolation showed a probability of survival at 10 years of 61%. It was the flattest survival curve, best reflecting the expected plateau, that is, that very few events would occur after 5 years. However, the committee considered that the spline model with 2 knots was also plausible, and this predicted a probability of survival at 10 years of about 59%. The company's Gompertz extrapolation showed a survival probability at 10 years that was between these 2 estimates. The committee concluded that the Gompertz or 2-knot spline extrapolations were the most plausible for overall survival, but all extrapolations were uncertain given the immaturity of the data.
## Gompertz or spline models are the most plausible for event-free survival, but all extrapolations are uncertain
The committee considered that the spline models better fitted the event-free survival data at the early part of the curve than the parametric models. It preferred the DSU's extrapolation using the spline model with 1 knot. It also took into account the Gompertz extrapolation that the company considered best reflected the expected plateau after 5 years and had used in its original submission and in its updated analysis submitted in response to consultation. The clinical experts advised that the monthly risk of progression of less than 10% after 5 years predicted by the Gompertz extrapolation was clinically plausible because in their experience relapse after 5 years was not seen. The committee concluded that the 1-knot spline or the Gompertz extrapolation for event-free survival could be plausible, but all the extrapolations were uncertain.
# Cure threshold
## A 10-year cure threshold is preferred but others may be plausible
The committee was aware that the long-term benefits of immunotherapy were uncertain. It recalled that most relapses happened before 3 years and that relapses after 5 years were rare (see section 3.13). It also recalled that in the in development NICE technology appraisal on dinutuximab alpha data showed that relapses did occur between 5 and 10 years, mostly in the dinutuximab arm, but did not appear to occur beyond 10 years. Dinutuximab alpha was not recommended for routine NHS use and there was an appeal hearing in September 2016. The appeal panel recommended that a reasonable approach might be to consider a range of plausible cure points and explore the strengths and weaknesses of each of the points. The committee considered that the 10-year cure point in the company's model was appropriate because it reflected the fact that some events may occur between 5 and 10 years. However, the uncertainties in the extrapolations reflected the limitations of the clinical evidence driving the model. Therefore, other cure thresholds presented in the company's and DSU's scenario analyses could also be plausible. The committee considered that events may occur after 5 years because this was seen in the dinutuximab alpha data (see section 3.13), but it accepted that the exact relationship between dinutuximab alpha and beta was unknown. Therefore, the committee agreed that although its preferred assumption was a 10-year cure threshold, other cure points could be plausible. It concluded that it would consider a range of cure thresholds in its decision-making.
# Costs
## In the failure health state patients are likely to have chemotherapy for 1 year
The committee noted that patients have additional lines of chemotherapy after disease progression (see section 3.6) and the costs of this should be included in the model. In its additional analyses the company estimated the proportion of newly progressed patients having chemotherapy from the matched-adjusted individual patient data from APN311-302, which the DSU considered appropriate. The company assumed that these patients would have chemotherapy for 1 year. The clinical experts noted that some patients may have later lines of treatment, but agreed that assuming a 1-year treatment duration in the failure health state was reasonable. The committee therefore concluded that this assumption in the company's model was appropriate.
## Infection-related costs are appropriately included in the model
The committee, recalling the rate of infection in APN311-302 (see section 3.7), asked that the cost of infection-related hospitalisation, including any infection-related complications, should be included in the model, in addition to the cost of an inpatient stay for infusion. These costs were included in the additional analyses. The costs of the increased infections associated with taking interleukin-2 were reflected in the company's scenario analyses including concomitant interleukin-2. The committee concluded that the costs of treating infections arising from treatment were appropriately included in the model.
## The changes to the company's cost assumptions are reasonable
The company adjusted the cost assumptions in its base case in line with the committee's request.
It estimated the cost for dinutuximab beta based on a weighted average that took into account the proportion of patients in different body surface area categories in APN311-302, rather than the number of vials needed for an average body surface area.
It adjusted the costs of chemotherapy to include wastage.
It calculated the administration costs per cycle using the cost of an inpatient stay rather than a chemotherapy procurement cost.
It revised the associated resource use for patients who have had chemotherapy but are still alive and in the failure health state.The DSU commented that the changes to the cost assumptions in the company's original model had been implemented correctly. The committee concluded that the company's revised cost assumptions were reasonable. It noted however, that the incremental cost-effectiveness ratios (ICERs) presented did not appropriately account for end-of-life costs, which would reduce the ICERs by approximately £1,000.
## It is appropriate to include a discontinuation rate; the DSU's approach is preferred
In its additional evidence submitted during consultation, the company applied a treatment discontinuation rate to the model to account for people reducing their dose or stopping treatment permanently in clinical practice. The company used the number of patients who had stopped treatment because of toxicity or tolerability in APN311-302. The DSU noted that the company's approach may have double-counted patients who stopped treatment because of toxicity and whose disease then progressed, who would already be captured by event-free survival data. This would therefore underestimate the proportion of patients having the treatment in each cycle. The DSU instead used the actual number of patients having treatment in each cycle from APN311-302 (patients not having interleukin-2) to model treatment discontinuation. The committee considered it was reasonable to take into account discontinuation because of toxicity or tolerability and concluded that the DSU's method was more appropriate because it avoided double-counting.
# Utilities
## The Ara et al. algorithm is appropriate to estimate age-specific UK EQ-5D values in the model
The committee noted that health-related quality of life was not captured in APN311-302. The company had originally reduced the UK EQ-5D general population values to reflect the fact that patients in the model have neuroblastoma. The committee recalled that the in development NICE technology appraisal on dinutuximab alpha included a published algorithm by Ara et al. (2010), which was used to estimate mean EQ-5D health state utility values for the general population. The ERG considered this method to be more appropriate than using a logistic regression. On request, the company used Ara et al. to estimate utility values in its additional analyses. The committee concluded that the Ara et al. algorithm was appropriate to estimate age-specific UK EQ-5D values in the modelling, which the company had done.
# Discount rate
## The 1.5% discount rate used in the company's base case is appropriate
The committee recalled that in the in development NICE technology appraisal on dinutuximab alpha it concluded that 'the non-reference case discount rate could apply because the dinutuximab alpha regimen could be considered to cure neuroblastoma in a small proportion of patients'. It also concluded that 'this discount rate should be applied to both costs and outcomes in line with the current methods guide'. The committee considered that the same reasoning applied for dinutuximab beta and it concluded that the 1.5% discount rate modelled by the company was appropriate.
# Results of the cost-effectiveness analyses
## The ICERs presented are above the range usually considered cost effective
The committee considered the ICER per quality-adjusted life year (QALY) gained using its preferred assumptions:
the 2014 trial data for isotretinoin (see section 3.11)
Gompertz or 2-knot spline overall survival extrapolation (see section 3.13)
Gompertz or 1-knot spline event-free survival extrapolation (see section 3.14)
including a range of cure thresholds (see section 3.15)
excluding concomitant interleukin-2 (see section 3.6)
the DSU's approach to modelling treatment discontinuation (see section 3.19)
the most appropriate cost and utility inputs (see section 3.16 to section 3.18 and section 3.20).The ICERs for dinutuximab beta compared with isotretinoin using the committee's preferred assumptions and the confidential commercial arrangement for dinutuximab beta were above £40,000 per QALY gained (the exact figures for the different extrapolation curves and cure thresholds are commercial in confidence and cannot be reported). This estimate was subject to other factors considered relevant by the committee (as summarised in section 3.28).
## Long-term survival benefit with dinutuximab beta is uncertain and is the main driver of the cost-effectiveness analysis
The committee noted that different extrapolations of long-term survival had a large effect on the ICER, even though the actual difference in the survival rate predicted by the extrapolations was small. The company expressed concern about the sensitivity of the ICERs to small differences in curve estimates. The committee was aware that the long-term survival estimate was the main source of uncertainty in the appraisal and it had therefore considered a range of plausible extrapolations (see section 3.12) and cure thresholds (see section 3.15). It also recognised the effect of small changes in survival estimates given the small numbers of patients in the analysis, and that because of this, long-term benefit was the main driver of the cost-effectiveness analysis.
# End of life
## Dinutuximab beta does not meet the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee noted that the modelled life expectancy for patients having isotretinoin alone was about 31 to 34 years, which did not meet the criterion for short life expectancy. The modelled incremental gain, using the DSU's range of most plausible ICERs and the latest data available for isotretinoin, was between 3 and 5 years, which met the criterion for survival gain. The committee acknowledged that the extent of survival gain potentially offered by dinutuximab beta was substantial. But it recognised that this estimate was uncertain and it could not be confident of the extent of proportional gain in relation to the high life expectancy. The committee therefore concluded that the end-of-life criteria were not met.
# Cancer Drugs Fund
## Data collection in the Cancer Drugs Fund would not resolve uncertainty about dinutuximab beta's long-term benefit
The committee had previously concluded that given dinutuximab beta's promising clinical benefit in the trial and the potential for longer-term data to be available in 2 to 3 years, it would consider dinutuximab beta for the Cancer Drugs Fund. After consultation the company reported that an amendment to the APN311-302 trial protocol would be needed to collect further follow-up data, and this amendment could take up to 2 years. The prospective data collection offered by the safety registry, set up as required by the European Medicines Agency, would also not produce timely long-term data. Establishing a UK registry was also considered. But given the small number of UK patients the committee considered that any data generated would not resolve uncertainty, given the disproportionate effect of small patient numbers on overall survival estimates (see section 3.23). The committee agreed that the feasibility of collecting the data needed to address the uncertainties was limited. The committee therefore concluded that the Cancer Drugs Fund would not be the appropriate way to address the clinical uncertainties.
# Other factors
## Some health-related benefits are not captured in the economic model
The committee considered whether there were any health-related benefits that were not captured in the economic analysis. It was aware that neuroblastoma is a devastating disease that affects children and young adults as well as their families and carers. The committee acknowledged that there were uncaptured health-related benefits. These included reduced quality of life because of the effect of stress and depression caused by the disease on young patients and their families, as well as the devastating effects of bereavement on families. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages, and noted NICE's social value judgements: principles for the development of NICE guidance, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as considering factors other than relative costs and benefits alone. The committee noted the fact that patients were children was partly addressed by accepting a 1.5% discount rate for costs and QALYs (see section 3.21). Despite this, it recognised the severity of the disease and the importance of generating potentially lifelong health benefits for this patient population. The committee was not presented with any quantitative data to show distinct and substantial uncaptured health-related benefits. However, it was confident that there were health-related benefits that were not captured in the company's model, which needed to be accounted for in its decision-making.
## The committee is prepared to be flexible in its decision-making given the rarity and severity of the disease
Although dinutuximab beta is an orphan drug because of the small number of patients affected by neuroblastoma, it could not be considered through the highly specialised technologies programme because it is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising orphan drugs for rare conditions, which is not helped by the limited potential for generating robust long-term data and the disproportionate effect of small numbers of patients on the cost-effectiveness analyses (see section 3.23 and section 3.25). When developing the social value judgements, the Citizens Council considered that rarity alone is not a mitigating factor for accepting high ICERs, but the committee should consider taking into account other factors such as disease severity in its decision-making. The committee concluded that the severity of high-risk neuroblastoma should be considered in its decision-making.
## Dinutuximab beta is a cost-effective use of NHS resources
The committee was aware of the uncertainty around the long-term clinical benefit of dinutuximab beta and the lack of practical or timely solutions to resolve this (see section 3.25), but it acknowledged that the potential survival gain offered by dinutuximab beta was substantial. It recognised that the marketing authorisation for dinutuximab beta was granted under exceptional circumstances because the data were immature. Also, because clinical benefit with dinutuximab alpha has been shown, immunotherapy (dinutuximab alpha or beta) has become standard care in some countries and it was therefore considered unethical not to offer immunotherapy within a trial to patients with neuroblastoma. It also acknowledged the company's efforts in exploring the potential data collection options and in adapting its commercial arrangement. In addition to the ICERs presented, the committee considered:
the patient population (see section 3.26)
the number of patients affected (see section 3.27)
the severity of the disease and the painful and debilitating current treatments (see section 3.1)
the potential for a significant survival benefit with dinutuximab beta (see section 3.24)
the end-of-life costs not captured in the ICERs (see section 3.18) and
the uncaptured benefits in the analysis (see section 3.26).The committee concluded that, taking into account all these factors, it was able to recommend dinutuximab beta as a cost-effective use of NHS resources.
No equality issues were identified.
|
{'Recommendations': "Dinutuximab beta is recommended as an option for treating high-risk neuroblastoma in people aged 12\xa0months and over whose disease has at least partially responded to induction chemotherapy, followed by myeloablative therapy and stem cell transplant, only if:\n\nthey have not already had anti-GD2 immunotherapy and\n\nthe company provides dinutuximab beta according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with dinutuximab beta that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For a child or young person, this decision should be made jointly by them or their parents or carers and their clinician.\n\nWhy the committee made these recommendations\n\nNeuroblastoma mainly affects children and young people. Treatments for high-risk neuroblastoma include chemotherapy, radiotherapy, stem cell transplant, surgery and isotretinoin. Dinutuximab beta is an important, potentially curative option for maintenance treatment of the disease.\n\nAn indirect comparison with isotretinoin suggests that dinutuximab beta increases survival and the length of time before the disease progresses, compared with current treatment.\n\nDinutuximab beta does not meet NICE's criteria for a life-extending treatment at the end of life. Also, the range of cost-effectiveness estimates presented is higher than what NICE usually considers a cost-effective use of NHS resources. But taking into account the uncaptured health-related benefits, the rarity and severity of the disease and the potential lifetime benefit for children with neuroblastoma, dinutuximab beta can be recommended for high-risk neuroblastoma.\n\nDinutuximab beta also has a marketing authorisation to treat relapsed or refractory disease. This indication was not considered in this appraisal because it is not relevant to current NHS practice; most people with relapsed or refractory disease have already had dinutuximab beta.", 'Information about dinutuximab beta': "Marketing authorisation indication\n\nDinutuximab beta (Qarziba, EUSA Pharma) has a marketing authorisation 'for the treatment of high-risk neuroblastoma in patients aged 12\xa0months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with a history of relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures.\n\nIn patients with a history of relapsed or refractory disease and in patients who have not achieved a complete response after first line therapy, dinutuximab beta should be combined with interleukin-2 (IL-2).'\n\nThe marketing authorisation was granted under 'exceptional circumstances'. This happens when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the drug for which authorisation is being sought, because of the rarity of the condition it is intended for, limited scientific knowledge in the area concerned, or ethical considerations involved in the collection of such data.\n\nDosage in the marketing authorisation\n\nThere are 2\xa0modes of administration:\n\ncontinuous intravenous infusion over the first 10\xa0days of each course at a daily dose of 10\xa0mg/m2 or\n\ndaily infusions of 20\xa0mg/m2 administered over 8\xa0hours, on the first 5\xa0days of each course.\n\nWhen IL-2 is combined with dinutuximab beta, it should be administered as subcutaneous injections of 6×106\xa0IU/m2/day, for 2\xa0periods of 5\xa0consecutive days, resulting in an overall dose of 60×106\xa0IU/m2 per course. The first 5-day course should start 7\xa0days before the first infusion of dinutuximab beta and the second 5-day course should start at the same time as dinutuximab beta infusion (days 1\xa0to\xa05 of each dinutuximab beta course).\n\n\n\nThe individual dose is determined based on the body surface area and should be a total of 100\xa0mg/m2 per course.\n\n\n\nBased on the severity of adverse drug reactions to dinutuximab beta, patients may have a dose reduction of 50% or a temporary interruption of the infusion. As a result, either the infusion period is prolonged or, if tolerated, the infusion rate may be increased up to 3\xa0ml/hour (continuous infusion), in order to administer the total dose.\n\nPrice\n\nThe dinutuximab beta list price is £7,610 per vial (excluding VAT; company submission).\n\nThe average cost of a course of treatment (body surface area of 0.63\xa0m2 and age\xa03) is £152,200.\n\n\n\nThe company has a commercial arrangement. This makes dinutuximab beta available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by EUSA Pharma and a review of this submission by the evidence review group (ERG). It also considered additional company analyses and a review of these by the NICE decision support unit (DSU). See the committee papers for full details of the evidence.\n\n# The condition\n\n## Dinutuximab beta is an important potential option for high-risk and relapsed or refractory neuroblastoma\n\nNeuroblastoma mainly affects children and young people. The patient experts stated that high-risk and relapsed or refractory neuroblastoma has a significant effect on children and young people and their families and carers. Children and young people with the condition have anxiety about their illness and treatment as well as discomfort and pain from the disease. The existing treatments and procedures for neuroblastoma are painful and debilitating, with severe and long-lasting side effects (including hearing loss, organ dysfunction, sterility, lack of growth, early onset of puberty, permanent disability, and secondary malignancies). The clinical and patient experts stated that a child's death has a significant effect on family members. The committee noted that treatment can involve many hospital visits and stays causing disruption to school, work and family life. It understood that parents and carers also have anxiety, emotional distress and disruption to their working life and income as well as strain on their relationships. The committee recognised that high-risk and relapsed or refractory neuroblastoma places a significant burden on patients, their families and carers. It concluded that new, effective treatment options would be welcomed.\n\n# Current treatments\n\n## Isotretinoin is the relevant comparator for decision-making for the maintenance treatment of high-risk neuroblastoma\n\nThe clinical and patient experts explained that the main aim of treatment is to extend event-free survival, but that ultimately a cure is needed. The committee acknowledged that since 2009 almost all patients with high-risk neuroblastoma in England, whose disease has at least partially responded to induction chemotherapy followed by myeloablative therapy and stem cell transplant, were enrolled in the immunotherapy phase of the HR-NBL-1 trial (APN311-302; comparing dinutuximab beta plus isotretinoin with dinutuximab beta plus isotretinoin plus interleukin-2). The committee agreed that dinutuximab beta cannot be considered established NHS practice because it has only been used in research as part of a clinical trial and is not routinely commissioned. The committee understood that before dinutuximab beta was available in the trial, maintenance therapy with isotretinoin was considered standard care in the NHS for high-risk neuroblastoma. It concluded that isotretinoin is the relevant comparator for the maintenance treatment of high-risk neuroblastoma that has at least partially responded to induction chemotherapy, followed by myeloablative therapy and stem cell transplant.\n\n## Most patients with relapsed or refractory neuroblastoma have already had dinutuximab beta in the clinical trial\n\nThe clinical experts explained that there is no defined treatment pathway for relapsed or refractory neuroblastoma, but treatment is usually chemotherapy, radiotherapy and surgery. They also explained that patients with relapsed or refractory neuroblastoma have a poor long-term prognosis, especially if they have relapsed after treatment for high-risk disease. The clinical experts explained that since 2009 in England almost all patients with relapsed or refractory neuroblastoma have had first-line maintenance treatment with dinutuximab beta in the APN311-302 trial (see section\xa03.2). A small number of patients with relapsed or refractory neuroblastoma may not have already had dinutuximab beta if they were initially diagnosed as having low or intermediate-risk disease. However, if their disease relapsed or became refractory to treatment, these patients would be considered as having high-risk neuroblastoma. The committee concluded that almost all patients with relapsed or refractory neuroblastoma in clinical practice have already had dinutuximab beta in APN311-302.\n\n# Clinical trial evidence\n\n## APN311-302 is the best available evidence, but does not address dinutuximab beta's relative effectiveness compared with isotretinoin\n\nThe clinical evidence for the population with high-risk neuroblastoma came from APN311-302, an open-label phase\xa03 trial comparing dinutuximab beta plus isotretinoin (n=189) with dinutuximab beta plus isotretinoin plus interleukin-2 (n=190). The primary outcome in the trial was event-free survival at 3\xa0years, with overall survival, overall response, incidence of relapsed or refractory disease and safety as secondary outcomes. The committee acknowledged that 55.4% of people randomised to dinutuximab beta and isotretinoin without interleukin-2 had not had an event at 3\xa0years compared with 61.2% in the group having interleukin-2. This difference was not statistically significant (p=0.3202). For overall survival, 64.1% of people randomised to dinutuximab beta and isotretinoin without interleukin-2 were still alive at 3\xa0years compared with 69.1% in the group having interleukin-2. This difference was not statistically significant (p=0.6114). The committee noted that median event-free and overall survival could not be estimated for either group because the data were immature. The ERG stated that no formal primary cut-off date for the analysis or time period for follow-up was specified for APN311-302. It also noted that because the trial was open label there could be performance bias in the assessment of event-free survival and overall response, but this was unlikely to affect overall survival. The committee acknowledged that the trial results showed that concomitant interleukin-2 did not improve event-free or overall survival, and that despite its limitations, APN311-302 was the best available evidence for dinutuximab beta. The committee concluded that because all patients in the trial had dinutuximab beta, the evidence did not inform the decision problem on the relative effectiveness of dinutuximab beta compared with isotretinoin.\n\n## The clinical effectiveness evidence for the population with relapsed or refractory disease is not relevant to NHS clinical practice\n\nThe evidence for this population came from 2\xa0observational studies of dinutuximab beta with isotretinoin and interleukin-2 in patients with relapsed or refractory disease after initial therapy: APN311-202 and APN311-303. The clinical experts explained that people in the NHS with high-risk neuroblastoma who have relapsed disease are likely to have had dinutuximab beta as part of their first-line maintenance therapy in the clinical trial (see section\xa03.3). The committee noted that none of the patients in APN311-202 and APN311-303 had already had dinutuximab beta. The company explained that it did not support retreatment with dinutuximab beta in the relapsed or refractory population. The clinical experts also explained that the small number of people with low or intermediate-risk disease who may not have already had dinutuximab beta would be considered as having high-risk neuroblastoma if the disease relapsed or became refractory to treatment (and in line with the recommendations in section\xa01.1 would be eligible for treatment). The committee recognised that the marketing authorisation included patients with relapsed or refractory disease, which could include a very small number of people with low or intermediate-risk disease that has relapsed but is not then considered high-risk. However, it had not seen any evidence for this small subgroup because the evidence for the relapsed and refractory population was not presented by category of initial risk. The committee agreed that the populations in APN311-202 and APN311-303 did not represent the population with relapsed or refractory disease in NHS clinical practice. This was because in England, these patients would be either considered high-risk and have already had dinutuximab beta or would be considered high-risk if their disease had relapsed or become refractory to treatment. It acknowledged that a potential small subgroup of patients with relapsed or refractory disease that was not considered high-risk was not the focus of the appraisal because no cost-effectiveness evidence was presented for this group. Therefore, the committee concluded, with agreement from the company and the experts, that the relapsed or refractory population would not be considered further in this appraisal.\n\n# Concomitant interleukin-2\n\n## Standard NHS practice does not include concomitant interleukin-2\n\nThe committee discussed whether interleukin-2 would be used in NHS practice in line with the dinutuximab beta marketing authorisation. This states that dinutuximab beta should be combined with interleukin-2 when induction therapy does not achieve a complete response. Clinical experts explained that adding interleukin-2 increases toxicity but does not appear to improve efficacy. The patient experts stated that a less toxic treatment allows patients to leave hospital sooner, which is important. The clinical experts explained that standard practice since APN311-302 finished recruiting is not to offer interleukin-2, even when there is residual disease. This is supported by the International Collaboration for Neuroblastoma Research and the UK Children's Cancer and Leukaemia Group and followed by paediatric oncologists in the NHS. In practice further lines of chemotherapy are often used to reduce the need for interleukin-2. The committee noted that this is not in line with the marketing authorisation for dinutuximab beta. But it concluded that standard NHS practice does not include concomitant interleukin-2 in most patients.\n\n# Adverse effects\n\n## Severe adverse effects occur with dinutuximab beta, but happen more frequently in patients also having interleukin-2\n\nIn APN311-302 severe adverse effects occurred more frequently in people having interleukin-2 (46% with interleukin-2 compared with 27% without interleukin-2). This is in line with clinical expert comments that concomitant interleukin-2 increases toxicity (see section\xa03.6). Of the 238\xa0infections reported, 132 were in people having interleukin-2 and 106\xa0were in people not having interleukin-2. There were more infections of grade\xa03 and 4 severity in the group having interleukin-2 than in the group who were not (exact figures are considered academic-in-confidence by the company). The committee concluded that dinutuximab beta was associated with severe adverse effects but these occurred more frequently in patients also having interleukin-2.\n\n# Indirect treatment comparison\n\n## A matched-adjusted indirect comparison shows that dinutuximab beta improves event-free and overall survival compared with isotretinoin\n\nThere was no direct evidence comparing dinutuximab beta with isotretinoin. This was because the European Neuroblastoma Research Group considered it unethical to include a control arm in APN311-302 after benefit was shown with dinutuximab alpha in ANBL0032 (a trial of dinutuximab alpha compared with isotretinoin; Yu et al. 2010). In response to the committee's request, the company provided a matched-adjusted indirect comparison using data from ANBL0032. For the dinutuximab beta arm of the analysis, the company pooled data from both arms of APN311-302 because all these patients had dinutuximab beta and there was no statistically significant difference in the event-free or overall survival results (see section\xa03.4). The matched-adjusted Kaplan–Meier curves for event-free and overall survival in the dinutuximab beta arm were similar to the observed trial data. The results of the analysis for dinutuximab beta compared with isotretinoin were:\n\nevent-free survival at 70\xa0months: hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.62 to 0.8\n\noverall survival at 70\xa0months: HR 0.63; 95% CI 0.54 to 0.86. The committee concluded that dinutuximab beta improved event-free and overall survival compared with isotretinoin.\n\n## The most recent data from ANBL0032 are the best available comparator data\n\nThe DSU explained that the results of the matched-adjusted indirect comparison should be interpreted with caution because the hazard ratios had been generated assuming the data follows an exponential distribution. It considered this unlikely because the estimates of the hazard ratios would vary according to the time interval chosen. It also noted that it was not possible to adjust the analysis to account for previous consolidation therapy. This differed between the 2\xa0trials and was a potential prognostic factor, and therefore may bias the results (although the direction or size of the potential bias was not known). The committee acknowledged consultation comments suggesting that an alternative comparison with an earlier phase of the HR-NBL-1 trial would help address this problem. However, the company did not have access to these data and the clinical experts considered that an alternative indirect treatment comparison would not resolve uncertainty and would be unlikely to produce different results. The DSU further noted that longer-term data were available from ANBL0032 in Yu et al. (2014), which it considered more appropriate to use in the analysis. It reproduced the analysis using the 2014 data. Because the patient population was the same as in the 2010 data, this did not affect the results of the company's analysis (see section\xa03.8). The committee agreed that the most recent data from ANBL0032 were the most appropriate to use in the indirect comparison and were the best available source of comparator data.\n\n# The company's economic model\n\n## The structure of the model is appropriate\n\nThe committee noted that the structure of the company's model was appropriate, but that the ERG had carried out a number of corrections. A partitioned survival method was used to model treatment effectiveness, which used the event-free and overall survival data from the matched-adjusted indirect comparison of dinutuximab beta and isotretinoin to determine mortality and disease progression for each cycle. The committee accepted the structure of the company's economic model and the ERG's corrections.\n\n# Modelling clinical effectiveness of isotretinoin\n\n## The most recent data for isotretinoin are the most appropriate to use in the model\n\nIn its original model the company used Kaplan–Meier data from APN311-302 and from ANBL0032 (as reported by Yu et al. 2010) up to 70\xa0months and then extrapolated event-free and overall survival over a 10-year period. However, the DSU noted that the longer-term data from ANBL0032 (Yu et al. 2014) included 12\xa0years of isotretinoin data. The DSU considered it more appropriate to use the Kaplan–Meier data from the 2014 analysis for the full 10\xa0years because this would reduce the uncertainty that arises from extrapolating data. In its revised analysis after consultation, the company used the Yu et al. (2014) data. However, the company was concerned that the 2014 data could be confounded because of crossover. The committee was aware that only 4\xa0of the 113\xa0patients had switched treatment and that the direction of any potential bias would be unknown. Given the small proportion of patients switching treatment it considered that any potential confounding was likely to be negligible. The committee recalled its preference for using the latest and most mature data from the in development NICE technology appraisal on dinutuximab alpha, noting that patient and clinical experts had agreed with this approach. It was aware that the 2014 analysis was not published but that the overall survival data had been considered by the European Medicines Agency in its regulatory assessment of dinutuximab alpha. It concluded that the 2014 data for isotretinoin were the most appropriate to use in the model.\n\n# Modelling clinical effectiveness of dinutuximab beta\n\n## Long-term benefit is the main source of uncertainty so a range of extrapolations are considered\n\nThe company extrapolated event-free and overall survival for the dinutuximab beta arm from 70\xa0months to 10\xa0years using a Gompertz parametric curve. The committee noted that the company assumed proportional hazards between dinutuximab beta and isotretinoin, which implied that the relative treatment effect is maintained over the lifetime of the model. The committee recalled that in the in development NICE technology appraisal on dinutuximab alpha the data were more mature and after 5\xa0years the event-free and overall survival curves began to converge, with the initial separation of the time-to-event curves diminishing. Given that dinutuximab alpha and dinutuximab beta are derived from the same antibodies, it was possible that a similar effect may be seen in the dinutuximab beta trial after longer follow-up. The DSU explored other extrapolations that enabled modelling of more complex hazard functions, allowing for the relative treatment effect to vary over time. The committee recognised that the long-term benefit of dinutuximab beta was the main source of uncertainty in the appraisal. It therefore considered a range of plausible extrapolations.\n\n## Gompertz or spline models are the most plausible for overall survival, but all extrapolations are uncertain\n\nThe committee considered that the spline models fitted the overall survival data better at the early part of the curve than the parametric models. The clinical experts explained that most relapses occurred between 1\xa0and\xa03 years, with relapses after 5\xa0years being rare, and noted that none of the extrapolation curves for the dinutuximab beta arm fully captured this plateau from 5\xa0years onwards. The committee recalled that in the 2014 analysis of ANBL0032, events did occur in the dinutuximab alpha arm after 5\xa0years. But it was also aware that a plateau from about 7\xa0years onwards was seen in the isotretinoin arm. The committee also noted that the point at which the plateau occurred in the extrapolated curves for the dinutuximab beta arm was at a lower survival rate than the Kaplan–Meier data showed. The DSU explained that this was because it was not possible for the models to fit to the exact shape of the curve, but the effect of different assumptions about long-term overall survival with dinutuximab beta was reflected in the scenario analyses exploring the effect of different cure thresholds. The scenario assuming a 5-year cure threshold for example would be equivalent to assuming that no further events occurred after 5\xa0years, and therefore the plateau in this scenario would occur at a point closer to the actual Kaplan–Meier data. The committee noted that the DSU's Gompertz extrapolation showed a probability of survival at 10\xa0years of 61%. It was the flattest survival curve, best reflecting the expected plateau, that is, that very few events would occur after 5\xa0years. However, the committee considered that the spline model with 2\xa0knots was also plausible, and this predicted a probability of survival at 10\xa0years of about 59%. The company's Gompertz extrapolation showed a survival probability at 10\xa0years that was between these 2\xa0estimates. The committee concluded that the Gompertz or 2-knot spline extrapolations were the most plausible for overall survival, but all extrapolations were uncertain given the immaturity of the data.\n\n## Gompertz or spline models are the most plausible for event-free survival, but all extrapolations are uncertain\n\nThe committee considered that the spline models better fitted the event-free survival data at the early part of the curve than the parametric models. It preferred the DSU's extrapolation using the spline model with 1\xa0knot. It also took into account the Gompertz extrapolation that the company considered best reflected the expected plateau after 5\xa0years and had used in its original submission and in its updated analysis submitted in response to consultation. The clinical experts advised that the monthly risk of progression of less than 10% after 5\xa0years predicted by the Gompertz extrapolation was clinically plausible because in their experience relapse after 5\xa0years was not seen. The committee concluded that the 1-knot spline or the Gompertz extrapolation for event-free survival could be plausible, but all the extrapolations were uncertain.\n\n# Cure threshold\n\n## A 10-year cure threshold is preferred but others may be plausible\n\nThe committee was aware that the long-term benefits of immunotherapy were uncertain. It recalled that most relapses happened before 3\xa0years and that relapses after 5\xa0years were rare (see section\xa03.13). It also recalled that in the in development NICE technology appraisal on dinutuximab alpha data showed that relapses did occur between 5\xa0and\xa010 years, mostly in the dinutuximab arm, but did not appear to occur beyond 10\xa0years. Dinutuximab alpha was not recommended for routine NHS use and there was an appeal hearing in September 2016. The appeal panel recommended that a reasonable approach might be to consider a range of plausible cure points and explore the strengths and weaknesses of each of the points. The committee considered that the 10-year cure point in the company's model was appropriate because it reflected the fact that some events may occur between 5 and 10\xa0years. However, the uncertainties in the extrapolations reflected the limitations of the clinical evidence driving the model. Therefore, other cure thresholds presented in the company's and DSU's scenario analyses could also be plausible. The committee considered that events may occur after 5\xa0years because this was seen in the dinutuximab alpha data (see section\xa03.13), but it accepted that the exact relationship between dinutuximab alpha and beta was unknown. Therefore, the committee agreed that although its preferred assumption was a 10-year cure threshold, other cure points could be plausible. It concluded that it would consider a range of cure thresholds in its decision-making.\n\n# Costs\n\n## In the failure health state patients are likely to have chemotherapy for 1\xa0year\n\nThe committee noted that patients have additional lines of chemotherapy after disease progression (see section\xa03.6) and the costs of this should be included in the model. In its additional analyses the company estimated the proportion of newly progressed patients having chemotherapy from the matched-adjusted individual patient data from APN311-302, which the DSU considered appropriate. The company assumed that these patients would have chemotherapy for 1\xa0year. The clinical experts noted that some patients may have later lines of treatment, but agreed that assuming a 1-year treatment duration in the failure health state was reasonable. The committee therefore concluded that this assumption in the company's model was appropriate.\n\n## Infection-related costs are appropriately included in the model\n\nThe committee, recalling the rate of infection in APN311-302 (see section\xa03.7), asked that the cost of infection-related hospitalisation, including any infection-related complications, should be included in the model, in addition to the cost of an inpatient stay for infusion. These costs were included in the additional analyses. The costs of the increased infections associated with taking interleukin-2 were reflected in the company's scenario analyses including concomitant interleukin-2. The committee concluded that the costs of treating infections arising from treatment were appropriately included in the model.\n\n## The changes to the company's cost assumptions are reasonable\n\nThe company adjusted the cost assumptions in its base case in line with the committee's request.\n\nIt estimated the cost for dinutuximab beta based on a weighted average that took into account the proportion of patients in different body surface area categories in APN311-302, rather than the number of vials needed for an average body surface area.\n\nIt adjusted the costs of chemotherapy to include wastage.\n\nIt calculated the administration costs per cycle using the cost of an inpatient stay rather than a chemotherapy procurement cost.\n\nIt revised the associated resource use for patients who have had chemotherapy but are still alive and in the failure health state.The DSU commented that the changes to the cost assumptions in the company's original model had been implemented correctly. The committee concluded that the company's revised cost assumptions were reasonable. It noted however, that the incremental cost-effectiveness ratios (ICERs) presented did not appropriately account for end-of-life costs, which would reduce the ICERs by approximately £1,000.\n\n## It is appropriate to include a discontinuation rate; the DSU's approach is preferred\n\nIn its additional evidence submitted during consultation, the company applied a treatment discontinuation rate to the model to account for people reducing their dose or stopping treatment permanently in clinical practice. The company used the number of patients who had stopped treatment because of toxicity or tolerability in APN311-302. The DSU noted that the company's approach may have double-counted patients who stopped treatment because of toxicity and whose disease then progressed, who would already be captured by event-free survival data. This would therefore underestimate the proportion of patients having the treatment in each cycle. The DSU instead used the actual number of patients having treatment in each cycle from APN311-302 (patients not having interleukin-2) to model treatment discontinuation. The committee considered it was reasonable to take into account discontinuation because of toxicity or tolerability and concluded that the DSU's method was more appropriate because it avoided double-counting.\n\n# Utilities\n\n## The Ara et al. algorithm is appropriate to estimate age-specific UK EQ-5D values in the model\n\nThe committee noted that health-related quality of life was not captured in APN311-302. The company had originally reduced the UK EQ-5D general population values to reflect the fact that patients in the model have neuroblastoma. The committee recalled that the in development NICE technology appraisal on dinutuximab alpha included a published algorithm by Ara et al. (2010), which was used to estimate mean EQ-5D health state utility values for the general population. The ERG considered this method to be more appropriate than using a logistic regression. On request, the company used Ara et al. to estimate utility values in its additional analyses. The committee concluded that the Ara et al. algorithm was appropriate to estimate age-specific UK EQ-5D values in the modelling, which the company had done.\n\n# Discount rate\n\n## The 1.5% discount rate used in the company's base case is appropriate\n\nThe committee recalled that in the in development NICE technology appraisal on dinutuximab alpha it concluded that 'the non-reference case discount rate could apply because the dinutuximab alpha regimen could be considered to cure neuroblastoma in a small proportion of patients'. It also concluded that 'this discount rate should be applied to both costs and outcomes in line with the current methods guide'. The committee considered that the same reasoning applied for dinutuximab beta and it concluded that the 1.5% discount rate modelled by the company was appropriate.\n\n# Results of the cost-effectiveness analyses\n\n## The ICERs presented are above the range usually considered cost effective\n\nThe committee considered the ICER per quality-adjusted life year (QALY) gained using its preferred assumptions:\n\nthe 2014 trial data for isotretinoin (see section\xa03.11)\n\nGompertz or 2-knot spline overall survival extrapolation (see section\xa03.13)\n\nGompertz or 1-knot spline event-free survival extrapolation (see section\xa03.14)\n\nincluding a range of cure thresholds (see section\xa03.15)\n\nexcluding concomitant interleukin-2 (see section\xa03.6)\n\nthe DSU's approach to modelling treatment discontinuation (see section\xa03.19)\n\nthe most appropriate cost and utility inputs (see section\xa03.16 to section\xa03.18 and section\xa03.20).The ICERs for dinutuximab beta compared with isotretinoin using the committee's preferred assumptions and the confidential commercial arrangement for dinutuximab beta were above £40,000 per QALY gained (the exact figures for the different extrapolation curves and cure thresholds are commercial in confidence and cannot be reported). This estimate was subject to other factors considered relevant by the committee (as summarised in section\xa03.28).\n\n## Long-term survival benefit with dinutuximab beta is uncertain and is the main driver of the cost-effectiveness analysis\n\nThe committee noted that different extrapolations of long-term survival had a large effect on the ICER, even though the actual difference in the survival rate predicted by the extrapolations was small. The company expressed concern about the sensitivity of the ICERs to small differences in curve estimates. The committee was aware that the long-term survival estimate was the main source of uncertainty in the appraisal and it had therefore considered a range of plausible extrapolations (see section\xa03.12) and cure thresholds (see section\xa03.15). It also recognised the effect of small changes in survival estimates given the small numbers of patients in the analysis, and that because of this, long-term benefit was the main driver of the cost-effectiveness analysis.\n\n# End of life\n\n## Dinutuximab beta does not meet the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee noted that the modelled life expectancy for patients having isotretinoin alone was about 31\xa0to\xa034\xa0years, which did not meet the criterion for short life expectancy. The modelled incremental gain, using the DSU's range of most plausible ICERs and the latest data available for isotretinoin, was between 3\xa0and\xa05\xa0years, which met the criterion for survival gain. The committee acknowledged that the extent of survival gain potentially offered by dinutuximab beta was substantial. But it recognised that this estimate was uncertain and it could not be confident of the extent of proportional gain in relation to the high life expectancy. The committee therefore concluded that the end-of-life criteria were not met.\n\n# Cancer Drugs Fund\n\n## Data collection in the Cancer Drugs Fund would not resolve uncertainty about dinutuximab beta's long-term benefit\n\nThe committee had previously concluded that given dinutuximab beta's promising clinical benefit in the trial and the potential for longer-term data to be available in 2\xa0to\xa03\xa0years, it would consider dinutuximab beta for the Cancer Drugs Fund. After consultation the company reported that an amendment to the APN311-302 trial protocol would be needed to collect further follow-up data, and this amendment could take up to 2\xa0years. The prospective data collection offered by the safety registry, set up as required by the European Medicines Agency, would also not produce timely long-term data. Establishing a UK registry was also considered. But given the small number of UK patients the committee considered that any data generated would not resolve uncertainty, given the disproportionate effect of small patient numbers on overall survival estimates (see section\xa03.23). The committee agreed that the feasibility of collecting the data needed to address the uncertainties was limited. The committee therefore concluded that the Cancer Drugs Fund would not be the appropriate way to address the clinical uncertainties.\n\n# Other factors\n\n## Some health-related benefits are not captured in the economic model\n\nThe committee considered whether there were any health-related benefits that were not captured in the economic analysis. It was aware that neuroblastoma is a devastating disease that affects children and young adults as well as their families and carers. The committee acknowledged that there were uncaptured health-related benefits. These included reduced quality of life because of the effect of stress and depression caused by the disease on young patients and their families, as well as the devastating effects of bereavement on families. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages, and noted NICE's social value judgements: principles for the development of NICE guidance, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as considering factors other than relative costs and benefits alone. The committee noted the fact that patients were children was partly addressed by accepting a 1.5% discount rate for costs and QALYs (see section\xa03.21). Despite this, it recognised the severity of the disease and the importance of generating potentially lifelong health benefits for this patient population. The committee was not presented with any quantitative data to show distinct and substantial uncaptured health-related benefits. However, it was confident that there were health-related benefits that were not captured in the company's model, which needed to be accounted for in its decision-making.\n\n## The committee is prepared to be flexible in its decision-making given the rarity and severity of the disease\n\nAlthough dinutuximab beta is an orphan drug because of the small number of patients affected by neuroblastoma, it could not be considered through the highly specialised technologies programme because it is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising orphan drugs for rare conditions, which is not helped by the limited potential for generating robust long-term data and the disproportionate effect of small numbers of patients on the cost-effectiveness analyses (see section\xa03.23 and section\xa03.25). When developing the social value judgements, the Citizens Council considered that rarity alone is not a mitigating factor for accepting high ICERs, but the committee should consider taking into account other factors such as disease severity in its decision-making. The committee concluded that the severity of high-risk neuroblastoma should be considered in its decision-making.\n\n## Dinutuximab beta is a cost-effective use of NHS resources\n\nThe committee was aware of the uncertainty around the long-term clinical benefit of dinutuximab beta and the lack of practical or timely solutions to resolve this (see section\xa03.25), but it acknowledged that the potential survival gain offered by dinutuximab beta was substantial. It recognised that the marketing authorisation for dinutuximab beta was granted under exceptional circumstances because the data were immature. Also, because clinical benefit with dinutuximab alpha has been shown, immunotherapy (dinutuximab alpha or beta) has become standard care in some countries and it was therefore considered unethical not to offer immunotherapy within a trial to patients with neuroblastoma. It also acknowledged the company's efforts in exploring the potential data collection options and in adapting its commercial arrangement. In addition to the ICERs presented, the committee considered:\n\nthe patient population (see section\xa03.26)\n\nthe number of patients affected (see section\xa03.27)\n\nthe severity of the disease and the painful and debilitating current treatments (see section\xa03.1)\n\nthe potential for a significant survival benefit with dinutuximab beta (see section\xa03.24)\n\nthe end-of-life costs not captured in the ICERs (see section\xa03.18) and\n\nthe uncaptured benefits in the analysis (see section\xa03.26).The committee concluded that, taking into account all these factors, it was able to recommend dinutuximab beta as a cost-effective use of NHS resources.\n\nNo equality issues were identified."}
|
https://www.nice.org.uk/guidance/ta538
|
Evidence-based recommendations on dinutuximab beta (Qarziba) for high-risk neuroblastoma in people aged 12 months and over.
|
bebee03018cdf2f0dec101604f51a23ac7f47bae
|
nice
|
Transurethral water vapour ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia
|
Transurethral water vapour ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia
Evidence-based recommendations on transurethral water vapour ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves using heated water vapour to destroy some of the prostate tissue.
# Recommendations
Current evidence on the safety and efficacy of transurethral water vapour ablation for urinary tract symptoms caused by benign prostatic hyperplasia is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
This procedure should only be done by a urologist with specific training in the procedure, who should carry out their initial procedures with an experienced mentor.# The condition, current treatments and procedure
# The condition
Lower urinary tract symptoms caused by benign prostatic hyperplasia commonly affect men over 50. Stromal and epithelial cells increase in number, causing the prostate to increase in size. It often occurs in the peri-urethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.
# Current treatments
Mild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5-alpha-reductase inhibitors. If other treatments have not worked, there are a range of surgical options that may be considered including transurethral resection of the prostate (TURP), transurethral vaporisation, holmium laser enucleation, insertion of prostatic urethral lift implants, prostatic artery embolisation or prostatectomy (see the NICE clinical guideline on lower urinary tract symptoms in men). Potential complications of some of these surgical procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction.
# The procedure
Transurethral water vapour ablation is usually done as day-case surgery using local anaesthetic including a peri-prostatic block, and sometimes sedation. A device similar to a rigid cystoscope is advanced into the prostatic urethra. Under direct visualisation, a retractable needle is inserted into the prostate and water vapour (at a temperature of about 103 degrees centigrade) is delivered for 8 to 10 seconds. At the same time, saline irrigation is used to cool and protect the surface of the urethra. Conductive heat transfer disrupts cell membranes in the prostate, leading to rapid cell death. The needle is retracted and repositioned several times so that thermoablation can be repeated in different areas of the gland, including the median lobe. The aim is to reduce the size of the prostate, leading to improvement in lower urinary tract symptoms 1 to 3 months after treatment, without impairing sexual function.
Patients may have to take antibiotics and have a urinary catheter for some days after the procedure. Some activities, including sexual intercourse, should be avoided for up to 1 month.
|
{'Recommendations': 'Current evidence on the safety and efficacy of transurethral water vapour ablation for urinary tract symptoms caused by benign prostatic hyperplasia is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThis procedure should only be done by a urologist with specific training in the procedure, who should carry out their initial procedures with an experienced mentor.', 'The condition, current treatments and procedure': '# The condition\n\nLower urinary tract symptoms caused by benign prostatic hyperplasia commonly affect men over 50. Stromal and epithelial cells increase in number, causing the prostate to increase in size. It often occurs in the peri-urethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.\n\n# Current treatments\n\nMild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5-alpha-reductase inhibitors. If other treatments have not worked, there are a range of surgical options that may be considered including transurethral resection of the prostate (TURP), transurethral vaporisation, holmium laser enucleation, insertion of prostatic urethral lift implants, prostatic artery embolisation or prostatectomy (see the NICE clinical guideline on lower urinary tract symptoms in men). Potential complications of some of these surgical procedures include bleeding, infection, urethral strictures, incontinence and sexual dysfunction.\n\n# The procedure\n\nTransurethral water vapour ablation is usually done as day-case surgery using local anaesthetic including a peri-prostatic block, and sometimes sedation. A device similar to a rigid cystoscope is advanced into the prostatic urethra. Under direct visualisation, a retractable needle is inserted into the prostate and water vapour (at a temperature of about 103\xa0degrees centigrade) is delivered for 8\xa0to\xa010 seconds. At the same time, saline irrigation is used to cool and protect the surface of the urethra. Conductive heat transfer disrupts cell membranes in the prostate, leading to rapid cell death. The needle is retracted and repositioned several times so that thermoablation can be repeated in different areas of the gland, including the median lobe. The aim is to reduce the size of the prostate, leading to improvement in lower urinary tract symptoms 1\xa0to\xa03 months after treatment, without impairing sexual function.\n\nPatients may have to take antibiotics and have a urinary catheter for some days after the procedure. Some activities, including sexual intercourse, should be avoided for up to 1\xa0month.'}
|
https://www.nice.org.uk/guidance/ipg625
|
Evidence-based recommendations on transurethral water vapour ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves using heated water vapour to destroy some of the prostate tissue.
|
4139ebdb99a7ef1b639936aa66f46e2c28a7e455
|
nice
|
Lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine
|
Lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine
Evidence-based recommendations on lenvatinib (Lenvima) and sorafenib (Nexavar) for progressive, locally advanced or metastatic differentiated thyroid cancer in adults who have had radioactive iodine.
# Recommendations
Lenvatinib and sorafenib are recommended as options for treating progressive, locally advanced or metastatic differentiated thyroid cancer (papillary, follicular or Hürthle cell) in adults whose disease does not respond to radioactive iodine, only if:
they have not had a tyrosine kinase inhibitor before or
they have had to stop taking a tyrosine kinase inhibitor within 3 months of starting it because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification).Lenvatinib and sorafenib are recommended only if the companies provide them according to the commercial arrangements.
This recommendation is not intended to affect treatment with lenvatinib or sorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Lenvatinib and sorafenib (tyrosine kinase inhibitors) are the only treatment options for progressive, locally advanced or metastatic differentiated thyroid cancer after surgery and radioactive iodine. For people who cannot have lenvatinib or sorafenib, best supportive care is the only option.
Clinical trial evidence shows that lenvatinib and sorafenib are both effective in delaying disease progression, but there is a higher response rate (that is, more tumours shrink) with lenvatinib and it may delay progression for longer. Clinical expert advice is that this response is associated with an improvement in symptoms, which is valued by patients. Lenvatinib and sorafenib also increase the length of time people live, but it is uncertain by how long.
The cost-effectiveness estimates are higher than what NICE normally considers acceptable, and lenvatinib and sorafenib do not meet NICE's end-of-life criteria. But the treatments do increase length of life and there are no other treatments available for the condition. Also, the cost-effectiveness estimates do not capture the benefits of people having a response to treatment, that is, an improvement in symptoms.
Taking all this into account, lenvatinib and sorafenib are recommended as treatment options for differentiated thyroid cancer after radioactive iodine. However, they are recommended only for people who have not had tyrosine kinase inhibitors before, or who have to stop them early because of tolerability (specifically, toxicity that cannot be managed by dose delay or dose modification). This is because there is not enough clinical evidence and no cost-effectiveness evidence to determine whether the treatments are effective when used sequentially.# Information about lenvatinib and sorafenib
Marketing authorisation indications
For lenvatinib (Lenvima, Eisai)
Adults with 'progressive, locally advanced or metastatic differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine'.
Sorafenib (Nexavar, Bayer)
Adults with 'progressive, locally advanced or metastatic differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine'.
Dosage in the marketing authorisations
For lenvatinib 24 mg (2×10 mg capsules and 1×4 mg capsule) once daily.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
For sorafenib 400 mg (2×200 mg tablets) twice daily (equivalent to a total daily dose of 800 mg).
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
Prices
For lenvatinib £1,437 per 30×10 mg pack and per 30×4 mg pack (excluding VAT; British national formulary online ).
The company has a commercial arrangement. This makes lenvatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
For sorafenib £3,576.56 per 112×200 mg pack (excluding VAT; British national formulary online ).
The company has a commercial arrangement. This makes sorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Treating differentiated thyroid cancer
## There is a need for active treatment options for disease that does not respond to radioactive iodine
The patient and clinical experts explained that differentiated thyroid cancer is rare. Surgery, followed by radioactive iodine (used to destroy any remaining cancer cells) is the most common treatment. The clinical expert advised that disease that does not respond to radioactive iodine can sometimes remain stable for long periods. In clinical practice, best supportive care is offered until the disease starts to progress and symptoms occur, or there is rapid progression that is likely to become symptomatic. Lenvatinib and sorafenib are the only licensed disease-modifying treatments available in England. Sorafenib is available through the Cancer Drugs Fund for people with inoperable or metastatic papillary or follicular thyroid cancer that has not responded to radioactive iodine. Lenvatinib is available through a compassionate use programme for people who cannot tolerate sorafenib or who have disease that has progressed on sorafenib. The patient expert explained that people with progressive disease that does not respond to radioactive iodine often have reduced quality of life because of pain, fatigue and difficulty carrying out daily activities. Both lenvatinib and sorafenib allow people to return to work and take part in family life, while increasing their quality of life. The clinical expert explained that the only alternative to lenvatinib and sorafenib was best supportive care, which includes treatment such as palliative radiotherapy, analgesia and bisphosphonates. The committee concluded that there was a need for active treatment options for people with disease that does not respond to radioactive iodine.
# Clinical evidence
## The SELECT and DECISION trials are relevant to clinical practice
Two multicentre double-blind randomised controlled trials compared lenvatinib (SELECT) and sorafenib (DECISION) with placebo. Patients in both arms of the trials had best supportive care in addition to their randomised treatment. SELECT included 392 patients and DECISION included 417 patients; both trials included only patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. In DECISION around 20% of patients had disease that was symptomatic at baseline but the proportion in SELECT was not clear. The clinical expert advised that the trials included patients with recently progressed disease that was very likely to become symptomatic and that realistically, all patients who were included would become symptomatic. The clinical expert further explained that the trial populations were very similar to people having treatment in clinical practice (that is, people with progressive disease that is symptomatic or that will become symptomatic very quickly). The committee understood that in the marketing authorisations, both treatments are indicated for progressive disease and this is not restricted to symptomatic disease. The committee therefore concluded that the trials were relevant to clinical practice.
# Progression-free survival results from SELECT and DECISION
## Both treatments improve progression-free survival compared with placebo
In SELECT, lenvatinib statistically significantly improved median investigator-assessed progression-free survival compared with placebo (16.6 months for lenvatinib compared with 3.7 months for placebo; hazard ratio 0.24, 95% confidence interval 0.16 to 0.35). Similar results were reported for independently-assessed progression-free survival. In DECISION, sorafenib statistically significantly improved median investigator-assessed progression-free survival compared with placebo (10.8 months for sorafenib compared with 5.4 months for placebo; HR 0.49, 95% CI 0.39 to 0.61). Similar results were reported for independently-assessed progression-free survival. The committee concluded that there was evidence to show that both treatments are clinically effective in improving progression-free survival compared with placebo.
# Overall survival results from SELECT and DECISION
## Lenvatinib and sorafenib improve overall survival but there is uncertainty from the crossover adjustment and anticancer treatment after progression
The proportion of people crossing over from placebo to active treatment after disease progression was 88% in SELECT and 75% in DECISION. The companies and the assessment group agreed that the rank preserving structural failure time (RPSFT) method was the most appropriate to adjust for the high level of crossover in both trials. In SELECT, median overall survival for lenvatinib was 41.6 months compared with 34.5 months for placebo. After correcting for crossover, there was a statistically significant overall survival benefit for lenvatinib compared with placebo (RPSFT-adjusted HR 0.54, 95% bootstrapping CI 0.36 to 0.80). In DECISION, the median overall survival for sorafenib was 39.4 months compared with 42.8 months for placebo. After correcting for crossover, there was no statistically significant improvement in overall survival for sorafenib compared with placebo (RPSFT-adjusted HR 0.77, 95% CI 0.58 to 1.02). The assessment group advised that the statistical assumption of proportional hazards (that is, there is a constant treatment effect over time) did not hold for any of the crossover corrected results for overall survival and these results should be interpreted with caution. Also, the committee noted that using anticancer treatments after progression in both trials may have confounded the overall survival results, although it could not be certain of the extent of this effect. The committee concluded that although lenvatinib and sorafenib improve overall survival, it was uncertain by how much because of the crossover adjustment and use of anticancer treatment after disease progression.
# Indirect treatment comparison
## An indirect treatment comparison is not appropriate to compare lenvatinib and sorafenib because of differences in the trials
Both companies carried out an indirect comparison to compare the clinical effectiveness of lenvatinib with sorafenib. The assessment group stated that an indirect comparison was not appropriate because:
The risk of disease progression in patients in the 2 placebo arms of SELECT and DECISION was inconsistent over time and suggested there were differences in the patient groups in each trial.
There were differences in trial characteristics, for example:
the use of anticancer treatment after disease progression in SELECT and DECISION
in DECISION, no patients had previously had tyrosine kinase inhibitors compared with 24% in SELECT
palliative radiotherapy (commonly used as part of best supportive care in clinical practice) was not allowed in SELECT.
There were within and between trial differences in patient characteristics, such as geographical region and time from diagnosis.
The statistical assumption of proportional hazards was not met for any outcome apart from unadjusted overall survival in DECISION.As a result, the assessment group advised caution when interpreting the results from the companies' indirect comparisons and did not use these as part of its base case. The clinical expert noted that differences in patient characteristics were unlikely to explain the differences in the placebo arms across the 2 trials. However, the committee acknowledged that the Kaplan–Meier plots for progression-free survival in the placebo arms of the trials were different enough to suggest there were other important differences limiting the robustness of the indirect treatment comparisons (see section 3.3). It concluded that an indirect comparison of lenvatinib and sorafenib using evidence from SELECT and DECISION was not appropriate.
# Clinical evidence for sequential treatment
## There is insufficient clinical trial evidence of the effectiveness of sequential treatment with lenvatinib and sorafenib
In SELECT 25% of patients in the lenvatinib arm had a previous tyrosine kinase inhibitor, including sorafenib, before having lenvatinib and some patients may have had sorafenib after progression on lenvatinib. However, previous treatment with a tyrosine kinase inhibitor was not allowed in DECISION. For the subgroup who had a previous tyrosine kinase inhibitor in SELECT, median progression-free survival for lenvatinib was 15.1 months compared with 3.6 months for placebo; the difference between the treatment groups was statistically significant (HR 0.22, 95% CI 0.12 to 0.41). Objective tumour response rate was 62.1% for lenvatinib compared with 3.7% for placebo. However, Eisai did not report overall survival results. The committee, noting that the subgroup included only about 25% of the patients in SELECT, acknowledged that lenvatinib appears to delay disease progression in this group of people. However, it had not seen any evidence of a survival benefit with lenvatinib or any benefit with sorafenib in this subgroup. Although the progression-free survival results and objective tumour response rates for the subgroup were similar to the results for the overall population in SELECT, the committee could not predict whether this would also apply to the overall survival results. The committee also noted that both Eisai and the assessment group had highlighted that the subgroup results should be treated with caution because of the small number of patients. Because of the uncertainty in the subgroup results, the assessment group considered that the most appropriate data for decision-making were the results from the intention-to-treat population. Because of the limitations and uncertainty in the subgroup data, the committee concluded that there was insufficient evidence to draw firm conclusions on whether the treatments were effective when used sequentially after progression (see section 3.23).
## The compassionate use programme for lenvatinib does not provide sufficient evidence for decision-making about sequential treatment
After the second committee meeting Eisai provided time-on-treatment data from a compassionate use programme, in which lenvatinib was available for 52 people in England who had either progressed after sorafenib, or could not have sorafenib because they could not tolerate it or it was contraindicated. Eisai acknowledged that the available data were limited, but argued that the estimated time on treatment for the 18 people who had stopped treatment (6.56 months) showed lenvatinib's benefit as a second-line treatment. The committee noted that Eisai had not presented any efficacy results from the compassionate use programme, so it was not possible to estimate the relative clinical effectiveness of lenvatinib in this subgroup. Therefore, the committee concluded that the time-on-treatment data from the compassionate use programme were not sufficient evidence for decision-making about whether lenvatinib was clinically effective when used after sorafenib.
## Published audits of lenvatinib do not provide sufficient evidence of the effectiveness of sequential treatment with lenvatinib and sorafenib
Eisai also provided clinical effectiveness data from audits of lenvatinib in France (n=75), Switzerland (n=13) and Italy (n=12); 47% of people in these audits had taken at least 1 previous tyrosine kinase inhibitor. Eisai only reported efficacy results for the whole (intention-to-treat) study populations because subgroup results were not available in the published papers. The French and Swiss audits reported median progression-free survival as 10 and 7.2 months, respectively. The Swiss audit reported median overall survival as 22.7 months; median overall survival was not reached in the French audit. Progression-free survival and overall survival results were not reported for the Italian audit. Because these audits contained a higher proportion of patients who had a previous tyrosine kinase inhibitor than in SELECT, Eisai stated that the efficacy results suggested a clinical benefit from the sequential use of lenvatinib. However, the assessment group was concerned that the efficacy results presented were for the whole study populations, rather than for the group of patients who had a previous tyrosine kinase inhibitor. Because of this, the assessment group considered that the audits did not provide enough evidence to draw conclusions about the effects of lenvatinib in this group. The assessment group also noted the large differences in patient characteristics across the studies (such as prognosis, sex, age, time from diagnosis and site of metastases), and advised that this would affect the interpretation of the efficacy findings. It emphasised that only 23% of the patients included in the French audit would have been eligible for inclusion in SELECT. It also stated that differences in the duration of treatment and length of follow-up between the studies would likely influence the survival estimates reported. The committee considered the company's data, but was aware that it had not seen efficacy results for the subgroup who had a previous tyrosine kinase inhibitor. Having also heard the assessment group's concerns about the heterogeneity between the studies, the committee concluded that the audits did not provide convincing evidence of the clinical effectiveness of sequential treatment with lenvatinib after sorafenib.
# Adverse events
## The decision to use lenvatinib or sorafenib is based on individual circumstances and consideration of the risks and benefits
Almost all patients in SELECT and DECISION had an adverse event while having lenvatinib (99.6%) or sorafenib (98.6%). Side effects such as sore hands and feet were more common with sorafenib and hypertension was more common with lenvatinib. The patient expert described how people may need to go to hospital because of side effects, but that these were manageable. The clinical expert explained that additional clinical monitoring visits are needed when starting both treatments and that there is little effect on quality of life when treatment-related symptoms are quickly identified and treated. The clinical expert advised that the choice between lenvatinib or sorafenib depends on individual circumstances such as pain and location of lesions. However, clinical effectiveness, particularly response rates and toxicity profiles are also considered. The clinical expert explained that response rates suggested a larger benefit for lenvatinib (SELECT; objective tumour response 65%, DECISION; objective tumour response 12%). The clinical expert also noted the importance of balancing the risks and benefits when considering treatment. The committee concluded that the decision to use lenvatinib or sorafenib is based on individual circumstances and consideration of the risks and benefits.
# Economic models
## A model with 3 health states comparing each treatment with best supportive care is preferred for decision-making
Eisai's model for lenvatinib included 4 health states (stable disease, response, progressive and death) whereas Bayer's model for sorafenib included only 3 health states (progression-free, progressed and death). The assessment group was concerned that Eisai used a single aggregate ratio to estimate the number of patients in the response state for the sorafenib arm because no individual patient level data from DECISION were available. Eisai's approach excluded differences in the time and duration of response in DECISION and affected utility estimates. Therefore the assessment group used a 3-state model, similar to Bayer's. Clinical advice to the assessment group suggested there was no additional benefit from including a separate response health state in the economic model. However, the clinical expert at the committee meeting explained that for symptomatic disease, response to treatment substantially affects quality of life (see section 3.19). The committee noted the difference in opinion but considered that there were no data presented measuring the effect of a response health state on costs and utility values. The assessment group's model used survival data and treatment duration taken directly from SELECT and DECISION and compared each treatment with best supportive care, whereas the company models also included an indirect comparison of lenvatinib and sorafenib. To assess the extent of the uncertainty when comparing the cost effectiveness of lenvatinib with sorafenib, the assessment group's model allowed a cross-trial comparison of the best supportive care arms from SELECT and DECISION and this had a large impact on the cost effectiveness of both treatments. The committee had previously concluded that an indirect comparison of lenvatinib and sorafenib was not appropriate (see section 3.5). Because there wasn't a 4-state model that modelled response for both treatments appropriately, the committee concluded that a 3-state model comparing each treatment with best supportive care was preferred for decision-making.
# Extrapolating survival
## The assessment group's method provided the best fit to the trial data but other extrapolations for progression-free survival are plausible
For progression-free survival, the assessment group used a single fitted exponential extrapolation that was unconstrained (that is, it did not pass through the origin) to extrapolate the trial data. In response to consultation, Bayer questioned this method because there was an artificial drop in the extrapolated portion of the curve for sorafenib, which underestimated long-term survival and was unlikely to reflect clinical practice. Bayer therefore presented 3 alternative approaches to estimate long-term progression-free survival. The assessment group criticised 2 of Bayer's alternative approaches because long-term survival was overestimated and the progression-free survival benefit therefore favoured sorafenib. It also noted that one of these alternative approaches, a piecewise extrapolation, was flawed because progression-free survival unexpectedly increased by around 35% at 16 months but time-to-event analyses can only decrease or remain constant over time. The assessment group explained that there may have been a phase of increased risk of progression or death at the end of the trial that could continue beyond the trial period. Therefore it fitted an exponential extrapolation to the tail of the progression-free survival curve to make use of the observed trial data. The committee understood that the assessment group's approach provided a close fit to the final events of disease progression in the trial, with a mean progression-free survival estimate that was neither too generous nor too conservative. The committee concluded that the assessment group's method provided the best fit to the trial data but considered that some of Bayer's alternative extrapolations were also clinically plausible.
## The assessment group's method provided the best fit to the trial data but other extrapolations for overall survival are plausible
For overall survival, the assessment group investigated longer-term survival trends in people with locally advanced or metastatic thyroid cancer in the US using the Surveillance, Epidemiology, and End Results (SEER) database. The database contains information on over 32,000 people who were followed up over 15 years. The assessment group explained that the SEER data followed a simple linear model that indicated that the risk of death was unchanged over the 15 years of follow-up. Therefore, the assessment group used a 2-phase exponential distribution in a piecewise model to extrapolate the Kaplan–Meier data from the trials. The clinical expert explained that historical data are unlikely to include the same population as the DECISION and SELECT trials. The assessment group also explored other parametric models and extrapolation methods for overall survival. It noted that the piecewise exponential model was the best-fitting option in 2 of the 4 trial arms, but no single extrapolation showed a clear advantage over another. Bayer used several alternative curves to extrapolate overall survival based on measures of fit to the trial data as well as published epidemiological evidence and clinical advice. Bayer considered that the fully parametric exponential and piecewise exponential models were similarly plausible, but suggested that a single exponential curve fitted the survival estimates reported in a survey of 7 UK clinical experts better than the assessment group's approach. The committee understood that the cost effectiveness of sorafenib improved substantially using Bayer's alternative extrapolations in the assessment group's model. But it noted that the single exponential extrapolation was a poor fit to the trial data and appeared to be an outlier compared with other survival extrapolations. The committee concluded that the assessment group's method fitted the trial data well but Bayer's alternative extrapolations were also clinically plausible and improved the cost effectiveness of sorafenib.
# Utility values
## Using utility values from DECISION is the most appropriate
The models used utility values from health questionnaire (EQ-5D-3L) data collected in DECISION. Eisai explained that no EQ-5D data were collected for lenvatinib in SELECT, therefore its model used utility values from the best supportive care arm of DECISION and applied disutilities for adverse events as a weighted proportion using values from a vignette study (Fordham et al. 2015). The study included 100 people from the UK but the assessment group advised that their baseline utility values were higher than for a general UK population of a similar age. The model from the assessment group and Bayer assumed that disutilities were included in the EQ-5D values from DECISION. The assessment group preferred to use data from DECISION in its base case because it considered that evidence from people with differentiated thyroid cancer was more relevant to current practice than data from a vignette study. The assessment group explained that because there were no utility values for lenvatinib, utility values from DECISION were used for both treatments. The committee noted that this made lenvatinib more cost effective and sorafenib less cost effective. It recognised that utility values from DECISION did not adequately capture the different tolerability of the treatments and the different responses to treatment (see section 3.19) and so the utility values for lenvatinib may have been underestimated. Because there were no other utility data the committee concluded that using utility values from DECISION was more appropriate than using the values from the vignette study.
# Resource use
## Changes to the assessment group's scenario analyses are clinically plausible and appropriate for decision-making
In its response to consultation, Eisai commented that the assessment group's estimates of resource use were not consistent with advice from 4 UK clinical experts. Eisai explained that in UK clinical practice hypertension is usually managed in primary care, bone scans are not carried out, there are fewer MRI scans and more frequent oncologist visits. The committee understood that when the estimates of resource used were changed in line with clinical practice in the assessment group's scenario analyses, both lenvatinib and sorafenib became more cost effective than best supportive care. The clinical expert confirmed that fewer investigations may be carried out in clinical practice than suggested in the assessment group's report, particularly before disease progression. The committee considered that resource use in the assessment group's base-case model may be overestimated. It concluded that the changes to the scenario analyses were clinically plausible and appropriate for decision-making.
# Treatment after disease progression
## The assessment group's model did not consistently include treatments taken after progression
In its response to consultation, Bayer commented that the assessment group's model included the cost of taking sorafenib after progression but it did not include the cost of taking other tyrosine kinase inhibitors after progression on lenvatinib. Bayer considered this to be inconsistent with the clinical trials and UK clinical practice. The assessment group acknowledged that in SELECT, patients were allowed to take tyrosine kinase inhibitors other than lenvatinib after disease progression. However, there were no data available from SELECT on tyrosine kinase inhibitor use that could be incorporated in the economic model. The committee understood that both Bayer and the assessment group reported scenario analyses without the cost of sorafenib taken after progression. In the assessment group's analyses this scenario had little effect on its base case but there was a substantial improvement in the cost effectiveness of sorafenib using Bayer's alternative extrapolations (see section 3.11 and section 3.12). The committee acknowledged the lack of data but concluded that the assessment group's modelling of treatment after progression was not consistent for lenvatinib and sorafenib.
# Revised base case
## The assessment group's model is preferred for decision-making, but alternative assumptions may be plausible
The committee considered that the assessment group's model was the most reliable to estimate cost effectiveness. The model:
compared each treatment with best supportive care only (assessment group's base case, see section 3.10)
used a 3-state model that did not include a separate state for people with disease that responded to treatment (assessment group's base case, see section 3.10)
used utility values from DECISION for both treatments (assessment group's base case, see section 3.13)
used alternative resource use estimates for both treatments (assessment group's scenario analysis, see section 3.14).After consultation, the assessment group revised its base case to correct the dose of lenvatinib, used another method to calculate costs for adverse events and corrected a discounting error. The committee understood that in the assessment group's revised base case, the method and time point for extrapolating survival data was unchanged. It noted the uncertainty in the choice of survival extrapolation. Although the committee preferred the assessment group's method of extrapolation and agreed it would use it in its decision-making, it also recognised that some alternative extrapolations preferred by Bayer may be clinically plausible (see section 3.11 and section 3.12).
# Cost-effectiveness results
## The ICERs for lenvatinib and sorafenib are more than £30,000 per QALY gained
For lenvatinib compared with best supportive care, the incremental cost-effectiveness ratio (ICER) using the committee's preferred assumptions and including the confidential commercial arrangement was more than £30,000 per quality-adjusted life year (QALY) gained.
For sorafenib compared with best supportive care, the ICER using the committee's preferred assumptions and the confidential commercial arrangement was more than £30,000 per QALY gained.
# Uncaptured benefits
## There are some health-related benefits from response to treatment that are not captured in the preferred analyses, which could reduce the ICERs
The committee recognised that differentiated thyroid cancer is rare, and that lenvatinib and sorafenib are the only targeted treatments available. It noted that both drugs delayed disease progression compared with best supportive care. Despite some methodological uncertainty because the proportional hazards assumption was not met, the model predicted substantial overall survival benefit. The committee understood that although there was a statistically significant reduction in EQ-5D values in the sorafenib arm in DECISION, this difference was not considered clinically meaningful. However, the clinical and patient experts advised that for symptomatic disease, response to treatment has a substantial effect on quality of life and this is valued by patients. This is particularly so for lenvatinib, which has a higher response rate than sorafenib (see section 3.9). The committee recalled that Eisai's model did not incorporate response appropriately for both treatments and recognised that the most plausible ICERs were based on the assessment group's model, which did not adequately capture this benefit. Therefore the committee concluded that there may be some additional health-related quality-of-life benefits from response to treatment that are not captured in the QALY calculations. It agreed that accounting for these uncaptured benefits could reduce the ICERs.
# End of life
## Both drugs meet the criterion for extension to life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The assessment group's model estimated a mean survival benefit of 25 months for lenvatinib compared with best supportive care and 13 months for sorafenib compared with best supportive care. The committee recognised it was likely that both treatments provided a substantial overall survival gain compared with best supportive care. But it agreed there was uncertainty around how long people live with progressed disease. The committee agreed that the end-of-life criterion for extension to life (that is, a mean of at least 3 additional months) was met for both lenvatinib and sorafenib.
## There is uncertainty about predicted overall survival and neither drug meets the criterion for short life expectancy
The assessment group's model predicted mean overall survival for best supportive care to be over 24 months (in the RPSFT-adjusted placebo arm in SELECT it was 30.2 months and in DECISION 43.8 months). However, the committee recalled that both lenvatinib and sorafenib provided a substantial overall survival benefit compared with best supportive care that is not normally seen with other drugs for other cancers. The committee discussed whether it could accept a longer life expectancy of more than 24 months because of the substantial survival benefit, noting that the end-of-life criteria allowed this flexibility. However, it was concerned that survival of up to 43.8 months was not likely to be considered end of life. Also, it noted that the data were not robust enough to establish how long people live with progressive locally advanced or metastatic differentiated thyroid cancer. The clinical expert explained that although it is not possible to know the overall survival estimates for a population who has not had treatment, locally advanced or metastatic differentiated thyroid cancer is considered a terminal disease. The committee noted that in the assessment group's alternative extrapolations, the predicted overall survival estimates for the best supportive care arm after 10 years were consistently longer than 24 months. It understood that Bayer reported subgroup analyses in patients with symptomatic disease, but recalled the clinical expert's view that the trial populations were very similar to people having treatment in clinical practice, that is, people with progressive disease that is symptomatic or that will become symptomatic very quickly (see section 3.2). It noted that the subgroup analyses in patients with symptomatic disease from DECISION were post-hoc exploratory analyses that may not be reliable. Also, the assessment group's estimates of overall survival in this post-hoc subgroup were greater than 24 months. The committee debated whether it could apply flexibility when interpreting the end-of-life criteria but recognised that a high degree of certainty is needed. Based on the evidence presented, the committee concluded that neither lenvatinib nor sorafenib met the criterion for short life expectancy and therefore the end-of-life criteria did not apply.
# Conclusions
## Lenvatinib and sorafenib are recommended for treating differentiated thyroid cancer after radioactive iodine
The committee noted that there were additional considerations that could reduce the ICERs for lenvatinib and sorafenib compared with best supportive care, including:
accounting for uncaptured benefit from response (see section 3.19)
some of Bayer's alternative extrapolations of survival data for sorafenib may be plausible (see section 3.11, section 3.12 and section 3.16).The committee also considered the substantial modelled survival benefit (25 months for lenvatinib and 13 months for sorafenib) for people with this rare disease and that there are no other treatment options (see section 3.1). Taking all of this into account, the committee recommended lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine.
## Lenvatinib and sorafenib are recommended only for people who have not had a tyrosine kinase inhibitor
Neither the companies nor the assessment group presented cost-effectiveness analyses according to previous tyrosine kinase inhibitor treatment. For sorafenib, this was not necessary because previous tyrosine kinase inhibitor treatment was not allowed in DECISION. Therefore sorafenib can only be considered and recommended by the committee as a first tyrosine kinase inhibitor treatment for this indication. Eisai's model for lenvatinib was based on the overall population from SELECT only. It did not present a cost-effectiveness analysis for the subgroup who had previous tyrosine kinase inhibitor treatment because of the small patient numbers. The assessment group did not have access to the overall survival results for this subgroup from SELECT, therefore it did not do a cost-effectiveness analysis for this group. However, it stated that the uncertainties about the small numbers in the subgroup and the assumption of proportional hazards in the crossover-adjusted overall survival results for the overall population (see section 3.4) would not allow a robust estimate of cost effectiveness of lenvatinib in this subgroup. The committee would have preferred to see cost-effectiveness estimates according to previous tyrosine kinase inhibitor treatment, although it acknowledged that the estimates may not be robust. The committee was aware that the cost-effectiveness estimates provided were based on the overall SELECT population including the small number of patients who had previously had tyrosine kinase inhibitor treatment. However, because of the uncertainty about the clinical effectiveness (see sections 3.6 to 3.8) and the cost effectiveness of the drugs when used sequentially, the committee concluded that its recommendation for sorafenib and lenvatinib was limited to people who have not had previous treatment with a tyrosine kinase inhibitor.
## The recommendation extends to people who have had to stop a tyrosine kinase inhibitor within 3 months of starting treatment because of toxicity
The committee was aware that some people who had a tyrosine kinase inhibitor as their initial treatment for differentiated thyroid cancer (after radioactive iodine) may have had to stop treatment because of toxicity. Aware of its recommendation about the sequential use of sorafenib and lenvatinib, the committee agreed that people who had to stop treatment with a tyrosine kinase inhibitor because of early intolerance would be considered as having had no previous treatment. The committee concluded that its recommendation extends to people who have had to stop a tyrosine kinase inhibitor within 3 months of starting treatment because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification).
## The recommendation does not include people having lenvatinib after disease progression on sorafenib (currently provided through compassionate use)
The committee discussed the issue of the compassionate use scheme for lenvatinib, in which the company is providing access to lenvatinib for people who cannot tolerate sorafenib or who have disease that has progressed on sorafenib. The committee acknowledged its recommendation does not include the latter group (people who have progressed on sorafenib). It understood from NHS England that patients who have commenced compassionate use treatment will be able to continue treatment as long as the patients and clinicians felt there was benefit.
# Other factors
No equality issues were identified.
|
{'Recommendations': "Lenvatinib and sorafenib are recommended as options for treating progressive, locally advanced or metastatic differentiated thyroid cancer (papillary, follicular or Hürthle cell) in adults whose disease does not respond to radioactive iodine, only if:\n\nthey have not had a tyrosine kinase inhibitor before or\n\nthey have had to stop taking a tyrosine kinase inhibitor within 3\xa0months of starting it because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification).Lenvatinib and sorafenib are recommended only if the companies provide them according to the commercial arrangements.\n\nThis recommendation is not intended to affect treatment with lenvatinib or sorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nLenvatinib and sorafenib (tyrosine kinase inhibitors) are the only treatment options for progressive, locally advanced or metastatic differentiated thyroid cancer after surgery and radioactive iodine. For people who cannot have lenvatinib or sorafenib, best supportive care is the only option.\n\nClinical trial evidence shows that lenvatinib and sorafenib are both effective in delaying disease progression, but there is a higher response rate (that is, more tumours shrink) with lenvatinib and it may delay progression for longer. Clinical expert advice is that this response is associated with an improvement in symptoms, which is valued by patients. Lenvatinib and sorafenib also increase the length of time people live, but it is uncertain by how long.\n\nThe cost-effectiveness estimates are higher than what NICE normally considers acceptable, and lenvatinib and sorafenib do not meet NICE's end-of-life criteria. But the treatments do increase length of life and there are no other treatments available for the condition. Also, the cost-effectiveness estimates do not capture the benefits of people having a response to treatment, that is, an improvement in symptoms.\n\nTaking all this into account, lenvatinib and sorafenib are recommended as treatment options for differentiated thyroid cancer after radioactive iodine. However, they are recommended only for people who have not had tyrosine kinase inhibitors before, or who have to stop them early because of tolerability (specifically, toxicity that cannot be managed by dose delay or dose modification). This is because there is not enough clinical evidence and no cost-effectiveness evidence to determine whether the treatments are effective when used sequentially.", 'Information about lenvatinib and sorafenib': "Marketing authorisation indications\n\nFor lenvatinib (Lenvima, Eisai)\n\nAdults with 'progressive, locally advanced or metastatic differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine'.\n\nSorafenib (Nexavar, Bayer)\n\nAdults with 'progressive, locally advanced or metastatic differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine'.\n\nDosage in the marketing authorisations\n\nFor lenvatinib 24\xa0mg (2×10\xa0mg capsules and 1×4\xa0mg capsule) once daily.\n\nTreatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.\n\nFor sorafenib 400\xa0mg (2×200\xa0mg tablets) twice daily (equivalent to a total daily dose of 800\xa0mg).\n\nTreatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.\n\nPrices\n\nFor lenvatinib £1,437 per 30×10\xa0mg pack and per 30×4\xa0mg pack (excluding VAT; British national formulary online [accessed July 2017]).\n\n\n\nThe company has a commercial arrangement. This makes lenvatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nFor sorafenib £3,576.56 per 112×200\xa0mg pack (excluding VAT; British national formulary online [accessed July 2017]).\n\n\n\nThe company has a commercial arrangement. This makes sorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Treating differentiated thyroid cancer\n\n## There is a need for active treatment options for disease that does not respond to radioactive iodine\n\nThe patient and clinical experts explained that differentiated thyroid cancer is rare. Surgery, followed by radioactive iodine (used to destroy any remaining cancer cells) is the most common treatment. The clinical expert advised that disease that does not respond to radioactive iodine can sometimes remain stable for long periods. In clinical practice, best supportive care is offered until the disease starts to progress and symptoms occur, or there is rapid progression that is likely to become symptomatic. Lenvatinib and sorafenib are the only licensed disease-modifying treatments available in England. Sorafenib is available through the Cancer Drugs Fund for people with inoperable or metastatic papillary or follicular thyroid cancer that has not responded to radioactive iodine. Lenvatinib is available through a compassionate use programme for people who cannot tolerate sorafenib or who have disease that has progressed on sorafenib. The patient expert explained that people with progressive disease that does not respond to radioactive iodine often have reduced quality of life because of pain, fatigue and difficulty carrying out daily activities. Both lenvatinib and sorafenib allow people to return to work and take part in family life, while increasing their quality of life. The clinical expert explained that the only alternative to lenvatinib and sorafenib was best supportive care, which includes treatment such as palliative radiotherapy, analgesia and bisphosphonates. The committee concluded that there was a need for active treatment options for people with disease that does not respond to radioactive iodine.\n\n# Clinical evidence\n\n## The SELECT and DECISION trials are relevant to clinical practice\n\nTwo multicentre double-blind randomised controlled trials compared lenvatinib (SELECT) and sorafenib (DECISION) with placebo. Patients in both arms of the trials had best supportive care in addition to their randomised treatment. SELECT included 392\xa0patients and DECISION included 417\xa0patients; both trials included only patients with Eastern Cooperative Oncology Group (ECOG) performance status 0\xa0to\xa02. In DECISION around 20% of patients had disease that was symptomatic at baseline but the proportion in SELECT was not clear. The clinical expert advised that the trials included patients with recently progressed disease that was very likely to become symptomatic and that realistically, all patients who were included would become symptomatic. The clinical expert further explained that the trial populations were very similar to people having treatment in clinical practice (that is, people with progressive disease that is symptomatic or that will become symptomatic very quickly). The committee understood that in the marketing authorisations, both treatments are indicated for progressive disease and this is not restricted to symptomatic disease. The committee therefore concluded that the trials were relevant to clinical practice.\n\n# Progression-free survival results from SELECT and DECISION\n\n## Both treatments improve progression-free survival compared with placebo\n\nIn SELECT, lenvatinib statistically significantly improved median investigator-assessed progression-free survival compared with placebo (16.6\xa0months for lenvatinib compared with 3.7\xa0months for placebo; hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.16 to 0.35). Similar results were reported for independently-assessed progression-free survival. In DECISION, sorafenib statistically significantly improved median investigator-assessed progression-free survival compared with placebo (10.8\xa0months for sorafenib compared with 5.4\xa0months for placebo; HR 0.49, 95% CI 0.39 to 0.61). Similar results were reported for independently-assessed progression-free survival. The committee concluded that there was evidence to show that both treatments are clinically effective in improving progression-free survival compared with placebo.\n\n# Overall survival results from SELECT and DECISION\n\n## Lenvatinib and sorafenib improve overall survival but there is uncertainty from the crossover adjustment and anticancer treatment after progression\n\nThe proportion of people crossing over from placebo to active treatment after disease progression was 88% in SELECT and 75% in DECISION. The companies and the assessment group agreed that the rank preserving structural failure time (RPSFT) method was the most appropriate to adjust for the high level of crossover in both trials. In SELECT, median overall survival for lenvatinib was 41.6\xa0months compared with 34.5\xa0months for placebo. After correcting for crossover, there was a statistically significant overall survival benefit for lenvatinib compared with placebo (RPSFT-adjusted HR 0.54, 95% bootstrapping CI 0.36 to 0.80). In DECISION, the median overall survival for sorafenib was 39.4\xa0months compared with 42.8\xa0months for placebo. After correcting for crossover, there was no statistically significant improvement in overall survival for sorafenib compared with placebo (RPSFT-adjusted HR 0.77, 95% CI 0.58 to 1.02). The assessment group advised that the statistical assumption of proportional hazards (that is, there is a constant treatment effect over time) did not hold for any of the crossover corrected results for overall survival and these results should be interpreted with caution. Also, the committee noted that using anticancer treatments after progression in both trials may have confounded the overall survival results, although it could not be certain of the extent of this effect. The committee concluded that although lenvatinib and sorafenib improve overall survival, it was uncertain by how much because of the crossover adjustment and use of anticancer treatment after disease progression.\n\n# Indirect treatment comparison\n\n## An indirect treatment comparison is not appropriate to compare lenvatinib and sorafenib because of differences in the trials\n\nBoth companies carried out an indirect comparison to compare the clinical effectiveness of lenvatinib with sorafenib. The assessment group stated that an indirect comparison was not appropriate because:\n\nThe risk of disease progression in patients in the 2\xa0placebo arms of SELECT and DECISION was inconsistent over time and suggested there were differences in the patient groups in each trial.\n\nThere were differences in trial characteristics, for example:\n\n\n\nthe use of anticancer treatment after disease progression in SELECT and DECISION\n\nin DECISION, no patients had previously had tyrosine kinase inhibitors compared with 24% in SELECT\n\npalliative radiotherapy (commonly used as part of best supportive care in clinical practice) was not allowed in SELECT.\n\n\n\nThere were within and between trial differences in patient characteristics, such as geographical region and time from diagnosis.\n\nThe statistical assumption of proportional hazards was not met for any outcome apart from unadjusted overall survival in DECISION.As a result, the assessment group advised caution when interpreting the results from the companies' indirect comparisons and did not use these as part of its base case. The clinical expert noted that differences in patient characteristics were unlikely to explain the differences in the placebo arms across the 2\xa0trials. However, the committee acknowledged that the Kaplan–Meier plots for progression-free survival in the placebo arms of the trials were different enough to suggest there were other important differences limiting the robustness of the indirect treatment comparisons (see section\xa03.3). It concluded that an indirect comparison of lenvatinib and sorafenib using evidence from SELECT and DECISION was not appropriate.\n\n# Clinical evidence for sequential treatment\n\n## There is insufficient clinical trial evidence of the effectiveness of sequential treatment with lenvatinib and sorafenib\n\nIn SELECT 25% of patients in the lenvatinib arm had a previous tyrosine kinase inhibitor, including sorafenib, before having lenvatinib and some patients may have had sorafenib after progression on lenvatinib. However, previous treatment with a tyrosine kinase inhibitor was not allowed in DECISION. For the subgroup who had a previous tyrosine kinase inhibitor in SELECT, median progression-free survival for lenvatinib was 15.1\xa0months compared with 3.6\xa0months for placebo; the difference between the treatment groups was statistically significant (HR 0.22, 95% CI 0.12 to 0.41). Objective tumour response rate was 62.1% for lenvatinib compared with 3.7% for placebo. However, Eisai did not report overall survival results. The committee, noting that the subgroup included only about 25% of the patients in SELECT, acknowledged that lenvatinib appears to delay disease progression in this group of people. However, it had not seen any evidence of a survival benefit with lenvatinib or any benefit with sorafenib in this subgroup. Although the progression-free survival results and objective tumour response rates for the subgroup were similar to the results for the overall population in SELECT, the committee could not predict whether this would also apply to the overall survival results. The committee also noted that both Eisai and the assessment group had highlighted that the subgroup results should be treated with caution because of the small number of patients. Because of the uncertainty in the subgroup results, the assessment group considered that the most appropriate data for decision-making were the results from the intention-to-treat population. Because of the limitations and uncertainty in the subgroup data, the committee concluded that there was insufficient evidence to draw firm conclusions on whether the treatments were effective when used sequentially after progression (see section\xa03.23).\n\n## The compassionate use programme for lenvatinib does not provide sufficient evidence for decision-making about sequential treatment\n\nAfter the second committee meeting Eisai provided time-on-treatment data from a compassionate use programme, in which lenvatinib was available for 52\xa0people in England who had either progressed after sorafenib, or could not have sorafenib because they could not tolerate it or it was contraindicated. Eisai acknowledged that the available data were limited, but argued that the estimated time on treatment for the 18\xa0people who had stopped treatment (6.56\xa0months) showed lenvatinib's benefit as a second-line treatment. The committee noted that Eisai had not presented any efficacy results from the compassionate use programme, so it was not possible to estimate the relative clinical effectiveness of lenvatinib in this subgroup. Therefore, the committee concluded that the time-on-treatment data from the compassionate use programme were not sufficient evidence for decision-making about whether lenvatinib was clinically effective when used after sorafenib.\n\n## Published audits of lenvatinib do not provide sufficient evidence of the effectiveness of sequential treatment with lenvatinib and sorafenib\n\nEisai also provided clinical effectiveness data from audits of lenvatinib in France (n=75), Switzerland (n=13) and Italy (n=12); 47% of people in these audits had taken at least 1\xa0previous tyrosine kinase inhibitor. Eisai only reported efficacy results for the whole (intention-to-treat) study populations because subgroup results were not available in the published papers. The French and Swiss audits reported median progression-free survival as 10 and 7.2\xa0months, respectively. The Swiss audit reported median overall survival as 22.7\xa0months; median overall survival was not reached in the French audit. Progression-free survival and overall survival results were not reported for the Italian audit. Because these audits contained a higher proportion of patients who had a previous tyrosine kinase inhibitor than in SELECT, Eisai stated that the efficacy results suggested a clinical benefit from the sequential use of lenvatinib. However, the assessment group was concerned that the efficacy results presented were for the whole study populations, rather than for the group of patients who had a previous tyrosine kinase inhibitor. Because of this, the assessment group considered that the audits did not provide enough evidence to draw conclusions about the effects of lenvatinib in this group. The assessment group also noted the large differences in patient characteristics across the studies (such as prognosis, sex, age, time from diagnosis and site of metastases), and advised that this would affect the interpretation of the efficacy findings. It emphasised that only 23% of the patients included in the French audit would have been eligible for inclusion in SELECT. It also stated that differences in the duration of treatment and length of follow-up between the studies would likely influence the survival estimates reported. The committee considered the company's data, but was aware that it had not seen efficacy results for the subgroup who had a previous tyrosine kinase inhibitor. Having also heard the assessment group's concerns about the heterogeneity between the studies, the committee concluded that the audits did not provide convincing evidence of the clinical effectiveness of sequential treatment with lenvatinib after sorafenib.\n\n# Adverse events\n\n## The decision to use lenvatinib or sorafenib is based on individual circumstances and consideration of the risks and benefits\n\nAlmost all patients in SELECT and DECISION had an adverse event while having lenvatinib (99.6%) or sorafenib (98.6%). Side effects such as sore hands and feet were more common with sorafenib and hypertension was more common with lenvatinib. The patient expert described how people may need to go to hospital because of side effects, but that these were manageable. The clinical expert explained that additional clinical monitoring visits are needed when starting both treatments and that there is little effect on quality of life when treatment-related symptoms are quickly identified and treated. The clinical expert advised that the choice between lenvatinib or sorafenib depends on individual circumstances such as pain and location of lesions. However, clinical effectiveness, particularly response rates and toxicity profiles are also considered. The clinical expert explained that response rates suggested a larger benefit for lenvatinib (SELECT; objective tumour response 65%, DECISION; objective tumour response 12%). The clinical expert also noted the importance of balancing the risks and benefits when considering treatment. The committee concluded that the decision to use lenvatinib or sorafenib is based on individual circumstances and consideration of the risks and benefits.\n\n# Economic models\n\n## A model with 3\xa0health states comparing each treatment with best supportive care is preferred for decision-making\n\nEisai's model for lenvatinib included 4\xa0health states (stable disease, response, progressive and death) whereas Bayer's model for sorafenib included only 3\xa0health states (progression-free, progressed and death). The assessment group was concerned that Eisai used a single aggregate ratio to estimate the number of patients in the response state for the sorafenib arm because no individual patient level data from DECISION were available. Eisai's approach excluded differences in the time and duration of response in DECISION and affected utility estimates. Therefore the assessment group used a 3-state model, similar to Bayer's. Clinical advice to the assessment group suggested there was no additional benefit from including a separate response health state in the economic model. However, the clinical expert at the committee meeting explained that for symptomatic disease, response to treatment substantially affects quality of life (see section\xa03.19). The committee noted the difference in opinion but considered that there were no data presented measuring the effect of a response health state on costs and utility values. The assessment group's model used survival data and treatment duration taken directly from SELECT and DECISION and compared each treatment with best supportive care, whereas the company models also included an indirect comparison of lenvatinib and sorafenib. To assess the extent of the uncertainty when comparing the cost effectiveness of lenvatinib with sorafenib, the assessment group's model allowed a cross-trial comparison of the best supportive care arms from SELECT and DECISION and this had a large impact on the cost effectiveness of both treatments. The committee had previously concluded that an indirect comparison of lenvatinib and sorafenib was not appropriate (see section\xa03.5). Because there wasn't a 4-state model that modelled response for both treatments appropriately, the committee concluded that a 3-state model comparing each treatment with best supportive care was preferred for decision-making.\n\n# Extrapolating survival\n\n## The assessment group's method provided the best fit to the trial data but other extrapolations for progression-free survival are plausible\n\nFor progression-free survival, the assessment group used a single fitted exponential extrapolation that was unconstrained (that is, it did not pass through the origin) to extrapolate the trial data. In response to consultation, Bayer questioned this method because there was an artificial drop in the extrapolated portion of the curve for sorafenib, which underestimated long-term survival and was unlikely to reflect clinical practice. Bayer therefore presented 3\xa0alternative approaches to estimate long-term progression-free survival. The assessment group criticised 2\xa0of Bayer's alternative approaches because long-term survival was overestimated and the progression-free survival benefit therefore favoured sorafenib. It also noted that one of these alternative approaches, a piecewise extrapolation, was flawed because progression-free survival unexpectedly increased by around 35% at 16\xa0months but time-to-event analyses can only decrease or remain constant over time. The assessment group explained that there may have been a phase of increased risk of progression or death at the end of the trial that could continue beyond the trial period. Therefore it fitted an exponential extrapolation to the tail of the progression-free survival curve to make use of the observed trial data. The committee understood that the assessment group's approach provided a close fit to the final events of disease progression in the trial, with a mean progression-free survival estimate that was neither too generous nor too conservative. The committee concluded that the assessment group's method provided the best fit to the trial data but considered that some of Bayer's alternative extrapolations were also clinically plausible.\n\n## The assessment group's method provided the best fit to the trial data but other extrapolations for overall survival are plausible\n\nFor overall survival, the assessment group investigated longer-term survival trends in people with locally advanced or metastatic thyroid cancer in the US using the Surveillance, Epidemiology, and End Results (SEER) database. The database contains information on over 32,000\xa0people who were followed up over 15\xa0years. The assessment group explained that the SEER data followed a simple linear model that indicated that the risk of death was unchanged over the 15\xa0years of follow-up. Therefore, the assessment group used a 2-phase exponential distribution in a piecewise model to extrapolate the Kaplan–Meier data from the trials. The clinical expert explained that historical data are unlikely to include the same population as the DECISION and SELECT trials. The assessment group also explored other parametric models and extrapolation methods for overall survival. It noted that the piecewise exponential model was the best-fitting option in 2 of the 4\xa0trial arms, but no single extrapolation showed a clear advantage over another. Bayer used several alternative curves to extrapolate overall survival based on measures of fit to the trial data as well as published epidemiological evidence and clinical advice. Bayer considered that the fully parametric exponential and piecewise exponential models were similarly plausible, but suggested that a single exponential curve fitted the survival estimates reported in a survey of 7\xa0UK clinical experts better than the assessment group's approach. The committee understood that the cost effectiveness of sorafenib improved substantially using Bayer's alternative extrapolations in the assessment group's model. But it noted that the single exponential extrapolation was a poor fit to the trial data and appeared to be an outlier compared with other survival extrapolations. The committee concluded that the assessment group's method fitted the trial data well but Bayer's alternative extrapolations were also clinically plausible and improved the cost effectiveness of sorafenib.\n\n# Utility values\n\n## Using utility values from DECISION is the most appropriate\n\nThe models used utility values from health questionnaire (EQ-5D-3L) data collected in DECISION. Eisai explained that no EQ-5D data were collected for lenvatinib in SELECT, therefore its model used utility values from the best supportive care arm of DECISION and applied disutilities for adverse events as a weighted proportion using values from a vignette study (Fordham et al. 2015). The study included 100\xa0people from the UK but the assessment group advised that their baseline utility values were higher than for a general UK population of a similar age. The model from the assessment group and Bayer assumed that disutilities were included in the EQ-5D values from DECISION. The assessment group preferred to use data from DECISION in its base case because it considered that evidence from people with differentiated thyroid cancer was more relevant to current practice than data from a vignette study. The assessment group explained that because there were no utility values for lenvatinib, utility values from DECISION were used for both treatments. The committee noted that this made lenvatinib more cost effective and sorafenib less cost effective. It recognised that utility values from DECISION did not adequately capture the different tolerability of the treatments and the different responses to treatment (see section\xa03.19) and so the utility values for lenvatinib may have been underestimated. Because there were no other utility data the committee concluded that using utility values from DECISION was more appropriate than using the values from the vignette study.\n\n# Resource use\n\n## Changes to the assessment group's scenario analyses are clinically plausible and appropriate for decision-making\n\nIn its response to consultation, Eisai commented that the assessment group's estimates of resource use were not consistent with advice from 4\xa0UK clinical experts. Eisai explained that in UK clinical practice hypertension is usually managed in primary care, bone scans are not carried out, there are fewer MRI scans and more frequent oncologist visits. The committee understood that when the estimates of resource used were changed in line with clinical practice in the assessment group's scenario analyses, both lenvatinib and sorafenib became more cost effective than best supportive care. The clinical expert confirmed that fewer investigations may be carried out in clinical practice than suggested in the assessment group's report, particularly before disease progression. The committee considered that resource use in the assessment group's base-case model may be overestimated. It concluded that the changes to the scenario analyses were clinically plausible and appropriate for decision-making.\n\n# Treatment after disease progression\n\n## The assessment group's model did not consistently include treatments taken after progression\n\nIn its response to consultation, Bayer commented that the assessment group's model included the cost of taking sorafenib after progression but it did not include the cost of taking other tyrosine kinase inhibitors after progression on lenvatinib. Bayer considered this to be inconsistent with the clinical trials and UK clinical practice. The assessment group acknowledged that in SELECT, patients were allowed to take tyrosine kinase inhibitors other than lenvatinib after disease progression. However, there were no data available from SELECT on tyrosine kinase inhibitor use that could be incorporated in the economic model. The committee understood that both Bayer and the assessment group reported scenario analyses without the cost of sorafenib taken after progression. In the assessment group's analyses this scenario had little effect on its base case but there was a substantial improvement in the cost effectiveness of sorafenib using Bayer's alternative extrapolations (see section\xa03.11 and section\xa03.12). The committee acknowledged the lack of data but concluded that the assessment group's modelling of treatment after progression was not consistent for lenvatinib and sorafenib.\n\n# Revised base case\n\n## The assessment group's model is preferred for decision-making, but alternative assumptions may be plausible\n\nThe committee considered that the assessment group's model was the most reliable to estimate cost effectiveness. The model:\n\ncompared each treatment with best supportive care only (assessment group's base case, see section\xa03.10)\n\nused a 3-state model that did not include a separate state for people with disease that responded to treatment (assessment group's base case, see section\xa03.10)\n\nused utility values from DECISION for both treatments (assessment group's base case, see section\xa03.13)\n\nused alternative resource use estimates for both treatments (assessment group's scenario analysis, see section\xa03.14).After consultation, the assessment group revised its base case to correct the dose of lenvatinib, used another method to calculate costs for adverse events and corrected a discounting error. The committee understood that in the assessment group's revised base case, the method and time point for extrapolating survival data was unchanged. It noted the uncertainty in the choice of survival extrapolation. Although the committee preferred the assessment group's method of extrapolation and agreed it would use it in its decision-making, it also recognised that some alternative extrapolations preferred by Bayer may be clinically plausible (see section\xa03.11 and section\xa03.12).\n\n# Cost-effectiveness results\n\n## The ICERs for lenvatinib and sorafenib are more than £30,000 per QALY gained\n\nFor lenvatinib compared with best supportive care, the incremental cost-effectiveness ratio (ICER) using the committee's preferred assumptions and including the confidential commercial arrangement was more than £30,000 per quality-adjusted life year (QALY) gained.\n\nFor sorafenib compared with best supportive care, the ICER using the committee's preferred assumptions and the confidential commercial arrangement was more than £30,000 per QALY gained.\n\n# Uncaptured benefits\n\n## There are some health-related benefits from response to treatment that are not captured in the preferred analyses, which could reduce the ICERs\n\nThe committee recognised that differentiated thyroid cancer is rare, and that lenvatinib and sorafenib are the only targeted treatments available. It noted that both drugs delayed disease progression compared with best supportive care. Despite some methodological uncertainty because the proportional hazards assumption was not met, the model predicted substantial overall survival benefit. The committee understood that although there was a statistically significant reduction in EQ-5D values in the sorafenib arm in DECISION, this difference was not considered clinically meaningful. However, the clinical and patient experts advised that for symptomatic disease, response to treatment has a substantial effect on quality of life and this is valued by patients. This is particularly so for lenvatinib, which has a higher response rate than sorafenib (see section\xa03.9). The committee recalled that Eisai's model did not incorporate response appropriately for both treatments and recognised that the most plausible ICERs were based on the assessment group's model, which did not adequately capture this benefit. Therefore the committee concluded that there may be some additional health-related quality-of-life benefits from response to treatment that are not captured in the QALY calculations. It agreed that accounting for these uncaptured benefits could reduce the ICERs.\n\n# End of life\n\n## Both drugs meet the criterion for extension to life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The assessment group's model estimated a mean survival benefit of 25\xa0months for lenvatinib compared with best supportive care and 13\xa0months for sorafenib compared with best supportive care. The committee recognised it was likely that both treatments provided a substantial overall survival gain compared with best supportive care. But it agreed there was uncertainty around how long people live with progressed disease. The committee agreed that the end-of-life criterion for extension to life (that is, a mean of at least 3\xa0additional months) was met for both lenvatinib and sorafenib.\n\n## There is uncertainty about predicted overall survival and neither drug meets the criterion for short life expectancy\n\nThe assessment group's model predicted mean overall survival for best supportive care to be over 24\xa0months (in the RPSFT-adjusted placebo arm in SELECT it was 30.2\xa0months and in DECISION 43.8\xa0months). However, the committee recalled that both lenvatinib and sorafenib provided a substantial overall survival benefit compared with best supportive care that is not normally seen with other drugs for other cancers. The committee discussed whether it could accept a longer life expectancy of more than 24\xa0months because of the substantial survival benefit, noting that the end-of-life criteria allowed this flexibility. However, it was concerned that survival of up to 43.8\xa0months was not likely to be considered end of life. Also, it noted that the data were not robust enough to establish how long people live with progressive locally advanced or metastatic differentiated thyroid cancer. The clinical expert explained that although it is not possible to know the overall survival estimates for a population who has not had treatment, locally advanced or metastatic differentiated thyroid cancer is considered a terminal disease. The committee noted that in the assessment group's alternative extrapolations, the predicted overall survival estimates for the best supportive care arm after 10\xa0years were consistently longer than 24\xa0months. It understood that Bayer reported subgroup analyses in patients with symptomatic disease, but recalled the clinical expert's view that the trial populations were very similar to people having treatment in clinical practice, that is, people with progressive disease that is symptomatic or that will become symptomatic very quickly (see section\xa03.2). It noted that the subgroup analyses in patients with symptomatic disease from DECISION were post-hoc exploratory analyses that may not be reliable. Also, the assessment group's estimates of overall survival in this post-hoc subgroup were greater than 24\xa0months. The committee debated whether it could apply flexibility when interpreting the end-of-life criteria but recognised that a high degree of certainty is needed. Based on the evidence presented, the committee concluded that neither lenvatinib nor sorafenib met the criterion for short life expectancy and therefore the end-of-life criteria did not apply.\n\n# Conclusions\n\n## Lenvatinib and sorafenib are recommended for treating differentiated thyroid cancer after radioactive iodine\n\nThe committee noted that there were additional considerations that could reduce the ICERs for lenvatinib and sorafenib compared with best supportive care, including:\n\naccounting for uncaptured benefit from response (see section\xa03.19)\n\nsome of Bayer's alternative extrapolations of survival data for sorafenib may be plausible (see section\xa03.11, section\xa03.12 and section\xa03.16).The committee also considered the substantial modelled survival benefit (25\xa0months for lenvatinib and 13\xa0months for sorafenib) for people with this rare disease and that there are no other treatment options (see section\xa03.1). Taking all of this into account, the committee recommended lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine.\n\n## Lenvatinib and sorafenib are recommended only for people who have not had a tyrosine kinase inhibitor\n\nNeither the companies nor the assessment group presented cost-effectiveness analyses according to previous tyrosine kinase inhibitor treatment. For sorafenib, this was not necessary because previous tyrosine kinase inhibitor treatment was not allowed in DECISION. Therefore sorafenib can only be considered and recommended by the committee as a first tyrosine kinase inhibitor treatment for this indication. Eisai's model for lenvatinib was based on the overall population from SELECT only. It did not present a cost-effectiveness analysis for the subgroup who had previous tyrosine kinase inhibitor treatment because of the small patient numbers. The assessment group did not have access to the overall survival results for this subgroup from SELECT, therefore it did not do a cost-effectiveness analysis for this group. However, it stated that the uncertainties about the small numbers in the subgroup and the assumption of proportional hazards in the crossover-adjusted overall survival results for the overall population (see section\xa03.4) would not allow a robust estimate of cost effectiveness of lenvatinib in this subgroup. The committee would have preferred to see cost-effectiveness estimates according to previous tyrosine kinase inhibitor treatment, although it acknowledged that the estimates may not be robust. The committee was aware that the cost-effectiveness estimates provided were based on the overall SELECT population including the small number of patients who had previously had tyrosine kinase inhibitor treatment. However, because of the uncertainty about the clinical effectiveness (see sections\xa03.6 to 3.8) and the cost effectiveness of the drugs when used sequentially, the committee concluded that its recommendation for sorafenib and lenvatinib was limited to people who have not had previous treatment with a tyrosine kinase inhibitor.\n\n## The recommendation extends to people who have had to stop a tyrosine kinase inhibitor within 3\xa0months of starting treatment because of toxicity\n\nThe committee was aware that some people who had a tyrosine kinase inhibitor as their initial treatment for differentiated thyroid cancer (after radioactive iodine) may have had to stop treatment because of toxicity. Aware of its recommendation about the sequential use of sorafenib and lenvatinib, the committee agreed that people who had to stop treatment with a tyrosine kinase inhibitor because of early intolerance would be considered as having had no previous treatment. The committee concluded that its recommendation extends to people who have had to stop a tyrosine kinase inhibitor within 3\xa0months of starting treatment because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification).\n\n## The recommendation does not include people having lenvatinib after disease progression on sorafenib (currently provided through compassionate use)\n\nThe committee discussed the issue of the compassionate use scheme for lenvatinib, in which the company is providing access to lenvatinib for people who cannot tolerate sorafenib or who have disease that has progressed on sorafenib. The committee acknowledged its recommendation does not include the latter group (people who have progressed on sorafenib). It understood from NHS England that patients who have commenced compassionate use treatment will be able to continue treatment as long as the patients and clinicians felt there was benefit.\n\n# Other factors\n\nNo equality issues were identified."}
|
https://www.nice.org.uk/guidance/ta535
|
Evidence-based recommendations on lenvatinib (Lenvima) and sorafenib (Nexavar) for progressive, locally advanced or metastatic differentiated thyroid cancer in adults who have had radioactive iodine.
|
bd88b00cfe706c8f57849ce60e1de7d52cc4fedc
|
nice
|
Alectinib for untreated ALK-positive advanced non-small-cell lung cancer
|
Alectinib for untreated ALK-positive advanced non-small-cell lung cancer
Evidence-based recommendations on alectinib (Alecensa) for untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer in adults.
# Recommendation
Alectinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides alectinib according to the commercial arrangement.
Why the committee made this recommendation
People with untreated ALK-positive advanced NSCLC are usually offered crizotinib.
The main evidence for alectinib comes from an ongoing clinical trial. This suggests that alectinib is more effective than crizotinib in delaying disease progression, including in the central nervous system. There is not enough evidence to tell how long alectinib prolongs life compared with crizotinib.
There is uncertainty about how treatments after disease progression affect people's quality and length of life. But using the most plausible assumptions and with the commercial arrangement, the cost-effectiveness estimates for alectinib compared with crizotinib are within the range NICE normally considers acceptable. Therefore, alectinib is recommended for untreated advanced ALK-positive NSCLC.# Information about alectinib
Marketing authorisation indication
Alectinib (Alecensa, Roche) as monotherapy is indicated 'for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)'.
Alectinib has been available in the UK through the early access to medicines scheme.
Dosage in the marketing authorisation
The recommended dose of alectinib is 600 mg (4×150 mg capsules) taken twice daily with food (total daily dose of 1,200 mg).
A validated ALK assay is necessary to identify ALK-positive NSCLC status, which should be established before alectinib therapy starts.
Treatment with alectinib should be continued until disease progression or unacceptable toxicity. Management of adverse events may need dose reduction, temporary interruption, or discontinuation of alectinib. The dose of alectinib should be reduced in steps of 150 mg twice daily based on tolerability. Alectinib should be permanently discontinued if patients cannot tolerate the 300 mg twice daily dose.
Price
£5,032.00 per pack of 224×150 mg capsules (British national formulary online ). Based on the company's economic model, if the mean treatment duration is 32 months, the average cost of a course of treatment is approximately £87,000 using the list price for alectinib.
The company has a commercial arrangement. This makes alectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## A new treatment option would benefit people with untreated ALK-positive advanced non-small-cell lung cancer
People with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. As a result, people with ALK-positive disease may be less likely to be included in lung cancer screening programmes. The committee understood that approximately 40% to 50% of all people with NSCLC develop central nervous system (CNS) metastases, which can reduce quality of life and survival prospects. The patient experts submitted comments highlighting that NSCLC has no cure, which can cause physical and psychological distress for people with the disease. The clinical experts welcomed the development of second-generation ALK inhibitors. In particular, they said that alectinib appears to show benefit in delaying disease progression in the CNS. The committee agreed that additional treatment options for delaying disease progression, particularly CNS disease progression, would benefit people with untreated ALK-positive advanced NSCLC.
# Clinical management
## Crizotinib is the appropriate comparator for this appraisal
The clinical experts advised that they routinely offer crizotinib for untreated ALK-positive advanced NSCLC in line with NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. The committee was aware that NICE also recommends ceritinib for this indication in NICE's technology appraisal guidance on ceritinib for untreated ALK-positive non-small-cell lung cancer. However, it understood that the ceritinib guidance was published in January 2018, and ceritinib was not routinely commissioned as a first-line treatment when the NICE scope and company submission for alectinib were written. The committee therefore concluded that first-line treatment with crizotinib was the appropriate comparator for this appraisal.
## In clinical practice, treatment with an ALK inhibitor may continue beyond disease progression
The alectinib summary of product characteristics states that treatment should continue until disease progression or unacceptable toxicity. But the crizotinib and ceritinib summaries of product characteristics do not specify that treatment should stop at disease progression. The clinical experts explained that in clinical practice, people may continue to have an ALK inhibitor beyond disease progression when the only other treatment option is chemotherapy. For example, if people having crizotinib (a first-generation ALK inhibitor) as a first-line treatment have disease progression they may switch to ceritinib (a second-generation ALK inhibitor) as soon as possible rather than continuing crizotinib; in line with NICE's technology appraisal guidance on ceritinib for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer. If people are having first-line ceritinib, treatment is more likely to continue beyond disease progression because the only available treatment options are chemotherapy for people who are well enough, or best supportive care. The clinical experts also explained that they would wait until the disease has progressed at multiple sites before changing treatment, because there are limited alternative options. Similarly, the clinical experts said they would prefer to continue alectinib after disease progression (even though this is outside its marketing authorisation and not how the drug was used for most people in the ALEX trial), because the only options available after alectinib are chemotherapy and best supportive care. They said that another ALK inhibitor would not be given after alectinib in UK clinical practice because there is no evidence to support giving crizotinib after alectinib, and ceritinib is not licensed for use after alectinib. The committee recognised that in practice treatment with alectinib may continue beyond disease progression, but agreed that the appraisal would focus on how the treatment is given according to alectinib's marketing authorisation.
# Clinical evidence
## The main evidence is from ALEX, an open-label randomised controlled trial
The main clinical evidence came from an open-label phase 3 randomised controlled trial (ALEX). ALEX compared the efficacy and safety of alectinib (n=152) with crizotinib (n=151) in adults with untreated ALK-positive advanced NSCLC. The primary outcome was investigator assessed progression-free survival, defined as the time from day of randomisation until the first documented progression event (determined using Response Evaluation Criteria In Solid Tumors v1.1) or death from any cause, whichever occurred first. As a secondary outcome, 2 separate independent review committees assessed progression-free survival using RECIST and CNS RECIST. Other secondary outcomes included overall survival, response rates and safety outcomes. Patients had treatment across 98 study sites in 29 countries, including the UK (n=3 patients). On disease progression, people could have subsequent treatment with a different drug (see section 3.12). The committee concluded that ALEX was a well-conducted trial, which provided high-quality evidence that was relevant to the appraisal.
## Evidence about CNS progression is relevant to this appraisal
The company highlighted that alectinib has potential benefit in delaying or preventing CNS disease progression. Because of this, it presented evidence for progression-free survival (that is, survival without any recorded disease progression) and CNS progression-free survival (that is, survival without any disease progression in the CNS). The committee was aware that CNS progression-free survival was not a pre-defined end point in ALEX. However, the clinical experts explained that developing CNS metastases can have a substantial effect on people's prognosis. The committee agreed that it was relevant to consider CNS progression-free survival.
## Assessing disease progression by independent review committee is appropriate
The ERG advised that, for consistency, the analyses of CNS progression-free survival and progression-free survival should use the same measurement criteria. The committee agreed with this approach. In ALEX, progression events were assessed by investigators and by 2 independent review committees. The committee understood that the primary outcome of ALEX was investigator assessed progression-free survival, and that independently assessed progression events was a secondary outcome. But because ALEX was an open-label trial, the committee considered that investigator assessments had a greater risk of bias. It agreed that analyses based on independent assessment of progression events were the most appropriate to use in its decision-making.
## Assessing disease progression using RECIST is preferable to using both RECIST and CNS RECIST
In ALEX, 2 separate independent review committees assessed progression. One of these committees assessed systemic progression using RECIST. The other committee assessed intracranial CNS progression using the adapted CNS RECIST. The company's initial analyses of disease progression were based on events captured using CNS RECIST and RECIST. The ERG was concerned that CNS RECIST is not routinely used in UK clinical practice, and may be more sensitive than RECIST (meaning that events would be detected earlier than they would in clinical practice). Because of this, the ERG preferred analyses of progression to use RECIST data only. The clinical experts confirmed that CNS RECIST is not routinely used in UK clinical practice. After consultation, the company provided progression analyses based on events captured using RECIST only. The committee agreed that the company's revised analyses were more appropriate than analyses based on CNS RECIST and RECIST.
## In ALEX, an ALK inhibitor is sometimes continued after asymptomatic disease progression, but this reflects clinical practice
The summary of product characteristics for alectinib states that treatment should continue until disease progression or unacceptable toxicity (see section 3.3). In ALEX, disease progression events could be symptomatic or asymptomatic. However, asymptomatic events were only detected through investigator assessment and not by the independent review committees. Patients with isolated, asymptomatic CNS disease progression could continue on the study treatment (alectinib or crizotinib) if the investigator believed that the patient would benefit. This meant that 5 patients continued with alectinib and 30 with crizotinib after disease progression, contrary to alectinib's marketing authorisation. However, the clinical experts explained that in clinical practice, assessment of progression is typically guided by symptoms as well as radiographic evidence. Therefore, people with asymptomatic CNS disease progression would not usually be identified and would continue on their current treatment until symptoms developed. The committee concluded that although the trial allowed use of an ALK inhibitor after asymptomatic disease progression, this reflected UK clinical practice.
# Clinical effectiveness
## Alectinib improves progression-free survival compared with crizotinib
In ALEX, alectinib statistically significantly improved progression-free survival compared with crizotinib. Median progression-free survival (assessed by investigator, February 2017 data cut) was 11.1 months with crizotinib and was not met for alectinib, producing a hazard ratio (HR) of 0.47 (95% confidence interval 0.34 to 0.65). There was also a statistically significant difference in median progression-free survival assessed by an independent review committee using RECIST (HR 0.50, 95% CI 0.36 to 0.70); median progression-free survival was 25.7 months for alectinib (95% CI 19.9 to not estimable) compared with 10.4 months for crizotinib (95% CI 7.7 to 14.6). After consultation, the company provided investigator assessed progression-free survival results from a more recent data cut; these results are academic in confidence. The committee concluded that alectinib was associated with a substantial benefit in progression-free survival compared with crizotinib.
## Alectinib improves CNS progression-free survival compared with crizotinib
The company presented Kaplan–Meier curves for CNS progression events identified by 2 separate independent review committees (1 committee assessed using CNS RECIST and RECIST, the other used RECIST only). The committee noted that the Kaplan–Meier curves diverged substantially in both analyses; the exact analyses are commercial in confidence. Because of this, the committee concluded that alectinib appears to have a benefit in CNS progression-free survival compared with crizotinib.
## There is uncertainty about the extent to which alectinib prolongs survival compared with crizotinib
ALEX was not powered to detect a significant difference in overall survival between alectinib and crizotinib. The committee was also aware that the overall survival data from the trial were immature and that median overall survival was not reached in either treatment arm. At the first committee meeting, the company presented results from the February 2017 data cut. These results did not show a statistically significant difference in overall survival between alectinib and crizotinib (HR 0.76, 95% CI 0.48 to 1.20), despite the statistically significant difference in progression-free survival. The clinical experts commented that, although the survival data were very immature, they would expect to see an increase in survival over time given the potential benefit of alectinib on CNS progression. After consultation, the company provided overall survival results from an updated data cut; these results are academic in confidence. The committee accepted that an increase in progression-free and CNS progression-free survival could plausibly translate to a benefit in overall survival, but considered that uncertainty remained about the extent of any such benefit. The committee concluded that there was insufficient evidence to confirm how much alectinib prolongs survival compared with crizotinib.
## There is substantial uncertainty about the effect of subsequent treatments on overall survival estimates in ALEX
In ALEX, after patients stopped their study drug they could have subsequent treatment with a different drug. The committee recalled that treatment after progression would be different for those on alectinib or crizotinib in clinical practice in England (see section 3.3). It noted that subsequent treatment data were only collected for 41% of patients who had progressed and stopped their study drug (see section 3.22). Because subsequent therapies could affect survival outcomes, the ERG was concerned that the missing data could confound overall survival and would need to be taken into account in the overall survival estimates. The committee agreed that the extent of the missing data, as well as the uncertainties about the choice and duration of subsequent treatments, could have a large effect on overall survival. It agreed that there was substantial uncertainty about the subsequent treatments people had in the trial and their effect on overall survival estimates in ALEX, which would need to be considered in its decision-making.
# Cost-effectiveness model structure
## Different modelled states for non-CNS and CNS-progressed disease are appropriate
To estimate cost effectiveness, the company used a partitioned survival model with 4 health states:
progression-free (people with no progression events)
non-CNS progressed disease (people with progression events outside the CNS)
CNS-progressed disease (people with progression events in the CNS, either with or without progression events elsewhere)
death.The company modelled states for non-CNS and CNS-progressed disease separately to capture alectinib's benefit in the CNS. The committee recognised that CNS progression was a relevant health outcome for the appraisal (see section 3.5) and accepted this model structure.
## It is acceptable for the CNS-progressed disease state to include people with or without progression events outside the CNS
In the CNS progression analysis, the company did not censor patients who had progression events outside the CNS. This meant that the CNS-progressed disease state included people whose first progression event was in the CNS ('primary') and patients who had progression outside the CNS before a CNS progression event ('secondary'). The ERG explained that, although the model did not distinguish between these patient groups, the costs and consequences of a CNS progression event always exceed those of a non-CNS event. Because of this, the ERG was satisfied that the costs and consequences of both primary and secondary CNS progression events were appropriately captured. The committee agreed with the ERG and accepted the company's modelling of the CNS-progressed disease state.
# Extrapolating clinical trial data in the economic model
## It is appropriate to model treatment effects independently
The company used extrapolations to model CNS progression-free survival, progression-free survival and overall survival. It assumed non-proportional hazards between the treatments (that is, the effect of alectinib relative to crizotinib changed over time). The company based this assumption on log-cumulative hazard plots for CNS progression-free survival and progression-free survival from ALEX. The committee agreed that it was appropriate to model the treatment effects independently.
## Basing the analyses of disease progression on RECIST is preferred
The company's initial analyses incorporated events from 2 independent review committee assessments in ALEX into progression-free survival and CNS progression-free survival analyses (see section 3.10); a main RECIST analysis and a separate analysis based on the adapted CNS RECIST. The ERG preferred the analyses based on RECIST only (which were provided as a scenario analysis by the company) because they were likely to be the most clinically relevant, and more comparable to other trials and NICE technology appraisal assessments. After consultation, the company did an updated analysis in which disease progression was modelled using events captured by RECIST only. The committee accepted that this revised approach was more clinically relevant.
## The company's progression-free survival modelling using the ALEX Kaplan–Meier data (independent review) and an exponential tail is acceptable
The company's base-case analysis of progression-free survival for alectinib and crizotinib used Kaplan–Meier data (as measured by independent review committee) from ALEX for the first 18 months, extrapolated with an exponential tail after 18 months. The company chose an exponential tail based on fit, and because it gave conservative estimates compared with the other distributions tested (it was the most conservative for alectinib and the second most conservative for crizotinib). The ERG agreed that the exponential tail for alectinib and crizotinib was conservative, but highlighted that using exponential extrapolations for 2 treatments implicitly assumes proportional hazards between them. The company's analysis had shown that the proportional hazards assumption does not hold for alectinib and crizotinib (see section 3.15). However, the ERG was satisfied that using Kaplan–Meier data for the first 18 months offsets the problem (although the hazards do become proportional over time). The ERG considered the 18-month Kaplan–Meier cut-off to be arbitrary, but felt that this would be the case for any cut-off point used to extrapolate the Kaplan–Meier data. The committee agreed with the ERG's comments and considered the company's modelling of progression-free survival to be acceptable.
## Extrapolating CNS progression-free survival using a gamma distribution is acceptable
Although it did not provide the best statistical fit, the company extrapolated CNS progression-free survival using a gamma distribution. It chose the gamma distribution because it was considered to reflect the plateau in long-term cumulative CNS metastasis incidence reported in the literature. The ERG highlighted that the gamma distribution was one of the worst fitting curves (based on statistical fit), and considered the log-normal or log-logistic distributions to be more plausible because they provided a better statistical fit. However, the committee noted that changing to these distributions had a negligible effect on the cost-effectiveness results. It therefore accepted the company's modelling of CNS progression-free survival, but agreed that a log-normal or log-logistic extrapolation may have been more appropriate.
## The most recent data on overall survival from ALEX are the best available for estimating cost effectiveness
After the first committee meeting, the company provided additional overall survival evidence based on a later data cut from ALEX; this evidence is academic in confidence. The company used these data as part of a scenario analysis. The ERG included this updated overall survival data in its own cost-effectiveness estimate for alectinib. The committee recognised that an inherent uncertainty remained in the ALEX overall survival data because of its immaturity and because of potential confounding from subsequent treatments (see section 3.11 and section 3.12). However, the committee concluded that the updated data cut was the best available data for estimating alectinib's potential survival benefit and cost effectiveness.
## Extrapolating overall survival using Kaplan–Meier data from the most recent ALEX data cut and an exponential tail is acceptable
The company assessed different extrapolations for overall survival for each treatment arm according to statistical and visual fit. It also compared survival estimates for crizotinib with overall survival data from the PROFILE 1014 trial, which compared crizotinib with chemotherapy in the same population. The company's initial model used an exponential extrapolation of overall survival for alectinib and crizotinib for the base case, because this was the second best fit to the PROFILE 1014 data and the company judged it to be clinically plausible based on its discussions with clinical experts. As with the progression-free survival analysis (see section 3.17), the ERG highlighted that using exponential extrapolations for both treatments assumes proportional hazards. To address this, the company's revised model extrapolated overall survival using Kaplan–Meier data (from the February 2017 data cut) for the first 18 months, and then switched to an exponential tail. After consultation, the company also presented a scenario analysis which extrapolated survival using Kaplan–Meier data from the updated data cut. Aware of the inherent uncertainty in the ALEX overall survival data (see section 3.11), the committee preferred the analysis based on the more mature overall survival data. The committee concluded that extrapolating overall survival using Kaplan–Meier data from ALEX (measured using the most recent data cut) and an exponential tail was acceptable.
# Resource use and costs
## It is reasonable to assume no wastage for alectinib and crizotinib
The company's initial model assumed that a full pack of alectinib or crizotinib would be provided at a lung cancer clinic every 28 days and incorporated wastage of treatment when a patient died or stopped treatment. The ERG highlighted that a full pack of crizotinib contains 30 days' treatment, whereas a full pack of alectinib contains 28 days' treatment. It considered that the company's model led to 2 days of additional wastage of crizotinib per cycle. The ERG amended the model assumption so that a pack of crizotinib was provided every 30 days. The clinical experts advised that in practice there would be no wastage while a person is on treatment. The committee concluded it was reasonable to assume no wastage for both alectinib and crizotinib because this best reflected clinical practice. After consultation, the company updated its analysis in line with the committee's preferred assumption.
## The distribution of subsequent treatments in the company's model reflects clinical practice
Data on the treatments taken after disease progression in ALEX were only captured for 41% of patients. The clinical experts advised that in routine practice they would expect around 70% to 80% of people on crizotinib to have treatment with ceritinib after progression. They highlighted that ceritinib (as a second-line treatment) may continue after any further disease progression. If people were to stop having ceritinib (as a second-line treatment), the experts estimated that 40% to 50% would have chemotherapy and 50% to 60% would have best supportive care. The clinical experts also explained that people having alectinib would not have subsequent treatment with a tyrosine kinase inhibitor. They estimated that 50% of people who progressed while taking alectinib would have subsequent chemotherapy, and that the remaining 50% would have best supportive care. After consultation the company submitted a revised analysis, which assumed a subsequent treatment distribution based on the clinical experts' estimates. The company modelled second-line subsequent treatments, followed by best supportive care. Although the clinical experts' estimates had included some third-line treatment with ceritinib, the ERG advised that limiting the analysis to second-line treatments helped to contain the uncertainty caused by the high proportion of missing data in ALEX (see section 3.12). The committee considered that the distribution of subsequent treatments in the company's updated model sufficiently reflected UK clinical practice.
## It is appropriate to assume that oncologist visits happen every 4 weeks
The company's initial model assumed that patients in the progression-free survival, CNS progression-free survival and progressed disease states visited an oncologist every 5 to 6 weeks. Clinical experts advised the ERG that in practice patients visited an oncologist every 4 weeks. The clinical experts at the meeting agreed that this reflected UK clinical practice. The committee concluded that it was appropriate to model oncologist visits every 4 weeks. After consultation, the company updated its modelling of oncologist visits in line with the committee's preference.
## The management of CNS progression events is adequately captured in the model
In its model, the company explored 3 treatment options for managing disease progression in the CNS: steroids, stereotactic radiosurgery and whole-brain radiotherapy. The company's initial base case assumed that 100% of patients with CNS metastases would have stereotactic radiosurgery and steroids. The company also presented a scenario analysis in which all patients had steroids, 23% of patients had stereotactic radiosurgery and 77% of patients had whole-brain radiotherapy. The clinical experts explained that treating CNS metastases is highly complex, and that the choice of treatment would depend on a variety of factors (such as age, health and prognosis). They advised that steroids would be offered to most people with CNS metastases. The clinical experts estimated that 20% to 25% of people with CNS metastases would have stereotactic radiosurgery, and 25% would have whole-brain radiotherapy, but that some people may have both. The clinical experts also suggested that surgical resection is sometimes used to manage CNS metastases. Although the committee recognised that treatment of CNS metastases is a complex area with variation in practice, it considered that the estimates that more closely reflect UK clinical practice (that is, 20% to 25% having stereotactic radiosurgery and 25% having whole-brain radiotherapy) were the best assumptions to use in the model. After consultation, the company submitted a revised analysis based on the clinical experts' estimated distributions of treatment for CNS metastases.
# Health-related quality of life
## It is preferable to model the role of subsequent treatments on quality of life
In its initial model, the company derived utility values for the progression-free and non-CNS progressed health states using a mixed-effects model based on EQ-5D data from ALEX. The utility values used in the economic model were 0.814 for the progression-free health state and 0.725 for the non-CNS progressed disease health state. The company assumed that the utility for the CNS-progressed disease state was 0.52 (from a study abstract by Roughley et al. 2014). After consultation, the company did an updated analysis which modelled different subsequent treatment distributions for alectinib and crizotinib in line with clinical practice (see section 3.22). The ERG highlighted that although the company's updated model took into account the costs of subsequent treatments, it did not model the effect of the different subsequent treatments on utilities. The ERG's preferred analysis modelled both the costs of the subsequent treatments and their effects on quality of life. The committee considered that it was good practice for cost-effectiveness analyses to capture quality of life when possible. Therefore, the committee concluded that it was preferable to model the role of subsequent treatments on costs and quality of life.
## It is acceptable for post-progression utility values to reflect differences in subsequent treatment distribution
The subsequent treatment distributions in the company's revised model differed between the alectinib and crizotinib treatment arms. To capture this in the modelling of quality of life, the ERG weighted the utility values according to the subsequent treatment distributions. In line with the company's revised analysis (see section 3.22), the ERG assumed that people in the alectinib arm did not have second-line treatment with tyrosine kinase inhibitors, and that people in the crizotinib arm did not have second-line treatment with chemotherapy. People who did not have second-line treatment (50% of the alectinib arm and 30% of the crizotinib arm) or who progressed on second-line treatment had best supportive care, which was assumed to have a utility of 0.47. The resulting weighted utilities were 0.565 for second-line treatment with chemotherapy, 0.649 for second-line treatment with a tyrosine kinase inhibitor, and 0.47 for best supportive care. The committee agreed that it was realistic to weight utilities to reflect subsequent treatment distribution.
## It is acceptable for post-progression utilities to reflect the site of disease progression
Although the ERG was in favour of modelling the role of subsequent treatments on quality of life, it highlighted that utilities based only on subsequent treatment would not capture the differences in quality of life between people with CNS and non-CNS progressed disease. Because of this, the ERG's preferred analysis accounted for the site of the disease progression. Utility values were weighted to reflect the different distributions of subsequent treatments between alectinib and crizotinib (see section 3.22). However, people with CNS-progressed disease were assumed to have the CNS-progressed disease utility (0.52 in the company's model) regardless of subsequent treatment. From the clinical experts' evidence at the first meeting, the committee was aware of the importance of site of disease progression on quality of life. The committee therefore concluded that it was acceptable for post-progression utilities to reflect this.
## A CNS-progressed disease utility value of 0.52 is preferred
Not enough data were collected in ALEX to estimate the utility value for the CNS-progressed disease state. Because of this, the company used a utility value taken from a study by Roughley et al. (0.52; see section 3.25). The ERG noted that the utilities reported by Roughley et al. for non-CNS progressed disease were consistently lower than the utilities derived from ALEX (0.65 compared with 0.725). Because of this, the ERG was concerned that the utility value for the CNS-progressed disease state taken from Roughley et al. (0.52) was lower than if it had been derived from ALEX. The ERG accounted for this by applying a percentage decrement (0.52 divided by 0.65) to the non-CNS progressed disease utility in ALEX (0.725) which gave an estimated utility of 0.58 for the CNS-progressed disease state. The committee was aware of the differences between the utilities reported in ALEX and Roughley et al., but also that in the first committee meeting it had accepted 0.52 as the CNS-progressed disease utility. The committee considered scenario analyses based on utilities with and without the Roughley et al. decrement. It noted that applying the decrement for people having chemotherapy after alectinib led to a utility value for CNS-progressed disease (0.58) that was higher than the utility value for non-CNS progressed disease (0.565; see section 3.26), which the committee considered to be clinically implausible. Because of this, the committee concluded that the CNS-progressed disease utility value of 0.52 was preferable.
# Cost-effectiveness results
## The company's base-case ICER comparing alectinib with crizotinib is lower than £20,000 per QALY gained
The committee considered the incremental cost-effectiveness ratios (ICERs) from the company's base case, recalculated by the ERG to include the confidential commercial arrangements for alectinib and crizotinib. The company's base-case ICER for alectinib compared with crizotinib was lower than £20,000 per quality-adjusted life year (QALY) gained. The committee concluded that the company's base case was not appropriate for decision-making because of concerns about the modelling of the role of subsequent treatments on quality of life (see section 3.25).
## The ERG's preferred assumptions increase the ICER
The ERG accepted the company's revised modelling of wastage, oncologist visits and the management of CNS metastases. The ERG also agreed with the company's updated approach of capturing progression events using RECIST only. The ERG's additional preferred assumptions were:
progressed disease utility values to be related to progression site (see section 3.27)
utilities weighted to reflect subsequent treatment distributions in each treatment arm (see section 3.26)
CNS-progressed disease utility value to be adjusted using the decrement from Roughley et al., increasing from 0.52 to 0.58 (see section 3.28)
cost-effectiveness modelling based on updated ALEX data cut of overall survival (see section 3.19).The committee noted that combining the ERG's preferred assumptions increased the ICER compared with the company's base case. When the confidential discounts from the commercial arrangements for both technologies were applied, the ERG's preferred base-case ICER for alectinib compared with crizotinib was between £20,000 and £30,000 per QALY gained.
## The most plausible ICER is between £20,000 and £30,000 per QALY gained
The committee largely agreed with the ERG's preferred assumptions. Although it was aware of the uncertainties about overall survival benefit and subsequent treatment in the appraisal, the committee concluded that the most plausible ICER for alectinib compared with crizotinib in people with untreated ALK-positive advanced NSCLC was between £20,000 and £30,000 per QALY gained. The committee agreed that alectinib, with the discount agreed in the commercial arrangement, was a cost-effective use of NHS resources for adults with untreated ALK-positive advanced NSCLC and was therefore recommended for routine use in the NHS.
# Innovation
## The benefits of alectinib are adequately captured in the model
The company explained that it considered alectinib to be innovative. The company and the clinical experts highlighted that alectinib has good penetration through the blood-brain barrier. The CNS is a common site of initial progression in ALK-positive NSCLC patients so CNS-active treatments are important targets for development. However, the clinical experts explained that although they consider alectinib to be novel and better at delaying disease progression than current standard care, they considered that alectinib's benefits were captured in the measurement of the QALYs. The committee concluded that alectinib may be innovative, but it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.
# Other considerations
No equality or social value judgement issues were identified.
|
{'Recommendation': "Alectinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides alectinib according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nPeople with untreated ALK-positive advanced NSCLC are usually offered crizotinib.\n\nThe main evidence for alectinib comes from an ongoing clinical trial. This suggests that alectinib is more effective than crizotinib in delaying disease progression, including in the central nervous system. There is not enough evidence to tell how long alectinib prolongs life compared with crizotinib.\n\nThere is uncertainty about how treatments after disease progression affect people's quality and length of life. But using the most plausible assumptions and with the commercial arrangement, the cost-effectiveness estimates for alectinib compared with crizotinib are within the range NICE normally considers acceptable. Therefore, alectinib is recommended for untreated advanced ALK-positive NSCLC.", 'Information about alectinib': "Marketing authorisation indication\n\nAlectinib (Alecensa, Roche) as monotherapy is indicated 'for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)'.\n\nAlectinib has been available in the UK through the early access to medicines scheme.\n\nDosage in the marketing authorisation\n\nThe recommended dose of alectinib is 600\xa0mg (4×150\xa0mg capsules) taken twice daily with food (total daily dose of 1,200\xa0mg).\n\nA validated ALK assay is necessary to identify ALK-positive NSCLC status, which should be established before alectinib therapy starts.\n\nTreatment with alectinib should be continued until disease progression or unacceptable toxicity. Management of adverse events may need dose reduction, temporary interruption, or discontinuation of alectinib. The dose of alectinib should be reduced in steps of 150\xa0mg twice daily based on tolerability. Alectinib should be permanently discontinued if patients cannot tolerate the 300\xa0mg twice daily dose.\n\nPrice\n\n£5,032.00 per pack of 224×150\xa0mg capsules (British national formulary [BNF] online [accessed February 2018]). Based on the company's economic model, if the mean treatment duration is 32\xa0months, the average cost of a course of treatment is approximately £87,000 using the list price for alectinib.\n\nThe company has a commercial arrangement. This makes alectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## A new treatment option would benefit people with untreated ALK-positive advanced non-small-cell lung cancer\n\nPeople with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. As a result, people with ALK-positive disease may be less likely to be included in lung cancer screening programmes. The committee understood that approximately 40% to 50% of all people with NSCLC develop central nervous system (CNS) metastases, which can reduce quality of life and survival prospects. The patient experts submitted comments highlighting that NSCLC has no cure, which can cause physical and psychological distress for people with the disease. The clinical experts welcomed the development of second-generation ALK inhibitors. In particular, they said that alectinib appears to show benefit in delaying disease progression in the CNS. The committee agreed that additional treatment options for delaying disease progression, particularly CNS disease progression, would benefit people with untreated ALK-positive advanced NSCLC.\n\n# Clinical management\n\n## Crizotinib is the appropriate comparator for this appraisal\n\nThe clinical experts advised that they routinely offer crizotinib for untreated ALK-positive advanced NSCLC in line with NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. The committee was aware that NICE also recommends ceritinib for this indication in NICE's technology appraisal guidance on ceritinib for untreated ALK-positive non-small-cell lung cancer. However, it understood that the ceritinib guidance was published in January 2018, and ceritinib was not routinely commissioned as a first-line treatment when the NICE scope and company submission for alectinib were written. The committee therefore concluded that first-line treatment with crizotinib was the appropriate comparator for this appraisal.\n\n## In clinical practice, treatment with an ALK inhibitor may continue beyond disease progression\n\nThe alectinib summary of product characteristics states that treatment should continue until disease progression or unacceptable toxicity. But the crizotinib and ceritinib summaries of product characteristics do not specify that treatment should stop at disease progression. The clinical experts explained that in clinical practice, people may continue to have an ALK inhibitor beyond disease progression when the only other treatment option is chemotherapy. For example, if people having crizotinib (a first-generation ALK inhibitor) as a first-line treatment have disease progression they may switch to ceritinib (a second-generation ALK inhibitor) as soon as possible rather than continuing crizotinib; in line with NICE's technology appraisal guidance on ceritinib for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer. If people are having first-line ceritinib, treatment is more likely to continue beyond disease progression because the only available treatment options are chemotherapy for people who are well enough, or best supportive care. The clinical experts also explained that they would wait until the disease has progressed at multiple sites before changing treatment, because there are limited alternative options. Similarly, the clinical experts said they would prefer to continue alectinib after disease progression (even though this is outside its marketing authorisation and not how the drug was used for most people in the ALEX trial), because the only options available after alectinib are chemotherapy and best supportive care. They said that another ALK inhibitor would not be given after alectinib in UK clinical practice because there is no evidence to support giving crizotinib after alectinib, and ceritinib is not licensed for use after alectinib. The committee recognised that in practice treatment with alectinib may continue beyond disease progression, but agreed that the appraisal would focus on how the treatment is given according to alectinib's marketing authorisation.\n\n# Clinical evidence\n\n## The main evidence is from ALEX, an open-label randomised controlled trial\n\nThe main clinical evidence came from an open-label phase\xa03 randomised controlled trial (ALEX). ALEX compared the efficacy and safety of alectinib (n=152) with crizotinib (n=151) in adults with untreated ALK-positive advanced NSCLC. The primary outcome was investigator assessed progression-free survival, defined as the time from day of randomisation until the first documented progression event (determined using Response Evaluation Criteria In Solid Tumors [RECIST] v1.1) or death from any cause, whichever occurred first. As a secondary outcome, 2\xa0separate independent review committees assessed progression-free survival using RECIST and CNS RECIST. Other secondary outcomes included overall survival, response rates and safety outcomes. Patients had treatment across 98\xa0study sites in 29\xa0countries, including the UK (n=3\xa0patients). On disease progression, people could have subsequent treatment with a different drug (see section\xa03.12). The committee concluded that ALEX was a well-conducted trial, which provided high-quality evidence that was relevant to the appraisal.\n\n## Evidence about CNS progression is relevant to this appraisal\n\nThe company highlighted that alectinib has potential benefit in delaying or preventing CNS disease progression. Because of this, it presented evidence for progression-free survival (that is, survival without any recorded disease progression) and CNS progression-free survival (that is, survival without any disease progression in the CNS). The committee was aware that CNS progression-free survival was not a pre-defined end point in ALEX. However, the clinical experts explained that developing CNS metastases can have a substantial effect on people's prognosis. The committee agreed that it was relevant to consider CNS progression-free survival.\n\n## Assessing disease progression by independent review committee is appropriate\n\nThe ERG advised that, for consistency, the analyses of CNS progression-free survival and progression-free survival should use the same measurement criteria. The committee agreed with this approach. In ALEX, progression events were assessed by investigators and by 2\xa0independent review committees. The committee understood that the primary outcome of ALEX was investigator assessed progression-free survival, and that independently assessed progression events was a secondary outcome. But because ALEX was an open-label trial, the committee considered that investigator assessments had a greater risk of bias. It agreed that analyses based on independent assessment of progression events were the most appropriate to use in its decision-making.\n\n## Assessing disease progression using RECIST is preferable to using both RECIST and CNS RECIST\n\nIn ALEX, 2\xa0separate independent review committees assessed progression. One of these committees assessed systemic progression using RECIST. The other committee assessed intracranial CNS progression using the adapted CNS RECIST. The company's initial analyses of disease progression were based on events captured using CNS RECIST and RECIST. The ERG was concerned that CNS RECIST is not routinely used in UK clinical practice, and may be more sensitive than RECIST (meaning that events would be detected earlier than they would in clinical practice). Because of this, the ERG preferred analyses of progression to use RECIST data only. The clinical experts confirmed that CNS RECIST is not routinely used in UK clinical practice. After consultation, the company provided progression analyses based on events captured using RECIST only. The committee agreed that the company's revised analyses were more appropriate than analyses based on CNS RECIST and RECIST.\n\n## In ALEX, an ALK inhibitor is sometimes continued after asymptomatic disease progression, but this reflects clinical practice\n\nThe summary of product characteristics for alectinib states that treatment should continue until disease progression or unacceptable toxicity (see section\xa03.3). In ALEX, disease progression events could be symptomatic or asymptomatic. However, asymptomatic events were only detected through investigator assessment and not by the independent review committees. Patients with isolated, asymptomatic CNS disease progression could continue on the study treatment (alectinib or crizotinib) if the investigator believed that the patient would benefit. This meant that 5\xa0patients continued with alectinib and 30\xa0with crizotinib after disease progression, contrary to alectinib's marketing authorisation. However, the clinical experts explained that in clinical practice, assessment of progression is typically guided by symptoms as well as radiographic evidence. Therefore, people with asymptomatic CNS disease progression would not usually be identified and would continue on their current treatment until symptoms developed. The committee concluded that although the trial allowed use of an ALK inhibitor after asymptomatic disease progression, this reflected UK clinical practice.\n\n# Clinical effectiveness\n\n## Alectinib improves progression-free survival compared with crizotinib\n\nIn ALEX, alectinib statistically significantly improved progression-free survival compared with crizotinib. Median progression-free survival (assessed by investigator, February 2017 data cut) was 11.1\xa0months with crizotinib and was not met for alectinib, producing a hazard ratio (HR) of 0.47 (95% confidence interval [CI] 0.34 to 0.65). There was also a statistically significant difference in median progression-free survival assessed by an independent review committee using RECIST (HR 0.50, 95% CI 0.36 to 0.70); median progression-free survival was 25.7\xa0months for alectinib (95% CI 19.9 to not estimable) compared with 10.4\xa0months for crizotinib (95% CI 7.7 to 14.6). After consultation, the company provided investigator assessed progression-free survival results from a more recent data cut; these results are academic in confidence. The committee concluded that alectinib was associated with a substantial benefit in progression-free survival compared with crizotinib.\n\n## Alectinib improves CNS progression-free survival compared with crizotinib\n\nThe company presented Kaplan–Meier curves for CNS progression events identified by 2\xa0separate independent review committees (1\xa0committee assessed using CNS RECIST and RECIST, the other used RECIST only). The committee noted that the Kaplan–Meier curves diverged substantially in both analyses; the exact analyses are commercial in confidence. Because of this, the committee concluded that alectinib appears to have a benefit in CNS progression-free survival compared with crizotinib.\n\n## There is uncertainty about the extent to which alectinib prolongs survival compared with crizotinib\n\nALEX was not powered to detect a significant difference in overall survival between alectinib and crizotinib. The committee was also aware that the overall survival data from the trial were immature and that median overall survival was not reached in either treatment arm. At the first committee meeting, the company presented results from the February 2017 data cut. These results did not show a statistically significant difference in overall survival between alectinib and crizotinib (HR\xa00.76, 95%\xa0CI 0.48 to 1.20), despite the statistically significant difference in progression-free survival. The clinical experts commented that, although the survival data were very immature, they would expect to see an increase in survival over time given the potential benefit of alectinib on CNS progression. After consultation, the company provided overall survival results from an updated data cut; these results are academic in confidence. The committee accepted that an increase in progression-free and CNS progression-free survival could plausibly translate to a benefit in overall survival, but considered that uncertainty remained about the extent of any such benefit. The committee concluded that there was insufficient evidence to confirm how much alectinib prolongs survival compared with crizotinib.\n\n## There is substantial uncertainty about the effect of subsequent treatments on overall survival estimates in ALEX\n\nIn ALEX, after patients stopped their study drug they could have subsequent treatment with a different drug. The committee recalled that treatment after progression would be different for those on alectinib or crizotinib in clinical practice in England (see section\xa03.3). It noted that subsequent treatment data were only collected for 41% of patients who had progressed and stopped their study drug (see section\xa03.22). Because subsequent therapies could affect survival outcomes, the ERG was concerned that the missing data could confound overall survival and would need to be taken into account in the overall survival estimates. The committee agreed that the extent of the missing data, as well as the uncertainties about the choice and duration of subsequent treatments, could have a large effect on overall survival. It agreed that there was substantial uncertainty about the subsequent treatments people had in the trial and their effect on overall survival estimates in ALEX, which would need to be considered in its decision-making.\n\n# Cost-effectiveness model structure\n\n## Different modelled states for non-CNS and CNS-progressed disease are appropriate\n\nTo estimate cost effectiveness, the company used a partitioned survival model with 4\xa0health states:\n\nprogression-free (people with no progression events)\n\nnon-CNS progressed disease (people with progression events outside the CNS)\n\nCNS-progressed disease (people with progression events in the CNS, either with or without progression events elsewhere)\n\ndeath.The company modelled states for non-CNS and CNS-progressed disease separately to capture alectinib's benefit in the CNS. The committee recognised that CNS progression was a relevant health outcome for the appraisal (see section\xa03.5) and accepted this model structure.\n\n## It is acceptable for the CNS-progressed disease state to include people with or without progression events outside the CNS\n\nIn the CNS progression analysis, the company did not censor patients who had progression events outside the CNS. This meant that the CNS-progressed disease state included people whose first progression event was in the CNS ('primary') and patients who had progression outside the CNS before a CNS progression event ('secondary'). The ERG explained that, although the model did not distinguish between these patient groups, the costs and consequences of a CNS progression event always exceed those of a non-CNS event. Because of this, the ERG was satisfied that the costs and consequences of both primary and secondary CNS progression events were appropriately captured. The committee agreed with the ERG and accepted the company's modelling of the CNS-progressed disease state.\n\n# Extrapolating clinical trial data in the economic model\n\n## It is appropriate to model treatment effects independently\n\nThe company used extrapolations to model CNS progression-free survival, progression-free survival and overall survival. It assumed non-proportional hazards between the treatments (that is, the effect of alectinib relative to crizotinib changed over time). The company based this assumption on log-cumulative hazard plots for CNS progression-free survival and progression-free survival from ALEX. The committee agreed that it was appropriate to model the treatment effects independently.\n\n## Basing the analyses of disease progression on RECIST is preferred\n\nThe company's initial analyses incorporated events from 2\xa0independent review committee assessments in ALEX into progression-free survival and CNS progression-free survival analyses (see section\xa03.10); a main RECIST analysis and a separate analysis based on the adapted CNS RECIST. The ERG preferred the analyses based on RECIST only (which were provided as a scenario analysis by the company) because they were likely to be the most clinically relevant, and more comparable to other trials and NICE technology appraisal assessments. After consultation, the company did an updated analysis in which disease progression was modelled using events captured by RECIST only. The committee accepted that this revised approach was more clinically relevant.\n\n## The company's progression-free survival modelling using the ALEX Kaplan–Meier data (independent review) and an exponential tail is acceptable\n\nThe company's base-case analysis of progression-free survival for alectinib and crizotinib used Kaplan–Meier data (as measured by independent review committee) from ALEX for the first 18\xa0months, extrapolated with an exponential tail after 18\xa0months. The company chose an exponential tail based on fit, and because it gave conservative estimates compared with the other distributions tested (it was the most conservative for alectinib and the second most conservative for crizotinib). The ERG agreed that the exponential tail for alectinib and crizotinib was conservative, but highlighted that using exponential extrapolations for 2\xa0treatments implicitly assumes proportional hazards between them. The company's analysis had shown that the proportional hazards assumption does not hold for alectinib and crizotinib (see section\xa03.15). However, the ERG was satisfied that using Kaplan–Meier data for the first 18\xa0months offsets the problem (although the hazards do become proportional over time). The ERG considered the 18-month Kaplan–Meier cut-off to be arbitrary, but felt that this would be the case for any cut-off point used to extrapolate the Kaplan–Meier data. The committee agreed with the ERG's comments and considered the company's modelling of progression-free survival to be acceptable.\n\n## Extrapolating CNS progression-free survival using a gamma distribution is acceptable\n\nAlthough it did not provide the best statistical fit, the company extrapolated CNS progression-free survival using a gamma distribution. It chose the gamma distribution because it was considered to reflect the plateau in long-term cumulative CNS metastasis incidence reported in the literature. The ERG highlighted that the gamma distribution was one of the worst fitting curves (based on statistical fit), and considered the log-normal or log-logistic distributions to be more plausible because they provided a better statistical fit. However, the committee noted that changing to these distributions had a negligible effect on the cost-effectiveness results. It therefore accepted the company's modelling of CNS progression-free survival, but agreed that a log-normal or log-logistic extrapolation may have been more appropriate.\n\n## The most recent data on overall survival from ALEX are the best available for estimating cost effectiveness\n\nAfter the first committee meeting, the company provided additional overall survival evidence based on a later data cut from ALEX; this evidence is academic in confidence. The company used these data as part of a scenario analysis. The ERG included this updated overall survival data in its own cost-effectiveness estimate for alectinib. The committee recognised that an inherent uncertainty remained in the ALEX overall survival data because of its immaturity and because of potential confounding from subsequent treatments (see section\xa03.11 and section\xa03.12). However, the committee concluded that the updated data cut was the best available data for estimating alectinib's potential survival benefit and cost effectiveness.\n\n## Extrapolating overall survival using Kaplan–Meier data from the most recent ALEX data cut and an exponential tail is acceptable\n\nThe company assessed different extrapolations for overall survival for each treatment arm according to statistical and visual fit. It also compared survival estimates for crizotinib with overall survival data from the PROFILE 1014 trial, which compared crizotinib with chemotherapy in the same population. The company's initial model used an exponential extrapolation of overall survival for alectinib and crizotinib for the base case, because this was the second best fit to the PROFILE 1014 data and the company judged it to be clinically plausible based on its discussions with clinical experts. As with the progression-free survival analysis (see section\xa03.17), the ERG highlighted that using exponential extrapolations for both treatments assumes proportional hazards. To address this, the company's revised model extrapolated overall survival using Kaplan–Meier data (from the February 2017 data cut) for the first 18\xa0months, and then switched to an exponential tail. After consultation, the company also presented a scenario analysis which extrapolated survival using Kaplan–Meier data from the updated data cut. Aware of the inherent uncertainty in the ALEX overall survival data (see section\xa03.11), the committee preferred the analysis based on the more mature overall survival data. The committee concluded that extrapolating overall survival using Kaplan–Meier data from ALEX (measured using the most recent data cut) and an exponential tail was acceptable.\n\n# Resource use and costs\n\n## It is reasonable to assume no wastage for alectinib and crizotinib\n\nThe company's initial model assumed that a full pack of alectinib or crizotinib would be provided at a lung cancer clinic every 28\xa0days and incorporated wastage of treatment when a patient died or stopped treatment. The ERG highlighted that a full pack of crizotinib contains 30\xa0days' treatment, whereas a full pack of alectinib contains 28\xa0days' treatment. It considered that the company's model led to 2\xa0days of additional wastage of crizotinib per cycle. The ERG amended the model assumption so that a pack of crizotinib was provided every 30\xa0days. The clinical experts advised that in practice there would be no wastage while a person is on treatment. The committee concluded it was reasonable to assume no wastage for both alectinib and crizotinib because this best reflected clinical practice. After consultation, the company updated its analysis in line with the committee's preferred assumption.\n\n## The distribution of subsequent treatments in the company's model reflects clinical practice\n\nData on the treatments taken after disease progression in ALEX were only captured for 41% of patients. The clinical experts advised that in routine practice they would expect around 70% to 80% of people on crizotinib to have treatment with ceritinib after progression. They highlighted that ceritinib (as a second-line treatment) may continue after any further disease progression. If people were to stop having ceritinib (as a second-line treatment), the experts estimated that 40% to 50% would have chemotherapy and 50% to 60% would have best supportive care. The clinical experts also explained that people having alectinib would not have subsequent treatment with a tyrosine kinase inhibitor. They estimated that 50% of people who progressed while taking alectinib would have subsequent chemotherapy, and that the remaining 50% would have best supportive care. After consultation the company submitted a revised analysis, which assumed a subsequent treatment distribution based on the clinical experts' estimates. The company modelled second-line subsequent treatments, followed by best supportive care. Although the clinical experts' estimates had included some third-line treatment with ceritinib, the ERG advised that limiting the analysis to second-line treatments helped to contain the uncertainty caused by the high proportion of missing data in ALEX (see section\xa03.12). The committee considered that the distribution of subsequent treatments in the company's updated model sufficiently reflected UK clinical practice.\n\n## It is appropriate to assume that oncologist visits happen every 4\xa0weeks\n\nThe company's initial model assumed that patients in the progression-free survival, CNS progression-free survival and progressed disease states visited an oncologist every 5\xa0to\xa06 weeks. Clinical experts advised the ERG that in practice patients visited an oncologist every 4\xa0weeks. The clinical experts at the meeting agreed that this reflected UK clinical practice. The committee concluded that it was appropriate to model oncologist visits every 4\xa0weeks. After consultation, the company updated its modelling of oncologist visits in line with the committee's preference.\n\n## The management of CNS progression events is adequately captured in the model\n\nIn its model, the company explored 3\xa0treatment options for managing disease progression in the CNS: steroids, stereotactic radiosurgery and whole-brain radiotherapy. The company's initial base case assumed that 100% of patients with CNS metastases would have stereotactic radiosurgery and steroids. The company also presented a scenario analysis in which all patients had steroids, 23% of patients had stereotactic radiosurgery and 77% of patients had whole-brain radiotherapy. The clinical experts explained that treating CNS metastases is highly complex, and that the choice of treatment would depend on a variety of factors (such as age, health and prognosis). They advised that steroids would be offered to most people with CNS metastases. The clinical experts estimated that 20% to 25% of people with CNS metastases would have stereotactic radiosurgery, and 25% would have whole-brain radiotherapy, but that some people may have both. The clinical experts also suggested that surgical resection is sometimes used to manage CNS metastases. Although the committee recognised that treatment of CNS metastases is a complex area with variation in practice, it considered that the estimates that more closely reflect UK clinical practice (that is, 20% to 25% having stereotactic radiosurgery and 25% having whole-brain radiotherapy) were the best assumptions to use in the model. After consultation, the company submitted a revised analysis based on the clinical experts' estimated distributions of treatment for CNS metastases.\n\n# Health-related quality of life\n\n## It is preferable to model the role of subsequent treatments on quality of life\n\nIn its initial model, the company derived utility values for the progression-free and non-CNS progressed health states using a mixed-effects model based on EQ-5D data from ALEX. The utility values used in the economic model were 0.814 for the progression-free health state and 0.725 for the non-CNS progressed disease health state. The company assumed that the utility for the CNS-progressed disease state was 0.52 (from a study abstract by Roughley et al. 2014). After consultation, the company did an updated analysis which modelled different subsequent treatment distributions for alectinib and crizotinib in line with clinical practice (see section\xa03.22). The ERG highlighted that although the company's updated model took into account the costs of subsequent treatments, it did not model the effect of the different subsequent treatments on utilities. The ERG's preferred analysis modelled both the costs of the subsequent treatments and their effects on quality of life. The committee considered that it was good practice for cost-effectiveness analyses to capture quality of life when possible. Therefore, the committee concluded that it was preferable to model the role of subsequent treatments on costs and quality of life.\n\n## It is acceptable for post-progression utility values to reflect differences in subsequent treatment distribution\n\nThe subsequent treatment distributions in the company's revised model differed between the alectinib and crizotinib treatment arms. To capture this in the modelling of quality of life, the ERG weighted the utility values according to the subsequent treatment distributions. In line with the company's revised analysis (see section\xa03.22), the ERG assumed that people in the alectinib arm did not have second-line treatment with tyrosine kinase inhibitors, and that people in the crizotinib arm did not have second-line treatment with chemotherapy. People who did not have second-line treatment (50% of the alectinib arm and 30% of the crizotinib arm) or who progressed on second-line treatment had best supportive care, which was assumed to have a utility of 0.47. The resulting weighted utilities were 0.565 for second-line treatment with chemotherapy, 0.649 for second-line treatment with a tyrosine kinase inhibitor, and 0.47 for best supportive care. The committee agreed that it was realistic to weight utilities to reflect subsequent treatment distribution.\n\n## It is acceptable for post-progression utilities to reflect the site of disease progression\n\nAlthough the ERG was in favour of modelling the role of subsequent treatments on quality of life, it highlighted that utilities based only on subsequent treatment would not capture the differences in quality of life between people with CNS and non-CNS progressed disease. Because of this, the ERG's preferred analysis accounted for the site of the disease progression. Utility values were weighted to reflect the different distributions of subsequent treatments between alectinib and crizotinib (see section\xa03.22). However, people with CNS-progressed disease were assumed to have the CNS-progressed disease utility (0.52 in the company's model) regardless of subsequent treatment. From the clinical experts' evidence at the first meeting, the committee was aware of the importance of site of disease progression on quality of life. The committee therefore concluded that it was acceptable for post-progression utilities to reflect this.\n\n## A CNS-progressed disease utility value of 0.52 is preferred\n\nNot enough data were collected in ALEX to estimate the utility value for the CNS-progressed disease state. Because of this, the company used a utility value taken from a study by Roughley et al. (0.52; see section\xa03.25). The ERG noted that the utilities reported by Roughley et al. for non-CNS progressed disease were consistently lower than the utilities derived from ALEX (0.65 compared with 0.725). Because of this, the ERG was concerned that the utility value for the CNS-progressed disease state taken from Roughley et al. (0.52) was lower than if it had been derived from ALEX. The ERG accounted for this by applying a percentage decrement (0.52 divided by 0.65) to the non-CNS progressed disease utility in ALEX (0.725) which gave an estimated utility of 0.58 for the CNS-progressed disease state. The committee was aware of the differences between the utilities reported in ALEX and Roughley et al., but also that in the first committee meeting it had accepted 0.52 as the CNS-progressed disease utility. The committee considered scenario analyses based on utilities with and without the Roughley et al. decrement. It noted that applying the decrement for people having chemotherapy after alectinib led to a utility value for CNS-progressed disease (0.58) that was higher than the utility value for non-CNS progressed disease (0.565; see section\xa03.26), which the committee considered to be clinically implausible. Because of this, the committee concluded that the CNS-progressed disease utility value of 0.52 was preferable.\n\n# Cost-effectiveness results\n\n## The company's base-case ICER comparing alectinib with crizotinib is lower than £20,000 per QALY gained\n\nThe committee considered the incremental cost-effectiveness ratios (ICERs) from the company's base case, recalculated by the ERG to include the confidential commercial arrangements for alectinib and crizotinib. The company's base-case ICER for alectinib compared with crizotinib was lower than £20,000 per quality-adjusted life year (QALY) gained. The committee concluded that the company's base case was not appropriate for decision-making because of concerns about the modelling of the role of subsequent treatments on quality of life (see section\xa03.25).\n\n## The ERG's preferred assumptions increase the ICER\n\nThe ERG accepted the company's revised modelling of wastage, oncologist visits and the management of CNS metastases. The ERG also agreed with the company's updated approach of capturing progression events using RECIST only. The ERG's additional preferred assumptions were:\n\nprogressed disease utility values to be related to progression site (see section\xa03.27)\n\nutilities weighted to reflect subsequent treatment distributions in each treatment arm (see section\xa03.26)\n\nCNS-progressed disease utility value to be adjusted using the decrement from Roughley et al., increasing from 0.52 to 0.58 (see section\xa03.28)\n\ncost-effectiveness modelling based on updated ALEX data cut of overall survival (see section\xa03.19).The committee noted that combining the ERG's preferred assumptions increased the ICER compared with the company's base case. When the confidential discounts from the commercial arrangements for both technologies were applied, the ERG's preferred base-case ICER for alectinib compared with crizotinib was between £20,000 and £30,000 per QALY gained.\n\n## The most plausible ICER is between £20,000 and £30,000 per QALY gained\n\nThe committee largely agreed with the ERG's preferred assumptions. Although it was aware of the uncertainties about overall survival benefit and subsequent treatment in the appraisal, the committee concluded that the most plausible ICER for alectinib compared with crizotinib in people with untreated ALK-positive advanced NSCLC was between £20,000 and £30,000 per QALY gained. The committee agreed that alectinib, with the discount agreed in the commercial arrangement, was a cost-effective use of NHS resources for adults with untreated ALK-positive advanced NSCLC and was therefore recommended for routine use in the NHS.\n\n# Innovation\n\n## The benefits of alectinib are adequately captured in the model\n\nThe company explained that it considered alectinib to be innovative. The company and the clinical experts highlighted that alectinib has good penetration through the blood-brain barrier. The CNS is a common site of initial progression in ALK-positive NSCLC patients so CNS-active treatments are important targets for development. However, the clinical experts explained that although they consider alectinib to be novel and better at delaying disease progression than current standard care, they considered that alectinib's benefits were captured in the measurement of the QALYs. The committee concluded that alectinib may be innovative, but it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.\n\n# Other considerations\n\nNo equality or social value judgement issues were identified."}
|
https://www.nice.org.uk/guidance/ta536
|
Evidence-based recommendations on alectinib (Alecensa) for untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer in adults.
|
ababff259cbcc1a82863699806927cc3d6cf20ca
|
nice
|
Ixekizumab for treating active psoriatic arthritis after inadequate response to DMARDs
|
Ixekizumab for treating active psoriatic arthritis after inadequate response to DMARDs
Evidence-based recommendations on ixekizumab (Taltz) for treating active psoriatic arthritis in adults.
# Recommendations
Ixekizumab alone, or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults, only if:
it is used as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or
the person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has not responded within the first 12 weeks or has stopped responding after the first 12 weeks or
TNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Ixekizumab is only recommended if the company provides it according to the commercial arrangement.
Assess the response to ixekizumab after 16 weeks of treatment. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2 of the 4 Psoriatic Arthritis Response Criteria (PsARC), 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation 1.3).
When using the PsARC, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
These recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Ixekizumab is a biological therapy, several of which are already recommended by NICE for treating psoriatic arthritis. Clinical trial evidence shows that ixekizumab is more effective than placebo at treating joint and skin symptoms. An indirect comparison suggests that ixekizumab is likely to be as effective at improving symptoms as some of the current treatments used in the NHS for psoriatic arthritis.
The cost-effectiveness estimates show that for some groups of people with psoriatic arthritis, ixekizumab is the most cost-effective treatment option. For other groups, the difference in health benefits between ixekizumab and the most cost-effective treatment is very small. Overall, the cost effectiveness of ixekizumab is acceptable when it is used after 2 disease-modifying anti-rheumatic drugs, as the first biological therapy, or after treatment with a TNF‑alpha inhibitor. Therefore, it can be recommended.# Information about ixekizumab
Marketing authorisation indication
Ixekizumab (Taltz, Eli Lilly) has a marketing authorisation, alone or in combination with methotrexate, 'for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drug (DMARD) therapies'.
Dosage in the marketing authorisation
mg by subcutaneous injection (2×80 mg injections) at week 0, followed by 80 mg (1 injection) every 4 weeks thereafter.
For patients with concomitant moderate to severe plaque psoriasis, the recommended dosing regimen is 160 mg by subcutaneous injection (2×80 mg injections) at week 0, followed by 80 mg (1 injection) at weeks 2, 4, 6, 8, 10 and 12, then maintenance dosing of 80 mg (1 injection) every 4 weeks.
Consideration should be given to stopping treatment in patients whose disease has shown no response after 16 to 20 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 20 weeks.
Price
£1,125 per 80‑mg syringe.
The company has a commercial arrangement. This makes ixekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition
## Psoriatic arthritis can substantially decrease quality of life
The patient experts explained that psoriatic arthritis can affect people at a young age (peak onset is 30 to 50 years old) and is a lifelong condition. Symptoms including joint stiffness, fatigue and pain can make day-to-day activities difficult and have a serious negative effect on people's quality of life. Most people develop joint symptoms a few years after skin psoriasis and adding a painful joint disease to the skin symptoms can have a substantial psychological impact. The committee concluded that psoriatic arthritis can substantially decrease quality of life.
# Treatment pathway and current management
## Ixekizumab will be used in people who have had at least 2 DMARDs
The committee was aware that the marketing authorisation for ixekizumab indicates treatment after 1 or more disease-modifying anti-rheumatic drugs (DMARDs). However, the company did not submit any clinical- or cost-effectiveness analyses for the population who have had 1 conventional DMARD because this is not in line with British Society for Rheumatology guidelines and previous NICE technology appraisal guidance. These recommend people have 2 conventional DMARDs before biological therapies. The clinical experts confirmed that in the NHS, people usually have 2 DMARDs before moving on to non-conventional DMARDs. DMARDs are usually trialled sequentially, but people who have severe symptoms may have 2 or more DMARDs at the same time. This is because 1 DMARD alone is unlikely to be effective at controlling the disease. The committee concluded that ixekizumab would be used in people who have had at least 2 DMARDs and that the company's positioning of ixekizumab in the treatment pathway was in line with clinical practice, and therefore appropriate.
## Patients and clinicians would welcome an additional effective treatment option
The clinical experts explained that a tumour necrosis factor (TNF)‑alpha inhibitor is usually offered as the first biological therapy, unless it is contraindicated. They added that ixekizumab has a different mechanism of action and would be a useful additional treatment option because there are only a limited number of biological therapies that are not TNF‑alpha inhibitors. Ixekizumab, like secukinumab, inhibits interleukin‑17A. The clinical experts stated that it is useful to have options within the same class of drug because the adverse events people have with drugs in the same class can be different. Also, the disease may not respond to 1 therapy in a class, but it may respond to another in the same class. However, they explained that there was no evidence for this in psoriatic arthritis, as there is in psoriasis. The committee also noted that in the trial, the evidence for ixekizumab in people who have had a biological therapy was specifically after TNF‑alpha inhibitors. The patient experts explained that because the disease can stop responding to biological DMARDs over time, and because psoriatic arthritis is a lifelong disease, all treatment options can be exhausted by some people. Also, people's symptoms and responses to therapies can be heterogeneous; some people have symptoms that improve with a certain treatment but other people may prioritise improvements in other symptoms for which the same therapy is less effective. The committee concluded that patients and clinicians would welcome an additional effective treatment option.
# Clinical trial evidence
## Ixekizumab reduces joint and skin symptoms compared with placebo
The clinical-effectiveness evidence for ixekizumab came from 2 randomised, double-blinded, placebo-controlled trials. SPIRIT‑P1 included patients who had not had previous treatment with a biological DMARD but all of the patients in SPIRIT‑P2 either had disease that had previously had an inadequate response to or could not tolerate a TNF‑alpha inhibitor. In both trials, a statistically significantly higher proportion of people having ixekizumab had reductions in joint and skin symptoms as assessed by the Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI) 75 respectively at 12 weeks, compared with placebo. A statistically significantly higher proportion of people having ixekizumab also saw improvements in their ability to do daily activities compared with placebo, as assessed by the health assessment questionnaire disability index (HAQ‑DI). The committee concluded that ixekizumab is an effective treatment compared with placebo.
## The SPIRIT trials are generalisable to NHS clinical practice
The committee noted that the SPIRIT trials included few patients from the UK. Also, 15% of patients in SPIRIT‑P1 had not had any previous DMARDs and only a small number had had 2 or more previous DMARDs. The committee was therefore concerned that the trials might not reflect clinical practice in the NHS, where most people only have biological therapies after 2 previous DMARDs (see section 3.2). The clinical experts noted that although only a small number of patients had 2 or more previous DMARDs in the SPIRIT trials, most patients had had at least 1. They explained that in their experience, the efficacy of a biological therapy does not differ between those who have had 1 previous DMARD and those who have had 2 previous DMARDs. This was supported by a company post-hoc analysis, which pooled all the patients across the SPIRIT trials who had had 2 or more previous DMARDs. Although this analysis was based on non-randomised data and therefore subject to potential bias, it suggested similar efficacy of ixekizumab in this group of patients as in the overall trial populations. The committee concluded that the results of the SPIRIT trials were generalisable to the NHS.
# Network meta-analysis
## The results of the network meta-analysis for the no previous biological DMARD population are uncertain but are suitable for decision-making
Some of the comparator trials included in the no previous biological DMARD network included a mix of patients who had 1 or 2 previous DMARDs, because there was not enough data for separate networks. The committee recalled the clinical expert comments explaining that although this does not reflect clinical practice in the NHS, treatment efficacy is not expected to differ between those who have had 1 previous DMARD and those who have had 2 previous DMARDs (see section 3.5). For some of the comparators included in the NICE scope, the only available data included a mix of patients who had and had not had a previous biological DMARD. This was the case for certolizumab pegol, secukinumab and apremilast. The committee was concerned that the use of mixed population data introduced a large amount of uncertainty into the network meta-analysis. However, the results showed ixekizumab to have similar effectiveness to secukinumab which the clinical experts agreed matched their expectations, as both therapies are interleukin‑17A inhibitors. The committee therefore concluded that the network meta-analysis was suitable for decision-making and that ixekizumab is as effective at treating psoriatic arthritis as several of the biological therapies, including secukinumab.
## Certolizumab pegol and secukinumab should be included in the previous biological DMARD network meta-analysis
Because more of the patients in the certolizumab pegol and secukinumab trials had not had a previous biological DMARD (around two thirds), the company only included these comparators in the no previous biological DMARD network. It did not include secukinumab and certolizumab pegol in the base-case network for the population who had had a previous biological DMARD, but did provide a scenario analysis including them. The ERG highlighted that if having previous biological therapy influences a treatment's efficacy, then the network meta-analysis results will not be representative of the treatment effect in each population. The clinical experts agreed that this was likely to be the case, because in clinical practice they had seen declining efficacy with increasing biological DMARD treatment. However, the committee considered that this problem would affect the analyses for both populations despite a bigger proportion of patients not having had a previous biological DMARD. The committee concluded that certolizumab pegol and secukinumab should be included in the base-case network for the previous biological DMARD population because these comparators reflect clinical practice and were included in the NICE scope. Based on the network meta-analysis including secukinumab and certolizumab pegol, the committee concluded that ixekizumab is as effective at treating psoriatic arthritis in the previous biological DMARD population as several of the biological therapies, including secukinumab and ustekinumab.
# The company's economic model
## The company's economic model is suitable for decision-making
The company submitted cost-effectiveness analyses for the populations who have had and have not had a previous biological DMARD and for 3 psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis and with concomitant moderate to severe psoriasis). The economic model was based on the assessment group's model developed for NICE's technology appraisal guidance on certolizumab pegol and secukinumab. In the model used in this appraisal, ixekizumab and other non-conventional DMARDs were looked at as part of a treatment sequence. The committee noted that as well as different clinical data inputs, the 2 main differences between the company's model and the model used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab were:
the utility algorithm was derived from data from the SPIRIT trials and
baseline PASI scores for the psoriasis severity subgroups were derived from the SPIRIT trials.Scenario analyses using the assumptions accepted by the committee for each of these parameters in NICE's technology appraisal guidance on certolizumab pegol and secukinumab showed that the incremental cost-effectiveness ratios (ICERs) for ixekizumab were not sensitive to these changes. The committee concluded that the company's economic model was suitable for decision-making.
## The ERG's analysis reflects the committee's preferred assumptions
The ERG's analysis included some assumptions that differed from those used in the company's base case. Specifically, it:
included corrections for an error in the network meta-analysis results for ixekizumab HAQ‑DI and an inconsistency in the way the calculation of PASI change based on PsARC response was reported in the company submission and implemented in the model
included certolizumab pegol and secukinumab in the previous biological DMARD network meta-analysis
capped utilities at the general population values, to account for the increasing age of patients in the model
used a standardised mortality ratio of 1.05 instead of 1.36, derived from a more recent cut of the data.The committee accepted that these changes were appropriate and noted that none of them individually had a large effect on the ixekizumab ICERs and cumulatively the effect was small.
# Cost-effectiveness results
## The difference in total QALYs between ixekizumab and secukinumab in the no previous biological DMARD population is small
The committee noted that in the no previous biological DMARD population, for the no psoriasis and mild to moderate psoriasis subpopulations, secukinumab was the most cost-effective treatment in the fully incremental analysis. Because there are confidential discounts for ixekizumab and some of the comparators, the exact cost-effectiveness results cannot be reported. However, the differences in total quality-adjusted life years (QALYs) between ixekizumab and secukinumab were small and in the moderate to severe subpopulation, ixekizumab was associated with higher total QALYs and lower costs than secukinumab. The committee recalled that these small differences in QALYs were based on uncertain data from the network meta-analysis (see section 3.6). Therefore, the cost-effectiveness estimates of the treatments in this population would be sensitive to small changes in the estimates of total QALYs. The committee concluded that it was important to consider this in its decision-making.
## Ixekizumab is the most cost-effective treatment in the previous biological DMARD population
For the previous biological DMARD population, ixekizumab was the most cost-effective treatment in the fully incremental analysis. However, the committee again noted that the differences in total QALYs between ixekizumab, secukinumab and ustekinumab were small.
## Ixekizumab is a cost-effective treatment option for people who have had, and who have not had, a previous biological DMARD
The committee noted that although ixekizumab was not the most cost-effective option in all of the psoriasis subgroups in the no previous biological DMARD population, the difference in total QALYs between it and the most cost-effective treatment was very small and based on uncertain data. Ixekizumab was the most cost-effective option in the previous biological DMARD population. Overall, the committee concluded that the cost effectiveness of ixekizumab, with the commercial arrangement, was acceptable when:
the criteria in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3 tender joints and at least 3 swollen joints, and the psoriatic arthritis has not responded adequately to trials of at least 2 conventional DMARDs, given either individually or together or
the person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12 weeks or had stopped responding after the 12 weeks or
TNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).
## PsARC response should be assessed at 16 weeks
The committee noted that the economic analysis was based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 12 weeks stop ixekizumab treatment. This matches the timing of the primary outcome assessment in the SPIRIT trials. However, the ixekizumab summary of product characteristics states that stopping treatment should be considered if there is no response after 16 to 20 weeks of treatment. The company provided a scenario analysis, which showed that using data for ixekizumab outcomes assessed at 16 weeks in the model resulted in similar ICERs to using 12‑week data. The committee concluded that PsARC response should be assessed at 16 weeks to decide if ixekizumab treatment should continue, because this is in line with the summary of product characteristics.
# Other factors
## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed
The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for ixekizumab. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
## There are no significant health benefits that have not been captured in the QALY
The committee noted that the company had suggested that ixekizumab is effective at treating symptoms such as nail psoriasis and dactylitis and that improvements in these might not be captured in the EQ‑5D and therefore the QALY. However, the clinical experts explained that some of the other treatments also address these symptoms, but these outcomes were not measured in the older clinical trials. Therefore, any additional benefits would also likely apply to some of the comparator treatments. The committee concluded that there were no significant health benefits that had not been captured in the QALY calculation.
|
{'Recommendations': "Ixekizumab alone, or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults, only if:\n\nit is used as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has not responded within the first 12\xa0weeks or has stopped responding after the first 12\xa0weeks or\n\nTNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Ixekizumab is only recommended if the company provides it according to the commercial arrangement.\n\nAssess the response to ixekizumab after 16\xa0weeks of treatment. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2\xa0of the 4\xa0Psoriatic Arthritis Response Criteria (PsARC), 1\xa0of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria. People whose disease has a Psoriasis Area and Severity Index (PASI)\xa075 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation\xa01.3).\n\nWhen using the PsARC, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nIxekizumab is a biological therapy, several of which are already recommended by NICE for treating psoriatic arthritis. Clinical trial evidence shows that ixekizumab is more effective than placebo at treating joint and skin symptoms. An indirect comparison suggests that ixekizumab is likely to be as effective at improving symptoms as some of the current treatments used in the NHS for psoriatic arthritis.\n\nThe cost-effectiveness estimates show that for some groups of people with psoriatic arthritis, ixekizumab is the most cost-effective treatment option. For other groups, the difference in health benefits between ixekizumab and the most cost-effective treatment is very small. Overall, the cost effectiveness of ixekizumab is acceptable when it is used after 2\xa0disease-modifying anti-rheumatic drugs, as the first biological therapy, or after treatment with a TNF‑alpha inhibitor. Therefore, it can be recommended.", 'Information about ixekizumab': "Marketing authorisation indication\n\nIxekizumab (Taltz, Eli Lilly) has a marketing authorisation, alone or in combination with methotrexate, 'for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drug (DMARD) therapies'.\n\nDosage in the marketing authorisation\n\nmg by subcutaneous injection (2×80\xa0mg injections) at week\xa00, followed by 80\xa0mg (1\xa0injection) every 4\xa0weeks thereafter.\n\nFor patients with concomitant moderate to severe plaque psoriasis, the recommended dosing regimen is 160\xa0mg by subcutaneous injection (2×80\xa0mg injections) at week\xa00, followed by 80\xa0mg (1\xa0injection) at weeks\xa02, 4, 6, 8, 10 and\xa012, then maintenance dosing of 80\xa0mg (1\xa0injection) every 4\xa0weeks.\n\nConsideration should be given to stopping treatment in patients whose disease has shown no response after 16\xa0to 20\xa0weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 20\xa0weeks.\n\nPrice\n\n£1,125 per 80‑mg syringe.\n\nThe company has a commercial arrangement. This makes ixekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition\n\n## Psoriatic arthritis can substantially decrease quality of life\n\nThe patient experts explained that psoriatic arthritis can affect people at a young age (peak onset is 30\xa0to 50\xa0years old) and is a lifelong condition. Symptoms including joint stiffness, fatigue and pain can make day-to-day activities difficult and have a serious negative effect on people's quality of life. Most people develop joint symptoms a few years after skin psoriasis and adding a painful joint disease to the skin symptoms can have a substantial psychological impact. The committee concluded that psoriatic arthritis can substantially decrease quality of life.\n\n# Treatment pathway and current management\n\n## Ixekizumab will be used in people who have had at least 2\xa0DMARDs\n\nThe committee was aware that the marketing authorisation for ixekizumab indicates treatment after 1\xa0or more disease-modifying anti-rheumatic drugs (DMARDs). However, the company did not submit any clinical- or cost-effectiveness analyses for the population who have had 1\xa0conventional DMARD because this is not in line with British Society for Rheumatology guidelines and previous NICE technology appraisal guidance. These recommend people have 2\xa0conventional DMARDs before biological therapies. The clinical experts confirmed that in the NHS, people usually have 2\xa0DMARDs before moving on to non-conventional DMARDs. DMARDs are usually trialled sequentially, but people who have severe symptoms may have 2\xa0or more DMARDs at the same time. This is because 1\xa0DMARD alone is unlikely to be effective at controlling the disease. The committee concluded that ixekizumab would be used in people who have had at least 2\xa0DMARDs and that the company's positioning of ixekizumab in the treatment pathway was in line with clinical practice, and therefore appropriate.\n\n## Patients and clinicians would welcome an additional effective treatment option\n\nThe clinical experts explained that a tumour necrosis factor (TNF)‑alpha inhibitor is usually offered as the first biological therapy, unless it is contraindicated. They added that ixekizumab has a different mechanism of action and would be a useful additional treatment option because there are only a limited number of biological therapies that are not TNF‑alpha inhibitors. Ixekizumab, like secukinumab, inhibits interleukin‑17A. The clinical experts stated that it is useful to have options within the same class of drug because the adverse events people have with drugs in the same class can be different. Also, the disease may not respond to 1\xa0therapy in a class, but it may respond to another in the same class. However, they explained that there was no evidence for this in psoriatic arthritis, as there is in psoriasis. The committee also noted that in the trial, the evidence for ixekizumab in people who have had a biological therapy was specifically after TNF‑alpha inhibitors. The patient experts explained that because the disease can stop responding to biological DMARDs over time, and because psoriatic arthritis is a lifelong disease, all treatment options can be exhausted by some people. Also, people's symptoms and responses to therapies can be heterogeneous; some people have symptoms that improve with a certain treatment but other people may prioritise improvements in other symptoms for which the same therapy is less effective. The committee concluded that patients and clinicians would welcome an additional effective treatment option.\n\n# Clinical trial evidence\n\n## Ixekizumab reduces joint and skin symptoms compared with placebo\n\nThe clinical-effectiveness evidence for ixekizumab came from 2\xa0randomised, double-blinded, placebo-controlled trials. SPIRIT‑P1 included patients who had not had previous treatment with a biological DMARD but all of the patients in SPIRIT‑P2 either had disease that had previously had an inadequate response to or could not tolerate a TNF‑alpha inhibitor. In both trials, a statistically significantly higher proportion of people having ixekizumab had reductions in joint and skin symptoms as assessed by the Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI)\xa075 respectively at 12\xa0weeks, compared with placebo. A statistically significantly higher proportion of people having ixekizumab also saw improvements in their ability to do daily activities compared with placebo, as assessed by the health assessment questionnaire disability index (HAQ‑DI). The committee concluded that ixekizumab is an effective treatment compared with placebo.\n\n## The SPIRIT trials are generalisable to NHS clinical practice\n\nThe committee noted that the SPIRIT trials included few patients from the UK. Also, 15% of patients in SPIRIT‑P1 had not had any previous DMARDs and only a small number had had 2\xa0or more previous DMARDs. The committee was therefore concerned that the trials might not reflect clinical practice in the NHS, where most people only have biological therapies after 2\xa0previous DMARDs (see section\xa03.2). The clinical experts noted that although only a small number of patients had 2\xa0or more previous DMARDs in the SPIRIT trials, most patients had had at least\xa01. They explained that in their experience, the efficacy of a biological therapy does not differ between those who have had 1\xa0previous DMARD and those who have had 2\xa0previous DMARDs. This was supported by a company post-hoc analysis, which pooled all the patients across the SPIRIT trials who had had 2\xa0or more previous DMARDs. Although this analysis was based on non-randomised data and therefore subject to potential bias, it suggested similar efficacy of ixekizumab in this group of patients as in the overall trial populations. The committee concluded that the results of the SPIRIT trials were generalisable to the NHS.\n\n# Network meta-analysis\n\n## The results of the network meta-analysis for the no previous biological DMARD population are uncertain but are suitable for decision-making\n\nSome of the comparator trials included in the no previous biological DMARD network included a mix of patients who had 1\xa0or 2\xa0previous DMARDs, because there was not enough data for separate networks. The committee recalled the clinical expert comments explaining that although this does not reflect clinical practice in the NHS, treatment efficacy is not expected to differ between those who have had 1\xa0previous DMARD and those who have had 2\xa0previous DMARDs (see section\xa03.5). For some of the comparators included in the NICE scope, the only available data included a mix of patients who had and had not had a previous biological DMARD. This was the case for certolizumab pegol, secukinumab and apremilast. The committee was concerned that the use of mixed population data introduced a large amount of uncertainty into the network meta-analysis. However, the results showed ixekizumab to have similar effectiveness to secukinumab which the clinical experts agreed matched their expectations, as both therapies are interleukin‑17A inhibitors. The committee therefore concluded that the network meta-analysis was suitable for decision-making and that ixekizumab is as effective at treating psoriatic arthritis as several of the biological therapies, including secukinumab.\n\n## Certolizumab pegol and secukinumab should be included in the previous biological DMARD network meta-analysis\n\nBecause more of the patients in the certolizumab pegol and secukinumab trials had not had a previous biological DMARD (around two thirds), the company only included these comparators in the no previous biological DMARD network. It did not include secukinumab and certolizumab pegol in the base-case network for the population who had had a previous biological DMARD, but did provide a scenario analysis including them. The ERG highlighted that if having previous biological therapy influences a treatment's efficacy, then the network meta-analysis results will not be representative of the treatment effect in each population. The clinical experts agreed that this was likely to be the case, because in clinical practice they had seen declining efficacy with increasing biological DMARD treatment. However, the committee considered that this problem would affect the analyses for both populations despite a bigger proportion of patients not having had a previous biological DMARD. The committee concluded that certolizumab pegol and secukinumab should be included in the base-case network for the previous biological DMARD population because these comparators reflect clinical practice and were included in the NICE scope. Based on the network meta-analysis including secukinumab and certolizumab pegol, the committee concluded that ixekizumab is as effective at treating psoriatic arthritis in the previous biological DMARD population as several of the biological therapies, including secukinumab and ustekinumab.\n\n# The company's economic model\n\n## The company's economic model is suitable for decision-making\n\nThe company submitted cost-effectiveness analyses for the populations who have had and have not had a previous biological DMARD and for 3\xa0psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis and with concomitant moderate to severe psoriasis). The economic model was based on the assessment group's model developed for NICE's technology appraisal guidance on certolizumab pegol and secukinumab. In the model used in this appraisal, ixekizumab and other non-conventional DMARDs were looked at as part of a treatment sequence. The committee noted that as well as different clinical data inputs, the 2\xa0main differences between the company's model and the model used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab were:\n\nthe utility algorithm was derived from data from the SPIRIT trials and\n\nbaseline PASI scores for the psoriasis severity subgroups were derived from the SPIRIT trials.Scenario analyses using the assumptions accepted by the committee for each of these parameters in NICE's technology appraisal guidance on certolizumab pegol and secukinumab showed that the incremental cost-effectiveness ratios (ICERs) for ixekizumab were not sensitive to these changes. The committee concluded that the company's economic model was suitable for decision-making.\n\n## The ERG's analysis reflects the committee's preferred assumptions\n\nThe ERG's analysis included some assumptions that differed from those used in the company's base case. Specifically, it:\n\nincluded corrections for an error in the network meta-analysis results for ixekizumab HAQ‑DI and an inconsistency in the way the calculation of PASI change based on PsARC response was reported in the company submission and implemented in the model\n\nincluded certolizumab pegol and secukinumab in the previous biological DMARD network meta-analysis\n\ncapped utilities at the general population values, to account for the increasing age of patients in the model\n\nused a standardised mortality ratio of\xa01.05 instead of\xa01.36, derived from a more recent cut of the data.The committee accepted that these changes were appropriate and noted that none of them individually had a large effect on the ixekizumab ICERs and cumulatively the effect was small.\n\n# Cost-effectiveness results\n\n## The difference in total QALYs between ixekizumab and secukinumab in the no previous biological DMARD population is small\n\nThe committee noted that in the no previous biological DMARD population, for the no psoriasis and mild to moderate psoriasis subpopulations, secukinumab was the most cost-effective treatment in the fully incremental analysis. Because there are confidential discounts for ixekizumab and some of the comparators, the exact cost-effectiveness results cannot be reported. However, the differences in total quality-adjusted life years (QALYs) between ixekizumab and secukinumab were small and in the moderate to severe subpopulation, ixekizumab was associated with higher total QALYs and lower costs than secukinumab. The committee recalled that these small differences in QALYs were based on uncertain data from the network meta-analysis (see section\xa03.6). Therefore, the cost-effectiveness estimates of the treatments in this population would be sensitive to small changes in the estimates of total QALYs. The committee concluded that it was important to consider this in its decision-making.\n\n## Ixekizumab is the most cost-effective treatment in the previous biological DMARD population\n\nFor the previous biological DMARD population, ixekizumab was the most cost-effective treatment in the fully incremental analysis. However, the committee again noted that the differences in total QALYs between ixekizumab, secukinumab and ustekinumab were small.\n\n## Ixekizumab is a cost-effective treatment option for people who have had, and who have not had, a previous biological DMARD\n\nThe committee noted that although ixekizumab was not the most cost-effective option in all of the psoriasis subgroups in the no previous biological DMARD population, the difference in total QALYs between it and the most cost-effective treatment was very small and based on uncertain data. Ixekizumab was the most cost-effective option in the previous biological DMARD population. Overall, the committee concluded that the cost effectiveness of ixekizumab, with the commercial arrangement, was acceptable when:\n\nthe criteria in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3\xa0tender joints and at least 3\xa0swollen joints, and the psoriatic arthritis has not responded adequately to trials of at least 2\xa0conventional DMARDs, given either individually or together or\n\nthe person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12\xa0weeks or had stopped responding after the 12\xa0weeks or\n\nTNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).\n\n## PsARC response should be assessed at 16\xa0weeks\n\nThe committee noted that the economic analysis was based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 12\xa0weeks stop ixekizumab treatment. This matches the timing of the primary outcome assessment in the SPIRIT trials. However, the ixekizumab summary of product characteristics states that stopping treatment should be considered if there is no response after 16\xa0to 20\xa0weeks of treatment. The company provided a scenario analysis, which showed that using data for ixekizumab outcomes assessed at 16\xa0weeks in the model resulted in similar ICERs to using 12‑week data. The committee concluded that PsARC response should be assessed at 16\xa0weeks to decide if ixekizumab treatment should continue, because this is in line with the summary of product characteristics.\n\n# Other factors\n\n## Clinicians should take into account factors that may affect PsARC and PASI and make any clinical adjustments needed\n\nThe committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for ixekizumab. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\n## There are no significant health benefits that have not been captured in the QALY\n\nThe committee noted that the company had suggested that ixekizumab is effective at treating symptoms such as nail psoriasis and dactylitis and that improvements in these might not be captured in the EQ‑5D and therefore the QALY. However, the clinical experts explained that some of the other treatments also address these symptoms, but these outcomes were not measured in the older clinical trials. Therefore, any additional benefits would also likely apply to some of the comparator treatments. The committee concluded that there were no significant health benefits that had not been captured in the QALY calculation."}
|
https://www.nice.org.uk/guidance/ta537
|
Evidence-based recommendations on ixekizumab (Taltz) for treating active psoriatic arthritis in adults.
|
31ddfc66d668159fee1c6de0e3ae4ffbd2524fae
|
nice
|
Community pharmacies: promoting health and wellbeing
|
Community pharmacies: promoting health and wellbeing
This guideline covers how community pharmacies can help maintain and improve people’s physical and mental health and wellbeing, including people with a long-term condition. It aims to encourage more people to use community pharmacies by integrating them within existing health and care pathways and ensuring they offer standard services and a consistent approach. It requires a collaborative approach from individual pharmacies and their representatives, local authorities and other commissioners.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Health and wellbeing hubs
This recommendation is for local authorities, clinical commissioning groups, health and wellbeing boards, community pharmacies and their representatives.
Work together to help all community pharmacies gradually integrate into existing care and referral pathways as health and wellbeing hubs. This could include arrangements for inward and outward referrals (see recommendation 1.6.1).
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on health and wellbeing hubs .
Full details of the evidence and the committee's discussion are in the evidence discussion for sections 1.1 and 1.2.
Loading. Please wait.
# Overarching principles of good practice for community pharmacy teams
## Use an integrated approach
Work with local health and social care organisations to ensure community pharmacy interventions are delivered according to local need and as part of wider services in the local area.
## Ensure consistent, high-quality services
Use a tailored approach when providing community pharmacy health and wellbeing interventions to maximise their impact and effect.
Local providers should ensure interventions are carried out only by staff members with the skills and competencies to do so. For example, follow NICE's recommendations on training in the guidelines on:
behaviour change: individual approaches
tobacco: preventing uptake, promoting quitting and treating dependence.
When possible, the same member of staff should deliver all sessions of an intervention (if multiple sessions are needed) to promote continuity of care.
Use information, resources and support aids available from statutory, community and voluntary sector organisations (for example, Healthwatch and Public Health England). Ensure the materials used are:
not based solely on commercial interests or incentives
clear and professionally produced.
## Address health inequalities
Address health inequalities by working with other agencies to identify underserved groups. Tailor health and wellbeing interventions to suit their individual needs and preferences and maximise their impact. For example:
use knowledge of the local community (particularly from staff who live in the community where they work) to take into account the context in which people live and work (their physical, economic and social environment)
make use of the skills staff members already have (for example, if they speak languages commonly used in the area)
take into account other personal factors such as gender, identity, ethnicity, faith, culture or any disability that may affect the approach taken (for example, provide information in an appropriate format for people who may have difficulty reading).
## Promote community pharmacies
Consider promoting community pharmacies. For example:
Local commissioners could make it clear that community pharmacies are an integral part of NHS primary care services and offer people a link into the local health and care network.
Individual pharmacies could publicise the skills and competencies of their staff to increase the public's knowledge of and confidence in the health and wellbeing services on offer.
## Proactively seek opportunities
Proactively seek opportunities to promote people's physical and mental health and wellbeing. This includes: awareness raising and information provision, advice and education, behavioural support and referral and signposting to other services. Describe the interventions on offer and the benefits. Do this for example, when someone:
Regularly buys over-the-counter medicines, such as painkillers. For example, if relevant offer advice on other ways of reducing lower back pain including self-management and exercise. (See recommendations on non-invasive treatments in NICE's guideline on low back pain and sciatica.)
Regularly collects a prescription for themselves or someone they care for. For example, provide education and advice on how improving their diet, being more physically active or reducing alcohol intake may help the condition and improve their physical or mental health and wellbeing.
Regularly uses the pharmacy for over-the-counter medication or one-off prescriptions and, where appropriate, routine or occasional non-healthcare purchases. For example, offer behavioural support for stopping smoking (see NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence); or information on effective sun protection (see NICE's guideline on sunlight exposure).
Is planning a pregnancy or is pregnant. For example, raise awareness of the benefits of, and provide information on, folic acid and other supplements (see NICE's guidelines on maternal and child nutrition and on vitamin D: supplement use in specific population groups).
For a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on overarching principles of good practice for community pharmacy teams .
Full details of the evidence and the committee's discussion are in the evidence discussion for sections 1.1 and 1.2.
Loading. Please wait.
# Awareness raising and providing information
Ensure any pharmacy awareness raising campaigns or information is in line with NICE's guidelines on behaviour change: individual approaches (in particular, the first bullet of recommendation 9) and behaviour change: general approaches (particularly principle 6).
Tell people what the purpose of the health information is that you want to give them. For example:
when handing out leaflets explain their content and importance
point out the relevance of any posters that are displayed or highlight how people can easily get further information on the topic (for example, using QR codes)
if distributing leaflets with dispensed medicines, explain to the person collecting them – such as a carer, family member, friend or delivery person – why they are included and how to find out more, so they can pass this information on.
For a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on awareness raising and providing information .
Full details of the evidence and the committee's discussion are in evidence review 1: providing information on health and wellbeing.
Loading. Please wait.
# Advice and education
Offer advice and education as the opportunity arises in line with NICE's guidelines on: behaviour change: individual approaches (see the recommendations on delivering very brief, brief and extended brief advice).
When someone uses pharmacy services to manage a long-term condition, use this as an opportunity to advise them on how to improve their general health and wellbeing. For example, follow recommendations on advice and education in NICE's guidelines on:
diabetes in adults (type 1, and type 2) and diabetes in children and young people (type 1 and type 2)
hypertension in adults for people with, or at risk of, hypertension (see the sections on lifestyle interventions and patient education and adherence to treatment).
Offer brief advice and education as the opportunity arises, on stopping smoking and reducing alcohol consumption:
For smoking cessation, follow NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence (in particular see the sections on commissioning and designing services, identifying people who smoke, information on stopping smoking for those using acute, maternity and mental health services, and advice on nicotine-containing e‑cigarettes).
For alcohol issues, follow the recommendations on brief advice in NICE's guideline on alcohol-use disorders. In particular see recommendation 5 on resources for screening and brief interventions and recommendation 10 on brief advice for adults.
Use support materials and approaches to aid these discussions, if available. (For example, advice and education on smoking could be supported by photo-ageing software, if it is available.)
For a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on advice and education .
Full details of the evidence and the committee's discussion are in evidence review 2: offering advice or education to promote health and wellbeing.
Loading. Please wait.
# Behavioural support
Offer behavioural support in line with NICE's guidelines on:
behaviour change: individual approaches (see the recommendations on using proven behaviour change techniques when designing interventions; and high intensity behaviour change interventions and programmes)
behaviour change: general approaches (see principles 4 and 5).
Help people to stop smoking by offering behavioural support programmes in line with NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence.
Help people to manage their weight by offering behavioural support programmes in line with NICE's guidelines on:
-besity: identification, assessment and management (see the section on behavioural interventions)
weight management: lifestyle services for overweight or obese adults (see recommendation 11)
preventing excess weight gain
and
-besity prevention.
Consider referring people to other behavioural support services within the local health and care network (for example, to voluntary or community services) for interventions that are not available in the pharmacy (see section 1.6).
For a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on behavioural support .
Full details of the evidence and the committee's discussion are in evidence review 3: offering behavioural support to promote health and wellbeing.
Loading. Please wait.
# Referrals and signposting
## Referrals
Local commissioners and pharmacies could consider establishing a formal referral process with other pharmacies and service providers. This includes GP services and those offered by local authorities and organisations in the community and voluntary sectors. Specifically:
Consider basing pharmacy assessments, triage activities and referrals on agreed tools that support continuing treatment.
Consider designing triage activities to reduce multiple assessments and waiting times after people are referred. For example, after identifying harmful or dependent alcohol consumption, consider providing access to alcohol services that does not require reassessment and a return to the start of the treatment pathway. (Harmful and dependent alcohol consumption could be identified using the AUDIT tool or another threshold used locally.)
Consider referring people to other services and triage within the agreed local care or referral pathway to give fast access to an appointment if needed. For example, refer people to:
GPs or other healthcare providers for:
-ngoing contraception
assessment for sleep apnoea if agreed local assessment tools are in place
support for high risk or dependent alcohol consumption
drug misuse recovery support
weight reduction services
local authority, NHS or community and voluntary sector organisations for:
weight loss programmes or support groups
mental health and wellbeing support
specialist treatment and recovery support for drug misuse and dependence
support for carers
adult and children's social care.
When making a formal referral to another service, explain to the person why they are being referred, where they are being referred to and the service they can expect. Provide them with written information about the service if it is available.
When the pharmacy accepts a formal referral from another service:
ensure all relevant information has been provided so that care can start at the first opportunity without the need for a reassessment
-ffer care as a walk-in service or, if this is not available or suitable, agree an appointment time and date with the person and give them the name of the staff member they will see.
## Signposting
If the community pharmacy cannot support specific needs or offer a formal referral, signpost people to other local services. For example:
sexual health services
stop smoking services
social care services
mental health and wellbeing support
-ther community services such as: Citizens Advice; housing, benefits or employment advice; support services for carers; and government and third sector debt advice websites.
## Record keeping, auditing and monitoring
Consider using minimum data sets and summary care records to encourage record keeping and auditing, particularly when exchanging information through formal referrals in the local care network.
For a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on referrals and signposting .
Full details of the evidence and the committee's discussion are in evidence review 4: signposting and referral to other services and support.
Loading. Please wait.
# Terms used in this guideline
This section defines terms that have been used in a specific way for this guideline. For other public health and social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.
## Photo-ageing
A smoking cessation intervention in which photos of participants are digitally aged so they can see images of themselves as a lifelong smoker and a non-smoker.
## Underserved groups
Adults and children from any background are 'underserved' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to access health services or attend healthcare appointments.
Many of these groups may be more likely to go to a community pharmacy than a GP or another primary care service. As an example, this includes: people who are housebound, homeless or sleep rough; people who misuse drugs or alcohol; and Gypsy, Traveller and Roma people. A full list can be found in the equality impact assessment for this guideline.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Referral within a formal care pathway
Is referral from a community pharmacy within a formal local care pathway framework more effective and cost effective than signposting alone in improving access to, and uptake of, services by underserved groups and the general population?
For a short explanation of why the committee made the recommendation for research, see the rationale section on health and wellbeing hubs .
More details about how this research could be conducted can be found in recommendations for research: in detail.
Loading. Please wait.
## Health and wellbeing interventions
How effective and cost effective are awareness raising, advice and education or behavioural support interventions delivered by community pharmacy teams to improve health and behavioural outcomes in underserved groups and the general population?
For a short explanation of why the committee made the recommendation for research, see the rationale sections on awareness raising and providing information , advice and education , and behavioural support .
More details about how this research could be conducted can be found in recommendations for research: in detail.
Loading. Please wait.
Loading. Please wait.
Loading. Please wait.
## Addressing health inequalities
What are the barriers to and facilitators for increasing access to community pharmacy services by underserved groups? How should health and wellbeing interventions be tailored to increase service uptake in underserved groups?
For a short explanation of why the committee made the recommendation for research, see the rationale section on addressing health inequalities .
More details about how this research could be conducted can be found in recommendations for research: in detail.
Loading. Please wait.
## Characteristics of a person delivering an intervention
How do the professional characteristics of pharmacy staff affect the effectiveness and cost effectiveness of delivering information, advice, education or behavioural support to underserved groups and the general population? (Characteristics include, for example, job roles such as health champion, as well as competencies and level of training.)
For a short explanation of why the committee made the recommendation for research, see the rationale section on ensure consistent, high-quality services .
More details about how this research could be conducted can be found in recommendations for research: in detail.
Loading. Please wait.
## Patient activation
How effective and cost effective is advice, education or behavioural support offered by community pharmacy teams to improve patient activation and measures of behaviour and health changes, particularly in areas where activation levels are lower? This includes evaluating factors such as frequency, intensity and duration of the intervention.
For a short explanation of why the committee made the recommendation for research, see the rationale section on behavioural support .
More details about how this research could be conducted can be found in recommendations for research: in detail.
Loading. Please wait.
# Other recommendations for research
## Local social prescribing interventions
How effective and cost effective is it for community pharmacy teams to provide local social prescribing interventions? What is the differential impact in both effectiveness and cost effectiveness of community pharmacies carrying out this activity compared with providing only referral or signposting to these interventions?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Health and wellbeing hubs
Recommendation 1.1.1
## Why the committee made the recommendation
The current NHS sustainability and transformation partnerships (STPs) and the Five Year Forward View both aim to improve the integration of healthcare services in the UK. The committee agreed that, as part of this, community pharmacies need to gradually become part of existing health and care pathways. This would mean they could act as health and wellbeing hubs, with inward and outward referrals established and consistently managed.
This will ensure they are aware of what services are offered locally and where formal referrals can be set up. But because it is not clear how to effectively refer in and out of pharmacies to improve people's care, the committee made research recommendation 1.
## How the recommendation might affect practice
Once community pharmacies are integrated with other local health and care services, the idea is that they can operate as neighbourhood health and wellbeing centres (health and wellbeing hubs). This means they would become the first place that people go to for support, advice and resources on staying well and healthy. It may involve working closely with community leaders to identify local resources and needs, develop related interventions and services, and collect data on impact and outcomes.
Some investment may be needed to carry out these activities and to set up a formal referral process within community pharmacies. But this is in line with the movement towards better integration of health and care services within the NHS, and national resources are being put in place to support this. For example, the Pharmacy Integration Fund was established to support clinical pharmacy integration within the NHS and the community.
Return to recommendation
# Overarching principles of good practice for community pharmacy teams
Recommendations 1.2.1 to 1.2.8
## Why the committee made the recommendations
Community pharmacies offer a socially inclusive, easily accessible service for all members of the public and, as such, should be the first place people go for help with a non-urgent health issue. A key way to encourage more people to use services is to ensure they are fully integrated within the health and care system – including with other pharmacies.
Better integration of community pharmacies in the wider health care system will have a positive impact on patient choice and result in better health outcomes for people in both primary care and the community.
The committee agreed that if more people are to use the interventions on offer they need to know what they can expect, regardless of which pharmacy they visit, so a consistent standard of service is important.
A typical community pharmacy is staffed by people with various levels of training and competencies in health promotion services. Healthy Living Pharmacies also have qualified health champions who take responsibility for the healthy living programme.
But there is a lack of research on how the training or other characteristics of the person delivering a health and wellbeing intervention influence its effectiveness or cost effectiveness. This includes a lack of research on whether using a recognised behaviour change competency framework (see NICE's guideline on behaviour change: individual approaches) has an impact on this. So the committee made research recommendation 4.
Evidence showed that people are more likely to trust information resources that are clear, professional and relatively free of any commercial links. The latter is particularly important because it makes it clear that there is no profit motive behind any information given.
An expert pointed out to the committee that because of their accessibility, community pharmacies could address health inequalities. In England, 90% of people (99% in the most deprived communities) live within a 20‑minute walk of a community pharmacy.
But more research is needed to determine whether community pharmacies are better than other health services at reaching underserved groups. In addition, there is no evidence on how these services should be tailored to benefit different groups. (People from different ethnic or socioeconomic groups, or of different ages, may gain more or less from the services on offer.) So the committee made research recommendation 3.
Another way to encourage the public to make full use of community pharmacy interventions could be to make them aware that many staff are qualified or specialists in certain areas. This could improve the public's perception of the pharmacy as a trusted source of health and wellbeing advice and support.
Community pharmacy interventions to help improve people's physical and mental health and wellbeing are usually delivered as the opportunity arises – when people come in for prescriptions, buy other products or make general enquiries.
The committee agreed that identifying opportunities to provide interventions and referrals should be encouraged. It would mean that more people using pharmacies could get support, either from the pharmacy itself or from other local multidisciplinary teams, to prevent health problems from developing or deteriorating. This, in turn, would reduce the burden on other areas of health and care.
## How the recommendations might affect practice
Establishing links to integrate community pharmacies with other health and care organisations may result in upfront costs such as the time it takes to develop pathways and make a referral. But this may be offset by:
more efficient use of resources in the wider system
better continuity of care
quicker access to the right treatment (including for underserved or underprivileged communities).
It may not always be practical or feasible for the same member of staff to deliver all sessions of an intervention, but where it is possible this will reduce variation in current practice.
Identifying underserved groups and tailoring interventions to suit an individual's needs and preferences may increase service uptake in these groups and help community pharmacies to potentially address health inequalities.
Promoting community pharmacies by highlighting the services on offer and the skills of pharmacy staff may have some resource impact. But this may be offset by an improvement in health outcomes resulting from more people using the services.
It may not always be practical or feasible to seek opportunities to promote health and wellbeing services within the pharmacy. But if staff are trained to identify opportunities to offer services then there should be no significant cost implications. The Making Every Contact Count initiative offers training for health and social care staff on how to identify opportunities to talk to people about their health and wellbeing and deliver brief interventions. Some funding to support or implement this training may be available.
General health and wellbeing advice is covered in general pharmacy training and some pharmacists and pharmacy technicians are trained in core public health priorities. Some staff will also have the Royal Society for Public Health Level 2 award in improving health. Some pharmacy staff may need additional training in effective behaviour change techniques, which may incur a small resource cost. Some free behaviour change training may be available, for example from Health Education England and the Centre for Pharmacy Postgraduate Education.
Return to recommendations
# Awareness raising and providing information
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
The way community pharmacies provide information on health and wellbeing varies across the UK, as does the way they present and use these resources.
Evidence showed that providing information to raise people's awareness of an issue is the first step to helping them change their behaviour. Evidence also showed that it is most effective to give people information as part of a discussion, rather than just handing them a leaflet or other resource.
But there is limited evidence on its effectiveness and cost effectiveness for specific issues such as alcohol or drug misuse, diabetes, falls, smoking, cancer, and mental health and wellbeing. So the committee made research recommendation 2.
## How the recommendations might affect practice
Speaking to people about the information you want to give them before you hand it out may involve a small amount of additional staff time (to explain why the information is relevant). But this cost could be offset by improved health outcomes and resource savings elsewhere in the health or care system. For example, the person might, as a result, seek advice or receive other support that prevents them from becoming ill or generally improves their health.
Some pharmacy staff, such as those who have become health champions, are competent to provide information in this way.
In addition, pharmacists and pharmacy technicians receive or have access to training in communication and consultation skills as part of their undergraduate, postgraduate and pre-registration training programmes. They can also get free training in these skills from The Centre for Pharmacy Post Graduate Education (funded by Health Education England).
Return to recommendations
# Advice and education
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
Community pharmacies are well placed to offer health and wellbeing advice and education to everyone in a local community, whether they have a long-term health condition or need help to adopt a healthier lifestyle. However, there is significant variation in what is offered.
Evidence showed that pharmacy staff can provide effective advice and education to people with diabetes and hypertension. It also showed that brief advice can help people stop smoking. There was limited evidence that the use of photo-ageing software to support such advice was effective and cost effective. But based on their experience, the committee agreed that it could be worth trying if resources were available on the premises.
In addition, advice and education can potentially help people reduce their alcohol consumption. But further research is needed to see if it is effective in: improving cancer awareness and people's sexual health and mental health and wellbeing, or preventing drug misuse and falls. So the committee made research recommendation 2.
## How the recommendations might affect practice
These recommendations should reduce variation in current practice.
General health and wellbeing advice is covered in general pharmacy training. Some pharmacists and pharmacy technicians are also trained in core public health priorities. Some staff will have gained the Royal Society for Public Health Level 2 award in improving health.
A lot of free training is available for pharmacy staff (such as the smoking cessation training provided by the National Centre for Smoking Cessation and Training). But some may involve a small cost. So pharmacy teams that currently provide the least health and wellbeing advice and education are likely to have the biggest expenditure as a result of implementing the recommendations.
Return to recommendations
# Behavioural support
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
The type of behavioural support offered by community pharmacy teams varies across the UK, so the committee recommended that they follow NICE guidelines for the relevant issue or condition.
Evidence showed that certain behavioural interventions, specifically interventions to help people stop smoking or manage their weight, are effective and cost effective when provided by community pharmacy teams.
Some evidence suggests that interventions delivered in community pharmacies that involve people setting their own health goals may help people improve their patient activation. However, more research is needed to support this and to show how delivering these interventions in community pharmacies can be used to improve people's health. So the committee made research recommendation 5.
Further research is also needed before behavioural interventions can be recommended in pharmacies for: improving cancer awareness, sexual and mental health and orthopaedic conditions, and preventing alcohol or drug misuse, diabetes and falls. So the committee made research recommendation 2.
The committee agreed that written information or support aids given alongside behavioural support may be beneficial. They also agreed that it is worth referring people to other services in the local care network for behavioural support if the pharmacy doesn't provide this itself.
## How the recommendations might affect practice
These recommendations should reduce variation in practice and ensure commissioners focus on behavioural support activities that have been shown to be both effective and cost effective.
Some pharmacy staff may need training in effective behaviour change techniques and this may incur a small resource cost. However, local authorities may provide their own training. In addition, some free behaviour change training may be available for pharmacy staff from, for example, Health Education England and the Centre for Pharmacy Postgraduate Education.
Return to recommendations
# Referrals and signposting
Recommendations 1.6.1 to 1.6.6
## Why the committee made the recommendations
Members of the public may need to be directed to other services for support, advice or treatment if it cannot be provided by the community pharmacy.
Formal referrals, involving an agreed process with another provider, may be more effective than signposting (giving people information on other organisations that can help). But often community pharmacy services are not part of a formalised care pathway. That means they cannot always make formal referrals to, or accept them from, other services. It also means that other services may not know what community pharmacies can offer.
An expert told the committee that links with other health and care providers were key to ensure effective continuity of care and to ensure people gain the most benefit from the system. The committee agreed this is particularly important for people who may not use other healthcare services, for example people from underserved groups.
The committee recommended that if community pharmacy teams do offer such a service, fast referrals will be needed for people at risk. In addition, it will be important to ensure people referred on are not reassessed as a matter of routine when they enter the care pathway. (Reassessment is a waste of resources and could also undermine the pharmacist's credibility.)
Based on their experience, the committee agreed it was useful to provide examples of the types of issues that community pharmacy teams could make referrals on, including to GPs, local authorities and social services.
Some evidence showed that people are more likely to take up the offer of a referral if they are given clear details about why they are being referred and what they can expect to happen. The committee also agreed that it was important for pharmacy staff to be fully informed when they accept a referral, so that assessments are not duplicated and people can enter at the correct point in the care pathway.
Some evidence showed that referral by community pharmacy teams increased service uptake more than signposting, but more evidence is needed to support a formal referral process. Establishing cost-effectiveness evidence for this in pharmacies is also important. That's because there may be cost implications for the time needed to make or accept individual referrals and for setting up the overall process, compared with signposting. So the committee made research recommendation 1.
If it is not possible to introduce a formal referral process, signposting people to other organisations is still important because it can increase the likelihood of people using the services. But committee members agreed with the evidence that formal referrals are more effective at increasing the uptake of services.
Recording and sharing information will prevent duplication in the care pathway, build relationships between service providers and encourage collaboration. Auditing could also help improve both efficiency and quality and inform the work of other organisations. But this can only be achieved if the service providers involved have a shared understanding of what data should be recorded and used for analysis (that is, the minimum data sets) and why.
## How the recommendations might affect practice
Integrating community pharmacy interventions into health and care pathways will have a positive impact on patient choice and result in better health outcomes for people in both primary care and the community.
Signposting is currently the standard approach within community pharmacies. But clear methods of referral to and from community pharmacies should make it easier for people to access services and increase uptake. Effective referrals will also encourage people to choose the pharmacy as their first point of contact with healthcare professionals, potentially reducing pressure on A&E and GP practices.
In the long term these benefits may offset any upfront costs such as the time it takes to develop pathways and make the referral.
In terms of resource impact, it may not be practical to record every intervention, but it is something that is covered by professional practice, so there is no potential resource impact.
Return to recommendations# Context
Community pharmacy contractors dispense NHS prescriptions under the NHS (Pharmaceutical Services and Local Pharmaceutical Services) Regulations 2013. As well as dispensing, community pharmacy contractors are required to:
promote healthy lifestyles
participate in 6 public health campaigns a year
dispose of unwanted medicines
provide support for self-care
signpost members of the community to appropriate services.
As of 7 November 2017, there were 11,699 community pharmacies in England (NHS Digital General Pharmaceutical Services in England – 2007/08 to 2016/17).
Most prescription items are dispensed by community pharmacies. In 2016/17, for example, they dispensed 91.6% of the 1,000 million plus items dispensed in the community ('General Pharmaceutical Services in England – 2007/08 to 2016/17'). In 2016, the net cost of prescriptions dispensed in the community was £9,205 million. Of the prescriptions dispensed, 89.4% were dispensed free of charge, with 61% provided free to people aged 60 and over (NHS Digital Prescriptions dispensed in the community, Statistics for England 2006 to 2016).
Community pharmacies are well positioned to promote health and wellbeing to their local community, including those from underserved groups, because 90% of people in England (including more than 99% of people in the most deprived communities) live within a 20‑minute walk of one. The location of community pharmacies, unlike other healthcare outlets, does not comply with the usual 'inverse care law' in that there is a greater concentration of community pharmacies in areas of deprivation. (The positive pharmacy care law: an area-level analysis of the relationship between community pharmacy distribution, urbanity and social deprivation in England Todd et al. 2014).
The risk of many health conditions can be reduced by people adopting healthier behaviours. These include: type 2 diabetes, cardiovascular disease, respiratory diseases such as chronic obstructive pulmonary disease, and other conditions related to obesity and smoking.
Community pharmacies can help raise awareness of health conditions, improve physical and mental health, and reduce both health inequalities and individual health risks by providing advice and services to everyone entering their premises. This includes people who do not visit GPs or other healthcare services. In addition, they may support other primary care services, such as GP practices.
The Community Pharmacy Contractual Framework is a negotiated agreement between NHS England and the Pharmaceutical Services Negotiating Committee, which represents community pharmacy contractors. The framework includes a range of health-promoting services that community pharmacies should provide (Essential service 4 'Promotion of healthy lifestyles' and Essential service 5 'Signposting').
As part of the framework, pharmacies must participate in up to 6 public health campaigns each year at the request of NHS England (Public health Pharmaceutical Services Negotiating Committee).
In May 2018, there were over 9,400 Healthy Living Pharmacies and at least 9,400 health champions. There is a profession-led self-assessment process for Level 1 Healthy Living Pharmacies. Levels 2 and 3 are led and implemented by local authorities (see Commissioning section). Public Health England's Healthy Living Pharmacies: Level 1 quality criteria sets out the enablers and quality requirements for this level. The framework for Level 2 services is being updated.
The NHS Five Year Forward View (NHS England) states that a 'radical upgrade in prevention' is needed to achieve financial stability for the NHS. It sets out how the NHS could improve the way it promotes wellbeing and prevents health conditions. Options include making greater use of pharmacies in preventing ill health, support for healthy living, supporting self-care for minor ailments and long-term conditions, medication review in care homes, and as part of more integrated local care models.
Public Health England's 7 priorities include obesity, smoking and alcohol (From evidence into action: opportunities to protect and improve the nation's health).
The community pharmacy offer for improving the public's health: a briefing for local government and health and wellbeing boards (Local Government Association and Public Health England) describes how health and wellbeing boards, local authorities and commissioners can work with community pharmacies to promote health and wellbeing.
Public Health England's Pharmacy: a way forward for public health. Opportunities for action through pharmacy for public health sets out opportunities for how pharmacy teams in the primary and community sectors can play a bigger part in helping people to better look after their health.
The Community Pharmacy Contractual Framework describes national commissioning arrangements for services to promote health and wellbeing. NHS England's regional teams commission all services in the framework.
The Community Pharmacy Contractual Framework includes specific mention of services to promote health and wellbeing, such as increased support for healthy living. This is to ensure there is a Royal Society of Public Health trained health champion in every community pharmacy, and that each community pharmacy obtains the Healthy Living Pharmacy Level 1 status.
Local authorities commission a range of public health services provided by community pharmacies, such as stop smoking, contraceptive and weight management services. Levels 2 and 3 of the Healthy Living Pharmacy framework are also commissioned by local authorities.
Local authorities and clinical commissioning groups can ask NHS England to commission services from community pharmacies on their behalf, such as advice services for people who are misusing drugs.
Most community pharmacies now have an up-to-date record of their Declaration of Service which details the services they offer following the Quality Payment Scheme incentive.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Health and wellbeing hubs\n\nThis recommendation is for local authorities, clinical commissioning groups, health and wellbeing boards, community pharmacies and their representatives.\n\nWork together to help all community pharmacies gradually integrate into existing care and referral pathways as health and wellbeing hubs. This could include arrangements for inward and outward referrals (see recommendation\xa01.6.1).\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on health and wellbeing hubs\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence discussion for sections\xa01.1 and\xa01.2.\n\nLoading. Please wait.\n\n# Overarching principles of good practice for community pharmacy teams\n\n## Use an integrated approach\n\nWork with local health and social care organisations to ensure community pharmacy interventions are delivered according to local need and as part of wider services in the local area.\n\n## Ensure consistent, high-quality services\n\nUse a tailored approach when providing community pharmacy health and wellbeing interventions to maximise their impact and effect.\n\nLocal providers should ensure interventions are carried out only by staff members with the skills and competencies to do so. For example, follow NICE's recommendations on training in the guidelines on:\n\nbehaviour change: individual approaches\n\ntobacco: preventing uptake, promoting quitting and treating dependence.\n\nWhen possible, the same member of staff should deliver all sessions of an intervention (if multiple sessions are needed) to promote continuity of care.\n\nUse information, resources and support aids available from statutory, community and voluntary sector organisations (for example, Healthwatch and Public Health England). Ensure the materials used are:\n\nnot based solely on commercial interests or incentives\n\nclear and professionally produced.\n\n## Address health inequalities\n\nAddress health inequalities by working with other agencies to identify underserved groups. Tailor health and wellbeing interventions to suit their individual needs and preferences and maximise their impact. For example:\n\nuse knowledge of the local community (particularly from staff who live in the community where they work) to take into account the context in which people live and work (their physical, economic and social environment)\n\nmake use of the skills staff members already have (for example, if they speak languages commonly used in the area)\n\ntake into account other personal factors such as gender, identity, ethnicity, faith, culture or any disability that may affect the approach taken (for example, provide information in an appropriate format for people who may have difficulty reading).\n\n## Promote community pharmacies\n\nConsider promoting community pharmacies. For example:\n\nLocal commissioners could make it clear that community pharmacies are an integral part of NHS primary care services and offer people a link into the local health and care network.\n\nIndividual pharmacies could publicise the skills and competencies of their staff to increase the public's knowledge of and confidence in the health and wellbeing services on offer.\n\n## Proactively seek opportunities\n\nProactively seek opportunities to promote people's physical and mental health and wellbeing. This includes: awareness raising and information provision, advice and education, behavioural support and referral and signposting to other services. Describe the interventions on offer and the benefits. Do this for example, when someone:\n\nRegularly buys over-the-counter medicines, such as painkillers. For example, if relevant offer advice on other ways of reducing lower back pain including self-management and exercise. (See recommendations on non-invasive treatments in NICE's guideline on low back pain and sciatica.)\n\nRegularly collects a prescription for themselves or someone they care for. For example, provide education and advice on how improving their diet, being more physically active or reducing alcohol intake may help the condition and improve their physical or mental health and wellbeing.\n\nRegularly uses the pharmacy for over-the-counter medication or one-off prescriptions and, where appropriate, routine or occasional non-healthcare purchases. For example, offer behavioural support for stopping smoking (see NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence); or information on effective sun protection (see NICE's guideline on sunlight exposure).\n\nIs planning a pregnancy or is pregnant. For example, raise awareness of the benefits of, and provide information on, folic acid and other supplements (see NICE's guidelines on maternal and child nutrition and on vitamin\xa0D: supplement use in specific population groups).\n\nFor a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on overarching principles of good practice for community pharmacy teams\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence discussion for sections 1.1\xa0and\xa01.2.\n\nLoading. Please wait.\n\n# Awareness raising and providing information\n\nEnsure any pharmacy awareness raising campaigns or information is in line with NICE's guidelines on behaviour change: individual approaches (in particular, the first bullet of recommendation\xa09) and behaviour change: general approaches (particularly principle\xa06).\n\nTell people what the purpose of the health information is that you want to give them. For example:\n\nwhen handing out leaflets explain their content and importance\n\npoint out the relevance of any posters that are displayed or highlight how people can easily get further information on the topic (for example, using QR\xa0codes)\n\nif distributing leaflets with dispensed medicines, explain to the person collecting them – such as a carer, family member, friend or delivery person – why they are included and how to find out more, so they can pass this information on.\n\nFor a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on awareness raising and providing information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa01: providing information on health and wellbeing.\n\nLoading. Please wait.\n\n# Advice and education\n\nOffer advice and education as the opportunity arises in line with NICE's guidelines on: behaviour change: individual approaches (see the recommendations on delivering very brief, brief and extended brief advice).\n\nWhen someone uses pharmacy services to manage a long-term condition, use this as an opportunity to advise them on how to improve their general health and wellbeing. For example, follow recommendations on advice and education in NICE's guidelines on:\n\ndiabetes in adults (type\xa01, and type\xa02) and diabetes in children and young people (type\xa01 and type\xa02)\n\nhypertension in adults for people with, or at risk of, hypertension (see the sections on lifestyle interventions and patient education and adherence to treatment).\n\nOffer brief advice and education as the opportunity arises, on stopping smoking and reducing alcohol consumption:\n\nFor smoking cessation, follow NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence (in particular see the sections on commissioning and designing services, identifying people who smoke, information on stopping smoking for those using acute, maternity and mental health services, and advice on nicotine-containing e‑cigarettes).\n\nFor alcohol issues, follow the recommendations on brief advice in NICE's guideline on alcohol-use disorders. In particular see recommendation\xa05 on resources for screening and brief interventions and recommendation\xa010 on brief advice for adults.\n\nUse support materials and approaches to aid these discussions, if available. (For example, advice and education on smoking could be supported by photo-ageing software, if it is available.)\n\nFor a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on advice and education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa02: offering advice or education to promote health and wellbeing.\n\nLoading. Please wait.\n\n# Behavioural support\n\nOffer behavioural support in line with NICE's guidelines on:\n\nbehaviour change: individual approaches (see the recommendations on using proven behaviour change techniques when designing interventions; and high intensity behaviour change interventions and programmes)\n\nbehaviour change: general approaches (see principles 4\xa0and\xa05).\n\nHelp people to stop smoking by offering behavioural support programmes in line with NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence.\n\nHelp people to manage their weight by offering behavioural support programmes in line with NICE's guidelines on:\n\nobesity: identification, assessment and management (see the section on behavioural interventions)\n\nweight management: lifestyle services for overweight or obese adults (see recommendation\xa011)\n\npreventing excess weight gain\n and\n\nobesity prevention.\n\nConsider referring people to other behavioural support services within the local health and care network (for example, to voluntary or community services) for interventions that are not available in the pharmacy (see section\xa01.6).\n\nFor a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on behavioural support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa03: offering behavioural support to promote health and wellbeing.\n\nLoading. Please wait.\n\n# Referrals and signposting\n\n## Referrals\n\nLocal commissioners and pharmacies could consider establishing a formal referral process with other pharmacies and service providers. This includes GP services and those offered by local authorities and organisations in the community and voluntary sectors. Specifically:\n\nConsider basing pharmacy assessments, triage activities and referrals on agreed tools that support continuing treatment.\n\nConsider designing triage activities to reduce multiple assessments and waiting times after people are referred. For example, after identifying harmful or dependent alcohol consumption, consider providing access to alcohol services that does not require reassessment and a return to the start of the treatment pathway. (Harmful and dependent alcohol consumption could be identified using the AUDIT tool or another threshold used locally.)\n\nConsider referring people to other services and triage within the agreed local care or referral pathway to give fast access to an appointment if needed. For example, refer people to:\n\nGPs or other healthcare providers for:\n\n\n\nongoing contraception\n\nassessment for sleep apnoea if agreed local assessment tools are in place\n\nsupport for high risk or dependent alcohol consumption\n\ndrug misuse recovery support\n\nweight reduction services\n\n\n\nlocal authority, NHS or community and voluntary sector organisations for:\n\n\n\nweight loss programmes or support groups\n\nmental health and wellbeing support\n\nspecialist treatment and recovery support for drug misuse and dependence\n\nsupport for carers\n\n\n\nadult and children's social care.\n\nWhen making a formal referral to another service, explain to the person why they are being referred, where they are being referred to and the service they can expect. Provide them with written information about the service if it is available.\n\nWhen the pharmacy accepts a formal referral from another service:\n\nensure all relevant information has been provided so that care can start at the first opportunity without the need for a reassessment\n\noffer care as a walk-in service or, if this is not available or suitable, agree an appointment time and date with the person and give them the name of the staff member they will see.\n\n## Signposting\n\nIf the community pharmacy cannot support specific needs or offer a formal referral, signpost people to other local services. For example:\n\nsexual health services\n\nstop smoking services\n\nsocial care services\n\nmental health and wellbeing support\n\nother community services such as: Citizens Advice; housing, benefits or employment advice; support services for carers; and government and third sector debt advice websites.\n\n## Record keeping, auditing and monitoring\n\nConsider using minimum data sets and summary care records to encourage record keeping and auditing, particularly when exchanging information through formal referrals in the local care network.\n\nFor a short explanation of why the committee made these recommendation and how they might affect practice, see the rationale and impact section on referrals and signposting\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa04: signposting and referral to other services and support.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For other public health and social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Photo-ageing\n\nA smoking cessation intervention in which photos of participants are digitally aged so they can see images of themselves as a lifelong smoker and a non-smoker.\n\n## Underserved groups\n\nAdults and children from any background are 'underserved' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to access health services or attend healthcare appointments.\n\nMany of these groups may be more likely to go to a community pharmacy than a GP or another primary care service. As an example, this includes: people who are housebound, homeless or sleep rough; people who misuse drugs or alcohol; and Gypsy, Traveller and Roma people. A full list can be found in the equality impact assessment for this guideline.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Referral within a formal care pathway\n\nIs referral from a community pharmacy within a formal local care pathway framework more effective and cost effective than signposting alone in improving access to, and uptake of, services by underserved groups and the general population?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on health and wellbeing hubs\xa0.\n\nMore details about how this research could be conducted can be found in recommendations for research: in detail.\n\nLoading. Please wait.\n\n## Health and wellbeing interventions\n\nHow effective and cost effective are awareness raising, advice and education or behavioural support interventions delivered by community pharmacy teams to improve health and behavioural outcomes in underserved groups and the general population?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale sections on awareness raising and providing information\xa0, advice and education\xa0, and behavioural support\xa0.\n\nMore details about how this research could be conducted can be found in recommendations for research: in detail.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n## Addressing health inequalities\n\nWhat are the barriers to and facilitators for increasing access to community pharmacy services by underserved groups? How should health and wellbeing interventions be tailored to increase service uptake in underserved groups?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on addressing health inequalities\xa0.\n\nMore details about how this research could be conducted can be found in recommendations for research: in detail.\n\nLoading. Please wait.\n\n## Characteristics of a person delivering an intervention\n\nHow do the professional characteristics of pharmacy staff affect the effectiveness and cost effectiveness of delivering information, advice, education or behavioural support to underserved groups and the general population? (Characteristics include, for example, job roles such as health champion, as well as competencies and level of training.)\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on ensure consistent, high-quality services\xa0.\n\nMore details about how this research could be conducted can be found in recommendations for research: in detail.\n\nLoading. Please wait.\n\n## Patient activation\n\nHow effective and cost effective is advice, education or behavioural support offered by community pharmacy teams to improve patient activation and measures of behaviour and health changes, particularly in areas where activation levels are lower? This includes evaluating factors such as frequency, intensity and duration of the intervention.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on behavioural support\xa0.\n\nMore details about how this research could be conducted can be found in recommendations for research: in detail.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Local social prescribing interventions\n\nHow effective and cost effective is it for community pharmacy teams to provide local social prescribing interventions? What is the differential impact in both effectiveness and cost effectiveness of community pharmacies carrying out this activity compared with providing only referral or signposting to these interventions?', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Health and wellbeing hubs\n\nRecommendation 1.1.1\n\n## Why the committee made the recommendation\n\nThe current NHS sustainability and transformation partnerships (STPs) and the Five Year Forward View both aim to improve the integration of healthcare services in the UK. The committee agreed that, as part of this, community pharmacies need to gradually become part of existing health and care pathways. This would mean they could act as health and wellbeing hubs, with inward and outward referrals established and consistently managed.\n\nThis will ensure they are aware of what services are offered locally and where formal referrals can be set up. But because it is not clear how to effectively refer in and out of pharmacies to improve people's care, the committee made research recommendation\xa01.\n\n## How the recommendation might affect practice\n\nOnce community pharmacies are integrated with other local health and care services, the idea is that they can operate as neighbourhood health and wellbeing centres (health and wellbeing hubs). This means they would become the first place that people go to for support, advice and resources on staying well and healthy. It may involve working closely with community leaders to identify local resources and needs, develop related interventions and services, and collect data on impact and outcomes.\n\nSome investment may be needed to carry out these activities and to set up a formal referral process within community pharmacies. But this is in line with the movement towards better integration of health and care services within the NHS, and national resources are being put in place to support this. For example, the Pharmacy Integration Fund was established to support clinical pharmacy integration within the NHS and the community.\n\nReturn to recommendation\n\n# Overarching principles of good practice for community pharmacy teams\n\nRecommendations 1.2.1 to 1.2.8\n\n## Why the committee made the recommendations\n\nCommunity pharmacies offer a socially inclusive, easily accessible service for all members of the public and, as such, should be the first place people go for help with a non-urgent health issue. A key way to encourage more people to use services is to ensure they are fully integrated within the health and care system – including with other pharmacies.\n\nBetter integration of community pharmacies in the wider health care system will have a positive impact on patient choice and result in better health outcomes for people in both primary care and the community.\n\nThe committee agreed that if more people are to use the interventions on offer they need to know what they can expect, regardless of which pharmacy they visit, so a consistent standard of service is important.\n\nA typical community pharmacy is staffed by people with various levels of training and competencies in health promotion services. Healthy Living Pharmacies also have qualified health champions who take responsibility for the healthy living programme.\n\nBut there is a lack of research on how the training or other characteristics of the person delivering a health and wellbeing intervention influence its effectiveness or cost effectiveness. This includes a lack of research on whether using a recognised behaviour change competency framework (see NICE's guideline on behaviour change: individual approaches) has an impact on this. So the committee made research recommendation\xa04.\n\nEvidence showed that people are more likely to trust information resources that are clear, professional and relatively free of any commercial links. The latter is particularly important because it makes it clear that there is no profit motive behind any information given.\n\nAn expert pointed out to the committee that because of their accessibility, community pharmacies could address health inequalities. In England, 90% of people (99% in the most deprived communities) live within a 20‑minute walk of a community pharmacy.\n\nBut more research is needed to determine whether community pharmacies are better than other health services at reaching underserved groups. In addition, there is no evidence on how these services should be tailored to benefit different groups. (People from different ethnic or socioeconomic groups, or of different ages, may gain more or less from the services on offer.) So the committee made research recommendation\xa03.\n\nAnother way to encourage the public to make full use of community pharmacy interventions could be to make them aware that many staff are qualified or specialists in certain areas. This could improve the public's perception of the pharmacy as a trusted source of health and wellbeing advice and support.\n\nCommunity pharmacy interventions to help improve people's physical and mental health and wellbeing are usually delivered as the opportunity arises – when people come in for prescriptions, buy other products or make general enquiries.\n\nThe committee agreed that identifying opportunities to provide interventions and referrals should be encouraged. It would mean that more people using pharmacies could get support, either from the pharmacy itself or from other local multidisciplinary teams, to prevent health problems from developing or deteriorating. This, in turn, would reduce the burden on other areas of health and care.\n\n## How the recommendations might affect practice\n\nEstablishing links to integrate community pharmacies with other health and care organisations may result in upfront costs such as the time it takes to develop pathways and make a referral. But this may be offset by:\n\nmore efficient use of resources in the wider system\n\nbetter continuity of care\n\nquicker access to the right treatment (including for underserved or underprivileged communities).\n\nIt may not always be practical or feasible for the same member of staff to deliver all sessions of an intervention, but where it is possible this will reduce variation in current practice.\n\nIdentifying underserved groups and tailoring interventions to suit an individual's needs and preferences may increase service uptake in these groups and help community pharmacies to potentially address health inequalities.\n\nPromoting community pharmacies by highlighting the services on offer and the skills of pharmacy staff may have some resource impact. But this may be offset by an improvement in health outcomes resulting from more people using the services.\n\nIt may not always be practical or feasible to seek opportunities to promote health and wellbeing services within the pharmacy. But if staff are trained to identify opportunities to offer services then there should be no significant cost implications. The Making Every Contact Count initiative offers training for health and social care staff on how to identify opportunities to talk to people about their health and wellbeing and deliver brief interventions. Some funding to support or implement this training may be available.\n\nGeneral health and wellbeing advice is covered in general pharmacy training and some pharmacists and pharmacy technicians are trained in core public health priorities. Some staff will also have the Royal Society for Public Health Level\xa02 award in improving health. Some pharmacy staff may need additional training in effective behaviour change techniques, which may incur a small resource cost. Some free behaviour change training may be available, for example from Health Education England and the Centre for Pharmacy Postgraduate Education.\n\nReturn to recommendations\n\n# Awareness raising and providing information\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThe way community pharmacies provide information on health and wellbeing varies across the UK, as does the way they present and use these resources.\n\nEvidence showed that providing information to raise people's awareness of an issue is the first step to helping them change their behaviour. Evidence also showed that it is most effective to give people information as part of a discussion, rather than just handing them a leaflet or other resource.\n\nBut there is limited evidence on its effectiveness and cost effectiveness for specific issues such as alcohol or drug misuse, diabetes, falls, smoking, cancer, and mental health and wellbeing. So the committee made research recommendation\xa02.\n\n## How the recommendations might affect practice\n\nSpeaking to people about the information you want to give them before you hand it out may involve a small amount of additional staff time (to explain why the information is relevant). But this cost could be offset by improved health outcomes and resource savings elsewhere in the health or care system. For example, the person might, as a result, seek advice or receive other support that prevents them from becoming ill or generally improves their health.\n\nSome pharmacy staff, such as those who have become health champions, are competent to provide information in this way.\n\nIn addition, pharmacists and pharmacy technicians receive or have access to training in communication and consultation skills as part of their undergraduate, postgraduate and pre-registration training programmes. They can also get free training in these skills from The Centre for Pharmacy Post Graduate Education (funded by Health Education England).\n\nReturn to recommendations\n\n# Advice and education\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nCommunity pharmacies are well placed to offer health and wellbeing advice and education to everyone in a local community, whether they have a long-term health condition or need help to adopt a healthier lifestyle. However, there is significant variation in what is offered.\n\nEvidence showed that pharmacy staff can provide effective advice and education to people with diabetes and hypertension. It also showed that brief advice can help people stop smoking. There was limited evidence that the use of photo-ageing software to support such advice was effective and cost effective. But based on their experience, the committee agreed that it could be worth trying if resources were available on the premises.\n\nIn addition, advice and education can potentially help people reduce their alcohol consumption. But further research is needed to see if it is effective in: improving cancer awareness and people's sexual health and mental health and wellbeing, or preventing drug misuse and falls. So the committee made research recommendation\xa02.\n\n## How the recommendations might affect practice\n\nThese recommendations should reduce variation in current practice.\n\nGeneral health and wellbeing advice is covered in general pharmacy training. Some pharmacists and pharmacy technicians are also trained in core public health priorities. Some staff will have gained the Royal Society for Public Health Level\xa02 award in improving health.\n\nA lot of free training is available for pharmacy staff (such as the smoking cessation training provided by the National Centre for Smoking Cessation and Training). But some may involve a small cost. So pharmacy teams that currently provide the least health and wellbeing advice and education are likely to have the biggest expenditure as a result of implementing the recommendations.\n\nReturn to recommendations\n\n# Behavioural support\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nThe type of behavioural support offered by community pharmacy teams varies across the UK, so the committee recommended that they follow NICE guidelines for the relevant issue or condition.\n\nEvidence showed that certain behavioural interventions, specifically interventions to help people stop smoking or manage their weight, are effective and cost effective when provided by community pharmacy teams.\n\nSome evidence suggests that interventions delivered in community pharmacies that involve people setting their own health goals may help people improve their patient activation. However, more research is needed to support this and to show how delivering these interventions in community pharmacies can be used to improve people's health. So the committee made research recommendation\xa05.\n\nFurther research is also needed before behavioural interventions can be recommended in pharmacies for: improving cancer awareness, sexual and mental health and orthopaedic conditions, and preventing alcohol or drug misuse, diabetes and falls. So the committee made research recommendation\xa02.\n\nThe committee agreed that written information or support aids given alongside behavioural support may be beneficial. They also agreed that it is worth referring people to other services in the local care network for behavioural support if the pharmacy doesn't provide this itself.\n\n## How the recommendations might affect practice\n\nThese recommendations should reduce variation in practice and ensure commissioners focus on behavioural support activities that have been shown to be both effective and cost effective.\n\nSome pharmacy staff may need training in effective behaviour change techniques and this may incur a small resource cost. However, local authorities may provide their own training. In addition, some free behaviour change training may be available for pharmacy staff from, for example, Health Education England and the Centre for Pharmacy Postgraduate Education.\n\nReturn to recommendations\n\n# Referrals and signposting\n\nRecommendations 1.6.1 to 1.6.6\n\n## Why the committee made the recommendations\n\nMembers of the public may need to be directed to other services for support, advice or treatment if it cannot be provided by the community pharmacy.\n\nFormal referrals, involving an agreed process with another provider, may be more effective than signposting (giving people information on other organisations that can help). But often community pharmacy services are not part of a formalised care pathway. That means they cannot always make formal referrals to, or accept them from, other services. It also means that other services may not know what community pharmacies can offer.\n\nAn expert told the committee that links with other health and care providers were key to ensure effective continuity of care and to ensure people gain the most benefit from the system. The committee agreed this is particularly important for people who may not use other healthcare services, for example people from underserved groups.\n\nThe committee recommended that if community pharmacy teams do offer such a service, fast referrals will be needed for people at risk. In addition, it will be important to ensure people referred on are not reassessed as a matter of routine when they enter the care pathway. (Reassessment is a waste of resources and could also undermine the pharmacist's credibility.)\n\nBased on their experience, the committee agreed it was useful to provide examples of the types of issues that community pharmacy teams could make referrals on, including to GPs, local authorities and social services.\n\nSome evidence showed that people are more likely to take up the offer of a referral if they are given clear details about why they are being referred and what they can expect to happen. The committee also agreed that it was important for pharmacy staff to be fully informed when they accept a referral, so that assessments are not duplicated and people can enter at the correct point in the care pathway.\n\nSome evidence showed that referral by community pharmacy teams increased service uptake more than signposting, but more evidence is needed to support a formal referral process. Establishing cost-effectiveness evidence for this in pharmacies is also important. That's because there may be cost implications for the time needed to make or accept individual referrals and for setting up the overall process, compared with signposting. So the committee made research recommendation\xa01.\n\nIf it is not possible to introduce a formal referral process, signposting people to other organisations is still important because it can increase the likelihood of people using the services. But committee members agreed with the evidence that formal referrals are more effective at increasing the uptake of services.\n\nRecording and sharing information will prevent duplication in the care pathway, build relationships between service providers and encourage collaboration. Auditing could also help improve both efficiency and quality and inform the work of other organisations. But this can only be achieved if the service providers involved have a shared understanding of what data should be recorded and used for analysis (that is, the minimum data sets) and why.\n\n## How the recommendations might affect practice\n\nIntegrating community pharmacy interventions into health and care pathways will have a positive impact on patient choice and result in better health outcomes for people in both primary care and the community.\n\nSignposting is currently the standard approach within community pharmacies. But clear methods of referral to and from community pharmacies should make it easier for people to access services and increase uptake. Effective referrals will also encourage people to choose the pharmacy as their first point of contact with healthcare professionals, potentially reducing pressure on A&E and GP practices.\n\nIn the long term these benefits may offset any upfront costs such as the time it takes to develop pathways and make the referral.\n\nIn terms of resource impact, it may not be practical to record every intervention, but it is something that is covered by professional practice, so there is no potential resource impact.\n\nReturn to recommendations", 'Context': "Community pharmacy contractors dispense NHS prescriptions under the NHS (Pharmaceutical Services and Local Pharmaceutical Services) Regulations\xa02013. As well as dispensing, community pharmacy contractors are required to:\n\npromote healthy lifestyles\n\nparticipate in 6\xa0public health campaigns a year\n\ndispose of unwanted medicines\n\nprovide support for self-care\n\nsignpost members of the community to appropriate services.\n\nAs of 7\xa0November 2017, there were 11,699\xa0community pharmacies in England (NHS Digital General Pharmaceutical Services in England – 2007/08 to 2016/17).\n\nMost prescription items are dispensed by community pharmacies. In 2016/17, for example, they dispensed 91.6% of the 1,000\xa0million plus items dispensed in the community ('General Pharmaceutical Services in England – 2007/08 to 2016/17'). In 2016, the net cost of prescriptions dispensed in the community was £9,205\xa0million. Of the prescriptions dispensed, 89.4% were dispensed free of charge, with 61% provided free to people aged 60\xa0and over (NHS Digital Prescriptions dispensed in the community, Statistics for England 2006 to\xa02016).\n\nCommunity pharmacies are well positioned to promote health and wellbeing to their local community, including those from underserved groups, because 90% of people in England (including more than 99% of people in the most deprived communities) live within a 20‑minute walk of one. The location of community pharmacies, unlike other healthcare outlets, does not comply with the usual 'inverse care law' in that there is a greater concentration of community pharmacies in areas of deprivation. (The positive pharmacy care law: an area-level analysis of the relationship between community pharmacy distribution, urbanity and social deprivation in England Todd et\xa0al.\xa02014).\n\nThe risk of many health conditions can be reduced by people adopting healthier behaviours. These include: type\xa02 diabetes, cardiovascular disease, respiratory diseases such as chronic obstructive pulmonary disease, and other conditions related to obesity and smoking.\n\nCommunity pharmacies can help raise awareness of health conditions, improve physical and mental health, and reduce both health inequalities and individual health risks by providing advice and services to everyone entering their premises. This includes people who do not visit GPs or other healthcare services. In addition, they may support other primary care services, such as GP practices.\n\nThe Community Pharmacy Contractual Framework is a negotiated agreement between NHS England and the Pharmaceutical Services Negotiating Committee, which represents community pharmacy contractors. The framework includes a range of health-promoting services that community pharmacies should provide (Essential service\xa04 'Promotion of healthy lifestyles' and Essential service\xa05 'Signposting').\n\nAs part of the framework, pharmacies must participate in up to 6\xa0public health campaigns each year at the request of NHS England (Public health [promotion of healthy lifestyles] Pharmaceutical Services Negotiating Committee).\n\nIn May 2018, there were over 9,400\xa0Healthy Living Pharmacies and at least 9,400\xa0health champions. There is a profession-led self-assessment process for Level\xa01 Healthy Living Pharmacies. Levels\xa02\xa0and\xa03 are led and implemented by local authorities (see Commissioning section). Public Health England's Healthy Living Pharmacies: Level\xa01 quality criteria sets out the enablers and quality requirements for this level. The framework for Level\xa02 services is being updated.\n\nThe NHS Five Year Forward View (NHS England) states that a 'radical upgrade in prevention' is needed to achieve financial stability for the NHS. It sets out how the NHS could improve the way it promotes wellbeing and prevents health conditions. Options include making greater use of pharmacies in preventing ill health, support for healthy living, supporting self-care for minor ailments and long-term conditions, medication review in care homes, and as part of more integrated local care models.\n\nPublic Health England's 7\xa0priorities include obesity, smoking and alcohol (From evidence into action: opportunities to protect and improve the nation's health).\n\nThe community pharmacy offer for improving the public's health: a briefing for local government and health and wellbeing boards (Local Government Association and Public Health England) describes how health and wellbeing boards, local authorities and commissioners can work with community pharmacies to promote health and wellbeing.\n\nPublic Health England's Pharmacy: a way forward for public health. Opportunities for action through pharmacy for public health sets out opportunities for how pharmacy teams in the primary and community sectors can play a bigger part in helping people to better look after their health.\n\nThe Community Pharmacy Contractual Framework describes national commissioning arrangements for services to promote health and wellbeing. NHS England's regional teams commission all services in the framework.\n\nThe Community Pharmacy Contractual Framework includes specific mention of services to promote health and wellbeing, such as increased support for healthy living. This is to ensure there is a Royal Society of Public Health trained health champion in every community pharmacy, and that each community pharmacy obtains the Healthy Living Pharmacy Level\xa01 status.\n\nLocal authorities commission a range of public health services provided by community pharmacies, such as stop smoking, contraceptive and weight management services. Levels\xa02\xa0and\xa03 of the Healthy Living Pharmacy framework are also commissioned by local authorities.\n\nLocal authorities and clinical commissioning groups can ask NHS England to commission services from community pharmacies on their behalf, such as advice services for people who are misusing drugs.\n\nMost community pharmacies now have an up-to-date record of their Declaration of Service which details the services they offer following the Quality Payment Scheme incentive."}
|
https://www.nice.org.uk/guidance/ng102
|
This guideline covers how community pharmacies can help maintain and improve people’s physical and mental health and wellbeing, including people with a long-term condition. It aims to encourage more people to use community pharmacies by integrating them within existing health and care pathways and ensuring they offer standard services and a consistent approach. It requires a collaborative approach from individual pharmacies and their representatives, local authorities and other commissioners.
|
2bc6c7cb8eb026f05e024e49c63052b1e311caba
|
nice
|
Dupilumab for treating moderate to severe atopic dermatitis
|
Dupilumab for treating moderate to severe atopic dermatitis
Evidence-based recommendations on dupilumab (Dupixent) for treating moderate to severe atopic dermatitis in adults.
# Recommendations
Dupilumab is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if:
the disease has not responded to at least 1 other systemic therapy, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are contraindicated or not tolerated
the company provides dupilumab according to the commercial arrangement.
Stop dupilumab at 16 weeks if the atopic dermatitis has not responded adequately. An adequate response is:
at least a 50% reduction in the Eczema Area and Severity Index score (EASI 50) from when treatment started and
at least a 4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started.
When using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with dupilumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current systemic treatment for moderate to severe atopic dermatitis (eczema) includes ciclosporin, methotrexate, azathioprine and mycophenolate mofetil. Dupilumab would be used after these treatments no longer work, and best supportive care is the only other available option. Dupilumab would likely be offered alongside topical corticosteroids.
The clinical evidence shows that dupilumab is very effective when used in this way. The most plausible cost-effectiveness estimates for dupilumab plus topical corticosteroids compared with best supportive care are within the range that NICE normally considers an acceptable use of NHS resources.# Information about dupilumab
Marketing authorisation indication
Dupilumab (Dupixent, Sanofi Genzyme) is indicated for the 'treatment of moderate to severe atopic dermatitis in adults who are candidates for systemic therapy'.
Dosage in the marketing authorisation
The recommended dose, given by subcutaneous injection, is initially 600 mg (2×300‑mg injections), followed by 300 mg given every other week. It can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. "Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment". Some patients whose disease shows partial response may subsequently improve with continued treatment beyond 16 weeks.
Price
£1,264.89 per pack of 2×2‑ml syringes of 150 mg/1 ml solution (excluding VAT; British national formulary online, accessed March 2018).
The company has a commercial arrangement. This makes dupilumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Sanofi Genzyme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Experience of people with atopic dermatitis
## Atopic dermatitis affects all aspects of a person's life
Atopic dermatitis is a chronic, recurrently flaring, generalised skin condition that can be life-limiting, debilitating and isolating. It can affect all aspects of life (physical, psychological, social and financial). Severe disease is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee noted that having treatments that improve the condition and which are associated with few or manageable adverse effects is important to people with atopic dermatitis.
# Assessing severity of atopic dermatitis
## Symptoms, signs and quality of life determine the severity of atopic dermatitis
The committee understood that there is variability in how clinicians assess severity in atopic dermatitis. They assess severity based on clinical signs and on patient-reported symptoms including effect on sleep and work, and how much patients need to use topical corticosteroids or systemic therapy. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative recommends using the Eczema Area and Severity Index (EASI) to assess signs (for example, skin lesions) and the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch). The clinical experts explained that the POEM is easier to administer in practice than the EASI. The committee understood that NHS clinicians routinely use the Dermatology Life Quality Index (DLQI) to assess quality of life in other skin conditions. It concluded that the EASI, DLQI and POEM are appropriate for assessing the severity of atopic dermatitis in NHS practice.
# Clinical management
## Atopic dermatitis can be treated with topical therapies, phototherapy and systemic immunosuppressant therapies
Although clinicians individualise therapy for patients, a typical treatment pathway involves emollients and topical corticosteroids (first line), topical calcineurin inhibitors (second line), phototherapy (third line) and systemic immunosuppressant therapies (fourth line) including ciclosporin (the only licensed drug), methotrexate, azathioprine and mycophenolate mofetil. These systemic therapies can have serious adverse effects and, if a drug is no longer effective, it will be stopped and another drug will be offered. For people whose disease does not respond to multiple systemic therapies, the only remaining treatment option is best supportive care, which may include education, psychological support, emollients, topical corticosteroids, bandages and hospitalisation. Managing exacerbations (flares) in atopic dermatitis includes using short-term potent topical corticosteroids, oral corticosteroids and systemic therapy.
# Positioning of dupilumab in the treatment pathway
## Dupilumab would be used after existing systemic therapies
The marketing authorisation for dupilumab is for 'moderate to severe atopic dermatitis in adults who are candidates for systemic therapy'. The company only submitted evidence for dupilumab as a fifth-line treatment, after systemic immunosuppressant therapies, as an alternative to best supportive care. The clinical experts explained that people are likely to have had at least 1 systemic therapy before dupilumab in clinical practice. The committee concluded that it would appraise dupilumab for moderate to severe atopic dermatitis, compared with best supportive care.
# Comparators
## The company's revised definition of best supportive care is appropriate for decision-making
The company defined best supportive care in its economic model as 'emollients, low-to-mid potency topical corticosteroids, and rescue therapy with higher potency topical or oral corticosteroids or topical calcineurin inhibitors'; it also included phototherapy and psychological support in its revised model, submitted in response to the appraisal consultation document. However, it excluded bandages because these were captured within 'day case' treatment and education because no reliable data were available. The ERG agreed with the company's revised approach in defining best supportive care. The committee concluded that the company's revised definition of best supportive care was adequate for decision-making.
# Clinical evidence
## The CAFÉ and CHRONOS trials provide the key clinical evidence for dupilumab
The main evidence for dupilumab came from 4 trials: 2 on dupilumab monotherapy (SOLO‑1 and SOLO‑2) and 2 on dupilumab plus topical corticosteroids as needed (CAFÉ and CHRONOS). All patients had best supportive care. The clinical experts explained that dupilumab is likely to be offered alongside topical corticosteroids. The committee therefore agreed to focus on the evidence on dupilumab 'combination therapy' with topical corticosteroids. CAFÉ and CHRONOS were randomised double-blind trials that included a total of 1,065 patients who had had chronic moderate to severe atopic dermatitis for at least 3 years that had not been controlled with topical medications for at least 6 months. Patients may or may not have had immunosuppressant therapy. The trials compared 2 doses of dupilumab (300 mg every week or 300 mg every other week ) with placebo. The committee agreed to focus only on the data for the licensed dose of dupilumab. The primary endpoints were assessed at the end of the 'induction period' (that is, 16 weeks after starting treatment):
CHRONOS (co-primary endpoints):
at least a 75% reduction in the EASI score from when treatment started (EASI 75) and
a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the Investigators' Global Assessment, and at least a 2‑point improvement from baseline.
CAFÉ: EASI 75.Patients in CHRONOS had an additional 36 weeks of treatment.
## The open-label extension study provides long-term clinical evidence for dupilumab
In response to the appraisal consultation document, the company provided data for up to 100 weeks from the start of an ongoing, open-label extension study. It included patients from previous dupilumab trials who had not had any adverse effects that led them to stop the trial, or patients screened for the SOLO studies but unable to enter them because of closure of the trials. Patients had weekly dupilumab (unlicensed dose) and could also use topical medications as needed. The company provided data for 2 subgroups: patients who had not had dupilumab before the study ('dupilumab-naive') or patients who had previously had dupilumab but with treatment gaps ranging from less than 6 weeks to more than 13 weeks ('dupilumab-exposed'). The committee concluded that evidence from this extension study, particularly that from the 'dupilumab-exposed' subgroup, would help in the understanding of dupilumab's long-term clinical effectiveness and to inform the assumptions in the economic model (see section 3.15 and section 3.17).
# Company's revised base case
## The base case focuses on a subgroup of patients from CAFÉ and CHRONOS, and data from placebo groups to represent best supportive care
Because the company considered that dupilumab would be used as a fifth-line treatment, after systemic therapies, it focused its base case on a subgroup of 299 patients from CAFÉ and CHRONOS who could not have ciclosporin, or whose condition had not responded to ciclosporin. The company used data from the placebo groups to represent best supportive care in its economic model. The committee concluded that the subgroup was sufficiently large to provide reliable estimates of clinical effectiveness.
## Clinical experts advise that the population in the company's subgroup is similar to patients in the NHS who would have dupilumab
The subgroup identified by the company included patients who were on average 38 years old; 60% were men and 91% were 'white'. Patients had atopic dermatitis for an average of 29 years, which covered an average of 58% of their body, and they had average scores of 34 on the EASI, 20 on the POEM and 15 on the DLQI. The clinical experts confirmed that the baseline characteristics of these patients were similar to those likely to be seen in the NHS. The committee concluded that the trial subgroup population generally reflected people who would be treated with dupilumab in NHS clinical practice.
## Analyses that consider patients to be 'non-responders' if they have rescue therapy are appropriate
In its revised base case, the company presented results from analyses that considered patients to be 'non-responders' if they had not provided data at week 16, or if they had rescue therapy or withdrew from the study. The committee concluded that these analyses were appropriate because the clinical experts stated that systemic treatments are usually stopped when they are no longer effective at controlling the condition and patients need rescue therapy.
## The combination of EASI 50 plus an improvement in the DLQI of at least 4 is an appropriate outcome for decision-making
To model the cost effectiveness of dupilumab, the company defined a clinical benefit in its base case of an EASI 50 (at least a 50% reduction in the EASI score from when treatment started) plus an improvement in the DLQI of at least 4. The clinical experts explained that EASI 50 and an improvement in the DLQI of at least 4 are sensitive to changes in treatment outcomes and more clinically relevant than an EASI 75 (at least a 75% reduction in the EASI score from when treatment started). The committee concluded that the composite endpoint of an EASI 50 plus an improvement in the DLQI of at least 4 was appropriate for decision-making.
## Dupilumab with topical corticosteroids as needed is substantially more clinically effective than placebo
The committee noted that patients having dupilumab plus topical corticosteroids as needed had a clinically and statistically significantly higher response rate in the EASI 50 plus an improvement in the DLQI of at least 4 at week 16 (73% of 130 patients) than patients having placebo plus topical corticosteroids as needed (28% of 169 patients). The committee noted that these results also included patients who had rescue therapy. It concluded that dupilumab was substantially more clinically effective than placebo, although it would have preferred to have seen the results of the analyses in which patients who had rescue therapy were considered to be 'non-responders' (see section 3.10).
## Patients in the trials had a relatively high 'placebo response'
The committee queried the high response rate seen in the placebo group (see section 3.12). One clinical expert explained that this was likely because nurses in the trials closely supervised topical therapy regimens, which can improve adherence and maximise effectiveness. While this level of supervision is feasible in a short-term trial, it is not sustainable for prolonged periods (after 6 months), so any 'placebo response' is likely to decline over time. The committee agreed that any benefit from supervision should have been applied equally to both the dupilumab and placebo groups, which should not have affected how the treatments performed relative to one another in the trial. The company noted that, in CAFÉ, there was a higher reduction in topical corticosteroid use in the dupilumab arm than the placebo arm. The committee concluded that the 'placebo response' in the trials was unlikely to have affected the treatment effect of dupilumab relative to placebo.
# Company's revised economic model
## The model combines a decision tree and Markov state transition
The company's model consisted of 2 components:
Decision tree up to 52 weeks: people entered the model either in the 'dupilumab' or the 'best supportive care' arm. Based on trial data, this part of the model evaluated treatment response at 2 time points, 16 weeks and 52 weeks after starting treatment.
At week 16 after starting treatment, people in the 'dupilumab' arm whose condition had responded continued to have dupilumab for a further 36 weeks (that is, up to week 52 after starting treatment). People whose condition had not responded, switched to best supportive care for the remaining 36 weeks, in line with the marketing authorisation. The clinical experts confirmed that this stopping rule reflects clinical practice. Everyone in 'best supportive care' remained in this arm and split according to treatment response into 'responders' or 'non-responders'.
At week 52 after starting treatment, people in the 'dupilumab' arm whose condition continued to respond moved into the 'maintenance' Markov state of the model; people whose condition had lost response moved into the 'best supportive care' Markov state. Everyone who had best supportive care moved into the 'best supportive care' Markov state and split according to treatment response into 'responders' or 'non-responders'.
Markov state transition with annual cycles from year 2 onwards: this component modelled long-term treatment (up to 61 years) of atopic dermatitis and included 3 states; maintenance on dupilumab, best supportive care and death. People having dupilumab maintenance therapy could stop dupilumab for any reason (loss of response, adverse effects, patient or physician preference) and move into the 'best supportive care' Markov state. Anyone could die at any time.In its combined decision tree and Markov state transition model, the company assumed that dupilumab improved quality of life, but did not extend length of life, compared with best supportive care. The committee concluded that the revised model structure was appropriate.
# Assumptions in the revised economic model
## A yearly stopping rate of 3.7% for people having dupilumab plus topical corticosteroids is plausible based on data from the open-label extension study
The company assumed that 3.7% of people having dupilumab plus topical corticosteroids as maintenance therapy stop treatment every year for any reason, and move onto best supportive care. This reflected the proportion of people in CHRONOS whose condition responded to treatment at 16 weeks who withdrew from the trial by 52 weeks. In response to the appraisal consultation document, the company provided sensitivity analyses on a range of stopping rates based on data from its open-label extension study, ranging from 2.1% in 'responders' at week 24 to 6.4% in the whole population at 52 weeks. The ERG agreed that the original stopping rate appear reasonable and consistent with the available data. The committee noted that the different stopping rates had minimal impact on the cost-effectiveness estimates, and agreed that the company's original stopping rate of 3.7% is plausible.
# Utility values in the revised economic model
## Utility values specific for people whose condition does not respond to dupilumab are appropriate
In its revised model, the company assumed that, if atopic dermatitis did not respond to dupilumab plus topical corticosteroids:
at week 16 after starting treatment, people accrued the average utility value of dupilumab 'non-responders' and best supportive care 'non-responders' (0.82)
from week 52 onwards, people accrued the utility value of best supportive care 'non-responders' (0.77).The ERG agreed that the company's revised approach to modelling utility values for dupilumab 'non-responders' was appropriate. These revisions had a minimal effect on the cost-effectiveness estimates. However, the committee agreed that it was appropriate to use the utility value specific to people whose condition had not responded to dupilumab plus topical corticosteroids at 16 weeks rather than the utility value from everyone having best supportive care (0.81), as the company had done in its original model.
## Assumptions on loss of utility benefit should be based on data from the open-label extension study and CHRONOS
In its revised base case, the company assumed in both treatment states that part of the clinical benefit of treatment (as determined at week 52 of the trials), and the associated utility benefit, were lost from year 2 after starting treatment onwards:
In the dupilumab maintenance state, the company assumed that 2% of the benefit would be lost in year 2, 5% in year 3, 7% in year 4, and 8% in year 5 and beyond. It used these estimates to adjust down the proportion of people who continued to have dupilumab (that is, those who lost the benefit of dupilumab moved to the best supportive care state and then accrued the utility associated with that state). The company based these assumptions for dupilumab on feedback from the experience of 5 dupilumab trial investigators, supported by evidence from its open-label extension study that showed a sustained treatment effect.
In the best supportive care state, the company assumed that 25% of the benefit would be lost in year 2, 50% in year 3, 75% in year 4, and 100% in year 5 and beyond. It used these estimates to adjust down the utility value applied over time, by applying in each year the average of the utility value for best supportive care during the trials (0.80), and the baseline utility value (0.66), weighted by the proportion of people who were assigned each utility value. Therefore, by the end of year 5, everyone in the best supportive care arm returned to the baseline utility (0.66) for the remainder of their time in the model.The company also provided analyses in which it changed its assumptions on the decline in quality of life (see table 1).
## Table 1 Assumptions in proportion of patients losing quality-of-life benefit in each time period for dupilumab and best supportive care in the company's revised base case and sensitivity analyses
Analyses
Proportion of patients losing quality-of-life benefit
Dupilumab
Best supportive care
Year 2
Year 3
Year 4
Year 5 and beyond
Year 2
Year 3
Year 4
Year 5 and beyond
Revised base case
Sensitivity analysis 1: BSC – CHRONOS 'time to rescue therapy/stopping study' projections using Weibull curve fit
Sensitivity analysis 2:
BSC – CHRONOS 'time to rescue therapy/stopping study' annual rate
Sensitivity analysis 3:
Dupilumab – relative decline based on topical corticosteroid use in CAFÉ, 38.4%
Abbreviations: BSC, best supportive care.
The committee agreed that the data from the open-label extension study provided supporting evidence for the sustained effect of dupilumab in the revised base case. The ERG expressed concerns about sensitivity analyses 1 and 2 for best supportive care; it was unclear whether the data were from 'responders' only. It also did not consider the use of rescue therapy to be a good indication of loss of utility benefit because it formed part of best supportive care, which could improve quality of life. The committee agreed that there was uncertainty surrounding the assumptions on loss of utility benefit for best supportive care. It noted that sensitivity analyses 1 and 2 resulted in some patients maintaining benefit from year 5 and beyond, which it considered to be more plausible than no patients maintaining any benefit at all (revised base case and sensitivity analysis 3). Therefore, the committee concluded that sensitivity analyses 1 and 2 were the most plausible analyses for decision-making.
# Costs in the economic model
## The costs associated with adverse events are appropriate
In its revised model, the company included the costs of 4 adverse events: injection site reactions, allergic conjunctivitis, infectious conjunctivitis and oral herpes. It used annual rates for injection site reactions. The company also revised its accident and emergency visit costs from £137.82 to £159.78. The ERG agreed with the company's changes. The committee accepted these changes but noted that these changes had a minor effect on the cost-effectiveness estimates.
# Cost-effectiveness estimate
## Dupilumab is cost effective in people for whom best supportive care is the only option
The incremental cost-effectiveness ratios for dupilumab plus topical corticosteroids as needed compared with best supportive care alone in the company's revised base case and plausible sensitivity analyses (see section 3.17) ranged from £27,410 to £28,495 per quality-adjusted life year (QALY) gained. The committee concluded that dupilumab plus topical corticosteroids is a cost-effective use of NHS resources for treating atopic dermatitis that has not responded to other systemic therapies, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or when these options are contraindicated or not tolerated.
## Dupilumab should be stopped after 16 weeks if treatment response is inadequate
The committee understood from the summary of product characteristics that 'consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment'. The committee was aware that a similar 'induction' phase was implemented in the clinical trials (see section 3.6) and applied by the company in the economic model. An adequate response is defined as at least a 50% reduction in the EASI score and at least a 4‑point reduction in DLQI from when treatment started in the economic model. The committee agreed that it would be appropriate to stop treatment with dupilumab after 16 weeks if treatment response is inadequate.
# Other factors
## There is a lack of evidence on the effect of moderate to severe atopic dermatitis on the quality of life of carers
The committee noted comments from stakeholders that the effect of moderate to severe atopic dermatitis on the quality of life of families and carers should be taken into account. Although the committee acknowledged that there could potentially be an effect on the quality of life of families and carers, it agreed that it had not seen any evidence to support this.
## EASI and DLQI may not be appropriate for all people with atopic dermatitis
The committee noted potential equality issues, namely that:
the EASI might underestimate the severity of atopic dermatitis in people with darker skin
the DLQI may miss anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI.
## Certain ethnic groups have different cytokine pathways
Feedback from patient and professional organisations highlighted that there are specific cytokine pathways in atopic dermatitis in different ethnic groups. For example, interleukin‑4 and interleukin‑13 cytokines predominate in most populations whereas, in some Asian populations, interleukin‑17 cytokines predominate. The committee understood that there is insufficient evidence to determine the extent to which different cytokine pathways modify treatment effect. Therefore, it did not consider that it needed to account for the variation in cytokine expression in different ethnic groups.
## Dupilumab is an innovative treatment
Patient and professional feedback highlighted the significant and substantial health-related benefits associated with treatment with dupilumab. The committee agreed that dupilumab is innovative and a step change in managing atopic dermatitis. However, it did not hear that there were any additional gains in health-related quality of life over those already included in the QALY calculations.
|
{'Recommendations': 'Dupilumab is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if:\n\nthe disease has not responded to at least 1\xa0other systemic therapy, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are contraindicated or not tolerated\n\nthe company provides dupilumab according to the commercial arrangement.\n\nStop dupilumab at 16\xa0weeks if the atopic dermatitis has not responded adequately. An adequate response is:\n\nat least a 50% reduction in the Eczema Area and Severity Index score (EASI\xa050) from when treatment started and\n\nat least a 4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started.\n\nWhen using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with dupilumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent systemic treatment for moderate to severe atopic dermatitis (eczema) includes ciclosporin, methotrexate, azathioprine and mycophenolate mofetil. Dupilumab would be used after these treatments no longer work, and best supportive care is the only other available option. Dupilumab would likely be offered alongside topical corticosteroids.\n\nThe clinical evidence shows that dupilumab is very effective when used in this way. The most plausible cost-effectiveness estimates for dupilumab plus topical corticosteroids compared with best supportive care are within the range that NICE normally considers an acceptable use of NHS resources.', 'Information about dupilumab': 'Marketing authorisation indication\n\nDupilumab (Dupixent, Sanofi Genzyme) is indicated for the \'treatment of moderate to severe atopic dermatitis in adults who are candidates for systemic therapy\'.\n\nDosage in the marketing authorisation\n\nThe recommended dose, given by subcutaneous injection, is initially 600\xa0mg (2×300‑mg injections), followed by 300\xa0mg given every other week. It can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. "Consideration should be given to discontinuing treatment in patients who have shown no response after 16\xa0weeks of treatment". Some patients whose disease shows partial response may subsequently improve with continued treatment beyond 16\xa0weeks.\n\nPrice\n\n£1,264.89 per pack of 2×2‑ml syringes of 150\xa0mg/1\xa0ml solution (excluding VAT; British national formulary online, accessed March 2018).\n\nThe company has a commercial arrangement. This makes dupilumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company\'s responsibility to let relevant NHS organisations know details of the discount.', 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Sanofi Genzyme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Experience of people with atopic dermatitis\n\n## Atopic dermatitis affects all aspects of a person's life\n\nAtopic dermatitis is a chronic, recurrently flaring, generalised skin condition that can be life-limiting, debilitating and isolating. It can affect all aspects of life (physical, psychological, social and financial). Severe disease is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee noted that having treatments that improve the condition and which are associated with few or manageable adverse effects is important to people with atopic dermatitis.\n\n# Assessing severity of atopic dermatitis\n\n## Symptoms, signs and quality of life determine the severity of atopic dermatitis\n\nThe committee understood that there is variability in how clinicians assess severity in atopic dermatitis. They assess severity based on clinical signs and on patient-reported symptoms including effect on sleep and work, and how much patients need to use topical corticosteroids or systemic therapy. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative recommends using the Eczema Area and Severity Index (EASI) to assess signs (for example, skin lesions) and the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch). The clinical experts explained that the POEM is easier to administer in practice than the EASI. The committee understood that NHS clinicians routinely use the Dermatology Life Quality Index (DLQI) to assess quality of life in other skin conditions. It concluded that the EASI, DLQI and POEM are appropriate for assessing the severity of atopic dermatitis in NHS practice.\n\n# Clinical management\n\n## Atopic dermatitis can be treated with topical therapies, phototherapy and systemic immunosuppressant therapies\n\nAlthough clinicians individualise therapy for patients, a typical treatment pathway involves emollients and topical corticosteroids (first line), topical calcineurin inhibitors (second line), phototherapy (third line) and systemic immunosuppressant therapies (fourth line) including ciclosporin (the only licensed drug), methotrexate, azathioprine and mycophenolate mofetil. These systemic therapies can have serious adverse effects and, if a drug is no longer effective, it will be stopped and another drug will be offered. For people whose disease does not respond to multiple systemic therapies, the only remaining treatment option is best supportive care, which may include education, psychological support, emollients, topical corticosteroids, bandages and hospitalisation. Managing exacerbations (flares) in atopic dermatitis includes using short-term potent topical corticosteroids, oral corticosteroids and systemic therapy.\n\n# Positioning of dupilumab in the treatment pathway\n\n## Dupilumab would be used after existing systemic therapies\n\nThe marketing authorisation for dupilumab is for 'moderate to severe atopic dermatitis in adults who are candidates for systemic therapy'. The company only submitted evidence for dupilumab as a fifth-line treatment, after systemic immunosuppressant therapies, as an alternative to best supportive care. The clinical experts explained that people are likely to have had at least 1\xa0systemic therapy before dupilumab in clinical practice. The committee concluded that it would appraise dupilumab for moderate to severe atopic dermatitis, compared with best supportive care.\n\n# Comparators\n\n## The company's revised definition of best supportive care is appropriate for decision-making\n\nThe company defined best supportive care in its economic model as 'emollients, low-to-mid potency topical corticosteroids, and rescue therapy with higher potency topical or oral corticosteroids or topical calcineurin inhibitors'; it also included phototherapy and psychological support in its revised model, submitted in response to the appraisal consultation document. However, it excluded bandages because these were captured within 'day case' treatment and education because no reliable data were available. The ERG agreed with the company's revised approach in defining best supportive care. The committee concluded that the company's revised definition of best supportive care was adequate for decision-making.\n\n# Clinical evidence\n\n## The CAFÉ and CHRONOS trials provide the key clinical evidence for dupilumab\n\nThe main evidence for dupilumab came from 4\xa0trials: 2\xa0on dupilumab monotherapy (SOLO‑1 and SOLO‑2) and 2\xa0on dupilumab plus topical corticosteroids as needed (CAFÉ and CHRONOS). All patients had best supportive care. The clinical experts explained that dupilumab is likely to be offered alongside topical corticosteroids. The committee therefore agreed to focus on the evidence on dupilumab 'combination therapy' with topical corticosteroids. CAFÉ and CHRONOS were randomised double-blind trials that included a total of 1,065\xa0patients who had had chronic moderate to severe atopic dermatitis for at least 3\xa0years that had not been controlled with topical medications for at least 6\xa0months. Patients may or may not have had immunosuppressant therapy. The trials compared 2\xa0doses of dupilumab (300\xa0mg every week [unlicensed] or 300\xa0mg every other week [licensed]) with placebo. The committee agreed to focus only on the data for the licensed dose of dupilumab. The primary endpoints were assessed at the end of the 'induction period' (that is, 16\xa0weeks after starting treatment):\n\nCHRONOS (co-primary endpoints):\n\n\n\nat least a 75% reduction in the EASI score from when treatment started (EASI\xa075) and\n\na rating of 'clear' (score of\xa00) or 'almost clear' (score of\xa01) on the Investigators' Global Assessment, and at least a 2‑point improvement from baseline.\n\n\n\nCAFÉ: EASI\xa075.Patients in CHRONOS had an additional 36\xa0weeks of treatment.\n\n## The open-label extension study provides long-term clinical evidence for dupilumab\n\nIn response to the appraisal consultation document, the company provided data for up to 100\xa0weeks from the start of an ongoing, open-label extension study. It included patients from previous dupilumab trials who had not had any adverse effects that led them to stop the trial, or patients screened for the SOLO studies but unable to enter them because of closure of the trials. Patients had weekly dupilumab (unlicensed dose) and could also use topical medications as needed. The company provided data for 2\xa0subgroups: patients who had not had dupilumab before the study ('dupilumab-naive') or patients who had previously had dupilumab but with treatment gaps ranging from less than 6\xa0weeks to more than 13\xa0weeks ('dupilumab-exposed'). The committee concluded that evidence from this extension study, particularly that from the 'dupilumab-exposed' subgroup, would help in the understanding of dupilumab's long-term clinical effectiveness and to inform the assumptions in the economic model (see section 3.15 and section 3.17).\n\n# Company's revised base case\n\n## The base case focuses on a subgroup of patients from CAFÉ and CHRONOS, and data from placebo groups to represent best supportive care\n\nBecause the company considered that dupilumab would be used as a fifth-line treatment, after systemic therapies, it focused its base case on a subgroup of 299\xa0patients from CAFÉ and CHRONOS who could not have ciclosporin, or whose condition had not responded to ciclosporin. The company used data from the placebo groups to represent best supportive care in its economic model. The committee concluded that the subgroup was sufficiently large to provide reliable estimates of clinical effectiveness.\n\n## Clinical experts advise that the population in the company's subgroup is similar to patients in the NHS who would have dupilumab\n\nThe subgroup identified by the company included patients who were on average 38\xa0years old; 60% were men and 91% were 'white'. Patients had atopic dermatitis for an average of 29\xa0years, which covered an average of 58% of their body, and they had average scores of 34\xa0on the EASI, 20\xa0on the POEM and 15\xa0on the DLQI. The clinical experts confirmed that the baseline characteristics of these patients were similar to those likely to be seen in the NHS. The committee concluded that the trial subgroup population generally reflected people who would be treated with dupilumab in NHS clinical practice.\n\n## Analyses that consider patients to be 'non-responders' if they have rescue therapy are appropriate\n\nIn its revised base case, the company presented results from analyses that considered patients to be 'non-responders' if they had not provided data at week\xa016, or if they had rescue therapy or withdrew from the study. The committee concluded that these analyses were appropriate because the clinical experts stated that systemic treatments are usually stopped when they are no longer effective at controlling the condition and patients need rescue therapy.\n\n## The combination of EASI\xa050 plus an improvement in the DLQI of at least\xa04 is an appropriate outcome for decision-making\n\nTo model the cost effectiveness of dupilumab, the company defined a clinical benefit in its base case of an EASI\xa050 (at least a 50% reduction in the EASI score from when treatment started) plus an improvement in the DLQI of at least\xa04. The clinical experts explained that EASI\xa050 and an improvement in the DLQI of at least\xa04 are sensitive to changes in treatment outcomes and more clinically relevant than an EASI 75 (at least a 75% reduction in the EASI score from when treatment started). The committee concluded that the composite endpoint of an EASI\xa050 plus an improvement in the DLQI of at least\xa04 was appropriate for decision-making.\n\n## Dupilumab with topical corticosteroids as needed is substantially more clinically effective than placebo\n\nThe committee noted that patients having dupilumab plus topical corticosteroids as needed had a clinically and statistically significantly higher response rate in the EASI\xa050 plus an improvement in the DLQI of at least\xa04 at week\xa016 (73% of 130 patients) than patients having placebo plus topical corticosteroids as needed (28% of 169\xa0patients). The committee noted that these results also included patients who had rescue therapy. It concluded that dupilumab was substantially more clinically effective than placebo, although it would have preferred to have seen the results of the analyses in which patients who had rescue therapy were considered to be 'non-responders' (see section 3.10).\n\n## Patients in the trials had a relatively high 'placebo response'\n\nThe committee queried the high response rate seen in the placebo group (see section\xa03.12). One clinical expert explained that this was likely because nurses in the trials closely supervised topical therapy regimens, which can improve adherence and maximise effectiveness. While this level of supervision is feasible in a short-term trial, it is not sustainable for prolonged periods (after 6\xa0months), so any 'placebo response' is likely to decline over time. The committee agreed that any benefit from supervision should have been applied equally to both the dupilumab and placebo groups, which should not have affected how the treatments performed relative to one another in the trial. The company noted that, in CAFÉ, there was a higher reduction in topical corticosteroid use in the dupilumab arm than the placebo arm. The committee concluded that the 'placebo response' in the trials was unlikely to have affected the treatment effect of dupilumab relative to placebo.\n\n# Company's revised economic model\n\n## The model combines a decision tree and Markov state transition\n\nThe company's model consisted of 2\xa0components:\n\nDecision tree up to 52\xa0weeks: people entered the model either in the 'dupilumab' or the 'best supportive care' arm. Based on trial data, this part of the model evaluated treatment response at 2\xa0time points, 16\xa0weeks and 52\xa0weeks after starting treatment.\n\n\n\nAt week\xa016 after starting treatment, people in the 'dupilumab' arm whose condition had responded continued to have dupilumab for a further 36\xa0weeks (that is, up to week\xa052 after starting treatment). People whose condition had not responded, switched to best supportive care for the remaining 36\xa0weeks, in line with the marketing authorisation. The clinical experts confirmed that this stopping rule reflects clinical practice. Everyone in 'best supportive care' remained in this arm and split according to treatment response into 'responders' or 'non-responders'.\n\nAt week\xa052 after starting treatment, people in the 'dupilumab' arm whose condition continued to respond moved into the 'maintenance' Markov state of the model; people whose condition had lost response moved into the 'best supportive care' Markov state. Everyone who had best supportive care moved into the 'best supportive care' Markov state and split according to treatment response into 'responders' or 'non-responders'.\n\n\n\nMarkov state transition with annual cycles from year\xa02 onwards: this component modelled long-term treatment (up to 61\xa0years) of atopic dermatitis and included 3\xa0states; maintenance on dupilumab, best supportive care and death. People having dupilumab maintenance therapy could stop dupilumab for any reason (loss of response, adverse effects, patient or physician preference) and move into the 'best supportive care' Markov state. Anyone could die at any time.In its combined decision tree and Markov state transition model, the company assumed that dupilumab improved quality of life, but did not extend length of life, compared with best supportive care. The committee concluded that the revised model structure was appropriate.\n\n# Assumptions in the revised economic model\n\n## A yearly stopping rate of 3.7% for people having dupilumab plus topical corticosteroids is plausible based on data from the open-label extension study\n\nThe company assumed that 3.7% of people having dupilumab plus topical corticosteroids as maintenance therapy stop treatment every year for any reason, and move onto best supportive care. This reflected the proportion of people in CHRONOS whose condition responded to treatment at 16\xa0weeks who withdrew from the trial by 52\xa0weeks. In response to the appraisal consultation document, the company provided sensitivity analyses on a range of stopping rates based on data from its open-label extension study, ranging from 2.1% in 'responders' at week\xa024 to 6.4% in the whole population at 52\xa0weeks. The ERG agreed that the original stopping rate appear reasonable and consistent with the available data. The committee noted that the different stopping rates had minimal impact on the cost-effectiveness estimates, and agreed that the company's original stopping rate of 3.7% is plausible.\n\n# Utility values in the revised economic model\n\n## Utility values specific for people whose condition does not respond to dupilumab are appropriate\n\nIn its revised model, the company assumed that, if atopic dermatitis did not respond to dupilumab plus topical corticosteroids:\n\nat week\xa016 after starting treatment, people accrued the average utility value of dupilumab 'non-responders' and best supportive care 'non-responders' (0.82)\n\nfrom week\xa052 onwards, people accrued the utility value of best supportive care 'non-responders' (0.77).The ERG agreed that the company's revised approach to modelling utility values for dupilumab 'non-responders' was appropriate. These revisions had a minimal effect on the cost-effectiveness estimates. However, the committee agreed that it was appropriate to use the utility value specific to people whose condition had not responded to dupilumab plus topical corticosteroids at 16\xa0weeks rather than the utility value from everyone having best supportive care (0.81), as the company had done in its original model.\n\n## Assumptions on loss of utility benefit should be based on data from the open-label extension study and CHRONOS\n\nIn its revised base case, the company assumed in both treatment states that part of the clinical benefit of treatment (as determined at week\xa052 of the trials), and the associated utility benefit, were lost from year\xa02 after starting treatment onwards:\n\nIn the dupilumab maintenance state, the company assumed that 2% of the benefit would be lost in year\xa02, 5% in year\xa03, 7% in year\xa04, and 8% in year\xa05 and beyond. It used these estimates to adjust down the proportion of people who continued to have dupilumab (that is, those who lost the benefit of dupilumab moved to the best supportive care state and then accrued the utility associated with that state). The company based these assumptions for dupilumab on feedback from the experience of 5\xa0dupilumab trial investigators, supported by evidence from its open-label extension study that showed a sustained treatment effect.\n\nIn the best supportive care state, the company assumed that 25% of the benefit would be lost in year\xa02, 50% in year\xa03, 75% in year\xa04, and 100% in year\xa05 and beyond. It used these estimates to adjust down the utility value applied over time, by applying in each year the average of the utility value for best supportive care during the trials (0.80), and the baseline utility value (0.66), weighted by the proportion of people who were assigned each utility value. Therefore, by the end of year\xa05, everyone in the best supportive care arm returned to the baseline utility (0.66) for the remainder of their time in the model.The company also provided analyses in which it changed its assumptions on the decline in quality of life (see table\xa01).\n\n## Table\xa01 Assumptions in proportion of patients losing quality-of-life benefit in each time period for dupilumab and best supportive care in the company's revised base case and sensitivity analyses\n\nAnalyses\n\nProportion of patients losing quality-of-life benefit\n\nDupilumab\n\nBest supportive care\n\nYear 2\n\nYear 3\n\nYear 4\n\nYear 5 and beyond\n\nYear 2\n\nYear 3\n\nYear 4\n\nYear 5 and beyond\n\nRevised base case\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\nSensitivity analysis\xa01: BSC – CHRONOS 'time to rescue therapy/stopping study' projections using Weibull curve fit\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\nSensitivity analysis\xa02:\n\nBSC – CHRONOS 'time to rescue therapy/stopping study' annual rate\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\nSensitivity analysis\xa03:\n\nDupilumab – relative decline based on topical corticosteroid use in CAFÉ, 38.4%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\n%\n\nAbbreviations: BSC, best supportive care.\n\nThe committee agreed that the data from the open-label extension study provided supporting evidence for the sustained effect of dupilumab in the revised base case. The ERG expressed concerns about sensitivity analyses\xa01 and\xa02 for best supportive care; it was unclear whether the data were from 'responders' only. It also did not consider the use of rescue therapy to be a good indication of loss of utility benefit because it formed part of best supportive care, which could improve quality of life. The committee agreed that there was uncertainty surrounding the assumptions on loss of utility benefit for best supportive care. It noted that sensitivity analyses\xa01 and\xa02 resulted in some patients maintaining benefit from year\xa05 and beyond, which it considered to be more plausible than no patients maintaining any benefit at all (revised base case and sensitivity analysis\xa03). Therefore, the committee concluded that sensitivity analyses\xa01 and\xa02 were the most plausible analyses for decision-making.\n\n# Costs in the economic model\n\n## The costs associated with adverse events are appropriate\n\nIn its revised model, the company included the costs of 4\xa0adverse events: injection site reactions, allergic conjunctivitis, infectious conjunctivitis and oral herpes. It used annual rates for injection site reactions. The company also revised its accident and emergency visit costs from £137.82 to £159.78. The ERG agreed with the company's changes. The committee accepted these changes but noted that these changes had a minor effect on the cost-effectiveness estimates.\n\n# Cost-effectiveness estimate\n\n## Dupilumab is cost effective in people for whom best supportive care is the only option\n\nThe incremental cost-effectiveness ratios for dupilumab plus topical corticosteroids as needed compared with best supportive care alone in the company's revised base case and plausible sensitivity analyses (see section 3.17) ranged from £27,410 to £28,495 per quality-adjusted life year (QALY) gained. The committee concluded that dupilumab plus topical corticosteroids is a cost-effective use of NHS resources for treating atopic dermatitis that has not responded to other systemic therapies, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or when these options are contraindicated or not tolerated.\n\n## Dupilumab should be stopped after 16\xa0weeks if treatment response is inadequate\n\nThe committee understood from the summary of product characteristics that 'consideration should be given to discontinuing treatment in patients who have shown no response after 16\xa0weeks of treatment'. The committee was aware that a similar 'induction' phase was implemented in the clinical trials (see section\xa03.6) and applied by the company in the economic model. An adequate response is defined as at least a 50% reduction in the EASI score and at least a 4‑point reduction in DLQI from when treatment started in the economic model. The committee agreed that it would be appropriate to stop treatment with dupilumab after 16\xa0weeks if treatment response is inadequate.\n\n# Other factors\n\n## There is a lack of evidence on the effect of moderate to severe atopic dermatitis on the quality of life of carers\n\nThe committee noted comments from stakeholders that the effect of moderate to severe atopic dermatitis on the quality of life of families and carers should be taken into account. Although the committee acknowledged that there could potentially be an effect on the quality of life of families and carers, it agreed that it had not seen any evidence to support this.\n\n## EASI and DLQI may not be appropriate for all people with atopic dermatitis\n\nThe committee noted potential equality issues, namely that:\n\nthe EASI might underestimate the severity of atopic dermatitis in people with darker skin\n\nthe DLQI may miss anxiety and depression.The committee concluded that, when using the EASI, healthcare professionals should take into account skin colour and how this could affect the EASI score. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or difficulties in communication that could affect a person's response to the DLQI.\n\n## Certain ethnic groups have different cytokine pathways\n\nFeedback from patient and professional organisations highlighted that there are specific cytokine pathways in atopic dermatitis in different ethnic groups. For example, interleukin‑4 and interleukin‑13 cytokines predominate in most populations whereas, in some Asian populations, interleukin‑17 cytokines predominate. The committee understood that there is insufficient evidence to determine the extent to which different cytokine pathways modify treatment effect. Therefore, it did not consider that it needed to account for the variation in cytokine expression in different ethnic groups.\n\n## Dupilumab is an innovative treatment\n\nPatient and professional feedback highlighted the significant and substantial health-related benefits associated with treatment with dupilumab. The committee agreed that dupilumab is innovative and a step change in managing atopic dermatitis. However, it did not hear that there were any additional gains in health-related quality of life over those already included in the QALY calculations."}
|
https://www.nice.org.uk/guidance/ta534
|
Evidence-based recommendations on dupilumab (Dupixent) for treating moderate to severe atopic dermatitis in adults.
|
b3cf796de1324793ffc9ae57545c85be32cdd712
|
nice
|
Low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing
|
Low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
# Recommendations
The evidence for low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing raises no major safety concerns. However, current evidence does not show efficacy. Therefore, this procedure should not be used for this indication. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
Fractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.
# Current treatments
Fractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes, healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when bony union has failed 6 to 9 months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.
# The procedure
The aim of low-intensity pulsed ultrasound is to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing.
An ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20 minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5 MHz, pulse width of 200 microseconds, repetition rate of 1 kHz, and a temporal average power of 30 milliwatts/cm2 is typically used. The exact treatment protocol and duration of treatment may vary.
Progress towards fracture healing is usually assessed radiographically. Treatment duration ranges from a few weeks to several months.
|
{'Recommendations': 'The evidence for low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing raises no major safety concerns. However, current evidence does not show efficacy. Therefore, this procedure should not be used for this indication. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': "# The condition\n\nFractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.\n\n# Current treatments\n\nFractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes, healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when bony union has failed 6\xa0to\xa09\xa0months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.\n\n# The procedure\n\nThe aim of low-intensity pulsed ultrasound is to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing.\n\nAn ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20\xa0minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5\xa0MHz, pulse width of 200\xa0microseconds, repetition rate of 1\xa0kHz, and a temporal average power of 30\xa0milliwatts/cm2 is typically used. The exact treatment protocol and duration of treatment may vary.\n\nProgress towards fracture healing is usually assessed radiographically. Treatment duration ranges from a few weeks to several months."}
|
https://www.nice.org.uk/guidance/ipg621
|
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of fresh fractures at low risk of non-healing in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
|
350b17f89fc0afe4b16009ab7f52100391fe96bc
|
nice
|
Low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing
|
Low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
# Recommendations
The evidence for low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing raises no major safety concerns. The current evidence on efficacy is very limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include details of patient selection, fracture site, and risk factors and comorbidities that delay fracture healing.# The condition, current treatments and procedure
# The condition
Fractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.
# Current treatments
Fractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes, healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when there is failure of bony union 6 to 9 months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.
# The procedure
The aim of low-intensity pulsed ultrasound is to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing.
An ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20 minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5 MHz, pulse width of 200 microseconds, repetition rate of 1 kHz, and a temporal average power of 30 milliwatts/cm2 is typically used. The exact treatment protocol and duration of treatment may vary.
Progress towards fracture healing is usually assessed radiographically. Treatment duration ranges from a few weeks to several months.
|
{'Recommendations': 'The evidence for low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing raises no major safety concerns. The current evidence on efficacy is very limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include details of patient selection, fracture site, and risk factors and comorbidities that delay fracture healing.', 'The condition, current treatments and procedure': "# The condition\n\nFractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.\n\n# Current treatments\n\nFractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes, healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when there is failure of bony union 6\xa0to\xa09\xa0months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.\n\n# The procedure\n\nThe aim of low-intensity pulsed ultrasound is to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing.\n\nAn ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20\xa0minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5\xa0MHz, pulse width of 200\xa0microseconds, repetition rate of 1\xa0kHz, and a temporal average power of 30\xa0milliwatts/cm2 is typically used. The exact treatment protocol and duration of treatment may vary.\n\nProgress towards fracture healing is usually assessed radiographically. Treatment duration ranges from a few weeks to several months."}
|
https://www.nice.org.uk/guidance/ipg622
|
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
|
ad2566d8e7362e4a3b5998bd8422107e0b7c2f4b
|
nice
|
Low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures
|
Low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
# Recommendations
The evidence for low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures raises no major safety concerns. The current evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on low-intensity pulsed ultrasound is recommended.
Audit and review clinical outcomes of all patients having low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.
The procedure should be used with other treatments for delayed-union and non-union fractures. It should be managed by specialists in treating these fractures.
NICE encourages further research into low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures. Further research should include details of patient selection, fracture site, and risk factors and comorbidities that delay fracture healing.# The condition, current treatments and procedure
# The condition
Fractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.
# Current treatments
Fractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when there is failure of bony union 6 to 9 months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.
# The procedure
The aim of low-intensity pulsed ultrasound is to promote healing by delivering micro-mechanical stress to the bone to stimulate bone healing. This procedure is used to treat fractures that are slower to heal than expected (delayed healing) and fractures that have failed to unite (non-union).
An ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20 minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5 MHz, pulse width of 200 microseconds, repetition rate of 1 kHz, and a temporal average power of 30 milliwatts per cm2 is typically used. The exact treatment protocol and duration of treatment may vary.
Progress towards fracture healing is usually assessed radiographically. The duration of treatment ranges from a few weeks to several months.
|
{'Recommendations': "The evidence for low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures raises no major safety concerns. The current evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on low-intensity pulsed ultrasound is recommended.\n\nAudit and review clinical outcomes of all patients having low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.\n\nThe procedure should be used with other treatments for delayed-union and non-union fractures. It should be managed by specialists in treating these fractures.\n\nNICE encourages further research into low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures. Further research should include details of patient selection, fracture site, and risk factors and comorbidities that delay fracture healing.", 'The condition, current treatments and procedure': "# The condition\n\nFractures are a common result of trauma, and are usually described as either closed (skin over the fracture site is intact) or open (involves an open wound). They may vary in complexity from a single break (transverse or oblique) to comminuted, in which the bone has broken into several pieces.\n\n# Current treatments\n\nFractures usually heal within a few weeks after treatment by closed or open reduction, and immobilisation using a cast or internal fixation. Sometimes healing may be delayed or not happen at all (non-union). There is no agreed precise definition of a fracture non-union but, typically, it is considered to be when there is failure of bony union 6\xa0to\xa09 months after the fracture. Risk factors for non-union of fractures include: systemic medical conditions (for example, diabetes, malnutrition, osteoporosis); smoking; use of non-steroidal anti-inflammatory drugs; local factors such as infection; vascular problems; magnitude of injury (for example, fracture location and gap, traumatic fractures); advanced age; and other iatrogenic factors. Treatment of non-union may need complex and prolonged management with implications for the patient's quality of life and functional capacity.\n\n# The procedure\n\nThe aim of low-intensity pulsed ultrasound is to promote healing by delivering micro-mechanical stress to the bone to stimulate bone healing. This procedure is used to treat fractures that are slower to heal than expected (delayed healing) and fractures that have failed to unite (non-union).\n\nAn ultrasound probe is positioned on the skin over the fracture and patients self-administer low-intensity pulsed ultrasound daily, usually for 20\xa0minutes. If a patient's limb is immobilised in a cast, a hole is cut into the cast for the ultrasound probe. The probe delivers acoustic radiation and coupling gel is used on the skin to aid conduction of the ultrasound signal. An operating frequency of 1.5\xa0MHz, pulse width of 200\xa0microseconds, repetition rate of 1\xa0kHz, and a temporal average power of 30\xa0milliwatts per\xa0cm2 is typically used. The exact treatment protocol and duration of treatment may vary.\n\nProgress towards fracture healing is usually assessed radiographically. The duration of treatment ranges from a few weeks to several months."}
|
https://www.nice.org.uk/guidance/ipg623
|
Evidence-based recommendations on low-intensity pulsed ultrasound to promote healing of delayed-union and non-union fractures in adults. This involves using an ultrasound probe on the skin at the site of the fracture.
|
414b86e1a53501a3fa98a33dcbed020b8f375669
|
nice
|
Superior capsular augmentation for massive rotator cuff tears
|
Superior capsular augmentation for massive rotator cuff tears
Evidence-based recommendations on superior capsular augmentation for massive rotator cuff tears in adults. This involves using a graft to stabilise the shoulder joint, reduce pain and improve shoulder function.
# Recommendations
Current evidence on the safety and efficacy of superior capsular augmentation for massive rotator cuff tears is limited in quantity and inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Research should address patient selection, type of graft and technique used, long-term outcomes including shoulder function, and patient-reported outcome measures.# The condition, current treatments and procedure
# The condition
Patients with rotator cuff tears may have shoulder pain and weakness accompanied by functional limitation leading to a reduced quality of life. Rotator cuff tears can be caused by an injury or can develop gradually. They can be minor or severe depending on the degree of damage to the tendon. Minor tears to the rotator cuff are very common and may not cause any symptoms at all. Diagnosis is usually by ultrasound or MRI.
# Current treatments
Conservative treatment may include physiotherapy, pharmacological treatments (including pain relief and topical or oral non-steroidal anti-inflammatory drugs) and corticosteroid injections. If the tear is severe or has not responded to other treatments, surgical interventions such as debridement, rotator cuff repair, bridging rotator cuff reconstruction, subacromial smoothing, tendon transfer, or shoulder arthroplasty may be needed.
# The procedure
Superior capsular augmentation aims to improve pain symptoms and shoulder function in patients with massive and otherwise irreparable rotator cuff tears. The intention is to reduce superior gleno-humeral translation and restore superior stability with minimal re-tear rates. The optimal repair uses the patient's own rotator cuff muscles and tendons, but if the tear is too large augmentation with other tissue may be needed.
Superior capsular augmentation is done arthroscopically or by open surgery, with the patient either in the lateral decubitus position, or the 'beach-chair' position, and under general anaesthesia. It involves using a fascia lata autograft, an allograft or a regenerative tissue matrix. The arm of the patient is kept in neutral abduction and in neutral rotation. The supraspinatus and infraspinatus are repaired as much as possible and a biceps tenotomy or tendonesis are done on any biceps tear or instability. The superior glenoid and greater tuberosity are debrided to prepare for reconstruction. Using suture anchors, the graft is attached medially to the glenoid superior tubercle and laterally to the greater tuberosity. Side-to-side sutures between the graft and the infraspinatus tendon, as well as between the graft and the residual anterior supraspinatus or subscapularis may also be added to improve force coupling. Post-operative rehabilitation is essential and can be long and difficult.
|
{'Recommendations': 'Current evidence on the safety and efficacy of superior capsular augmentation for massive rotator cuff tears is limited in quantity and inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nResearch should address patient selection, type of graft and technique used, long-term outcomes including shoulder function, and patient-reported outcome measures.', 'The condition, current treatments and procedure': "# The condition\n\nPatients with rotator cuff tears may have shoulder pain and weakness accompanied by functional limitation leading to a reduced quality of life. Rotator cuff tears can be caused by an injury or can develop gradually. They can be minor or severe depending on the degree of damage to the tendon. Minor tears to the rotator cuff are very common and may not cause any symptoms at all. Diagnosis is usually by ultrasound or MRI.\n\n# Current treatments\n\nConservative treatment may include physiotherapy, pharmacological treatments (including pain relief and topical or oral non-steroidal anti-inflammatory drugs) and corticosteroid injections. If the tear is severe or has not responded to other treatments, surgical interventions such as debridement, rotator cuff repair, bridging rotator cuff reconstruction, subacromial smoothing, tendon transfer, or shoulder arthroplasty may be needed.\n\n# The procedure\n\nSuperior capsular augmentation aims to improve pain symptoms and shoulder function in patients with massive and otherwise irreparable rotator cuff tears. The intention is to reduce superior gleno-humeral translation and restore superior stability with minimal re-tear rates. The optimal repair uses the patient's own rotator cuff muscles and tendons, but if the tear is too large augmentation with other tissue may be needed.\n\nSuperior capsular augmentation is done arthroscopically or by open surgery, with the patient either in the lateral decubitus position, or the 'beach-chair' position, and under general anaesthesia. It involves using a fascia lata autograft, an allograft or a regenerative tissue matrix. The arm of the patient is kept in neutral abduction and in neutral rotation. The supraspinatus and infraspinatus are repaired as much as possible and a biceps tenotomy or tendonesis are done on any biceps tear or instability. The superior glenoid and greater tuberosity are debrided to prepare for reconstruction. Using suture anchors, the graft is attached medially to the glenoid superior tubercle and laterally to the greater tuberosity. Side-to-side sutures between the graft and the infraspinatus tendon, as well as between the graft and the residual anterior supraspinatus or subscapularis may also be added to improve force coupling. Post-operative rehabilitation is essential and can be long and difficult."}
|
https://www.nice.org.uk/guidance/ipg619
|
Evidence-based recommendations on superior capsular augmentation for massive rotator cuff tears in adults. This involves using a graft to stabilise the shoulder joint, reduce pain and improve shoulder function.
|
04860ff7070d457b8df2a70f04072e3972d3ba37
|
nice
|
Transaxial interbody lumbosacral fusion for severe chronic low back pain
|
Transaxial interbody lumbosacral fusion for severe chronic low back pain
Evidence-based recommendations on transaxial interbody lumbosacral fusion for low back pain in adults. This involves removing a damaged disc through a small cut at the base of the spine, and replacing it with an artificial implant.
# Recommendations
Evidence on the safety of transaxial interbody lumbosacral fusion for severe chronic low back pain shows that there are serious but well-recognised complications. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
This procedure should only be done by a surgeon with specific training in the procedure, who should carry out their initial procedures with an experienced mentor.
Clinicians should enter data onto the British Spine Registry.# The condition, current treatments and procedure
# The condition
Chronic low back pain may result from degenerative changes in the intervertebral discs or spinal facet joints.
# Current treatments
Conservative treatments include pain relief, non steroidal anti-inflammatory medication and manual therapy (see NICE's guideline on low back pain and sciatica). For people with severe, lifestyle-limiting, chronic low back pain that does not respond to conservative treatments, surgery may be appropriate. This may include bony fusion of vertebrae (to immobilise segments of the vertebral column thought to be responsible for back pain, using either a posterior or anterior approach) or inserting a prosthetic intervertebral disc (which preserves lumbar mobility to reduce the risk of degenerative changes in adjacent intervertebral disc spaces). Other surgical alternatives include non‑rigid stabilisation techniques.
# The procedure
Transaxial interbody lumbosacral fusion is done with the patient under general anaesthesia. A small incision is made lateral to the coccyx and a guide-pin introducer is inserted under fluoroscopic guidance. Air insufflation may be used to improve visualisation of the rectum during fluoroscopy. The guide-pin introducer is advanced over the sacrum's midline anterior surface towards the L5–S1 space. A reamer is then passed over the guidewire to the endplate of S1. As with conventional spinal fusion, the disc is removed through the canal created by the reamer. A mixture typically consisting of commercially available bone graft material, patient's own bone extracted from the surgical site and blood is prepared in the operating theatre and injected into the disc space. A special rod is screwed between the L5 and S1 vertebrae along the canal created by the reamer to maintain segmental height and alignment. Using a posterior approach, pedicle or facet joint screws may be used to provide extra stabilisation.
The potential benefits of the transaxial approach include faster recovery and less postoperative morbidity compared with conventional spinal fusion surgery.
|
{'Recommendations': 'Evidence on the safety of transaxial interbody lumbosacral fusion for severe chronic low back pain shows that there are serious but well-recognised complications. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThis procedure should only be done by a surgeon with specific training in the procedure, who should carry out their initial procedures with an experienced mentor.\n\nClinicians should enter data onto the British Spine Registry.', 'The condition, current treatments and procedure': "# The condition\n\nChronic low back pain may result from degenerative changes in the intervertebral discs or spinal facet joints.\n\n# Current treatments\n\nConservative treatments include pain relief, non steroidal anti-inflammatory medication and manual therapy (see NICE's guideline on low back pain and sciatica). For people with severe, lifestyle-limiting, chronic low back pain that does not respond to conservative treatments, surgery may be appropriate. This may include bony fusion of vertebrae (to immobilise segments of the vertebral column thought to be responsible for back pain, using either a posterior or anterior approach) or inserting a prosthetic intervertebral disc (which preserves lumbar mobility to reduce the risk of degenerative changes in adjacent intervertebral disc spaces). Other surgical alternatives include non‑rigid stabilisation techniques.\n\n# The procedure\n\nTransaxial interbody lumbosacral fusion is done with the patient under general anaesthesia. A small incision is made lateral to the coccyx and a guide-pin introducer is inserted under fluoroscopic guidance. Air insufflation may be used to improve visualisation of the rectum during fluoroscopy. The guide-pin introducer is advanced over the sacrum's midline anterior surface towards the L5–S1 space. A reamer is then passed over the guidewire to the endplate of S1. As with conventional spinal fusion, the disc is removed through the canal created by the reamer. A mixture typically consisting of commercially available bone graft material, patient's own bone extracted from the surgical site and blood is prepared in the operating theatre and injected into the disc space. A special rod is screwed between the L5 and S1 vertebrae along the canal created by the reamer to maintain segmental height and alignment. Using a posterior approach, pedicle or facet joint screws may be used to provide extra stabilisation.\n\nThe potential benefits of the transaxial approach include faster recovery and less postoperative morbidity compared with conventional spinal fusion surgery."}
|
https://www.nice.org.uk/guidance/ipg620
|
Evidence-based recommendations on transaxial interbody lumbosacral fusion for low back pain in adults. This involves removing a damaged disc through a small cut at the base of the spine, and replacing it with an artificial implant.
|
63b0ada447c68ccc1bfd89051ceb6660e7420287
|
nice
|
Ocrelizumab for treating relapsing–remitting multiple sclerosis
|
Ocrelizumab for treating relapsing–remitting multiple sclerosis
Evidence-based recommendations on ocrelizumab (Ocrevus) for treating relapsing–remitting multiple sclerosis in adults.
# Recommendations
Ocrelizumab is recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features, only if:
alemtuzumab is contraindicated or otherwise unsuitable and
the company provides ocrelizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with ocrelizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current NHS treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab and teriflunomide.
Clinical trial results show that ocrelizumab reduces the number of relapses and slows disability progression compared with interferon beta‑1a for people with relapsing–remitting multiple sclerosis. There is no evidence directly comparing ocrelizumab with other treatments. Indirect analyses suggest that ocrelizumab reduces the number of relapses compared with interferon beta‑1b, glatiramer acetate, dimethyl fumarate, fingolimod and teriflunomide, and is as effective as alemtuzumab and natalizumab. These analyses suggest that ocrelizumab slows disease progression in the total relapsing–remitting multiple sclerosis population compared with some treatments but not others. Also, it is uncertain whether ocrelizumab slows disease progression in the subgroups of highly active and rapidly evolving severe disease.
The most plausible cost-effectiveness estimates for ocrelizumab compared with most relevant comparators are in the range that NICE normally considers an acceptable use of NHS resources. However, because it is more costly than alemtuzumab, ocrelizumab can only be recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features if alemtuzumab is contraindicated or otherwise unsuitable.# Information about ocrelizumab
Marketing authorisation indication
Ocrelizumab (Ocrevus, Roche) has a marketing authorisation in the UK 'for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features'.
Dosage in the marketing authorisation
Ocrelizumab is administered by intravenous infusion. The first dose is administered as 2×300 mg infusions 2 weeks apart; subsequent doses are administered as a single 600 mg infusion every 6 months. A minimum interval of 5 months should be maintained between each dose.
Price
The list price for ocrelizumab is £4,790 per 300‑mg vial (company submission).
The company has a commercial arrangement. This makes ocrelizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition and current treatment pathway
## Patients would value a treatment with less frequent dosing or monitoring
The clinical and patient experts stated that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that symptoms of relapsing–remitting multiple sclerosis and the adverse effects from treatment can limit people's ability to work, and to engage in social and family life. The dosing frequency and monitoring needs of some treatments can disrupt people's lives and careers. The committee noted that ocrelizumab is given as an infusion during an outpatient appointment once every 6 months and less frequent monitoring for adverse effects is needed than with some other treatments. It heard that a treatment administered once every 6 months, with fewer adverse effects and monitoring needs than other treatments, would be less disruptive and so be valued by patients.
## Ocrelizumab could be used first line or after prior therapy
The clinical experts explained that multiple sclerosis can be unpredictable in the early stages of disease and there is often a period of observation before starting treatment. Many patients start treatment with a first-line treatment such as beta interferon, glatiramer acetate, dimethyl fumarate or teriflunomide before moving on to other therapies if the disease stops responding or if adverse effects occur. Other patients, particularly those with frequent or severe relapses, start treatment with a more effective therapy such as alemtuzumab; some clinicians offer rituximab but this is not routine practice in the UK. The committee heard that ocrelizumab would be offered to patients as a first-line therapy in those being considered for, but unable to tolerate the side effects of, alemtuzumab, or offered to patients after prior therapy. Clinical experts also noted that there are no clear rules for sequencing of treatments or for stopping therapy. However, in practice, clinicians would generally stop all treatments when patients can no longer walk or when their disease moves to secondary progressive multiple sclerosis.
## Patient preference is an important consideration when making shared decisions about treatment
The committee discussed the factors that may influence patients' choice of treatment. It was aware that the various treatment options available have different methods and schedules of administration, and noted that people will have different preferences. The committee was aware that careful monitoring is needed after treatment with alemtuzumab; consultation comments from patients groups highlighted that some people do not want to have alemtuzumab because of concerns about adverse effects and monitoring needs. It noted these comments but also considered that alemtuzumab's dosing schedule and mode of action may appeal to other patients. The committee concluded that differences in dosing schedule, adverse effects and monitoring between ocrelizumab and alemtuzumab may influence patient choice, and that it is important to take this into account when making decisions about treatment.
# Comparators
## Alemtuzumab, beta interferons, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab and teriflunomide are relevant comparators
The company limited its submission to relapsing–remitting multiple sclerosis rather than relapsing forms of multiple sclerosis, as specified in its marketing authorisation. When discussing relevant comparators used in current NHS practice in England, the clinical experts stated that it was appropriate to exclude best supportive care because patients having ocrelizumab would be fit enough to have other therapies. The committee noted that daclizumab was recently withdrawn from the UK market because of safety concerns, so was no longer a relevant comparator. It was also aware that cladribine had recently been recommended by NICE for adults with highly active relapsing multiple sclerosis. The clinical experts stated that this would be a relevant comparator for ocrelizumab, but noted that NICE recommended cladribine after the appraisal for ocrelizumab had started. The committee concluded that the relevant comparators were alemtuzumab, beta interferons, dimethyl fumarate, fingolimod (for highly active disease), glatiramer acetate, natalizumab (rapidly evolving severe disease) and teriflunomide.
## Individual comparisons of ocrelizumab with beta interferons and glatiramer acetate are appropriate
In response to consultation, the company compared ocrelizumab with beta interferons and glatiramer acetate separately. It also presented a scenario analysis in which it assumed that the efficacy of the beta interferons and glatiramer acetate were equivalent to the efficacy of interferon beta‑1a using data from OPERA I and II trials. The committee noted that, in the ongoing appraisal of beta interferons and glatiramer acetate for treating multiple sclerosis, it had concluded that the clinical effectiveness, but not the cost effectiveness, of the beta interferons and glatiramer acetate could be considered similar. Therefore, the committee concluded that it was appropriate to compare ocrelizumab with each individual treatment, to fully assess its cost effectiveness compared with current practice.
# Clinical evidence
## Patients in OPERA I and II represent those seen in NHS practice
The key evidence for the clinical effectiveness of ocrelizumab compared with interferon beta‑1a came from 2 trials, OPERA I (n=821) and OPERA II (n=835). These were phase III randomised controlled trials in adults with relapsing multiple sclerosis, with 2 or more relapses in the last 2 years or with 1 relapse in the last year. The trial included people 55 years or younger. The committee heard from clinical experts that this is common across similar trials and that only a few people over 55 years would likely have ocrelizumab. Further, the clinical experts did not expect the efficacy of ocrelizumab to vary with age, but could not rule out that it would be affected by age-related changes in the brain. The committee accepted that the baseline characteristics of the patients in OPERA I and II reflected people with multiple sclerosis treated in the NHS. It concluded that the results of the clinical trials were generalisable to NHS clinical practice.
## Ocrelizumab reduces relapses and slows disability progression compared with interferon beta‑1a
The committee noted that the annualised relapse rate in OPERA I and OPERA II was statistically significantly lower for ocrelizumab compared with interferon beta‑1a in both trials (see table 1). It also noted that fewer patients had confirmed disability progression at 3 months and 6 months for ocrelizumab compared with interferon beta‑1a, and that the difference was statistically significant (see table 1). The committee concluded that ocrelizumab reduces relapses and slows disability progression compared with interferon beta‑1a.
## Table 1 OPERA I and II annualised relapse rate and confirmed disability progression
Outcome
Ocrelizumab (600 mg)
Interferon beta‑1a (44 micrograms)
Annualised relapse rate at week 96 (OPERA I)
(95% CI 0.12 to 0.20)
(95% CI 0.24 to 0.36)
Annualised relapse rate at week 96 (OPERA II)
(95% CI 0.12 to 0.20)
(95% CI 0.23 to 0.36)
Confirmed disability progression at 3 months- (pooled analysis OPERA I and OPERA II)
(95% CI 7.6 to 11.9)
(95% CI 12.6 to 17.8)
Confirmed disability progression at 6 months- (pooled analysis OPERA I and OPERA II)
(95% CI 5.7 to 9.5)
(95% CI 9.6 to 14.4)
Abbreviations: CI, confidence interval.
*Kaplan–Meier estimate for the proportion of patients with the outcomes specified in the table, 96 weeks from the start of trial.
## Open-label extension data show sustained efficacy of ocrelizumab over 4 years
Patients from both the ocrelizumab and interferon beta‑1a arms of the OPERA I and II trials could enter into an open-label extension study if they had completed 96 weeks of treatment. This study included 80% of the patients from the randomised controlled trials. A total of 4 years of data were therefore available on the safety and efficacy of ocrelizumab. The results of the open-label extension study showed that the effect on the annualised relapse rate was sustained for patients taking ocrelizumab into the third and fourth years. The committee was concerned that the results might be susceptible to selection bias because:
% of patients had dropped out of the follow-on study by year 4
patients were eligible for the open-label extension study only if clinicians considered that they could benefit from further treatment with ocrelizumab.The company explained that most people dropped out of the study for reasons unrelated to the treatment. The committee noted the limitations of the data from the extension study because it was open label and there was no comparative treatment. It concluded that the treatment effect of ocrelizumab could be sustained over a 4‑year period for many but probably not all patients, and that there were no data beyond 4 years.
# Mixed treatment comparisons
## Ocrelizumab reduces relapses compared with most comparators in the whole relapsing–remitting multiple sclerosis population
Because the company provided direct comparative evidence only for interferon beta‑1a, it provided a network meta-analysis to estimate ocrelizumab's effectiveness compared with the relevant comparators (see section 3.4). The company chose 30 studies to inform its mixed treatment comparison for annualised relapse rates in the whole relapsing–remitting multiple sclerosis population. There was uncertainty in the results because most comparisons were informed by a single trial, and many of the comparators were indirectly compared with ocrelizumab by 1 or more intermediate comparator. However, the committee concluded that there was a lower annualised relapse rate for ocrelizumab in the whole population compared with all the comparators except alemtuzumab.
## The results of the jointly modelled outcomes for continued disease progression at 3 months and 6 months are uncertain
The clinical experts explained that confirmed disability progression at 6 months is considered a more specific measure than at 3 months. This is because the time taken to recover from a relapse varies and people may recover from a relapse after 3 months. However, the committee acknowledged that it was more common for clinical trials to pre-specify confirmed disability progression sustained for 3 months. It heard that there were fewer data for the outcome at 6 months. The committee considered that joint modelling of outcomes at 3 and 6 months could be done using data from trials that report confirmed disability progression both at 3 and 6 months, and that this could be used to infer missing 6‑month data. In response to consultation, the company provided new mixed treatment comparisons for the outcome of confirmed disability progression using 2 different models, both made use of the 3- and 6‑month data. Model 1 used 3‑month data when 6‑month data was not available. Model 2 modelled outcomes at 3 and 6 months to infer missing data. It then estimated the missing values based on this information. The company preferred to use results from model 1 because they underestimated the effectiveness of ocrelizumab compared with the results from model 2. Also, organisations such as Cochrane and the Institute for Clinical and Economic Review have used the model 1 method. The ERG explained that model 2 was a more complex approach, but was most likely to make the best use of the available data. The committee considered that both models had limitations: model 1 assumed that 3‑month data could be used as a proxy for 6‑month data; model 2 assumed a relationship between 3- and 6‑month data. However, the company had not explained the relationship that had been assumed in model 2 or whether the model fit had been assessed, so there was further uncertainty surrounding the results of this model. The committee concluded that the company's updated models, which made use of 3- and 6‑month data, were preferred to its previous approach using 3‑month data only, and that the results of models 1 and 2 could be used for decision-making.
## Ocrelizumab slows disability progression in the whole relapsing–remitting multiple sclerosis population compared with some treatments
The point estimates of the updated mixed treatment comparison (models 1 and 2) for confirmed disability progression generally improved in favour of ocrelizumab compared with the company's original base-case mixed treatment comparison. The confidence intervals also narrowed, but the committee heard from the ERG that the uncertainty of the implementation of the models meant that all of the uncertainty might not be captured in the confidence intervals. In the whole population of relapsing–remitting multiple sclerosis for both models, disease progression was statistically significantly slower with ocrelizumab than with most comparators. There were more statistically significant differences between ocrelizumab and comparators in model 2 (interferon beta‑1a, interferon beta‑1b, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod) than in model 1 (interferon beta‑1a, interferon beta‑1b, glatiramer acetate, teriflunomide) for confirmed disability progression at 6 months. The committee noted that pegylated interferon beta‑1a appeared to be an outlier in the updated mixed treatment comparisons because it appeared to be more effective than other beta interferons and high-efficacy treatments such as natalizumab. The committee heard that this was contrary to clinical experience, so it disregarded the comparison with pegylated interferon for this appraisal. The committee concluded that ocrelizumab slowed disability progression in the whole relapsing–remitting multiple sclerosis population compared with interferon beta-1a, interferon beta‑1b, glatiramer acetate and teriflunomide, but not compared with some other treatments.
## The mixed treatment comparison results are highly uncertain in the highly active and rapidly evolving severe subgroups
The ERG urged caution when interpreting the results of the subgroup analyses and explained that the company's updated mixed treatment analyses had not resolved the existing uncertainties. This was because data for the subgroups were not available for all comparators in the network and, when not available, data for the whole relapsing–remitting multiple sclerosis population were used. The ERG explained that the network assumed that the treatment effect was the same in the whole relapsing–remitting population as the subgroup populations. The mixed treatment comparison showed a statistically significant reduction in relapses in the highly active subgroup for ocrelizumab compared with fingolimod. However, the differences in annualised relapse rate for ocrelizumab compared with all other comparators were not statistically significant in the subgroup analyses. The committee concluded that it was uncertain whether ocrelizumab reduced relapses or slowed disability progression compared with alemtuzumab, fingolimod and natalizumab in highly active and rapidly evolving severe multiple sclerosis.
# Adverse events
## Adverse events with ocrelizumab are less frequent than with other high-efficacy treatments
In the OPERA I and II trials, infusion-related reactions, upper respiratory tract infections and nasopharyngitis were more common in patients having ocrelizumab than in patients having interferon beta‑1a. Other adverse events were similar across the 2 treatment arms. Clinical experts considered that the risk of progressive multifocal leukoencephalopathy (PML) from treatment with ocrelizumab cannot be ruled out because it has been seen with other anti‑CD20 antibodies, but they explained it is likely to be much lower than the risk from natalizumab. However, the length of follow-up in the OPERA I and II trials is not yet long enough to assume that there is no risk of PML. The committee heard that up to one-third of patients having alemtuzumab experience autoimmune diseases such as thyroid diseases, so monitoring is needed for 48 months after stopping treatment. It also heard that, in the OPERA trials, the number of cases of breast cancer reported was higher for patients having ocrelizumab than for interferon beta‑1a. However, the number of cases in the ocrelizumab arm were low and there was no statistically significant difference between the rate of breast cancer for patients having ocrelizumab compared with the general population. The company explained that this safety concern was part of its pharmacovigilance programme and that a post-authorisation safety study was investigating the risk of breast cancer in patients having ocrelizumab. The patient experts explained that, in their experience, adverse events such as fatigue and ability to concentrate experienced with other treatments, such as beta interferons, do not occur with ocrelizumab. The committee concluded that the adverse events were likely to be less frequent with ocrelizumab than with other similar therapies, including alemtuzumab.
# The company's economic model
## The model structure and ERG corrections are appropriate
The company's economic model structure was based on advancing disability (Expanded Disability Status Scale states) but included disutility for relapses and carers. The committee was aware that patients accrued quality-adjusted life years (QALYs) mainly by gaining quality of life from delayed disability, but also gained life years by delayed progression to higher EDSS states associated with higher rates of dying. The committee knew that the model did not capture sequences of treatments. It noted that the company's model was similar to models used in previous NICE technology appraisal guidance. It was aware that the ERG had made a small correction to the model and increased the number of decimal places for the annualised relapse rate to increase precision. The committee accepted this correction. It also accepted the structure of the company's economic model and concluded that it was appropriate for decision-making.
# Health-state costs
## The UK MS Survey is the most appropriate source for EDSS health-state costs
The committee discussed the annual costs associated with each EDSS health state in the model. In response to consultation, the company used EDSS health-state costs from the UK MS Survey data (2015/16); previously, the company had used costs from Tyas et al. (2007). The committee noted that both sources were associated with uncertainty and that the UK MS Survey costs had been used in previous NICE technology appraisal guidance (beta interferons, dimethyl fumarate, fingolimod, glatiramer acetate and natalizumab). The committee concluded that both could be considered suitable for decision-making. It concluded further that, because it had preferred the UK MS Survey as the source of EDSS state costs in previous appraisals, it preferred to use this source for decision-making in this appraisal.
# Utility values
## Utilities for patients with rapidly evolving severe disease might be overestimated in the economic model
The company assumed that quality of life was the same for patients in the whole relapsing–remitting population as for patients in the highly active disease and rapidly evolving severe disease subgroups. The clinical experts explained that it is unlikely that quality of life for people with rapidly evolving severe disease, which is characterised by a high frequency of relapses, would be the same as quality of life for people with relapsing–remitting multiple sclerosis. The committee was aware that a disutility was applied in the economic model for relapses. However, this may have overestimated quality of life for people with rapidly evolving severe disease. It concluded that the company's economic model likely overestimated utilities for patients with rapidly evolving severe disease.
# Disability progression
## Improvements in disability reflect the natural history of treated disease
The committee noted that benefits to patients in the model were derived from treatment slowing progression to more advanced states of disability (as measured by EDSS). It also noted that the economic model allowed patients' disability to improve at the same rate for ocrelizumab and all comparators. The committee considered whether newer treatments are more likely to improve EDSS than older treatments. It heard from patient experts that, in their experience, treatment with ocrelizumab improves persisting symptoms following relapses on earlier treatments. The clinical experts stated that it was reasonable that ocrelizumab might improve EDSS state more than other treatments, particularly in patients having severe relapses. The committee concluded that the effectiveness of ocrelizumab to improve EDSS had potentially been underestimated in the company's model.
# Adverse events in the economic model
## PML is a possible adverse event with ocrelizumab
In response to consultation, the company included PML as an adverse event for ocrelizumab in their economic model at an annual rate of 0.00028%, based on global safety data for people having rituximab. The company explained that worldwide data gathered in over 40,000 patients having ocrelizumab shows that there have been 3 cases of PML after treatment with ocrelizumab. However, all 3 cases have been causally attributed to previous treatments because PML had been misdiagnosed as increasing disease activity before the patients switched treatment. The committee recalled its earlier conclusion that the risk of PML with ocrelizumab cannot be ruled out (see section 3.13). It noted that the ERG had done 2 scenario analyses, varying the risk of PML for ocrelizumab to 1.0% and 2.1%. These analyses increased the incremental cost-effectiveness ratios (ICERs) slightly. The committee concluded that there is a risk of PML after treatment with ocrelizumab, and that the company's updated economic model using data based on rituximab could be accepted for decision-making.
# Waning of treatment efficacy
## Treatment efficacy is likely to wane over time with ocrelizumab
The company assumed in its base case that the treatment effect with ocrelizumab and all comparators did not wane over time. The company explained that, in its view, even though treatment waning had been assumed in previous appraisals, there was no evidence to support this. The company presented data from its follow-on study (see section 3.8) showing no waning in the frequency of relapses after up to 4 years. The company went on to explain that treatment waning for ocrelizumab is unlikely since a pooled analysis in the OPERA I and II trials found that a low proportion of patients having ocrelizumab had expression of anti-drug antibodies against ocrelizumab (0.4%) compared with patients having interferon beta‑1a with anti-drug antibodies against interferon beta‑1a (21.3%). However, the company was unable to provide the committee with evidence of an association between the presence of antibodies and treatment efficacy. The clinical experts explained that they would expect the efficacy of most treatments for multiple sclerosis to wane over time, either because the immune system develops neutralising antibodies that may prevent the treatment from working, or because the disease worsens. The committee concluded that the treatment effect of ocrelizumab was likely to wane in the long term.
# Stopping treatment
## Stopping treatment can be considered a proxy for treatment waning
The company explained that another reason it had not included treatment waning for ocrelizumab and comparators was because, in clinical practice, the patient is likely to switch to another treatment if the treatment they are having is no longer effective. The committee was aware that the company did not include treatment switching in the model. The ERG explained that the company's model assumed that treatment stops after patients progress to an EDSS state higher than 6 because this reflects NHS clinical practice (see section 3.2). The model also included an annual treatment discontinuation rate taken from the mixed treatment comparison for ocrelizumab and each comparator (see table 2). The committee considered that a large proportion of patients who stop treatment are likely to do so because treatment effectiveness reduces over time and as the disease progresses. It considered therefore that stopping treatment could be a proxy for waning, but that some patients having ocrelizumab may continue treatment despite a waning effect if there are no better treatment options. The committee also noted that treatment might be stopped because of its adverse effects, so stopping treatment could reflect this rather than a lack of effectiveness. However, it noted that most patients having alemtuzumab have only up to 2 doses, so stopping treatment for the above reasons is difficult to assess. It recognised that these factors meant that, in the economic model, the difference in waning of effect between treatments may have been underestimated. The committee concluded that the rate of stopping treatments could have acted as a proxy to account for treatment waning in the absence of evidence for a waning effect for ocrelizumab after 4 years.
## Table 2 Annual probability of stopping treatment
Disease-modifying treatment
All-cause discontinuation (%)
Pegylated interferon beta‑1a
Interferon beta‑1a (Rebif)
Interferon beta‑1a (Avonex)
Teriflunomide
Dimethyl fumarate
Glatiramer acetate
Fingolimod
Ocrelizumab
Interferon beta‑1b (Betaferon)
Alemtuzumab
Natalizumab
# Cost-effectiveness estimates
## Ocrelizumab is a cost-effective use of NHS resources in the whole relapsing–remitting multiple sclerosis population
The committee's preferred assumptions were:
using mixed treatment comparison estimates for confirmed disability progression that made use of the and 3- and 6‑month data (see section 3.10)
including the risk of PML for ocrelizumab (see section 3.18)
provide cost-effectiveness estimates for each beta interferon and glatiramer acetate compared with ocrelizumab (see section 3.5)
using UK MS Survey as the source of EDSS costs (see section 3.15)
using treatment stopping rates for ocrelizumab and all comparators from the mixed treatment comparison (see table 2) in the absence of evidence for a treatment waning effect (see section 3.20).Using these assumptions, the most plausible ICERs were below £30,000 per QALY gained in the relapsing–remitting multiple sclerosis population compared with all relevant comparators, apart from alemtuzumab, which dominated all comparisons, and pegylated interferon beta‑1a. For pegylated interferon beta‑1a, the ICER was above £30,000 per QALY gained using confirmed disability estimates from model 2 and above £50,000 per QALY gained using model 1. However, the committee had agreed that data for pegylated interferon beta‑1a were outliers in the network meta analyses (see section 3.11). Therefore, the committee concluded that ocrelizumab could be considered a cost-effective use of NHS resources in the whole relapsing–remitting multiple sclerosis population, if alemtuzumab is contraindicated or otherwise unsuitable.
## Despite uncertainty, ocrelizumab can be considered cost effective for treating highly active and rapidly evolving severe multiple sclerosis
The committee recalled its earlier conclusion that the clinical effectiveness of ocrelizumab in the rapidly evolving severe and the highly active subgroups was uncertain (see section 3.12). In the rapidly evolving severe subgroup, ocrelizumab was cheaper and less effective than natalizumab. The most plausible ICER for ocrelizumab compared with natalizumab was about £350,000 saved per QALY lost when using model 2 for confirmed disability progression estimates, and about £125,000 saved per QALY lost when using model 1. However, the committee considered that it was uncertain whether a QALY loss or gain would be seen and that ocrelizumab had the potential to be more effective than natalizumab. The ICERs for ocrelizumab compared with fingolimod included the commercial arrangement for the drugs. These ICERs are confidential and the exact values cannot be reported here. In the highly active subgroup, the most plausible ICER for ocrelizumab compared with fingolimod was below £20,000 per QALY gained. The committee concluded that, although there was a lot of uncertainty in the clinical-effectiveness data, the ICERs generated by the economic model for treating highly active and rapidly evolving severe multiple sclerosis represented a cost-effective use of NHS resources.
# Innovation
## Innovation is adequately captured in the economic model for ocrelizumab
The committee was aware that this is not the first treatment directed at the B‑lymphocyte antigen CD20 for multiple sclerosis. However, it is the first B‑lymphocyte antigen CD20 to be licensed for the whole relapsing–remitting multiple sclerosis population. It heard from clinical experts that they considered it to have a better safety profile than some other high-efficacy treatments, so people with relapsing–remitting multiple sclerosis would need less frequent monitoring compared with other treatments such as alemtuzumab. It also has a low frequency of infusions, which people with relapsing–remitting multiple sclerosis value. Further, it appears to delay progression to secondary progressive multiple sclerosis. The committee recognised that some benefits relating to improvements in EDSS may not have been adequately captured in the modelling. However, it concluded that innovation for ocrelizumab's dosing, efficacy and safety profile had been adequately captured in the economic model.
|
{'Recommendations': 'Ocrelizumab is recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features, only if:\n\nalemtuzumab is contraindicated or otherwise unsuitable and\n\nthe company provides ocrelizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with ocrelizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent NHS treatments for relapsing–remitting multiple sclerosis include alemtuzumab, beta interferons, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab and teriflunomide.\n\nClinical trial results show that ocrelizumab reduces the number of relapses and slows disability progression compared with interferon beta‑1a for people with relapsing–remitting multiple sclerosis. There is no evidence directly comparing ocrelizumab with other treatments. Indirect analyses suggest that ocrelizumab reduces the number of relapses compared with interferon beta‑1b, glatiramer acetate, dimethyl fumarate, fingolimod and teriflunomide, and is as effective as alemtuzumab and natalizumab. These analyses suggest that ocrelizumab slows disease progression in the total relapsing–remitting multiple sclerosis population compared with some treatments but not others. Also, it is uncertain whether ocrelizumab slows disease progression in the subgroups of highly active and rapidly evolving severe disease.\n\nThe most plausible cost-effectiveness estimates for ocrelizumab compared with most relevant comparators are in the range that NICE normally considers an acceptable use of NHS resources. However, because it is more costly than alemtuzumab, ocrelizumab can only be recommended as an option for treating relapsing–remitting multiple sclerosis in adults with active disease defined by clinical or imaging features if alemtuzumab is contraindicated or otherwise unsuitable.', 'Information about ocrelizumab': "Marketing authorisation indication\n\nOcrelizumab (Ocrevus, Roche) has a marketing authorisation in the UK 'for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features'.\n\nDosage in the marketing authorisation\n\nOcrelizumab is administered by intravenous infusion. The first dose is administered as 2×300\xa0mg infusions 2\xa0weeks apart; subsequent doses are administered as a single 600\xa0mg infusion every 6\xa0months. A minimum interval of 5\xa0months should be maintained between each dose.\n\nPrice\n\nThe list price for ocrelizumab is £4,790 per 300‑mg vial (company submission).\n\nThe company has a commercial arrangement. This makes ocrelizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition and current treatment pathway\n\n## Patients would value a treatment with less frequent dosing or monitoring\n\nThe clinical and patient experts stated that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that symptoms of relapsing–remitting multiple sclerosis and the adverse effects from treatment can limit people's ability to work, and to engage in social and family life. The dosing frequency and monitoring needs of some treatments can disrupt people's lives and careers. The committee noted that ocrelizumab is given as an infusion during an outpatient appointment once every 6\xa0months and less frequent monitoring for adverse effects is needed than with some other treatments. It heard that a treatment administered once every 6\xa0months, with fewer adverse effects and monitoring needs than other treatments, would be less disruptive and so be valued by patients.\n\n## Ocrelizumab could be used first line or after prior therapy\n\nThe clinical experts explained that multiple sclerosis can be unpredictable in the early stages of disease and there is often a period of observation before starting treatment. Many patients start treatment with a first-line treatment such as beta interferon, glatiramer acetate, dimethyl fumarate or teriflunomide before moving on to other therapies if the disease stops responding or if adverse effects occur. Other patients, particularly those with frequent or severe relapses, start treatment with a more effective therapy such as alemtuzumab; some clinicians offer rituximab but this is not routine practice in the UK. The committee heard that ocrelizumab would be offered to patients as a first-line therapy in those being considered for, but unable to tolerate the side effects of, alemtuzumab, or offered to patients after prior therapy. Clinical experts also noted that there are no clear rules for sequencing of treatments or for stopping therapy. However, in practice, clinicians would generally stop all treatments when patients can no longer walk or when their disease moves to secondary progressive multiple sclerosis.\n\n## Patient preference is an important consideration when making shared decisions about treatment\n\nThe committee discussed the factors that may influence patients' choice of treatment. It was aware that the various treatment options available have different methods and schedules of administration, and noted that people will have different preferences. The committee was aware that careful monitoring is needed after treatment with alemtuzumab; consultation comments from patients groups highlighted that some people do not want to have alemtuzumab because of concerns about adverse effects and monitoring needs. It noted these comments but also considered that alemtuzumab's dosing schedule and mode of action may appeal to other patients. The committee concluded that differences in dosing schedule, adverse effects and monitoring between ocrelizumab and alemtuzumab may influence patient choice, and that it is important to take this into account when making decisions about treatment.\n\n# Comparators\n\n## Alemtuzumab, beta interferons, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab and teriflunomide are relevant comparators\n\nThe company limited its submission to relapsing–remitting multiple sclerosis rather than relapsing forms of multiple sclerosis, as specified in its marketing authorisation. When discussing relevant comparators used in current NHS practice in England, the clinical experts stated that it was appropriate to exclude best supportive care because patients having ocrelizumab would be fit enough to have other therapies. The committee noted that daclizumab was recently withdrawn from the UK market because of safety concerns, so was no longer a relevant comparator. It was also aware that cladribine had recently been recommended by NICE for adults with highly active relapsing multiple sclerosis. The clinical experts stated that this would be a relevant comparator for ocrelizumab, but noted that NICE recommended cladribine after the appraisal for ocrelizumab had started. The committee concluded that the relevant comparators were alemtuzumab, beta interferons, dimethyl fumarate, fingolimod (for highly active disease), glatiramer acetate, natalizumab (rapidly evolving severe disease) and teriflunomide.\n\n## Individual comparisons of ocrelizumab with beta interferons and glatiramer acetate are appropriate\n\nIn response to consultation, the company compared ocrelizumab with beta interferons and glatiramer acetate separately. It also presented a scenario analysis in which it assumed that the efficacy of the beta interferons and glatiramer acetate were equivalent to the efficacy of interferon beta‑1a using data from OPERA\xa0I and\xa0II trials. The committee noted that, in the ongoing appraisal of beta interferons and glatiramer acetate for treating multiple sclerosis, it had concluded that the clinical effectiveness, but not the cost effectiveness, of the beta interferons and glatiramer acetate could be considered similar. Therefore, the committee concluded that it was appropriate to compare ocrelizumab with each individual treatment, to fully assess its cost effectiveness compared with current practice.\n\n# Clinical evidence\n\n## Patients in OPERA\xa0I and\xa0II represent those seen in NHS practice\n\nThe key evidence for the clinical effectiveness of ocrelizumab compared with interferon beta‑1a came from 2\xa0trials, OPERA\xa0I (n=821) and OPERA\xa0II (n=835). These were phase\xa0III randomised controlled trials in adults with relapsing multiple sclerosis, with 2\xa0or more relapses in the last 2\xa0years or with 1\xa0relapse in the last year. The trial included people 55\xa0years or younger. The committee heard from clinical experts that this is common across similar trials and that only a few people over 55\xa0years would likely have ocrelizumab. Further, the clinical experts did not expect the efficacy of ocrelizumab to vary with age, but could not rule out that it would be affected by age-related changes in the brain. The committee accepted that the baseline characteristics of the patients in OPERA\xa0I and\xa0II reflected people with multiple sclerosis treated in the NHS. It concluded that the results of the clinical trials were generalisable to NHS clinical practice.\n\n## Ocrelizumab reduces relapses and slows disability progression compared with interferon beta‑1a\n\nThe committee noted that the annualised relapse rate in OPERA\xa0I and OPERA\xa0II was statistically significantly lower for ocrelizumab compared with interferon beta‑1a in both trials (see table\xa01). It also noted that fewer patients had confirmed disability progression at 3\xa0months and 6\xa0months for ocrelizumab compared with interferon beta‑1a, and that the difference was statistically significant (see table\xa01). The committee concluded that ocrelizumab reduces relapses and slows disability progression compared with interferon beta‑1a.\n\n## Table\xa01 OPERA\xa0I and\xa0II annualised relapse rate and confirmed disability progression\n\nOutcome\n\nOcrelizumab (600\xa0mg)\n\nInterferon beta‑1a (44\xa0micrograms)\n\nAnnualised relapse rate at week\xa096 (OPERA\xa0I)\n\n(95%\xa0CI 0.12 to 0.20)\n\n(95%\xa0CI 0.24 to 0.36)\n\nAnnualised relapse rate at week\xa096 (OPERA\xa0II)\n\n(95%\xa0CI 0.12 to 0.20)\n\n(95%\xa0CI 0.23 to 0.36)\n\nConfirmed disability progression at 3\xa0months* (pooled analysis OPERA\xa0I and OPERA\xa0II)\n\n(95%\xa0CI 7.6 to 11.9)\n\n(95%\xa0CI 12.6 to 17.8)\n\nConfirmed disability progression at 6\xa0months* (pooled analysis OPERA\xa0I and OPERA\xa0II)\n\n(95%\xa0CI 5.7 to 9.5)\n\n(95%\xa0CI 9.6 to 14.4)\n\nAbbreviations: CI, confidence interval.\n\n*Kaplan–Meier estimate for the proportion of patients with the outcomes specified in the table, 96\xa0weeks from the start of trial.\n\n## Open-label extension data show sustained efficacy of ocrelizumab over 4\xa0years\n\nPatients from both the ocrelizumab and interferon beta‑1a arms of the OPERA\xa0I and\xa0II trials could enter into an open-label extension study if they had completed 96\xa0weeks of treatment. This study included 80% of the patients from the randomised controlled trials. A total of 4\xa0years of data were therefore available on the safety and efficacy of ocrelizumab. The results of the open-label extension study showed that the effect on the annualised relapse rate was sustained for patients taking ocrelizumab into the third and fourth years. The committee was concerned that the results might be susceptible to selection bias because:\n\n% of patients had dropped out of the follow-on study by year\xa04\n\npatients were eligible for the open-label extension study only if clinicians considered that they could benefit from further treatment with ocrelizumab.The company explained that most people dropped out of the study for reasons unrelated to the treatment. The committee noted the limitations of the data from the extension study because it was open label and there was no comparative treatment. It concluded that the treatment effect of ocrelizumab could be sustained over a 4‑year period for many but probably not all patients, and that there were no data beyond 4\xa0years.\n\n# Mixed treatment comparisons\n\n## Ocrelizumab reduces relapses compared with most comparators in the whole relapsing–remitting multiple sclerosis population\n\nBecause the company provided direct comparative evidence only for interferon beta‑1a, it provided a network meta-analysis to estimate ocrelizumab's effectiveness compared with the relevant comparators (see section\xa03.4). The company chose 30\xa0studies to inform its mixed treatment comparison for annualised relapse rates in the whole relapsing–remitting multiple sclerosis population. There was uncertainty in the results because most comparisons were informed by a single trial, and many of the comparators were indirectly compared with ocrelizumab by 1\xa0or more intermediate comparator. However, the committee concluded that there was a lower annualised relapse rate for ocrelizumab in the whole population compared with all the comparators except alemtuzumab.\n\n## The results of the jointly modelled outcomes for continued disease progression at 3\xa0months and 6\xa0months are uncertain\n\nThe clinical experts explained that confirmed disability progression at 6\xa0months is considered a more specific measure than at 3\xa0months. This is because the time taken to recover from a relapse varies and people may recover from a relapse after 3\xa0months. However, the committee acknowledged that it was more common for clinical trials to pre-specify confirmed disability progression sustained for 3\xa0months. It heard that there were fewer data for the outcome at 6\xa0months. The committee considered that joint modelling of outcomes at 3\xa0and 6\xa0months could be done using data from trials that report confirmed disability progression both at 3\xa0and 6\xa0months, and that this could be used to infer missing 6‑month data. In response to consultation, the company provided new mixed treatment comparisons for the outcome of confirmed disability progression using 2\xa0different models, both made use of the 3- and 6‑month data. Model\xa01 used 3‑month data when 6‑month data was not available. Model\xa02 modelled outcomes at 3\xa0and 6\xa0months to infer missing data. It then estimated the missing values based on this information. The company preferred to use results from model\xa01 because they underestimated the effectiveness of ocrelizumab compared with the results from model\xa02. Also, organisations such as Cochrane and the Institute for Clinical and Economic Review have used the model\xa01 method. The ERG explained that model\xa02 was a more complex approach, but was most likely to make the best use of the available data. The committee considered that both models had limitations: model\xa01 assumed that 3‑month data could be used as a proxy for 6‑month data; model\xa02 assumed a relationship between 3- and 6‑month data. However, the company had not explained the relationship that had been assumed in model\xa02 or whether the model fit had been assessed, so there was further uncertainty surrounding the results of this model. The committee concluded that the company's updated models, which made use of 3- and 6‑month data, were preferred to its previous approach using 3‑month data only, and that the results of models\xa01 and\xa02 could be used for decision-making.\n\n## Ocrelizumab slows disability progression in the whole relapsing–remitting multiple sclerosis population compared with some treatments\n\nThe point estimates of the updated mixed treatment comparison (models\xa01 and\xa02) for confirmed disability progression generally improved in favour of ocrelizumab compared with the company's original base-case mixed treatment comparison. The confidence intervals also narrowed, but the committee heard from the ERG that the uncertainty of the implementation of the models meant that all of the uncertainty might not be captured in the confidence intervals. In the whole population of relapsing–remitting multiple sclerosis for both models, disease progression was statistically significantly slower with ocrelizumab than with most comparators. There were more statistically significant differences between ocrelizumab and comparators in model\xa02 (interferon beta‑1a, interferon beta‑1b, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod) than in model\xa01 (interferon beta‑1a, interferon beta‑1b, glatiramer acetate, teriflunomide) for confirmed disability progression at 6\xa0months. The committee noted that pegylated interferon beta‑1a appeared to be an outlier in the updated mixed treatment comparisons because it appeared to be more effective than other beta interferons and high-efficacy treatments such as natalizumab. The committee heard that this was contrary to clinical experience, so it disregarded the comparison with pegylated interferon for this appraisal. The committee concluded that ocrelizumab slowed disability progression in the whole relapsing–remitting multiple sclerosis population compared with interferon beta-1a, interferon beta‑1b, glatiramer acetate and teriflunomide, but not compared with some other treatments.\n\n## The mixed treatment comparison results are highly uncertain in the highly active and rapidly evolving severe subgroups\n\nThe ERG urged caution when interpreting the results of the subgroup analyses and explained that the company's updated mixed treatment analyses had not resolved the existing uncertainties. This was because data for the subgroups were not available for all comparators in the network and, when not available, data for the whole relapsing–remitting multiple sclerosis population were used. The ERG explained that the network assumed that the treatment effect was the same in the whole relapsing–remitting population as the subgroup populations. The mixed treatment comparison showed a statistically significant reduction in relapses in the highly active subgroup for ocrelizumab compared with fingolimod. However, the differences in annualised relapse rate for ocrelizumab compared with all other comparators were not statistically significant in the subgroup analyses. The committee concluded that it was uncertain whether ocrelizumab reduced relapses or slowed disability progression compared with alemtuzumab, fingolimod and natalizumab in highly active and rapidly evolving severe multiple sclerosis.\n\n# Adverse events\n\n## Adverse events with ocrelizumab are less frequent than with other high-efficacy treatments\n\nIn the OPERA\xa0I and\xa0II trials, infusion-related reactions, upper respiratory tract infections and nasopharyngitis were more common in patients having ocrelizumab than in patients having interferon beta‑1a. Other adverse events were similar across the 2\xa0treatment arms. Clinical experts considered that the risk of progressive multifocal leukoencephalopathy (PML) from treatment with ocrelizumab cannot be ruled out because it has been seen with other anti‑CD20 antibodies, but they explained it is likely to be much lower than the risk from natalizumab. However, the length of follow-up in the OPERA\xa0I and\xa0II trials is not yet long enough to assume that there is no risk of PML. The committee heard that up to one-third of patients having alemtuzumab experience autoimmune diseases such as thyroid diseases, so monitoring is needed for 48\xa0months after stopping treatment. It also heard that, in the OPERA trials, the number of cases of breast cancer reported was higher for patients having ocrelizumab than for interferon beta‑1a. However, the number of cases in the ocrelizumab arm were low and there was no statistically significant difference between the rate of breast cancer for patients having ocrelizumab compared with the general population. The company explained that this safety concern was part of its pharmacovigilance programme and that a post-authorisation safety study was investigating the risk of breast cancer in patients having ocrelizumab. The patient experts explained that, in their experience, adverse events such as fatigue and ability to concentrate experienced with other treatments, such as beta interferons, do not occur with ocrelizumab. The committee concluded that the adverse events were likely to be less frequent with ocrelizumab than with other similar therapies, including alemtuzumab.\n\n# The company's economic model\n\n## The model structure and ERG corrections are appropriate\n\nThe company's economic model structure was based on advancing disability (Expanded Disability Status Scale [EDSS] states) but included disutility for relapses and carers. The committee was aware that patients accrued quality-adjusted life years (QALYs) mainly by gaining quality of life from delayed disability, but also gained life years by delayed progression to higher EDSS states associated with higher rates of dying. The committee knew that the model did not capture sequences of treatments. It noted that the company's model was similar to models used in previous NICE technology appraisal guidance. It was aware that the ERG had made a small correction to the model and increased the number of decimal places for the annualised relapse rate to increase precision. The committee accepted this correction. It also accepted the structure of the company's economic model and concluded that it was appropriate for decision-making.\n\n# Health-state costs\n\n## The UK MS Survey is the most appropriate source for EDSS health-state costs\n\nThe committee discussed the annual costs associated with each EDSS health state in the model. In response to consultation, the company used EDSS health-state costs from the UK MS Survey data (2015/16); previously, the company had used costs from Tyas et al. (2007). The committee noted that both sources were associated with uncertainty and that the UK MS Survey costs had been used in previous NICE technology appraisal guidance (beta interferons, dimethyl fumarate, fingolimod, glatiramer acetate and natalizumab). The committee concluded that both could be considered suitable for decision-making. It concluded further that, because it had preferred the UK MS Survey as the source of EDSS state costs in previous appraisals, it preferred to use this source for decision-making in this appraisal.\n\n# Utility values\n\n## Utilities for patients with rapidly evolving severe disease might be overestimated in the economic model\n\nThe company assumed that quality of life was the same for patients in the whole relapsing–remitting population as for patients in the highly active disease and rapidly evolving severe disease subgroups. The clinical experts explained that it is unlikely that quality of life for people with rapidly evolving severe disease, which is characterised by a high frequency of relapses, would be the same as quality of life for people with relapsing–remitting multiple sclerosis. The committee was aware that a disutility was applied in the economic model for relapses. However, this may have overestimated quality of life for people with rapidly evolving severe disease. It concluded that the company's economic model likely overestimated utilities for patients with rapidly evolving severe disease.\n\n# Disability progression\n\n## Improvements in disability reflect the natural history of treated disease\n\nThe committee noted that benefits to patients in the model were derived from treatment slowing progression to more advanced states of disability (as measured by EDSS). It also noted that the economic model allowed patients' disability to improve at the same rate for ocrelizumab and all comparators. The committee considered whether newer treatments are more likely to improve EDSS than older treatments. It heard from patient experts that, in their experience, treatment with ocrelizumab improves persisting symptoms following relapses on earlier treatments. The clinical experts stated that it was reasonable that ocrelizumab might improve EDSS state more than other treatments, particularly in patients having severe relapses. The committee concluded that the effectiveness of ocrelizumab to improve EDSS had potentially been underestimated in the company's model.\n\n# Adverse events in the economic model\n\n## PML is a possible adverse event with ocrelizumab\n\nIn response to consultation, the company included PML as an adverse event for ocrelizumab in their economic model at an annual rate of 0.00028%, based on global safety data for people having rituximab. The company explained that worldwide data gathered in over 40,000\xa0patients having ocrelizumab shows that there have been 3\xa0cases of PML after treatment with ocrelizumab. However, all 3\xa0cases have been causally attributed to previous treatments because PML had been misdiagnosed as increasing disease activity before the patients switched treatment. The committee recalled its earlier conclusion that the risk of PML with ocrelizumab cannot be ruled out (see section\xa03.13). It noted that the ERG had done 2\xa0scenario analyses, varying the risk of PML for ocrelizumab to 1.0% and 2.1%. These analyses increased the incremental cost-effectiveness ratios (ICERs) slightly. The committee concluded that there is a risk of PML after treatment with ocrelizumab, and that the company's updated economic model using data based on rituximab could be accepted for decision-making.\n\n# Waning of treatment efficacy\n\n## Treatment efficacy is likely to wane over time with ocrelizumab\n\nThe company assumed in its base case that the treatment effect with ocrelizumab and all comparators did not wane over time. The company explained that, in its view, even though treatment waning had been assumed in previous appraisals, there was no evidence to support this. The company presented data from its follow-on study (see section\xa03.8) showing no waning in the frequency of relapses after up to 4\xa0years. The company went on to explain that treatment waning for ocrelizumab is unlikely since a pooled analysis in the OPERA\xa0I and\xa0II trials found that a low proportion of patients having ocrelizumab had expression of anti-drug antibodies against ocrelizumab (0.4%) compared with patients having interferon beta‑1a with anti-drug antibodies against interferon beta‑1a (21.3%). However, the company was unable to provide the committee with evidence of an association between the presence of antibodies and treatment efficacy. The clinical experts explained that they would expect the efficacy of most treatments for multiple sclerosis to wane over time, either because the immune system develops neutralising antibodies that may prevent the treatment from working, or because the disease worsens. The committee concluded that the treatment effect of ocrelizumab was likely to wane in the long term.\n\n# Stopping treatment\n\n## Stopping treatment can be considered a proxy for treatment waning\n\nThe company explained that another reason it had not included treatment waning for ocrelizumab and comparators was because, in clinical practice, the patient is likely to switch to another treatment if the treatment they are having is no longer effective. The committee was aware that the company did not include treatment switching in the model. The ERG explained that the company's model assumed that treatment stops after patients progress to an EDSS state higher than\xa06 because this reflects NHS clinical practice (see section\xa03.2). The model also included an annual treatment discontinuation rate taken from the mixed treatment comparison for ocrelizumab and each comparator (see table\xa02). The committee considered that a large proportion of patients who stop treatment are likely to do so because treatment effectiveness reduces over time and as the disease progresses. It considered therefore that stopping treatment could be a proxy for waning, but that some patients having ocrelizumab may continue treatment despite a waning effect if there are no better treatment options. The committee also noted that treatment might be stopped because of its adverse effects, so stopping treatment could reflect this rather than a lack of effectiveness. However, it noted that most patients having alemtuzumab have only up to 2\xa0doses, so stopping treatment for the above reasons is difficult to assess. It recognised that these factors meant that, in the economic model, the difference in waning of effect between treatments may have been underestimated. The committee concluded that the rate of stopping treatments could have acted as a proxy to account for treatment waning in the absence of evidence for a waning effect for ocrelizumab after 4\xa0years.\n\n## Table\xa02 Annual probability of stopping treatment\n\nDisease-modifying treatment\n\nAll-cause discontinuation (%)\n\nPegylated interferon beta‑1a\n\n\n\nInterferon beta‑1a (Rebif)\n\n\n\nInterferon beta‑1a (Avonex)\n\n\n\nTeriflunomide\n\n\n\nDimethyl fumarate\n\n\n\nGlatiramer acetate\n\n\n\nFingolimod\n\n\n\nOcrelizumab\n\n\n\nInterferon beta‑1b (Betaferon)\n\n\n\nAlemtuzumab\n\n\n\nNatalizumab\n\n\n\n# Cost-effectiveness estimates\n\n## Ocrelizumab is a cost-effective use of NHS resources in the whole relapsing–remitting multiple sclerosis population\n\nThe committee's preferred assumptions were:\n\nusing mixed treatment comparison estimates for confirmed disability progression that made use of the and 3- and 6‑month data (see section 3.10)\n\nincluding the risk of PML for ocrelizumab (see section 3.18)\n\nprovide cost-effectiveness estimates for each beta interferon and glatiramer acetate compared with ocrelizumab (see section 3.5)\n\nusing UK MS Survey as the source of EDSS costs (see section 3.15)\n\nusing treatment stopping rates for ocrelizumab and all comparators from the mixed treatment comparison (see table\xa02) in the absence of evidence for a treatment waning effect (see section 3.20).Using these assumptions, the most plausible ICERs were below £30,000 per QALY gained in the relapsing–remitting multiple sclerosis population compared with all relevant comparators, apart from alemtuzumab, which dominated all comparisons, and pegylated interferon beta‑1a. For pegylated interferon beta‑1a, the ICER was above £30,000 per QALY gained using confirmed disability estimates from model\xa02 and above £50,000 per QALY gained using model\xa01. However, the committee had agreed that data for pegylated interferon beta‑1a were outliers in the network meta analyses (see section 3.11). Therefore, the committee concluded that ocrelizumab could be considered a cost-effective use of NHS resources in the whole relapsing–remitting multiple sclerosis population, if alemtuzumab is contraindicated or otherwise unsuitable.\n\n## Despite uncertainty, ocrelizumab can be considered cost effective for treating highly active and rapidly evolving severe multiple sclerosis\n\nThe committee recalled its earlier conclusion that the clinical effectiveness of ocrelizumab in the rapidly evolving severe and the highly active subgroups was uncertain (see section 3.12). In the rapidly evolving severe subgroup, ocrelizumab was cheaper and less effective than natalizumab. The most plausible ICER for ocrelizumab compared with natalizumab was about £350,000 saved per QALY lost when using model\xa02 for confirmed disability progression estimates, and about £125,000 saved per QALY lost when using model\xa01. However, the committee considered that it was uncertain whether a QALY loss or gain would be seen and that ocrelizumab had the potential to be more effective than natalizumab. The ICERs for ocrelizumab compared with fingolimod included the commercial arrangement for the drugs. These ICERs are confidential and the exact values cannot be reported here. In the highly active subgroup, the most plausible ICER for ocrelizumab compared with fingolimod was below £20,000 per QALY gained. The committee concluded that, although there was a lot of uncertainty in the clinical-effectiveness data, the ICERs generated by the economic model for treating highly active and rapidly evolving severe multiple sclerosis represented a cost-effective use of NHS resources.\n\n# Innovation\n\n## Innovation is adequately captured in the economic model for ocrelizumab\n\nThe committee was aware that this is not the first treatment directed at the B‑lymphocyte antigen CD20 for multiple sclerosis. However, it is the first B‑lymphocyte antigen CD20 to be licensed for the whole relapsing–remitting multiple sclerosis population. It heard from clinical experts that they considered it to have a better safety profile than some other high-efficacy treatments, so people with relapsing–remitting multiple sclerosis would need less frequent monitoring compared with other treatments such as alemtuzumab. It also has a low frequency of infusions, which people with relapsing–remitting multiple sclerosis value. Further, it appears to delay progression to secondary progressive multiple sclerosis. The committee recognised that some benefits relating to improvements in EDSS may not have been adequately captured in the modelling. However, it concluded that innovation for ocrelizumab's dosing, efficacy and safety profile had been adequately captured in the economic model."}
|
https://www.nice.org.uk/guidance/ta533
|
Evidence-based recommendations on ocrelizumab (Ocrevus) for treating relapsing–remitting multiple sclerosis in adults.
|
7e2ada75727baf16e14de2bf5809a010834dd245
|
nice
|
Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer
|
Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer
Evidence-based recommendations on pembrolizumab (Keytruda) for untreated PD-L1-positive metastatic non-small-cell lung cancer in adults.
# Recommendation
Pembrolizumab is recommended as an option for untreated PD‑L1-positive metastatic non-small-cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 (with at least a 50% tumour proportion score) and have no epidermal growth factor receptor- or anaplastic lymphoma kinase-positive mutations, only if:
pembrolizumab is stopped at 2 years of uninterrupted treatment or earlier in the event of disease progression and
the company provides pembrolizumab according to the commercial access agreement.
Why the committee made this recommendation
People with untreated metastatic PD‑L1-positive NSCLC are usually offered platinum-based chemotherapy (docetaxel, gemcitabine, paclitaxel, vinorelbine or pemetrexed, with a platinum-based drug).
Clinical trial evidence shows that pembrolizumab increases the length of time people live by nearly 16 months compared with chemotherapy. Although there is uncertainty about the long-term treatment benefit of pembrolizumab after treatment is stopped, there was sufficient evidence of an important extension-to-life benefit in people with untreated stage 4 metastatic PD‑L1-positive NSCLC compared with standard care.
The most plausible cost-effectiveness estimate for pembrolizumab compared with chemotherapy is within the range NICE normally considers acceptable for an end-of-life treatment. Therefore it can be recommended as an option for untreated metastatic PD‑L1-positive (with at least a 50% tumour proportion score) NSCLC if treatment is stopped after 2 years.# Information about pembrolizumab
Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation for 'the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD‑L1 with at least a 50% tumour proportion score with no epidermal growth factor receptor or anaplastic lymphoma kinase-positive tumour mutations'.
Dosage in the marketing authorisation
mg every 3 weeks by intravenous infusion. The summary of product characteristics recommends treatment with pembrolizumab until disease progression or unacceptable toxicity.
Price
Pembrolizumab is available at a cost of £1,315.00 per 50‑mg vial (excluding VAT; British national formulary online, accessed March 2017).
The average cost of a course of treatment is £84,002 based on the list price.
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know the details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## Pembrolizumab is an important option for untreated metastatic PD‑L1-positive non-small-cell lung cancer
The clinical experts explained that people with untreated metastatic non-small-cell lung cancer (NSCLC) whose tumours express PD‑L1 with at least a 50% tumour proportion score and who have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)‑positive tumour mutations have limited treatment options. The committee understood that patients can be on treatment for a long time and this can cause unpleasant side effects. Symptoms such as breathlessness and cough are difficult to treat. The clinical experts explained that new treatments, which offer survival benefits with fewer side effects than standard care, are needed for this population. The patient experts explained that symptoms can be debilitating, so improving quality of life and even small extensions in length of life are of considerable importance to this patient group. The committee understood that pembrolizumab is generally well tolerated. It concluded that pembrolizumab is an important treatment option for people with untreated metastatic PD‑L1-positive NSCLC.
## PD‑L1 testing could be implemented as standard practice in the NHS
The committee noted that the marketing authorisation for pembrolizumab only covers people with untreated metastatic NSCLC if their tumour expresses PD‑L1 with at least a 50% tumour proportion score. The NHS England clinical lead stated that all lung cancer centres should be able to offer testing for PD‑L1 status. The clinical expert explained that testing involves an immunohistochemical assay and facilities for this are widely available in histopathology laboratories. However, they noted that PD‑L1 tests are complex to interpret and the standard time needed for assessment is 20 minutes. The committee concluded that PD‑L1 testing could be standardised quickly and, with training, implemented as standard clinical practice in the NHS.
## Pembrolizumab is an alternative to chemotherapy
The committee understood from the clinical experts that management of untreated metastatic PD‑L1-positive NSCLC in clinical practice is platinum-based combination chemotherapy (that is, cisplatin or carboplatin and either pemetrexed or gemcitabine). Docetaxel, gemcitabine, paclitaxel or vinorelbine alone (single-agent chemotherapy) is recommended for people who cannot tolerate combination therapy (NICE's guideline on lung cancer: diagnosis and management). NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC recommends pemetrexed with cisplatin for adenocarcinoma or large-cell carcinoma. Pemetrexed is also recommended as a maintenance treatment for locally advanced or metastatic non-squamous NSCLC in adults whose disease has not progressed after pemetrexed and cisplatin therapy (NICE's technology appraisal guidance on pemetrexed maintenance treatment for non-squamous NSCLC after pemetrexed and cisplatin), and after platinum-based chemotherapy plus gemcitabine, paclitaxel or docetaxel (NICE's technology appraisal guidance on pemetrexed for the maintenance treatment of NSCLC). The committee understood that pembrolizumab would be considered as an alternative to platinum-based combination therapy. The committee concluded that pembrolizumab was appropriately positioned in the clinical pathway as an option for people with untreated metastatic PD‑L1-positive NSCLC, that is, as an alternative to platinum-based combination chemotherapy.
# Clinical effectiveness
## The KEYNOTE-024 trial is generalisable to clinical practice in England
The clinical effectiveness evidence for pembrolizumab came from KEYNOTE‑024. This was an open-label phase 3 randomised controlled trial, comparing pembrolizumab with standard care. Standard care therapies included platinum-based combinations with either gemcitabine or paclitaxel, and a platinum-based combination with pemetrexed (with or without pemetrexed maintenance for non-squamous disease). The ERG explained that no evidence was available for single-agent chemotherapy and the clinical experts noted that it is mainly used as an option for previously treated disease. The clinical experts explained that although fewer patients in KEYNOTE‑024 had a pemetrexed-containing regimen than expected, they considered that the standard care treatments were likely to be the same as those used in clinical practice in England. The committee was aware that the inclusion criteria in KEYNOTE‑024 were that patients had untreated stage 4 metastatic PD‑L1-positive NSCLC (with tumours expressing at least 50% PD‑L1 and no EGFR- or ALK-positive mutations) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The NHS England clinical lead said that there were more people with an ECOG performance status of 0 in KEYNOTE‑024 than those who had pembrolizumab through the Cancer Drugs Fund. The clinical experts explained that although the proportion of patients with squamous disease was smaller than expected, and patients with stage 3 disease were not included, the overall population in KEYNOTE‑024 was comparable to the population seen in clinical practice in England. The committee therefore concluded that KEYNOTE‑024 was generalisable to clinical practice in England.
## Pembrolizumab offers 15 months more overall survival benefit than standard care
The committee was aware of the results from the final analysis of overall survival in KEYNOTE‑024. The median duration of follow‑up was 25.2 months; 14.9% of people remained on pembrolizumab compared with 1.3% on standard care. The committee noted that the intention-to-treat results (hazard ratio 0.63; 95% confidence interval 0.47 to 0.86) suggested a statistically significant survival benefit for pembrolizumab compared with standard care. Median overall survival was 30.0 months for people on pembrolizumab and 14.2 months for those on standard care. The committee was aware that the trial protocol allowed people to switch from the standard care arm to have immunotherapy treatment on disease progression. The trial's data and safety monitoring committee also recommended that KEYNOTE‑024 should be stopped at the second interim analysis to give patients in the standard care arm the opportunity to have pembrolizumab. The company considered that no adjustment to the results was needed to account for people switching from standard care to pembrolizumab because in NHS clinical practice, immunotherapy is now becoming standard treatment for disease that has progressed after chemotherapy. The committee agreed that no adjustment was needed to account for treatment switching in the trial. It concluded that, based on the trial data, there was sufficient evidence that pembrolizumab has an important extension-to-life benefit in people with untreated stage 4 metastatic PD‑L1-positive NSCLC compared with standard care.
## A 2-year treatment duration with pembrolizumab is clinically plausible
The committee was aware that the maximum possible treatment duration with pembrolizumab in KEYNOTE‑024 was 2 years (35 cycles). It noted that, despite this, the summary of product characteristics states that treatment should continue until disease progression or unacceptable toxicity. The ERG noted that no patients in the pembrolizumab arm had completed 2 years' therapy. The clinical experts explained that the best treatment duration with pembrolizumab was unknown. The clinical and patient experts stated that although pembrolizumab has low toxicity, long courses of intravenous infusions can be a burden to patients. They further agreed that stopping treatment at 2 years independent of disease status would be acceptable to patients. The committee noted comments from the NHS England clinical lead that benefits to patients may occur when the immune system responds sufficiently to the treatment against the cancer, and patients may not need continued treatment until disease progression. The NHS England clinical lead also stated that, if NHS trusts continue treatment beyond 2 years for individual patients, NHS England will not reimburse them for this non-commissioned use of the drug if NICE recommendations state that treatment should be stopped at 2 years. The committee concluded that limiting pembrolizumab treatment to 2 years was clinically plausible, but the best treatment duration was unknown.
# Cost effectiveness
## The company's economic model is appropriate for decision-making
The committee discussed the company's cost-effectiveness evidence and the ERG's review. It noted that the company's model included the agreed commercial access agreement discount for pembrolizumab and an estimated discount for pemetrexed. The committee accepted the structure of the company's economic model and considered it appropriate for decision-making.
## Including a 2-year stopping rule in line with the clinical trial is appropriate
The committee discussed the assumption in the company's model that at 2 years, all patients, including patients whose disease had not progressed, would stop treatment. It understood that this assumption was based on the KEYNOTE‑024 protocol. The committee recalled its conclusion that limiting pembrolizumab treatment to 2 years is clinically plausible, and that patient and clinical experts agreed that stopping treatment at 2 years independent of disease status would be acceptable to patients (see section 3.6). The committee concluded that implementing a 2‑year stopping rule in the model was appropriate.
## The different time points for extrapolating overall survival are equally plausible
The committee noted that in the company's sensitivity analyses, the most influential parameter in the cost-effectiveness analysis was the extrapolation of overall survival in the pembrolizumab and standard care arms. To estimate overall survival, the company's base-case analysis used 33‑week Kaplan–Meier data from KEYNOTE‑024. After 33 weeks, the company fitted separate exponential models to the data. The company's base-case incremental cost-effectiveness ratio (ICER) using this approach was £30,244 per quality-adjusted life year (QALY) gained. In scenario analyses the company explored alternative time points to extrapolate the trial data; 23 and 43 weeks of Kaplan–Meier data. Both these analyses increased the company's base-case ICER; to £31,321 per QALY gained for the 23‑week time point and £33,829 per QALY gained for the 43‑week time point. The committee noted the ERG's scenario analyses, which suggested that the 43‑week point was a better visual fit for the data. The committee agreed that the time at which the distribution is applied to the Kaplan–Meier data is arbitrary and each time point used can be considered equally plausible. It also noted that the choice of time point had a limited effect on the ICER. The committee agreed that the ERG's suggestion of 43 weeks for extrapolating the Kaplan–Meier data from KEYNOTE‑024 was plausible. However, because of the high level of uncertainty around the extrapolation of overall survival data, the other time points were equally plausible.
## The company's choice of distribution to extrapolate overall survival is plausible but associated with uncertainty
The ERG highlighted that although the final overall survival analysis from the company includes an additional 6 months of data, this only accounts for 10% of the 20‑year time horizon. The committee noted that the company's choice of exponential extrapolation to model overall survival for people having pembrolizumab or standard care was pessimistic compared with all but one of the other distributions. The ERG highlighted that the ICER for pembrolizumab compared with standard care varied substantially when alternative distributions were used (for example, a generalised gamma distribution decreased the ICER; a Weibull distribution increased the ICER). However, it acknowledged that confidence in any distribution decreases as time from the last available data point increases. The ERG stated that the uncertainty around the overall survival extrapolation even at 2 years is the main source of uncertainty in the cost-effectiveness analyses, but the company's approach was plausible. The committee concluded that there was a high level of uncertainty around the extrapolation of the overall survival data, but agreed that the company's choice of extrapolation was plausible.
## A long-term treatment effect of pembrolizumab after stopping treatment is plausible but its duration is uncertain
The committee noted that the duration of treatment effect is an area of uncertainty for new immunotherapies. The company stated that there is no evidence that the treatment effect stops, as shown by the tail of the pembrolizumab Kaplan–Meier overall survival curve based on the latest KEYNOTE‑024 data (July 2017). The committee noted the company's scenario analyses, which explored stopping the treatment effect by setting the overall survival hazard ratio at 1 at different time points in the model. This increased the company's base-case ICER from £30,244 per QALY gained to £44,483 and £36,156 per QALY gained for the 3- and 5‑year scenarios. The committee agreed that although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its duration was uncertain. The committee concluded that the company's scenarios were plausible and would be taken into account in its decision-making.
## A 5-year survival rate of 8–11% for standard care is reasonable for decision-making
In NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer (TA447), the committee agreed that the estimated 5‑year survival in the standard care arm was 2.4%, 2.7% and 4.5% when the data were extrapolated from the 22‑week, 14‑week and 30‑week time points respectively. The committee noted that the 5‑year survival estimate extrapolated from 30 weeks was close to a 5% estimate by the National Lung Cancer Audit (NLCA). The ERG highlighted that the NLCA dataset was a reliable source of evidence but not all patients had chemotherapy (which has been shown to extend life), so 5.0% is likely to be an underestimate of the survival rate. The committee recalled that since TA447 was published, immunotherapy is now being used as an option after chemotherapy. It noted the company's revised base case, which takes into account people having immunotherapy after progression following chemotherapy and that this would likely increase the 5‑year overall survival rate from the 5% that the committee previously agreed was plausible. The committee noted that the company's revised estimate for 5‑year overall survival for people in the standard care arm was between 8% and 11% depending on the time point used for extrapolating the Kaplan–Meier data (23, 33 or 43 weeks). The committee acknowledged that there was uncertainty in accurately estimating 5‑year overall survival, but it considered that the company's estimates of overall survival for the standard care arm at these time points were all plausible. The committee concluded that the analyses using a survival rate of 8–11% at 5 years for the standard care arm were reasonable for its decision-making.
## The utility values in KEYNOTE-024 appear implausible, but many patients had a good performance status
The committee discussed the utility data used in the company model. It noted that EQ‑5D data were collected in KEYNOTE‑024; these data are the preferred measure of health-related quality of life in adults. The utility values for pembrolizumab and standard care were pooled (adjusted for age) and divided into 4 groups based on time to death (from less than 30 days to at least 360 days). The committee noted that in the company's sensitivity analyses, the utility values for long-term survivors were the second most influential parameter in the cost-effectiveness analysis. The committee understood that given the number of patients in KEYNOTE‑024 (n=305), dividing the utility data into 4 groups based on time to death may have increased the uncertainty around the utility values for each state. The ERG highlighted that the utilities derived from KEYNOTE‑024 were also implausibly high; the values at 360 days before death were higher than the UK population norm for people of the same age. The committee was aware that 87% of patients in the standard care arm and 97% of patients in the pembrolizumab arm of KEYNOTE‑024 were current or former smokers, which is higher than in the general population. It also recognised that the utility values from KEYNOTE‑024 used the tariff derived from a representative sample of the UK population and values from patients with the condition. The ERG noted that although the utility values for some people with metastatic lung cancer could be higher than the population norm, NICE's reference case methods specify the use of a general population utility tariff applied to patient quality-of-life data. The committee also considered that the utility values did not support the evidence in the company's submission, which described patients with NSCLC as having the highest prevalence of psychological distress (3 times more than in other cancers), leading to a poorer prognosis and greater patient burden. However, the NHS England clinical lead noted that around a third of patients in KEYNOTE‑024 had an ECOG performance status of 0 and led relatively normal lives. The committee agreed with the ERG that the utility values from KEYNOTE‑024 appeared implausible and did not seem in line with the physical symptoms described by the patient experts, but it was aware that a substantial number of people in KEYNOTE‑024 had a good ECOG performance status.
## The ERG's approach of capping the utility value to the UK population norm is preferred
The committee considered the analysis in which the utility values for at least 360 days to death were set to the UK population norm. Using these utilities had a limited effect on the company's base-case ICER of £30,244 per QALY gained. The ERG explored using much lower utility values from NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC, which would increase this ICER (by reducing the change in QALYs by 0.16). But it highlighted that this scenario did not use time to death utilities, and was therefore only an exploratory analysis. The committee agreed that simply adjusting utility to the population norm is a conservative assumption given the physical symptoms and psychological distress reported by patients with NSCLC. Accounting for the uncertainty in the utility values, the committee acknowledged that the ICER could fall between that from the analysis setting the utility for 360 days to death to that of the UK population norm, and the analysis using utilities from the pemetrexed guidance. However, it concluded that there were limitations associated with the utility values from the pemetrexed guidance and preferred to use values from KEYNOTE‑024 combined with the ERG's approach of setting the utility value for 360 days to death to the UK population norm.
## The dosage of pembrolizumab used in the economic model should be in line with the marketing authorisation
The marketing authorisation for pembrolizumab states that it should be given as a fixed dose of 200 mg every 3 weeks by intravenous infusion for untreated PD‑L1-positive metastatic NSCLC. For people who have previously had chemotherapy, the dose should be 2 mg/kg every 3 weeks. The ERG highlighted that in the economic model, the company assumed the fixed 200 mg dose of pembrolizumab for people in the standard care group (who go on to have pembrolizumab after disease progression), which is not in line with the marketing authorisation or how it is given in NHS clinical practice. The NHS England clinical lead confirmed that in practice, pembrolizumab would be administered in line with its marketing authorisation. The ERG did an exploratory analysis that corrected the pembrolizumab dosage in the model in line with the marketing authorisation. This increased the ICER by about £5,000 per QALY gained. The committee concluded that the dosage of pembrolizumab in the model should reflect the marketing authorisation.
## The most plausible ICER for decision-making lies between the company's ICER and the ERG's ICER
The committee discussed the ICERs for pembrolizumab compared with standard care. It was aware that the company's base-case ICER was £30,244 per QALY gained (including a 2‑year stopping rule). The committee agreed that, although the choice of overall survival extrapolation could have a large effect on the cost-effectiveness estimates, the data were still immature and the estimate of overall survival was associated with uncertainty. The committee acknowledged that the ICER changed very little depending on which time point was used to extrapolate overall survival (£31,321 per QALY gained when survival data were extrapolated from 23 weeks and £33,829 per QALY gained when extrapolated from 43 weeks; see section 3.9). It agreed that extrapolations at these time points gave a plausible estimate of overall survival (8 to 11%) at 5 years for standard care given that immunotherapy is now used after chemotherapy (see section 3.12). The company also explored alternative assumptions about the period of treatment benefit associated with pembrolizumab treatment; these scenarios gave ICERs ranging from £30,244 to £44,483 per QALY gained (see section 3.11). The committee agreed with the ERG's suggested amendments, which included:
setting the utility value for at least 360 days to death at the UK population norm (see section 3.13) and
bringing the cost associated with pembrolizumab after chemotherapy in line with the marketing authorisation (see section 3.15).Setting the utility value to the UK population norm had a minimal impact on the company's ICER, whereas amending the cost of using pembrolizumab after chemotherapy in line with the marketing authorisation increased the ICER. The decision-making ICERs cannot be presented because they include the commercial access agreement reduction for pemetrexed. The committee noted that the most plausible cost-effectiveness estimates were associated with uncertainty, particularly for overall survival and the duration of treatment effect. However, it agreed that the ICERs, ranging from £30,000 per QALY gained to less than £50,000 per QALY gained, on which it was basing its decision were associated with uncertainty, particularly for overall survival and the duration of treatment effect. The committee concluded that all the scenarios presented were plausible. Therefore, the most plausible cost-effectiveness estimate was likely to be between the ranges presented by the company and the ERG.
# Innovation
## There were no additional benefits not already captured in the economic analysis
The committee considered the innovative nature of pembrolizumab. The patient and clinical experts explained that in the past 20 years, there have been few improvements for untreated metastatic NSCLC in people whose tumours have no EGFR- or ALK-positive mutations, and that there is an important unmet need for people with this condition. The clinical experts also said that pembrolizumab is innovative in its potential to have a significant and substantial effect on health-related benefits. The committee understood that improvements in survival and reduced adverse effects are important for people with this condition. It concluded that pembrolizumab could be considered an important treatment option for this population, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis.
# End of life
## Pembrolizumab meets NICE's end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether life expectancy without pembrolizumab would be less than 24 months. It noted the company's evidence, which showed that people with NSCLC have an average life expectancy of less than 24 months. The committee discussed whether a survival benefit of over 3 months can be expected for pembrolizumab compared with standard care. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is 36.0 months compared with 22.3 months for standard care. Therefore the committee felt confident that pembrolizumab is likely to offer, on average, considerably more than 3 months' extension to life compared with standard care. The committee concluded that pembrolizumab met the life expectancy and life extension criteria to be considered a life-extending, end-of-life treatment.
# Conclusion
## Pembrolizumab is recommended for routine use in the NHS
The committee agreed that the most plausible ICER for pembrolizumab compared with standard care was likely to be within the range normally considered to be a cost-effective use of NHS resources. Therefore, it concluded that pembrolizumab could be recommended for routine use as an option for people with untreated PD‑L1-positive metastatic NSCLC (with at least a 50% tumour proportion score) and no EGFR- or ALK-positive tumour mutations, only if pembrolizumab is stopped at 2 years of uninterrupted treatment, or earlier in the event of disease progression, and if the company provides pembrolizumab according to the commercial access agreement.
|
{'Recommendation': 'Pembrolizumab is recommended as an option for untreated PD‑L1-positive metastatic non-small-cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 (with at least a 50% tumour proportion score) and have no epidermal growth factor receptor- or anaplastic lymphoma kinase-positive mutations, only if:\n\npembrolizumab is stopped at 2\xa0years of uninterrupted treatment or earlier in the event of disease progression and\n\nthe company provides pembrolizumab according to the commercial access agreement.\n\nWhy the committee made this recommendation\n\nPeople with untreated metastatic PD‑L1-positive NSCLC are usually offered platinum-based chemotherapy (docetaxel, gemcitabine, paclitaxel, vinorelbine or pemetrexed, with a platinum-based drug).\n\nClinical trial evidence shows that pembrolizumab increases the length of time people live by nearly 16\xa0months compared with chemotherapy. Although there is uncertainty about the long-term treatment benefit of pembrolizumab after treatment is stopped, there was sufficient evidence of an important extension-to-life benefit in people with untreated stage\xa04 metastatic PD‑L1-positive NSCLC compared with standard care.\n\nThe most plausible cost-effectiveness estimate for pembrolizumab compared with chemotherapy is within the range NICE normally considers acceptable for an end-of-life treatment. Therefore it can be recommended as an option for untreated metastatic PD‑L1-positive (with at least a 50% tumour proportion score) NSCLC if treatment is stopped after 2\xa0years.', 'Information about pembrolizumab': "Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) has a marketing authorisation for 'the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD‑L1 with at least a 50% tumour proportion score with no epidermal growth factor receptor or anaplastic lymphoma kinase-positive tumour mutations'.\n\nDosage in the marketing authorisation\n\nmg every 3\xa0weeks by intravenous infusion. The summary of product characteristics recommends treatment with pembrolizumab until disease progression or unacceptable toxicity.\n\nPrice\n\nPembrolizumab is available at a cost of £1,315.00 per 50‑mg vial (excluding VAT; British national formulary online, accessed March\xa02017).\n\nThe average cost of a course of treatment is £84,002 based on the list price.\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know the details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Pembrolizumab is an important option for untreated metastatic PD‑L1-positive non-small-cell lung cancer\n\nThe clinical experts explained that people with untreated metastatic non-small-cell lung cancer (NSCLC) whose tumours express PD‑L1 with at least a 50% tumour proportion score and who have no epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)‑positive tumour mutations have limited treatment options. The committee understood that patients can be on treatment for a long time and this can cause unpleasant side effects. Symptoms such as breathlessness and cough are difficult to treat. The clinical experts explained that new treatments, which offer survival benefits with fewer side effects than standard care, are needed for this population. The patient experts explained that symptoms can be debilitating, so improving quality of life and even small extensions in length of life are of considerable importance to this patient group. The committee understood that pembrolizumab is generally well tolerated. It concluded that pembrolizumab is an important treatment option for people with untreated metastatic PD‑L1-positive NSCLC.\n\n## PD‑L1 testing could be implemented as standard practice in the NHS\n\nThe committee noted that the marketing authorisation for pembrolizumab only covers people with untreated metastatic NSCLC if their tumour expresses PD‑L1 with at least a 50% tumour proportion score. The NHS England clinical lead stated that all lung cancer centres should be able to offer testing for PD‑L1 status. The clinical expert explained that testing involves an immunohistochemical assay and facilities for this are widely available in histopathology laboratories. However, they noted that PD‑L1 tests are complex to interpret and the standard time needed for assessment is 20\xa0minutes. The committee concluded that PD‑L1 testing could be standardised quickly and, with training, implemented as standard clinical practice in the NHS.\n\n## Pembrolizumab is an alternative to chemotherapy\n\nThe committee understood from the clinical experts that management of untreated metastatic PD‑L1-positive NSCLC in clinical practice is platinum-based combination chemotherapy (that is, cisplatin or carboplatin and either pemetrexed or gemcitabine). Docetaxel, gemcitabine, paclitaxel or vinorelbine alone (single-agent chemotherapy) is recommended for people who cannot tolerate combination therapy (NICE's guideline on lung cancer: diagnosis and management). NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC recommends pemetrexed with cisplatin for adenocarcinoma or large-cell carcinoma. Pemetrexed is also recommended as a maintenance treatment for locally advanced or metastatic non-squamous NSCLC in adults whose disease has not progressed after pemetrexed and cisplatin therapy (NICE's technology appraisal guidance on pemetrexed maintenance treatment for non-squamous NSCLC after pemetrexed and cisplatin), and after platinum-based chemotherapy plus gemcitabine, paclitaxel or docetaxel (NICE's technology appraisal guidance on pemetrexed for the maintenance treatment of NSCLC). The committee understood that pembrolizumab would be considered as an alternative to platinum-based combination therapy. The committee concluded that pembrolizumab was appropriately positioned in the clinical pathway as an option for people with untreated metastatic PD‑L1-positive NSCLC, that is, as an alternative to platinum-based combination chemotherapy.\n\n# Clinical effectiveness\n\n## The KEYNOTE-024 trial is generalisable to clinical practice in England\n\nThe clinical effectiveness evidence for pembrolizumab came from KEYNOTE‑024. This was an open-label phase\xa03 randomised controlled trial, comparing pembrolizumab with standard care. Standard care therapies included platinum-based combinations with either gemcitabine or paclitaxel, and a platinum-based combination with pemetrexed (with or without pemetrexed maintenance for non-squamous disease). The ERG explained that no evidence was available for single-agent chemotherapy and the clinical experts noted that it is mainly used as an option for previously treated disease. The clinical experts explained that although fewer patients in KEYNOTE‑024 had a pemetrexed-containing regimen than expected, they considered that the standard care treatments were likely to be the same as those used in clinical practice in England. The committee was aware that the inclusion criteria in KEYNOTE‑024 were that patients had untreated stage\xa04 metastatic PD‑L1-positive NSCLC (with tumours expressing at least 50% PD‑L1 and no EGFR- or ALK-positive mutations) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01. The NHS England clinical lead said that there were more people with an ECOG performance status of\xa00 in KEYNOTE‑024 than those who had pembrolizumab through the Cancer Drugs Fund. The clinical experts explained that although the proportion of patients with squamous disease was smaller than expected, and patients with stage\xa03 disease were not included, the overall population in KEYNOTE‑024 was comparable to the population seen in clinical practice in England. The committee therefore concluded that KEYNOTE‑024 was generalisable to clinical practice in England.\n\n## Pembrolizumab offers 15\xa0months more overall survival benefit than standard care\n\nThe committee was aware of the results from the final analysis of overall survival in KEYNOTE‑024. The median duration of follow‑up was 25.2\xa0months; 14.9% of people remained on pembrolizumab compared with 1.3% on standard care. The committee noted that the intention-to-treat results (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.47 to 0.86) suggested a statistically significant survival benefit for pembrolizumab compared with standard care. Median overall survival was 30.0\xa0months for people on pembrolizumab and 14.2\xa0months for those on standard care. The committee was aware that the trial protocol allowed people to switch from the standard care arm to have immunotherapy treatment on disease progression. The trial's data and safety monitoring committee also recommended that KEYNOTE‑024 should be stopped at the second interim analysis to give patients in the standard care arm the opportunity to have pembrolizumab. The company considered that no adjustment to the results was needed to account for people switching from standard care to pembrolizumab because in NHS clinical practice, immunotherapy is now becoming standard treatment for disease that has progressed after chemotherapy. The committee agreed that no adjustment was needed to account for treatment switching in the trial. It concluded that, based on the trial data, there was sufficient evidence that pembrolizumab has an important extension-to-life benefit in people with untreated stage\xa04 metastatic PD‑L1-positive NSCLC compared with standard care.\n\n## A 2-year treatment duration with pembrolizumab is clinically plausible\n\nThe committee was aware that the maximum possible treatment duration with pembrolizumab in KEYNOTE‑024 was 2\xa0years (35\xa0cycles). It noted that, despite this, the summary of product characteristics states that treatment should continue until disease progression or unacceptable toxicity. The ERG noted that no patients in the pembrolizumab arm had completed 2\xa0years' therapy. The clinical experts explained that the best treatment duration with pembrolizumab was unknown. The clinical and patient experts stated that although pembrolizumab has low toxicity, long courses of intravenous infusions can be a burden to patients. They further agreed that stopping treatment at 2\xa0years independent of disease status would be acceptable to patients. The committee noted comments from the NHS England clinical lead that benefits to patients may occur when the immune system responds sufficiently to the treatment against the cancer, and patients may not need continued treatment until disease progression. The NHS England clinical lead also stated that, if NHS trusts continue treatment beyond 2\xa0years for individual patients, NHS England will not reimburse them for this non-commissioned use of the drug if NICE recommendations state that treatment should be stopped at 2\xa0years. The committee concluded that limiting pembrolizumab treatment to 2\xa0years was clinically plausible, but the best treatment duration was unknown.\n\n# Cost effectiveness\n\n## The company's economic model is appropriate for decision-making\n\nThe committee discussed the company's cost-effectiveness evidence and the ERG's review. It noted that the company's model included the agreed commercial access agreement discount for pembrolizumab and an estimated discount for pemetrexed. The committee accepted the structure of the company's economic model and considered it appropriate for decision-making.\n\n## Including a 2-year stopping rule in line with the clinical trial is appropriate\n\nThe committee discussed the assumption in the company's model that at 2\xa0years, all patients, including patients whose disease had not progressed, would stop treatment. It understood that this assumption was based on the KEYNOTE‑024 protocol. The committee recalled its conclusion that limiting pembrolizumab treatment to 2\xa0years is clinically plausible, and that patient and clinical experts agreed that stopping treatment at 2\xa0years independent of disease status would be acceptable to patients (see section\xa03.6). The committee concluded that implementing a 2‑year stopping rule in the model was appropriate.\n\n## The different time points for extrapolating overall survival are equally plausible\n\nThe committee noted that in the company's sensitivity analyses, the most influential parameter in the cost-effectiveness analysis was the extrapolation of overall survival in the pembrolizumab and standard care arms. To estimate overall survival, the company's base-case analysis used 33‑week Kaplan–Meier data from KEYNOTE‑024. After 33\xa0weeks, the company fitted separate exponential models to the data. The company's base-case incremental cost-effectiveness ratio (ICER) using this approach was £30,244 per quality-adjusted life year (QALY) gained. In scenario analyses the company explored alternative time points to extrapolate the trial data; 23\xa0and\xa043\xa0weeks of Kaplan–Meier data. Both these analyses increased the company's base-case ICER; to £31,321 per QALY gained for the 23‑week time point and £33,829 per QALY gained for the 43‑week time point. The committee noted the ERG's scenario analyses, which suggested that the 43‑week point was a better visual fit for the data. The committee agreed that the time at which the distribution is applied to the Kaplan–Meier data is arbitrary and each time point used can be considered equally plausible. It also noted that the choice of time point had a limited effect on the ICER. The committee agreed that the ERG's suggestion of 43\xa0weeks for extrapolating the Kaplan–Meier data from KEYNOTE‑024 was plausible. However, because of the high level of uncertainty around the extrapolation of overall survival data, the other time points were equally plausible.\n\n## The company's choice of distribution to extrapolate overall survival is plausible but associated with uncertainty\n\nThe ERG highlighted that although the final overall survival analysis from the company includes an additional 6\xa0months of data, this only accounts for 10% of the 20‑year time horizon. The committee noted that the company's choice of exponential extrapolation to model overall survival for people having pembrolizumab or standard care was pessimistic compared with all but one of the other distributions. The ERG highlighted that the ICER for pembrolizumab compared with standard care varied substantially when alternative distributions were used (for example, a generalised gamma distribution decreased the ICER; a Weibull distribution increased the ICER). However, it acknowledged that confidence in any distribution decreases as time from the last available data point increases. The ERG stated that the uncertainty around the overall survival extrapolation even at 2\xa0years is the main source of uncertainty in the cost-effectiveness analyses, but the company's approach was plausible. The committee concluded that there was a high level of uncertainty around the extrapolation of the overall survival data, but agreed that the company's choice of extrapolation was plausible.\n\n## A long-term treatment effect of pembrolizumab after stopping treatment is plausible but its duration is uncertain\n\nThe committee noted that the duration of treatment effect is an area of uncertainty for new immunotherapies. The company stated that there is no evidence that the treatment effect stops, as shown by the tail of the pembrolizumab Kaplan–Meier overall survival curve based on the latest KEYNOTE‑024 data (July\xa02017). The committee noted the company's scenario analyses, which explored stopping the treatment effect by setting the overall survival hazard ratio at\xa01 at different time points in the model. This increased the company's base-case ICER from £30,244 per QALY gained to £44,483 and £36,156 per QALY gained for the 3- and 5‑year scenarios. The committee agreed that although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its duration was uncertain. The committee concluded that the company's scenarios were plausible and would be taken into account in its decision-making.\n\n## A 5-year survival rate of 8–11% for standard care is reasonable for decision-making\n\nIn NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer (TA447), the committee agreed that the estimated 5‑year survival in the standard care arm was 2.4%, 2.7% and 4.5% when the data were extrapolated from the 22‑week, 14‑week and 30‑week time points respectively. The committee noted that the 5‑year survival estimate extrapolated from 30\xa0weeks was close to a 5% estimate by the National Lung Cancer Audit (NLCA). The ERG highlighted that the NLCA dataset was a reliable source of evidence but not all patients had chemotherapy (which has been shown to extend life), so 5.0% is likely to be an underestimate of the survival rate. The committee recalled that since TA447 was published, immunotherapy is now being used as an option after chemotherapy. It noted the company's revised base case, which takes into account people having immunotherapy after progression following chemotherapy and that this would likely increase the 5‑year overall survival rate from the 5% that the committee previously agreed was plausible. The committee noted that the company's revised estimate for 5‑year overall survival for people in the standard care arm was between 8% and 11% depending on the time point used for extrapolating the Kaplan–Meier data (23, 33 or 43\xa0weeks). The committee acknowledged that there was uncertainty in accurately estimating 5‑year overall survival, but it considered that the company's estimates of overall survival for the standard care arm at these time points were all plausible. The committee concluded that the analyses using a survival rate of 8–11% at 5\xa0years for the standard care arm were reasonable for its decision-making.\n\n## The utility values in KEYNOTE-024 appear implausible, but many patients had a good performance status\n\nThe committee discussed the utility data used in the company model. It noted that EQ‑5D data were collected in KEYNOTE‑024; these data are the preferred measure of health-related quality of life in adults. The utility values for pembrolizumab and standard care were pooled (adjusted for age) and divided into 4\xa0groups based on time to death (from less than 30\xa0days to at least 360\xa0days). The committee noted that in the company's sensitivity analyses, the utility values for long-term survivors were the second most influential parameter in the cost-effectiveness analysis. The committee understood that given the number of patients in KEYNOTE‑024 (n=305), dividing the utility data into 4\xa0groups based on time to death may have increased the uncertainty around the utility values for each state. The ERG highlighted that the utilities derived from KEYNOTE‑024 were also implausibly high; the values at 360\xa0days before death were higher than the UK population norm for people of the same age. The committee was aware that 87% of patients in the standard care arm and 97% of patients in the pembrolizumab arm of KEYNOTE‑024 were current or former smokers, which is higher than in the general population. It also recognised that the utility values from KEYNOTE‑024 used the tariff derived from a representative sample of the UK population and values from patients with the condition. The ERG noted that although the utility values for some people with metastatic lung cancer could be higher than the population norm, NICE's reference case methods specify the use of a general population utility tariff applied to patient quality-of-life data. The committee also considered that the utility values did not support the evidence in the company's submission, which described patients with NSCLC as having the highest prevalence of psychological distress (3\xa0times more than in other cancers), leading to a poorer prognosis and greater patient burden. However, the NHS England clinical lead noted that around a third of patients in KEYNOTE‑024 had an ECOG performance status of\xa00 and led relatively normal lives. The committee agreed with the ERG that the utility values from KEYNOTE‑024 appeared implausible and did not seem in line with the physical symptoms described by the patient experts, but it was aware that a substantial number of people in KEYNOTE‑024 had a good ECOG performance status.\n\n## The ERG's approach of capping the utility value to the UK population norm is preferred\n\nThe committee considered the analysis in which the utility values for at least 360\xa0days to death were set to the UK population norm. Using these utilities had a limited effect on the company's base-case ICER of £30,244 per QALY gained. The ERG explored using much lower utility values from NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC, which would increase this ICER (by reducing the change in QALYs by\xa00.16). But it highlighted that this scenario did not use time to death utilities, and was therefore only an exploratory analysis. The committee agreed that simply adjusting utility to the population norm is a conservative assumption given the physical symptoms and psychological distress reported by patients with NSCLC. Accounting for the uncertainty in the utility values, the committee acknowledged that the ICER could fall between that from the analysis setting the utility for 360\xa0days to death to that of the UK population norm, and the analysis using utilities from the pemetrexed guidance. However, it concluded that there were limitations associated with the utility values from the pemetrexed guidance and preferred to use values from KEYNOTE‑024 combined with the ERG's approach of setting the utility value for 360\xa0days to death to the UK population norm.\n\n## The dosage of pembrolizumab used in the economic model should be in line with the marketing authorisation\n\nThe marketing authorisation for pembrolizumab states that it should be given as a fixed dose of 200\xa0mg every 3\xa0weeks by intravenous infusion for untreated PD‑L1-positive metastatic NSCLC. For people who have previously had chemotherapy, the dose should be 2\xa0mg/kg every 3\xa0weeks. The ERG highlighted that in the economic model, the company assumed the fixed 200\xa0mg dose of pembrolizumab for people in the standard care group (who go on to have pembrolizumab after disease progression), which is not in line with the marketing authorisation or how it is given in NHS clinical practice. The NHS England clinical lead confirmed that in practice, pembrolizumab would be administered in line with its marketing authorisation. The ERG did an exploratory analysis that corrected the pembrolizumab dosage in the model in line with the marketing authorisation. This increased the ICER by about £5,000 per QALY gained. The committee concluded that the dosage of pembrolizumab in the model should reflect the marketing authorisation.\n\n## The most plausible ICER for decision-making lies between the company's ICER and the ERG's ICER\n\nThe committee discussed the ICERs for pembrolizumab compared with standard care. It was aware that the company's base-case ICER was £30,244 per QALY gained (including a 2‑year stopping rule). The committee agreed that, although the choice of overall survival extrapolation could have a large effect on the cost-effectiveness estimates, the data were still immature and the estimate of overall survival was associated with uncertainty. The committee acknowledged that the ICER changed very little depending on which time point was used to extrapolate overall survival (£31,321 per QALY gained when survival data were extrapolated from 23\xa0weeks and £33,829 per QALY gained when extrapolated from 43\xa0weeks; see section\xa03.9). It agreed that extrapolations at these time points gave a plausible estimate of overall survival (8\xa0to 11%) at 5\xa0years for standard care given that immunotherapy is now used after chemotherapy (see section\xa03.12). The company also explored alternative assumptions about the period of treatment benefit associated with pembrolizumab treatment; these scenarios gave ICERs ranging from £30,244 to £44,483 per QALY gained (see section\xa03.11). The committee agreed with the ERG's suggested amendments, which included:\n\nsetting the utility value for at least 360\xa0days to death at the UK population norm (see section\xa03.13) and\n\nbringing the cost associated with pembrolizumab after chemotherapy in line with the marketing authorisation (see section\xa03.15).Setting the utility value to the UK population norm had a minimal impact on the company's ICER, whereas amending the cost of using pembrolizumab after chemotherapy in line with the marketing authorisation increased the ICER. The decision-making ICERs cannot be presented because they include the commercial access agreement reduction for pemetrexed. The committee noted that the most plausible cost-effectiveness estimates were associated with uncertainty, particularly for overall survival and the duration of treatment effect. However, it agreed that the ICERs, ranging from £30,000 per QALY gained to less than £50,000 per QALY gained, on which it was basing its decision were associated with uncertainty, particularly for overall survival and the duration of treatment effect. The committee concluded that all the scenarios presented were plausible. Therefore, the most plausible cost-effectiveness estimate was likely to be between the ranges presented by the company and the ERG.\n\n# Innovation\n\n## There were no additional benefits not already captured in the economic analysis\n\nThe committee considered the innovative nature of pembrolizumab. The patient and clinical experts explained that in the past 20\xa0years, there have been few improvements for untreated metastatic NSCLC in people whose tumours have no EGFR- or ALK-positive mutations, and that there is an important unmet need for people with this condition. The clinical experts also said that pembrolizumab is innovative in its potential to have a significant and substantial effect on health-related benefits. The committee understood that improvements in survival and reduced adverse effects are important for people with this condition. It concluded that pembrolizumab could be considered an important treatment option for this population, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis.\n\n# End of life\n\n## Pembrolizumab meets NICE's end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether life expectancy without pembrolizumab would be less than 24\xa0months. It noted the company's evidence, which showed that people with NSCLC have an average life expectancy of less than 24\xa0months. The committee discussed whether a survival benefit of over 3\xa0months can be expected for pembrolizumab compared with standard care. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is 36.0\xa0months compared with 22.3\xa0months for standard care. Therefore the committee felt confident that pembrolizumab is likely to offer, on average, considerably more than 3\xa0months' extension to life compared with standard care. The committee concluded that pembrolizumab met the life expectancy and life extension criteria to be considered a life-extending, end-of-life treatment.\n\n# Conclusion\n\n## Pembrolizumab is recommended for routine use in the NHS\n\nThe committee agreed that the most plausible ICER for pembrolizumab compared with standard care was likely to be within the range normally considered to be a cost-effective use of NHS resources. Therefore, it concluded that pembrolizumab could be recommended for routine use as an option for people with untreated PD‑L1-positive metastatic NSCLC (with at least a 50% tumour proportion score) and no EGFR- or ALK-positive tumour mutations, only if pembrolizumab is stopped at 2\xa0years of uninterrupted treatment, or earlier in the event of disease progression, and if the company provides pembrolizumab according to the commercial access agreement."}
|
https://www.nice.org.uk/guidance/ta531
|
Evidence-based recommendations on pembrolizumab (Keytruda) for untreated PD-L1-positive metastatic non-small-cell lung cancer in adults.
|
fbc76fb5540792bf931f77b8f6a2623f1b891c49
|
nice
|
Biomarker tests to help diagnose preterm labour in women with intact membranes
|
Biomarker tests to help diagnose preterm labour in women with intact membranes
Evidence-based recommendations on biomarker tests to help diagnose preterm labour in women with intact membranes. The tests are Actim Partus, PartoSure and the Rapid fetal fibronectin (fFN) 10Q Cassette Kit (at thresholds other than 50 nanograms/millilitre).
# Recommendations
There is currently insufficient evidence to recommend the routine adoption of Actim Partus and PartoSure to help diagnose preterm labour in women with intact membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable.
There is currently insufficient evidence to recommend the routine adoption of the Rapid fetal fibronectin (fFN) 10Q Cassette Kit (using thresholds other than 50 nanograms/millilitre to guide clinical management) to help diagnose preterm labour in women with intact membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable. Recommendations on qualitative fetal fibronectin testing with a fixed threshold of 50 ng/ml are covered by NICE's guideline on preterm labour and birth, and are not affected by this diagnostics guidance.
Further research is needed on the accuracy of the tests and their effect on clinical outcomes. Centres using the tests to help diagnose preterm labour in women with intact membranes are encouraged to take part in studies to address the research considerations (see section 5.12 to section 5.16). Data are needed on:
the impact of gestational age on the accuracy of the tests
how the tests affect clinical decision-making
the effect of the tests on outcomes for mother and baby.# Clinical need and practice
# The problem addressed
Biomarker tests (PartoSure, Actim Partus and the Rapid fetal fibronectin 10Q Cassette Kit) are intended for use with other clinical information to assess the risk of preterm birth in women with symptoms of preterm labour who have intact amniotic membranes. These tests may be used instead of qualitative fetal fibronectin testing (using a threshold of 50 nanograms/millilitre ) or clinical assessment alone, when transvaginal ultrasound measurement of cervical length is not available or not acceptable. The results would help clinicians decide whether women need to be admitted to hospital for treatment to delay birth and improve neonatal outcomes.
The biomarker tests may result in more accurate diagnosis of preterm labour than tests currently used in NHS clinical practice. This could lead to improved health outcomes for women and their babies, and cost savings through reducing the length of hospital stay, reducing unnecessary hospital admissions, and minimising unnecessary transfers between hospitals. The tests may also enable better resource planning based on the expected need for transfers between hospitals and neonatal intensive care.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of biomarker tests (Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN 10Q Cassette Kit) to help diagnose preterm labour in women with intact amniotic membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable.
# The condition
## Preterm labour and birth
Preterm labour is defined as regular contractions of the uterus resulting in changes in the cervix that start before 37 weeks of pregnancy. Preterm labour and birth is fairly common in the UK, with 8% of babies born before 37 weeks of pregnancy. However, less than 1% of babies are born between 22 and 28 weeks of pregnancy (Royal College of Obstetricians and Gynaecologists 2014).
The World Health Organization defines preterm birth as:
extremely preterm (less than 28 weeks of pregnancy)
very preterm (28 to less than 32 weeks of pregnancy)
moderate to late preterm (32 to less than 37 weeks of pregnancy).
Around 25% of preterm births are planned because of maternal factors such as pre‑eclampsia, or fetal factors such as extreme growth restriction. But most preterm births occur because labour starts early naturally. Known risk factors for preterm labour include:
previous preterm delivery
twins or other multiple pregnancies
genital tract infections
preterm premature rupture of membranes
problems with the uterus, cervix or placenta
some chronic conditions, such as high blood pressure and diabetes
smoking or drug use
being underweight or overweight before pregnancy and
stressful life events.
The Department of Health and Social Care's toolkit for high-quality neonatal services (2009) describes 3 types of hospital units providing neonatal care for preterm babies:
Special care units (level 1) provide special care for their local population, and may also provide some high dependency services.
Local neonatal units (level 2) provide neonatal care for their local population, except for the sickest babies. Most babies born after 27 weeks of pregnancy will usually have full care, including short periods of intensive care, in their local neonatal unit.
Neonatal intensive care units (level 3) are sited alongside specialist obstetric and fetomaternal medicine services. They provide the whole range of medical neonatal care for their local population, along with additional care for babies and their families referred from the neonatal network.
Clinical experts have noted that most babies born after 35 weeks of pregnancy will be looked after on postnatal wards with their mothers.
Preterm birth can potentially lead to short-term health problems in a newborn baby; for example, problems breathing and feeding, and higher risk of infection. The main concerns include:
chronic lung disease at 36 weeks (corrected age)
intraventricular haemorrhage
necrotising enterocolitis
retinopathy of prematurity.
Babies who are born early, particularly those born before 28 weeks of pregnancy, may have lifelong disabilities. These include physical disabilities, learning disabilities, behavioural problems, and visual and hearing problems.
# The diagnostics and care pathways
## Clinical assessment
NICE's guideline on preterm labour and birth states that women reporting symptoms of preterm labour who have intact membranes should have a clinical assessment.
If the clinical assessment suggests that the woman is in suspected preterm labour and she is 29 weeks plus 6 days pregnant or less, treatment for preterm labour is recommended.
Clinical experts have noted that, in practice, not all women in suspected preterm labour who are 29 weeks plus 6 days pregnant or less have treatment. They have stated that these women often have diagnostic testing because there are insufficient resources available to admit or transfer all women, there is concern about the effect of unnecessary treatment and women may prefer to avoid hospital admission and transfer when possible.
## Transvaginal ultrasound measurement of cervical length
If the clinical assessment suggests that the woman is in suspected preterm labour and she is 30 weeks plus 0 days pregnant or more, transvaginal ultrasound measurement of cervical length should be considered to determine the likelihood of birth within 48 hours. If cervical length is more than 15 mm, it is unlikely that the woman is in preterm labour. If cervical length is 15 mm or less, preterm labour should be diagnosed and treatment offered.
NICE's guideline on preterm labour and birth notes that ultrasound scans should be done by healthcare professionals with training in, and experience of, transvaginal ultrasound measurement of cervical length. The guideline committee also noted that transvaginal ultrasound scanning is not routinely available across the NHS because equipment or expertise is limited, and that investment in technology and training may be needed for its universal implementation in the NHS. These limitations also increase the likelihood that biomarker testing will be carried out.
## Fetal fibronectin testing
If transvaginal ultrasound measurement of cervical length is indicated but is not available or not acceptable, fetal fibronectin testing should be considered to determine the likelihood of birth within 48 hours for women who are 30 weeks plus 0 days pregnant or more. If the fetal fibronectin test result is negative (concentration 50 ng/ml or less), it is unlikely that the woman is in preterm labour. If the fetal fibronectin test result is positive (concentration more than 50 ng/ml), preterm labour should be diagnosed and treatment offered. NICE's guideline on preterm labour and birth notes that if fetal fibronectin testing is anticipated, the swab should be taken before any digital vaginal examination.
If a woman in suspected preterm labour who is 30 weeks plus 0 days pregnant or more does not have transvaginal ultrasound measurement of cervical length or fetal fibronectin testing to exclude preterm labour, treatment should be offered consistent with her being in diagnosed preterm labour.
A women in suspected preterm labour, but with a negative diagnostic test result suggesting that preterm labour is unlikely, may go home or may continue to be monitored and have treatment in hospital. If the woman goes home, she is advised to return to hospital if symptoms suggesting preterm labour persist or recur.
NICE's guideline on preterm labour and birth notes that transvaginal ultrasound measurement of cervical length and fetal fibronectin testing should not be used in combination to diagnose preterm labour.
The European Association of Perinatal Medicine's recommendations on preterm labour and birth management state that 2 methods can be used to improve the accuracy of the diagnosis of preterm labour in women with symptoms:
transvaginal ultrasound cervical length measurement
measurement of biochemical markers in cervical-vaginal secretions (fetal fibronectin or placental alpha macroglobulin‑1 or insulin-like growth factor binding protein‑1 ).# The diagnostic tests
Three interventions and 2 comparators were included in this assessment.
# The interventions
## Actim Partus
Actim Partus is a CE‑marked qualitative immunochromatographic point-of-care test designed to detect phosphorylated IGFBP‑1 (insulin-like growth factor binding protein‑1) in cervical secretions during pregnancy. Phosphorylated IGFBP‑1 is a protein made by the cells lining the uterus. When delivery is imminent, small amounts of phosphorylated IGFBP‑1 leak into the cervix.
The Actim Partus test kit contains a sterile polyester swab for specimen collection, a tube of specimen extraction buffer and a dipstick in a sealed foil pouch. No other instrumentation or consumables are needed. The sample is collected from the cervical os during a sterile speculum examination. The results are available in 5 minutes or less. Two lines indicate a positive result; 1 line is a negative result that indicates the woman will not deliver within 7 to 14 days; if no lines appear, the test is invalid.
The dipstick contains 2 monoclonal antibodies to human IGFBP‑1. One is bound to blue latex particles (the detecting label). The other is immobilised on a carrier membrane to catch the complex of antigen and latex-labelled antibody and indicate a positive result. If phosphorylated IGFBP‑1 is present in the sample, it binds to the antibody labelled with latex particles. The particles flow to the results area of the dipstick, and if phosphorylated IGFBP‑1 is bound to them, they bind to the catching antibody. A test line will appear if the concentration of phosphorylated IGFBP‑1 in the sample exceeds the detection limit of the test. A control line confirms correct performance of the test.
Actim Partus is for use in pregnant women with signs and symptoms of preterm labour and intact amniotic membranes, after 22 weeks plus 0 days of pregnancy. The test can be used if vaginal infections, vaginal medications and semen are present, but active vaginal bleeding may cause a false positive result. The test has a limit of detection of 10 nanograms/millilitre (ng/ml) and a measuring range of 10 to 8,000 ng/ml.
## PartoSure
PartoSure is a CE‑marked qualitative lateral flow, immunochromatographic point-of-care test designed to detect placental alpha microglobulin‑1 (PAMG‑1) in vaginal secretions during pregnancy. PAMG‑1 is a protein released from the lining of the uterus into the amniotic cavity throughout pregnancy. It is found in very high concentrations in amniotic fluid and in very low concentrations in normal vaginal discharge. Studies have demonstrated a strong correlation between the presence of PAMG‑1 in cervicovaginal discharge and imminent delivery.
The PartoSure test kit contains a test strip, a vaginal swab and a plastic vial containing a solvent solution. No other instrumentation or consumables are needed. The sample may be collected with or without a speculum. The results are available in 5 minutes or less. Two lines indicate a positive result and a high risk of delivery within 7 days; 1 line indicates a negative result and a low risk of delivery within 7 to 14 days; no lines indicate an invalid result.
The test strip has a reactive area containing monoclonal anti-PAMG-1 antibodies bound to a gold particle (the detecting label). The sample flows through the reactive area and if PAMG‑1 is present, it binds to an anti-PAMG‑1 antibody, forming an antigen-antibody complex. This complex then flows to the test region of the strip where it is immobilised by a second anti-PAMG‑1 antibody. A test line appears if the concentration of PAMG‑1 in the sample exceeds the detection limit of the test. Unbound antigen-antibody complexes continue to flow along the test strip and are immobilised by another antibody, leading to the appearance of the internal control line.
PartoSure is for use in pregnant women with signs and symptoms of preterm labour, intact amniotic membranes and minimal cervical dilatation (3 cm or less), between 20 weeks plus 0 days and 36 weeks plus 6 days of pregnancy. The test can be used if vaginal infections, urine, semen and trace amounts of blood are present, but should not be used if there is significant discharge of blood. It can also be used shortly after a vaginal examination. The test has a limit of detection of 1 ng/ml and a measuring range of 1 to 40,000 ng/ml.
## Rapid fetal fibronectin 10Q Cassette Kit
The Rapid fetal fibronectin (fFN) 10Q Cassette is a CE‑marked test for use in the PeriLynx System or the Rapid fFN 10Q System. It is designed for the quantitative detection of fetal fibronectin in cervicovaginal secretions to assess the risk of preterm delivery within 7 to 14 days. Fetal fibronectin is an adhesive glycoprotein that holds the membranes of the uterus to the fetal membranes. After 35 weeks of pregnancy, it begins to break down naturally, and is detectable in vaginal secretions. Fetal fibronectin detected between 22 and 35 weeks of pregnancy is an indicator of preterm birth risk.
NICE's guideline on preterm labour and birth recommends fetal fibronectin testing to determine the likelihood of birth within 48 hours for women who are 30 weeks plus 0 days pregnant or more, if transvaginal ultrasound measurement of cervical length is indicated but is not available or not acceptable. The guideline recommends a threshold of 50 ng/ml to interpret the test results. However, clinical experts have noted that a quantitative fetal fibronectin test would enable other thresholds to be used.
The Rapid fFN 10Q Cassette test can be done near the woman. In addition to the test kit, an analyser, printer, Rapid fFN Control Kit, QCette (quality control device) and pipette are needed. The sample is collected from the posterior fornix of the vagina during a speculum examination. It is incubated in the analyser for 7 minutes and then analysed, which takes 2 to 3 minutes. The analyser reports fetal fibronectin concentrations ranging from 0 to 500 ng/ml; concentrations greater than 500 ng/ml are displayed as 'greater than 500 ng/ml'. The instructions for use do not give any thresholds, therefore laboratories would need to set and validate their own thresholds. Internal controls are done automatically with every test.
The Rapid fFN 10Q Cassette is for use in pregnant women with signs and symptoms of early preterm labour, intact amniotic membranes and minimal cervical dilatation (less than 3 cm), between 22 weeks plus 0 days and 35 weeks plus 6 days of pregnancy. Assay interference from blood, bacteria, bilirubin and semen has not been ruled out. However, a negative test result (less than 10 ng/ml) in the presence of blood or semen is valid. Also, the fetal fibronectin concentration may be affected by cervical disruption caused by, but not limited to, sex, digital cervical examination or vaginal probe ultrasound.
# The comparators
## Fetal fibronectin
Fetal fibronectin testing, at a threshold of 50 ng/ml, is recommended in NICE's guideline on preterm labour and birth (see section 2.16 to section 2.19 of this guideline).
The fetal fibronectin test is available as a quantitative enzyme-linked immunosorbent assay (ELISA), and as a qualitative membrane immunosorbent assay. Examples include:
Fetal Fibronectin Enzyme Immunoassay; a quantitative assay with a recommended threshold of 50 ng/ml (Hologic)
Rapid fFN for the TLilQ System; a qualitative immunochromatographic assay with a limit of detection of 50 ng/ml (Hologic)
QuikCheck Fetal Fibronectin Test; a qualitative test with a limit of detection of 50 ng/ml (Hologic).
## Clinical assessment
Clinical assessment is described in the NICE guideline on preterm labour and birth and in section 2.11 to section 2.13 of this guideline.# Evidence
The diagnostics advisory committee considered evidence on the biomarker tests (PartoSure, Actim Partus and Rapid fetal fibronectin 10Q Cassette Kit) for diagnosing preterm labour from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) did 2 systematic reviews of the clinical-effectiveness evidence for Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN 10Q Cassette Kit; 1 for diagnostic accuracy and 1 for clinical outcomes.
The EAG also did a non-systematic update of their report to include 7 new studies submitted for PartoSure with stakeholder comments on the diagnostics assessment report.
For the diagnostic accuracy review, studies were included if:
they recruited women with signs and symptoms of preterm labour who were not in established labour and who had intact amniotic membranes
the population was described as preterm
twin or multiple pregnancies made up 20% or less of the total population recruited
at least 1 index test was reported and at least 1 of the following reference standards or comparators was included:
preterm delivery within 48 hours
preterm delivery within 7 days
clinical assessment of symptoms
fetal fibronectin at a threshold of 50 nanograms/millilitre (ng/ml)
they were prospective or retrospective diagnostic accuracy studies with random or consecutively recruited women; both single- and two‑gate designs were eligible.A single-gate study recruits patients whose disease status is unknown before testing (a consecutive series), whereas a two-gate study recruits patients with the target condition and patients who do not have the target condition (a case-control study).
All studies included in the diagnostic accuracy review were appraised using the QUADAS‑2 tool. In total, 20 studies met the inclusion criteria for the diagnostic accuracy review.
The EAG also searched for studies in which clinical outcomes were reported, but did not identify any studies. The inclusion criteria were restricted to controlled studies only because the EAG considered that uncontrolled study designs are likely to be susceptible to bias.
## Study characteristics
Of the 20 diagnostic accuracy studies, data for more than 1 index test were reported in 2 studies (Hadzi‑Lega et al. 2017, APOSTEL‑1 2016), 16 studies assessed Actim Partus, 4 assessed PartoSure and 2 assessed fetal fibronectin at thresholds other than 50 ng/ml (APOSTEL‑1, EUIFS 2016). All 20 studies assessed the index tests against a reference standard of preterm delivery within 7 days, and 7 studies also assessed the index tests against a reference standard of preterm delivery within 48 hours.
The characteristics of women in the study varied and this introduced heterogeneity:
Mean maternal age was 25 to 31 years.
The proportion of multiple pregnancies was 0 to 20%.
The mean number of previous term pregnancies was 0.4 to 2.9 per person.
The proportion of previous preterm deliveries was 0 to 30%.
The proportion of previous miscarriages was 4 to 27%.
The prevalence of preterm birth within 7 days was 1.7 to 73.3%.
The prevalence of preterm birth within 48 hours was 2.4 to 58.3%.
The women were 20 weeks to 37 weeks pregnant.
The reporting of whether delivery was spontaneous or as a result of medical intervention varied between studies. Only 11 studies provided details on delivery; in 4, the authors stated that they excluded women from test accuracy calculations if birth occurred because of medical intervention before the 7‑day or 48‑hour reference standard.
## Diagnostic accuracy
In the 16 studies that included data for Actim Partus, the prevalence of birth within 7 days of testing was 1.7 to 73.3%. Across the studies, sensitivity estimates were 33.3 to 94.7%. The 3 studies (Cooper 2012, Danti 2011, Riboni 2011) with the lowest sensitivity estimates also had a lower prevalence of preterm birth (1.7 to 6.7%) than the other studies (9.8 to 73.3%). Specificity was 50.0 to 93.5%. The EAG did not identify any major differences in methods or participant characteristics in the 3 studies with the lowest specificity estimates. The pooled analysis of these 16 studies estimated a sensitivity of 77% (95% confidence interval 68 to 83%) and a specificity of 81% (95% CI 76 to 85%).
There were 6 studies that tested each sample with both Actim Partus and fetal fibronectin at a threshold of 50 ng/ml. Using delivery within 7 days as the reference standard, sensitivity for Actim Partus was lower than for fetal fibronectin in 1 study (APOSTEL‑1 2016), higher in 2 studies (Ting 2017, Tripathi 2016) and the same for both tests in the remaining 3 studies (Cooper 2012, Eroglu 2007, Riboni 2011). Specificity was higher for Actim Partus than for fetal fibronectin in 4 of the 6 studies, and lower in the 2 remaining studies (Cooper, Tripathi). Cooper only reported test accuracy results for a proportion of the total Actim Partus group (58 fewer women had results for the qualitative fFN test).
In response to stakeholder comments on the diagnostics assessment report, the EAG updated the diagnostic accuracy estimates for Actim Partus to include 18 studies identified by a company. The updated pooled sensitivity decreased compared with the original review; from 77% (95% CI 68 to 83%) to 74.3% (95% CI 64.2 to 82.3%) and specificity increased slightly from 81% (95% CI 76 to 85%) to 81.2% (95% CI 76.2 to 85.4%).
In the 4 studies that included diagnostic accuracy for PartoSure, the prevalence of birth within 7 days of testing was 2.4 to 17.2%. Specificity was similar across studies, 90.2 to 97.5%, but sensitivity was 0 to 100%. Werlen et al. (2015) reported 0% sensitivity because only 1 of 41 women tested positive and this was a false positive. The pooled analysis of the 4 studies estimated a sensitivity of 83% (95% CI 61 to 94%) and a specificity of 95% (95% CI 89 to 98%).
Nikolova et al. (2015) assessed fetal fibronectin at a threshold of 50 ng/ml and PartoSure in the same samples (66 of the total 203 women). Against the 7‑day reference standard, sensitivity for PartoSure was 80% (95% CI 63.1 to 91.6%) and for fetal fibronectin it was 50% (95% CI 21.1 to 79.0%). Specificity for PartoSure was 94.6% (95% CI 90.1 to 97.5%) and for fetal fibronectin it was 72.2% (95% CI 58.4 to 83.5%).
In response to stakeholder comments on the diagnostics assessment report, the EAG updated the diagnostic accuracy estimates for PartoSure to include 9 studies identified by a company. The updated pooled sensitivity decreased compared with the original review; from 83% (95% CI 61 to 94%) to 68.5% (95% CI 51.2 to 81.9%) and pooled specificity slightly increased from 95% (95% CI 89 to 98%) to 96.6% (95% CI 95.1 to 97.6%).
There were 2 studies (APOSTEL‑1 2016, EUIFS 2016) that included diagnostic accuracy for quantitative fetal fibronectin. The prevalence of preterm birth within 7 days was 10.5% (EUIFS) to 19.7% (APOSTEL‑1). In both studies sensitivity decreased as the threshold increased and specificity increased as the threshold increased.
The EAG reviewed 1 unpublished study (Ravi et al.) that included evidence for quantitative fetal fibronectin, submitted with stakeholder comments on the diagnostics assessment report. This presented sensitivity values lower than APOSTEL‑1 and EUIFS, but higher specificity values. The details of the study cannot be reported here because they are confidential.
There were 6 studies that assessed the diagnostic accuracy of Actim Partus. The prevalence of delivery within 48 hours of testing was 5.3 to 58.3%. Sensitivity was 65.7 to 100.0% and specificity was 56.0 to 82.4%. The pooled analysis of the 6 studies estimated a sensitivity of 87% (95% CI 74 to 94%) and a specificity of 73% (95% CI 62 to 82%).
Only 1 study (Werlen et al. 2015) assessed the diagnostic accuracy of PartoSure against the 48‑hour reference standard. The prevalence of preterm birth was 2.4%. Sensitivity was 0% (95% CI 0 to 97.5%) and specificity was 97.5% (95% CI 86.8 to 99.9%). Sensitivity was 0% because only 1 of 41 women tested positive and this was a false positive.
The EAG identified studies in the diagnostic accuracy systematic review that included data for fetal fibronectin at a threshold of 50 ng/ml. The generalisability of these data was assessed by comparing them with results from 3 recently published systematic reviews of fetal fibronectin.
Of the 20 studies included in the diagnostic accuracy review, 8 included accuracy data for quantitative fetal fibronectin at 50 ng/ml. Of these, 2 studies (APOSTEL‑1 2016, EUIFS 2016) used a quantitative fetal fibronectin test, 3 used the QuikCheck qualitative fetal fibronectin test (Eroglu 2007, Nikolova 2015, Tripathi 2016), 1 used an ELISA-based laboratory test (Riboni 2011), and in the remaining 2 studies (Cooper 2012, Ting 2007), it was not clear which fetal fibronectin test was used.
For the 8 studies looking at the diagnostic accuracy of fetal fibronectin at a threshold of 50 ng/ml against a 7‑day reference standard, sensitivity was 23.8 to 91.3% and specificity was 62.2 to 99.1%. These results were similar to those from the 3 existing literature reviews.
## Diagnostic accuracy data informing the economic model
The EAG concluded that there was too much heterogeneity in the pooled results to use them for indirect comparisons between tests in the economic modelling. It decided to prioritise studies that reported results for more than 1 test in the same population. Therefore, 2 studies (APOSTEL‑1 2016, Hadzi‑Lega et al. 2017) were used in the base case for the economic model.
# Cost effectiveness
## Review of economic evidence
The EAG did a systematic search to identify studies that investigated the cost effectiveness of Actim Partus, PartoSure and quantitative fetal fibronectin. One study (Gibson et al. 2013) assessed the effect of a fetal fibronectin test (at thresholds of 10, 50, 200 and 500 ng/ml) on the use of antenatal corticosteroids. There were a further 3 observational cost–minimisation studies that reported costs and resource use data, but these were published over 10 years ago and it was not certain whether the protocols used in the studies reflected current clinical practice.
The EAG also identified 6 economic models. A cost–minimisation modelling approach was used in 2 studies. Chuck and Nguyen (2015) looked at the cost of adopting fetal fibronectin in Alberta, Canada and estimated that introducing the test between 2008 and 2013 increased costs by US $4 million. Conversely, the Deshpande et al. (2013) study was done in the UK and found that the Rapid fetal fibronectin test saved the NHS £23.88 per patient compared with clinical examination alone.
Cost-effectiveness modelling was used in 3 studies (Boyd et al. 2011, Mozurkewich et al. 2000 and van Baaren et al. 2017) and in the NICE guideline on preterm labour and birth. The NICE guideline model was hypothetical and assessed what the specificity and sensitivity of the tests (cervical length measurement by ultrasound, Actim Partus and fetal fibronectin) would need to be for them to be considered cost effective compared with a no-test, treat-all strategy. It accounted for the effect of test accuracy on cost effectiveness at different gestational ages and found that testing was not cost effective below 30 weeks of pregnancy. The main assumptions in the NICE guideline model were:
the choice of diagnostic strategy had no significant effect on the mother's health outcomes
clinicians did not deviate from the diagnostic protocol
neonatal morbidity outcomes were based on respiratory distress syndrome and intraventricular haemorrhage
the lifetime quality of life and costs are the same for both full-term and preterm babies.
## Modelling approach
The EAG developed a de novo economic model to evaluate the cost effectiveness of quantitative fetal fibronectin using the Rapid fFN 10Q Cassette Kit at thresholds other than 50 ng/ml, Actim Partus and PartoSure compared with fetal fibronectin at 50 ng/ml. The model was based on the NICE guideline model, but several parameters used to populate the model were updated. The base case took the perspective of the NHS and personal social services and had a lifetime time horizon (100 years). A discount rate of 3.5% was applied to both costs and effects.
The population was women with intact membranes presenting with symptoms of threatened preterm labour between 24 and 36 weeks of pregnancy. It was assumed that, before entering the model, a clinical assessment had been done that could not rule out preterm labour.
A decision tree structure that included a diagnostic phase followed by treatment and long-term outcomes was used. The model started with an assessment of preterm labour, and then modelled the decision of whether to admit to hospital or discharge home, and whether to offer corticosteroids. It evaluated:
the interventions (Actim Partus, PartoSure and quantitative fetal fibronectin at thresholds of 10, 200 and 500 ng/ml)
a no-test, treat-all strategy, which assumes that all women entering the model are admitted to hospital
the comparator (fetal fibronectin at a threshold of 50 ng/ml).Longer-term costs and quality-adjusted life years (QALYs) were then calculated for each branch of the decision tree.
The model was populated with data from the diagnostic accuracy review, published literature and expert opinion. Estimates of diagnostic accuracy for fetal fibronectin and Actim Partus were taken from APOSTEL‑1, which included a direct comparison of the 2 tests. None of the studies directly compared PartoSure with fetal fibronectin, so diagnostic accuracy was estimated using data from APOSTEL‑1 and Hadzi‑Lega et al. Scenario analyses were done using data from alternative sources: Cooper et al. 2012, Abbott et al. 2013 and an EAG meta-analysis. The diagnostic accuracy estimates are in table 1.
Diagnostic accuracy values used in the economic model
Diagnostic test (threshold)
Sensitivity
Specificity
fFN (10 ng/ml)
fFN (50 ng/ml)
fFN (200 ng/ml)
fFN (500 ng/ml)
Actim Partus
Abbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.
Diagnostic test (threshold)
Sensitivity
Specificity
PartoSure
Actim Partus
Abbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.
Diagnostic test (threshold)
Sensitivity
Specificity
Actim Partus
fFN (50 ng/ml)
Abbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.
Diagnostic test (threshold)
Sensitivity
Specificity
fFN (10 ng/ml)
fFN (50 ng/ml)
fFN (200 ng/ml)
fFN (500 ng/ml)
Abbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.
Diagnostic test (threshold)
Sensitivity
Specificity
Actim Partus
fFN (50 ng/ml)
Abbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.
The following costs, from companies, published literature and routine sources of NHS costs, were used in the model:
fetal fibronectin test: £66 (includes 15 minutes of midwife time)
Actim Partus test: £35 (includes 10 minutes of midwife time)
PartoSure test: £52 (includes 10 minutes of midwife time)
maternal steroid injection: £5
tocolytics (atosiban plus infusion equipment): £362
inpatient hospital stay: £1,325
in utero transfer: £965
long-term healthcare costs of intraventricular haemorrhage: £114,648
neonatal hospital costs for respiratory distress syndrome: £5,587
neonatal hospital costs: baby dies before discharge: £22,834.
Health-related quality-of-life estimates for babies were included in the base case, and a scenario analysis also included maternal health-related quality-of-life estimates. A utility for severe persistent asthma was applied to 56% of children with respiratory distress syndrome based on clinical expert opinion. Utilities used in the model are shown in table 2.
Variable
Patient
Source
Utility
'Severe' RDS (severe persistent asthma used as proxy)
Child
Carroll and Downs 2009
IVH grades 3 to 4 (moderate cerebral palsy used as proxy)
Child
Carroll and Downs via Bastek et al. 2012
Death
Child
Vandenbussche et al. 1999
Preterm survivor
Child
Cooke 2004
Mother with previous adverse child outcome
Mother
Couto et al. 2009
Mother with no adverse child outcome
Mother
Couto et al. 2009
Abbreviations: IVH, intraventricular haemorrhage; RDS, respiratory distress syndrome.
## Base-case results
The following assumptions were applied in the base-case analysis:
The population entered the model after a clinical examination which did not rule out preterm labour.
QALY outcomes were the same for women with false positive results (who did not deliver before the reference standard), true negative results and false negative results.
All treatment decisions were driven by the test result, and clinical judgement did not override this.
Diagnostic accuracy was equivalent across all gestational ages.
The prevalence of preterm birth within 7 days of testing was 3%, and the preterm birth rate was 12.1%.
Antenatal corticosteroids were only effective within 7 days of delivery; babies born more than 7 days after treatment did not benefit.
In utero transfers were only available for women presenting to a level 1 or 2 hospital at less than 28 weeks of pregnancy.
Tocolysis was used for all in utero transfers at less than 28 weeks of pregnancy.
Only intraventricular haemorrhage resulted in longer-term costs.
Babies who survived beyond 1 year had a long-term quality of life equivalent to the average for preterm babies who survived.
The base-case results were given for groups of women presenting at 33, 30 and 26 weeks of pregnancy. Results were also stratified according to the level of neonatal care available at the place of birth.
Base-case results for women presenting at 30 weeks of pregnancy at a level 2 hospital are shown in table 3. Most tests were cheaper and less effective than fetal fibronectin 50 ng/ml, apart from a treat-all strategy and fetal fibronectin at 10 ng/ml, which resulted in very small QALY gains and additional cost. Many of the tests were cheaper and less effective than the comparator; this means that the results are in the south-west quadrant of the cost-effectiveness plane.
Test
Total costs (£)
Total QALYs
ICER (£ per QALY)
(versus fFN 50 ng/ml)
PartoSure
fFN 500 ng/ml
Actim Partus
fFN 200 ng/ml
fFN 50 ng/ml
fFN 10 ng/ml
Treat all
- ICER represents cost saved per QALY lost, it is in the south-west quadrant of the cost-effectiveness plane.
Abbreviations: fFN, fetal fibronectin; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ng/ml, nanograms per millilitre.
The incremental cost-effectiveness ratios (ICERs) for the tests for women in a level 2 hospital at 26 weeks of pregnancy reduced compared with the base-case results. This reduction applied to tests that were cheaper and less effective than the comparator (which became less cost effective) and to tests that cost more and were more effective than the comparator (which became more cost effective).
The ICERs for the tests for women in a level 2 hospital at 33 weeks of pregnancy increased compared with the base-case results. This increase applied to tests that were cheaper and less effective than the comparator (which became more cost effective) and to tests that cost more and were more effective than the comparator (which became less cost effective).
The EAG updated the results of the analyses using data from 2 additional studies (Nikolova et al. and Wing et al. 2017) that were highlighted in stakeholder comments on the diagnostics assessment report. For PartoSure compared with fetal fibronectin at 50 ng/ml, the addition of accuracy data from these studies resulted in a greater QALY loss than was seen in the EAG's base case. However, using the accuracy estimates from Nikolova et al. resulted in greater cost savings and using the accuracy estimates from Wing et al. resulted in lower cost savings.
The effect of changing assumptions about the accuracy of the tests was explored in 2 scenario analyses. Alternative diagnostic accuracy data from Cooper et al. (2016) were used to calculate ICERs for Actim Partus compared with fetal fibronectin at a threshold of 50 ng/ml. In this analysis Actim Partus was dominated by fetal fibronectin (that is, fetal fibronectin was more effective and less expensive). Also, alternative diagnostic accuracy data were obtained for fetal fibronectin at thresholds of 10, 200 and 500 ng/ml compared with fetal fibronectin at a threshold of 50 ng/ml from an unpublished study by Abbott et al. The results of this analysis are academic in confidence.
The scenario analysis with the greatest effect on the ICERs was limiting the time horizon of the analysis to the first year after birth. The ICERs became less favourable for all interventions and increased by more than 20 times the base-case value.
Assuming that antenatal steroids have partial benefits if given more than 7 days before birth also had a considerable effect on all the ICERs. This produced more favourable ICERs for PartoSure, the treat-all strategy and fetal fibronectin at a threshold of 10 ng/ml. However, it produced less favourable ICERs for Actim Partus and fetal fibronectin at thresholds of 200 ng/ml and 500 ng/ml.
Deterministic sensitivity analyses were done by varying the base-case parameters by 20%. These analyses found that the ICERs were most sensitive to changes in health-related quality of life of preterm babies who survived. Other parameters affecting the ICERs were cost of hospital admission, prevalence of preterm birth within 7 days, effectiveness of steroid treatment and baseline mortality risk.
The EAG also ran probabilistic sensitivity analyses and presented the results as cost-effectiveness acceptability curves. Probabilistic ICERs were not presented.# Committee discussion
# Care pathway
The committee discussed current practice for diagnosing and managing preterm labour in women with intact membranes. The clinical experts explained that the incidence of birth before 37 weeks of pregnancy in the UK was around 8% and an estimated 50,000 to 60,000 babies are born preterm each year. Women with suspected preterm labour have a clinical assessment and a fetal fibronectin (fFN) test is commonly used to help determine whether labour is established. Although NICE's guideline on preterm labour and birth recommends transvaginal ultrasound as the preferred diagnostic option, this is not available everywhere. Also, it needs healthcare professionals with appropriate training to perform and interpret the scan. The committee noted that the NICE guideline recommends that all women who present at less than 30 weeks of pregnancy have treatment based on clinical assessment alone, but heard that in practice many of these women also have a fFN test, or another test. The committee concluded that for women who present at 30 weeks or above, the most appropriate comparator was fFN at a threshold of 50 nanograms/millilitre (ng/ml). For women who present at less than 30 weeks, a treat-all management pathway and fFN testing should be considered to reflect variation in current practice.
# Patient experience
The committee discussed the effect that suspected preterm labour can have on pregnant women and their partners. The patient experts explained that preterm labour is associated with substantial anxiety, particularly when a diagnosis is difficult to confirm. For example, women who have a false positive result might be transferred to a higher level hospital unnecessarily. The committee noted that understanding whether preterm labour is established is of considerable importance to pregnant women. It heard about the importance of communicating the risks and benefits associated with the different diagnostic options so that women are able to understand the test results. The possibility of false negative results should also be explained and women given reassurance that they can return to hospital if they feel that their symptoms have not resolved despite a negative test result.
# Clinical effectiveness
## Diagnostic accuracy
The committee discussed the studies included in the diagnostic accuracy review. It noted that 16 studies were available for Actim Partus, 2 studies were available for fFN using thresholds of 10 ng/ml, 200 ng/ml and 500 ng/ml and 4 studies were available for PartoSure. It acknowledged that 7 studies had been submitted by 1 company after the diagnostics assessment report had been completed. The variation in estimates of diagnostic accuracy from the additional studies was similar to that seen in the studies assessed by the external assessment group (EAG), and so added further uncertainty to the results.
The committee noted that the studies included in the review were done outside of the UK. It understood that the management of preterm labour was likely to vary from country to country and that this had the potential to affect test accuracy. The EAG was unable to explore the likely effect of this variation because many studies did not provide details on how preterm labour was managed, particularly whether the delivery was spontaneous or induced for medical reasons. This variable had a direct effect on how the reference standards of birth within 48 hours or 7 days of testing were interpreted, and on determining true and false positive index test results. The committee concluded that because of shortcomings in how the results of the included studies were reported, it was not able to judge whether the results were generalisable to the NHS.
The committee considered the results of the EAG's diagnostic accuracy meta-analyses, and noted that the accuracy estimates differed substantially between studies. The studies included in the review recruited a wide range of women and the EAG raised concerns that there was substantial heterogeneity in a number of important patient characteristics, including gestational age, multiple pregnancy and history of preterm birth. The EAG explained that it did not consider the pooled diagnostic accuracy results to be reliable, because variables that may affect test accuracy such as the use of tocolytics, mode of delivery and gestational age were not reported in many of the studies. Therefore the EAG had not been able to explore which variables were driving the differences in test accuracy estimates between studies. More detailed reporting of the results would be needed for the EAG to have confidence in the pooled diagnostic accuracy results. The EAG further cautioned that the confidence intervals around the pooled estimates were unlikely to sufficiently characterise the uncertainty in the included studies. The committee concluded that there was substantial uncertainty in the pooled results. It also considered that there was a need for further robust diagnostic accuracy studies which aim to address the methodological limitations identified by the EAG (see section 5.14).
The committee questioned whether gestational age was likely to affect the accuracy of the tests. It noted that the EAG had not been able to do subgroup analyses by gestational age because insufficient data were available. The clinical experts explained that it was plausible that test accuracy could vary by gestational age, because the causes of preterm labour might be different at certain gestational ages. Although the biomarkers detected by each of the tests are thought to be associated with a common preterm labour biochemical signal, their expression may differ depending on the cause of preterm labour. For example, the biomarkers may perform differently in women with preterm labour caused by placental bleeding compared with preterm labour caused by ascending infection. The committee concluded that further evidence is needed on the effect of gestational age on test accuracy (see section 5.14).
The committee discussed how the test results would be used to guide clinical management. The EAG explained that it had not found any studies which reported the effect of the tests on decision-making, but noted that its search had been restricted to controlled study designs only. The clinical experts explained that biomarker test results are used as an aid to decision-making and are not intended to provide a final decision on the treatment pathway for a woman with symptoms of preterm labour. The importance given to biomarker test results varies in practice depending on the presenting symptoms and clinical history. The clinical experts noted that negative results are often interpreted with caution. They highlighted a study (Dutta et al. 2011) which looked at clinicians' compliance with test results and found that 20 to 30% of women with negative test results had corticosteroid treatment as if they were in preterm labour. The committee considered that it was uncertain how differences in test accuracy might translate to differences in patient outcomes in practice, particularly quality of life for the mother and child. It concluded that further research was needed to collect these data (see section 5.15 and section 5.16).
# Cost effectiveness
The committee noted that because the EAG considered the results of the meta-analyses to be unreliable, the EAG preferred to use data from studies comparing at least 2 of the biomarker tests in the same population to assess their relative accuracy in the economic model. The committee understood that this approach was taken to minimise bias in the accuracy estimates, which might arise because of differences in study design. It noted that no studies assessed all 3 biomarker tests in the same population. The EAG used diagnostic accuracy results from 2 studies (APOSTEL‑1 and Hadzi‑Lega et al. 2017) in the base-case analysis, although this was subsequently revised to include additional studies for PartoSure. The clinical experts noted that the studies were unlikely to be representative of women in NHS clinical practice. In APOSTEL‑1 there was a high proportion of women who would be considered high risk, with 23% of women having previous preterm delivery. The clinical experts explained that this would be lower in practice. Also, Hadzi‑Lega et al. included a small number of women (n=57) and was carried out in Macedonia, where the care pathway was likely to vary considerably compared with NHS clinical practice. The committee concluded that the women in the studies included in the model (APOSTEL‑1 and Hadzi‑Lega et al.) did not represent those seen in NHS clinical practice.
The committee was aware that the EAG's de novo model comprised a decision tree, which took account of both the neonatal care options available at a hospital (levels 1 to 3) and gestational age. The EAG explained that all tests included in the model were compared with no treatment. The committee considered the quality-adjusted life-year (QALY) payoffs that had been attached to each of the test outcomes. The EAG explained that because of a lack of clinical outcome data, equal QALYs had been assumed for true negative, false positive and false negative results. The patient and clinical experts noted that this approach did not adequately capture the outcomes that could arise from testing. False positive results may be associated with substantial anxiety and may also result in unnecessary treatment, particularly because the model assumed that clinical judgement did not influence the interpretation of test results. Also, although in practice women with false negative results are likely to return with ongoing symptoms, the patient experts said that sometimes these results reassure women and they may not return to hospital in time for effective treatment. This could severely affect the longer-term health of the child born preterm. Therefore the committee considered that the costs and longer-term health outcomes of the child were unlikely to have been adequately captured for false negative results. It concluded that, to capture the full effect of testing, future models should incorporate the effect of changes in both sensitivity and specificity.
The committee considered the costs used in the economic model. It noted stakeholder comments received during consultation on tocolytic costs used in the model. The EAG explained that it had assumed that atosiban would be used in a scenario analysis in which in utero transfers occurred, but was aware that nifedipine is the first-line tocolytic recommended in the NICE guideline on preterm labour and birth. The clinical experts stated that nifedipine was much less expensive than atosiban. The committee noted that although this cost did not affect the base-case results, if nifedipine had been used in the scenario analysis, the observed cost savings would have been lower. It also considered whether the economic model adequately captured the costs relating to adverse events and long-term health outcomes of the mother and child. The clinical experts explained that the cost of intraventricular haemorrhage in the economic model was likely to be an underestimate, at an average cost of £114,648 per child, and noted that it had been estimated using costing data for cerebral palsy. They also explained that they would expect the lifetime healthcare costs to be at least 10 times higher than those in the model, particularly for babies who were extremely preterm and more likely to have a severe form of intraventricular haemorrhage (grades 3 to 4). Also the committee noted that the model did not account for costs relating to necrotising enterocolitis, which can be significant, and it excluded costs of neonatal and maternal sepsis. The EAG explained that not all costs for long-term health events could be included because there were no data about this. The committee concluded that the model was likely to considerably underestimate the longer-term costs of preterm birth.
The committee discussed the economic model's results. It recalled its consideration of the limitations in the clinical data available for the biomarker tests. These included the lack of studies on clinical outcomes, poor reporting of studies, the heterogeneity and lack of head-to-head studies comparing all 3 tests (see section 5.3 to section 5.7). This led to many simplifying assumptions in the economic model, which the committee did not consider to be clinically plausible. It noted that probabilistic ICERs had not been presented, and that the fully incremental analyses appeared to contain errors. It therefore considered the available pairwise deterministic ICERs, but noted that probabilistic ICERs would have been preferred. Many of the deterministic ICERs for the tests compared with fetal fibronectin at a threshold of 50 ng/ml were in the south-west quadrant of the cost-effectiveness plane, that is, the index tests were cheaper and less effective than the comparator. The committee noted that the QALY loss in most comparisons was relatively small (−0.006). However, because of the limitations in the clinical data and the implementation of the model (see section 5.8 and section 5.9), it was not possible to determine the magnitude or direction of the health-related outcomes that might occur in practice. Also, it noted that the model's predicted cost savings may not be realised in practice (see section 5.10). The committee agreed that the degree of uncertainty in the current clinical evidence was too high for it to be able to use the ICERs for decision-making. It considered that the scope of any further revisions to the assumptions in the modelling would be limited without more robust clinical data. The committee concluded that without robust diagnostic accuracy and clinical outcome data, it was not able to recommend Actim Partus, quantitative fFN testing using the Rapid fFN 10Q Cassette Kit at thresholds other than 50 ng/ml and PartoSure for use in the NHS to diagnose preterm labour in women with intact membranes.
# Research considerations
The clinical experts explained that there are 2 ongoing UK studies looking at the use of biomarker tests for preterm labour in the NHS; QUIDs II and PETRA. QUIDs II plans to recruit over 2,000 women and includes Actim Partus, PartoSure and quantitative fFN testing. It is scheduled to complete by September 2018. PETRA plans to recruit over 1,000 women and includes quantitative fFN testing. It is scheduled to report by the end of 2018. The committee considered that the results of these studies could provide diagnostic accuracy data that are generalisable to NHS practice and additional data on patient-reported outcomes. Also, it noted that QUIDs II would provide comparative accuracy data for all 3 interventions from the same population, which should overcome some of the bias introduced to the analyses by indirect comparisons.
The committee questioned how reproducible the test results were in clinical practice. The companies explained that each test has a recommended sample collection protocol which should be followed, although the clinical experts commented that it was uncertain how strictly these were followed in practice. The EAG noted that the reproducibility of PartoSure in practice had been explored (Werlen et al. 2015), but that equivalent data were not available for Actim Partus or quantitative fFN testing. The committee encouraged the companies to do similar studies to show the reproducibility of Actim Partus and quantitative fFN testing using the Rapid fFN 10Q Cassette Kit.
The committee noted the need for further diagnostic accuracy studies to assess whether the accuracy of Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN 10Q Cassette Kit differs by gestational age (see section 5.6). Studies should also aim to collect data that help to identify if a birth occurred spontaneously or because of medical intervention, including whether the woman had tocolytics and the mode of delivery (see section 5.5).
The committee noted that there were no data on how the test results affect clinical decision-making. It considered that further studies should be done to address this uncertainty (see section 5.7). This could be incorporated into a clinical outcome study, or could be done as a standalone study with clinical experts being asked to provide a management plan for a clinical scenario both with and without knowledge of the biomarker test result.
The committee noted that further studies should be done to assess the effect of Actim Partus, PartoSure and quantitative fetal fibronectin testing using the Rapid fFN 10Q Cassette Kit on maternal and neonatal outcomes, including quality of life (see section 5.7). When possible, these studies should also collect data on resource use associated with preterm birth.
|
{'Recommendations': "There is currently insufficient evidence to recommend the routine adoption of Actim Partus and PartoSure to help diagnose preterm labour in women with intact membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable.\n\nThere is currently insufficient evidence to recommend the routine adoption of the Rapid fetal fibronectin (fFN)\xa010Q Cassette Kit (using thresholds other than 50\xa0nanograms/millilitre [ng/ml] to guide clinical management) to help diagnose preterm labour in women with intact membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable. Recommendations on qualitative fetal fibronectin testing with a fixed threshold of 50\xa0ng/ml are covered by NICE's guideline on preterm labour and birth, and are not affected by this diagnostics guidance.\n\nFurther research is needed on the accuracy of the tests and their effect on clinical outcomes. Centres using the tests to help diagnose preterm labour in women with intact membranes are encouraged to take part in studies to address the research considerations (see section\xa05.12 to\xa0section 5.16). Data are needed on:\n\nthe impact of gestational age on the accuracy of the tests\n\nhow the tests affect clinical decision-making\n\nthe effect of the tests on outcomes for mother and baby.", 'Clinical need and practice': "# The problem addressed\n\nBiomarker tests (PartoSure, Actim Partus and the Rapid fetal fibronectin [fFN]\xa010Q Cassette Kit) are intended for use with other clinical information to assess the risk of preterm birth in women with symptoms of preterm labour who have intact amniotic membranes. These tests may be used instead of qualitative fetal fibronectin testing (using a threshold of 50\xa0nanograms/millilitre [ng/ml]) or clinical assessment alone, when transvaginal ultrasound measurement of cervical length is not available or not acceptable. The results would help clinicians decide whether women need to be admitted to hospital for treatment to delay birth and improve neonatal outcomes.\n\nThe biomarker tests may result in more accurate diagnosis of preterm labour than tests currently used in NHS clinical practice. This could lead to improved health outcomes for women and their babies, and cost savings through reducing the length of hospital stay, reducing unnecessary hospital admissions, and minimising unnecessary transfers between hospitals. The tests may also enable better resource planning based on the expected need for transfers between hospitals and neonatal intensive care.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of biomarker tests (Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN\xa010Q Cassette Kit) to help diagnose preterm labour in women with intact amniotic membranes when transvaginal ultrasound measurement of cervical length is not available or not acceptable.\n\n# The condition\n\n## Preterm labour and birth\n\nPreterm labour is defined as regular contractions of the uterus resulting in changes in the cervix that start before 37\xa0weeks of pregnancy. Preterm labour and birth is fairly common in the UK, with 8% of babies born before 37\xa0weeks of pregnancy. However, less than\xa01% of babies are born between 22\xa0and 28\xa0weeks of pregnancy (Royal College of Obstetricians and Gynaecologists\xa02014).\n\nThe World Health Organization defines preterm birth as:\n\nextremely preterm (less than 28\xa0weeks of pregnancy)\n\nvery preterm (28\xa0to less than 32\xa0weeks of pregnancy)\n\nmoderate to late preterm (32\xa0to less than 37\xa0weeks of pregnancy).\n\nAround 25% of preterm births are planned because of maternal factors such as pre‑eclampsia, or fetal factors such as extreme growth restriction. But most preterm births occur because labour starts early naturally. Known risk factors for preterm labour include:\n\nprevious preterm delivery\n\ntwins or other multiple pregnancies\n\ngenital tract infections\n\npreterm premature rupture of membranes\n\nproblems with the uterus, cervix or placenta\n\nsome chronic conditions, such as high blood pressure and diabetes\n\nsmoking or drug use\n\nbeing underweight or overweight before pregnancy and\n\nstressful life events.\n\nThe Department of Health and Social Care's toolkit for high-quality neonatal services (2009) describes 3\xa0types of hospital units providing neonatal care for preterm babies:\n\nSpecial care units (level\xa01) provide special care for their local population, and may also provide some high dependency services.\n\nLocal neonatal units (level\xa02) provide neonatal care for their local population, except for the sickest babies. Most babies born after 27\xa0weeks of pregnancy will usually have full care, including short periods of intensive care, in their local neonatal unit.\n\nNeonatal intensive care units (level\xa03) are sited alongside specialist obstetric and fetomaternal medicine services. They provide the whole range of medical neonatal care for their local population, along with additional care for babies and their families referred from the neonatal network.\n\nClinical experts have noted that most babies born after 35\xa0weeks of pregnancy will be looked after on postnatal wards with their mothers.\n\nPreterm birth can potentially lead to short-term health problems in a newborn baby; for example, problems breathing and feeding, and higher risk of infection. The main concerns include:\n\nchronic lung disease at 36\xa0weeks (corrected age)\n\nintraventricular haemorrhage\n\nnecrotising enterocolitis\n\nretinopathy of prematurity.\n\nBabies who are born early, particularly those born before 28\xa0weeks of pregnancy, may have lifelong disabilities. These include physical disabilities, learning disabilities, behavioural problems, and visual and hearing problems.\n\n# The diagnostics and care pathways\n\n## Clinical assessment\n\nNICE's guideline on preterm labour and birth states that women reporting symptoms of preterm labour who have intact membranes should have a clinical assessment.\n\nIf the clinical assessment suggests that the woman is in suspected preterm labour and she is 29\xa0weeks plus 6\xa0days pregnant or less, treatment for preterm labour is recommended.\n\nClinical experts have noted that, in practice, not all women in suspected preterm labour who are 29\xa0weeks plus 6\xa0days pregnant or less have treatment. They have stated that these women often have diagnostic testing because there are insufficient resources available to admit or transfer all women, there is concern about the effect of unnecessary treatment and women may prefer to avoid hospital admission and transfer when possible.\n\n## Transvaginal ultrasound measurement of cervical length\n\nIf the clinical assessment suggests that the woman is in suspected preterm labour and she is 30\xa0weeks plus 0\xa0days pregnant or more, transvaginal ultrasound measurement of cervical length should be considered to determine the likelihood of birth within 48\xa0hours. If cervical length is more than 15\xa0mm, it is unlikely that the woman is in preterm labour. If cervical length is 15\xa0mm or less, preterm labour should be diagnosed and treatment offered.\n\nNICE's guideline on preterm labour and birth notes that ultrasound scans should be done by healthcare professionals with training in, and experience of, transvaginal ultrasound measurement of cervical length. The guideline committee also noted that transvaginal ultrasound scanning is not routinely available across the NHS because equipment or expertise is limited, and that investment in technology and training may be needed for its universal implementation in the NHS. These limitations also increase the likelihood that biomarker testing will be carried out.\n\n## Fetal fibronectin testing\n\nIf transvaginal ultrasound measurement of cervical length is indicated but is not available or not acceptable, fetal fibronectin testing should be considered to determine the likelihood of birth within 48\xa0hours for women who are 30\xa0weeks plus 0\xa0days pregnant or more. If the fetal fibronectin test result is negative (concentration 50\xa0ng/ml or less), it is unlikely that the woman is in preterm labour. If the fetal fibronectin test result is positive (concentration more than 50\xa0ng/ml), preterm labour should be diagnosed and treatment offered. NICE's guideline on preterm labour and birth notes that if fetal fibronectin testing is anticipated, the swab should be taken before any digital vaginal examination.\n\nIf a woman in suspected preterm labour who is 30\xa0weeks plus 0\xa0days pregnant or more does not have transvaginal ultrasound measurement of cervical length or fetal fibronectin testing to exclude preterm labour, treatment should be offered consistent with her being in diagnosed preterm labour.\n\nA women in suspected preterm labour, but with a negative diagnostic test result suggesting that preterm labour is unlikely, may go home or may continue to be monitored and have treatment in hospital. If the woman goes home, she is advised to return to hospital if symptoms suggesting preterm labour persist or recur.\n\nNICE's guideline on preterm labour and birth notes that transvaginal ultrasound measurement of cervical length and fetal fibronectin testing should not be used in combination to diagnose preterm labour.\n\nThe European Association of Perinatal Medicine's recommendations on preterm labour and birth management state that 2\xa0methods can be used to improve the accuracy of the diagnosis of preterm labour in women with symptoms:\n\ntransvaginal ultrasound cervical length measurement\n\nmeasurement of biochemical markers in cervical-vaginal secretions (fetal fibronectin or placental alpha macroglobulin‑1 [PAMG‑1] or insulin-like growth factor binding protein‑1 [IGFBP‑1]).", 'The diagnostic tests': "Three interventions and 2\xa0comparators were included in this assessment.\n\n# The interventions\n\n## Actim Partus\n\nActim Partus is a CE‑marked qualitative immunochromatographic point-of-care test designed to detect phosphorylated IGFBP‑1 (insulin-like growth factor binding protein‑1) in cervical secretions during pregnancy. Phosphorylated IGFBP‑1 is a protein made by the cells lining the uterus. When delivery is imminent, small amounts of phosphorylated IGFBP‑1 leak into the cervix.\n\nThe Actim Partus test kit contains a sterile polyester swab for specimen collection, a tube of specimen extraction buffer and a dipstick in a sealed foil pouch. No other instrumentation or consumables are needed. The sample is collected from the cervical os during a sterile speculum examination. The results are available in 5\xa0minutes or less. Two lines indicate a positive result; 1\xa0line is a negative result that indicates the woman will not deliver within 7\xa0to 14\xa0days; if no lines appear, the test is invalid.\n\nThe dipstick contains 2\xa0monoclonal antibodies to human IGFBP‑1. One is bound to blue latex particles (the detecting label). The other is immobilised on a carrier membrane to catch the complex of antigen and latex-labelled antibody and indicate a positive result. If phosphorylated IGFBP‑1 is present in the sample, it binds to the antibody labelled with latex particles. The particles flow to the results area of the dipstick, and if phosphorylated IGFBP‑1 is bound to them, they bind to the catching antibody. A test line will appear if the concentration of phosphorylated IGFBP‑1 in the sample exceeds the detection limit of the test. A control line confirms correct performance of the test.\n\nActim Partus is for use in pregnant women with signs and symptoms of preterm labour and intact amniotic membranes, after 22\xa0weeks plus 0\xa0days of pregnancy. The test can be used if vaginal infections, vaginal medications and semen are present, but active vaginal bleeding may cause a false positive result. The test has a limit of detection of 10\xa0nanograms/millilitre (ng/ml) and a measuring range of 10\xa0to 8,000\xa0ng/ml.\n\n## PartoSure\n\nPartoSure is a CE‑marked qualitative lateral flow, immunochromatographic point-of-care test designed to detect placental alpha microglobulin‑1 (PAMG‑1) in vaginal secretions during pregnancy. PAMG‑1 is a protein released from the lining of the uterus into the amniotic cavity throughout pregnancy. It is found in very high concentrations in amniotic fluid and in very low concentrations in normal vaginal discharge. Studies have demonstrated a strong correlation between the presence of PAMG‑1 in cervicovaginal discharge and imminent delivery.\n\nThe PartoSure test kit contains a test strip, a vaginal swab and a plastic vial containing a solvent solution. No other instrumentation or consumables are needed. The sample may be collected with or without a speculum. The results are available in 5\xa0minutes or less. Two lines indicate a positive result and a high risk of delivery within 7\xa0days; 1\xa0line indicates a negative result and a low risk of delivery within 7\xa0to 14\xa0days; no lines indicate an invalid result.\n\nThe test strip has a reactive area containing monoclonal anti-PAMG-1 antibodies bound to a gold particle (the detecting label). The sample flows through the reactive area and if PAMG‑1 is present, it binds to an anti-PAMG‑1 antibody, forming an antigen-antibody complex. This complex then flows to the test region of the strip where it is immobilised by a second anti-PAMG‑1 antibody. A test line appears if the concentration of PAMG‑1 in the sample exceeds the detection limit of the test. Unbound antigen-antibody complexes continue to flow along the test strip and are immobilised by another antibody, leading to the appearance of the internal control line.\n\nPartoSure is for use in pregnant women with signs and symptoms of preterm labour, intact amniotic membranes and minimal cervical dilatation (3\xa0cm or less), between 20\xa0weeks plus 0\xa0days and 36\xa0weeks plus 6\xa0days of pregnancy. The test can be used if vaginal infections, urine, semen and trace amounts of blood are present, but should not be used if there is significant discharge of blood. It can also be used shortly after a vaginal examination. The test has a limit of detection of 1\xa0ng/ml and a measuring range of 1\xa0to 40,000\xa0ng/ml.\n\n## Rapid fetal fibronectin 10Q Cassette Kit\n\nThe Rapid fetal fibronectin (fFN)\xa010Q Cassette is a CE‑marked test for use in the PeriLynx System or the Rapid fFN\xa010Q System. It is designed for the quantitative detection of fetal fibronectin in cervicovaginal secretions to assess the risk of preterm delivery within 7\xa0to 14\xa0days. Fetal fibronectin is an adhesive glycoprotein that holds the membranes of the uterus to the fetal membranes. After 35\xa0weeks of pregnancy, it begins to break down naturally, and is detectable in vaginal secretions. Fetal fibronectin detected between 22\xa0and 35\xa0weeks of pregnancy is an indicator of preterm birth risk.\n\nNICE's guideline on preterm labour and birth recommends fetal fibronectin testing to determine the likelihood of birth within 48\xa0hours for women who are 30\xa0weeks plus 0\xa0days pregnant or more, if transvaginal ultrasound measurement of cervical length is indicated but is not available or not acceptable. The guideline recommends a threshold of 50\xa0ng/ml to interpret the test results. However, clinical experts have noted that a quantitative fetal fibronectin test would enable other thresholds to be used.\n\nThe Rapid fFN\xa010Q Cassette test can be done near the woman. In addition to the test kit, an analyser, printer, Rapid fFN Control Kit, QCette (quality control device) and pipette are needed. The sample is collected from the posterior fornix of the vagina during a speculum examination. It is incubated in the analyser for 7\xa0minutes and then analysed, which takes 2\xa0to 3\xa0minutes. The analyser reports fetal fibronectin concentrations ranging from 0\xa0to 500\xa0ng/ml; concentrations greater than 500\xa0ng/ml are displayed as 'greater than 500\xa0ng/ml'. The instructions for use do not give any thresholds, therefore laboratories would need to set and validate their own thresholds. Internal controls are done automatically with every test.\n\nThe Rapid fFN\xa010Q Cassette is for use in pregnant women with signs and symptoms of early preterm labour, intact amniotic membranes and minimal cervical dilatation (less than 3\xa0cm), between 22\xa0weeks plus 0\xa0days and 35\xa0weeks plus 6\xa0days of pregnancy. Assay interference from blood, bacteria, bilirubin and semen has not been ruled out. However, a negative test result (less than 10\xa0ng/ml) in the presence of blood or semen is valid. Also, the fetal fibronectin concentration may be affected by cervical disruption caused by, but not limited to, sex, digital cervical examination or vaginal probe ultrasound.\n\n# The comparators\n\n## Fetal fibronectin\n\nFetal fibronectin testing, at a threshold of 50\xa0ng/ml, is recommended in NICE's guideline on preterm labour and birth (see section\xa02.16 to\xa0section 2.19 of this guideline).\n\nThe fetal fibronectin test is available as a quantitative enzyme-linked immunosorbent assay (ELISA), and as a qualitative membrane immunosorbent assay. Examples include:\n\nFetal Fibronectin Enzyme Immunoassay; a quantitative assay with a recommended threshold of 50\xa0ng/ml (Hologic)\n\nRapid fFN for the TLilQ System; a qualitative immunochromatographic assay with a limit of detection of 50\xa0ng/ml (Hologic)\n\nQuikCheck Fetal Fibronectin Test; a qualitative test with a limit of detection of 50\xa0ng/ml (Hologic).\n\n## Clinical assessment\n\nClinical assessment is described in the NICE guideline on preterm labour and birth and in section\xa02.11 to\xa0section 2.13 of this guideline.", 'Evidence': "The diagnostics advisory committee considered evidence on the biomarker tests (PartoSure, Actim Partus and Rapid fetal fibronectin [fFN]\xa010Q Cassette Kit) for diagnosing preterm labour from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did 2\xa0systematic reviews of the clinical-effectiveness evidence for Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN\xa010Q Cassette Kit; 1\xa0for diagnostic accuracy and 1\xa0for clinical outcomes.\n\nThe EAG also did a non-systematic update of their report to include 7\xa0new studies submitted for PartoSure with stakeholder comments on the diagnostics assessment report.\n\nFor the diagnostic accuracy review, studies were included if:\n\nthey recruited women with signs and symptoms of preterm labour who were not in established labour and who had intact amniotic membranes\n\nthe population was described as preterm\n\ntwin or multiple pregnancies made up 20% or less of the total population recruited\n\nat least 1\xa0index test was reported and at least 1\xa0of the following reference standards or comparators was included:\n\n\n\npreterm delivery within 48\xa0hours\n\npreterm delivery within 7\xa0days\n\nclinical assessment of symptoms\n\nfetal fibronectin at a threshold of 50\xa0nanograms/millilitre (ng/ml)\n\n\n\nthey were prospective or retrospective diagnostic accuracy studies with random or consecutively recruited women; both single- and two‑gate designs were eligible.A single-gate study recruits patients whose disease status is unknown before testing (a consecutive series), whereas a two-gate study recruits patients with the target condition and patients who do not have the target condition (a case-control study).\n\nAll studies included in the diagnostic accuracy review were appraised using the QUADAS‑2 tool. In total, 20\xa0studies met the inclusion criteria for the diagnostic accuracy review.\n\nThe EAG also searched for studies in which clinical outcomes were reported, but did not identify any studies. The inclusion criteria were restricted to controlled studies only because the EAG considered that uncontrolled study designs are likely to be susceptible to bias.\n\n## Study characteristics\n\nOf the 20\xa0diagnostic accuracy studies, data for more than 1\xa0index test were reported in 2\xa0studies (Hadzi‑Lega et al. 2017, APOSTEL‑1 2016), 16\xa0studies assessed Actim Partus, 4\xa0assessed PartoSure and 2\xa0assessed fetal fibronectin at thresholds other than 50\xa0ng/ml (APOSTEL‑1, EUIFS 2016). All 20\xa0studies assessed the index tests against a reference standard of preterm delivery within 7\xa0days, and 7\xa0studies also assessed the index tests against a reference standard of preterm delivery within 48\xa0hours.\n\nThe characteristics of women in the study varied and this introduced heterogeneity:\n\nMean maternal age was 25\xa0to 31\xa0years.\n\nThe proportion of multiple pregnancies was 0 to\xa020%.\n\nThe mean number of previous term pregnancies was 0.4\xa0to\xa02.9 per person.\n\nThe proportion of previous preterm deliveries was 0 to\xa030%.\n\nThe proportion of previous miscarriages was 4 to\xa027%.\n\nThe prevalence of preterm birth within 7\xa0days was 1.7 to\xa073.3%.\n\nThe prevalence of preterm birth within 48\xa0hours was 2.4 to\xa058.3%.\n\nThe women were 20\xa0weeks to 37\xa0weeks pregnant.\n\nThe reporting of whether delivery was spontaneous or as a result of medical intervention varied between studies. Only 11\xa0studies provided details on delivery; in 4,\xa0the authors stated that they excluded women from test accuracy calculations if birth occurred because of medical intervention before the 7‑day or 48‑hour reference standard.\n\n## Diagnostic accuracy\n\nIn the 16\xa0studies that included data for Actim Partus, the prevalence of birth within 7\xa0days of testing was 1.7 to 73.3%. Across the studies, sensitivity estimates were 33.3 to 94.7%. The 3\xa0studies (Cooper 2012, Danti 2011, Riboni 2011) with the lowest sensitivity estimates also had a lower prevalence of preterm birth (1.7 to 6.7%) than the other studies (9.8 to 73.3%). Specificity was 50.0 to 93.5%. The EAG did not identify any major differences in methods or participant characteristics in the 3\xa0studies with the lowest specificity estimates. The pooled analysis of these 16\xa0studies estimated a sensitivity of 77% (95% confidence interval [CI] 68 to 83%) and a specificity of 81% (95% CI 76 to 85%).\n\nThere were 6\xa0studies that tested each sample with both Actim Partus and fetal fibronectin at a threshold of 50\xa0ng/ml. Using delivery within 7\xa0days as the reference standard, sensitivity for Actim Partus was lower than for fetal fibronectin in 1\xa0study (APOSTEL‑1 2016), higher in 2\xa0studies (Ting 2017, Tripathi 2016) and the same for both tests in the remaining 3\xa0studies (Cooper 2012, Eroglu 2007, Riboni 2011). Specificity was higher for Actim Partus than for fetal fibronectin in 4\xa0of the 6\xa0studies, and lower in the 2\xa0remaining studies (Cooper, Tripathi). Cooper only reported test accuracy results for a proportion of the total Actim Partus group (58\xa0fewer women had results for the qualitative fFN test).\n\nIn response to stakeholder comments on the diagnostics assessment report, the EAG updated the diagnostic accuracy estimates for Actim Partus to include 18\xa0studies identified by a company. The updated pooled sensitivity decreased compared with the original review; from 77% (95% CI 68 to 83%) to 74.3% (95% CI 64.2 to 82.3%) and specificity increased slightly from 81% (95% CI 76 to 85%) to 81.2% (95% CI 76.2 to 85.4%).\n\nIn the 4\xa0studies that included diagnostic accuracy for PartoSure, the prevalence of birth within 7\xa0days of testing was 2.4 to 17.2%. Specificity was similar across studies, 90.2 to 97.5%, but sensitivity was 0 to 100%. Werlen et al. (2015) reported 0% sensitivity because only 1\xa0of 41\xa0women tested positive and this was a false positive. The pooled analysis of the 4\xa0studies estimated a sensitivity of 83% (95% CI 61 to 94%) and a specificity of 95% (95% CI 89 to 98%).\n\nNikolova et al. (2015) assessed fetal fibronectin at a threshold of 50\xa0ng/ml and PartoSure in the same samples (66\xa0of the total 203\xa0women). Against the 7‑day reference standard, sensitivity for PartoSure was 80% (95% CI 63.1 to 91.6%) and for fetal fibronectin it was 50% (95% CI 21.1 to 79.0%). Specificity for PartoSure was 94.6% (95% CI 90.1 to 97.5%) and for fetal fibronectin it was 72.2% (95% CI 58.4 to 83.5%).\n\nIn response to stakeholder comments on the diagnostics assessment report, the EAG updated the diagnostic accuracy estimates for PartoSure to include 9\xa0studies identified by a company. The updated pooled sensitivity decreased compared with the original review; from 83% (95% CI 61 to 94%) to 68.5% (95% CI 51.2 to 81.9%) and pooled specificity slightly increased from 95% (95% CI 89 to 98%) to 96.6% (95% CI 95.1 to 97.6%).\n\nThere were 2\xa0studies (APOSTEL‑1 2016, EUIFS 2016) that included diagnostic accuracy for quantitative fetal fibronectin. The prevalence of preterm birth within 7\xa0days was 10.5% (EUIFS) to 19.7% (APOSTEL‑1). In both studies sensitivity decreased as the threshold increased and specificity increased as the threshold increased.\n\nThe EAG reviewed 1\xa0unpublished study (Ravi et al.) that included evidence for quantitative fetal fibronectin, submitted with stakeholder comments on the diagnostics assessment report. This presented sensitivity values lower than APOSTEL‑1 and EUIFS, but higher specificity values. The details of the study cannot be reported here because they are confidential.\n\nThere were 6\xa0studies that assessed the diagnostic accuracy of Actim Partus. The prevalence of delivery within 48\xa0hours of testing was 5.3 to 58.3%. Sensitivity was 65.7 to 100.0% and specificity was 56.0 to 82.4%. The pooled analysis of the 6\xa0studies estimated a sensitivity of 87% (95% CI 74 to 94%) and a specificity of 73% (95% CI 62 to 82%).\n\nOnly 1\xa0study (Werlen et al. 2015) assessed the diagnostic accuracy of PartoSure against the 48‑hour reference standard. The prevalence of preterm birth was 2.4%. Sensitivity was 0% (95% CI 0 to 97.5%) and specificity was 97.5% (95% CI 86.8 to 99.9%). Sensitivity was 0% because only 1\xa0of 41\xa0women tested positive and this was a false positive.\n\nThe EAG identified studies in the diagnostic accuracy systematic review that included data for fetal fibronectin at a threshold of 50\xa0ng/ml. The generalisability of these data was assessed by comparing them with results from 3\xa0recently published systematic reviews of fetal fibronectin.\n\nOf the 20\xa0studies included in the diagnostic accuracy review, 8\xa0included accuracy data for quantitative fetal fibronectin at 50\xa0ng/ml. Of these, 2\xa0studies (APOSTEL‑1 2016, EUIFS 2016) used a quantitative fetal fibronectin test, 3\xa0used the QuikCheck qualitative fetal fibronectin test (Eroglu 2007, Nikolova 2015, Tripathi 2016), 1\xa0used an ELISA-based laboratory test (Riboni 2011), and in the remaining 2\xa0studies (Cooper 2012, Ting 2007), it was not clear which fetal fibronectin test was used.\n\nFor the 8\xa0studies looking at the diagnostic accuracy of fetal fibronectin at a threshold of 50\xa0ng/ml against a 7‑day reference standard, sensitivity was 23.8 to 91.3% and specificity was 62.2 to 99.1%. These results were similar to those from the 3\xa0existing literature reviews.\n\n## Diagnostic accuracy data informing the economic model\n\nThe EAG concluded that there was too much heterogeneity in the pooled results to use them for indirect comparisons between tests in the economic modelling. It decided to prioritise studies that reported results for more than 1\xa0test in the same population. Therefore, 2\xa0studies (APOSTEL‑1 2016, Hadzi‑Lega et al. 2017) were used in the base case for the economic model.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nThe EAG did a systematic search to identify studies that investigated the cost effectiveness of Actim Partus, PartoSure and quantitative fetal fibronectin. One study (Gibson et al. 2013) assessed the effect of a fetal fibronectin test (at thresholds of\xa010, 50, 200 and 500\xa0ng/ml) on the use of antenatal corticosteroids. There were a further 3\xa0observational cost–minimisation studies that reported costs and resource use data, but these were published over 10\xa0years ago and it was not certain whether the protocols used in the studies reflected current clinical practice.\n\nThe EAG also identified 6\xa0economic models. A cost–minimisation modelling approach was used in 2\xa0studies. Chuck and Nguyen (2015) looked at the cost of adopting fetal fibronectin in Alberta, Canada and estimated that introducing the test between 2008 and 2013 increased costs by US\xa0$4\xa0million. Conversely, the Deshpande et al. (2013) study was done in the UK and found that the Rapid fetal fibronectin test saved the NHS £23.88 per patient compared with clinical examination alone.\n\nCost-effectiveness modelling was used in 3\xa0studies (Boyd et al. 2011, Mozurkewich et al. 2000 and van Baaren et al. 2017) and in the NICE guideline on preterm labour and birth. The NICE guideline model was hypothetical and assessed what the specificity and sensitivity of the tests (cervical length measurement by ultrasound, Actim Partus and fetal fibronectin) would need to be for them to be considered cost effective compared with a no-test, treat-all strategy. It accounted for the effect of test accuracy on cost effectiveness at different gestational ages and found that testing was not cost effective below 30\xa0weeks of pregnancy. The main assumptions in the NICE guideline model were:\n\nthe choice of diagnostic strategy had no significant effect on the mother's health outcomes\n\nclinicians did not deviate from the diagnostic protocol\n\nneonatal morbidity outcomes were based on respiratory distress syndrome and intraventricular haemorrhage\n\nthe lifetime quality of life and costs are the same for both full-term and preterm babies.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model to evaluate the cost effectiveness of quantitative fetal fibronectin using the Rapid fFN\xa010Q Cassette Kit at thresholds other than 50\xa0ng/ml, Actim Partus and PartoSure compared with fetal fibronectin at 50\xa0ng/ml. The model was based on the NICE guideline model, but several parameters used to populate the model were updated. The base case took the perspective of the NHS and personal social services and had a lifetime time horizon (100\xa0years). A discount rate of 3.5% was applied to both costs and effects.\n\nThe population was women with intact membranes presenting with symptoms of threatened preterm labour between 24\xa0and 36\xa0weeks of pregnancy. It was assumed that, before entering the model, a clinical assessment had been done that could not rule out preterm labour.\n\nA decision tree structure that included a diagnostic phase followed by treatment and long-term outcomes was used. The model started with an assessment of preterm labour, and then modelled the decision of whether to admit to hospital or discharge home, and whether to offer corticosteroids. It evaluated:\n\nthe interventions (Actim Partus, PartoSure and quantitative fetal fibronectin at thresholds of\xa010, 200 and 500\xa0ng/ml)\n\na no-test, treat-all strategy, which assumes that all women entering the model are admitted to hospital\n\nthe comparator (fetal fibronectin at a threshold of 50\xa0ng/ml).Longer-term costs and quality-adjusted life years (QALYs) were then calculated for each branch of the decision tree.\n\nThe model was populated with data from the diagnostic accuracy review, published literature and expert opinion. Estimates of diagnostic accuracy for fetal fibronectin and Actim Partus were taken from APOSTEL‑1, which included a direct comparison of the 2\xa0tests. None of the studies directly compared PartoSure with fetal fibronectin, so diagnostic accuracy was estimated using data from APOSTEL‑1 and Hadzi‑Lega et al. Scenario analyses were done using data from alternative sources: Cooper et al. 2012, Abbott et al. 2013 and an EAG meta-analysis. The diagnostic accuracy estimates are in table\xa01.\n\nDiagnostic accuracy values used in the economic model\n\nDiagnostic test (threshold)\n\nSensitivity\n\nSpecificity\n\nfFN (10\xa0ng/ml)\n\n\n\n\n\nfFN (50\xa0ng/ml)\n\n\n\n\n\nfFN (200\xa0ng/ml)\n\n\n\n\n\nfFN (500\xa0ng/ml)\n\n\n\n\n\nActim Partus\n\n\n\n\n\nAbbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.\n\nDiagnostic test (threshold)\n\nSensitivity\n\nSpecificity\n\nPartoSure\n\n\n\n\n\nActim Partus\n\n\n\n\n\nAbbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.\n\nDiagnostic test (threshold)\n\nSensitivity\n\nSpecificity\n\nActim Partus\n\n\n\n\n\nfFN (50\xa0ng/ml)\n\n\n\n\n\nAbbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.\n\nDiagnostic test (threshold)\n\nSensitivity\n\nSpecificity\n\nfFN (10\xa0ng/ml)\n\n\n\n\n\nfFN (50\xa0ng/ml)\n\n\n\n\n\nfFN (200\xa0ng/ml)\n\n\n\n\n\nfFN (500\xa0ng/ml)\n\n\n\n\n\nAbbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.\n\nDiagnostic test (threshold)\n\nSensitivity\n\nSpecificity\n\nActim Partus\n\n\n\n\n\nfFN (50\xa0ng/ml)\n\n\n\n\n\nAbbreviations: fFN, fetal fibronectin; ng/ml, nanograms per millilitre; EAG, external assessment group.\n\nThe following costs, from companies, published literature and routine sources of NHS costs, were used in the model:\n\nfetal fibronectin test: £66 (includes 15\xa0minutes of midwife time)\n\nActim Partus test: £35 (includes 10\xa0minutes of midwife time)\n\nPartoSure test: £52 (includes 10\xa0minutes of midwife time)\n\nmaternal steroid injection: £5\n\ntocolytics (atosiban plus infusion equipment): £362\n\ninpatient hospital stay: £1,325\n\nin utero transfer: £965\n\nlong-term healthcare costs of intraventricular haemorrhage: £114,648\n\nneonatal hospital costs for respiratory distress syndrome: £5,587\n\nneonatal hospital costs: baby dies before discharge: £22,834.\n\nHealth-related quality-of-life estimates for babies were included in the base case, and a scenario analysis also included maternal health-related quality-of-life estimates. A utility for severe persistent asthma was applied to 56% of children with respiratory distress syndrome based on clinical expert opinion. Utilities used in the model are shown in table\xa02.\n\nVariable\n\nPatient\n\nSource\n\nUtility\n\n'Severe' RDS (severe persistent asthma used as proxy)\n\nChild\n\nCarroll and Downs 2009\n\n\n\nIVH grades 3 to 4 (moderate cerebral palsy used as proxy)\n\nChild\n\nCarroll and Downs via Bastek et al. 2012\n\n\n\nDeath\n\nChild\n\nVandenbussche et al. 1999\n\n\n\nPreterm survivor\n\nChild\n\nCooke 2004\n\n\n\nMother with previous adverse child outcome\n\nMother\n\nCouto et al. 2009\n\n\n\nMother with no adverse child outcome\n\nMother\n\nCouto et al. 2009\n\n\n\nAbbreviations: IVH, intraventricular haemorrhage; RDS, respiratory distress syndrome.\n\n## Base-case results\n\nThe following assumptions were applied in the base-case analysis:\n\nThe population entered the model after a clinical examination which did not rule out preterm labour.\n\nQALY outcomes were the same for women with false positive results (who did not deliver before the reference standard), true negative results and false negative results.\n\nAll treatment decisions were driven by the test result, and clinical judgement did not override this.\n\nDiagnostic accuracy was equivalent across all gestational ages.\n\nThe prevalence of preterm birth within 7\xa0days of testing was 3%, and the preterm birth rate was\xa012.1%.\n\nAntenatal corticosteroids were only effective within 7\xa0days of delivery; babies born more than 7\xa0days after treatment did not benefit.\n\nIn utero transfers were only available for women presenting to a level\xa01 or\xa02 hospital at less than 28\xa0weeks of pregnancy.\n\nTocolysis was used for all in\xa0utero transfers at less than 28\xa0weeks of pregnancy.\n\nOnly intraventricular haemorrhage resulted in longer-term costs.\n\nBabies who survived beyond 1\xa0year had a long-term quality of life equivalent to the average for preterm babies who survived.\n\nThe base-case results were given for groups of women presenting at 33, 30 and 26\xa0weeks of pregnancy. Results were also stratified according to the level of neonatal care available at the place of birth.\n\nBase-case results for women presenting at 30\xa0weeks of pregnancy at a level\xa02 hospital are shown in table\xa03. Most tests were cheaper and less effective than fetal fibronectin 50\xa0ng/ml, apart from a treat-all strategy and fetal fibronectin at 10\xa0ng/ml, which resulted in very small QALY gains and additional cost. Many of the tests were cheaper and less effective than the comparator; this means that the results are in the south-west quadrant of the cost-effectiveness plane.\n\nTest\n\nTotal costs (£)\n\nTotal QALYs\n\nICER (£ per QALY)\n\n(versus fFN 50\xa0ng/ml)\n\nPartoSure\n\n,895\n\n\n\n,925*\n\nfFN 500\xa0ng/ml\n\n,004\n\n\n\n,013*\n\nActim Partus\n\n,055\n\n\n\n,033*\n\nfFN 200\xa0ng/ml\n\n,159\n\n\n\n,213*\n\nfFN 50\xa0ng/ml\n\n,401\n\n\n\n–\n\nfFN 10\xa0ng/ml\n\n,690\n\n\n\n,270\n\nTreat all\n\n,171\n\n\n\n,757\n\n* ICER represents cost saved per QALY lost, it is in the south-west quadrant of the cost-effectiveness plane.\n\nAbbreviations: fFN, fetal fibronectin; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ng/ml, nanograms per millilitre.\n\nThe incremental cost-effectiveness ratios (ICERs) for the tests for women in a level\xa02 hospital at 26\xa0weeks of pregnancy reduced compared with the base-case results. This reduction applied to tests that were cheaper and less effective than the comparator (which became less cost effective) and to tests that cost more and were more effective than the comparator (which became more cost effective).\n\nThe ICERs for the tests for women in a level\xa02 hospital at 33\xa0weeks of pregnancy increased compared with the base-case results. This increase applied to tests that were cheaper and less effective than the comparator (which became more cost effective) and to tests that cost more and were more effective than the comparator (which became less cost effective).\n\nThe EAG updated the results of the analyses using data from 2\xa0additional studies (Nikolova et al. and Wing et al. 2017) that were highlighted in stakeholder comments on the diagnostics assessment report. For PartoSure compared with fetal fibronectin at 50\xa0ng/ml, the addition of accuracy data from these studies resulted in a greater QALY loss than was seen in the EAG's base case. However, using the accuracy estimates from Nikolova et al. resulted in greater cost savings and using the accuracy estimates from Wing et al. resulted in lower cost savings.\n\nThe effect of changing assumptions about the accuracy of the tests was explored in 2\xa0scenario analyses. Alternative diagnostic accuracy data from Cooper et al. (2016) were used to calculate ICERs for Actim Partus compared with fetal fibronectin at a threshold of 50\xa0ng/ml. In this analysis Actim Partus was dominated by fetal fibronectin (that is, fetal fibronectin was more effective and less expensive). Also, alternative diagnostic accuracy data were obtained for fetal fibronectin at thresholds of\xa010, 200 and 500\xa0ng/ml compared with fetal fibronectin at a threshold of 50\xa0ng/ml from an unpublished study by Abbott et al. The results of this analysis are academic in confidence.\n\nThe scenario analysis with the greatest effect on the ICERs was limiting the time horizon of the analysis to the first year after birth. The ICERs became less favourable for all interventions and increased by more than 20\xa0times the base-case value.\n\nAssuming that antenatal steroids have partial benefits if given more than 7\xa0days before birth also had a considerable effect on all the ICERs. This produced more favourable ICERs for PartoSure, the treat-all strategy and fetal fibronectin at a threshold of 10\xa0ng/ml. However, it produced less favourable ICERs for Actim Partus and fetal fibronectin at thresholds of 200\xa0ng/ml and 500\xa0ng/ml.\n\nDeterministic sensitivity analyses were done by varying the base-case parameters by 20%. These analyses found that the ICERs were most sensitive to changes in health-related quality of life of preterm babies who survived. Other parameters affecting the ICERs were cost of hospital admission, prevalence of preterm birth within 7\xa0days, effectiveness of steroid treatment and baseline mortality risk.\n\nThe EAG also ran probabilistic sensitivity analyses and presented the results as cost-effectiveness acceptability curves. Probabilistic ICERs were not presented.", 'Committee discussion': "# Care pathway\n\nThe committee discussed current practice for diagnosing and managing preterm labour in women with intact membranes. The clinical experts explained that the incidence of birth before 37\xa0weeks of pregnancy in the UK was around 8% and an estimated 50,000\xa0to 60,000\xa0babies are born preterm each year. Women with suspected preterm labour have a clinical assessment and a fetal fibronectin (fFN) test is commonly used to help determine whether labour is established. Although NICE's guideline on preterm labour and birth recommends transvaginal ultrasound as the preferred diagnostic option, this is not available everywhere. Also, it needs healthcare professionals with appropriate training to perform and interpret the scan. The committee noted that the NICE guideline recommends that all women who present at less than 30\xa0weeks of pregnancy have treatment based on clinical assessment alone, but heard that in practice many of these women also have a fFN test, or another test. The committee concluded that for women who present at 30\xa0weeks or above, the most appropriate comparator was fFN at a threshold of 50\xa0nanograms/millilitre (ng/ml). For women who present at less than 30\xa0weeks, a treat-all management pathway and fFN testing should be considered to reflect variation in current practice.\n\n# Patient experience\n\nThe committee discussed the effect that suspected preterm labour can have on pregnant women and their partners. The patient experts explained that preterm labour is associated with substantial anxiety, particularly when a diagnosis is difficult to confirm. For example, women who have a false positive result might be transferred to a higher level hospital unnecessarily. The committee noted that understanding whether preterm labour is established is of considerable importance to pregnant women. It heard about the importance of communicating the risks and benefits associated with the different diagnostic options so that women are able to understand the test results. The possibility of false negative results should also be explained and women given reassurance that they can return to hospital if they feel that their symptoms have not resolved despite a negative test result.\n\n# Clinical effectiveness\n\n## Diagnostic accuracy\n\nThe committee discussed the studies included in the diagnostic accuracy review. It noted that 16\xa0studies were available for Actim Partus, 2\xa0studies were available for fFN using thresholds of 10\xa0ng/ml, 200\xa0ng/ml and 500\xa0ng/ml and 4\xa0studies were available for PartoSure. It acknowledged that 7\xa0studies had been submitted by 1\xa0company after the diagnostics assessment report had been completed. The variation in estimates of diagnostic accuracy from the additional studies was similar to that seen in the studies assessed by the external assessment group (EAG), and so added further uncertainty to the results.\n\nThe committee noted that the studies included in the review were done outside of the UK. It understood that the management of preterm labour was likely to vary from country to country and that this had the potential to affect test accuracy. The EAG was unable to explore the likely effect of this variation because many studies did not provide details on how preterm labour was managed, particularly whether the delivery was spontaneous or induced for medical reasons. This variable had a direct effect on how the reference standards of birth within 48\xa0hours or 7\xa0days of testing were interpreted, and on determining true and false positive index test results. The committee concluded that because of shortcomings in how the results of the included studies were reported, it was not able to judge whether the results were generalisable to the NHS.\n\nThe committee considered the results of the EAG's diagnostic accuracy meta-analyses, and noted that the accuracy estimates differed substantially between studies. The studies included in the review recruited a wide range of women and the EAG raised concerns that there was substantial heterogeneity in a number of important patient characteristics, including gestational age, multiple pregnancy and history of preterm birth. The EAG explained that it did not consider the pooled diagnostic accuracy results to be reliable, because variables that may affect test accuracy such as the use of tocolytics, mode of delivery and gestational age were not reported in many of the studies. Therefore the EAG had not been able to explore which variables were driving the differences in test accuracy estimates between studies. More detailed reporting of the results would be needed for the EAG to have confidence in the pooled diagnostic accuracy results. The EAG further cautioned that the confidence intervals around the pooled estimates were unlikely to sufficiently characterise the uncertainty in the included studies. The committee concluded that there was substantial uncertainty in the pooled results. It also considered that there was a need for further robust diagnostic accuracy studies which aim to address the methodological limitations identified by the EAG (see section\xa05.14).\n\nThe committee questioned whether gestational age was likely to affect the accuracy of the tests. It noted that the EAG had not been able to do subgroup analyses by gestational age because insufficient data were available. The clinical experts explained that it was plausible that test accuracy could vary by gestational age, because the causes of preterm labour might be different at certain gestational ages. Although the biomarkers detected by each of the tests are thought to be associated with a common preterm labour biochemical signal, their expression may differ depending on the cause of preterm labour. For example, the biomarkers may perform differently in women with preterm labour caused by placental bleeding compared with preterm labour caused by ascending infection. The committee concluded that further evidence is needed on the effect of gestational age on test accuracy (see section\xa05.14).\n\nThe committee discussed how the test results would be used to guide clinical management. The EAG explained that it had not found any studies which reported the effect of the tests on decision-making, but noted that its search had been restricted to controlled study designs only. The clinical experts explained that biomarker test results are used as an aid to decision-making and are not intended to provide a final decision on the treatment pathway for a woman with symptoms of preterm labour. The importance given to biomarker test results varies in practice depending on the presenting symptoms and clinical history. The clinical experts noted that negative results are often interpreted with caution. They highlighted a study (Dutta et al. 2011) which looked at clinicians' compliance with test results and found that 20 to 30% of women with negative test results had corticosteroid treatment as if they were in preterm labour. The committee considered that it was uncertain how differences in test accuracy might translate to differences in patient outcomes in practice, particularly quality of life for the mother and child. It concluded that further research was needed to collect these data (see section\xa05.15 and\xa0section 5.16).\n\n# Cost effectiveness\n\nThe committee noted that because the EAG considered the results of the meta-analyses to be unreliable, the EAG preferred to use data from studies comparing at least 2\xa0of the biomarker tests in the same population to assess their relative accuracy in the economic model. The committee understood that this approach was taken to minimise bias in the accuracy estimates, which might arise because of differences in study design. It noted that no studies assessed all 3\xa0biomarker tests in the same population. The EAG used diagnostic accuracy results from 2\xa0studies (APOSTEL‑1 and Hadzi‑Lega et al. 2017) in the base-case analysis, although this was subsequently revised to include additional studies for PartoSure. The clinical experts noted that the studies were unlikely to be representative of women in NHS clinical practice. In APOSTEL‑1 there was a high proportion of women who would be considered high risk, with 23% of women having previous preterm delivery. The clinical experts explained that this would be lower in practice. Also, Hadzi‑Lega et al. included a small number of women (n=57) and was carried out in Macedonia, where the care pathway was likely to vary considerably compared with NHS clinical practice. The committee concluded that the women in the studies included in the model (APOSTEL‑1 and Hadzi‑Lega et al.) did not represent those seen in NHS clinical practice.\n\nThe committee was aware that the EAG's de novo model comprised a decision tree, which took account of both the neonatal care options available at a hospital (levels\xa01 to\xa03) and gestational age. The EAG explained that all tests included in the model were compared with no treatment. The committee considered the quality-adjusted life-year (QALY) payoffs that had been attached to each of the test outcomes. The EAG explained that because of a lack of clinical outcome data, equal QALYs had been assumed for true negative, false positive and false negative results. The patient and clinical experts noted that this approach did not adequately capture the outcomes that could arise from testing. False positive results may be associated with substantial anxiety and may also result in unnecessary treatment, particularly because the model assumed that clinical judgement did not influence the interpretation of test results. Also, although in practice women with false negative results are likely to return with ongoing symptoms, the patient experts said that sometimes these results reassure women and they may not return to hospital in time for effective treatment. This could severely affect the longer-term health of the child born preterm. Therefore the committee considered that the costs and longer-term health outcomes of the child were unlikely to have been adequately captured for false negative results. It concluded that, to capture the full effect of testing, future models should incorporate the effect of changes in both sensitivity and specificity.\n\nThe committee considered the costs used in the economic model. It noted stakeholder comments received during consultation on tocolytic costs used in the model. The EAG explained that it had assumed that atosiban would be used in a scenario analysis in which in\xa0utero transfers occurred, but was aware that nifedipine is the first-line tocolytic recommended in the NICE guideline on preterm labour and birth. The clinical experts stated that nifedipine was much less expensive than atosiban. The committee noted that although this cost did not affect the base-case results, if nifedipine had been used in the scenario analysis, the observed cost savings would have been lower. It also considered whether the economic model adequately captured the costs relating to adverse events and long-term health outcomes of the mother and child. The clinical experts explained that the cost of intraventricular haemorrhage in the economic model was likely to be an underestimate, at an average cost of £114,648 per child, and noted that it had been estimated using costing data for cerebral palsy. They also explained that they would expect the lifetime healthcare costs to be at least 10\xa0times higher than those in the model, particularly for babies who were extremely preterm and more likely to have a severe form of intraventricular haemorrhage (grades\xa03 to\xa04). Also the committee noted that the model did not account for costs relating to necrotising enterocolitis, which can be significant, and it excluded costs of neonatal and maternal sepsis. The EAG explained that not all costs for long-term health events could be included because there were no data about this. The committee concluded that the model was likely to considerably underestimate the longer-term costs of preterm birth.\n\nThe committee discussed the economic model's results. It recalled its consideration of the limitations in the clinical data available for the biomarker tests. These included the lack of studies on clinical outcomes, poor reporting of studies, the heterogeneity and lack of head-to-head studies comparing all 3\xa0tests (see section\xa05.3 to\xa0section 5.7). This led to many simplifying assumptions in the economic model, which the committee did not consider to be clinically plausible. It noted that probabilistic ICERs had not been presented, and that the fully incremental analyses appeared to contain errors. It therefore considered the available pairwise deterministic ICERs, but noted that probabilistic ICERs would have been preferred. Many of the deterministic ICERs for the tests compared with fetal fibronectin at a threshold of 50\xa0ng/ml were in the south-west quadrant of the cost-effectiveness plane, that is, the index tests were cheaper and less effective than the comparator. The committee noted that the QALY loss in most comparisons was relatively small (−0.006). However, because of the limitations in the clinical data and the implementation of the model (see section\xa05.8 and\xa0section 5.9), it was not possible to determine the magnitude or direction of the health-related outcomes that might occur in practice. Also, it noted that the model's predicted cost savings may not be realised in practice (see section\xa05.10). The committee agreed that the degree of uncertainty in the current clinical evidence was too high for it to be able to use the ICERs for decision-making. It considered that the scope of any further revisions to the assumptions in the modelling would be limited without more robust clinical data. The committee concluded that without robust diagnostic accuracy and clinical outcome data, it was not able to recommend Actim Partus, quantitative fFN testing using the Rapid fFN\xa010Q Cassette Kit at thresholds other than 50\xa0ng/ml and PartoSure for use in the NHS to diagnose preterm labour in women with intact membranes.\n\n# Research considerations\n\nThe clinical experts explained that there are 2\xa0ongoing UK studies looking at the use of biomarker tests for preterm labour in the NHS; QUIDs\xa0II and PETRA. QUIDs\xa0II plans to recruit over 2,000\xa0women and includes Actim Partus, PartoSure and quantitative fFN testing. It is scheduled to complete by September 2018. PETRA plans to recruit over 1,000\xa0women and includes quantitative fFN testing. It is scheduled to report by the end of 2018. The committee considered that the results of these studies could provide diagnostic accuracy data that are generalisable to NHS practice and additional data on patient-reported outcomes. Also, it noted that QUIDs\xa0II would provide comparative accuracy data for all 3\xa0interventions from the same population, which should overcome some of the bias introduced to the analyses by indirect comparisons.\n\nThe committee questioned how reproducible the test results were in clinical practice. The companies explained that each test has a recommended sample collection protocol which should be followed, although the clinical experts commented that it was uncertain how strictly these were followed in practice. The EAG noted that the reproducibility of PartoSure in practice had been explored (Werlen et al. 2015), but that equivalent data were not available for Actim Partus or quantitative fFN testing. The committee encouraged the companies to do similar studies to show the reproducibility of Actim Partus and quantitative fFN testing using the Rapid fFN\xa010Q Cassette Kit.\n\nThe committee noted the need for further diagnostic accuracy studies to assess whether the accuracy of Actim Partus, PartoSure and quantitative fetal fibronectin using the Rapid fFN\xa010Q Cassette Kit differs by gestational age (see section\xa05.6). Studies should also aim to collect data that help to identify if a birth occurred spontaneously or because of medical intervention, including whether the woman had tocolytics and the mode of delivery (see section\xa05.5).\n\nThe committee noted that there were no data on how the test results affect clinical decision-making. It considered that further studies should be done to address this uncertainty (see section\xa05.7). This could be incorporated into a clinical outcome study, or could be done as a standalone study with clinical experts being asked to provide a management plan for a clinical scenario both with and without knowledge of the biomarker test result.\n\nThe committee noted that further studies should be done to assess the effect of Actim Partus, PartoSure and quantitative fetal fibronectin testing using the Rapid fFN\xa010Q Cassette Kit on maternal and neonatal outcomes, including quality of life (see section\xa05.7). When possible, these studies should also collect data on resource use associated with preterm birth."}
|
https://www.nice.org.uk/guidance/dg33
|
Evidence-based recommendations on biomarker tests to help diagnose preterm labour in women with intact membranes. The tests are Actim Partus, PartoSure and the Rapid fetal fibronectin (fFN) 10Q Cassette Kit (at thresholds other than 50 nanograms/millilitre).
|
32fa46c04af8b133d2a91fe2bf5e565ace6ae3e3
|
nice
|
Crizotinib for treating ROS1-positive advanced non-small-cell lung cancer
|
Crizotinib for treating ROS1-positive advanced non-small-cell lung cancer
Evidence-based recommendations on crizotinib (Xalkori) for treating ROS1-positive advanced non-small-cell lung cancer in adults.
# Recommendations
Crizotinib is recommended for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced non-small-cell lung cancer (NSCLC) in adults, only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with crizotinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
ROS1‑positive advanced NSCLC is a recently discovered type of NSCLC and there are limited data about how well existing treatments work.
Evidence for crizotinib in ROS1‑positive advanced NSCLC comes from a small, single-arm study that included mostly people with previously treated disease. Although the study showed crizotinib to be effective at shrinking tumours and slowing disease progression, the lack of data comparing it with other treatments makes the size of the benefit uncertain.
Because of the limited evidence in ROS1‑positive NSCLC, the company presented data from 2 randomised controlled trials for crizotinib in ALK‑positive NSCLC instead (comparing crizotinib with chemotherapy) as proxy data for ROS1‑positive advanced NSCLC. However, using data from a proxy population is far from ideal, and makes the assessment of clinical and cost effectiveness highly uncertain.
Crizotinib meets NICE's criteria to be considered a life-extending end-of-life treatment, but there are uncertainties in the clinical- and cost-effectiveness estimates. For previously treated disease, the range of cost-effectiveness estimates was broader than for untreated disease and all estimates are higher than what NICE normally considers acceptable for end-of-life treatments. Crizotinib therefore cannot be recommended for routine use in the NHS to treat ROS1‑positive advanced NSCLC.
Crizotinib is innovative but there were no relevant additional benefits that had not been captured in the quality-adjusted life-year calculations. Collecting further data on its use in the Cancer Drugs Fund would help address uncertainties in crizotinib's survival benefit, and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC. Using crizotinib in a managed approach would also encourage standardisation of ROS1 status testing in non-squamous NSCLC. Therefore, crizotinib can be recommended for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC.# Information about crizotinib
Marketing authorisation
Crizotinib (Xalkori, Pfizer) as monotherapy is indicated 'for the treatment of adults with ROS1‑positive advanced non-small-cell lung cancer (NSCLC)'.
Dosage in the marketing authorisation
mg twice daily (500 mg daily) taken orally.
Dosing interruption and/or dose reduction may be needed based on individual safety and tolerability. If necessary, dose may be reduced to 200 mg twice daily and then 250 mg once daily.
An accurate and validated assessment for ROS1 should be done by laboratories with demonstrated proficiency in the specific test being used before starting crizotinib therapy. It is important that a well-validated and robust methodology is chosen to avoid false-negative or false-positive results.
For further details see the summary of product characteristics.
The summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma.
Price
The list price of crizotinib is £4,689 for 60 capsules (excluding VAT; British national formulary online, accessed December 2017).
The company has a commercial arrangement. This makes crizotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## The ROS1 oncogene is a recent discovery and both patients and clinicians would welcome a targeted therapy
The clinical experts observed that less than 2% of people with non-small-cell lung cancer (NSCLC) have ROS1‑positive advanced NSCLC. The ROS1 oncogene is thought to be found almost exclusively in non-squamous NSCLC, mainly in tumours with adenocarcinoma histology. The committee noted that the ROS1 oncogene was only recently discovered; so limited information is available on the natural history, patient characteristics and the clinical effectiveness of chemotherapy for tumours that are ROS1‑positive. The clinical experts highlighted that from the limited information available, there appear to be similarities between ROS1‑positive advanced NSCLC and ALK‑positive NSCLC: for example, both are most often seen in younger patients who do not smoke. In the absence of any targeted therapy until now, ROS1‑positive advanced NSCLC is treated with cytotoxic chemotherapy that can cause unpleasant side effects. The committee noted the patient expert's statement that people with advanced or metastatic NSCLC often feel debilitated by multiple and distressing symptoms. It also noted that the clinical experts considered crizotinib a step-change in treatment because it is taken orally, and offers a marked improvement in quality of life. The committee concluded that crizotinib has a better safety PROFILE than standard care (cytotoxic chemotherapy) and would be valued by both patients and clinicians.
# ROS1 testing
## ROS1 status should be tested upfront in all non-squamous NSCLC
The marketing authorisation for crizotinib states that it is necessary to have an accurate and validated assay for ROS1 before treatment with crizotinib is started. The company proposed initial testing with immunohistochemistry (IHC), and follow-up confirmation testing for positive cases with the highly accurate FISH (fluorescence in situ hybridisation) test. The clinical experts explained that only a few centres test for ROS1, and that assay methods vary. The committee understood that although the marketing authorisation for crizotinib did not specify non-squamous disease, ROS1‑positive NSCLC is almost exclusively seen in non-squamous tumours (see section 3.1) and therefore the testing would most likely be in people with non-squamous tumours only. The committee discussed when ROS1 testing should be done: it could be done at diagnosis, along with testing for other mutations (such as EGFR and ALK), or later, once people have tested negatively for other mutations (because the different mutations are mutually exclusive). The clinical experts highlighted practical difficulties in testing different mutations at different stages, because more biopsy samples might be needed and the risk of delayed or missed diagnoses with sequential testing. The committee also noted that any delay in diagnosing ROS1‑positive advanced NSCLC would delay access to therapy. It agreed that testing for ROS1 status in all newly diagnosed non-squamous NSCLC would be the best strategy, in line with testing for other types of tumour expression in NSCLC.
# Comparators
## There are different comparators for crizotinib in untreated and previously treated disease
The committee noted that crizotinib's UK marketing authorisation does not specify whether it should be used to treat squamous or non-squamous disease. It also noted that the summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma. The committee understood that the ROS1 oncogene is mainly present in adenocarcinoma, which is a subtype of non-squamous NSCLC. It agreed that crizotinib would most likely be used in patients with non-squamous NSCLC in clinical practice in the NHS. In line with the final scope issued by NICE, the committee considered untreated and previously treated ROS1‑positive advanced NSCLC separately when determining the most appropriate comparators for crizotinib.
## Untreated disease: pemetrexed plus platinum-based therapy is the appropriate comparator
The company considered that pemetrexed plus platinum-based chemotherapy (cisplatin or carboplatin) was the appropriate comparator for crizotinib in untreated ROS1‑positive advanced NSCLC. As such, it excluded all other comparators identified in the final scope issued by NICE. The committee understood that NICE's guideline on lung cancer diagnosis and management recommends platinum-based combination chemotherapy for untreated disease (and docetaxel, gemcitabine, paclitaxel or vinorelbine alone for people who cannot tolerate combination chemotherapy). NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC recommends pemetrexed plus cisplatin for adenocarcinoma or large-cell carcinoma. Pemetrexed is also recommended as maintenance treatment after pemetrexed plus cisplatin for locally advanced or metastatic non-squamous NSCLC in adults whose disease has not progressed (NICE technology appraisal guidance on pemetrexed maintenance treatment for non-squamous NSCLC after pemetrexed and cisplatin), and after platinum-based chemotherapy plus gemcitabine, paclitaxel or docetaxel (NICE technology appraisal guidance on pemetrexed for the maintenance treatment of NSCLC). The company excluded pemetrexed as maintenance treatment after pemetrexed plus cisplatin, stating that only around 15% of patients would be eligible. It also noted that patients newly diagnosed with ROS1‑positive advanced NSCLC are generally young and physically fit, and so it was appropriate to exclude single-agent chemotherapy as a comparator (because this is only recommended for people who cannot tolerate combination chemotherapy). The committee understood that the ROS1 oncogene is most common in non-squamous NSCLC and concluded that pemetrexed plus platinum-based chemotherapy was the most appropriate comparator for crizotinib in untreated, ROS1‑positive advanced NSCLC.
## Previously treated disease: it is inappropriate to exclude standard care docetaxel plus nintedanib as a comparator
For crizotinib in previously treated ROS1‑positive advanced NSCLC, the company considered docetaxel alone to be the best comparator. It excluded nintedanib plus docetaxel as a comparator, despite NICE's technology appraisal guidance on nintedanib for previously treated locally advanced, metastatic, or locally recurrent NSCLC recommending this as an option for previously treated NSCLC of adenocarcinoma histology. The company stated that it was not possible to compare crizotinib with nintedanib plus docetaxel, because data on nintedanib plus docetaxel were available only for unselected NSCLC. In response to consultation, the company further explained that using pooled chemotherapy in the analysis (that is, docetaxel or pemetrexed in line with treatment options in PROFILE 1007) is a conservative approach because pemetrexed is more effective than docetaxel. However, the committee understood that nintedanib plus docetaxel is more effective than docetaxel alone for treating adenocarcinoma, such that it is considered standard care in the NHS for people who can tolerate it. The committee was not convinced by the company's rationale for excluding nintedanib plus docetaxel as a comparator. It concluded that the company should have included nintedanib plus docetaxel as a comparator, because it is thought that the ROS1 oncogene is most common in non-squamous NSCLC and agreed to consider this omission in its decision-making.
# Clinical effectiveness
## Direct evidence for crizotinib's effectiveness in ROS1‑positive advanced NSCLC is extremely limited because there are no comparative data
The clinical-effectiveness evidence for crizotinib in ROS1‑positive advanced NSCLC is from a small (n=53), single-arm study called PROFILE 1001. The trial was done at 8 sites across the US, Australia and South Korea. Only 7 patients had untreated disease; the other 46 had had at least 1 previous chemotherapy. Most patients (96%) had NSCLC of adenocarcinoma histology but 2 patients had non-adenocarcinoma histology. Patients were followed-up for a median of 25.4 months. As determined by the investigators, 5 patients had complete response and 32 patients had partial response (according to Response Evaluation Criteria In Solid Tumours ) giving an overall objective response rate of 69.8% (95% confidence interval 55.7 to 81.7). Median overall survival was not reached at the time of analysis and the company does not intend to carry out any interim analysis in the near future. Median progression-free survival was 19.8 months. The clinical experts stated that these results were clinically meaningful because, in unselected NSCLC, chemotherapy provides progression-free survival of around 5 months in untreated disease and just 3 months in previously treated disease. From the evidence available from PROFILE 1001, the committee agreed that crizotinib can induce durable tumour shrinkage and slow disease progression, particularly in previously treated ROS1‑positive advanced NSCLC. In response to consultation, the company highlighted that its original submission included results from a UK clinical audit by the Royal Marsden and other small studies in ROS1‑positive advanced NSCLC that supported the efficacy and safety of crizotinib. The committee noted that the clinical audit reported a median progression-free survival of 12.1 months for both untreated and previously treated disease, and that the OxOnc study reported a median overall survival of 32.5 months at the data cut-off in July 2016 (median overall survival was not reached in the other studies). The committee also noted that although the OxOnc study recruited more patients than PROFILE 1001, it was done in Asia and therefore may not be applicable to UK settings. The committee noted that there is no available evidence on the effectiveness of crizotinib compared with chemotherapy for ROS1‑positive advanced NSCLC and concluded that the lack of comparative data makes any assessment of comparative effectiveness (and any economic analysis) very challenging.
## The effectiveness of crizotinib compared with chemotherapy is based on its use in ALK‑positive advanced NSCLC and so is highly uncertain
Because of the limited clinical-effectiveness data available for ROS1‑positive advanced NSCLC, the company provided results from 2 randomised controlled trials that compared crizotinib with chemotherapy in untreated (PROFILE 1014) and previously treated (PROFILE 1007) ALK‑positive NSCLC. The company stated that these results could be extrapolated to ROS1‑positive advanced NSCLC. Both trials were considered during the development of previous NICE technology appraisal guidance (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). The committee was aware that in both the PROFILE 1014 and PROFILE 1007 trials, progression-free survival was statistically significantly longer with crizotinib compared with chemotherapy (pemetrexed plus platinum for untreated disease and pemetrexed plus docetaxel for previously treated disease). The committee was also aware that the overall survival results (unadjusted for patient crossover) from PROFILE 1014 and PROFILE 1007 suggested that there were no statistically significant differences between crizotinib and chemotherapy in each of these trials. However, the crossover-adjusted hazard ratio results suggested that crizotinib statistically significantly improved overall survival compared with chemotherapy in patients with ALK‑positive advanced NSCLC. The committee noted the ERG's comments that in both trials, the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) was not valid for progression-free survival so any hazard ratios for progression-free survival should be interpreted with caution. The ERG also highlighted that the overall survival estimates were unreliable because of high rates of crossover, and that statistical methods for adjustment were not reported transparently. The committee agreed that the results showed crizotinib to be more effective than chemotherapy for ALK‑positive NSCLC, but that its relative effectiveness in ROS1‑positive advanced NSCLC remained uncertain.
## The only comparative evidence for crizotinib in ROS1‑positive advanced NSCLC is from proxy data in ALK‑positive NSCLC
The committee discussed the relevance of the PROFILE 1014 and PROFILE 1007 results to ROS1‑positive advanced NSCLC. In its submission, the company strongly advocated that data from ALK‑positive NSCLC could be used as a proxy for ROS1‑positive advanced NSCLC. It stated that:
The kinase domains of ALK and ROS1 share 77% of amino acids in the ATP-binding sites.
Both ALK‑positive and ROS1‑positive advanced NSCLC are similar in terms of clinical behaviour including response to crizotinib, patient characteristics and histology (both are predominantly adenocarcinoma).
The European Medicines Agency supported the generalisability of data from ALK‑positive NSCLC to ROS1‑positive advanced NSCLC when granting crizotinib's marketing authorisation in this indication.
Twelve UK clinical experts from a company-sponsored advisory board agreed that the data were an appropriate proxy for ROS1‑positive advanced NSCLC.The committee considered the histology of ALK‑positive NSCLC. It understood that the inclusion criteria in PROFILE 1014 specified non-squamous NSCLC and most patients (93%) in PROFILE 1007 had adenocarcinoma histology. The ALK‑positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC and that the testing for the ALK mutation is routinely done in the non-squamous population only. The committee therefore accepted the company's view that both are predominantly of adenocarcinoma histology. The clinical experts stated that in their experience ROS1‑positive advanced NSCLC is even more sensitive to crizotinib than ALK‑positive NSCLC. The committee acknowledged this, but noted the ERG's concern that any documented similarities between ALK‑positive and ROS1‑positive advanced NSCLC may not hold true as more patients with ROS1‑positive advanced NSCLC are identified. The committee noted that median progression-free survival in the ROS1‑positive trial (PROFILE 1001) and the ALK‑positive trials (PROFILE 1014 and PROFILE 1007) differed enough (19.3 months compared with 10.9 months and 7.7 months respectively) to seriously question the comparability of the 2 patient populations. The committee was aware that there are no randomised trials planned for crizotinib in ROS1‑positive advanced NSCLC and comparative data on efficacy is not expected. Furthermore, even the non-comparative data for its use in ROS1‑positive advanced NSCLC were very limited, particularly for untreated disease. The committee agreed that using data from a proxy population was far from ideal, and considered whether it should accept analyses based on treatment effects from a proxy population. Having taken into account the relatively small patient population and the clinical experts' views on the innovative nature of crizotinib, the committee agreed to explore the proxy data in its decision-making. However, it regarded this approach as very unusual and stated that this should not set a precedent for the use of data from proxy populations in future appraisals.
# Cost-effectiveness analyses
## All cost-effectiveness analyses are based on proxy data so results are extremely uncertain
The committee recognised that the company had presented a revised base-case analysis in response to consultation incorporating some of the committee's preferred assumptions, and a number of scenario analyses that explored alternative values for the overall and post-progression survival benefit of crizotinib. All analyses included a higher utility value for people taking pemetrexed plus platinum-based chemotherapy (see section 3.12) and higher costs for treating pulmonary embolism (see section 3.13). It also incorporated testing costs for untreated disease and assumed sequential testing for previously treated disease (see section 3.2). The committee understood that all the testing costs were for non-squamous NSCLC only.
The revised base case incorporated an overall survival benefit for crizotinib of 18.2 months for untreated disease and 20.9 months for previously treated disease.
The scenario analyses incorporated a range of values for the overall and post-progression survival benefit of crizotinib explored the impact of excluding testing costs.The committee noted that the revised analyses still extrapolated data for both crizotinib and the comparators from ALK‑positive NSCLC and that it had not presented a revised analysis of the PROFILE 1001 scenario (that used data from ROS1‑positive NSCLC population to model the intervention arm but extrapolated the relative effectiveness from ALK‑positive NSCLC to model the comparator arm). It considered that even with the new analyses, there was still a high degree of uncertainty because of the use of proxy data. Without any reliable evidence on the effectiveness of the comparator treatments in ROS1‑positive advanced NSCLC (see section 3.6), the committee concluded that all of the cost-effectiveness estimates were associated with uncertainty that needed to be accounted for in its decision-making.
# Overall survival
## The relationship between overall and progression-free survival is unclear and the size of crizotinib's overall survival benefit is difficult to establish
The ERG had questioned the company's original modelled overall survival gain with crizotinib (see table 1), given that the modelled progression-free survival gain was considerably less (9.5 months for untreated disease and 5.7 months for previously treated disease). The committee recalled that the overall survival data from PROFILE 1014 and PROFILE 1007 were confounded by high crossover rates, and that adjustment methods had not been reported transparently (see section 3.7). The clinical experts explained that progression-free survival gains would be expected to result in some overall survival benefit, but the exact relationship is difficult to predict. Nevertheless, the experts agreed that a modelled overall survival gain almost 3 times higher than the modelled progression-free survival gain was most likely to be an overestimate. In its response to consultation and based on clinical expert opinion, the company reported analyses using a range of values for overall and post-progression survival to explore the additional survival benefit with crizotinib.
## Table 1 Summary of the company's analyses
Survival gain for crizotinib (months)
Analysis
Untreated disease
Previously treated disease
OS
PPS
OS
PPS
Original base case
Revised base case
Scenarios (adapted from ERG)
Other scenarios
Abbreviations: ERG, evidence review group; OS, overall survival; PPS, post-progression survival.
- The company considered that these scenarios were not clinically plausible.
Survival gains are from the ERG's critique of the company's response to consultation. The company presented further analyses but these were marked as commercial in confidence so cannot be reported here.
The company highlighted that that overall survival gains of at least 13.1 months for untreated disease and at least 16.2 months for previously treated disease had been accepted for crizotinib in the ALK‑positive population (see NICE technology appraisal guidance on crizotinib for untreated ALK-positive advanced non-small-cell lung cancer and crizotinib for previously treated ALK-positive advanced NSCLC) and considered these clinically plausible. The ERG agreed that some post-progression clinical benefit with crizotinib was plausible, but noted that the size of the benefit was highly uncertain and the company's estimates of survival gain were not adequately justified. The committee understood that compared with its original analyses, the company's revised base case included a more conservative post-progression benefit for untreated disease but a larger benefit for previously treated disease (see table 1). The committee concluded that even with the new analyses from the company, there was considerable uncertainty around the size of survival benefit in the progression free and progressed states because the relationship between overall survival and progression-free survival is unclear.
## The mid-point between the ERG's and company's new scenario analyses for overall survival modelling is preferred
To explore the uncertainty in the overall survival benefit with crizotinib, the ERG did 2 scenario analyses in its critique of the company's original submission:
In the first, the ERG applied the hazard ratio for progression-free survival to the unadjusted (for crossover) overall survival curve of the crizotinib treatment arm.
In the second, the ERG assumed no survival benefit other than survival gained in the progression-free state. For this scenario, the ERG adapted the overall survival curve for the comparator to make survival in the progressed state equal for both treatment arms. This means that any survival benefit was attributable to the survival benefit in the progression-free state.For the first scenario analysis, the committee was not convinced that the hazard ratio from 1 outcome could be applied equally to another. The committee considered the ERG's second scenario analysis to be more informative in terms of overall survival modelling, but it did not agree with the way the ERG implemented the analysis. The committee considered that adjusting the crizotinib overall survival curve (to make the survival gain in the post-progression state equal to the modelled survival in the post-progression state of the comparator arm) would have been a better approach. Overall, the committee considered that some relative advantage for crizotinib after disease progression was plausible. In its response to consultation, the company did 4 scenario analyses to explore the clinical plausibility of each of the overall survival models (see section 3.10). This included the company's amendments to the ERG's second scenario analysis that adapted the overall survival curve for crizotinib and included a clinical benefit for crizotinib in the progressed state. The committee understood that these scenarios improved the cost effectiveness of crizotinib for both untreated and previously treated disease. The committee was aware from correspondence with 1 of the clinical experts who had attended the first committee meeting that the company's modelled survival benefits for untreated and previously treated disease were plausible for this small group of young patients with few comorbidities. The expert explained that response to crizotinib in patients with the ROS1‑positive mutation is similar to patients with the ALK‑positive mutation, so an average survival benefit of 24 months is reasonable for both untreated and previously treated disease. The committee concluded that the overall survival gain for crizotinib was somewhere between the company's new scenario analyses using the lower bounds of clinical benefit (that is, an overall survival benefit of 13.1 months for untreated disease and 16.2 months for previously treated disease) and the ERG's estimates assuming no benefit in the progressed state, but reiterated that this analysis was still based on a proxy population and therefore considerable uncertainty remained.
# Utility values
## The company's new utility values for the comparator in untreated disease are appropriate for decision-making
The company used a utility value of 0.81 for people having crizotinib in both the progression-free and progressed disease states. For people having the pemetrexed plus platinum-based chemotherapy, the company used a utility value of 0.72. People subsequently having docetaxel or best supportive care were given utility values of 0.61 and 0.47 respectively. The committee noted that almost all the values used (with the exception of the utility value for people having pemetrexed plus platinum-based chemotherapy) were the same values accepted by the appraisal committees during the development of NICE technology appraisal guidance on crizotinib for ALK‑positive NSCLC (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). During the appraisal of crizotinib for untreated ALK‑positive advanced NSCLC, the ERG had provided exploratory analyses using a utility value for people having pemetrexed plus platinum-based chemotherapy of 0.75 which was deemed appropriate by the committee at the time. The committee agreed that for consistency it would take this slightly higher utility value into account, and that this would decrease crizotinib's perceived cost effectiveness. The committee also noted that the company had not included disutility to account for any adverse reactions, and agreed that this would add further uncertainty to the results. In response to consultation, the company preferred to use a utility of 0.75 for pemetrexed plus platinum-based chemotherapy when patients were not taking treatment and 0.72 when patients were taking treatment. The committee noted that this approach had only a small effect on the cost-effectiveness results and concluded that the utility values used in the company's new analyses were appropriate for decision-making.
# Costs
## It is appropriate to include revised costs for treating pulmonary embolism and administering crizotinib
The company included higher costs for treating pulmonary embolism as part of its revised base case, noting that these costs were consistent with values used during the development of NICE technology appraisal guidance on ceritinib for untreated ALK-positive NSCLC. The ERG noted that including higher costs for treating pulmonary embolism had only a small effect on the cost effectiveness of crizotinib. The committee understood that the company did not change the administration costs of crizotinib in its revised base case, and noted that including the NHS reference cost for delivering oral chemotherapy (HRG code SB11Z) increased the incremental cost-effectiveness ratios (ICERs) for both untreated and previously treated disease. It also understood that a similar administration cost using HRG code SB11Z was included in a previous NICE technology appraisal in the ALK‑positive population (crizotinib for previously treated ALK-positive advanced NSCLC). The committee concluded that it was appropriate to include higher costs for treating pulmonary embolism and administering crizotinib.
# The most plausible ICERs
## The most plausible ICERs for crizotinib are uncertain and not clearly within the range normally considered to be cost-effective use of NHS resources
The committee agreed that the new ICERs presented by the company were highly uncertain because of the use of proxy data from ALK‑positive advanced NSCLC and uncertainties in the overall survival extrapolation. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee recalled that, as a starting point for its discussion, it would consider ICERs at the mid-point between the company's new scenario that included a clinical benefit for crizotinib in the progressed state (assuming an overall survival gain of 13.1 months for untreated disease and 16.2 months for previously treated disease) and the ERG's scenario assuming no survival benefit in the progressed state (see section 3.11). Having considered that some post-progression clinical benefit with crizotinib was plausible but the size was uncertain (see section 3.10), and having established its preferred assumptions for upfront testing costs (see section 3.2) and higher administration costs (see section 3.13), the committee considered that the most plausible ICERs would be:
For crizotinib compared with pemetrexed plus platinum-based chemotherapy in untreated disease: around or above £50,000 per quality-adjusted life year (QALY) gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). However, the committee agreed that this estimate came with far too much uncertainty to conclude on a figure below £50,000 without further evidence.
For crizotinib compared with docetaxel in previously treated disease: well above £50,000 per QALY gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). The committee agreed that had crizotinib been compared with nintedanib plus docetaxel, the ICER would be even higher.
# End of life
## Crizotinib meets both criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's technology appraisal process and methods. The company stated that there is limited data on overall survival with chemotherapy in people with ROS1‑positive advanced NSCLC. In the proxy population with ALK‑positive NSCLC, median overall survival ranged from 6 months to 22 months and there is no evidence that it would be better in people with ROS1‑positive advanced NSCLC. The company also highlighted that median overall survival was not reached in PROFILE 1001, and median progression-free survival was 19.3 months, so overall survival with crizotinib in ROS1‑positive advanced NSCLC would be at least 19.3 months. The committee agreed that crizotinib for ROS1‑positive advanced NSCLC met the first criterion to be considered a life-extending treatment at the end of life. The committee noted that the mean overall survival gained with crizotinib, as estimated in the company's revised base case, was 18.2 months for untreated disease and 20.9 months for previously treated disease. Therefore crizotinib may offer, on average, at least 3 months' extension to life compared with standard care. However, it noted the considerable uncertainty around the company's modelling of overall survival and considered that any estimate of an overall survival gain compared with standard care was very uncertain. The committee noted that crizotinib was considered life-extending for people with both untreated and previously treated ALK‑positive NSCLC. Based on the clinical experts' testimony that the ALK‑positive NSCLC population could be used as a proxy for people with ROS1‑positive advanced NSCLC, the committee thought it likely that there was an overall survival gain with crizotinib of over 3 months. The committee concluded that crizotinib met both criteria to be considered a life-extending, end-of-life treatment.
## Crizotinib cannot be recommended for routine use in the NHS
Despite meeting both end-of-life criteria, the most plausible ICERs for crizotinib compared with standard care in the company's revised base case were not clearly within the range normally considered to be a cost-effective use of NHS resources. Given the high level of uncertainty in the analyses, the committee concluded that it could not recommend crizotinib for routine use in the NHS to treat ROS1‑positive advanced NSCLC.
# Innovation
## Crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC
The company stated that crizotinib is innovative because it is the first targeted therapy for ROS1‑positive advanced NSCLC. The US Food and Drug Administration also assigned crizotinib a breakthrough therapy designation, and the marketing authorisation was granted through a priority review. The committee emphasised that the European Medicines Agency had approved crizotinib in this indication based on just 1 single-arm study. The company highlighted that as an oral therapy, crizotinib gives patient more autonomy. Moreover, the company claimed that its quick and durable effect may have wider societal benefits that were not captured in the cost-effectiveness analysis. The committee agreed that crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC. However, the committee concluded that there were no relevant additional benefits that had not been captured in the QALY calculations.
# Cancer Drugs Fund
## Using crizotinib in the Cancer Drugs Fund would provide important data and encourage standardisation of ROS1 testing
Having concluded that crizotinib could not be recommended for routine use in the NHS to treat ROS1‑positive NSCLC, the committee considered whether it could be recommended for use in the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee was aware that the overall survival data from PROFILE 1001 were immature and no further analysis was expected in near future. The company stated that some clinical experts consider further comparative trials to be unethical, because of crizotinib's efficacy in treating ROS1‑positive NSCLC in PROFILE 1001. The committee was aware that there are ongoing single-arm observational studies that will provide additional information. However, these studies would only partly address the uncertainties about crizotinib's relative clinical effectiveness. The committee agreed with NHS England that because ROS1‑positive lung cancer has only recently been described, and information on the population characteristics, natural history and prognosis is limited, it would be of great value to collect data about the use of crizotinib in ROS1‑positive advanced NSCLC through the Cancer Drugs Fund. The committee concluded that collecting data on the demographics of people with ROS1‑positive advanced NSCLC, treatment length and disease progression on crizotinib would help to address the uncertainties around the survival benefit and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC populations. The clinical experts commented that the clinical community would welcome an opportunity to contribute to this data collection through the Cancer Drugs Fund; the representative from NHS England indicated that such data could be collected for up to 5 years. The committee further concluded that crizotinib's use through the Cancer Drugs Fund would also encourage standardisation of ROS1 testing.
## Crizotinib is recommend for use in the Cancer Drugs Fund for both untreated and previously treated ROS1‑positive NSCLC
Having determined that the most plausible ICER for crizotinib in untreated disease was around or above £50,000 per QALY gained, the committee concluded that crizotinib had plausible potential to represent cost effectiveness through its use in the Cancer Drugs Fund. The ICER based on the current evidence is higher than the range normally considered to be a cost-effective use of NHS resources, but the committee considered that crizotinib's clinical effectiveness was promising and its use through the Cancer Drugs Fund would provide important data to resolve the clinical uncertainties and encourage standardisation of ROS1 testing. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee noted that when testing for ROS1 became routine practice, most people with ROS1‑positive NSCLC would first have crizotinib and the number of people eligible for crizotinib as a later-line treatment would decrease over time. The committee therefore agreed that it would not make a distinction between untreated and previously treated disease in its recommendations. The committee concluded that it could recommended crizotinib as an option for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC, only if the conditions in the managed access agreement are followed.
## Crizotinib is most likely to be used in the Cancer Drugs Fund for non-squamous NSCLC only
The committee further considered the population for which crizotinib would most likely be used within the Cancer Drugs Fund. It recalled that: in clinical practice, crizotinib is most likely to be used for non-squamous NSCLC; the comparators chosen by the company were for non-squamous NSCLC; the trial results from PROFILE 1001 and the ALK‑positive proxy data from PROFILE 1014 and 1007 were almost exclusively in people with non-squamous histology and predominately in adenocarcinoma; and the testing costs included in the cost-effectiveness analysis were based on a non-squamous lung cancer population. The committee was aware that the incidence of ROS1 in squamous NSCLC is around 1.7% to 1.8%, but recognised that testing of ROS1 status in all patients with NSCLC would be very costly for the Cancer Drugs Fund. It accepted that ROS1 testing and the use of crizotinib in the Cancer Drugs Fund would be in people with non-squamous NSCLC only.
# Other factors
## ROS1 testing at diagnosis would reduce potential inequitable access to targeted therapies
The company commented that regional variations in access to ROS1 testing could lead to inequitable access, and advocated testing at diagnosis of all non-squamous NSCLC for ROS1 status. The company highlighted that sequential testing (that is, done after testing for EGFR and ALK) would also delay access to crizotinib. The committee agreed that variation in access to treatment does not normally constitute an equality issue under equality legislation. However, the committee considered this potential equality issue and agreed that if crizotinib becomes an available treatment option, ROS1 testing should be done at diagnosis to help prevent potential inequality of access.
|
{'Recommendations': "Crizotinib is recommended for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced non-small-cell lung cancer (NSCLC) in adults, only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with crizotinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nROS1‑positive advanced NSCLC is a recently discovered type of NSCLC and there are limited data about how well existing treatments work.\n\nEvidence for crizotinib in ROS1‑positive advanced NSCLC comes from a small, single-arm study that included mostly people with previously treated disease. Although the study showed crizotinib to be effective at shrinking tumours and slowing disease progression, the lack of data comparing it with other treatments makes the size of the benefit uncertain.\n\nBecause of the limited evidence in ROS1‑positive NSCLC, the company presented data from 2 randomised controlled trials for crizotinib in ALK‑positive NSCLC instead (comparing crizotinib with chemotherapy) as proxy data for ROS1‑positive advanced NSCLC. However, using data from a proxy population is far from ideal, and makes the assessment of clinical and cost effectiveness highly uncertain.\n\nCrizotinib meets NICE's criteria to be considered a life-extending end-of-life treatment, but there are uncertainties in the clinical- and cost-effectiveness estimates. For previously treated disease, the range of cost-effectiveness estimates was broader than for untreated disease and all estimates are higher than what NICE normally considers acceptable for end-of-life treatments. Crizotinib therefore cannot be recommended for routine use in the NHS to treat ROS1‑positive advanced NSCLC.\n\nCrizotinib is innovative but there were no relevant additional benefits that had not been captured in the quality-adjusted life-year calculations. Collecting further data on its use in the Cancer Drugs Fund would help address uncertainties in crizotinib's survival benefit, and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC. Using crizotinib in a managed approach would also encourage standardisation of ROS1 status testing in non-squamous NSCLC. Therefore, crizotinib can be recommended for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC.", 'Information about crizotinib': "Marketing authorisation\n\nCrizotinib (Xalkori, Pfizer) as monotherapy is indicated 'for the treatment of adults with ROS1‑positive advanced non-small-cell lung cancer (NSCLC)'.\n\nDosage in the marketing authorisation\n\nmg twice daily (500\xa0mg daily) taken orally.\n\nDosing interruption and/or dose reduction may be needed based on individual safety and tolerability. If necessary, dose may be reduced to 200\xa0mg twice daily and then 250\xa0mg once daily.\n\nAn accurate and validated assessment for ROS1 should be done by laboratories with demonstrated proficiency in the specific test being used before starting crizotinib therapy. It is important that a well-validated and robust methodology is chosen to avoid false-negative or false-positive results.\n\nFor further details see the summary of product characteristics.\n\nThe summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma.\n\nPrice\n\nThe list price of crizotinib is £4,689 for 60 capsules (excluding VAT; British national formulary [BNF] online, accessed December 2017).\n\nThe company has a commercial arrangement. This makes crizotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## The ROS1 oncogene is a recent discovery and both patients and clinicians would welcome a targeted therapy\n\nThe clinical experts observed that less than 2% of people with non-small-cell lung cancer (NSCLC) have ROS1‑positive advanced NSCLC. The ROS1 oncogene is thought to be found almost exclusively in non-squamous NSCLC, mainly in tumours with adenocarcinoma histology. The committee noted that the ROS1 oncogene was only recently discovered; so limited information is available on the natural history, patient characteristics and the clinical effectiveness of chemotherapy for tumours that are ROS1‑positive. The clinical experts highlighted that from the limited information available, there appear to be similarities between ROS1‑positive advanced NSCLC and ALK‑positive NSCLC: for example, both are most often seen in younger patients who do not smoke. In the absence of any targeted therapy until now, ROS1‑positive advanced NSCLC is treated with cytotoxic chemotherapy that can cause unpleasant side effects. The committee noted the patient expert's statement that people with advanced or metastatic NSCLC often feel debilitated by multiple and distressing symptoms. It also noted that the clinical experts considered crizotinib a step-change in treatment because it is taken orally, and offers a marked improvement in quality of life. The committee concluded that crizotinib has a better safety PROFILE\xa0than standard care (cytotoxic chemotherapy) and would be valued by both patients and clinicians.\n\n# ROS1 testing\n\n## ROS1 status should be tested upfront in all non-squamous NSCLC\n\nThe marketing authorisation for crizotinib states that it is necessary to have an accurate and validated assay for ROS1 before treatment with crizotinib is started. The company proposed initial testing with immunohistochemistry (IHC), and follow-up confirmation testing for positive cases with the highly accurate FISH (fluorescence in situ hybridisation) test. The clinical experts explained that only a few centres test for ROS1, and that assay methods vary. The committee understood that although the marketing authorisation for crizotinib did not specify non-squamous disease, ROS1‑positive NSCLC is almost exclusively seen in non-squamous tumours (see section\xa03.1) and therefore the testing would most likely be in people with non-squamous tumours only. The committee discussed when ROS1 testing should be done: it could be done at diagnosis, along with testing for other mutations (such as EGFR and ALK), or later, once people have tested negatively for other mutations (because the different mutations are mutually exclusive). The clinical experts highlighted practical difficulties in testing different mutations at different stages, because more biopsy samples might be needed and the risk of delayed or missed diagnoses with sequential testing. The committee also noted that any delay in diagnosing ROS1‑positive advanced NSCLC would delay access to therapy. It agreed that testing for ROS1 status in all newly diagnosed non-squamous NSCLC would be the best strategy, in line with testing for other types of tumour expression in NSCLC.\n\n# Comparators\n\n## There are different comparators for crizotinib in untreated and previously treated disease\n\nThe committee noted that crizotinib's UK marketing authorisation does not specify whether it should be used to treat squamous or non-squamous disease. It also noted that the summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma. The committee understood that the ROS1 oncogene is mainly present in adenocarcinoma, which is a subtype of non-squamous NSCLC. It agreed that crizotinib would most likely be used in patients with non-squamous NSCLC in clinical practice in the NHS. In line with the final scope issued by NICE, the committee considered untreated and previously treated ROS1‑positive advanced NSCLC separately when determining the most appropriate comparators for crizotinib.\n\n## Untreated disease: pemetrexed plus platinum-based therapy is the appropriate comparator\n\nThe company considered that pemetrexed plus platinum-based chemotherapy (cisplatin or carboplatin) was the appropriate comparator for crizotinib in untreated ROS1‑positive advanced NSCLC. As such, it excluded all other comparators identified in the final scope issued by NICE. The committee understood that NICE's guideline on\xa0lung cancer diagnosis and management recommends platinum-based combination chemotherapy for untreated disease (and docetaxel, gemcitabine, paclitaxel or vinorelbine alone for people who cannot tolerate combination chemotherapy). NICE's technology appraisal guidance on\xa0pemetrexed for the first-line treatment of NSCLC\xa0recommends pemetrexed plus cisplatin for adenocarcinoma or large-cell carcinoma. Pemetrexed is also recommended as maintenance treatment after pemetrexed plus cisplatin for locally advanced or metastatic non-squamous NSCLC in adults whose disease has not progressed (NICE technology appraisal guidance on\xa0pemetrexed maintenance treatment for non-squamous NSCLC after pemetrexed and cisplatin), and after platinum-based chemotherapy plus gemcitabine, paclitaxel or docetaxel (NICE technology appraisal guidance on\xa0pemetrexed for the maintenance treatment of NSCLC). The company excluded pemetrexed as maintenance treatment after pemetrexed plus cisplatin, stating that only around 15% of patients would be eligible. It also noted that patients newly diagnosed with ROS1‑positive advanced NSCLC are generally young and physically fit, and so it was appropriate to exclude single-agent chemotherapy as a comparator (because this is only recommended for people who cannot tolerate combination chemotherapy). The committee understood that the ROS1 oncogene is most common in non-squamous NSCLC and concluded that pemetrexed plus platinum-based chemotherapy was the most appropriate comparator for crizotinib in untreated, ROS1‑positive advanced NSCLC.\n\n## Previously treated disease: it is inappropriate to exclude standard care docetaxel plus nintedanib as a comparator\n\nFor crizotinib in previously treated ROS1‑positive advanced NSCLC, the company considered docetaxel alone to be the best comparator. It excluded nintedanib plus docetaxel as a comparator, despite NICE's technology appraisal guidance on\xa0nintedanib for previously treated locally advanced, metastatic, or locally recurrent NSCLC recommending this as an option for previously treated NSCLC of adenocarcinoma histology. The company stated that it was not possible to compare crizotinib with nintedanib plus docetaxel, because data on nintedanib plus docetaxel were available only for unselected NSCLC. In response to consultation, the company further explained that using pooled chemotherapy in the analysis (that is, docetaxel or pemetrexed in line with treatment options in PROFILE\xa01007) is a conservative approach because pemetrexed is more effective than docetaxel. However, the committee understood that nintedanib plus docetaxel is more effective than docetaxel alone for treating adenocarcinoma, such that it is considered standard care in the NHS for people who can tolerate it. The committee was not convinced by the company's rationale for excluding nintedanib plus docetaxel as a comparator. It concluded that the company should have included nintedanib plus docetaxel as a comparator, because it is thought that the ROS1 oncogene is most common in non-squamous NSCLC and agreed to consider this omission in its decision-making.\n\n# Clinical effectiveness\n\n## Direct evidence for crizotinib's effectiveness in ROS1‑positive advanced NSCLC is extremely limited because there are no comparative data\n\nThe clinical-effectiveness evidence for crizotinib in ROS1‑positive advanced NSCLC is from a small (n=53), single-arm study called PROFILE\xa01001. The trial was done at 8 sites across the US, Australia and South Korea. Only 7 patients had untreated disease; the other 46 had had at least 1 previous chemotherapy. Most patients (96%) had NSCLC of adenocarcinoma histology but 2 patients had non-adenocarcinoma histology. Patients were followed-up for a median of 25.4\xa0months. As determined by the investigators, 5 patients had complete response and 32 patients had partial response (according to Response Evaluation Criteria In Solid Tumours [RECIST]) giving an overall objective response rate of 69.8% (95% confidence interval [CI] 55.7 to 81.7). Median overall survival was not reached at the time of analysis and the company does not intend to carry out any interim analysis in the near future. Median progression-free survival was 19.8\xa0months. The clinical experts stated that these results were clinically meaningful because, in unselected NSCLC, chemotherapy provides progression-free survival of around 5\xa0months in untreated disease and just 3\xa0months in previously treated disease. From the evidence available from PROFILE\xa01001, the committee agreed that crizotinib can induce durable tumour shrinkage and slow disease progression, particularly in previously treated ROS1‑positive advanced NSCLC. In response to consultation, the company highlighted that its original submission included results from a UK clinical audit by the Royal Marsden and other small studies in ROS1‑positive advanced NSCLC that supported the efficacy and safety of crizotinib. The committee noted that the clinical audit reported a median progression-free survival of 12.1\xa0months for both untreated and previously treated disease, and that the OxOnc study reported a median overall survival of 32.5\xa0months at the data cut-off in July 2016 (median overall survival was not reached in the other studies). The committee also noted that although the OxOnc study recruited more patients than PROFILE\xa01001, it was done in Asia and therefore may not be applicable to UK settings. The committee noted that there is no available evidence on the effectiveness of crizotinib compared with chemotherapy for ROS1‑positive advanced NSCLC and concluded that the lack of comparative data makes any assessment of comparative effectiveness (and any economic analysis) very challenging.\n\n## The effectiveness of crizotinib compared with chemotherapy is based on its use in ALK‑positive advanced NSCLC and so is highly uncertain\n\nBecause of the limited clinical-effectiveness data available for ROS1‑positive advanced NSCLC, the company provided results from 2 randomised controlled trials that compared crizotinib with chemotherapy in untreated (PROFILE\xa01014) and previously treated (PROFILE\xa01007) ALK‑positive NSCLC. The company stated that these results could be extrapolated to ROS1‑positive advanced NSCLC. Both trials were considered during the development of previous NICE technology appraisal guidance (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). The committee was aware that in both the PROFILE\xa01014 and PROFILE\xa01007 trials, progression-free survival was statistically significantly longer with crizotinib compared with chemotherapy (pemetrexed plus platinum for untreated disease and pemetrexed plus docetaxel for previously treated disease). The committee was also aware that the overall survival results (unadjusted for patient crossover) from PROFILE\xa01014 and PROFILE\xa01007 suggested that there were no statistically significant differences between crizotinib and chemotherapy in each of these trials. However, the crossover-adjusted hazard ratio results suggested that crizotinib statistically significantly improved overall survival compared with chemotherapy in patients with ALK‑positive advanced NSCLC. The committee noted the ERG's comments that in both trials, the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) was not valid for progression-free survival so any hazard ratios for progression-free survival should be interpreted with caution. The ERG also highlighted that the overall survival estimates were unreliable because of high rates of crossover, and that statistical methods for adjustment were not reported transparently. The committee agreed that the results showed crizotinib to be more effective than chemotherapy for ALK‑positive NSCLC, but that its relative effectiveness in ROS1‑positive advanced NSCLC remained uncertain.\n\n## The only comparative evidence for crizotinib in ROS1‑positive advanced NSCLC is from proxy data in ALK‑positive NSCLC\n\nThe committee discussed the relevance of the PROFILE\xa01014 and PROFILE\xa01007 results to ROS1‑positive advanced NSCLC. In its submission, the company strongly advocated that data from ALK‑positive NSCLC could be used as a proxy for ROS1‑positive advanced NSCLC. It stated that:\n\nThe kinase domains of ALK and ROS1 share 77% of amino acids in the ATP-binding sites.\n\nBoth ALK‑positive and ROS1‑positive advanced NSCLC are similar in terms of clinical behaviour including response to crizotinib, patient characteristics and histology (both are predominantly adenocarcinoma).\n\nThe European Medicines Agency supported the generalisability of data from ALK‑positive NSCLC to ROS1‑positive advanced NSCLC when granting crizotinib's marketing authorisation in this indication.\n\nTwelve UK clinical experts from a company-sponsored advisory board agreed that the data were an appropriate proxy for ROS1‑positive advanced NSCLC.The committee considered the histology of ALK‑positive NSCLC. It understood that the inclusion criteria in PROFILE\xa01014 specified non-squamous NSCLC and most patients (93%) in PROFILE\xa01007 had adenocarcinoma histology. The ALK‑positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC and that the testing for the ALK mutation is routinely done in the non-squamous population only. The committee therefore accepted the company's view that both are predominantly of adenocarcinoma histology. The clinical experts stated that in their experience ROS1‑positive advanced NSCLC is even more sensitive to crizotinib than ALK‑positive NSCLC. The committee acknowledged this, but noted the ERG's concern that any documented similarities between ALK‑positive and ROS1‑positive advanced NSCLC may not hold true as more patients with ROS1‑positive advanced NSCLC are identified. The committee noted that median progression-free survival in the ROS1‑positive trial (PROFILE\xa01001) and the ALK‑positive trials (PROFILE\xa01014 and PROFILE\xa01007) differed enough (19.3\xa0months compared with 10.9\xa0months and 7.7\xa0months respectively) to seriously question the comparability of the 2 patient populations. The committee was aware that there are no randomised trials planned for crizotinib in ROS1‑positive advanced NSCLC and comparative data on efficacy is not expected. Furthermore, even the non-comparative data for its use in ROS1‑positive advanced NSCLC were very limited, particularly for untreated disease. The committee agreed that using data from a proxy population was far from ideal, and considered whether it should accept analyses based on treatment effects from a proxy population. Having taken into account the relatively small patient population and the clinical experts' views on the innovative nature of crizotinib, the committee agreed to explore the proxy data in its decision-making. However, it regarded this approach as very unusual and stated that this should not set a precedent for the use of data from proxy populations in future appraisals.\n\n# Cost-effectiveness analyses\n\n## All cost-effectiveness analyses are based on proxy data so results are extremely uncertain\n\nThe committee recognised that the company had presented a revised base-case analysis in response to consultation incorporating some of the committee's preferred assumptions, and a number of scenario analyses that explored alternative values for the overall and post-progression survival benefit of crizotinib. All analyses included a higher utility value for people taking pemetrexed plus platinum-based chemotherapy (see section\xa03.12) and higher costs for treating pulmonary embolism (see section\xa03.13). It also incorporated testing costs for untreated disease and assumed sequential testing for previously treated disease (see section\xa03.2). The committee understood that all the testing costs were for non-squamous NSCLC only.\n\nThe revised base case incorporated an overall survival benefit for crizotinib of 18.2\xa0months for untreated disease and 20.9\xa0months for previously treated disease.\n\nThe scenario analyses incorporated a range of values for the overall and post-progression survival benefit of crizotinib explored the impact of excluding testing costs.The committee noted that the revised analyses still extrapolated data for both crizotinib and the comparators from ALK‑positive NSCLC and that it had not presented a revised analysis of the PROFILE\xa01001 scenario (that used data from ROS1‑positive NSCLC population to model the intervention arm but extrapolated the relative effectiveness from ALK‑positive NSCLC to model the comparator arm). It considered that even with the new analyses, there was still a high degree of uncertainty because of the use of proxy data. Without any reliable evidence on the effectiveness of the comparator treatments in ROS1‑positive advanced NSCLC (see section\xa03.6), the committee concluded that all of the cost-effectiveness estimates were associated with uncertainty that needed to be accounted for in its decision-making.\n\n# Overall survival\n\n## The relationship between overall and progression-free survival is unclear and the size of crizotinib's overall survival benefit is difficult to establish\n\nThe ERG had questioned the company's original modelled overall survival gain with crizotinib (see table\xa01), given that the modelled progression-free survival gain was considerably less (9.5\xa0months for untreated disease and 5.7\xa0months for previously treated disease). The committee recalled that the overall survival data from PROFILE\xa01014 and PROFILE\xa01007 were confounded by high crossover rates, and that adjustment methods had not been reported transparently (see section\xa03.7). The clinical experts explained that progression-free survival gains would be expected to result in some overall survival benefit, but the exact relationship is difficult to predict. Nevertheless, the experts agreed that a modelled overall survival gain almost 3 times higher than the modelled progression-free survival gain was most likely to be an overestimate. In its response to consultation and based on clinical expert opinion, the company reported analyses using a range of values for overall and post-progression survival to explore the additional survival benefit with crizotinib.\n\n## Table 1 Summary of the company's analyses\n\n\n\nSurvival gain for crizotinib (months)\n\nAnalysis\n\nUntreated disease\n\nPreviously treated disease\n\n\n\nOS\n\nPPS\n\nOS\n\nPPS\n\nOriginal base case\n\n\n\n\n\n\n\n\n\nRevised base case\n\n\n\n\n\n\n\n\n\nScenarios (adapted from ERG)\n\n*\n\n*\n\n*\n\n*\n\n\n\n\n\nOther scenarios\n\n\n\n\n\n\n\n\n\nAbbreviations: ERG, evidence review group; OS, overall survival; PPS, post-progression survival.\n\n* The company considered that these scenarios were not clinically plausible.\n\nSurvival gains are from the ERG's critique of the company's response to consultation. The company presented further analyses but these were marked as commercial in confidence so cannot be reported here.\n\nThe company highlighted that that overall survival gains of at least 13.1\xa0months for untreated disease and at least 16.2\xa0months for previously treated disease had been accepted for crizotinib in the ALK‑positive population (see NICE technology appraisal guidance on crizotinib for untreated ALK-positive advanced non-small-cell lung cancer and crizotinib for previously treated ALK-positive advanced NSCLC) and considered these clinically plausible. The ERG agreed that some post-progression clinical benefit with crizotinib was plausible, but noted that the size of the benefit was highly uncertain and the company's estimates of survival gain were not adequately justified. The committee understood that compared with its original analyses, the company's revised base case included a more conservative post-progression benefit for untreated disease but a larger benefit for previously treated disease (see table\xa01). The committee concluded that even with the new analyses from the company, there was considerable uncertainty around the size of survival benefit in the progression free and progressed states because the relationship between overall survival and progression-free survival is unclear.\n\n## The mid-point between the ERG's and company's new scenario analyses for overall survival modelling is preferred\n\nTo explore the uncertainty in the overall survival benefit with crizotinib, the ERG did 2 scenario analyses in its critique of the company's original submission:\n\nIn the first, the ERG applied the hazard ratio for progression-free survival to the unadjusted (for crossover) overall survival curve of the crizotinib treatment arm.\n\nIn the second, the ERG assumed no survival benefit other than survival gained in the progression-free state. For this scenario, the ERG adapted the overall survival curve for the comparator to make survival in the progressed state equal for both treatment arms. This means that any survival benefit was attributable to the survival benefit in the progression-free state.For the first scenario analysis, the committee was not convinced that the hazard ratio from 1 outcome could be applied equally to another. The committee considered the ERG's second scenario analysis to be more informative in terms of overall survival modelling, but it did not agree with the way the ERG implemented the analysis. The committee considered that adjusting the crizotinib overall survival curve (to make the survival gain in the post-progression state equal to the modelled survival in the post-progression state of the comparator arm) would have been a better approach. Overall, the committee considered that some relative advantage for crizotinib after disease progression was plausible. In its response to consultation, the company did 4 scenario analyses to explore the clinical plausibility of each of the overall survival models (see section\xa03.10). This included the company's amendments to the ERG's second scenario analysis that adapted the overall survival curve for crizotinib and included a clinical benefit for crizotinib in the progressed state. The committee understood that these scenarios improved the cost effectiveness of crizotinib for both untreated and previously treated disease. The committee was aware from correspondence with 1 of the clinical experts who had attended the first committee meeting that the company's modelled survival benefits for untreated and previously treated disease were plausible for this small group of young patients with few comorbidities. The expert explained that response to crizotinib in patients with the ROS1‑positive mutation is similar to patients with the ALK‑positive mutation, so an average survival benefit of 24\xa0months is reasonable for both untreated and previously treated disease. The committee concluded that the overall survival gain for crizotinib was somewhere between the company's new scenario analyses using the lower bounds of clinical benefit (that is, an overall survival benefit of 13.1\xa0months for untreated disease and 16.2\xa0months for previously treated disease) and the ERG's estimates assuming no benefit in the progressed state, but reiterated that this analysis was still based on a proxy population and therefore considerable uncertainty remained.\n\n# Utility values\n\n## The company's new utility values for the comparator in untreated disease are appropriate for decision-making\n\nThe company used a utility value of 0.81 for people having crizotinib in both the progression-free and progressed disease states. For people having the pemetrexed plus platinum-based chemotherapy, the company used a utility value of 0.72. People subsequently having docetaxel or best supportive care were given utility values of 0.61 and 0.47 respectively. The committee noted that almost all the values used (with the exception of the utility value for people having pemetrexed plus platinum-based chemotherapy) were the same values accepted by the appraisal committees during the development of NICE technology appraisal guidance on crizotinib for ALK‑positive NSCLC (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). During the appraisal of crizotinib for untreated ALK‑positive advanced NSCLC, the ERG had provided exploratory analyses using a utility value for people having pemetrexed plus platinum-based chemotherapy of 0.75 which was deemed appropriate by the committee at the time. The committee agreed that for consistency it would take this slightly higher utility value into account, and that this would decrease crizotinib's perceived cost effectiveness. The committee also noted that the company had not included disutility to account for any adverse reactions, and agreed that this would add further uncertainty to the results. In response to consultation, the company preferred to use a utility of 0.75 for pemetrexed plus platinum-based chemotherapy when patients were not taking treatment and 0.72 when patients were taking treatment. The committee noted that this approach had only a small effect on the cost-effectiveness results and concluded that the utility values used in the company's new analyses were appropriate for decision-making.\n\n# Costs\n\n## It is appropriate to include revised costs for treating pulmonary embolism and administering crizotinib\n\nThe company included higher costs for treating pulmonary embolism as part of its revised base case, noting that these costs were consistent with values used during the development of NICE technology appraisal guidance on ceritinib for untreated ALK-positive NSCLC. The ERG noted that including higher costs for treating pulmonary embolism had only a small effect on the cost effectiveness of crizotinib. The committee understood that the company did not change the administration costs of crizotinib in its revised base case, and noted that including the NHS reference cost for delivering oral chemotherapy (HRG code SB11Z) increased the incremental cost-effectiveness ratios (ICERs) for both untreated and previously treated disease. It also understood that a similar administration cost using HRG code SB11Z was included in a previous NICE technology appraisal in the ALK‑positive population (crizotinib for previously treated ALK-positive advanced NSCLC). The committee concluded that it was appropriate to include higher costs for treating pulmonary embolism and administering crizotinib.\n\n# The most plausible ICERs\n\n## The most plausible ICERs for crizotinib are uncertain and not clearly within the range normally considered to be cost-effective use of NHS resources\n\nThe committee agreed that the new ICERs presented by the company were highly uncertain because of the use of proxy data from ALK‑positive advanced NSCLC and uncertainties in the overall survival extrapolation. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee recalled that, as a starting point for its discussion, it would consider ICERs at the mid-point between the company's new scenario that included a clinical benefit for crizotinib in the progressed state (assuming an overall survival gain of 13.1\xa0months for untreated disease and 16.2\xa0months for previously treated disease) and the ERG's scenario assuming no survival benefit in the progressed state (see section\xa03.11). Having considered that some post-progression clinical benefit with crizotinib was plausible but the size was uncertain (see section\xa03.10), and having established its preferred assumptions for upfront testing costs (see section\xa03.2) and higher administration costs (see section\xa03.13), the committee considered that the most plausible ICERs would be:\n\nFor crizotinib compared with pemetrexed plus platinum-based chemotherapy in untreated disease: around or above £50,000 per\xa0quality-adjusted life year (QALY) gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). However, the committee agreed that this estimate came with far too much uncertainty to conclude on a figure below £50,000 without further evidence.\n\nFor crizotinib compared with docetaxel in previously treated disease: well above £50,000 per\xa0QALY gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). The committee agreed that had crizotinib been compared with nintedanib plus docetaxel, the ICER would be even higher.\n\n# End of life\n\n## Crizotinib meets both criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's technology appraisal process and methods. The company stated that there is limited data on overall survival with chemotherapy in people with ROS1‑positive advanced NSCLC. In the proxy population with ALK‑positive NSCLC, median overall survival ranged from 6\xa0months to 22\xa0months and there is no evidence that it would be better in people with ROS1‑positive advanced NSCLC. The company also highlighted that median overall survival was not reached in PROFILE\xa01001, and median progression-free survival was 19.3\xa0months, so overall survival with crizotinib in ROS1‑positive advanced NSCLC would be at least 19.3\xa0months. The committee agreed that crizotinib for ROS1‑positive advanced NSCLC met the first criterion to be considered a life-extending treatment at the end of life. The committee noted that the mean overall survival gained with crizotinib, as estimated in the company's revised base case, was 18.2\xa0months for untreated disease and 20.9\xa0months for previously treated disease. Therefore crizotinib may offer, on average, at least 3\xa0months' extension to life compared with standard care. However, it noted the considerable uncertainty around the company's modelling of overall survival and considered that any estimate of an overall survival gain compared with standard care was very uncertain. The committee noted that crizotinib was considered life-extending for people with both untreated and previously treated ALK‑positive NSCLC. Based on the clinical experts' testimony that the ALK‑positive NSCLC population could be used as a proxy for people with ROS1‑positive advanced NSCLC, the committee thought it likely that there was an overall survival gain with crizotinib of over 3\xa0months. The committee concluded that crizotinib met both criteria to be considered a life-extending, end-of-life treatment.\n\n## Crizotinib cannot be recommended for routine use in the NHS\n\nDespite meeting both end-of-life criteria, the most plausible ICERs for crizotinib compared with standard care in the company's revised base case were not clearly within the range normally considered to be a cost-effective use of NHS resources. Given the high level of uncertainty in the analyses, the committee concluded that it could not recommend crizotinib for routine use in the NHS to treat ROS1‑positive advanced NSCLC.\n\n# Innovation\n\n## Crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC\n\nThe company stated that crizotinib is innovative because it is the first targeted therapy for ROS1‑positive advanced NSCLC. The US Food and Drug Administration also assigned crizotinib a breakthrough therapy designation, and the marketing authorisation was granted through a priority review. The committee emphasised that the European Medicines Agency had approved crizotinib in this indication based on just 1 single-arm study. The company highlighted that as an oral therapy, crizotinib gives patient more autonomy. Moreover, the company claimed that its quick and durable effect may have wider societal benefits that were not captured in the cost-effectiveness analysis. The committee agreed that crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC. However, the committee concluded that there were no relevant additional benefits that had not been captured in the QALY calculations.\n\n# Cancer Drugs Fund\n\n## Using crizotinib in the Cancer Drugs Fund would provide important data and encourage standardisation of ROS1 testing\n\nHaving concluded that crizotinib could not be recommended for routine use in the NHS to treat ROS1‑positive NSCLC, the committee considered whether it could be recommended for use in the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee was aware that the overall survival data from PROFILE\xa01001 were immature and no further analysis was expected in near future. The company stated that some clinical experts consider further comparative trials to be unethical, because of crizotinib's efficacy in treating ROS1‑positive NSCLC in PROFILE\xa01001. The committee was aware that there are ongoing single-arm observational studies that will provide additional information. However, these studies would only partly address the uncertainties about crizotinib's relative clinical effectiveness. The committee agreed with NHS England that because ROS1‑positive lung cancer has only recently been described, and information on the population characteristics, natural history and prognosis is limited, it would be of great value to collect data about the use of crizotinib in ROS1‑positive advanced NSCLC through the Cancer Drugs Fund. The committee concluded that collecting data on the demographics of people with ROS1‑positive advanced NSCLC, treatment length and disease progression on crizotinib would help to address the uncertainties around the survival benefit and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC populations. The clinical experts commented that the clinical community would welcome an opportunity to contribute to this data collection through the Cancer Drugs Fund; the representative from NHS England indicated that such data could be collected for up to 5\xa0years. The committee further concluded that crizotinib's use through the Cancer Drugs Fund would also encourage standardisation of ROS1 testing.\n\n## Crizotinib is recommend for use in the Cancer Drugs Fund for both untreated and previously treated ROS1‑positive NSCLC\n\nHaving determined that the most plausible ICER for crizotinib in untreated disease was around or above £50,000 per\xa0QALY gained, the committee concluded that crizotinib had plausible potential to represent cost effectiveness through its use in the Cancer Drugs Fund. The ICER based on the current evidence is higher than the range normally considered to be a cost-effective use of NHS resources, but the committee considered that crizotinib's clinical effectiveness was promising and its use through the Cancer Drugs Fund would provide important data to resolve the clinical uncertainties and encourage standardisation of ROS1 testing. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee noted that when testing for ROS1 became routine practice, most people with ROS1‑positive NSCLC would first have crizotinib and the number of people eligible for crizotinib as a later-line treatment would decrease over time. The committee therefore agreed that it would not make a distinction between untreated and previously treated disease in its recommendations. The committee concluded that it could recommended crizotinib as an option for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC, only if the conditions in the managed access agreement are followed.\n\n## Crizotinib is most likely to be used in the Cancer Drugs Fund for non-squamous NSCLC only\n\nThe committee further considered the population for which crizotinib would most likely be used within the Cancer Drugs Fund. It recalled that: in clinical practice, crizotinib is most likely to be used for non-squamous NSCLC; the comparators chosen by the company were for non-squamous NSCLC; the trial results from PROFILE\xa01001 and the ALK‑positive proxy data from PROFILE\xa01014 and 1007 were almost exclusively in people with non-squamous histology and predominately in adenocarcinoma; and the testing costs included in the cost-effectiveness analysis were based on a non-squamous lung cancer population. The committee was aware that the incidence of ROS1 in squamous NSCLC is around 1.7% to 1.8%, but recognised that testing of ROS1 status in all patients with NSCLC would be very costly for the Cancer Drugs Fund. It accepted that ROS1 testing and the use of crizotinib in the Cancer Drugs Fund would be in people with non-squamous NSCLC only.\n\n# Other factors\n\n## ROS1 testing at diagnosis would reduce potential inequitable access to targeted therapies\n\nThe company commented that regional variations in access to ROS1 testing could lead to inequitable access, and advocated testing at diagnosis of all non-squamous NSCLC for ROS1 status. The company highlighted that sequential testing (that is, done after testing for EGFR and ALK) would also delay access to crizotinib. The committee agreed that variation in access to treatment does not normally constitute an equality issue under equality legislation. However, the committee considered this potential equality issue and agreed that if crizotinib becomes an available treatment option, ROS1 testing should be done at diagnosis to help prevent potential inequality of access."}
|
https://www.nice.org.uk/guidance/ta529
|
Evidence-based recommendations on crizotinib (Xalkori) for treating ROS1-positive advanced non-small-cell lung cancer in adults.
|
928f3f46b4cb6bea4b84c5235ef07c8f346f3968
|
nice
|
Nivolumab for treating locally advanced unresectable or metastatic urothelial cancer after platinum-containing chemotherapy
|
Nivolumab for treating locally advanced unresectable or metastatic urothelial cancer after platinum-containing chemotherapy
Evidence-based recommendations on nivolumab (Opdivo) for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.
# Recommendations
Nivolumab is not recommended, within its marketing authorisation, for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy.
This recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment options for people with locally advanced unresectable or metastatic urothelial carcinoma who have had platinum-containing therapy are limited. They are usually offered docetaxel, paclitaxel and best supportive care.
Nivolumab has been studied in a clinical trial, but it has not been directly compared with other treatments. So it is not clear how effective nivolumab is compared with current clinical practice.
Nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The committee agreed that the assumptions incorporated in the evidence review group's (ERG's) revised base case were mostly consistent with its preferred assumptions. The committee agreed that the most plausible incremental cost-effectiveness ratios (ICERs) were somewhere between the ERG's estimates of £58,791 per quality-adjusted life year (QALY) gained (compared with paclitaxel) and £78,869 per QALY gained (compared with docetaxel), above what NICE normally considers to be acceptable for end-of-life treatments. There was substantial uncertainty because the model used a simulated treatment comparison, so the ICER could be considerably higher. Therefore nivolumab could not be recommended for routine use in the NHS for locally advanced, unresectable or metastatic urothelial cancer after platinum-containing chemotherapy.
Because neither data collection from clinical practice or the ongoing trials would resolve the identified uncertainty, nivolumab is not suitable for use within the Cancer Drugs Fund for people with unresectable or metastatic urothelial cancer after platinum-containing therapy.# Information about nivolumab
Marketing authorisation indication
Nivolumab (Opdivo, Bristol-Myers Squibb) as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of platinum-containing therapy.
Dosage in the marketing authorisation
mg/kg by intravenous infusion every 2 weeks.
Price
£439 per 40‑mg vial or £1,097 per 100‑mg vial (excluding VAT; British national formulary online, accessed September 2017).
The company has a commercial arrangement, which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition
## Urothelial carcinoma substantially decreases quality of life
Urothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. The patient experts commented that chemotherapy is associated with unpleasant adverse effects such as fatigue, nausea and vomiting and places people at more risk of infection. The committee was aware that many people with the disease are older and may have comorbidities, which can affect the choice of treatment. The committee recognised that locally advanced unresectable or metastatic urothelial carcinoma has a substantial effect on quality of life.
# Clinical management
## There is unmet need for effective treatment options
Initial treatment is usually with a cisplatin-containing chemotherapy regimen. Treatment options for people whose disease progresses after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care. The clinical experts explained that none of these treatments offer lasting benefit and that prognosis is poor, even for people having their first therapy. The patient experts explained that the adverse effects of chemotherapy can have a large negative effect on quality of life and that regular hospital visits for treatment disrupt usual activities. The clinical experts noted that there have been no new treatments for locally advanced unresectable or metastatic urothelial carcinoma for a number of years and that, unlike for other cancers, there is no targeted or personalised treatment available after platinum-containing chemotherapy. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced unresectable or metastatic urothelial carcinoma who have had platinum-containing chemotherapy.
# Comparators
## Paclitaxel, docetaxel and best supportive care are relevant comparators for people who have had platinum-containing chemotherapy
The company submitted clinical- and cost-effectiveness analyses comparing nivolumab with paclitaxel, docetaxel and best supportive care. The committee understood that because nivolumab is an immunotherapy with a different adverse effect profile to taxanes (such as paclitaxel and docetaxel), there may be some people for whom nivolumab is suitable who would otherwise have best supportive care. It recognised that introducing immunotherapy may change clinical practice in the future, but that best supportive care is currently a treatment option for urothelial carcinoma and is therefore a relevant comparator. The committee understood that re-treatment with first-line chemotherapy was used before a standard second-line treatment option became available, and that now most clinicians would use a taxane. The clinical experts explained that re-treatment with a first-line chemotherapy would most likely be for disease that had responded well, in people whose disease has not progressed for a long period of time after first-line treatment and who are fit enough to have re-treatment with platinum. Second-line treatment is with a taxane. The clinical experts explained that paclitaxel is used as current standard of care in the UK because of its availability and favourable adverse effect profile compared with docetaxel. Clinical experts in other ongoing immunotherapy appraisals for this population explained that both paclitaxel and docetaxel could be considered clinically equivalent and are both used in clinical practice. The committee concluded that docetaxel, paclitaxel and best supportive care are appropriate comparators, but re-treatment with first-line chemotherapy is not.
# Clinical trial evidence
## The CheckMate trials are broadly generalisable to UK clinical practice
The clinical-effectiveness evidence for nivolumab comes from 2 phase II, single-arm trials; CheckMate 275 and CheckMate 032. The trials included:
patients with locally advanced unresectable or metastatic urothelial carcinoma with disease progression or recurrence after treatment with at least 1 platinum-containing agent (CheckMate 275) and
patients with carcinoma of the renal pelvis, ureter, bladder or urethra, and disease progression after treatment with at least 1 platinum-containing chemotherapy (CheckMate 032).There is a lack of UK patients in the trials and more patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 compared with those seen in clinical practice, which might affect the generalisability of the results. The ERG stated that 23% of people in CheckMate 032 switched to nivolumab plus ipilimumab at disease progression. The committee noted that this would bias the efficacy results from this study, but acknowledged that when pooled with CheckMate 275, the proportion of patients switching treatment in the entire pooled population is low, and therefore the overall effect is minimal. It also noted a difference in the mean age of people in the trial (66 years) compared with clinical practice, which the experts suggested is around 75 years. The clinical experts explained that this could suggest a role for using nivolumab in younger people whose disease has newly progressed. The committee accepted that the patient populations in the CheckMate trials are broadly generalisable to those seen in UK practice.
## The CheckMate trials provide efficacy estimates for nivolumab but no randomised controlled trial evidence is available
Data from CheckMate 275 reported an objective response rate of 20.0% (95% confidence interval 15.4 to 25.3) and median overall survival of 8.57 months (95% CI 6.05 to 11.27). The data originally presented for CheckMate 032 reported an objective response rate of 24.4% (95% CI 15.3 to 35.4) and median overall survival of 6.51 months (95% CI 1.91 to not estimable). The company provided updated clinical-effectiveness data for both CheckMate 275 and CheckMate 032. The updated results are confidential and cannot be presented here. The company included the latest CheckMate 032 data in its economic analysis. The company stated that the updated results from CheckMate 275 confirm the original data presented at the first appraisal committee meeting, but did not include the updated figures in its economic analysis. The committee agreed that the availability of the latest CheckMate 275 data is not likely to have a substantial effect on clinical-effectiveness estimates. It was concerned that, without a trial directly comparing nivolumab with other treatments, it is difficult to reliably assess the relative treatment benefit of nivolumab. The committee also noted that the trial data are immature and based on small numbers of patients, and therefore there is considerable uncertainty in the results. The clinical experts highlighted that people whose disease responds to treatment with an immunotherapy such as nivolumab can have a lasting response, good quality of life and prolonged survival. They explained that the novel mechanism of action of immunotherapies such as nivolumab represent an important new treatment option in clinical practice. The committee concluded that it would be challenging to accurately assess the relative treatment benefit of nivolumab without any available randomised controlled trial evidence.
# Indirect comparison
## The results of the simulated treatment comparison need to be treated with caution because the analysis was unanchored
Nivolumab has only been studied in single-arm trials for previously treated urothelial cell carcinoma. To compare nivolumab with the relevant comparators the company did a simulated treatment comparison and network meta-analysis. This was an unanchored comparison because none of the evidence included in the analysis shared a common comparator. The committee was aware that bias is introduced into a simulated treatment comparison if all important prognostic factors are not accounted for. It considered that it is unlikely that all of the important prognostic factors had been accounted for in the simulated treatment comparison, therefore affecting the robustness of the results. The ERG explained that the way to test the external validity of the simulated treatment comparison is the out-of-sample method. This could be used to assess the presence of bias in the comparison model. The company explained that because of the limited availability of data, this validation method would not provide an accurate estimation of bias. The ERG noted that the effect of using alternative prognostic factors in the prediction model could have been assessed in a sensitivity analysis, and this should have been done to test the robustness of the comparison. The committee concluded that, because of the concerns about the robustness of the simulated treatment comparison, the results of the analysis need to be treated with caution.
## The network meta-analysis produced results which are inconsistent with current clinical expectations about the effectiveness of nivolumab
The company linked the results of the individual simulated treatment comparisons together through a network meta-analysis, using a fractional polynomial model. The committee noted that this is not a conventional modelling approach for a network meta-analysis. It was concerned that a lack of evidence in the network increased the reliance on the fractional polynomial model to estimate relative treatment benefit of nivolumab. The ERG explained that the fractional polynomial model is a highly flexible form of analysis. But, it expressed reservations about the robustness of the fractional polynomial model and noted that incremental cost-effectiveness ratio (ICER) estimates were highly sensitive to the parameterisation of the model. The company stated that the evidence base for paclitaxel that informs the comparison with nivolumab is the most robust of the comparisons presented; it comes from a UK-only, randomised controlled trial. The committee acknowledged that although the evidence for paclitaxel came from a relevant randomised control trial, only the results for the paclitaxel arm were included in the indirect comparison. This removed the benefits of randomisation. The committee noted that including the results from a simulated treatment comparison which was not robust would affect the meta-analysis results, although it is unclear to what extent. The committee agreed that the results of the indirect comparison should be treated with caution. This is because the optimal parameterisation of the fractional polynomial is unknown and the network of evidence is sparse. The time varying hazard ratios used to infer relative treatment effect of nivolumab for overall survival and progression-free survival were estimated using the results of the network meta-analysis. The committee understood that results from the company's network meta-analysis suggest that, compared with docetaxel and best supportive care, the relative effectiveness of nivolumab decreases with time. It agreed that this was inconsistent with clinical expectations about the effectiveness of nivolumab given that it is expected to have a long-lasting effect because of its novel mechanism of action. The committee concluded that the relative-effectiveness estimates inferred from the network meta-analysis are counterintuitive and associated with uncertainty, which needs to be accounted for in its decision-making.
# Adverse events
## Nivolumab is well tolerated
The clinical experts explained that in their experience of using nivolumab, it is well tolerated and has a preferable adverse effect profile compared with comparator chemotherapies. They stated that the rate of serious adverse effects from nivolumab are similar to those seen for chemotherapies. They noted that the mortality risk from current treatments has decreased as clinical understanding improves after more widespread use of the treatment. The committee noted that a similar trend could happen if nivolumab was recommended, with treatment-related mortality dropping as clinical understanding improves. It noted that it is challenging to make a robust comparison of adverse events without randomised control trial evidence. The committee acknowledged that nivolumab is associated with some rare but unpleasant and potentially serious adverse events that are specific to immunotherapy. It concluded that nivolumab may be a tolerable alternative to chemotherapies as more experience is gained with this type of treatment.
# Assumptions used in economic model
## The use of standard parametric time-to-event survival analysis is preferred to a response-based approach
The company stated that standard parametric time-to-event models are unsuitable for modelling the possible sustained and long-term response to treatment expected with nivolumab. To account for this, the company modelled survival using a response-based analysis. This approach modelled survival for people until a pre-determined time point (landmark), when survival was individually assessed according to response to treatment. The company opted for an 8‑week landmark point, based on the median time to response in the CheckMate trials. The ERG explained that alternative landmarks were not fully explored and therefore the effect on the ICER was not appropriately assessed. The company used the Kaplan–Meier estimates up until the landmark, at which point parametric distributions were fitted to the responder and non-responder curves to model progression-free survival and overall survival. The ERG stated that the company did not provide a mathematical justification to support their argument that a different response cannot be accurately described by standard parametric survival models. It explained that standard approaches are flexible enough to accurately model different responses, without needing to introduce unnecessary assumptions in to the analysis. The committee noted it had not seen any firm evidence to show that the response-based model was an adequate method to model long-term outcomes. The ERG preferred to estimate overall and progression-free survival by fitting a generalised gamma function to the trial data. The committee agreed that the response-based approach could be explored for modelling survival but agreed with the ERG that the company's approach introduced unnecessary complexity into the modelling of survival. Therefore more evidence would be needed to support its appropriateness in preference to established modelling methods.
## Using a conventional parametric time-to-event survival analysis is considered to be the most appropriate
The clinical experts explained that people with urothelial carcinoma that has been treated with platinum-containing chemotherapy have a mean life expectancy of around 12 months, and that survival at 5 years is uncommon. The committee understood that the overall-survival data for nivolumab are too immature to provide a reference for the estimates generated in the survival models. The committee was aware that model projections for 5‑year survival from other immunotherapy appraisals are about 10%, which was in line with the clinical expert opinion. It agreed that this estimate was an acceptable reference to validate the estimates produced by the different modelling approaches. The clinical experts stated that around 2 to 3% of people would be expected to be alive 5 years after treatment with current standard of care. It noted that estimates for 5‑year survival in the response-based model are around 20% for nivolumab and around 6 to 8% for taxanes (values derived from the company's economic model). The ERG explained that the 5‑year survival estimates from its preferred survival model are around 13% for nivolumab and between 2 and 5% for taxanes. The committee noted that in the company's model, the slope of the overall-survival curve for people whose disease responds to nivolumab is nearly flat. This suggests that the proportion of people in this group who stay alive would decrease slowly. The committee had concerns that the overall-survival prospects of this group may exceed that of an equivalent disease-free population, which would be implausible. It agreed that the overall-survival curve produces an implausible estimation of survival in the long term, because the response-based model does not appear to accurately characterise survival outcomes in this population. It was concerned that the company's model overestimates the number of people who would be alive at 5 years and that people surviving past 5 years are effectively considered cured. This claim is not supported by the evidence. The committee preferred the ERG's approach to modelling survival, because it produces estimates that are more consistent with clinical expert opinion and are therefore more clinically plausible. The committee concluded that the use of conventional parametric time-to-event survival analysis was the most appropriate method on which to base its decision.
## The conventional fully fitted survival model is the most appropriate for estimating survival outcomes
The company presented an alternative scenario to model survival rather than the ERG's non-response-based approach. In the non-response-based analysis, survival was estimated using a piecewise model (using Kaplan–Meier data for the first part of the time horizon before switching to a parametric distribution for the extrapolation of longer-term survival estimates). The committee acknowledged that this method of modelling survival has been applied in other immunotherapy appraisals. It understood that both the conventional (fully fitted) and piecewise approaches have enough evidence to support their suitability for modelling survival, and have shown validity in other appraisals. The committee noted that there was little description of the company's assumptions used in the piecewise model approach. There was also no justification or exploration of the type of extrapolations that could be used or the time point selected to switch from the Kaplan–Meier data to the parametric model. The company commented that the probabilistic sensitivity analysis did not fully work for the piecewise model and could not be presented. For these reasons the committee could not accept the outputs of the piecewise model presented by the company. It reaffirmed its conclusion that for this appraisal the conventional fully fitted survival model (ERG's approach) was the most appropriate for estimating survival outcomes.
## Pooling of utility estimates from CheckMate 275 and CheckMate 032 in the model is appropriate for this appraisal
EQ-5D data were collected directly in CheckMate 275 and CheckMate 032, which is the preferred measure of health-related quality of life in adults. Pre-progression utilities (0.736) and post-progression utilities (0.623) were derived from pooling CheckMate 275 and CheckMate 032 values, with missing values being imputed. Disutilities for adverse events were derived from the literature. The ERG explained that the utility decrements used by the company were inconsistent with those used in a previous nivolumab appraisal. The committee noted that in the company's estimation of the treatment effect of nivolumab, both CheckMate trials were pooled, and it agreed that a consistent approach should be taken for estimating utility values. The committee concluded that the pooling of utility estimates from the 2 trials is acceptable in this case.
## The application of a 2-year treatment stopping rule reduced costs associated with nivolumab but the effect on long-term efficacy is unknown
The company presented evidence from an ongoing study (CheckMate 003) of nivolumab in a different disease area. CheckMate 003 applied a stopping rule for nivolumab at 2 years (when all patients stop treatment). The company noted that people in CheckMate 003 continued to benefit from treatment beyond the point at which it was stopped. The company included a 2‑year treatment stopping rule into its revised economic analysis. It explained that a 2‑year stopping rule has been accepted in another immunotherapy appraisal of urothelial carcinoma. The committee recalled that when it accepted the 2‑year stopping rule for another immunotherapy appraisal, the trial protocol for the study informing the economic analysis had mandated a maximum treatment duration of 2 years. The ERG explained that applying the 2‑year stopping rule in the economic model stopped costs associated with nivolumab, but treatment benefit of nivolumab was assumed unchanged. The ERG did not include a 2‑year stopping rule in its revised analysis, because the effect on clinical outcomes after treatment stops is unclear. The committee noted that the duration of continued effect after treatment has stopped is an area of uncertainty for new immunotherapies, but it agreed that a lifetime continued treatment effect is implausible. The committee concluded that implementing a treatment stopping rule while assuming lifetime treatment benefit was inappropriate.
## Assumption of a lifetime treatment benefit is implausible and scenarios varying this parameter in the economic model produced illogical results
The company presented scenarios in which the continued treatment effect ended after 3 years or 5 years from the start of the model. In the comparison of nivolumab and docetaxel, the committee understood that stopping treatment benefit for nivolumab at 3 or 5 years reduced the ICER compared with the company's base case (using a response-based model in both scenarios). It noted that the ICERs would be expected to increase when the additional benefit of nivolumab on survival was assumed to stop at these time points (that is, assume a hazard ratio of 1). The committee understood that quality-adjusted life year (QALY) gains accrued in the model for nivolumab must happen in the short term if stopping treatment benefit at 3 years or 5 years decreases the ICER. It agreed that the change seen in the ICER is contradictory to the company's statement that people treated with nivolumab will have a long-lasting response with nivolumab. Stopping treatment benefit in the comparison of nivolumab and paclitaxel increased the ICER compared with the company's base case. The committee noted that paclitaxel and docetaxel can be considered clinically equivalent (see section 3.3). It agreed that inconsistencies in the direction of change in the ICERs confirmed its concerns about the validity of the company's economic model outputs, because it implies results that contradict current clinical expectations about the long-term treatment benefit of nivolumab. The committee concluded that the model gives counterintuitive results when different durations of treatment benefit are used.
# Cost-effectiveness estimates
## The choice of survival modelling approach has the largest effect on the ICER
The company's deterministic revised base-case ICERs are £28,263 per QALY gained compared with docetaxel and £23,497 per QALY gained compared with paclitaxel, both with a 2‑year treatment stopping rule applied for nivolumab. The ERG made 3 amendments to the company's base case:
used a non-response-based, conventional survival analysis
assumed that only doses delayed by 7 days or more are missed doses
did not include a 2‑year treatment stopping rule.The change from the company's preferred response-based modelling approach to a conventional time-to-event survival analysis approach has the largest effect on the ICER. The ERG's preferred deterministic ICERs including the 3 amendments are £78,869 per QALY gained compared with docetaxel and £58,791 per QALY gained compared with paclitaxel.
## Probabilistic ICERs are preferred to deterministic but were not presented
The committee noted that the company and the ERG did not produce probabilistic ICERs in their post-appraisal consultation document reports. The ERG stated that the company's probabilistic ICERs, presented at the first appraisal committee meeting, are unstable even at a high number of iterations. It also explained that the probabilistic sensitivity analysis is insufficient, because it did not include relative effectiveness which was the largest contributor to decision uncertainty. The company explained this omission from the analysis by stating that sampling the time-dependent hazard ratios in each period independently would yield counterintuitive results. The committee recalled that the probabilistic ICERs generated from the response-based model are higher than the deterministic ICERs. It also recalled that the disparity between probabilistic and deterministic ICERs is mostly resolved using the conventional survival modelling approach. The committee concluded that it would have preferred to have made its assessment of cost effectiveness using probabilistic ICERs, and agreed that the probabilistic ICERs would likely be higher than the deterministic values reported.
## ICERs produced from the economic model need to be treated with caution, and the most plausible ICER is likely to be over £50,000 per QALY gained
The committee agreed that the company's economic model had not responded as expected in a number of scenarios. It noted that the network meta-analysis produced estimates that are inconsistent with clinical expectations (see section 3.7). The committee recalled that any analyses using these estimates need to be treated with caution, and that the response-based approach resulted in survival estimates that are implausibly high (see section 3.9). It noted that the company's piecewise survival model could not be accepted because there was little description of the assumptions used in the model (see section 3.11). The committee agreed that stopping the ongoing treatment benefit in the model produced counterintuitive results (see section 3.14). It also understood that the ICERs reported by the company and the ERG are deterministic, and that probabilistic ICERs are likely to be higher (see section 3.16). The committee recognised that all ICERs produced from the analyses need to be treated with caution. It agreed that the assumptions in the ERG's revised base case are mostly consistent with its preferences. Therefore, the committee's estimate of the most plausible ICER is based on the ERG's revised base-case analysis. The committee agreed that the most plausible ICER is somewhere between the ERG's estimates of £58,791 per QALY gained (compared with paclitaxel) and £78,869 per QALY gained (compared with docetaxel). The committee would expect probabilistic ICERs to be higher still. Given the counterintuitive results from the economic model, the committee agreed that the ICERs need to be treated with caution. It concluded that, based on the evidence provided, its estimate of the most plausible ICER would be over £50,000 per QALY gained.
# PD-L1 subgroups
## There is not enough evidence to suggest that PD-L1 expression is predictive of survival outcomes or treatment response
In the first appraisal committee meeting, the committee considered whether there are any subgroups for whom nivolumab may be more cost effective. Nivolumab inhibits the PD‑L1 protein and therefore it may be more clinically and cost effective in people with higher levels of PD‑L1 expression. In CheckMate 275, there was a statistically significant difference in median overall survival in people with PD‑L1 of more than 1% (11.63 months) compared with those with less than 1% (5.95 months). Similar trends were seen for progression-free survival outcomes in both the CheckMate trials. The committee noted that nivolumab appears to be more clinically effective in people with higher levels of PD‑L1 based on the subgroup analyses presented by the company. The clinical experts stated that there is not enough evidence to separately assess the effectiveness of nivolumab according to PD‑L1 expression. The committee considered the European Medicine Agency's interpretation of the clinical evidence, noting that 12‑month survival in the 'PD‑L1 less than 1%' subgroup appears similar to that seen in larger trials for single-agent chemotherapy. The committee concluded that there is not enough evidence to suggest that PD‑L1 expression is predictive of outcome and it was unable to make recommendations for any subgroups based on PD‑L1 expression.
# End of life
## Life expectancy for people with urothelial carcinoma is less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.
For people with locally advanced or metastatic disease who have had platinum-containing chemotherapy, data from the company's model and from the literature show that overall survival is much less than 24 months for people having treatment with standard care (14.4 to 21.4 months). The clinical experts agreed that they would expect people with locally advanced or metastatic urothelial carcinoma, who have had a platinum-containing chemotherapy, to live for less than 24 months. The committee concluded that the population meets the short life expectancy criterion.
## Nivolumab is likely to extend life by at least 3 months
The committee noted that because of the lack of phase III data directly comparing nivolumab with other treatments, it is difficult to make robust conclusions about overall survival gain. But, data from the company's model and from the literature suggest a difference in median survival of at least 17.8 months. The committee noted the ERG's comments that these estimates are from the economic model, which used data from single-arm trials, and are therefore based on very weak evidence. The committee acknowledged the limitations in the evidence but accepted that, on balance, it is likely that nivolumab extends life by more than 3 months.
## Nivolumab meets the criteria for end-of-life treatments
The committee recognised that there are important limitations in the evidence available. It concluded that the end-of-life criteria are likely to be met for this population, although it has not been presented with robust evidence for the extension-to-life criterion.
# Routine commissioning
## Nivolumab is not recommended for routine use in the NHS
The committee concluded that the most plausible ICERs (see section 3.15) are higher than those usually considered a cost-effective use of NHS resources for end-of-life treatments. The clinical- and cost-effectiveness estimates are highly uncertain because they are based on the simulated treatment comparison, and this needed to be accounted for when considering the maximum acceptable ICER. The committee did not recommend nivolumab for routine use in the NHS for people with locally advanced unresectable or metastatic urothelial carcinoma after platinum-containing therapy.
# Cancer Drugs Fund
Having concluded that nivolumab could not be recommended for routine use, the committee considered if it could be recommended for treating metastatic or unresectable urothelial cancer after platinum-containing therapy within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides.
## Nivolumab does not have the potential to be recommended for routine use
The committee's preferred ICERs are all substantially higher than the range usually considered a cost-effective use of NHS resources for end-of-life treatments. Furthermore, given the evidence base and modelling approaches adopted, the uncertainty around the cost effectiveness of nivolumab is increased substantially. The committee concluded that there is no plausible potential that nivolumab will satisfy the criteria for routine use in this population, not least because there are no planned or ongoing trials that could address the key clinical uncertainties identified. It did not recommend nivolumab for use within the Cancer Drugs Fund as an option for people with metastatic or unresectable urothelial cancer after platinum-containing therapy.
# Other factors
No equality issues were identified.
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism is not relevant in considering the cost effectiveness of nivolumab.
The company did not highlight any additional benefits that had not been captured in the QALY.
# Proposal for the Cancer Drugs Fund
## Nivolumab is not suitable for inclusion in the Cancer Drugs Fund
After release of the final appraisal determination, the company requested to submit a proposal for use in the Cancer Drugs Fund. This included:
a proposed confidential commercial access agreement (only for use within the Cancer Drugs Fund, and could not be applied in routine commissioning)
an updated simulated treatment comparison including the latest CheckMate 275 data
a revised economic analysis using the committee's preferred assumptions (see section 3.17) that incorporates the updated simulated treatment comparison and
a proposal for data collection from the CheckMate 275 and CheckMate 032 trials to address the clinical uncertainty.The committee noted that results of the simulated treatment comparison that includes the latest CheckMate 275 data were substantially different from previous analyses and considerably underestimate the overall survival of people who have taxane therapy compared with the observed data from CheckMate 275. It recalled that the latest CheckMate 275 data were not likely to have a substantial effect on the estimation of clinical effectiveness (see section 3.5). It concluded the latest results of the updated simulated treatment comparison were implausible and agreed that the revised economic analyses incorporating these results could not be used in its decision-making. The committee reinforced the conclusion that any results from the simulated treatment comparison must be treated with caution.
The committee recalled that it had concluded that the ongoing CheckMate 275 and CheckMate 032 trials could not address the key clinical uncertainties identified, because they provided no comparative data (see section 3.25). The committee considered that this was the main clinical uncertainty in this appraisal. It heard from the Cancer Drugs Fund clinical lead that collection of data from patients treated in the NHS would not improve the robustness of the simulated treatment comparison, because detailed prognostic data could not be collected. The committee fully explored whether the availability of any future data would help to reduce the clinical uncertainty. It agreed that it was unlikely that any data collected during a period in the Cancer Drugs Fund (including from research already underway) will be able to inform a subsequent review of a Cancer Drugs Fund recommendation. The committee concluded it could not recommend nivolumab for use within the Cancer Drugs Fund. Therefore, nivolumab is not recommended, within its marketing authorisation, as an option for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy.
|
{'Recommendations': "Nivolumab is not recommended, within its marketing authorisation, for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy.\n\nThis recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment options for people with locally advanced unresectable or metastatic urothelial carcinoma who have had platinum-containing therapy are limited. They are usually offered docetaxel, paclitaxel and best supportive care.\n\nNivolumab has been studied in a clinical trial, but it has not been directly compared with other treatments. So it is not clear how effective nivolumab is compared with current clinical practice.\n\nNivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The committee agreed that the assumptions incorporated in the evidence review group's (ERG's) revised base case were mostly consistent with its preferred assumptions. The committee agreed that the most plausible incremental cost-effectiveness ratios (ICERs) were somewhere between the ERG's estimates of £58,791 per quality-adjusted life year (QALY) gained (compared with paclitaxel) and £78,869 per QALY gained (compared with docetaxel), above what NICE normally considers to be acceptable for end-of-life treatments. There was substantial uncertainty because the model used a simulated treatment comparison, so the ICER could be considerably higher. Therefore nivolumab could not be recommended for routine use in the NHS for locally advanced, unresectable or metastatic urothelial cancer after platinum-containing chemotherapy.\n\nBecause neither data collection from clinical practice or the ongoing trials would resolve the identified uncertainty, nivolumab is not suitable for use within the Cancer Drugs Fund for people with unresectable or metastatic urothelial cancer after platinum-containing therapy.", 'Information about nivolumab': 'Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol-Myers Squibb) as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of platinum-containing therapy.\n\nDosage in the marketing authorisation\n\nmg/kg by intravenous infusion every 2\xa0weeks.\n\nPrice\n\n£439 per 40‑mg vial or £1,097 per 100‑mg vial (excluding VAT; British national formulary online, accessed September\xa02017).\n\nThe company has a commercial arrangement, which would apply if the technology had been recommended.', 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition\n\n## Urothelial carcinoma substantially decreases quality of life\n\nUrothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. The patient experts commented that chemotherapy is associated with unpleasant adverse effects such as fatigue, nausea and vomiting and places people at more risk of infection. The committee was aware that many people with the disease are older and may have comorbidities, which can affect the choice of treatment. The committee recognised that locally advanced unresectable or metastatic urothelial carcinoma has a substantial effect on quality of life.\n\n# Clinical management\n\n## There is unmet need for effective treatment options\n\nInitial treatment is usually with a cisplatin-containing chemotherapy regimen. Treatment options for people whose disease progresses after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care. The clinical experts explained that none of these treatments offer lasting benefit and that prognosis is poor, even for people having their first therapy. The patient experts explained that the adverse effects of chemotherapy can have a large negative effect on quality of life and that regular hospital visits for treatment disrupt usual activities. The clinical experts noted that there have been no new treatments for locally advanced unresectable or metastatic urothelial carcinoma for a number of years and that, unlike for other cancers, there is no targeted or personalised treatment available after platinum-containing chemotherapy. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced unresectable or metastatic urothelial carcinoma who have had platinum-containing chemotherapy.\n\n# Comparators\n\n## Paclitaxel, docetaxel and best supportive care are relevant comparators for people who have had platinum-containing chemotherapy\n\nThe company submitted clinical- and cost-effectiveness analyses comparing nivolumab with paclitaxel, docetaxel and best supportive care. The committee understood that because nivolumab is an immunotherapy with a different adverse effect profile to taxanes (such as paclitaxel and docetaxel), there may be some people for whom nivolumab is suitable who would otherwise have best supportive care. It recognised that introducing immunotherapy may change clinical practice in the future, but that best supportive care is currently a treatment option for urothelial carcinoma and is therefore a relevant comparator. The committee understood that re-treatment with first-line chemotherapy was used before a standard second-line treatment option became available, and that now most clinicians would use a taxane. The clinical experts explained that re-treatment with a first-line chemotherapy would most likely be for disease that had responded well, in people whose disease has not progressed for a long period of time after first-line treatment and who are fit enough to have re-treatment with platinum. Second-line treatment is with a taxane. The clinical experts explained that paclitaxel is used as current standard of care in the UK because of its availability and favourable adverse effect profile compared with docetaxel. Clinical experts in other ongoing immunotherapy appraisals for this population explained that both paclitaxel and docetaxel could be considered clinically equivalent and are both used in clinical practice. The committee concluded that docetaxel, paclitaxel and best supportive care are appropriate comparators, but re-treatment with first-line chemotherapy is not.\n\n# Clinical trial evidence\n\n## The CheckMate trials are broadly generalisable to UK clinical practice\n\nThe clinical-effectiveness evidence for nivolumab comes from 2\xa0phase\xa0II, single-arm trials; CheckMate\xa0275 and CheckMate\xa0032. The trials included:\n\npatients with locally advanced unresectable or metastatic urothelial carcinoma with disease progression or recurrence after treatment with at least 1\xa0platinum-containing agent (CheckMate\xa0275) and\n\npatients with carcinoma of the renal pelvis, ureter, bladder or urethra, and disease progression after treatment with at least 1\xa0platinum-containing chemotherapy (CheckMate\xa0032).There is a lack of UK patients in the trials and more patients with an Eastern Cooperative Oncology Group (ECOG) performance status of\xa00 compared with those seen in clinical practice, which might affect the generalisability of the results. The ERG stated that 23% of people in CheckMate\xa0032 switched to nivolumab plus ipilimumab at disease progression. The committee noted that this would bias the efficacy results from this study, but acknowledged that when pooled with CheckMate\xa0275, the proportion of patients switching treatment in the entire pooled population is low, and therefore the overall effect is minimal. It also noted a difference in the mean age of people in the trial (66\xa0years) compared with clinical practice, which the experts suggested is around 75\xa0years. The clinical experts explained that this could suggest a role for using nivolumab in younger people whose disease has newly progressed. The committee accepted that the patient populations in the CheckMate trials are broadly generalisable to those seen in UK practice.\n\n## The CheckMate trials provide efficacy estimates for nivolumab but no randomised controlled trial evidence is available\n\nData from CheckMate\xa0275 reported an objective response rate of 20.0% (95% confidence interval [CI] 15.4 to 25.3) and median overall survival of 8.57\xa0months (95% CI 6.05 to 11.27). The data originally presented for CheckMate\xa0032 reported an objective response rate of 24.4% (95% CI 15.3 to 35.4) and median overall survival of 6.51\xa0months (95% CI 1.91 to not estimable). The company provided updated clinical-effectiveness data for both CheckMate\xa0275 and CheckMate\xa0032. The updated results are confidential and cannot be presented here. The company included the latest CheckMate\xa0032 data in its economic analysis. The company stated that the updated results from CheckMate\xa0275 confirm the original data presented at the first appraisal committee meeting, but did not include the updated figures in its economic analysis. The committee agreed that the availability of the latest CheckMate\xa0275 data is not likely to have a substantial effect on clinical-effectiveness estimates. It was concerned that, without a trial directly comparing nivolumab with other treatments, it is difficult to reliably assess the relative treatment benefit of nivolumab. The committee also noted that the trial data are immature and based on small numbers of patients, and therefore there is considerable uncertainty in the results. The clinical experts highlighted that people whose disease responds to treatment with an immunotherapy such as nivolumab can have a lasting response, good quality of life and prolonged survival. They explained that the novel mechanism of action of immunotherapies such as nivolumab represent an important new treatment option in clinical practice. The committee concluded that it would be challenging to accurately assess the relative treatment benefit of nivolumab without any available randomised controlled trial evidence.\n\n# Indirect comparison\n\n## The results of the simulated treatment comparison need to be treated with caution because the analysis was unanchored\n\nNivolumab has only been studied in single-arm trials for previously treated urothelial cell carcinoma. To compare nivolumab with the relevant comparators the company did a simulated treatment comparison and network meta-analysis. This was an unanchored comparison because none of the evidence included in the analysis shared a common comparator. The committee was aware that bias is introduced into a simulated treatment comparison if all important prognostic factors are not accounted for. It considered that it is unlikely that all of the important prognostic factors had been accounted for in the simulated treatment comparison, therefore affecting the robustness of the results. The ERG explained that the way to test the external validity of the simulated treatment comparison is the out-of-sample method. This could be used to assess the presence of bias in the comparison model. The company explained that because of the limited availability of data, this validation method would not provide an accurate estimation of bias. The ERG noted that the effect of using alternative prognostic factors in the prediction model could have been assessed in a sensitivity analysis, and this should have been done to test the robustness of the comparison. The committee concluded that, because of the concerns about the robustness of the simulated treatment comparison, the results of the analysis need to be treated with caution.\n\n## The network meta-analysis produced results which are inconsistent with current clinical expectations about the effectiveness of nivolumab\n\nThe company linked the results of the individual simulated treatment comparisons together through a network meta-analysis, using a fractional polynomial model. The committee noted that this is not a conventional modelling approach for a network meta-analysis. It was concerned that a lack of evidence in the network increased the reliance on the fractional polynomial model to estimate relative treatment benefit of nivolumab. The ERG explained that the fractional polynomial model is a highly flexible form of analysis. But, it expressed reservations about the robustness of the fractional polynomial model and noted that incremental cost-effectiveness ratio (ICER) estimates were highly sensitive to the parameterisation of the model. The company stated that the evidence base for paclitaxel that informs the comparison with nivolumab is the most robust of the comparisons presented; it comes from a UK-only, randomised controlled trial. The committee acknowledged that although the evidence for paclitaxel came from a relevant randomised control trial, only the results for the paclitaxel arm were included in the indirect comparison. This removed the benefits of randomisation. The committee noted that including the results from a simulated treatment comparison which was not robust would affect the meta-analysis results, although it is unclear to what extent. The committee agreed that the results of the indirect comparison should be treated with caution. This is because the optimal parameterisation of the fractional polynomial is unknown and the network of evidence is sparse. The time varying hazard ratios used to infer relative treatment effect of nivolumab for overall survival and progression-free survival were estimated using the results of the network meta-analysis. The committee understood that results from the company's network meta-analysis suggest that, compared with docetaxel and best supportive care, the relative effectiveness of nivolumab decreases with time. It agreed that this was inconsistent with clinical expectations about the effectiveness of nivolumab given that it is expected to have a long-lasting effect because of its novel mechanism of action. The committee concluded that the relative-effectiveness estimates inferred from the network meta-analysis are counterintuitive and associated with uncertainty, which needs to be accounted for in its decision-making.\n\n# Adverse events\n\n## Nivolumab is well tolerated\n\nThe clinical experts explained that in their experience of using nivolumab, it is well tolerated and has a preferable adverse effect profile compared with comparator chemotherapies. They stated that the rate of serious adverse effects from nivolumab are similar to those seen for chemotherapies. They noted that the mortality risk from current treatments has decreased as clinical understanding improves after more widespread use of the treatment. The committee noted that a similar trend could happen if nivolumab was recommended, with treatment-related mortality dropping as clinical understanding improves. It noted that it is challenging to make a robust comparison of adverse events without randomised control trial evidence. The committee acknowledged that nivolumab is associated with some rare but unpleasant and potentially serious adverse events that are specific to immunotherapy. It concluded that nivolumab may be a tolerable alternative to chemotherapies as more experience is gained with this type of treatment.\n\n# Assumptions used in economic model\n\n## The use of standard parametric time-to-event survival analysis is preferred to a response-based approach\n\nThe company stated that standard parametric time-to-event models are unsuitable for modelling the possible sustained and long-term response to treatment expected with nivolumab. To account for this, the company modelled survival using a response-based analysis. This approach modelled survival for people until a pre-determined time point (landmark), when survival was individually assessed according to response to treatment. The company opted for an 8‑week landmark point, based on the median time to response in the CheckMate trials. The ERG explained that alternative landmarks were not fully explored and therefore the effect on the ICER was not appropriately assessed. The company used the Kaplan–Meier estimates up until the landmark, at which point parametric distributions were fitted to the responder and non-responder curves to model progression-free survival and overall survival. The ERG stated that the company did not provide a mathematical justification to support their argument that a different response cannot be accurately described by standard parametric survival models. It explained that standard approaches are flexible enough to accurately model different responses, without needing to introduce unnecessary assumptions in to the analysis. The committee noted it had not seen any firm evidence to show that the response-based model was an adequate method to model long-term outcomes. The ERG preferred to estimate overall and progression-free survival by fitting a generalised gamma function to the trial data. The committee agreed that the response-based approach could be explored for modelling survival but agreed with the ERG that the company's approach introduced unnecessary complexity into the modelling of survival. Therefore more evidence would be needed to support its appropriateness in preference to established modelling methods.\n\n## Using a conventional parametric time-to-event survival analysis is considered to be the most appropriate\n\nThe clinical experts explained that people with urothelial carcinoma that has been treated with platinum-containing chemotherapy have a mean life expectancy of around 12\xa0months, and that survival at 5\xa0years is uncommon. The committee understood that the overall-survival data for nivolumab are too immature to provide a reference for the estimates generated in the survival models. The committee was aware that model projections for 5‑year survival from other immunotherapy appraisals are about 10%, which was in line with the clinical expert opinion. It agreed that this estimate was an acceptable reference to validate the estimates produced by the different modelling approaches. The clinical experts stated that around 2\xa0to\xa03% of people would be expected to be alive 5\xa0years after treatment with current standard of care. It noted that estimates for 5‑year survival in the response-based model are around 20% for nivolumab and around 6\xa0to\xa08% for taxanes (values derived from the company's economic model). The ERG explained that the 5‑year survival estimates from its preferred survival model are around 13% for nivolumab and between 2\xa0and\xa05% for taxanes. The committee noted that in the company's model, the slope of the overall-survival curve for people whose disease responds to nivolumab is nearly flat. This suggests that the proportion of people in this group who stay alive would decrease slowly. The committee had concerns that the overall-survival prospects of this group may exceed that of an equivalent disease-free population, which would be implausible. It agreed that the overall-survival curve produces an implausible estimation of survival in the long term, because the response-based model does not appear to accurately characterise survival outcomes in this population. It was concerned that the company's model overestimates the number of people who would be alive at 5\xa0years and that people surviving past 5\xa0years are effectively considered cured. This claim is not supported by the evidence. The committee preferred the ERG's approach to modelling survival, because it produces estimates that are more consistent with clinical expert opinion and are therefore more clinically plausible. The committee concluded that the use of conventional parametric time-to-event survival analysis was the most appropriate method on which to base its decision.\n\n## The conventional fully fitted survival model is the most appropriate for estimating survival outcomes\n\nThe company presented an alternative scenario to model survival rather than the ERG's non-response-based approach. In the non-response-based analysis, survival was estimated using a piecewise model (using Kaplan–Meier data for the first part of the time horizon before switching to a parametric distribution for the extrapolation of longer-term survival estimates). The committee acknowledged that this method of modelling survival has been applied in other immunotherapy appraisals. It understood that both the conventional (fully fitted) and piecewise approaches have enough evidence to support their suitability for modelling survival, and have shown validity in other appraisals. The committee noted that there was little description of the company's assumptions used in the piecewise model approach. There was also no justification or exploration of the type of extrapolations that could be used or the time point selected to switch from the Kaplan–Meier data to the parametric model. The company commented that the probabilistic sensitivity analysis did not fully work for the piecewise model and could not be presented. For these reasons the committee could not accept the outputs of the piecewise model presented by the company. It reaffirmed its conclusion that for this appraisal the conventional fully fitted survival model (ERG's approach) was the most appropriate for estimating survival outcomes.\n\n## Pooling of utility estimates from CheckMate\xa0275 and CheckMate\xa0032 in the model is appropriate for this appraisal\n\nEQ-5D data were collected directly in CheckMate\xa0275 and CheckMate\xa0032, which is the preferred measure of health-related quality of life in adults. Pre-progression utilities (0.736) and post-progression utilities (0.623) were derived from pooling CheckMate\xa0275 and CheckMate\xa0032 values, with missing values being imputed. Disutilities for adverse events were derived from the literature. The ERG explained that the utility decrements used by the company were inconsistent with those used in a previous nivolumab appraisal. The committee noted that in the company's estimation of the treatment effect of nivolumab, both CheckMate trials were pooled, and it agreed that a consistent approach should be taken for estimating utility values. The committee concluded that the pooling of utility estimates from the 2\xa0trials is acceptable in this case.\n\n## The application of a 2-year treatment stopping rule reduced costs associated with nivolumab but the effect on long-term efficacy is unknown\n\nThe company presented evidence from an ongoing study (CheckMate\xa0003) of nivolumab in a different disease area. CheckMate\xa0003 applied a stopping rule for nivolumab at 2\xa0years (when all patients stop treatment). The company noted that people in CheckMate\xa0003 continued to benefit from treatment beyond the point at which it was stopped. The company included a 2‑year treatment stopping rule into its revised economic analysis. It explained that a 2‑year stopping rule has been accepted in another immunotherapy appraisal of urothelial carcinoma. The committee recalled that when it accepted the 2‑year stopping rule for another immunotherapy appraisal, the trial protocol for the study informing the economic analysis had mandated a maximum treatment duration of 2\xa0years. The ERG explained that applying the 2‑year stopping rule in the economic model stopped costs associated with nivolumab, but treatment benefit of nivolumab was assumed unchanged. The ERG did not include a 2‑year stopping rule in its revised analysis, because the effect on clinical outcomes after treatment stops is unclear. The committee noted that the duration of continued effect after treatment has stopped is an area of uncertainty for new immunotherapies, but it agreed that a lifetime continued treatment effect is implausible. The committee concluded that implementing a treatment stopping rule while assuming lifetime treatment benefit was inappropriate.\n\n## Assumption of a lifetime treatment benefit is implausible and scenarios varying this parameter in the economic model produced illogical results\n\nThe company presented scenarios in which the continued treatment effect ended after 3\xa0years or 5\xa0years from the start of the model. In the comparison of nivolumab and docetaxel, the committee understood that stopping treatment benefit for nivolumab at 3\xa0or\xa05\xa0years reduced the ICER compared with the company's base case (using a response-based model in both scenarios). It noted that the ICERs would be expected to increase when the additional benefit of nivolumab on survival was assumed to stop at these time points (that is, assume a hazard ratio of\xa01). The committee understood that quality-adjusted life year (QALY) gains accrued in the model for nivolumab must happen in the short term if stopping treatment benefit at 3\xa0years or 5\xa0years decreases the ICER. It agreed that the change seen in the ICER is contradictory to the company's statement that people treated with nivolumab will have a long-lasting response with nivolumab. Stopping treatment benefit in the comparison of nivolumab and paclitaxel increased the ICER compared with the company's base case. The committee noted that paclitaxel and docetaxel can be considered clinically equivalent (see section\xa03.3). It agreed that inconsistencies in the direction of change in the ICERs confirmed its concerns about the validity of the company's economic model outputs, because it implies results that contradict current clinical expectations about the long-term treatment benefit of nivolumab. The committee concluded that the model gives counterintuitive results when different durations of treatment benefit are used.\n\n# Cost-effectiveness estimates\n\n## The choice of survival modelling approach has the largest effect on the ICER\n\nThe company's deterministic revised base-case ICERs are £28,263 per QALY gained compared with docetaxel and £23,497 per QALY gained compared with paclitaxel, both with a 2‑year treatment stopping rule applied for nivolumab. The ERG made 3\xa0amendments to the company's base case:\n\nused a non-response-based, conventional survival analysis\n\nassumed that only doses delayed by 7\xa0days or more are missed doses\n\ndid not include a 2‑year treatment stopping rule.The change from the company's preferred response-based modelling approach to a conventional time-to-event survival analysis approach has the largest effect on the ICER. The ERG's preferred deterministic ICERs including the 3\xa0amendments are £78,869 per QALY gained compared with docetaxel and £58,791 per QALY gained compared with paclitaxel.\n\n## Probabilistic ICERs are preferred to deterministic but were not presented\n\nThe committee noted that the company and the ERG did not produce probabilistic ICERs in their post-appraisal consultation document reports. The ERG stated that the company's probabilistic ICERs, presented at the first appraisal committee meeting, are unstable even at a high number of iterations. It also explained that the probabilistic sensitivity analysis is insufficient, because it did not include relative effectiveness which was the largest contributor to decision uncertainty. The company explained this omission from the analysis by stating that sampling the time-dependent hazard ratios in each period independently would yield counterintuitive results. The committee recalled that the probabilistic ICERs generated from the response-based model are higher than the deterministic ICERs. It also recalled that the disparity between probabilistic and deterministic ICERs is mostly resolved using the conventional survival modelling approach. The committee concluded that it would have preferred to have made its assessment of cost effectiveness using probabilistic ICERs, and agreed that the probabilistic ICERs would likely be higher than the deterministic values reported.\n\n## ICERs produced from the economic model need to be treated with caution, and the most plausible ICER is likely to be over £50,000 per QALY gained\n\nThe committee agreed that the company's economic model had not responded as expected in a number of scenarios. It noted that the network meta-analysis produced estimates that are inconsistent with clinical expectations (see section\xa03.7). The committee recalled that any analyses using these estimates need to be treated with caution, and that the response-based approach resulted in survival estimates that are implausibly high (see section\xa03.9). It noted that the company's piecewise survival model could not be accepted because there was little description of the assumptions used in the model (see section\xa03.11). The committee agreed that stopping the ongoing treatment benefit in the model produced counterintuitive results (see section\xa03.14). It also understood that the ICERs reported by the company and the ERG are deterministic, and that probabilistic ICERs are likely to be higher (see section\xa03.16). The committee recognised that all ICERs produced from the analyses need to be treated with caution. It agreed that the assumptions in the ERG's revised base case are mostly consistent with its preferences. Therefore, the committee's estimate of the most plausible ICER is based on the ERG's revised base-case analysis. The committee agreed that the most plausible ICER is somewhere between the ERG's estimates of £58,791 per QALY gained (compared with paclitaxel) and £78,869 per QALY gained (compared with docetaxel). The committee would expect probabilistic ICERs to be higher still. Given the counterintuitive results from the economic model, the committee agreed that the ICERs need to be treated with caution. It concluded that, based on the evidence provided, its estimate of the most plausible ICER would be over £50,000 per QALY gained.\n\n# PD-L1 subgroups\n\n## There is not enough evidence to suggest that PD-L1 expression is predictive of survival outcomes or treatment response\n\nIn the first appraisal committee meeting, the committee considered whether there are any subgroups for whom nivolumab may be more cost effective. Nivolumab inhibits the PD‑L1 protein and therefore it may be more clinically and cost effective in people with higher levels of PD‑L1 expression. In CheckMate\xa0275, there was a statistically significant difference in median overall survival in people with PD‑L1 of more than 1% (11.63\xa0months) compared with those with less than 1% (5.95\xa0months). Similar trends were seen for progression-free survival outcomes in both the CheckMate trials. The committee noted that nivolumab appears to be more clinically effective in people with higher levels of PD‑L1 based on the subgroup analyses presented by the company. The clinical experts stated that there is not enough evidence to separately assess the effectiveness of nivolumab according to PD‑L1 expression. The committee considered the European Medicine Agency's interpretation of the clinical evidence, noting that 12‑month survival in the 'PD‑L1 less than 1%' subgroup appears similar to that seen in larger trials for single-agent chemotherapy. The committee concluded that there is not enough evidence to suggest that PD‑L1 expression is predictive of outcome and it was unable to make recommendations for any subgroups based on PD‑L1 expression.\n\n# End of life\n\n## Life expectancy for people with urothelial carcinoma is less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.\n\nFor people with locally advanced or metastatic disease who have had platinum-containing chemotherapy, data from the company's model and from the literature show that overall survival is much less than 24\xa0months for people having treatment with standard care (14.4 to 21.4\xa0months). The clinical experts agreed that they would expect people with locally advanced or metastatic urothelial carcinoma, who have had a platinum-containing chemotherapy, to live for less than 24\xa0months. The committee concluded that the population meets the short life expectancy criterion.\n\n## Nivolumab is likely to extend life by at least 3\xa0months\n\nThe committee noted that because of the lack of phase\xa0III data directly comparing nivolumab with other treatments, it is difficult to make robust conclusions about overall survival gain. But, data from the company's model and from the literature suggest a difference in median survival of at least 17.8\xa0months. The committee noted the ERG's comments that these estimates are from the economic model, which used data from single-arm trials, and are therefore based on very weak evidence. The committee acknowledged the limitations in the evidence but accepted that, on balance, it is likely that nivolumab extends life by more than 3\xa0months.\n\n## Nivolumab meets the criteria for end-of-life treatments\n\nThe committee recognised that there are important limitations in the evidence available. It concluded that the end-of-life criteria are likely to be met for this population, although it has not been presented with robust evidence for the extension-to-life criterion.\n\n# Routine commissioning\n\n## Nivolumab is not recommended for routine use in the NHS\n\nThe committee concluded that the most plausible ICERs (see section\xa03.15) are higher than those usually considered a cost-effective use of NHS resources for end-of-life treatments. The clinical- and cost-effectiveness estimates are highly uncertain because they are based on the simulated treatment comparison, and this needed to be accounted for when considering the maximum acceptable ICER. The committee did not recommend nivolumab for routine use in the NHS for people with locally advanced unresectable or metastatic urothelial carcinoma after platinum-containing therapy.\n\n# Cancer Drugs Fund\n\nHaving concluded that nivolumab could not be recommended for routine use, the committee considered if it could be recommended for treating metastatic or unresectable urothelial cancer after platinum-containing therapy within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides.\n\n## Nivolumab does not have the potential to be recommended for routine use\n\nThe committee's preferred ICERs are all substantially higher than the range usually considered a cost-effective use of NHS resources for end-of-life treatments. Furthermore, given the evidence base and modelling approaches adopted, the uncertainty around the cost effectiveness of nivolumab is increased substantially. The committee concluded that there is no plausible potential that nivolumab will satisfy the criteria for routine use in this population, not least because there are no planned or ongoing trials that could address the key clinical uncertainties identified. It did not recommend nivolumab for use within the Cancer Drugs Fund as an option for people with metastatic or unresectable urothelial cancer after platinum-containing therapy.\n\n# Other factors\n\nNo equality issues were identified.\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism is not relevant in considering the cost effectiveness of nivolumab.\n\nThe company did not highlight any additional benefits that had not been captured in the QALY.\n\n# Proposal for the Cancer Drugs Fund\n\n## Nivolumab is not suitable for inclusion in the Cancer Drugs Fund\n\nAfter release of the final appraisal determination, the company requested to submit a proposal for use in the Cancer Drugs Fund. This included:\n\na proposed confidential commercial access agreement (only for use within the Cancer Drugs Fund, and could not be applied in routine commissioning)\n\nan updated simulated treatment comparison including the latest CheckMate\xa0275 data\n\na revised economic analysis using the committee's preferred assumptions (see section\xa03.17) that incorporates the updated simulated treatment comparison and\n\na proposal for data collection from the CheckMate\xa0275 and CheckMate\xa0032 trials to address the clinical uncertainty.The committee noted that results of the simulated treatment comparison that includes the latest CheckMate\xa0275 data were substantially different from previous analyses and considerably underestimate the overall survival of people who have taxane therapy compared with the observed data from CheckMate\xa0275. It recalled that the latest CheckMate\xa0275 data were not likely to have a substantial effect on the estimation of clinical effectiveness (see section\xa03.5). It concluded the latest results of the updated simulated treatment comparison were implausible and agreed that the revised economic analyses incorporating these results could not be used in its decision-making. The committee reinforced the conclusion that any results from the simulated treatment comparison must be treated with caution.\n\nThe committee recalled that it had concluded that the ongoing CheckMate\xa0275 and CheckMate\xa0032 trials could not address the key clinical uncertainties identified, because they provided no comparative data (see section\xa03.25). The committee considered that this was the main clinical uncertainty in this appraisal. It heard from the Cancer Drugs Fund clinical lead that collection of data from patients treated in the NHS would not improve the robustness of the simulated treatment comparison, because detailed prognostic data could not be collected. The committee fully explored whether the availability of any future data would help to reduce the clinical uncertainty. It agreed that it was unlikely that any data collected during a period in the Cancer Drugs Fund (including from research already underway) will be able to inform a subsequent review of a Cancer Drugs Fund recommendation. The committee concluded it could not recommend nivolumab for use within the Cancer Drugs Fund. Therefore, nivolumab is not recommended, within its marketing authorisation, as an option for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy."}
|
https://www.nice.org.uk/guidance/ta530
|
Evidence-based recommendations on nivolumab (Opdivo) for treating locally advanced unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.
|
eea2c6c434c69266975766690155e0f21ddb340a
|
nice
|
Beta interferons and glatiramer acetate for treating multiple sclerosis
|
Beta interferons and glatiramer acetate for treating multiple sclerosis
Evidence-based recommendations on beta interferons (Avonex, Betaferon, Extavia, Rebif) and glatiramer acetate (Copaxone) for treating multiple sclerosis in adults.
# Recommendations
Interferon beta‑1a is recommended as an option for treating multiple sclerosis, only if:
the person has relapsing–remitting multiple sclerosis and
the companies provide it according to commercial arrangements.
Interferon beta‑1b (Extavia) is recommended as an option for treating multiple sclerosis, only if:
the person has relapsing–remitting multiple sclerosis and has had 2 or more relapses within the last 2 years or
the person has secondary progressive multiple sclerosis with continuing relapses and
the company provides it according to the commercial arrangement.
Glatiramer acetate is recommended as an option for treating multiple sclerosis, only if:
the person has relapsing–remitting multiple sclerosis and
the company provides it according to the commercial arrangement.
Interferon beta‑1b (Betaferon) is not recommended within its marketing authorisation as an option for treating multiple sclerosis.
These recommendations are not intended to affect treatment with a beta interferon or glatiramer acetate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by them, their clinician, and their parents or carers.
Why the committee made these recommendations
Evidence from clinical trials and the Department of Health's Risk Sharing Scheme shows that glatiramer acetate and the beta interferons are effective for treating multiple sclerosis. It also shows that all the treatments work similarly in slowing progression of disability and in reducing the number of multiple sclerosis-related relapses.
The cost-effectiveness estimates for both interferon beta‑1b (Extavia) and glatiramer acetate compared with best supportive care are within the range that NICE usually considers a cost-effective use of NHS resources. Extavia needs mixing before it is injected and some people with multiple sclerosis might find this difficult. Taking this into consideration, interferon beta‑1a is also considered an appropriate use of NHS resources even though the range of cost-effectiveness estimates are above what NICE usually considers acceptable. Therefore, interferon beta‑1a, interferon beta‑1b (Extavia) and glatiramer acetate are recommended as options for treating multiple sclerosis in the NHS.
The most likely cost-effectiveness estimate for interferon beta‑1b (Betaferon) is higher than what NICE considers acceptable and it also has to be mixed before use. Therefore, Betaferon is not recommended for multiple sclerosis because it would not be a good use of NHS resources.
The committee is unable to make recommendations specifically for treating clinically isolated syndrome because the diagnostic criteria for multiple sclerosis and clinically isolated syndrome changed in 2010, and the evidence comes from clinical trials done before 2010 so is no longer generalisable to current UK clinical practice.# Information about the beta interferons and glatiramer acetate
Marketing authorisation indications
Avonex (interferon beta‑1a; Biogen Idec Ltd) is licensed for the treatment of 'patients diagnosed with relapsing multiple sclerosis'. In clinical trials, 'this was characterised by two or more acute exacerbations (relapses) in the previous three years without evidence of continuous progression between relapses'. It is also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'.
Rebif (interferon beta‑1a; Merck Serono Ltd) is licensed for the treatment of 'patients with relapsing multiple sclerosis'. In clinical trials, 'this was characterised by two or more acute exacerbations in the previous two years'. It is also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'.
Betaferon (interferon beta‑1b; Bayer Plc) and Extavia (interferon beta‑1b; Novartis Pharmaceuticals UK Ltd) are licensed for the treatment of 'patients with relapsing–remitting multiple sclerosis and two or more relapses within the last two years'. They are also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'. They are also licensed for the treatment of 'patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses'.
Copaxone (glatiramer acetate; Teva UK Ltd) is licensed for 'the treatment of relapsing forms of multiple sclerosis'. Generic versions (such as Brabio, Mylan) are also available in the UK.
Dosages in the marketing authorisations
Avonex is given by intramuscular injection weekly at a dose of 30 micrograms.
Rebif is given by subcutaneous injection 3 times per week at a dose of 44 or 22 micrograms.
Betaferon and Extavia are given by subcutaneous injection every other day at a dose of 250 micrograms.
Glatiramer acetate is given by subcutaneous injection once daily at a dose of 20 mg or 3 times a week at a dose of 40 mg.
See the summaries of product characteristics for full dosage schedules.
Prices
The list price for Avonex is £163.60 per pre‑filled pen containing 30 micrograms (excluding VAT, British National Formulary online, March 2017).
The list price for Rebif is £51.13 per pre‑filled syringe containing 22 micrograms or £67.77 per pre‑filled syringe containing 44 micrograms (excluding VAT, BNF online, March 2017).
The list price for Betaferon and Extavia is £39.78 per vial containing 300 micrograms (excluding VAT, BNF online, March 2017).
The list price for Copaxone is £18.36 per pre‑filled syringe containing 20 mg or £42.83 per pre‑filled syringe containing 40 mg (excluding VAT, BNF online, March 2017). The list price for Brabio is £16.52 per pre‑filled syringe containing 20 mg or £38.55 per pre‑filled syringe containing 40 mg (excluding VAT, BNF online, June 2018).
Costs may vary in different settings because of negotiated procurement discounts.
Four companies have commercial arrangements. These make Avonex, Copaxone, Extavia and Rebif available to the NHS with a discount. The size of each discount is commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of each discount.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Remit and objective of this appraisal
## This appraisal is a review of NICE technology appraisal guidance on beta interferons and glatiramer acetate for the treatment of multiple sclerosis
NICE's original technology appraisal guidance on beta interferons and glatiramer acetate for the treatment of multiple sclerosis concluded that these technologies were more clinically effective than best supportive care, but were not a cost-effective use of NHS resources. The Department of Health then established a Risk Sharing Scheme (RSS), which provided the drugs to patients in the NHS and monitored their effectiveness. The scheme was set up so that if the drugs were less effective than anticipated, the prices would fall and if they were more effective than anticipated, an increase in price would be permitted. Because the RSS has now ended, NICE is again appraising these drugs. All patients with relapsing–remitting or secondary progressive multiple sclerosis with relapses who are able to walk were eligible for treatment under the RSS. The scheme did not include people with clinically isolated syndrome or primary progressive multiple sclerosis. The committee understood that the RSS did not include treatment with Extavia, but noted that it is the same as Betaferon.
## This appraisal compares beta interferons and glatiramer acetate with best supportive care
Since NICE originally appraised these drugs, it has recommended other treatment options for relapsing–remitting multiple sclerosis including alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab and teriflunomide. The specific subgroup and line of therapy recommended for each treatment is defined in each appraisal. These appraisals generally compared the newer drugs with the older beta interferons and glatiramer acetate, under the assumption that the older drugs were provided to the NHS in a cost-effective way through the RSS. The committee understood that its remit was to revisit the original appraisal, and to compare beta interferons and glatiramer acetate with best supportive care, rather than with the newer drugs.
# The condition and current treatment pathway
## Multiple sclerosis is a chronic, disabling neurological condition
The clinical and patient experts stated that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that relapsing–remitting multiple sclerosis can limit people's ability to work, and to engage in social and family life. Having a wide range of first-line treatments increases the chance of finding a treatment that works for people with this complex disease, and most try 1 or more of the beta interferons and glatiramer acetate before moving on to other therapies. People whose disease progresses from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, but who continue to have relapses, may continue to have beta interferon. The committee understood that most people have treatment until they can no longer walk, when they stop treatment. The committee also understood from the responses to the appraisal consultation document that the frequency of treatment administration may have an effect on adherence to, and therefore the effectiveness of, treatment.
# Clinical effectiveness in clinically isolated syndrome
## Clinically isolated syndrome is less relevant than it once was
A single demyelinating event is known as clinically isolated syndrome, and people experiencing this have a higher chance of developing multiple sclerosis than people who have never had such an event. The committee understood from clinical experts that the diagnostic criteria for multiple sclerosis changed in 2010. The committee was aware that updated diagnostic criteria published in 2017 did not affect the definition of clinically isolated syndrome. Clinically isolated syndrome is less relevant than it once was, and about half of people previously considered to have the condition are now considered to have multiple sclerosis. Increasingly, MRI evidence is used to diagnose multiple sclerosis at an earlier stage, and the updated diagnostic criteria also allows using cerebrospinal fluid in the early diagnoses of multiple sclerosis. The committee agreed that the treatment pathway for clinically isolated syndrome had evolved.
## There is insufficient evidence to make any recommendations for clinically isolated syndrome
The companies did not include clinically isolated syndrome in their meta-analyses, and people with clinically isolated syndrome were not included in the RSS. The assessment group conducted a network meta-analysis for clinically isolated syndrome, which included 5 trials. These used outcome measures based on pre‑2010 diagnostic criteria. The committee agreed that all the treatments delayed time to clinically definite multiple sclerosis compared with placebo as it was defined before 2010. However, the committee understood that many patients in the trials would have been diagnosed and treated for multiple sclerosis rather than clinically isolated syndrome if current diagnostic criteria were used instead. Therefore, the committee was concerned that clinical trials using the pre‑2010 diagnostic criteria for clinically isolated syndrome were no longer relevant to current UK practice. The committee agreed that a post-hoc analysis which re‑identified patients using the 2010 diagnostic criteria showed encouraging results. However, it was concerned that this was based on a single study and had not been validated by any subsequent trials. The committee concluded that there was insufficient evidence using the current diagnostic criteria to make any recommendations for treating clinically isolated syndrome.
# Clinical effectiveness in relapsing–remitting multiple sclerosis
## Evidence comes from clinical trials and the RSS
The committee considered evidence from 4 network meta-analyses of clinical trials from:
the assessment group
Biogen (interferon beta‑1a, Avonex)
Merck Serono (interferon beta‑1a, Rebif)
Teva (glatiramer acetate, Copaxone).In addition to the data from clinical trials, the committee also considered data collected from patients participating in the RSS.
# Clinical trials
## The trials are broadly generalisable but subject to bias
The committee considered the generalisability of the clinical trials to patients in the NHS. The assessment group stated that the trials involving people with relapsing–remitting multiple sclerosis had limitations including differences in design and short length of follow‑up. This meant they were at risk of bias because injection-site reactions could have meant that patients in the trials were not blinded to their treatment. The clinical experts stated that unblinding was unlikely to have biased the results for disability progression, which was assessed by investigators blinded to treatment allocation. It concluded that the trials were broadly generalisable and relevant for this appraisal.
# Disability progression outcome measure
## Trial data for confirmed disability progression sustained for 6 months is preferable
The committee discussed whether disability progression sustained for 3 months or for 6 months best reflected disability progression in people with relapsing–remitting multiple sclerosis. It recognised that some trials provided both 3- and 6‑month data, and that all trials reported 3‑month data. It was aware that, in previous appraisals, the committee preferred to use confirmed disability progression for 6 months. The clinical experts explained that the time taken to recover from a relapse can vary and that people may still continue to recover after 3 months. The committee agreed that the outcome for confirmed disability progression sustained for 6 months was better at capturing the benefits of treatment. The assessment group stated that it preferred to use confirmed progression at 3 months because the quality and size of its evidence network at this time point was better than that for a confirmed progression at 6 months. The committee concluded that it preferred 6‑month data where available, but that it was important to use a consistent measure across all treatments.
# Companies' and assessment group's network meta-analyses
## The assessment group's network meta-analysis is preferable
The assessment group stated that some of the companies' meta-analyses had limitations, including, but not limited to, methods that were not transparent or analyses that did not include relevant trials. The committee also noted that the point estimates for the results broadly corresponded to results from the assessment group's network meta-analysis (see section 3.10). However, the companies' analyses had wider statistical intervals and showed fewer statistically significant differences between technologies. The assessment group stated that it used a frequentist approach for its meta-analysis, whereas the companies used a Bayesian approach. The committee agreed that this could explain some of the differences in results between the assessment group's and companies' analyses. The committee agreed to focus on the assessment group's network meta-analyses.
# Results of assessment group's network meta-analysis
## All treatments are similarly effective in reducing the number of relapses and slowing disability progression compared with placebo
The committee considered the results of the network meta-analysis (see table 1) by outcome for people with relapsing–remitting multiple sclerosis.
Annualised relapse rate: all the beta interferons and glatiramer acetate reduced the annualised relapse rate compared with placebo. When comparing each of the beta interferons and glatiramer acetate with each other, the results did not show that any one was statistically significantly better. The clinical experts considered the drugs under appraisal to be broadly similar in clinical effectiveness. The committee concluded that all the therapies were similarly effective in reducing the number of relapses compared with best supportive care.
Confirmed disability progression: the treatments delayed disability compared with placebo but did not differ statistically significantly from each other. The committee concluded that the beta interferons and glatiramer acetate had similar effectiveness, and that they all delayed disability progression when compared with placebo.
Adverse events: the committee considered the risk of stopping treatment because of adverse events. It noted that all the treatments were associated with more adverse events than placebo. It also noted that, although some of the drugs were associated with a higher risk of adverse events than others, the confidence intervals surrounding these estimates were very large. Beta interferons and glatiramer acetate have well-established safety profiles. Comparisons between treatments showed differences in the frequency of specific adverse events. However, there was no evidence to suggest that the risk of stopping treatment because of adverse events at 24 months was different between treatments. The committee concluded that all the drugs would cause some adverse effects.
Quality of life: The committee was aware that the systematic review informing the network meta-analysis found little evidence comparing the quality-of-life benefits to patients between treatments. It understood that it was not possible to do a network meta-analysis. The committee concluded that, while all treatments were likely to improve quality of life, the difference between treatments was uncertain.
## Table 1 Results from the assessment group's network meta-analysis for relapsing–remitting multiple sclerosis
Drug
ARRRR (95% CI)
a
TTP3HR (95% CI)
TTP6HR (95% CI)
AEsRiR (95% CI)
Glatiramer 40 mg 3 times weekly
Glatiramer 20 mg daily
IFN beta‑1a 44 micrograms 3 times weekly
IFN beta‑1b 250 micrograms every other day
IFN beta‑1a 22 micrograms 3 times a week
IFN beta‑1a 30 micrograms weekly
(0.53, 1.00)b
All drugs were compared with placebo.
a Results from outlier trial (Bornstein et al. 1987) were excluded.
b Upper 95% confidence interval does not cross 1.00.
Abbreviations: AEs, stopping treatment because of adverse events at 24 months; ARR, annualised relapse rate; CI, confidence interval; HR, hazard ratio; IFN, interferon; RiR, risk ratio; RR, rate ratio; TTP3, time to disability progression confirmed at 3 months; TTP6, time to disability progression confirmed at 6 months.
# Risk Sharing Scheme
## RSS data are more likely to reflect effectiveness in clinical practice than data from the clinical trials
The committee discussed the RSS, which included NHS patients treated with either a beta interferon or glatiramer acetate. A representative from the RSS stated that the scheme included a large number of people and ran for 10 years. The committee recognised that the RSS provided longer follow‑up than the trials, and that it reflected the people who would be offered these therapies in NHS practice. It concluded that it preferred the effectiveness data from the RSS.
## The RSS used a summary measure of disease progression as its primary outcome
The primary outcome measuring effectiveness in the RSS was the change over time relative to baseline of a weighted sum of the proportions of patients who progressed to each Expanded Disability Status Scale (EDSS) score. This was weighted by utility, to account for the non-linearity of the EDSS scale (that is, for example, a change in EDSS from 0 to 1 does not have the same impact as a change from 8 to 9). The Department of Health stated that to use the outcome measure of the RSS it was necessary to derive an 'implied' hazard ratio. The Department of Health used data reflecting the natural history of disease in people not taking disease-modifying treatments from the British Columbia Multiple Sclerosis cohort for comparison because there was no comparator in the RSS (that is, nobody had best supportive care). People in the RSS were matched to people in the historical British Columbia cohort by EDSS score and age of onset. A hazard ratio for disease progression was applied to progression probabilities in the British Columbia cohort to derive the progression probabilities for people in the RSS. This 'implied' hazard ratio was derived to obtain the same change in mean utility between baseline and year 10 as that seen in the RSS cohort. The committee agreed that the 'implied' hazard ratio represented the relative effectiveness of the treatments in slowing disease progression for people in the RSS when compared with that expected for people in the British Columbia Multiple Sclerosis cohort on supportive care.
## All treatments in the RSS slowed disease progression
The implied hazard ratio pooling all treatments in the RSS (the value is not directly comparable with the trial-based hazard ratios) showed that the treatments delayed disease progression compared with best supportive care (hazard ratio 0.79; 95% confidence interval 0.77 to 0.81). Companies have indicated that the hazard ratios for individual drugs are confidential, but that all the drugs delayed disease progression similarly compared with best supportive care. The committee concluded that, consistent with the data from trials considered in the assessment group's network meta-analysis, all the technologies offered in the RSS delayed disease progression compared with best supportive care.
## Pooled RSS estimates are preferable
The assessment group used the pooled effectiveness estimates from the RSS in its base-case analyses, rather than the results for the individual technologies from the RSS. The committee agreed that this was appropriate because:
The network meta-analysis results of trials did not show that any particular beta interferon or glatiramer acetate was better than another (see section 3.10).
Data for each individual technology in the RSS could be subject to selection bias. That is, because people in the RSS were not randomised to a specific treatment, the treatment choice, and also the outcomes, may have been affected by differences in the patient characteristics. The committee noted evidence provided by Teva in response to the appraisal consultation document that there was a difference between the baseline characteristics of patients having glatiramer acetate and those having beta interferons. It concluded that it had seen no evidence to suggest that these differences were clinically significant.
The pooled analysis from the RSS included people who switched to another treatment, whereas people who switched were excluded from the analyses for individual treatments. The committee considered that, although few people switched treatments, people who do switch may have a worse prognosis than those who do not. This means that the hazard ratios are lower (that is, the treatments appear more effective) in the analyses for the individual treatments than in the pooled analysis. The committee also noted an analysis provided by Teva in response to the appraisal consultation document, which used the individual implied hazard ratio for glatiramer acetate and included all patients who switched treatments. It noted that, because similar data from other companies were unavailable, no conclusions could be drawn.Based on the above considerations, the committee concluded that it would use the RSS estimates representing the pooled effect in its decision-making.
## Pooled RSS estimates should also be used for Extavia
Extavia was not included in the RSS because it was licensed after the scheme started. The committee understood that Extavia is the same as Betaferon, which the RSS included. The committee concluded that it was appropriate to assume that the effectiveness of Extavia was the same as that of Betaferon in the RSS.
# Waning of treatment efficacy
## Efficacy does not remain constant over time
The committee discussed whether the effectiveness of beta interferons and glatiramer acetate was likely to remain constant or wane over time. The clinical experts stated that most treatments for multiple sclerosis become less effective over time, either because the person's immune system develops neutralising antibodies or because the disease worsens and becomes resistant to treatment. The Department of Health stated that, in the RSS, the effect of the treatments waned after the first 2 years. The committee concluded that, for decision-making, it was appropriate to assume that efficacy does not remain constant over time.
# Cost effectiveness in relapsing–remitting multiple sclerosis
## Versions of the RSS model come from 5 sources
The committee discussed the economic models and modelling assumptions for relapsing–remitting multiple sclerosis from 5 sources: 3 companies (Biogen, Merck Serono and Teva), the assessment group, and the Department of Health:
The Department of Health provided the RSS model to the assessment group. The overall structure of all submitted models was similar to models used in previous NICE technology appraisals. The sources of data used as model inputs differed across the models.
All models estimated disease progression through 21 health states defined by EDSS scores (ranging from 0 to 9.5). The models described the progression of disability in patients with relapsing–remitting multiple sclerosis (10 states) to secondary progressive multiple sclerosis (10 states) and to death.
In each cycle of the model, a patient with relapsing–remitting multiple sclerosis could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The disease could also advance from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, but could not then move back to relapsing–remitting disease.
The treatments increased quality-adjusted life years (QALYs) relative to best supportive care primarily by delaying disability progression and also by reducing the number of relapses. The model also incorporated EDSS-related (and other) mortality and therefore the treatments also increased life expectancy.
The treatment effect used in the models varied, representing either pooled or individual treatment estimates for effectiveness from either the RSS or from network meta-analyses of trials.
The assessment group model included the assumption that 5% of patients per year stop treatment; this was equal across all the treatments, and was based on what had been seen in the RSS.
The assessment group changed the assumptions about mortality in the RSS model to avoid double-counting of multiple sclerosis-related mortality (see section 3.20).
The assessment group excluded treatment costs in EDSS states 7 to 9 (see section 3.26).
# Natural history of the disease in subgroup analyses
## The RSS used the British Columbia cohort as a comparator
The RSS model used a database from British Columbia to reflect the natural history of multiple sclerosis for people who do not have disease-modifying treatments. The RSS model had originally used a database from London Ontario instead but, in contrast to the British Columbia database, this did not include the possibility that patients' EDSS scores could improve. The committee noted that including the possibility that EDSS scores could improve was appropriate because EDSS scores for patients treated with disease-modifying drugs in the RSS did improve. The committee was aware that the British Columbia dataset was relatively old, with data collection having begun in 1980, and that supportive care may have since changed. However, it was also aware that the alternative dataset, from London Ontario, was even older and was also smaller. The committee concluded that it was appropriate to use the British Columbia database to model the natural history of multiple sclerosis for people who had not had disease-modifying treatments.
# Time horizon and waning of treatment effect
## The approach to waning of effectiveness over time differs from previous appraisals
The assessment group, the Department of Health and the companies chose a time horizon of 50 years for their base-case analyses. The committee agreed that this was long enough to reflect a lifetime horizon, but noted the uncertainties about extrapolating over a lifetime. It also noted that the RSS had a follow‑up period of 10 years and that no treatment waning assumption was needed for this period because it was captured within the treatment effectiveness data. In addition, it noted that, to extrapolate the waning effect over the treatment lifetime, the RSS model applied a 50% reduction in effect after 10 years. NICE's previous technology appraisals (such as alemtuzumab and dimethyl fumarate) assumed a reduction in treatment effect of 25% after 2 years, and of 50% after 5 years. The committee considered that it was appropriate to use a different assumption for the waning effect in this appraisal because the RSS provided longer follow‑up data than the trials in the previous appraisals. It noted that the same reduction in waning effect was applied at the end of the 10‑year follow‑up period as in the previous appraisals. The committee concluded that assuming a 50% reduction in effect after 10 years was appropriate.
# Mortality
## The assessment group modified the RSS model to avoid double-counting of mortality
In the original RSS model, mortality was included in 2 ways. First, the model included multiple sclerosis-related mortality for all transitions to EDSS health-state 10. Second, the model included an increased risk of mortality to account for the increased risk of non-multiple sclerosis-related death in people with multiple sclerosis. The assessment group was concerned that this approach double-counted mortality and so removed the increased risk of mortality from non-multiple sclerosis-related causes from its analysis.
## The standardised mortality ratios in Pokorski et al. (1997) overestimate mortality risk in patients with multiple sclerosis
An alternative approach to modelling mortality was suggested by Merck Serono, which was based on an assumption that had been used in several previous NICE appraisals (alemtuzumab, fingolimod and teriflunomide). This approach applied mortality ratios from Pokorski et al. to each EDSS health state, which resulted in a greater risk of mortality in people with multiple sclerosis than modelled in both the original RSS approach and the assessment group's approach. The committee was concerned that this overestimated mortality, particularly for lower EDSS states, because it was based on outdated data from a period before there had been improvements in multiple sclerosis care and when the background mortality rate was higher. It was also concerned that, in the Pokorski et al. study, EDSS was measured only at the first clinical visit but that the actual EDSS score at time of death depended on the speed of EDSS progression. The committee agreed that the approach using the mortality ratios from Pokorski et al. had limitations and overestimated mortality.
## The standardised mortality ratio reported in Jick et al. (2014) overestimates mortality risk in low EDSS states and underestimates it in high EDSS states
The committee considered an alternative approach based on a more recent study (Jick et al., 2014), which reported lower rates of mortality for multiple sclerosis compared with Pokorski et al. (1997) and which had been applied in a recent appraisal for cladribine. The committee understood that although these data were more recent, the publication did not provide separate mortality ratios for different EDSS states. Therefore, models based on Jick et al. apply the same mortality ratio for each EDSS state. The committee was concerned that this approach resulted in clinically implausible mortality rates in low EDSS states and underestimated mortality in high EDSS states. The committee concluded that the approach to mortality was a source of uncertainty, but accepted the approach taken by the assessment group because it was the most clinically plausible.
# Treatment stopping rates
## Rates of stopping treatment from the RSS are appropriate to use in the economic model
In its model, the assessment group included rates of stopping treatment from the RSS, in which 5% of people stopped treatment each year. The Department of Health stated that stopping rates were similar across treatments. Biogen had concerns that the stopping rates assumed for beta interferons in NICE's technology appraisal of daclizumab (the guidance has been withdrawn because the marketing authorisation for daclizumab has been withdrawn) were higher (about 10% each year). The committee was aware that the daclizumab appraisal focused on a subgroup of people treated with daclizumab who had a more severe form of multiple sclerosis (that is, rapidly evolving severe multiple sclerosis and multiple sclerosis that has been previously treated with disease-modifying therapy). In addition, it understood from the Department of Health that higher stopping rates implausibly improved the cost effectiveness of treatments. The committee concluded that, for this appraisal, it was appropriate to use the same stopping rate from the RSS for all treatments.
# Utility values
## Disutility to carers should be considered
The committee discussed the quality of life for people with relapsing–remitting multiple sclerosis, and the burden that their carers experience. The assessment group did not include disutility to carers in its base case because it had questioned whether this was consistent with the NICE reference case. The companies and the Department of Health did include disutilities to carers in their base-case analyses. The base cases in previous NICE technology appraisals for multiple sclerosis (such as dimethyl fumarate and natalizumab) also included disutility to carers. The committee concluded that it would include disutility to carers when making its decision.
# Health-state costs
## The UK MS Survey is the most appropriate source for EDSS health-state costs
The committee discussed the annual costs associated with each EDSS health state in the model. It noted that the RSS model used Kobelt et al. (2000) in its base case and that this differed from other NICE technology appraisals, which used other sources such as:
the UK MS Survey used in NICE technology appraisal guidance on dimethyl fumarate, fingolimod and natalizumab
Tyas et al. (2007) used in NICE technology appraisal guidance on alemtuzumab and teriflunomide.The committee noted the following about the various sources:
Kobelt et al. estimated substantially higher costs in EDSS health states 7 to 9 than the other sources. Kobelt et al. included indirect costs of sickness absence, early retirement and changes in working hours, which would not be borne by the NHS or personal social services (PSS). Notably, the study did not use recent unit costs, but costs adjusted for inflation from 1999/2000 prices to 15 years later. For these reasons, the committee did not further consider costs from Kobelt et al.
The UK MS Survey represented the largest data set (responses from 2,048 people), and included separate estimates of costs funded by the UK government and costs funded by the NHS and PSS. The UK government-funded costs included costs other than what the NHS and PSS would cover, and it was unclear what these included. The committee was satisfied that the NHS and PSS costs estimated from the UK MS Survey were the best available and could be used in this appraisal.
Tyas et al. reflected another analysis of data from the UK MS Survey. However, it reported costs funded by the UK government only, and did not separately consider costs funded by the NHS and PSS. Because of this, the committee did not consider costs from Tyas et al. further.The committee concluded that it would consider analyses using the UK MS Survey costs for EDSS health states.
# Treatment costs
## Treatment costs should not be applied to EDSS states 7 to 9
Teva stated that treatment costs should not be applied to EDSS states 7 to 9 because it is unlikely that these people would have treatment with glatiramer acetate or the beta interferons in clinical practice. The assessment group explained that, while many people do not stop treatment at advanced EDSS states, removing treatment costs at EDSS states 7 to 9 reflected a pathway using the drugs within their licensed indications. The committee concluded that it would base its conclusions on analyses without treatment costs applied to EDSS states 7 to 9.
# Cost of informal care
## Costs not covered by the NHS or PSS do not meet the NICE reference case
Teva stated that the committee should consider the cost of informal care in this appraisal. NICE's guide to methods of technology appraisal states that only 'costs borne by patients may be included when they are reimbursed by the NHS or personal social services' as part of the NICE reference case. The committee noted that, although family or carers may provide informal care, it had not been presented with evidence that the NHS or PSS would otherwise provide this informal care. It agreed that there was insufficient evidence to include the costs of informal care in the cost-effectiveness analysis. The committee also noted consultation comments from Merck that the committee should consider the additional support provided to patients by companies through schemes such as patient support programmes, and nursing support and training. The committee concluded that this support would be implicitly reflected in the price of the treatments and their benefits, and did not consider it further.
# Equality considerations
## Stakeholders consider glatiramer acetate to be the safest drug for anyone who is planning to become pregnant
Healthcare Improvement Scotland and several stakeholders during consultation stated that glatiramer acetate is the safest drug for anyone who wants to become pregnant. Although glatiramer acetate is not contraindicated during pregnancy, its marketing authorisation suggests that it is preferable to avoid its use during pregnancy. The committee understood from consultation comments that glatiramer acetate is considered the safest drug available during the pre-conception period.
## Special considerations should be given to people who cannot prepare beta interferon‑1b treatments
The committee noted comments from consultation before the fourth committee meeting that interferon beta‑1b is supplied as a solvent and powder, which patients (or carers) must mix each time they administer the treatment. This process is more difficult than treatments employing ready-to-use injection devices. The committee understood that some people will therefore have difficulty using Extavia and Betaferon, particularly people with manual dexterity, visual or cognitive difficulties, which are common in people with multiple sclerosis. The committee concluded that consideration should be given to this group of people with respect to the ease of preparation and administration of beta interferons.
# Innovation
## The technologies were innovative compared with best supportive care when they became available on the NHS
The committee considered that beta interferons and glatiramer acetate may have been considered innovative compared with best supportive care when they became available in the NHS. Several newer technologies have since become available that were considered innovative when compared with beta interferons and glatiramer acetate. The committee noted that the benefits of ease of preparation and administration using auto-injection devices (see section 3.29) were not captured in the cost-effectiveness analysis and took this into account.
# Cost-effectiveness results
## Interferon beta‑1a, interferon beta‑1b (Extavia) and glatiramer acetate are a cost-effective use of NHS resources
The committee considered the cost-effectiveness results for beta interferons and glatiramer acetate, taking into account its preferences, including waning in treatment effect (see section 3.19), using the pooled RSS results (see section 3.14 and section 3.15) and the patient access schemes where applicable. Specific incremental cost-effectiveness ratio (ICER) values cannot be reported as this would allow the back-calculation of confidential discounts.
The ICER for interferon beta‑1b (Extavia) compared with best supportive care was below £30,000 per QALY gained. The committee concluded that Extavia was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis or secondary progressive multiple sclerosis with continued relapses.
The committee noted that the ICERs for interferon beta‑1a compared with best supportive care were above £30,000 per QALY gained. It took into account the equality considerations applied with respect to the group of people who will find the preparation and administration of Extavia challenging (see section 3.29) because it was the only beta interferon that was cost effective at a threshold of less than £30,000 per QALY gained. The committee agreed that alternative beta interferons should be available for patients. The committee concluded that interferon beta‑1a was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis in this context.
The ICER for glatiramer acetate compared with best supportive care was below £30,000 per QALY gained. The committee was aware that a generic version of glatiramer acetate (Brabio) is available in the NHS, and understood that the price of glatiramer acetate is likely to fall in the future. The committee concluded that glatiramer acetate was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis.
The committee considered glatiramer acetate, interferon beta‑1a and interferon beta‑1b to be broadly similar in clinical effectiveness (see section 3.10). However, it noted that (interferon beta‑1b) Betaferon was the most expensive technology. In addition, the ICER for Betaferon was above £30,000 per QALY gained. The committee concluded that Betaferon was not a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis.
|
{'Recommendations': "Interferon beta‑1a is recommended as an option for treating multiple sclerosis, only if:\n\nthe person has relapsing–remitting multiple sclerosis and\n\nthe companies provide it according to commercial arrangements.\n\nInterferon beta‑1b (Extavia) is recommended as an option for treating multiple sclerosis, only if:\n\nthe person has relapsing–remitting multiple sclerosis and has had 2\xa0or more relapses within the last 2\xa0years or\n\nthe person has secondary progressive multiple sclerosis with continuing relapses and\n\nthe company provides it according to the commercial arrangement.\n\nGlatiramer acetate is recommended as an option for treating multiple sclerosis, only if:\n\nthe person has relapsing–remitting multiple sclerosis and\n\nthe company provides it according to the commercial arrangement.\n\nInterferon beta‑1b (Betaferon) is not recommended within its marketing authorisation as an option for treating multiple sclerosis.\n\nThese recommendations are not intended to affect treatment with a beta interferon or glatiramer acetate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by them, their clinician, and their parents or carers.\n\nWhy the committee made these recommendations\n\nEvidence from clinical trials and the Department of Health's Risk Sharing Scheme shows that glatiramer acetate and the beta interferons are effective for treating multiple sclerosis. It also shows that all the treatments work similarly in slowing progression of disability and in reducing the number of multiple sclerosis-related relapses.\n\nThe cost-effectiveness estimates for both interferon beta‑1b (Extavia) and glatiramer acetate compared with best supportive care are within the range that NICE usually considers a cost-effective use of NHS resources. Extavia needs mixing before it is injected and some people with multiple sclerosis might find this difficult. Taking this into consideration, interferon beta‑1a is also considered an appropriate use of NHS resources even though the range of cost-effectiveness estimates are above what NICE usually considers acceptable. Therefore, interferon beta‑1a, interferon beta‑1b (Extavia) and glatiramer acetate are recommended as options for treating multiple sclerosis in the NHS.\n\nThe most likely cost-effectiveness estimate for interferon beta‑1b (Betaferon) is higher than what NICE considers acceptable and it also has to be mixed before use. Therefore, Betaferon is not recommended for multiple sclerosis because it would not be a good use of NHS resources.\n\nThe committee is unable to make recommendations specifically for treating clinically isolated syndrome because the diagnostic criteria for multiple sclerosis and clinically isolated syndrome changed in 2010, and the evidence comes from clinical trials done before 2010 so is no longer generalisable to current UK clinical practice.", 'Information about the beta interferons and glatiramer acetate': "Marketing authorisation indications\n\nAvonex (interferon beta‑1a; Biogen Idec Ltd) is licensed for the treatment of 'patients diagnosed with relapsing multiple sclerosis'. In clinical trials, 'this was characterised by two or more acute exacerbations (relapses) in the previous three years without evidence of continuous progression between relapses'. It is also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'.\n\nRebif (interferon beta‑1a; Merck Serono Ltd) is licensed for the treatment of 'patients with relapsing multiple sclerosis'. In clinical trials, 'this was characterised by two or more acute exacerbations in the previous two years'. It is also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'.\n\nBetaferon (interferon beta‑1b; Bayer Plc) and Extavia (interferon beta‑1b; Novartis Pharmaceuticals UK Ltd) are licensed for the treatment of 'patients with relapsing–remitting multiple sclerosis and two or more relapses within the last two years'. They are also licensed for the treatment of 'patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis'. They are also licensed for the treatment of 'patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses'.\n\nCopaxone (glatiramer acetate; Teva UK Ltd) is licensed for 'the treatment of relapsing forms of multiple sclerosis'. Generic versions (such as Brabio, Mylan) are also available in the UK.\n\nDosages in the marketing authorisations\n\nAvonex is given by intramuscular injection weekly at a dose of 30\xa0micrograms.\n\nRebif is given by subcutaneous injection 3\xa0times per week at a dose of 44\xa0or 22\xa0micrograms.\n\nBetaferon and Extavia are given by subcutaneous injection every other day at a dose of 250\xa0micrograms.\n\nGlatiramer acetate is given by subcutaneous injection once daily at a dose of 20\xa0mg or 3\xa0times a week at a dose of 40\xa0mg.\n\nSee the summaries of product characteristics for full dosage schedules.\n\nPrices\n\nThe list price for Avonex is £163.60 per pre‑filled pen containing 30\xa0micrograms (excluding VAT, British National Formulary [BNF] online, March 2017).\n\nThe list price for Rebif is £51.13 per pre‑filled syringe containing 22\xa0micrograms or £67.77 per pre‑filled syringe containing 44\xa0micrograms (excluding VAT, BNF online, March 2017).\n\nThe list price for Betaferon and Extavia is £39.78 per vial containing 300\xa0micrograms (excluding VAT, BNF online, March 2017).\n\nThe list price for Copaxone is £18.36 per pre‑filled syringe containing 20\xa0mg or £42.83 per pre‑filled syringe containing 40\xa0mg (excluding VAT, BNF online, March 2017). The list price for Brabio is £16.52 per pre‑filled syringe containing 20\xa0mg or £38.55 per pre‑filled syringe containing 40\xa0mg (excluding VAT, BNF online, June 2018).\n\nCosts may vary in different settings because of negotiated procurement discounts.\n\nFour companies have commercial arrangements. These make Avonex, Copaxone, Extavia and Rebif available to the NHS with a discount. The size of each discount is commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of each discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Remit and objective of this appraisal\n\n## This appraisal is a review of NICE technology appraisal guidance on beta interferons and glatiramer acetate for the treatment of multiple sclerosis\n\nNICE's original technology appraisal guidance on beta interferons and glatiramer acetate for the treatment of multiple sclerosis concluded that these technologies were more clinically effective than best supportive care, but were not a cost-effective use of NHS resources. The Department of Health then established a Risk Sharing Scheme (RSS), which provided the drugs to patients in the NHS and monitored their effectiveness. The scheme was set up so that if the drugs were less effective than anticipated, the prices would fall and if they were more effective than anticipated, an increase in price would be permitted. Because the RSS has now ended, NICE is again appraising these drugs. All patients with relapsing–remitting or secondary progressive multiple sclerosis with relapses who are able to walk were eligible for treatment under the RSS. The scheme did not include people with clinically isolated syndrome or primary progressive multiple sclerosis. The committee understood that the RSS did not include treatment with Extavia, but noted that it is the same as Betaferon.\n\n## This appraisal compares beta interferons and glatiramer acetate with best supportive care\n\nSince NICE originally appraised these drugs, it has recommended other treatment options for relapsing–remitting multiple sclerosis including alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab and teriflunomide. The specific subgroup and line of therapy recommended for each treatment is defined in each appraisal. These appraisals generally compared the newer drugs with the older beta interferons and glatiramer acetate, under the assumption that the older drugs were provided to the NHS in a cost-effective way through the RSS. The committee understood that its remit was to revisit the original appraisal, and to compare beta interferons and glatiramer acetate with best supportive care, rather than with the newer drugs.\n\n# The condition and current treatment pathway\n\n## Multiple sclerosis is a chronic, disabling neurological condition\n\nThe clinical and patient experts stated that multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that relapsing–remitting multiple sclerosis can limit people's ability to work, and to engage in social and family life. Having a wide range of first-line treatments increases the chance of finding a treatment that works for people with this complex disease, and most try 1\xa0or more of the beta interferons and glatiramer acetate before moving on to other therapies. People whose disease progresses from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, but who continue to have relapses, may continue to have beta interferon. The committee understood that most people have treatment until they can no longer walk, when they stop treatment. The committee also understood from the responses to the appraisal consultation document that the frequency of treatment administration may have an effect on adherence to, and therefore the effectiveness of, treatment.\n\n# Clinical effectiveness in clinically isolated syndrome\n\n## Clinically isolated syndrome is less relevant than it once was\n\nA single demyelinating event is known as clinically isolated syndrome, and people experiencing this have a higher chance of developing multiple sclerosis than people who have never had such an event. The committee understood from clinical experts that the diagnostic criteria for multiple sclerosis changed in 2010. The committee was aware that updated diagnostic criteria published in 2017 did not affect the definition of clinically isolated syndrome. Clinically isolated syndrome is less relevant than it once was, and about half of people previously considered to have the condition are now considered to have multiple sclerosis. Increasingly, MRI evidence is used to diagnose multiple sclerosis at an earlier stage, and the updated diagnostic criteria also allows using cerebrospinal fluid in the early diagnoses of multiple sclerosis. The committee agreed that the treatment pathway for clinically isolated syndrome had evolved.\n\n## There is insufficient evidence to make any recommendations for clinically isolated syndrome\n\nThe companies did not include clinically isolated syndrome in their meta-analyses, and people with clinically isolated syndrome were not included in the RSS. The assessment group conducted a network meta-analysis for clinically isolated syndrome, which included 5\xa0trials. These used outcome measures based on pre‑2010 diagnostic criteria. The committee agreed that all the treatments delayed time to clinically definite multiple sclerosis compared with placebo as it was defined before 2010. However, the committee understood that many patients in the trials would have been diagnosed and treated for multiple sclerosis rather than clinically isolated syndrome if current diagnostic criteria were used instead. Therefore, the committee was concerned that clinical trials using the pre‑2010 diagnostic criteria for clinically isolated syndrome were no longer relevant to current UK practice. The committee agreed that a post-hoc analysis which re‑identified patients using the 2010 diagnostic criteria showed encouraging results. However, it was concerned that this was based on a single study and had not been validated by any subsequent trials. The committee concluded that there was insufficient evidence using the current diagnostic criteria to make any recommendations for treating clinically isolated syndrome.\n\n# Clinical effectiveness in relapsing–remitting multiple sclerosis\n\n## Evidence comes from clinical trials and the RSS\n\nThe committee considered evidence from 4\xa0network meta-analyses of clinical trials from:\n\nthe assessment group\n\nBiogen (interferon beta‑1a, Avonex)\n\nMerck Serono (interferon beta‑1a, Rebif)\n\nTeva (glatiramer acetate, Copaxone).In addition to the data from clinical trials, the committee also considered data collected from patients participating in the RSS.\n\n# Clinical trials\n\n## The trials are broadly generalisable but subject to bias\n\nThe committee considered the generalisability of the clinical trials to patients in the NHS. The assessment group stated that the trials involving people with relapsing–remitting multiple sclerosis had limitations including differences in design and short length of follow‑up. This meant they were at risk of bias because injection-site reactions could have meant that patients in the trials were not blinded to their treatment. The clinical experts stated that unblinding was unlikely to have biased the results for disability progression, which was assessed by investigators blinded to treatment allocation. It concluded that the trials were broadly generalisable and relevant for this appraisal.\n\n# Disability progression outcome measure\n\n## Trial data for confirmed disability progression sustained for 6\xa0months is preferable\n\nThe committee discussed whether disability progression sustained for 3\xa0months or for 6\xa0months best reflected disability progression in people with relapsing–remitting multiple sclerosis. It recognised that some trials provided both 3-\xa0and 6‑month data, and that all trials reported 3‑month data. It was aware that, in previous appraisals, the committee preferred to use confirmed disability progression for 6\xa0months. The clinical experts explained that the time taken to recover from a relapse can vary and that people may still continue to recover after 3\xa0months. The committee agreed that the outcome for confirmed disability progression sustained for 6\xa0months was better at capturing the benefits of treatment. The assessment group stated that it preferred to use confirmed progression at 3\xa0months because the quality and size of its evidence network at this time point was better than that for a confirmed progression at 6\xa0months. The committee concluded that it preferred 6‑month data where available, but that it was important to use a consistent measure across all treatments.\n\n# Companies' and assessment group's network meta-analyses\n\n## The assessment group's network meta-analysis is preferable\n\nThe assessment group stated that some of the companies' meta-analyses had limitations, including, but not limited to, methods that were not transparent or analyses that did not include relevant trials. The committee also noted that the point estimates for the results broadly corresponded to results from the assessment group's network meta-analysis (see section\xa03.10). However, the companies' analyses had wider statistical intervals and showed fewer statistically significant differences between technologies. The assessment group stated that it used a frequentist approach for its meta-analysis, whereas the companies used a Bayesian approach. The committee agreed that this could explain some of the differences in results between the assessment group's and companies' analyses. The committee agreed to focus on the assessment group's network meta-analyses.\n\n# Results of assessment group's network meta-analysis\n\n## All treatments are similarly effective in reducing the number of relapses and slowing disability progression compared with placebo\n\nThe committee considered the results of the network meta-analysis (see table\xa01) by outcome for people with relapsing–remitting multiple sclerosis.\n\nAnnualised relapse rate: all the beta interferons and glatiramer acetate reduced the annualised relapse rate compared with placebo. When comparing each of the beta interferons and glatiramer acetate with each other, the results did not show that any one was statistically significantly better. The clinical experts considered the drugs under appraisal to be broadly similar in clinical effectiveness. The committee concluded that all the therapies were similarly effective in reducing the number of relapses compared with best supportive care.\n\nConfirmed disability progression: the treatments delayed disability compared with placebo but did not differ statistically significantly from each other. The committee concluded that the beta interferons and glatiramer acetate had similar effectiveness, and that they all delayed disability progression when compared with placebo.\n\nAdverse events: the committee considered the risk of stopping treatment because of adverse events. It noted that all the treatments were associated with more adverse events than placebo. It also noted that, although some of the drugs were associated with a higher risk of adverse events than others, the confidence intervals surrounding these estimates were very large. Beta interferons and glatiramer acetate have well-established safety profiles. Comparisons between treatments showed differences in the frequency of specific adverse events. However, there was no evidence to suggest that the risk of stopping treatment because of adverse events at 24\xa0months was different between treatments. The committee concluded that all the drugs would cause some adverse effects.\n\nQuality of life: The committee was aware that the systematic review informing the network meta-analysis found little evidence comparing the quality-of-life benefits to patients between treatments. It understood that it was not possible to do a network meta-analysis. The committee concluded that, while all treatments were likely to improve quality of life, the difference between treatments was uncertain.\n\n## Table\xa01 Results from the assessment group's network meta-analysis for relapsing–remitting multiple sclerosis\n\nDrug\n\nARRRR (95%\xa0CI)\n \n a\n\nTTP3HR (95%\xa0CI)\n\nTTP6HR (95%\xa0CI)\n\nAEsRiR (95%\xa0CI)\n\nGlatiramer 40\xa0mg 3\xa0times weekly\n\n(0.54, 0.80)\n\n–\n\n–\n\n–\n\nGlatiramer 20\xa0mg daily\n\n(0.61, 0.75)\n\n(0.60, 0.97)\n\n(0.53, 1.26)\n\n(0.88, 7.64)\n\nIFN beta‑1a 44\xa0micrograms 3\xa0times weekly\n\n(0.61, 0.76)\n\n(0.46, 0.86)\n\n(0.24, 0.93)\n\n(0.81, 18.29)\n\nIFN beta‑1b 250\xa0micrograms every other day\n\n(0.63, 0.77)\n\n(0.59, 1.02)\n\n(0.18, 0.63)\n\n(1.07, 18.29)\n\nIFN beta‑1a 22\xa0micrograms 3\xa0times a week\n\n(0.62, 0.85)\n\n(0.49, 0.96)\n\n–\n\n(0.21, 16.83)\n\nIFN beta‑1a 30\xa0micrograms weekly\n\n(0.73, 0.89)\n\n(0.53, 1.00)b\n\n(0.49, 0.94)\n\n(0.52, 5.02)\n\nAll drugs were compared with placebo.\n\na Results from outlier trial (Bornstein et al. 1987) were excluded.\n\nb Upper 95% confidence interval does not cross 1.00.\n\nAbbreviations: AEs, stopping treatment because of adverse events at 24\xa0months; ARR, annualised relapse rate; CI, confidence interval; HR, hazard ratio; IFN, interferon; RiR, risk ratio; RR, rate ratio; TTP3, time to disability progression confirmed at 3\xa0months; TTP6, time to disability progression confirmed at 6\xa0months.\n\n# Risk Sharing Scheme\n\n## RSS data are more likely to reflect effectiveness in clinical practice than data from the clinical trials\n\nThe committee discussed the RSS, which included NHS patients treated with either a beta interferon or glatiramer acetate. A representative from the RSS stated that the scheme included a large number of people and ran for 10\xa0years. The committee recognised that the RSS provided longer follow‑up than the trials, and that it reflected the people who would be offered these therapies in NHS practice. It concluded that it preferred the effectiveness data from the RSS.\n\n## The RSS used a summary measure of disease progression as its primary outcome\n\nThe primary outcome measuring effectiveness in the RSS was the change over time relative to baseline of a weighted sum of the proportions of patients who progressed to each Expanded Disability Status Scale (EDSS) score. This was weighted by utility, to account for the non-linearity of the EDSS scale (that is, for example, a change in EDSS from 0\xa0to\xa01 does not have the same impact as a change from 8\xa0to\xa09). The Department of Health stated that to use the outcome measure of the RSS it was necessary to derive an 'implied' hazard ratio. The Department of Health used data reflecting the natural history of disease in people not taking disease-modifying treatments from the British Columbia Multiple Sclerosis cohort for comparison because there was no comparator in the RSS (that is, nobody had best supportive care). People in the RSS were matched to people in the historical British Columbia cohort by EDSS score and age of onset. A hazard ratio for disease progression was applied to progression probabilities in the British Columbia cohort to derive the progression probabilities for people in the RSS. This 'implied' hazard ratio was derived to obtain the same change in mean utility between baseline and year\xa010 as that seen in the RSS cohort. The committee agreed that the 'implied' hazard ratio represented the relative effectiveness of the treatments in slowing disease progression for people in the RSS when compared with that expected for people in the British Columbia Multiple Sclerosis cohort on supportive care.\n\n## All treatments in the RSS slowed disease progression\n\nThe implied hazard ratio pooling all treatments in the RSS (the value is not directly comparable with the trial-based hazard ratios) showed that the treatments delayed disease progression compared with best supportive care (hazard ratio\xa00.79; 95%\xa0confidence interval 0.77\xa0to\xa00.81). Companies have indicated that the hazard ratios for individual drugs are confidential, but that all the drugs delayed disease progression similarly compared with best supportive care. The committee concluded that, consistent with the data from trials considered in the assessment group's network meta-analysis, all the technologies offered in the RSS delayed disease progression compared with best supportive care.\n\n## Pooled RSS estimates are preferable\n\nThe assessment group used the pooled effectiveness estimates from the RSS in its base-case analyses, rather than the results for the individual technologies from the RSS. The committee agreed that this was appropriate because:\n\nThe network meta-analysis results of trials did not show that any particular beta interferon or glatiramer acetate was better than another (see section\xa03.10).\n\nData for each individual technology in the RSS could be subject to selection bias. That is, because people in the RSS were not randomised to a specific treatment, the treatment choice, and also the outcomes, may have been affected by differences in the patient characteristics. The committee noted evidence provided by Teva in response to the appraisal consultation document that there was a difference between the baseline characteristics of patients having glatiramer acetate and those having beta interferons. It concluded that it had seen no evidence to suggest that these differences were clinically significant.\n\nThe pooled analysis from the RSS included people who switched to another treatment, whereas people who switched were excluded from the analyses for individual treatments. The committee considered that, although few people switched treatments, people who do switch may have a worse prognosis than those who do not. This means that the hazard ratios are lower (that is, the treatments appear more effective) in the analyses for the individual treatments than in the pooled analysis. The committee also noted an analysis provided by Teva in response to the appraisal consultation document, which used the individual implied hazard ratio for glatiramer acetate and included all patients who switched treatments. It noted that, because similar data from other companies were unavailable, no conclusions could be drawn.Based on the above considerations, the committee concluded that it would use the RSS estimates representing the pooled effect in its decision-making.\n\n## Pooled RSS estimates should also be used for Extavia\n\nExtavia was not included in the RSS because it was licensed after the scheme started. The committee understood that Extavia is the same as Betaferon, which the RSS included. The committee concluded that it was appropriate to assume that the effectiveness of Extavia was the same as that of Betaferon in the RSS.\n\n# Waning of treatment efficacy\n\n## Efficacy does not remain constant over time\n\nThe committee discussed whether the effectiveness of beta interferons and glatiramer acetate was likely to remain constant or wane over time. The clinical experts stated that most treatments for multiple sclerosis become less effective over time, either because the person's immune system develops neutralising antibodies or because the disease worsens and becomes resistant to treatment. The Department of Health stated that, in the RSS, the effect of the treatments waned after the first 2\xa0years. The committee concluded that, for decision-making, it was appropriate to assume that efficacy does not remain constant over time.\n\n# Cost effectiveness in relapsing–remitting multiple sclerosis\n\n## Versions of the RSS model come from 5\xa0sources\n\nThe committee discussed the economic models and modelling assumptions for relapsing–remitting multiple sclerosis from 5\xa0sources: 3\xa0companies (Biogen, Merck Serono and Teva), the assessment group, and the Department of Health:\n\nThe Department of Health provided the RSS model to the assessment group. The overall structure of all submitted models was similar to models used in previous NICE technology appraisals. The sources of data used as model inputs differed across the models.\n\nAll models estimated disease progression through 21\xa0health states defined by EDSS scores (ranging from\xa00 to\xa09.5). The models described the progression of disability in patients with relapsing–remitting multiple sclerosis (10\xa0states) to secondary progressive multiple sclerosis (10\xa0states) and to death.\n\nIn each cycle of the model, a patient with relapsing–remitting multiple sclerosis could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The disease could also advance from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, but could not then move back to relapsing–remitting disease.\n\nThe treatments increased quality-adjusted life years (QALYs) relative to best supportive care primarily by delaying disability progression and also by reducing the number of relapses. The model also incorporated EDSS-related (and other) mortality and therefore the treatments also increased life expectancy.\n\nThe treatment effect used in the models varied, representing either pooled or individual treatment estimates for effectiveness from either the RSS or from network meta-analyses of trials.\n\nThe assessment group model included the assumption that 5% of patients per year stop treatment; this was equal across all the treatments, and was based on what had been seen in the RSS.\n\nThe assessment group changed the assumptions about mortality in the RSS model to avoid double-counting of multiple sclerosis-related mortality (see section\xa03.20).\n\nThe assessment group excluded treatment costs in EDSS states 7\xa0to\xa09 (see section\xa03.26).\n\n# Natural history of the disease in subgroup analyses\n\n## The RSS used the British Columbia cohort as a comparator\n\nThe RSS model used a database from British Columbia to reflect the natural history of multiple sclerosis for people who do not have disease-modifying treatments. The RSS model had originally used a database from London Ontario instead but, in contrast to the British Columbia database, this did not include the possibility that patients' EDSS scores could improve. The committee noted that including the possibility that EDSS scores could improve was appropriate because EDSS scores for patients treated with disease-modifying drugs in the RSS did improve. The committee was aware that the British Columbia dataset was relatively old, with data collection having begun in 1980, and that supportive care may have since changed. However, it was also aware that the alternative dataset, from London Ontario, was even older and was also smaller. The committee concluded that it was appropriate to use the British Columbia database to model the natural history of multiple sclerosis for people who had not had disease-modifying treatments.\n\n# Time horizon and waning of treatment effect\n\n## The approach to waning of effectiveness over time differs from previous appraisals\n\nThe assessment group, the Department of Health and the companies chose a time horizon of 50\xa0years for their base-case analyses. The committee agreed that this was long enough to reflect a lifetime horizon, but noted the uncertainties about extrapolating over a lifetime. It also noted that the RSS had a follow‑up period of 10\xa0years and that no treatment waning assumption was needed for this period because it was captured within the treatment effectiveness data. In addition, it noted that, to extrapolate the waning effect over the treatment lifetime, the RSS model applied a 50% reduction in effect after 10\xa0years. NICE's previous technology appraisals (such as alemtuzumab and dimethyl fumarate) assumed a reduction in treatment effect of 25% after 2\xa0years, and of 50% after 5\xa0years. The committee considered that it was appropriate to use a different assumption for the waning effect in this appraisal because the RSS provided longer follow‑up data than the trials in the previous appraisals. It noted that the same reduction in waning effect was applied at the end of the 10‑year follow‑up period as in the previous appraisals. The committee concluded that assuming a 50% reduction in effect after 10\xa0years was appropriate.\n\n# Mortality\n\n## The assessment group modified the RSS model to avoid double-counting of mortality\n\nIn the original RSS model, mortality was included in 2\xa0ways. First, the model included multiple sclerosis-related mortality for all transitions to EDSS health-state\xa010. Second, the model included an increased risk of mortality to account for the increased risk of non-multiple sclerosis-related death in people with multiple sclerosis. The assessment group was concerned that this approach double-counted mortality and so removed the increased risk of mortality from non-multiple sclerosis-related causes from its analysis.\n\n## The standardised mortality ratios in Pokorski et al. (1997) overestimate mortality risk in patients with multiple sclerosis\n\nAn alternative approach to modelling mortality was suggested by Merck Serono, which was based on an assumption that had been used in several previous NICE appraisals (alemtuzumab, fingolimod and teriflunomide). This approach applied mortality ratios from Pokorski et al. to each EDSS health state, which resulted in a greater risk of mortality in people with multiple sclerosis than modelled in both the original RSS approach and the assessment group's approach. The committee was concerned that this overestimated mortality, particularly for lower EDSS states, because it was based on outdated data from a period before there had been improvements in multiple sclerosis care and when the background mortality rate was higher. It was also concerned that, in the Pokorski et al. study, EDSS was measured only at the first clinical visit but that the actual EDSS score at time of death depended on the speed of EDSS progression. The committee agreed that the approach using the mortality ratios from Pokorski et al. had limitations and overestimated mortality.\n\n## The standardised mortality ratio reported in Jick et al. (2014) overestimates mortality risk in low EDSS states and underestimates it in high EDSS states\n\nThe committee considered an alternative approach based on a more recent study (Jick et al., 2014), which reported lower rates of mortality for multiple sclerosis compared with Pokorski et al. (1997) and which had been applied in a recent appraisal for cladribine. The committee understood that although these data were more recent, the publication did not provide separate mortality ratios for different EDSS states. Therefore, models based on Jick et al. apply the same mortality ratio for each EDSS state. The committee was concerned that this approach resulted in clinically implausible mortality rates in low EDSS states and underestimated mortality in high EDSS states. The committee concluded that the approach to mortality was a source of uncertainty, but accepted the approach taken by the assessment group because it was the most clinically plausible.\n\n# Treatment stopping rates\n\n## Rates of stopping treatment from the RSS are appropriate to use in the economic model\n\nIn its model, the assessment group included rates of stopping treatment from the RSS, in which 5% of people stopped treatment each year. The Department of Health stated that stopping rates were similar across treatments. Biogen had concerns that the stopping rates assumed for beta interferons in NICE's technology appraisal of daclizumab (the guidance has been withdrawn because the marketing authorisation for daclizumab has been withdrawn) were higher (about 10% each year). The committee was aware that the daclizumab appraisal focused on a subgroup of people treated with daclizumab who had a more severe form of multiple sclerosis (that is, rapidly evolving severe multiple sclerosis and multiple sclerosis that has been previously treated with disease-modifying therapy). In addition, it understood from the Department of Health that higher stopping rates implausibly improved the cost effectiveness of treatments. The committee concluded that, for this appraisal, it was appropriate to use the same stopping rate from the RSS for all treatments.\n\n# Utility values\n\n## Disutility to carers should be considered\n\nThe committee discussed the quality of life for people with relapsing–remitting multiple sclerosis, and the burden that their carers experience. The assessment group did not include disutility to carers in its base case because it had questioned whether this was consistent with the NICE reference case. The companies and the Department of Health did include disutilities to carers in their base-case analyses. The base cases in previous NICE technology appraisals for multiple sclerosis (such as dimethyl fumarate and natalizumab) also included disutility to carers. The committee concluded that it would include disutility to carers when making its decision.\n\n# Health-state costs\n\n## The UK MS Survey is the most appropriate source for EDSS health-state costs\n\nThe committee discussed the annual costs associated with each EDSS health state in the model. It noted that the RSS model used Kobelt et al. (2000) in its base case and that this differed from other NICE technology appraisals, which used other sources such as:\n\nthe UK MS Survey used in NICE technology appraisal guidance on dimethyl fumarate, fingolimod and natalizumab\n\nTyas et al. (2007) used in NICE technology appraisal guidance on alemtuzumab and teriflunomide.The committee noted the following about the various sources:\n\nKobelt et al. estimated substantially higher costs in EDSS health states 7\xa0to\xa09 than the other sources. Kobelt et al. included indirect costs of sickness absence, early retirement and changes in working hours, which would not be borne by the NHS or personal social services (PSS). Notably, the study did not use recent unit costs, but costs adjusted for inflation from 1999/2000 prices to 15\xa0years later. For these reasons, the committee did not further consider costs from Kobelt et al.\n\nThe UK MS Survey represented the largest data set (responses from 2,048\xa0people), and included separate estimates of costs funded by the UK government and costs funded by the NHS and PSS. The UK government-funded costs included costs other than what the NHS and PSS would cover, and it was unclear what these included. The committee was satisfied that the NHS and PSS costs estimated from the UK MS Survey were the best available and could be used in this appraisal.\n\nTyas et al. reflected another analysis of data from the UK MS Survey. However, it reported costs funded by the UK government only, and did not separately consider costs funded by the NHS and PSS. Because of this, the committee did not consider costs from Tyas et al. further.The committee concluded that it would consider analyses using the UK MS Survey costs for EDSS health states.\n\n# Treatment costs\n\n## Treatment costs should not be applied to EDSS states 7\xa0to\xa09\n\nTeva stated that treatment costs should not be applied to EDSS states 7\xa0to\xa09 because it is unlikely that these people would have treatment with glatiramer acetate or the beta interferons in clinical practice. The assessment group explained that, while many people do not stop treatment at advanced EDSS states, removing treatment costs at EDSS states 7\xa0to\xa09 reflected a pathway using the drugs within their licensed indications. The committee concluded that it would base its conclusions on analyses without treatment costs applied to EDSS states 7\xa0to\xa09.\n\n# Cost of informal care\n\n## Costs not covered by the NHS or PSS do not meet the NICE reference case\n\nTeva stated that the committee should consider the cost of informal care in this appraisal. NICE's guide to methods of technology appraisal states that only 'costs borne by patients may be included when they are reimbursed by the NHS or personal social services' as part of the NICE reference case. The committee noted that, although family or carers may provide informal care, it had not been presented with evidence that the NHS or PSS would otherwise provide this informal care. It agreed that there was insufficient evidence to include the costs of informal care in the cost-effectiveness analysis. The committee also noted consultation comments from Merck that the committee should consider the additional support provided to patients by companies through schemes such as patient support programmes, and nursing support and training. The committee concluded that this support would be implicitly reflected in the price of the treatments and their benefits, and did not consider it further.\n\n# Equality considerations\n\n## Stakeholders consider glatiramer acetate to be the safest drug for anyone who is planning to become pregnant\n\nHealthcare Improvement Scotland and several stakeholders during consultation stated that glatiramer acetate is the safest drug for anyone who wants to become pregnant. Although glatiramer acetate is not contraindicated during pregnancy, its marketing authorisation suggests that it is preferable to avoid its use during pregnancy. The committee understood from consultation comments that glatiramer acetate is considered the safest drug available during the pre-conception period.\n\n## Special considerations should be given to people who cannot prepare beta interferon‑1b treatments\n\nThe committee noted comments from consultation before the fourth committee meeting that interferon beta‑1b is supplied as a solvent and powder, which patients (or carers) must mix each time they administer the treatment. This process is more difficult than treatments employing ready-to-use injection devices. The committee understood that some people will therefore have difficulty using Extavia and Betaferon, particularly people with manual dexterity, visual or cognitive difficulties, which are common in people with multiple sclerosis. The committee concluded that consideration should be given to this group of people with respect to the ease of preparation and administration of beta interferons.\n\n# Innovation\n\n## The technologies were innovative compared with best supportive care when they became available on the NHS\n\nThe committee considered that beta interferons and glatiramer acetate may have been considered innovative compared with best supportive care when they became available in the NHS. Several newer technologies have since become available that were considered innovative when compared with beta interferons and glatiramer acetate. The committee noted that the benefits of ease of preparation and administration using auto-injection devices (see section 3.29) were not captured in the cost-effectiveness analysis and took this into account.\n\n# Cost-effectiveness results\n\n## Interferon beta‑1a, interferon beta‑1b (Extavia) and glatiramer acetate are a cost-effective use of NHS resources\n\nThe committee considered the cost-effectiveness results for beta interferons and glatiramer acetate, taking into account its preferences, including waning in treatment effect (see section 3.19), using the pooled RSS results (see section\xa03.14 and section 3.15) and the patient access schemes where applicable. Specific incremental cost-effectiveness ratio (ICER) values cannot be reported as this would allow the back-calculation of confidential discounts.\n\nThe ICER for interferon beta‑1b (Extavia) compared with best supportive care was below £30,000 per QALY gained. The committee concluded that Extavia was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis or secondary progressive multiple sclerosis with continued relapses.\n\nThe committee noted that the ICERs for interferon beta‑1a compared with best supportive care were above £30,000 per QALY gained. It took into account the equality considerations applied with respect to the group of people who will find the preparation and administration of Extavia challenging (see section 3.29) because it was the only beta interferon that was cost effective at a threshold of less than £30,000 per QALY gained. The committee agreed that alternative beta interferons should be available for patients. The committee concluded that interferon beta‑1a was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis in this context.\n\nThe ICER for glatiramer acetate compared with best supportive care was below £30,000 per QALY gained. The committee was aware that a generic version of glatiramer acetate (Brabio) is available in the NHS, and understood that the price of glatiramer acetate is likely to fall in the future. The committee concluded that glatiramer acetate was a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis.\n\nThe committee considered glatiramer acetate, interferon beta‑1a and interferon beta‑1b to be broadly similar in clinical effectiveness (see section\xa03.10). However, it noted that (interferon beta‑1b) Betaferon was the most expensive technology. In addition, the ICER for Betaferon was above £30,000 per QALY gained. The committee concluded that Betaferon was not a cost-effective use of NHS resources for people with relapsing–remitting multiple sclerosis."}
|
https://www.nice.org.uk/guidance/ta527
|
Evidence-based recommendations on beta interferons (Avonex, Betaferon, Extavia, Rebif) and glatiramer acetate (Copaxone) for treating multiple sclerosis in adults.
|
153857e8b138aa256894e5931681e0f376bf0f54
|
nice
|
Hearing loss in adults: assessment and management
|
Hearing loss in adults: assessment and management
This guideline covers some aspects of assessing and managing hearing loss in primary, community and secondary care. It aims to improve the quality of life for adults with hearing loss by advising healthcare staff on assessing hearing difficulties, managing earwax and referring people for audiological or specialist assessment and management.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessment and referral
## Hearing difficulties or suspected hearing difficulties
For adults who present for the first time with hearing difficulties, or in whom you suspect hearing difficulties:
exclude impacted wax and acute infections such as otitis externa, then
arrange an audiological assessment (for more information, see recommendation 1.5.1) and
refer for additional diagnostic assessment if needed (see the recommendations on sudden or rapid onset of hearing loss and hearing loss with specific additional symptoms or signs).
## Sudden or rapid onset of hearing loss
Refer adults with sudden onset or rapid worsening of hearing loss in one or both ears, which is not explained by external or middle ear causes, as follows.
If the hearing loss developed suddenly (over a period of 3 days or less) within the past 30 days, refer immediately (to be seen within 24 hours) to an ear, nose and throat service or an emergency department.
If the hearing loss developed suddenly more than 30 days ago, refer urgently (to be seen within 2 weeks) to an ear, nose and throat or audiovestibular medicine service.
If the hearing loss worsened rapidly (over a period of 4 to 90 days), refer urgently (to be seen within 2 weeks) to an ear, nose and throat or audiovestibular medicine service.
## Hearing loss with specific additional symptoms or signs
Refer immediately (to be seen within 24 hours) adults with acquired unilateral hearing loss and altered sensation or facial droop on the same side to an ear, nose and throat service or, if stroke is suspected, follow a local stroke referral pathway. For information about diagnosis and initial management of stroke, see the NICE guideline on stroke and transient ischaemic attack in over 16s.
Refer immediately (to be seen within 24 hours) adults with hearing loss who are immunocompromised and have otalgia (ear ache) with otorrhoea (discharge from the ear) that has not responded to treatment within 72 hours to an ear, nose and throat service.
Consider making an urgent referral (to be seen within 2 weeks) to an ear, nose and throat service for adults of Chinese or south-east Asian family origin who have hearing loss and a middle ear effusion not associated with an upper respiratory tract infection. For information about recognition and referral for suspected cancer, see the NICE guideline on suspected cancer.
Consider referring adults with hearing loss that is not explained by acute external or middle ear causes to an ear, nose and throat, audiovestibular medicine or specialist audiology service for diagnostic investigation, using a local pathway, if they present with any of the following:
unilateral or asymmetric hearing loss as a primary concern
hearing loss that fluctuates and is not associated with an upper respiratory tract infection
hyperacusis (intolerance to everyday sounds that causes significant distress and affects a person's day-to-day activities)
persistent tinnitus that is unilateral, pulsatile, has significantly changed in nature or is causing distress
vertigo that has not fully resolved or is recurrent
hearing loss that is not age related.
Consider referring adults with hearing loss to an ear, nose and throat service if, after initial treatment of any earwax (see the recommendations on removing earwax) or acute infection, they have any of:
partial or complete obstruction of the external auditory canal that prevents full examination of the eardrum or taking an aural impression
pain affecting either ear (including in and around the ear) that has lasted for 1 week or more and has not responded to first-line treatment
a history of discharge (other than wax) from either ear that has not resolved, has not responded to prescribed treatment, or recurs
abnormal appearance of the outer ear or the eardrum, such as:
inflammation
polyp formation
perforated eardrum
abnormal bony or skin growths
swelling of the outer ear
blood in the ear canal
a middle ear effusion in the absence of, or that persists after, an acute upper respiratory tract infection.
## Adults with suspected or diagnosed dementia, mild cognitive impairment or a learning disability
Consider referring adults with diagnosed or suspected dementia or mild cognitive impairment to an audiology service for a hearing assessment because hearing loss may be a comorbid condition.
Consider referring adults with diagnosed dementia or mild cognitive impairment to an audiology service for a hearing assessment every 2 years if they have not previously been diagnosed with hearing loss.
Consider referring people with a diagnosed learning disability to an audiology service for a hearing assessment when they transfer from child to adult services, and then every 2 years.
# Removing earwax
Offer to remove earwax for adults in primary care or community ear care services if the earwax is contributing to hearing loss or other symptoms, or needs to be removed in order to examine the ear or take an impression of the ear canal.
Do not offer adults manual syringing to remove earwax.
Consider ear irrigation using an electronic irrigator, microsuction or another method of earwax removal (such as manual removal using a probe) for adults in primary or community ear care services if:
the practitioner (such as a community nurse or audiologist):
has training and expertise in using the method to remove earwax
is aware of any contraindications to the method
the correct equipment is available.
When carrying out ear irrigation in adults:
use pre-treatment wax softeners, either immediately before ear irrigation or for up to 5 days beforehand
if irrigation is unsuccessful:
repeat use of wax softeners or
instil water into the ear canal 15 minutes before repeating ear irrigation
if irrigation is unsuccessful after the second attempt, refer the person to a specialist ear care service or an ear, nose and throat service for removal of earwax.
Advise adults not to remove earwax or clean their ears by inserting small objects, such as cotton buds, into the ear canal. Explain that this could damage the ear canal and eardrum, and push the wax further down into the ear.
# Investigation using MRI
Offer MRI of the internal auditory meati to adults with hearing loss and localising symptoms or signs (such as facial nerve weakness) that might indicate a vestibular schwannoma or CPA (cerebellopontine angle) lesion, irrespective of pure tone thresholds.
Consider MRI of the internal auditory meati for adults with sensorineural hearing loss and no localising signs if there is an asymmetry on pure tone audiometry of 15 dB or more at any 2 adjacent test frequencies, using test frequencies of 0.5, 1, 2, 4 and 8 kHz.
# Treating idiopathic sudden sensorineural hearing loss
Consider a steroid to treat idiopathic sudden sensorineural hearing loss in adults.
# Assessment and management in audiology services
Include and record the following as part of the audiological assessment for adults:
a full history including relevant symptoms, comorbidities, cognitive ability, physical mobility and dexterity
the person's hearing and communication needs at home, at work or in education, and in social situations
any psychosocial difficulties related to hearing
the person's expectations and motivations with respect to their hearing loss and the listening and communication strategies available to them
any restrictions on activity, assessed using a self-report instrument such as the Glasgow Hearing Aid Benefit Profile or the Client-Orientated Scale of Improvement
-toscopy
pure tone audiometry
tympanometry if indicated.
After the audiological assessment:
discuss with the person:
the pure tone audiogram and the impact their hearing loss might have on communication
hearing deficits (such as listening in noisy environments) that are not obvious from the audiogram
-ptions for managing their hearing needs, such as acoustic or bone conduction hearing aids, assistive listening devices and communication strategies, and the potential benefits and limitations of each option
-ptions for managing single-sided deafness if needed
referral for implantable devices such as cochlear implants, bone-anchored hearing aids, middle ear implants or auditory brain stem implants, if these might be suitable (see NICE's technology appraisal guidance on cochlear implants for children and adults with severe to profound deafness and NICE's interventional procedures guidance on auditory brain stem implants)
referral for medical or surgical treatments, if these might be suitable
agree and record a personalised care plan, taking into account the person's preferences, including goals, and give the person a copy.
Give the person and, if they wish, their family or carers, information about:
the causes of hearing loss, how hearing loss affects the ability to communicate and hear, and how it can be managed
-rganisations and support groups for people with hearing loss.
# Hearing aids and assistive listening devices
## Hearing aids
Offer hearing aids to adults whose hearing loss affects their ability to communicate and hear, including awareness of warning sounds and the environment, and appreciation of music.
Offer 2 hearing aids to adults with aidable hearing loss in both ears. Explain that wearing 2 hearing aids can help to make speech easier to understand when there is background noise, make it easier to tell where sounds are coming from, and improve sound quality.
Consider using motivational interviewing or engagement strategies and goal setting when discussing hearing aids with adults for the first time, to encourage acceptance and use of hearing aids.
Show the hearing aids when they are first offered and discuss their suitability with the person.
When prescribing and fitting hearing aids, explain the features on the hearing aid that can help the person to hear in background noise, such as directional microphone and noise reduction settings.
Advise adults with hearing aids about choosing microphone and noise reduction settings that will meet their needs in different environments, and ensure that they know how to use them.
Give adults with hearing aids information about getting used to hearing aids, cleaning and caring for their hearing aids, and troubleshooting.
## Assistive listening devices
Give adults with hearing loss information about assistive listening devices such as personal loops, personal communicators, TV amplifiers, telephone devices, smoke alarms, doorbell sensors, and technologies such as streamers and apps.
Tell adults with hearing loss about organisations that can demonstrate and provide advice on how to obtain assistive listening devices, such as social services, the fire service, or the government through programmes such as Access to Work or Disabled Student Allowance.
# Follow-up in audiology services
Offer adults with hearing aids a face-to-face follow‑up audiology appointment 6 to 12 weeks after the hearing aids are fitted, with the option to attend this appointment by telephone or electronic communication if the person prefers.
At the follow‑up audiology appointment for adults with hearing aids:
ask the person if they have any concerns or questions
address any difficulties with inserting, removing or maintaining their hearing aids
provide information on communication, social care or rehabilitation support services if needed
tell the person how to contact audiology services in the future for aftercare, including repairs and adjustments to accommodate changes in their hearing
ensure that the person's hearing aids and other devices meet their needs by checking:
the comfort, sound quality and volume of hearing aids, including microphone and noise reduction settings, and fine-tuning them if needed
hearing aid cleaning, battery life and use with a telephone
use of assistive listening devices
hours the hearing aid has been used, if shown by automatic data logging
review the goals identified in the personalised care plan and agree how to address any that have not been met (for information on the personalised care plan, see recommendation 1.5.2)
update the personalised care plan and provide them with a copy.
For adults with hearing loss in both ears who chose a single hearing aid, consider a second hearing aid at the follow‑up appointment.
For adults with hearing loss who have chosen a management strategy other than hearing aids, such as assistive listening devices or communication strategies, offer a follow‑up appointment when the effectiveness of the device or strategy can be evaluated.
Tell adults with hearing loss who have chosen not to have a hearing aid or other device how to contact audiology services in the future.
Consider having a system in place for recalling people with hearing devices for regular reassessment of their hearing needs and devices.
# Information and support
Follow the principles on tailoring healthcare services for each person and enabling people to actively participate in their care in the NICE guideline on patient experience in adult NHS services by, for example:
taking into account the person's ability to access services and their personal preferences when offering appointments
taking measures, such as reducing background noise, to ensure that the clinical and care environment is conducive to communication for people with hearing loss, particularly in group settings such as waiting rooms, clinics and care homes
establishing the most effective way of communicating with each person, including the use of hearing loop systems and other assistive listening devices
ensuring that staff are trained and have demonstrated competence in communication skills for people with hearing loss
encouraging people with hearing loss to give feedback about the health and social care services they receive, and responding to their feedback.# Putting this guideline into practice
See NICE's tools and resources to help you put this guideline into practice.
One issue was highlighted that might need specific thought when implementing the recommendations on follow-up in audiology services (recommendations 1.7.1 and 1.7.2) on the follow‑up appointment in audiology services for people who have had hearing aids fitted. People who attend this appointment by telephone or electronic communication, rather than in person, might need to be offered an additional face-to-face appointment if their hearing aids need to be adjusted or they are having problems using them.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Hearing loss is a major public health issue affecting about 9 million people in England. Because age-related hearing loss is the most common type of hearing loss, it is estimated that by 2035 there will be around 13 million people with hearing loss in England – a fifth of the population. The psychological, financial and health burden of hearing loss can be reduced by prompt and accurate referral, robust assessment and correct management.
The care offered to people with hearing difficulties varies from place to place, and many people face delays in having their hearing loss identified and managed. Most hearing difficulties are age related and need assessment and management by the local audiology team. Earwax may complicate the clinical picture and cause hearing difficulties, and can be treated in primary or community care. Other causes of hearing difficulties need prompt, or even urgent, investigation and treatment by specialist services.
This guideline aims to improve the quality of life for adults with hearing loss by providing advice for healthcare staff on who to refer for audiological assessment, how to manage earwax in primary and community care and when to refer people for specialist assessment and management. The guideline also offers advice on assessment and follow‑up in audiology services, and information and support for people with hearing loss. In addition, the guideline considers best practice in the management of idiopathic sudden sensorineural hearing loss and MRI as an investigation for hearing loss.
It is important that the person with hearing loss has the opportunity to participate in making decisions about management, in partnership with their healthcare professionals, and this is reflected in the guideline.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Idiopathic sudden sensorineural hearing loss
What is the most effective route of administration of steroids as a first-line treatment for idiopathic sudden sensorineural hearing loss?
## Why this is important
Idiopathic sudden sensorineural hearing loss (SSNHL) is usually unilateral, can range from mild to total and can be temporary or permanent. SSNHL has a significant impact on people's lives, causing considerable concern and disability, particularly if there is already a hearing deficit in the other ear.
First-line treatment options for idiopathic SSNHL can include oral steroids, intra‑tympanic steroid injections or a combination of both. There is a paucity of evidence assessing the effectiveness of these different treatment options. There is heterogeneity in doses and types of steroids and this makes the findings unreliable. Therefore, it is difficult to establish the most clinically and cost-effective route of administration of steroids as first-line treatment for idiopathic SSNHL. This has a direct impact on the care provided to people with SSNHL and on our ability to develop robust guidelines and policy.
# Earwax
What is the clinical and cost effectiveness of microsuction compared with irrigation to remove earwax?
## Why this is important
A build-up of earwax in the ear canal can cause hearing loss and discomfort, contributes to infections, and can exacerbate stress, social isolation and depression. Moreover, earwax can prevent adequate clinical examination of the ear, delaying investigations and management; GPs cannot check for infection and audiologists cannot test hearing and fit hearing aids if the ear canal is blocked with wax. Excessive earwax is common, especially in older adults and those who use hearing aids and earbud-type earphones. In the UK, it is estimated that 2.3 million people each year have problems with earwax sufficient to need intervention.
Earwax is usually treated initially with ear drops. However, if this is unsuccessful, the wax can be removed using irrigation (flushing the wax out using water) or microsuction (using a vacuum to suck the wax out under a microscope). There are few studies comparing these different techniques in terms of effectiveness, efficiency and adverse events.
# Use of hearing aids and incidence of dementia
In adults with hearing loss, does the use of hearing aids reduce the incidence of dementia?
## Why this is important
In the ageing UK population, the incidence of dementia is increasing. Dementia has considerable long-term costs for people with dementia, their families and the NHS, and there is no effective treatment to prevent its progression.
Hearing loss is associated with an increased incidence of dementia. It is estimated that among people with mild to moderate hearing loss, the incidence of dementia is double that of people with normal hearing, and that the ratio increases to 5 times that of people with normal hearing in those with severe hearing loss. The cause of this association is unknown; there may be common factors causing both dementia and hearing loss, such as lifestyle, genetic susceptibility, environmental factors or age-related factors such as cardiovascular disease. Hearing loss may cause dementia either directly (for example, neuroplastic changes caused by hearing deprivation or increased listening demands) or indirectly via social isolation and depression (which are known be associated with cognitive decline and dementia). Conversely, it is possible that cognitive decline has an impact on sensory function (for example, affecting attention and listening skills). Currently, there is no good evidence to show that hearing loss causes dementia or that hearing aids delay the onset or reduce the incidence of dementia. Hearing aids do, however, have the potential to improve functioning and quality of life, and this could delay the progress of dementia or improve its management.
# Hearing loss prevalence in people who under-present for hearing loss
What is the prevalence of hearing loss among populations who under-present for possible hearing loss?
## Why this is important
The research question aims to identify the prevalence of hearing loss among populations who may be unaware of their own hearing loss or lack motivation and capability to seek help for this.
A full population prevalence study matched to audiology service usage will help identify populations who under-present for possible hearing loss. The research will also identify factors that can act as red flags to prompt health and social care professionals to proactively consider the possibility of hearing loss.
The evidence review for the NICE guideline on adult hearing loss highlighted significant health benefits for people whose hearing loss is identified and addressed at an early stage, yet people often delay seeking treatment for up to 10 years. There are certain groups who are particularly disadvantaged because their health issues lead to a lack of awareness of their deteriorating or suboptimal hearing, or a failure to report their difficulties. These include people with learning disabilities, dementia and mild cognitive impairment.
Given the importance of early detection, this research is urgently needed to identify populations who are under-represented and any factors that would lead health and social care professionals to consider the possibility of hearing loss.
# Monitoring and follow-up for adults with hearing loss
What is the clinical and cost effectiveness of monitoring and follow‑up for adults with hearing loss post-intervention compared with usual care?
## Why this is important
The evidence review for the NICE guideline on hearing loss found a lack of evidence to establish the benefits of monitoring and follow‑up, how they should be delivered and across what time periods. Robust evidence is needed to establish the clinical and cost effectiveness of monitoring and follow‑up, and to understand how and when they might best be used in clinical practice. This will inform future guidelines and policy.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment and referral\n\n## Hearing difficulties or suspected hearing difficulties\n\nFor adults who present for the first time with hearing difficulties, or in whom you suspect hearing difficulties:\n\nexclude impacted wax and acute infections such as otitis externa, then\n\narrange an audiological assessment (for more information, see recommendation\xa01.5.1) and\n\nrefer for additional diagnostic assessment if needed (see the recommendations\xa0on sudden or rapid onset of hearing loss and hearing loss with specific additional symptoms or signs).\n\n## Sudden or rapid onset of hearing loss\n\nRefer adults with sudden onset or rapid worsening of hearing loss in one or both ears, which is not explained by external or middle ear causes, as follows.\n\nIf the hearing loss developed suddenly (over a period of 3\xa0days or less) within the past 30\xa0days, refer immediately (to be seen within 24\xa0hours) to an ear, nose and throat service or an emergency department.\n\nIf the hearing loss developed suddenly more than 30\xa0days ago, refer urgently (to be seen within 2\xa0weeks) to an ear, nose and throat or audiovestibular medicine service.\n\nIf the hearing loss worsened rapidly (over a period of 4\xa0to 90\xa0days), refer urgently (to be seen within 2\xa0weeks) to an ear, nose and throat or audiovestibular medicine service.\n\n## Hearing loss with specific additional symptoms or signs\n\nRefer immediately (to be seen within 24\xa0hours) adults with acquired unilateral hearing loss and altered sensation or facial droop on the same side to an ear, nose and throat service or, if stroke is suspected, follow a local stroke referral pathway. For information about diagnosis and initial management of stroke, see the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\nRefer immediately (to be seen within 24\xa0hours) adults with hearing loss who are immunocompromised and have otalgia (ear ache) with otorrhoea (discharge from the ear) that has not responded to treatment within 72\xa0hours to an ear, nose and throat service.\n\nConsider making an urgent referral (to be seen within 2\xa0weeks) to an ear, nose and throat service for adults of Chinese or south-east Asian family origin who have hearing loss and a middle ear effusion not associated with an upper respiratory tract infection. For information about recognition and referral for suspected cancer, see the NICE guideline on suspected cancer.\n\nConsider referring adults with hearing loss that is not explained by acute external or middle ear causes to an ear, nose and throat, audiovestibular medicine or specialist audiology service for diagnostic investigation, using a local pathway, if they present with any of the following:\n\nunilateral or asymmetric hearing loss as a primary concern\n\nhearing loss that fluctuates and is not associated with an upper respiratory tract infection\n\nhyperacusis (intolerance to everyday sounds that causes significant distress and affects a person's day-to-day activities)\n\npersistent tinnitus that is unilateral, pulsatile, has significantly changed in nature or is causing distress\n\nvertigo that has not fully resolved or is recurrent\n\nhearing loss that is not age related.\n\nConsider referring adults with hearing loss to an ear, nose and throat service if, after initial treatment of any earwax (see the recommendations on removing earwax) or acute infection, they have any of:\n\npartial or complete obstruction of the external auditory canal that prevents full examination of the eardrum or taking an aural impression\n\npain affecting either ear (including in and around the ear) that has lasted for 1\xa0week or more and has not responded to first-line treatment\n\na history of discharge (other than wax) from either ear that has not resolved, has not responded to prescribed treatment, or recurs\n\nabnormal appearance of the outer ear or the eardrum, such as:\n\n\n\ninflammation\n\npolyp formation\n\nperforated eardrum\n\nabnormal bony or skin growths\n\nswelling of the outer ear\n\nblood in the ear canal\n\n\n\na middle ear effusion in the absence of, or that persists after, an acute upper respiratory tract infection.\n\n## Adults with suspected or diagnosed dementia, mild cognitive impairment or a learning disability\n\nConsider referring adults with diagnosed or suspected dementia or mild cognitive impairment to an audiology service for a hearing assessment because hearing loss may be a comorbid condition.\n\nConsider referring adults with diagnosed dementia or mild cognitive impairment to an audiology service for a hearing assessment every 2\xa0years if they have not previously been diagnosed with hearing loss.\n\nConsider referring people with a diagnosed learning disability to an audiology service for a hearing assessment when they transfer from child to adult services, and then every 2\xa0years.\n\n# Removing earwax\n\nOffer to remove earwax for adults in primary care or community ear care services if the earwax is contributing to hearing loss or other symptoms, or needs to be removed in order to examine the ear or take an impression of the ear canal.\n\nDo not offer adults manual syringing to remove earwax.\n\nConsider ear irrigation using an electronic irrigator, microsuction or another method of earwax removal (such as manual removal using a probe) for adults in primary or community ear care services if:\n\nthe practitioner (such as a community nurse or audiologist):\n\n\n\nhas training and expertise in using the method to remove earwax\n\nis aware of any contraindications to the method\n\n\n\nthe correct equipment is available.\n\nWhen carrying out ear irrigation in adults:\n\nuse pre-treatment wax softeners, either immediately before ear irrigation or for up to 5\xa0days beforehand\n\nif irrigation is unsuccessful:\n\n\n\nrepeat use of wax softeners or\n\ninstil water into the ear canal 15\xa0minutes before repeating ear irrigation\n\n\n\nif irrigation is unsuccessful after the second attempt, refer the person to a specialist ear care service or an ear, nose and throat service for removal of earwax.\n\nAdvise adults not to remove earwax or clean their ears by inserting small objects, such as cotton buds, into the ear canal. Explain that this could damage the ear canal and eardrum, and push the wax further down into the ear.\n\n# Investigation using MRI\n\nOffer MRI of the internal auditory meati to adults with hearing loss and localising symptoms or signs (such as facial nerve weakness) that might indicate a vestibular schwannoma or CPA (cerebellopontine angle) lesion, irrespective of pure tone thresholds.\n\nConsider MRI of the internal auditory meati for adults with sensorineural hearing loss and no localising signs if there is an asymmetry on pure tone audiometry of 15\xa0dB or more at any 2\xa0adjacent test frequencies, using test frequencies of 0.5, 1, 2, 4 and 8\xa0kHz.\n\n# Treating idiopathic sudden sensorineural hearing loss\n\nConsider a steroid to treat idiopathic sudden sensorineural hearing loss in adults.\n\n# Assessment and management in audiology services\n\nInclude and record the following as part of the audiological assessment for adults:\n\na full history including relevant symptoms, comorbidities, cognitive ability, physical mobility and dexterity\n\nthe person's hearing and communication needs at home, at work or in education, and in social situations\n\nany psychosocial difficulties related to hearing\n\nthe person's expectations and motivations with respect to their hearing loss and the listening and communication strategies available to them\n\nany restrictions on activity, assessed using a self-report instrument such as the Glasgow Hearing Aid Benefit Profile or the Client-Orientated Scale of Improvement\n\notoscopy\n\npure tone audiometry\n\ntympanometry if indicated.\n\nAfter the audiological assessment:\n\ndiscuss with the person:\n\n\n\nthe pure tone audiogram and the impact their hearing loss might have on communication\n\nhearing deficits (such as listening in noisy environments) that are not obvious from the audiogram\n\noptions for managing their hearing needs, such as acoustic or bone conduction hearing aids, assistive listening devices and communication strategies, and the potential benefits and limitations of each option\n\noptions for managing single-sided deafness if needed\n\nreferral for implantable devices such as cochlear implants, bone-anchored hearing aids, middle ear implants or auditory brain stem implants, if these might be suitable (see NICE's technology appraisal guidance on cochlear implants for children and adults with severe to profound deafness and NICE's interventional procedures guidance on auditory brain stem implants)\n\nreferral for medical or surgical treatments, if these might be suitable\n\n\n\nagree and record a personalised care plan, taking into account the person's preferences, including goals, and give the person a copy.\n\nGive the person and, if they wish, their family or carers, information about:\n\nthe causes of hearing loss, how hearing loss affects the ability to communicate and hear, and how it can be managed\n\norganisations and support groups for people with hearing loss.\n\n# Hearing aids and assistive listening devices\n\n## Hearing aids\n\nOffer hearing aids to adults whose hearing loss affects their ability to communicate and hear, including awareness of warning sounds and the environment, and appreciation of music.\n\nOffer 2\xa0hearing aids to adults with aidable hearing loss in both ears. Explain that wearing 2\xa0hearing aids can help to make speech easier to understand when there is background noise, make it easier to tell where sounds are coming from, and improve sound quality.\n\nConsider using motivational interviewing or engagement strategies and goal setting when discussing hearing aids with adults for the first time, to encourage acceptance and use of hearing aids.\n\nShow the hearing aids when they are first offered and discuss their suitability with the person.\n\nWhen prescribing and fitting hearing aids, explain the features on the hearing aid that can help the person to hear in background noise, such as directional microphone and noise reduction settings.\n\nAdvise adults with hearing aids about choosing microphone and noise reduction settings that will meet their needs in different environments, and ensure that they know how to use them.\n\nGive adults with hearing aids information about getting used to hearing aids, cleaning and caring for their hearing aids, and troubleshooting.\n\n## Assistive listening devices\n\nGive adults with hearing loss information about assistive listening devices such as personal loops, personal communicators, TV amplifiers, telephone devices, smoke alarms, doorbell sensors, and technologies such as streamers and apps.\n\nTell adults with hearing loss about organisations that can demonstrate and provide advice on how to obtain assistive listening devices, such as social services, the fire service, or the government through programmes such as Access to Work or Disabled Student Allowance.\n\n# Follow-up in audiology services\n\nOffer adults with hearing aids a face-to-face follow‑up audiology appointment 6\xa0to\xa012\xa0weeks after the hearing aids are fitted, with the option to attend this appointment by telephone or electronic communication if the person prefers.\n\nAt the follow‑up audiology appointment for adults with hearing aids:\n\nask the person if they have any concerns or questions\n\naddress any difficulties with inserting, removing or maintaining their hearing aids\n\nprovide information on communication, social care or rehabilitation support services if needed\n\ntell the person how to contact audiology services in the future for aftercare, including repairs and adjustments to accommodate changes in their hearing\n\nensure that the person's hearing aids and other devices meet their needs by checking:\n\n\n\nthe comfort, sound quality and volume of hearing aids, including microphone and noise reduction settings, and fine-tuning them if needed\n\nhearing aid cleaning, battery life and use with a telephone\n\nuse of assistive listening devices\n\nhours the hearing aid has been used, if shown by automatic data logging\n\n\n\nreview the goals identified in the personalised care plan and agree how to address any that have not been met (for information on the personalised care plan, see recommendation\xa01.5.2)\n\nupdate the personalised care plan and provide them with a copy.\n\nFor adults with hearing loss in both ears who chose a single hearing aid, consider a second hearing aid at the follow‑up appointment.\n\nFor adults with hearing loss who have chosen a management strategy other than hearing aids, such as assistive listening devices or communication strategies, offer a follow‑up appointment when the effectiveness of the device or strategy can be evaluated.\n\nTell adults with hearing loss who have chosen not to have a hearing aid or other device how to contact audiology services in the future.\n\nConsider having a system in place for recalling people with hearing devices for regular reassessment of their hearing needs and devices.\n\n# Information and support\n\nFollow the principles on tailoring healthcare services for each person and enabling people to actively participate in their care in the NICE guideline on patient experience in adult NHS services by, for example:\n\ntaking into account the person's ability to access services and their personal preferences when offering appointments\n\ntaking measures, such as reducing background noise, to ensure that the clinical and care environment is conducive to communication for people with hearing loss, particularly in group settings such as waiting rooms, clinics and care homes\n\nestablishing the most effective way of communicating with each person, including the use of hearing loop systems and other assistive listening devices\n\nensuring that staff are trained and have demonstrated competence in communication skills for people with hearing loss\n\nencouraging people with hearing loss to give feedback about the health and social care services they receive, and responding to their feedback.", 'Putting this guideline into practice': "See NICE's tools and resources to help you put this guideline into practice.\n\nOne issue was highlighted that might need specific thought when implementing the recommendations\xa0on follow-up in audiology services (recommendations 1.7.1 and 1.7.2) on the follow‑up appointment in audiology services for people who have had hearing aids fitted. People who attend this appointment by telephone or electronic communication, rather than in person, might need to be offered an additional face-to-face appointment if their hearing aids need to be adjusted or they are having problems using them.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': 'Hearing loss is a major public health issue affecting about 9\xa0million people in England. Because age-related hearing loss is the most common type of hearing loss, it is estimated that by 2035 there will be around 13\xa0million people with hearing loss in England – a fifth of the population. The psychological, financial and health burden of hearing loss can be reduced by prompt and accurate referral, robust assessment and correct management.\n\nThe care offered to people with hearing difficulties varies from place to place, and many people face delays in having their hearing loss identified and managed. Most hearing difficulties are age related and need assessment and management by the local audiology team. Earwax may complicate the clinical picture and cause hearing difficulties, and can be treated in primary or community care. Other causes of hearing difficulties need prompt, or even urgent, investigation and treatment by specialist services.\n\nThis guideline aims to improve the quality of life for adults with hearing loss by providing advice for healthcare staff on who to refer for audiological assessment, how to manage earwax in primary and community care and when to refer people for specialist assessment and management. The guideline also offers advice on assessment and follow‑up in audiology services, and information and support for people with hearing loss. In addition, the guideline considers best practice in the management of idiopathic sudden sensorineural hearing loss and MRI as an investigation for hearing loss.\n\nIt is important that the person with hearing loss has the opportunity to participate in making decisions about management, in partnership with their healthcare professionals, and this is reflected in the guideline.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Idiopathic sudden sensorineural hearing loss\n\nWhat is the most effective route of administration of steroids as a first-line treatment for idiopathic sudden sensorineural hearing loss?\n\n## Why this is important\n\nIdiopathic sudden sensorineural hearing loss (SSNHL) is usually unilateral, can range from mild to total and can be temporary or permanent. SSNHL has a significant impact on people's lives, causing considerable concern and disability, particularly if there is already a hearing deficit in the other ear.\n\nFirst-line treatment options for idiopathic SSNHL can include oral steroids, intra‑tympanic steroid injections or a combination of both. There is a paucity of evidence assessing the effectiveness of these different treatment options. There is heterogeneity in doses and types of steroids and this makes the findings unreliable. Therefore, it is difficult to establish the most clinically and cost-effective route of administration of steroids as first-line treatment for idiopathic SSNHL. This has a direct impact on the care provided to people with SSNHL and on our ability to develop robust guidelines and policy.\n\n# Earwax\n\nWhat is the clinical and cost effectiveness of microsuction compared with irrigation to remove earwax?\n\n## Why this is important\n\nA build-up of earwax in the ear canal can cause hearing loss and discomfort, contributes to infections, and can exacerbate stress, social isolation and depression. Moreover, earwax can prevent adequate clinical examination of the ear, delaying investigations and management; GPs cannot check for infection and audiologists cannot test hearing and fit hearing aids if the ear canal is blocked with wax. Excessive earwax is common, especially in older adults and those who use hearing aids and earbud-type earphones. In the UK, it is estimated that 2.3\xa0million people each year have problems with earwax sufficient to need intervention.\n\nEarwax is usually treated initially with ear drops. However, if this is unsuccessful, the wax can be removed using irrigation (flushing the wax out using water) or microsuction (using a vacuum to suck the wax out under a microscope). There are few studies comparing these different techniques in terms of effectiveness, efficiency and adverse events.\n\n# Use of hearing aids and incidence of dementia\n\nIn adults with hearing loss, does the use of hearing aids reduce the incidence of dementia?\n\n## Why this is important\n\nIn the ageing UK population, the incidence of dementia is increasing. Dementia has considerable long-term costs for people with dementia, their families and the NHS, and there is no effective treatment to prevent its progression.\n\nHearing loss is associated with an increased incidence of dementia. It is estimated that among people with mild to moderate hearing loss, the incidence of dementia is double that of people with normal hearing, and that the ratio increases to 5\xa0times that of people with normal hearing in those with severe hearing loss. The cause of this association is unknown; there may be common factors causing both dementia and hearing loss, such as lifestyle, genetic susceptibility, environmental factors or age-related factors such as cardiovascular disease. Hearing loss may cause dementia either directly (for example, neuroplastic changes caused by hearing deprivation or increased listening demands) or indirectly via social isolation and depression (which are known be associated with cognitive decline and dementia). Conversely, it is possible that cognitive decline has an impact on sensory function (for example, affecting attention and listening skills). Currently, there is no good evidence to show that hearing loss causes dementia or that hearing aids delay the onset or reduce the incidence of dementia. Hearing aids do, however, have the potential to improve functioning and quality of life, and this could delay the progress of dementia or improve its management.\n\n# Hearing loss prevalence in people who under-present for hearing loss\n\nWhat is the prevalence of hearing loss among populations who under-present for possible hearing loss?\n\n## Why this is important\n\nThe research question aims to identify the prevalence of hearing loss among populations who may be unaware of their own hearing loss or lack motivation and capability to seek help for this.\n\nA full population prevalence study matched to audiology service usage will help identify populations who under-present for possible hearing loss. The research will also identify factors that can act as red flags to prompt health and social care professionals to proactively consider the possibility of hearing loss.\n\nThe evidence review for the NICE guideline on adult hearing loss highlighted significant health benefits for people whose hearing loss is identified and addressed at an early stage, yet people often delay seeking treatment for up to 10\xa0years. There are certain groups who are particularly disadvantaged because their health issues lead to a lack of awareness of their deteriorating or suboptimal hearing, or a failure to report their difficulties. These include people with learning disabilities, dementia and mild cognitive impairment.\n\nGiven the importance of early detection, this research is urgently needed to identify populations who are under-represented and any factors that would lead health and social care professionals to consider the possibility of hearing loss.\n\n# Monitoring and follow-up for adults with hearing loss\n\nWhat is the clinical and cost effectiveness of monitoring and follow‑up for adults with hearing loss post-intervention compared with usual care?\n\n## Why this is important\n\nThe evidence review for the NICE guideline on hearing loss found a lack of evidence to establish the benefits of monitoring and follow‑up, how they should be delivered and across what time periods. Robust evidence is needed to establish the clinical and cost effectiveness of monitoring and follow‑up, and to understand how and when they might best be used in clinical practice. This will inform future guidelines and policy."}
|
https://www.nice.org.uk/guidance/ng98
|
This guideline covers some aspects of assessing and managing hearing loss in primary, community and secondary care. It aims to improve the quality of life for adults with hearing loss by advising healthcare staff on assessing hearing difficulties, managing earwax and referring people for audiological or specialist assessment and management.
|
1a7dcec25ed0ff9b6b4d612baaa8f8c4ba8188ff
|
nice
|
Dementia: assessment, management and support for people living with dementia and their carers
|
Dementia: assessment, management and support for people living with dementia and their carers
This guideline covers diagnosing and managing dementia (including Alzheimer’s disease). It aims to improve care by making recommendations on training staff and helping carers to support people living with dementia.
# About this guideline
Dementia is a term used to describe a range of cognitive and behavioural symptoms that can include memory loss, problems with reasoning and communication and change in personality, and a reduction in a person's ability to carry out daily activities, such as shopping, washing, dressing and cooking. The most common types of dementia are: Alzheimer's disease, vascular dementia, mixed dementia, dementia with Lewy bodies and frontotemporal dementia. Dementia is a progressive condition, which means that the symptoms will gradually get worse. This progression will vary from person to person and each will experience dementia in a different way – people may often have some of the same general symptoms, but the degree to which these affect each person will vary (Dementia Gateway, Social Care Institute for Excellence).
A report published by the Alzheimer's Society found that in 2013 there were approximately 815,000 people living with dementia in the UK. If current trends continue, this number is expected to increase to 1,143,000 by 2025. In England, the National Dementia and Antipsychotic Prescribing Audit found that approximately 31,000 people were newly diagnosed with dementia in 2011. This is an increase of 8% between 2006 and 2011. Finally, in December 2017, there were 456,739 people on GP registers with a formal diagnosis of dementia, up from approximately 290,000 people in 2009/10, with the majority of this difference accounted for by an increase in diagnosis rates.
The Alzheimer's Society report found that in 2013 the total cost of dementia in the UK was estimated to be £26.3 billion. Of this, approximately £4.3 billion consists of health care, and approximately £10.3 billion consists of social care. The remaining £11.6 billion accounts for estimated unpaid care contributions.
# Why is it needed?
Providing care and support is very complex, because of the number of people living with dementia and the variation in the symptoms each person faces. This has led to considerable variation in practice. Areas that pose particular challenges for services and practitioners may include:
coordinating care and support between different services
what support carers need, and how this should be provided
staff training.
This guideline makes evidence-based recommendations aiming to support these areas of practice.
Dementia also has significant costs for health and social care services. Because of this, it is important to ensure that people living with dementia can get the care and support they need, and that services provide this in an efficient and cost-effective way.
In addition, new methods for diagnosing and assessing dementia have been developed. Amyloid imaging techniques have been licensed for use in the UK, and new evidence is available for cerebrospinal fluid examination. There is also evidence on different approaches to assess and diagnose dementia subtypes. The guideline makes new recommendations on dementia diagnosis, based on a review of the latest evidence.
# What does it cover?
This guideline addresses how dementia should be assessed and diagnosed. It covers person-centred care and support, tailored to the specific needs of each person living with dementia. As part of this, it can help professionals involve people living with dementia and their carers in decision-making, so they can get the care and support they need. It also addresses care coordination and staff training, and how dementia may impact on the care offered for other conditions.
The guideline does not cover every aspect of dementia care or support, or areas where recommendations would be the same for people with or without dementia. It focuses on areas where:
there is variation in practice, and enough evidence is available to identify what works best
people living with dementia need different care and support to people in the same situation who do not have dementia.
# How has it been developed?
This guideline has been developed by a multidisciplinary guideline committee, using an extensive review of research evidence. To ensure that the committee had the necessary social care expertise, a subgroup of social care practitioners was recruited to develop recommendations in this area.
Given the costs of dementia and the financial pressures facing health and social care services, the committee focused on making recommendations in areas where there is good evidence available. This will help services make the most of limited resources. For areas with a lack of evidence, the committee has made recommendations for future research (on health and social care topics) to address gaps in the evidence base. Future updates of the guideline will look at any relevant new research that has been published.
Some recommendations are made with more certainty than others. We word our recommendations to reflect this. In the sections on interventions we use 'offer' to reflect a strong recommendation, usually where there is clear evidence of benefit. We use 'consider' to reflect a recommendation for which the evidence of benefit is less certain. For more information see making decisions using NICE guidelines.
# How does it relate to statutory and non-statutory guidance?
The guideline complements existing legislation and guidance. It describes how services and professionals can provide high-quality care and support.
The Prime Minister's Challenge on Dementia 2020 sets out the UK Government's strategy for transforming dementia care within the UK. The aims of the strategy include:
improving diagnosis, assessment and care for people living with dementia
ensuring that all people living with dementia have equal access to diagnosis
providing all NHS staff with training on dementia appropriate to their role
ensuring that every person diagnosed with dementia receives meaningful care.
Since the 2006 NICE guideline on dementia was developed, key new legislation has been implemented. The Care Act 2014 created a new legislative framework for adult social care, and also gives carers a legal right to assessment and support.
## Relevant legislation and statutory guidance
NHS England (2015) Accessible Information Standard
Care Act 2014
Health and Social Care Act 2008 (Regulated Activities) Regulations 2014
Department of Health (2014) Care Act 2014: Statutory Guidance for Implementation
Department of Health (2014) Positive and Proactive Care: Reducing the need for restrictive interventions
Health and Social Care Act 2012
Equality Act 2010
Mental Capacity Act 2005
Human Rights Act 1998
## Relevant policies and non-statutory guidance
Information Commissioner's Office (2017) Guide to the General Data Protection Regulation
NHS England (2017) Dementia: Good Care Planning
NHS England (2015) Implementation guide and resource pack for dementia care
Skills for Health, Health Education England and Skills for Care (2015) Dementia Core Skills Education and Training Framework. This framework was commissioned and funded by the Department of Health and developed in collaboration by Skills for Health and Health Education England in partnership with Skills for Care
Department of Health (2014) NHS Outcomes Framework 2015 to 2016
Department of Health (2014) Adult Social Care Outcomes Framework 2015 to 2016# Person-centred care
This guideline offers best‑practice advice on care and support for people living with dementia and their families and carers. The principles of person‑centred care underpin good practice in dementia care, and they are reflected in the recommendations. These principles assert:
the human value of people living with dementia (regardless of age or cognitive impairment) and their families and carers
the individuality of people living with dementia, and how their personality and life experiences influence their response to dementia
the importance of the person's perspective
the importance of relationships and interactions with others to the person living with dementia, and their potential for promoting wellbeing.
Finally, the principles emphasise the importance of taking account of the needs of carers (whether they are family and friends or paid care‑workers), and supporting and enhancing their input.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
NICE has also produced:
a guideline on decision making and mental capacity, which provides further details on how practitioners can support decision-making for people who may lack capacity now or in the future
patient decision aids on antipsychotic medicines for treating agitation, aggression and distress in people living with dementia and enteral (tube) feeding for people living with severe dementia.
# Involving people living with dementia in decisions about their care
## Involving people in decision-making
Encourage and enable people living with dementia to give their own views and opinions about their care.
If needed, use additional or modified ways of communicating (for example visual aids or simplified text).
Consider using a structured tool to assess the likes and dislikes, routines and personal history of a person living with dementia.
## Providing information
Provide people living with dementia and their family members or carers (as appropriate) with information that is relevant to their circumstances and the stage of their condition.
Be aware of the obligation to provide accessible information as detailed in the NHS Accessible Information Standard. For more guidance on providing information and discussing people's preferences with them, see the NICE guidelines on patient experience in adult NHS services and people's experience in adult social care services.
At diagnosis, offer the person and their family members or carers (as appropriate) oral and written information that explains:
what their dementia subtype is and the changes to expect as the condition progresses
which healthcare professionals and social care teams will be involved in their care and how to contact them
if appropriate, how dementia affects driving, and that they need to tell the Driver and Vehicle Licensing Agency (DVLA) and their car insurer about their dementia diagnosis
their legal rights and responsibilities
their right to reasonable adjustments (in line with the Equality Act 2010) if they are working or looking for work
how the following groups can help and how to contact them:
local support groups, online forums and national charities
financial and legal advice services
advocacy services.
If it has not been documented earlier, ask the person at diagnosis:
for their consent for services to share information
which people they would like services to share information with (for example family members or carers)
what information they would like services to share. Document these decisions in the person's records.
After diagnosis, direct people and their family members or carers (as appropriate) to relevant services for information and support (see recommendations 1.3.1 and 1.3.2 on care coordination).
For people who do not want follow-up appointments and who are not using other services, ask if they would like to be contacted again at a specified future date.
Ensure that people living with dementia and their carers know how to get more information and who from if their needs change.
Tell people living with dementia (at all stages of the condition) about research studies they could participate in.
## Advance care planning
Offer early and ongoing opportunities for people living with dementia and people involved in their care (see recommendation 1.1.7) to discuss:
the benefits of planning ahead
lasting power of attorney (for health and welfare decisions and property and financial affairs decisions)
an advance statement about their wishes, preferences, beliefs and values regarding their future care
advance decisions to refuse treatment
their preferences for place of care and place of death.Explain that they will be given chances to review and change any advance statements and decisions they have made.
At each care review, offer people the chance to review and change any advance statements and decisions they have made.
# Diagnosis
## Initial assessment in non-specialist settings
At the initial assessment take a history (including cognitive, behavioural and psychological symptoms, and the impact symptoms have on their daily life):
from the person with suspected dementia and
if possible, from someone who knows the person well (such as a family member).
If dementia is still suspected after initial assessment:
conduct a physical examination and
undertake appropriate blood and urine tests to exclude reversible causes of cognitive decline and
use cognitive testing.
When using cognitive testing, use a validated brief structured cognitive instrument such as:
the 10-point cognitive screener (10-CS)
the 6-item cognitive impairment test (6CIT)
the 6-item screener
the Memory Impairment Screen (MIS)
the Mini-Cog
Test Your Memory (TYM).
Do not rule out dementia solely because the person has a normal score on a cognitive instrument.
When taking a history from someone who knows the person with suspected dementia, consider supplementing this with a structured instrument such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) or the Functional Activities Questionnaire (FAQ).
Refer the person to a specialist dementia diagnostic service (such as a memory clinic or community old age psychiatry service) if:
reversible causes of cognitive decline (including delirium, depression, sensory impairment or cognitive impairment from medicines associated with increased anticholinergic burden) have been investigated and
dementia is still suspected.
If the person has suspected rapidly-progressive dementia, refer them to a neurological service with access to tests (including cerebrospinal fluid examination) for Creutzfeldt–Jakob disease and similar conditions.
For more guidance on assessing for dementia in people with learning disabilities, see the NICE guideline on mental health problems in people with learning disabilities.
## Diagnosis in specialist dementia diagnostic services
Diagnose a dementia subtype (if possible) if initial specialist assessment (including an appropriate neurological examination and cognitive testing) confirms cognitive decline and reversible causes have been ruled out.
If Alzheimer's disease is suspected, include a test of verbal episodic memory in the assessment.
Consider neuropsychological testing if it is unclear:
whether the person has cognitive impairment or
whether their cognitive impairment is caused by dementia or
what the correct subtype diagnosis is.
Use validated criteria to guide clinical judgement when diagnosing dementia subtypes, such as:
International consensus criteria for dementia with Lewy bodies
International FTD criteria for frontotemporal dementia (progressive non-fluent aphasia and semantic dementia)
International Frontotemporal Dementia Consortium criteria for behavioural variant frontotemporal dementia
NINDS-AIREN criteria (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences) for vascular dementia
NIA criteria (National Institute on Aging) for Alzheimer's disease
Movement disorders Society criteria for Parkinson's disease dementia
International criteria for Creutzfeldt-Jakob disease.
Offer structural imaging to rule out reversible causes of cognitive decline and to assist with subtype diagnosis, unless dementia is well established and the subtype is clear.
Only consider further tests (recommendations 1.2.15–28) if:
it would help to diagnose a dementia subtype and
knowing more about the dementia subtype would change management.
If the diagnosis is uncertain (see recommendation 1.2.14) and Alzheimer's disease is suspected, consider either:
FDG-PET (fluorodeoxyglucose-positron emission tomography-CT), or perfusion SPECT (single‑photon emission CT) if FDG-PET is unavailableor
examining cerebrospinal fluid for:
either total tau or total tau and phosphorylated-tau 181 and
either amyloid beta 1–42 or amyloid beta 1–42 and amyloid beta 1–40.
If a diagnosis cannot be made after one of these tests, consider using the other one.
Be aware that the older a person is, the more likely they are to get a false positive with cerebrospinal fluid examination.
Do not rule out Alzheimer's disease based solely on the results of CT or MRI scans.
Do not use Apolipoprotein E genotyping or electroencephalography to diagnose Alzheimer's disease.
Be aware that young-onset Alzheimer's disease has a genetic cause in some people.
If the diagnosis is uncertain (see recommendation 1.2.14) and dementia with Lewy bodies is suspected, use 123I‑FP‑CIT SPECT.
If 123I‑FP‑CIT SPECT is unavailable, consider 123I‑MIBG cardiac scintigraphy.
Do not rule out dementia with Lewy bodies based solely on normal results on 123I‑FP‑CIT SPECT or 123I‑MIBG cardiac scintigraphy.
If the diagnosis is uncertain (see recommendation 1.2.14) and frontotemporal dementia is suspected, use either:
FDG-PET or
perfusion SPECT.
Do not rule out frontotemporal dementia based solely on the results of structural, perfusion or metabolic imaging tests.
Be aware that frontotemporal dementia has a genetic cause in some people.
If the dementia subtype is uncertain and vascular dementia is suspected, use MRI. If MRI is unavailable or contraindicated, use CT.
Do not diagnose vascular dementia based solely on vascular lesion burden.
Be aware that young-onset vascular dementia has a genetic cause in some people.
## Case finding
Only conduct case finding for suspected dementia as part of a clinical trial that also provides an intervention to people diagnosed with dementia.
## Telling the difference between delirium and dementia in people without a diagnosis of either
For people who are in hospital and have cognitive impairment with an unknown cause, consider using one of the following to find out whether they have delirium or delirium superimposed on dementia, compared with dementia alone:
the long confusion assessment method (CAM)
the Observational Scale of Level of Arousal (OSLA).
Do not use standardised instruments (including cognitive instruments) alone to distinguish delirium from delirium superimposed on dementia.
If it is not possible to tell whether a person has delirium, dementia, or delirium superimposed on dementia, treat for delirium first. For guidance on treating delirium, see treating delirium in the NICE guideline on delirium.
## Review after diagnosis
After a person is diagnosed with dementia, ensure they and their family members or carers (as appropriate) have access to a memory service or equivalent hospital- or primary-care-based multidisciplinary dementia service.
Memory services and equivalent hospital- and primary-care-based multidisciplinary dementia services should offer a choice of flexible access or prescheduled monitoring appointments.
When people living with dementia or their carers have a primary care appointment, assess for any emerging dementia-related needs and ask them if they need any more support.
# Care coordination
Provide people living with dementia with a single named health or social care professional who is responsible for coordinating their care.
Named professionals should:
arrange an initial assessment of the person's needs, which should be face to face if possible
provide information about available services and how to access them
involve the person's family members or carers (as appropriate) in support and decision-making
give special consideration to the views of people who do not have capacity to make decisions about their care, in line with the principles of the Mental Capacity Act 2005
ensure that people are aware of their rights to and the availability of local advocacy services, and if appropriate to the immediate situation an independent mental capacity advocate
develop a care and support plan, and:
agree and review it with the involvement of the person, their family members or carers (as appropriate) and relevant professionals
specify in the plan when and how often it will be reviewed
evaluate and record progress towards the objectives at each review
ensure it covers the management of any comorbidities
provide a copy of the plan to the person and their family members or carers (as appropriate).
## Transferring information between services and care settings
When developing care and support plans and advance care and support plans, request consent to transfer these to different care settings as needed.
Service providers should ensure that information (such as care and support plans and advance care and support plans) can be easily transferred between different care settings (for example home, inpatient, community and residential care).
Staff delivering care and support should maximise continuity and consistency of care. Ensure that relevant information is shared and recorded in the person's care and support plan.
## Making services accessible
Service providers should design services to be accessible to as many people living with dementia as possible, including:
people who do not have a carer or whose carer cannot support them on their own
people who do not have access to affordable transport, or find transport difficult to use
people who have other responsibilities (such as work, children or being a carer themselves)
people with learning disabilities, sensory impairment (such as sight or hearing loss) or physical disabilities
people who may be less likely to access health and social care services, such as people from black, Asian and minority ethnic groups.
# Interventions to promote cognition, independence and wellbeing
Offer a range of activities to promote wellbeing that are tailored to the person's preferences.
Offer group cognitive stimulation therapy to people living with mild to moderate dementia.
Consider group reminiscence therapy for people living with mild to moderate dementia.
Consider cognitive rehabilitation or occupational therapy to support functional ability in people living with mild to moderate dementia.
Do not offer acupuncture to treat dementia.
Do not offer ginseng, vitamin E supplements, or herbal formulations to treat dementia.
Do not offer cognitive training to treat mild to moderate Alzheimer's disease.
Do not offer interpersonal therapy to treat the cognitive symptoms of mild to moderate Alzheimer's disease.
Do not offer non-invasive brain stimulation (including transcranial magnetic stimulation) to treat mild to moderate Alzheimer's disease, except as part of a randomised controlled trial.
# Pharmacological interventions for dementia
## Managing medicines for all dementia subtypes
For guidance on managing medicines (including covert administration), see the NICE guidelines on managing medicines for adults receiving social care in the community and managing medicines in care homes.
## Pharmacological management of Alzheimer's disease
The three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer's disease under all of the conditions specified in 1.5.5 and 1.5.6.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.
Memantine monotherapy is recommended as an option for managing Alzheimer's disease for people with:
moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or
severe Alzheimer's disease.Treatment should be under the conditions specified in 1.5.5.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.
For people with an established diagnosis of Alzheimer's disease who are already taking an AChE inhibitor:
consider memantine in addition to an AChE inhibitor if they have moderate disease
-ffer memantine in addition to an AChE inhibitor if they have severe disease.
Treatment should be under the following conditions:
For people who are not taking an AChE inhibitor or memantine, prescribers should only start treatment with these on the advice of a clinician who has the necessary knowledge and skills. This could include:
secondary care medical specialists such as psychiatrists, geriatricians and neurologists
-ther healthcare professionals (such as GPs, nurse consultants and advanced nurse practitioners), if they have specialist expertise in diagnosing and treating Alzheimer's disease.
Once a decision has been made to start an AChE inhibitor or memantine, the first prescription may be made in primary care.
For people with an established diagnosis of Alzheimer's disease who are already taking an AChE inhibitor, primary care prescribers may start treatment with memantine (see recommendation 1.5.4) without taking advice from a specialist clinician.
Ensure that local arrangements for prescribing, supply and treatment review follow the NICE guideline on medicines optimisation.
Do not stop AChE inhibitors in people with Alzheimer's disease because of disease severity alone.
If prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.
When using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results and make any adjustments they consider appropriate. Healthcare professionals should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.
When assessing the severity of Alzheimer's disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so. These include:
if the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient's dementia because of the patient's learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or
if it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or
if there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia.In such cases healthcare professionals should determine the need for initiation or continuation of treatment by using another appropriate method of assessment.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.
Do not offer the following specifically to slow the progress of Alzheimer's disease, except as part of a randomised controlled trial:
diabetes medicines
hypertension medicines
statins
non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.
## Pharmacological management of non-Alzheimer's dementia
June 2018 – the use of the medicines in recommendations 1.5.10 to 1.5.14 was off label. See NICE's information on prescribing medicines.
Offer donepezil or rivastigmine to people with mild to moderate dementia with Lewy bodies.
Only consider galantamine for people with mild to moderate dementia with Lewy bodies if donepezil and rivastigmine are not tolerated.
Consider donepezil or rivastigmine for people with severe dementia with Lewy bodies.
Consider memantine for people with dementia with Lewy bodies if AChE inhibitors are not tolerated or are contraindicated.
Only consider AChE inhibitors or memantine for people with vascular dementia if they have suspected comorbid Alzheimer's disease, Parkinson's disease dementia or dementia with Lewy bodies.
Do not offer AChE inhibitors or memantine to people with frontotemporal dementia. Note that logopenic aphasia, which has previously been included in some diagnostic guidelines for frontotemporal dementia, has now been shown to most commonly be caused by Alzheimer's disease
Do not offer AChE inhibitors or memantine to people with cognitive impairment caused by multiple sclerosis.
For guidance on pharmacological management of Parkinson's disease dementia, see Parkinson's disease dementia in the NICE guideline on Parkinson's disease.
# Medicines that may cause cognitive impairment
Be aware that some commonly prescribed medicines are associated with increased anticholinergic burden, and therefore cognitive impairment.
Consider minimising the use of medicines associated with increased anticholinergic burden, and if possible look for alternatives:
when assessing whether to refer a person with suspected dementia for diagnosis
during medication reviews with people living with dementia.
Be aware that there are validated tools for assessing anticholinergic burden (for example, the Anticholinergic Cognitive Burden Scale), but there is insufficient evidence to recommend one over the others.
For guidance on carrying out medication reviews, see medication review in the NICE guideline on medicines optimisation.
# Managing non-cognitive symptoms
## Agitation, aggression, distress and psychosis
Before starting non-pharmacological or pharmacological treatment for distress in people living with dementia, conduct a structured assessment to:
explore possible reasons for their distress and
check for and address clinical or environmental causes (for example pain, delirium or inappropriate care).
As initial and ongoing management, offer psychosocial and environmental interventions to reduce distress in people living with dementia.
Only offer antipsychotics for people living with dementia who are either:
at risk of harming themselves or others or
experiencing agitation, hallucinations or delusions that are causing them severe distress.Follow the 2012 MHRA advice for health and social care professionals on prescribing antipsychotics to people living with dementia.June 2018 – note that this is an off-label use for almost all antipsychotics (see prescribing risperidone and haloperidol). See NICE's information on prescribing medicines.
Be aware that for people with dementia with Lewy bodies or Parkinson's disease dementia, antipsychotics can worsen the motor features of the condition, and in some cases cause severe antipsychotic sensitivity reactions. For more guidance, see the advice on managing delusions and hallucinations in the NICE guideline on Parkinson's disease. Be aware that interventions may need to be modified for people living with dementia.
Before starting antipsychotics, discuss the benefits and harms with the person and their family members or carers (as appropriate). Consider using a decision aid to support this discussion. NICE has produced a patient decision aid on antipsychotic medicines for treating agitation, aggression and distress in people living with dementia.
When using antipsychotics:
use the lowest effective dose and use them for the shortest possible time
reassess the person at least every 6 weeks, to check whether they still need medication.
Stop treatment with antipsychotics:
if the person is not getting a clear ongoing benefit from taking them and
after discussion with the person taking them and their family members or carers (as appropriate).
Ensure that people living with dementia can continue to access psychosocial and environmental interventions for distress while they are taking antipsychotics and after they have stopped taking them.
For people living with dementia who experience agitation or aggression, offer personalised activities to promote engagement, pleasure and interest.
Do not offer valproate to manage agitation or aggression in people living with dementia, unless it is indicated for another condition. If relevant, follow MHRA advice that valproate medicines are contraindicated in women and girls of childbearing potential unless a Pregnancy Prevention Programme is in place.
## Depression and anxiety
For people living with mild to moderate dementia who have mild to moderate depression and/or anxiety, consider psychological treatments.
Do not routinely offer antidepressants to manage mild to moderate depression in people living with mild to moderate dementia, unless they are indicated for a pre-existing severe mental health problem.
## Sleep problems
Do not offer melatonin to manage insomnia in people living with Alzheimer's disease.
For people living with dementia who have sleep problems, consider a personalised multicomponent sleep management approach that includes sleep hygiene education, exposure to daylight, exercise and personalised activities.
## Parkinson's disease
For guidance on managing Parkinson's disease symptoms in people with Parkinson's disease dementia or dementia with Lewy bodies, see the NICE guideline on Parkinson's disease. Be aware that interventions may need to be modified for people living with dementia.
# Assessing and managing other long-term conditions in people living with dementia
Ensure that people living with dementia have equivalent access to diagnosis, treatment and care services for comorbidities to people who do not have dementia. For more guidance on assessing and managing multimorbidity, see the NICE guidelines on multimorbidity and older people with social care needs and multiple long-term conditions.
For more guidance on providing support for older adults with learning disabilities, see the NICE guideline on care and support of people growing older with learning disabilities.
## Pain
Consider using a structured observational pain assessment tool:
alongside self-reported pain and standard clinical assessment for people living with moderate to severe dementia
alongside standard clinical assessment for people living with dementia who are unable to self-report pain.
For people living with dementia who are in pain, consider using a stepwise treatment protocol that balances pain management and potential adverse events.
Repeat pain assessments for people living with dementia:
who seem to be in pain
who show signs of behavioural changes that may be caused by pain
after any pain management intervention.
## Falls
For guidance on managing the risk of falling for people living with dementia (in community and inpatient settings), see the NICE guideline on falls in older people. When using this guideline:
take account of the additional support people living with dementia may need to participate effectively
be aware that multifactorial falls interventions may not be suitable for a person living with severe dementia.
## Diabetes
For guidance on setting HbA1c targets for people living with severe dementia who have type 2 diabetes, see recommendation 1.6.9 in the NICE guideline on type 2 diabetes in adults.
## Incontinence
For guidance on pharmacological treatment of overactive bladder, see the NICE technology appraisal on mirabegron for treating symptoms of overactive bladder.
For guidance on treating faecal incontinence, see recommendations 1.7.2 and 1.7.8 in the NICE guideline on faecal incontinence.
## Sensory impairment
For guidance on hearing assessments for people with suspected or diagnosed dementia, see adults with suspected dementia in the NICE guideline on hearing loss.
Encourage people living with dementia to have eye tests every 2 years. Consider referring people who cannot organise appointments themselves.
# Risks during hospital admission
Be aware of the increased risk of delirium in people living with dementia who are admitted to hospital. See the NICE guideline on delirium for interventions to prevent and treat delirium.
When thinking about admission to hospital for a person living with severe dementia, carry out an assessment that balances their current medical needs with the additional harms they may face in hospital, for example:
disorientation
a longer length of stay
increased mortality
increased morbidity on discharge
delirium
the effects of being in an impersonal or institutional environment.
When thinking about admission to hospital for a person living with dementia, take into account:
any advance care and support plans
the value of keeping them in a familiar environment.
# Palliative care
From diagnosis, offer people living with dementia flexible, needs-based palliative care that takes into account how unpredictable dementia progression can be.
For people living with dementia who are approaching the end of life, use an anticipatory healthcare planning process (see recommendation 1.1.12 on advance care planning). Involve the person and their family members or carers (as appropriate) as far as possible, and use the principles of best-interest decision-making if the person does not have capacity to make decisions about their care.
For standards and measures on palliative care, see the NICE quality standard on end of life care for adults.
For guidance on care for people in the last days of life, see the NICE guideline on care of dying adults.
For guidance on best interests decision-making, see the NICE guideline on decision-making and mental capacity.
Encourage and support people living with dementia to eat and drink, taking into account their nutritional needs.
Consider involving a speech and language therapist if there are concerns about a person's safety when eating and drinking.
Do not routinely use enteral feeding in people living with severe dementia, unless indicated for a potentially reversible comorbidity. NICE has produced a patient decision aid on enteral (tube) feeding for people living with severe dementia.
# Supporting carers
Offer carers of people living with dementia a psychoeducation and skills training intervention that includes:
education about dementia, its symptoms and the changes to expect as the condition progresses
developing personalised strategies and building carer skills
training to help them provide care, including how to understand and respond to changes in behaviour
training to help them adapt their communication styles to improve interactions with the person living with dementia
advice on how to look after their own physical and mental health, and their emotional and spiritual wellbeing
advice on planning enjoyable and meaningful activities to do with the person they care for
information about relevant services (including support services and psychological therapies for carers) and how to access them
advice on planning for the future.
Ensure that the support provided to carers is:
tailored to their needs and preferences and to what they want it to achieve (for example, providing information on carer's employment rights for carers who work or want to work)
designed to help them support people living with dementia
available at a location they can get to easily
provided in a format suitable for them (for example individual or group sessions, or online training and support)
available from diagnosis and as needed after this.
Be aware that carer interventions are likely to be most effective when provided as group sessions.
Advise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).
Be aware that carers of people living with dementia are at an increased risk of depression. For guidance on identifying and managing depression, see the NICE guideline on depression in adults.
# Moving to different care settings
For guidance on managing transition between care settings for people living with dementia, see:
the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs
the NICE guideline on transition between inpatient mental health settings and community or care home settings
section 1.2 of the NICE guideline on medicines optimisation.Follow the principles in these guidelines for transitions between other settings (for example from home to a care home or respite care).
Review the person's needs and wishes (including any care and support plans and advance care and support plans) after every transition.
# Staff training and education
Care and support providers should provide all staff with training in person-centred and outcome-focused care for people living with dementia, which should include:
understanding the signs and symptoms of dementia, and the changes to expect as the condition progresses
understanding the person as an individual, and their life story
respecting the person's individual identity, sexuality and culture
understanding the needs of the person and their family members or carers
the principles of the Mental Capacity Act 2005 and the Care Act 2014.
Care providers should provide additional face-to-face training and mentoring to staff who deliver care and support to people living with dementia. This should include:
understanding the organisation's model of dementia care and how it provides care
how to monitor and respond to the lived experience of people living with dementia, including adapting communication styles
initial training on understanding, reacting to and helping people living with dementia who experience agitation, aggression, pain, or other behaviours indicating distress
follow-up sessions where staff can receive additional feedback and discuss particular situations
advice on interventions that reduce the need for antipsychotics and allow doses to be safely reduced
promoting freedom of movement and minimising the use of restraint
if relevant to staff, the specific needs of younger people living with dementia and people who are working or looking for work.
Consider giving carers and/or family members the opportunity to attend and take part in staff dementia training sessions.
Consider training staff to provide multi-sensory stimulation for people with moderate to severe dementia and communication difficulties.
Ensure that all health and social care staff are aware of:
the extent of their responsibility to protect confidentiality under data protection legislation and
any rights that family members, carers and others have to information about the person's care (see recommendation 1.3.5 on information sharing between different care settings).
Health and social care professionals advising people living with dementia (including professionals involved in diagnosis) should be trained in starting and holding difficult and emotionally challenging conversations.
# Terms used in this guideline
## Case finding
A strategy of actively assessing people who are at risk for a particular disease, before they present with symptoms and before there is clinical suspicion of the condition. It does not refer to situations such as assessing people for dementia after an acute episode of delirium, where clinical suspicion of dementia is likely to already be raised.
## Cognitive rehabilitation
Identifying functional goals that are relevant to the person living with dementia, and working with them and their family members or carers to achieve these. The emphasis is on improving or maintaining functioning in everyday life, building on the person's strengths and finding ways to compensate for impairments, and supporting independence. Cognitive rehabilitation does not aim to improve cognition, but addresses the disability resulting from the impact of cognitive impairment on everyday functioning and activity. Rehabilitation is sometimes referred to as 'reablement'.
## Cognitive stimulation
Engaging in a range of activities and discussions (usually in a group) that are aimed at general improvement of cognitive and social functioning.
## Cognitive training
Guided practice on a set of standard tasks that are designed to reflect particular cognitive functions. There may be a range of difficulty levels, to fit the tasks to each person's level of ability.
## Interpersonal therapy
Brief structured attachment-focused therapies for people with mild to moderate depression. These therapies are based on the idea that difficulties interacting with other people can cause psychological symptoms such as depressed mood, which then make the difficulties with interaction worse, causing a cycle. Interpersonal therapies aim to help people interact more effectively with others, and through this improve the psychological symptoms. Therapy typically focuses on relationship issues such as conflict, difficulty starting or maintaining relationships, grief and loss, and life changes.
## Prescribing risperidone and haloperidol
The marketing authorisation for risperidone only covers short-term treatment (up to 6 weeks) of persistent aggression in people with moderate to severe Alzheimer's disease unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others. The marketing authorisation for haloperidol only covers treatment of persistent aggression and psychotic symptoms in people with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others.
## Refer
A referral to a diagnostic service does not have to involve a clinic appointment. People can be seen in community settings (such as their home or a care home), or advice can be provided to the referrer without a formal appointment being made. The key issue is to ensure that dementia specialists are involved, both for advice on diagnosis and to ensure appropriate access to post-diagnostic support and treatment. Specialists are those with the appropriate knowledge and skills and include secondary care medical specialists (for example psychiatrists, geriatricians and neurologists) and other healthcare professionals (for example GPs, nurse consultants and advanced nurse practitioners) with specialist expertise in assessing and diagnosing dementia.
## Social care terms
For social care terms see the Think Local, Act Personal Care and Support Jargon Buster.
## Specialist clinician
Specialist clinicians (for the purpose of starting and monitoring treatment with cholinesterase inhibitors and memantine) are those with the appropriate knowledge and skills and include secondary care medical specialists (for example psychiatrists, geriatricians and neurologists) and other healthcare professionals (for example GPs, nurse consultants and advanced nurse practitioners) with specialist expertise in diagnosing and treating Alzheimer's disease.
## Verbal episodic memory
Episodic memories include information about recent or past events and experiences (rather than factual knowledge, or habits and skills). They may be recent, or from the distant past (remote or long-term episodic memory). Tests to assess episodic memory may use either verbal or visual material. Examples of verbal episodic memory tests include reading the person a list of words or a short story and asking them to recall this information, both immediately and after a delay.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Case management
What is the effectiveness and cost effectiveness of high-intensity case management compared with usual care on quality of life (for the person living with dementia and for their carers) and the timing of entry to long-term care?
## Why this is important
There is evidence that case management is an effective intervention for people living with dementia. However, the effectiveness and cost effectiveness of high-intensity case management has not been tested in the UK. It has a high upfront cost, but there is some evidence from settings outside the UK that it may reduce the use of other services, leading to cost savings across the whole system. Because of the cost, robust evidence of effectiveness and cost effectiveness from a UK setting is needed.
# Staff training
What is the cost effectiveness of using a dementia-specific addition to the Care Certificate for community staff, including dementia-specific elements on managing anxiety, communication, nutritional status and personal care?
## Why this is important
Robust evidence demonstrates the effectiveness of intensive training for staff heavily involved in providing care and support for people living with dementia. However, it is not clear if it is effective to provide basic training to all staff who come into contact with people living with dementia, or how this training should be provided. One possibility is an expanded version of the Care Certificate that includes additional dementia-specific elements. Because this training would need to be given to a large number of staff, there needs to be good evidence of benefits, specifically in improving quality of life for people living with dementia and their carers, to justify the upfront costs.
# Anticholinergic burden
Does actively reducing anticholinergic burden in people living with dementia improve cognitive outcomes compared with usual care?
## Why this is important
Many people living with dementia are still prescribed medicines with a high anticholinergic burden (which can be caused by individual medicines or by combinations of medicines). It is often unclear if this prescribing is appropriate, or whether actively reducing the number of these medicines would improve cognition. Randomised controlled trials could be conducted, using structured tools to assess anticholinergic burden and actively switching medicines if possible. This would help to identify whether cognition can be improved without adversely affecting the management of the conditions these medicines are prescribed for.
# Managing delirium superimposed on dementia
What are the most clinically and cost-effective non-pharmacological interventions for helping the long-term recovery of people with delirium superimposed on dementia?
## Why this is important
The acute management of delirium superimposed on dementia is likely to be similar to the management of delirium in people without dementia. However, there may be differences in the interventions needed to aid long-term recovery, particularly because people with different severities of dementia will have different baseline cognitive status. Research on the most effective non-pharmacological methods of promoting long-term recovery would help to identify whether alternative approaches are needed for people living with dementia.
# Care and support planning
What are the most effective methods of care planning for people who do not have regular contact with an informal carer?
## Why this is important
Many randomised controlled trials of care planning or case management specifically exclude people without an informal carer. Conducting similar studies on case management and care planning for people without an informal carer would fill this gap in the evidence base, and help to identify whether these people have different needs.
|
{'About this guideline': "Dementia is a term used to describe a range of cognitive and behavioural symptoms that can include memory loss, problems with reasoning and communication and change in personality, and a reduction in a person's ability to carry out daily activities, such as shopping, washing, dressing and cooking. The most common types of dementia are: Alzheimer's disease, vascular dementia, mixed dementia, dementia with Lewy bodies and frontotemporal dementia. Dementia is a progressive condition, which means that the symptoms will gradually get worse. This progression will vary from person to person and each will experience dementia in a different way – people may often have some of the same general symptoms, but the degree to which these affect each person will vary (Dementia Gateway, Social Care Institute for Excellence).\n\nA report published by the Alzheimer's Society found that in 2013 there were approximately 815,000 people living with dementia in the UK. If current trends continue, this number is expected to increase to 1,143,000 by 2025. In England, the National Dementia and Antipsychotic Prescribing Audit found that approximately 31,000 people were newly diagnosed with dementia in 2011. This is an increase of 8% between 2006 and 2011. Finally, in December 2017, there were 456,739 people on GP registers with a formal diagnosis of dementia, up from approximately 290,000 people in 2009/10, with the majority of this difference accounted for by an increase in diagnosis rates.\n\nThe Alzheimer's Society report found that in 2013 the total cost of dementia in the UK was estimated to be £26.3 billion. Of this, approximately £4.3 billion consists of health care, and approximately £10.3 billion consists of social care. The remaining £11.6 billion accounts for estimated unpaid care contributions.\n\n# Why is it needed?\n\nProviding care and support is very complex, because of the number of people living with dementia and the variation in the symptoms each person faces. This has led to considerable variation in practice. Areas that pose particular challenges for services and practitioners may include:\n\ncoordinating care and support between different services\n\nwhat support carers need, and how this should be provided\n\nstaff training.\n\nThis guideline makes evidence-based recommendations aiming to support these areas of practice.\n\nDementia also has significant costs for health and social care services. Because of this, it is important to ensure that people living with dementia can get the care and support they need, and that services provide this in an efficient and cost-effective way.\n\nIn addition, new methods for diagnosing and assessing dementia have been developed. Amyloid imaging techniques have been licensed for use in the UK, and new evidence is available for cerebrospinal fluid examination. There is also evidence on different approaches to assess and diagnose dementia subtypes. The guideline makes new recommendations on dementia diagnosis, based on a review of the latest evidence.\n\n# What does it cover?\n\nThis guideline addresses how dementia should be assessed and diagnosed. It covers person-centred care and support, tailored to the specific needs of each person living with dementia. As part of this, it can help professionals involve people living with dementia and their carers in decision-making, so they can get the care and support they need. It also addresses care coordination and staff training, and how dementia may impact on the care offered for other conditions.\n\nThe guideline does not cover every aspect of dementia care or support, or areas where recommendations would be the same for people with or without dementia. It focuses on areas where:\n\nthere is variation in practice, and enough evidence is available to identify what works best\n\npeople living with dementia need different care and support to people in the same situation who do not have dementia.\n\n# How has it been developed?\n\nThis guideline has been developed by a multidisciplinary guideline committee, using an extensive review of research evidence. To ensure that the committee had the necessary social care expertise, a subgroup of social care practitioners was recruited to develop recommendations in this area.\n\nGiven the costs of dementia and the financial pressures facing health and social care services, the committee focused on making recommendations in areas where there is good evidence available. This will help services make the most of limited resources. For areas with a lack of evidence, the committee has made recommendations for future research (on health and social care topics) to address gaps in the evidence base. Future updates of the guideline will look at any relevant new research that has been published.\n\nSome recommendations are made with more certainty than others. We word our recommendations to reflect this. In the sections on interventions we use 'offer' to reflect a strong recommendation, usually where there is clear evidence of benefit. We use 'consider' to reflect a recommendation for which the evidence of benefit is less certain. For more information see making decisions using NICE guidelines.\n\n# How does it relate to statutory and non-statutory guidance?\n\nThe guideline complements existing legislation and guidance. It describes how services and professionals can provide high-quality care and support.\n\nThe Prime Minister's Challenge on Dementia 2020 sets out the UK Government's strategy for transforming dementia care within the UK. The aims of the strategy include:\n\nimproving diagnosis, assessment and care for people living with dementia\n\nensuring that all people living with dementia have equal access to diagnosis\n\nproviding all NHS staff with training on dementia appropriate to their role\n\nensuring that every person diagnosed with dementia receives meaningful care.\n\nSince the 2006 NICE guideline on dementia was developed, key new legislation has been implemented. The Care Act 2014 created a new legislative framework for adult social care, and also gives carers a legal right to assessment and support.\n\n## Relevant legislation and statutory guidance\n\nNHS England (2015) Accessible Information Standard\n\nCare Act 2014\n\nHealth and Social Care Act 2008 (Regulated Activities) Regulations 2014\n\nDepartment of Health (2014) Care Act 2014: Statutory Guidance for Implementation\n\nDepartment of Health (2014) Positive and Proactive Care: Reducing the need for restrictive interventions\n\nHealth and Social Care Act 2012\n\nEquality Act 2010\n\nMental Capacity Act 2005\n\nHuman Rights Act 1998\n\n## Relevant policies and non-statutory guidance\n\nInformation Commissioner's Office (2017) Guide to the General Data Protection Regulation\n\nNHS England (2017) Dementia: Good Care Planning\n\nNHS England (2015) Implementation guide and resource pack for dementia care\n\nSkills for Health, Health Education England and Skills for Care (2015) Dementia Core Skills Education and Training Framework. This framework was commissioned and funded by the Department of Health and developed in collaboration by Skills for Health and Health Education England in partnership with Skills for Care\n\nDepartment of Health (2014) NHS Outcomes Framework 2015 to 2016\n\nDepartment of Health (2014) Adult Social Care Outcomes Framework 2015 to 2016", 'Person-centred care': "This guideline offers best‑practice advice on care and support for people living with dementia and their families and carers. The principles of person‑centred care underpin good practice in dementia care, and they are reflected in the recommendations. These principles assert:\n\nthe human value of people living with dementia (regardless of age or cognitive impairment) and their families and carers\n\nthe individuality of people living with dementia, and how their personality and life experiences influence their response to dementia\n\nthe importance of the person's perspective\n\nthe importance of relationships and interactions with others to the person living with dementia, and their potential for promoting wellbeing.\n\nFinally, the principles emphasise the importance of taking account of the needs of carers (whether they are family and friends or paid care‑workers), and supporting and enhancing their input.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nNICE has also produced:\n\na guideline on decision making and mental capacity, which provides further details on how practitioners can support decision-making for people who may lack capacity now or in the future\n\npatient decision aids on antipsychotic medicines for treating agitation, aggression and distress in people living with dementia and enteral (tube) feeding for people living with severe dementia.\n\n# Involving people living with dementia in decisions about their care\n\n## Involving people in decision-making\n\nEncourage and enable people living with dementia to give their own views and opinions about their care.\n\nIf needed, use additional or modified ways of communicating (for example visual aids or simplified text).\n\nConsider using a structured tool to assess the likes and dislikes, routines and personal history of a person living with dementia.\n\n## Providing information\n\nProvide people living with dementia and their family members or carers (as appropriate) with information that is relevant to their circumstances and the stage of their condition.\n\nBe aware of the obligation to provide accessible information as detailed in the NHS Accessible Information Standard. For more guidance on providing information and discussing people's preferences with them, see the NICE guidelines on patient experience in adult NHS services and people's experience in adult social care services.\n\nAt diagnosis, offer the person and their family members or carers (as appropriate) oral and written information that explains:\n\nwhat their dementia subtype is and the changes to expect as the condition progresses\n\nwhich healthcare professionals and social care teams will be involved in their care and how to contact them\n\nif appropriate, how dementia affects driving, and that they need to tell the Driver and Vehicle Licensing Agency (DVLA) and their car insurer about their dementia diagnosis\n\ntheir legal rights and responsibilities\n\ntheir right to reasonable adjustments (in line with the Equality Act 2010) if they are working or looking for work\n\nhow the following groups can help and how to contact them:\n\n\n\nlocal support groups, online forums and national charities\n\nfinancial and legal advice services\n\nadvocacy services.\n\n\n\nIf it has not been documented earlier, ask the person at diagnosis:\n\nfor their consent for services to share information\n\nwhich people they would like services to share information with (for example family members or carers)\n\nwhat information they would like services to share. Document these decisions in the person's records.\n\nAfter diagnosis, direct people and their family members or carers (as appropriate) to relevant services for information and support (see recommendations 1.3.1 and 1.3.2 on care coordination).\n\nFor people who do not want follow-up appointments and who are not using other services, ask if they would like to be contacted again at a specified future date.\n\nEnsure that people living with dementia and their carers know how to get more information and who from if their needs change.\n\nTell people living with dementia (at all stages of the condition) about research studies they could participate in.\n\n## Advance care planning\n\nOffer early and ongoing opportunities for people living with dementia and people involved in their care (see recommendation 1.1.7) to discuss:\n\nthe benefits of planning ahead\n\nlasting power of attorney (for health and welfare decisions and property and financial affairs decisions)\n\nan advance statement about their wishes, preferences, beliefs and values regarding their future care\n\nadvance decisions to refuse treatment\n\ntheir preferences for place of care and place of death.Explain that they will be given chances to review and change any advance statements and decisions they have made.\n\nAt each care review, offer people the chance to review and change any advance statements and decisions they have made.\n\n# Diagnosis\n\n## Initial assessment in non-specialist settings\n\nAt the initial assessment take a history (including cognitive, behavioural and psychological symptoms, and the impact symptoms have on their daily life):\n\nfrom the person with suspected dementia and\n\nif possible, from someone who knows the person well (such as a family member).\n\nIf dementia is still suspected after initial assessment:\n\nconduct a physical examination and\n\nundertake appropriate blood and urine tests to exclude reversible causes of cognitive decline and\n\nuse cognitive testing.\n\nWhen using cognitive testing, use a validated brief structured cognitive instrument such as:\n\nthe 10-point cognitive screener (10-CS)\n\nthe 6-item cognitive impairment test (6CIT)\n\nthe 6-item screener\n\nthe Memory Impairment Screen (MIS)\n\nthe Mini-Cog\n\nTest Your Memory (TYM).\n\nDo not rule out dementia solely because the person has a normal score on a cognitive instrument.\n\nWhen taking a history from someone who knows the person with suspected dementia, consider supplementing this with a structured instrument such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) or the Functional Activities Questionnaire (FAQ).\n\nRefer the person to a specialist dementia diagnostic service (such as a memory clinic or community old age psychiatry service) if:\n\nreversible causes of cognitive decline (including delirium, depression, sensory impairment [such as sight or hearing loss] or cognitive impairment from medicines associated with increased anticholinergic burden) have been investigated and\n\ndementia is still suspected.\n\nIf the person has suspected rapidly-progressive dementia, refer them to a neurological service with access to tests (including cerebrospinal fluid examination) for Creutzfeldt–Jakob disease and similar conditions.\n\nFor more guidance on assessing for dementia in people with learning disabilities, see the NICE guideline on mental health problems in people with learning disabilities.\n\n## Diagnosis in specialist dementia diagnostic services\n\nDiagnose a dementia subtype (if possible) if initial specialist assessment (including an appropriate neurological examination and cognitive testing) confirms cognitive decline and reversible causes have been ruled out.\n\nIf Alzheimer's disease is suspected, include a test of verbal episodic memory in the assessment.\n\nConsider neuropsychological testing if it is unclear:\n\nwhether the person has cognitive impairment or\n\nwhether their cognitive impairment is caused by dementia or\n\nwhat the correct subtype diagnosis is.\n\nUse validated criteria to guide clinical judgement when diagnosing dementia subtypes, such as:\n\nInternational consensus criteria for dementia with Lewy bodies\n\nInternational FTD criteria for frontotemporal dementia (progressive non-fluent aphasia and semantic dementia)\n\nInternational Frontotemporal Dementia Consortium criteria for behavioural variant frontotemporal dementia\n\nNINDS-AIREN criteria (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences) for vascular dementia\n\nNIA criteria (National Institute on Aging) for Alzheimer's disease\n\nMovement disorders Society criteria for Parkinson's disease dementia\n\nInternational criteria for Creutzfeldt-Jakob disease.\n\nOffer structural imaging to rule out reversible causes of cognitive decline and to assist with subtype diagnosis, unless dementia is well established and the subtype is clear.\n\nOnly consider further tests (recommendations 1.2.15–28) if:\n\nit would help to diagnose a dementia subtype and\n\nknowing more about the dementia subtype would change management.\n\nIf the diagnosis is uncertain (see recommendation 1.2.14) and Alzheimer's disease is suspected, consider either:\n\nFDG-PET (fluorodeoxyglucose-positron emission tomography-CT), or perfusion SPECT (single‑photon emission CT) if FDG-PET is unavailableor\n\nexamining cerebrospinal fluid for:\n\n\n\neither total tau or total tau and phosphorylated-tau 181 and\n\neither amyloid beta 1–42 or amyloid beta 1–42 and amyloid beta 1–40.\n\n\n\nIf a diagnosis cannot be made after one of these tests, consider using the other one.\n\nBe aware that the older a person is, the more likely they are to get a false positive with cerebrospinal fluid examination.\n\nDo not rule out Alzheimer's disease based solely on the results of CT or MRI scans.\n\nDo not use Apolipoprotein E genotyping or electroencephalography to diagnose Alzheimer's disease.\n\nBe aware that young-onset Alzheimer's disease has a genetic cause in some people.\n\nIf the diagnosis is uncertain (see recommendation 1.2.14) and dementia with Lewy bodies is suspected, use 123I‑FP‑CIT SPECT.\n\nIf 123I‑FP‑CIT SPECT is unavailable, consider 123I‑MIBG cardiac scintigraphy.\n\nDo not rule out dementia with Lewy bodies based solely on normal results on 123I‑FP‑CIT SPECT or 123I‑MIBG cardiac scintigraphy.\n\nIf the diagnosis is uncertain (see recommendation 1.2.14) and frontotemporal dementia is suspected, use either:\n\nFDG-PET or\n\nperfusion SPECT.\n\nDo not rule out frontotemporal dementia based solely on the results of structural, perfusion or metabolic imaging tests.\n\nBe aware that frontotemporal dementia has a genetic cause in some people.\n\nIf the dementia subtype is uncertain and vascular dementia is suspected, use MRI. If MRI is unavailable or contraindicated, use CT.\n\nDo not diagnose vascular dementia based solely on vascular lesion burden.\n\nBe aware that young-onset vascular dementia has a genetic cause in some people.\n\n## Case finding\n\nOnly conduct case finding for suspected dementia as part of a clinical trial that also provides an intervention to people diagnosed with dementia.\n\n## Telling the difference between delirium and dementia in people without a diagnosis of either\n\nFor people who are in hospital and have cognitive impairment with an unknown cause, consider using one of the following to find out whether they have delirium or delirium superimposed on dementia, compared with dementia alone:\n\nthe long confusion assessment method (CAM)\n\nthe Observational Scale of Level of Arousal (OSLA).\n\nDo not use standardised instruments (including cognitive instruments) alone to distinguish delirium from delirium superimposed on dementia.\n\nIf it is not possible to tell whether a person has delirium, dementia, or delirium superimposed on dementia, treat for delirium first. For guidance on treating delirium, see treating delirium in the NICE guideline on delirium.\n\n## Review after diagnosis\n\nAfter a person is diagnosed with dementia, ensure they and their family members or carers (as appropriate) have access to a memory service or equivalent hospital- or primary-care-based multidisciplinary dementia service.\n\nMemory services and equivalent hospital- and primary-care-based multidisciplinary dementia services should offer a choice of flexible access or prescheduled monitoring appointments.\n\nWhen people living with dementia or their carers have a primary care appointment, assess for any emerging dementia-related needs and ask them if they need any more support.\n\n# Care coordination\n\nProvide people living with dementia with a single named health or social care professional who is responsible for coordinating their care.\n\nNamed professionals should:\n\narrange an initial assessment of the person's needs, which should be face to face if possible\n\nprovide information about available services and how to access them\n\ninvolve the person's family members or carers (as appropriate) in support and decision-making\n\ngive special consideration to the views of people who do not have capacity to make decisions about their care, in line with the principles of the Mental Capacity Act 2005\n\nensure that people are aware of their rights to and the availability of local advocacy services, and if appropriate to the immediate situation an independent mental capacity advocate\n\ndevelop a care and support plan, and:\n\n\n\nagree and review it with the involvement of the person, their family members or carers (as appropriate) and relevant professionals\n\nspecify in the plan when and how often it will be reviewed\n\nevaluate and record progress towards the objectives at each review\n\nensure it covers the management of any comorbidities\n\nprovide a copy of the plan to the person and their family members or carers (as appropriate).\n\n\n\n## Transferring information between services and care settings\n\nWhen developing care and support plans and advance care and support plans, request consent to transfer these to different care settings as needed.\n\nService providers should ensure that information (such as care and support plans and advance care and support plans) can be easily transferred between different care settings (for example home, inpatient, community and residential care).\n\nStaff delivering care and support should maximise continuity and consistency of care. Ensure that relevant information is shared and recorded in the person's care and support plan.\n\n## Making services accessible\n\nService providers should design services to be accessible to as many people living with dementia as possible, including:\n\npeople who do not have a carer or whose carer cannot support them on their own\n\npeople who do not have access to affordable transport, or find transport difficult to use\n\npeople who have other responsibilities (such as work, children or being a carer themselves)\n\npeople with learning disabilities, sensory impairment (such as sight or hearing loss) or physical disabilities\n\npeople who may be less likely to access health and social care services, such as people from black, Asian and minority ethnic groups.\n\n# Interventions to promote cognition, independence and wellbeing\n\nOffer a range of activities to promote wellbeing that are tailored to the person's preferences.\n\nOffer group cognitive stimulation therapy to people living with mild to moderate dementia.\n\nConsider group reminiscence therapy for people living with mild to moderate dementia.\n\nConsider cognitive rehabilitation or occupational therapy to support functional ability in people living with mild to moderate dementia.\n\nDo not offer acupuncture to treat dementia.\n\nDo not offer ginseng, vitamin E supplements, or herbal formulations to treat dementia.\n\nDo not offer cognitive training to treat mild to moderate Alzheimer's disease.\n\nDo not offer interpersonal therapy to treat the cognitive symptoms of mild to moderate Alzheimer's disease.\n\nDo not offer non-invasive brain stimulation (including transcranial magnetic stimulation) to treat mild to moderate Alzheimer's disease, except as part of a randomised controlled trial.\n\n# Pharmacological interventions for dementia\n\n## Managing medicines for all dementia subtypes\n\nFor guidance on managing medicines (including covert administration), see the NICE guidelines on managing medicines for adults receiving social care in the community and managing medicines in care homes.\n\n## Pharmacological management of Alzheimer's disease\n\nThe three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer's disease under all of the conditions specified in 1.5.5 and 1.5.6.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.\n\nMemantine monotherapy is recommended as an option for managing Alzheimer's disease for people with:\n\nmoderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or\n\nsevere Alzheimer's disease.Treatment should be under the conditions specified in 1.5.5.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.\n\nFor people with an established diagnosis of Alzheimer's disease who are already taking an AChE inhibitor:\n\nconsider memantine in addition to an AChE inhibitor if they have moderate disease\n\noffer memantine in addition to an AChE inhibitor if they have severe disease.\n\nTreatment should be under the following conditions:\n\nFor people who are not taking an AChE inhibitor or memantine, prescribers should only start treatment with these on the advice of a clinician who has the necessary knowledge and skills. This could include:\n\n\n\nsecondary care medical specialists such as psychiatrists, geriatricians and neurologists\n\nother healthcare professionals (such as GPs, nurse consultants and advanced nurse practitioners), if they have specialist expertise in diagnosing and treating Alzheimer's disease.\n\n\n\nOnce a decision has been made to start an AChE inhibitor or memantine, the first prescription may be made in primary care.\n\nFor people with an established diagnosis of Alzheimer's disease who are already taking an AChE inhibitor, primary care prescribers may start treatment with memantine (see recommendation 1.5.4) without taking advice from a specialist clinician.\n\nEnsure that local arrangements for prescribing, supply and treatment review follow the NICE guideline on medicines optimisation.\n\nDo not stop AChE inhibitors in people with Alzheimer's disease because of disease severity alone.\n\nIf prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.\n\nWhen using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results and make any adjustments they consider appropriate. Healthcare professionals should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.\n\nWhen assessing the severity of Alzheimer's disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so. These include:\n\nif the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient's dementia because of the patient's learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or\n\nif it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or\n\nif there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia.In such cases healthcare professionals should determine the need for initiation or continuation of treatment by using another appropriate method of assessment.This recommendation is from NICE technology appraisal guidance on donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease.\n\nDo not offer the following specifically to slow the progress of Alzheimer's disease, except as part of a randomised controlled trial:\n\ndiabetes medicines\n\nhypertension medicines\n\nstatins\n\nnon-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.\n\n## Pharmacological management of non-Alzheimer's dementia\n\nJune 2018 – the use of the medicines in recommendations 1.5.10 to 1.5.14 was off label. See NICE's information on prescribing medicines.\n\nOffer donepezil or rivastigmine to people with mild to moderate dementia with Lewy bodies.\n\nOnly consider galantamine for people with mild to moderate dementia with Lewy bodies if donepezil and rivastigmine are not tolerated.\n\nConsider donepezil or rivastigmine for people with severe dementia with Lewy bodies.\n\nConsider memantine for people with dementia with Lewy bodies if AChE inhibitors are not tolerated or are contraindicated.\n\nOnly consider AChE inhibitors or memantine for people with vascular dementia if they have suspected comorbid Alzheimer's disease, Parkinson's disease dementia or dementia with Lewy bodies.\n\nDo not offer AChE inhibitors or memantine to people with frontotemporal dementia. Note that logopenic aphasia, which has previously been included in some diagnostic guidelines for frontotemporal dementia, has now been shown to most commonly be caused by Alzheimer's disease\n\nDo not offer AChE inhibitors or memantine to people with cognitive impairment caused by multiple sclerosis.\n\nFor guidance on pharmacological management of Parkinson's disease dementia, see Parkinson's disease dementia in the NICE guideline on Parkinson's disease.\n\n# Medicines that may cause cognitive impairment\n\nBe aware that some commonly prescribed medicines are associated with increased anticholinergic burden, and therefore cognitive impairment.\n\nConsider minimising the use of medicines associated with increased anticholinergic burden, and if possible look for alternatives:\n\nwhen assessing whether to refer a person with suspected dementia for diagnosis\n\nduring medication reviews with people living with dementia.\n\nBe aware that there are validated tools for assessing anticholinergic burden (for example, the Anticholinergic Cognitive Burden Scale), but there is insufficient evidence to recommend one over the others.\n\nFor guidance on carrying out medication reviews, see medication review in the NICE guideline on medicines optimisation.\n\n# Managing non-cognitive symptoms\n\n## Agitation, aggression, distress and psychosis\n\nBefore starting non-pharmacological or pharmacological treatment for distress in people living with dementia, conduct a structured assessment to:\n\nexplore possible reasons for their distress and\n\ncheck for and address clinical or environmental causes (for example pain, delirium or inappropriate care).\n\nAs initial and ongoing management, offer psychosocial and environmental interventions to reduce distress in people living with dementia.\n\nOnly offer antipsychotics for people living with dementia who are either:\n\nat risk of harming themselves or others or\n\nexperiencing agitation, hallucinations or delusions that are causing them severe distress.Follow the 2012 MHRA advice for health and social care professionals on prescribing antipsychotics to people living with dementia.June 2018 – note that this is an off-label use for almost all antipsychotics (see prescribing risperidone and haloperidol). See NICE's information on prescribing medicines.\n\nBe aware that for people with dementia with Lewy bodies or Parkinson's disease dementia, antipsychotics can worsen the motor features of the condition, and in some cases cause severe antipsychotic sensitivity reactions. For more guidance, see the advice on managing delusions and hallucinations in the NICE guideline on Parkinson's disease. Be aware that interventions may need to be modified for people living with dementia.\n\nBefore starting antipsychotics, discuss the benefits and harms with the person and their family members or carers (as appropriate). Consider using a decision aid to support this discussion. NICE has produced a patient decision aid on antipsychotic medicines for treating agitation, aggression and distress in people living with dementia.\n\nWhen using antipsychotics:\n\nuse the lowest effective dose and use them for the shortest possible time\n\nreassess the person at least every 6 weeks, to check whether they still need medication.\n\nStop treatment with antipsychotics:\n\nif the person is not getting a clear ongoing benefit from taking them and\n\nafter discussion with the person taking them and their family members or carers (as appropriate).\n\nEnsure that people living with dementia can continue to access psychosocial and environmental interventions for distress while they are taking antipsychotics and after they have stopped taking them.\n\nFor people living with dementia who experience agitation or aggression, offer personalised activities to promote engagement, pleasure and interest.\n\nDo not offer valproate to manage agitation or aggression in people living with dementia, unless it is indicated for another condition. If relevant, follow MHRA advice that valproate medicines are contraindicated in women and girls of childbearing potential unless a Pregnancy Prevention Programme is in place.\n\n## Depression and anxiety\n\nFor people living with mild to moderate dementia who have mild to moderate depression and/or anxiety, consider psychological treatments.\n\nDo not routinely offer antidepressants to manage mild to moderate depression in people living with mild to moderate dementia, unless they are indicated for a pre-existing severe mental health problem.\n\n## Sleep problems\n\nDo not offer melatonin to manage insomnia in people living with Alzheimer's disease.\n\nFor people living with dementia who have sleep problems, consider a personalised multicomponent sleep management approach that includes sleep hygiene education, exposure to daylight, exercise and personalised activities.\n\n## Parkinson's disease\n\nFor guidance on managing Parkinson's disease symptoms in people with Parkinson's disease dementia or dementia with Lewy bodies, see the NICE guideline on Parkinson's disease. Be aware that interventions may need to be modified for people living with dementia.\n\n# Assessing and managing other long-term conditions in people living with dementia\n\nEnsure that people living with dementia have equivalent access to diagnosis, treatment and care services for comorbidities to people who do not have dementia. For more guidance on assessing and managing multimorbidity, see the NICE guidelines on multimorbidity and older people with social care needs and multiple long-term conditions.\n\nFor more guidance on providing support for older adults with learning disabilities, see the NICE guideline on care and support of people growing older with learning disabilities.\n\n## Pain\n\nConsider using a structured observational pain assessment tool:\n\nalongside self-reported pain and standard clinical assessment for people living with moderate to severe dementia\n\nalongside standard clinical assessment for people living with dementia who are unable to self-report pain.\n\nFor people living with dementia who are in pain, consider using a stepwise treatment protocol that balances pain management and potential adverse events.\n\nRepeat pain assessments for people living with dementia:\n\nwho seem to be in pain\n\nwho show signs of behavioural changes that may be caused by pain\n\nafter any pain management intervention.\n\n## Falls\n\nFor guidance on managing the risk of falling for people living with dementia (in community and inpatient settings), see the NICE guideline on falls in older people. When using this guideline:\n\ntake account of the additional support people living with dementia may need to participate effectively\n\nbe aware that multifactorial falls interventions may not be suitable for a person living with severe dementia.\n\n## Diabetes\n\nFor guidance on setting HbA1c targets for people living with severe dementia who have type 2 diabetes, see recommendation 1.6.9 in the NICE guideline on type 2 diabetes in adults.\n\n## Incontinence\n\nFor guidance on pharmacological treatment of overactive bladder, see the NICE technology appraisal on mirabegron for treating symptoms of overactive bladder.\n\nFor guidance on treating faecal incontinence, see recommendations 1.7.2 and 1.7.8 in the NICE guideline on faecal incontinence.\n\n## Sensory impairment\n\nFor guidance on hearing assessments for people with suspected or diagnosed dementia, see adults with suspected dementia in the NICE guideline on hearing loss.\n\nEncourage people living with dementia to have eye tests every 2 years. Consider referring people who cannot organise appointments themselves.\n\n# Risks during hospital admission\n\nBe aware of the increased risk of delirium in people living with dementia who are admitted to hospital. See the NICE guideline on delirium for interventions to prevent and treat delirium.\n\nWhen thinking about admission to hospital for a person living with severe dementia, carry out an assessment that balances their current medical needs with the additional harms they may face in hospital, for example:\n\ndisorientation\n\na longer length of stay\n\nincreased mortality\n\nincreased morbidity on discharge\n\ndelirium\n\nthe effects of being in an impersonal or institutional environment.\n\nWhen thinking about admission to hospital for a person living with dementia, take into account:\n\nany advance care and support plans\n\nthe value of keeping them in a familiar environment.\n\n# Palliative care\n\nFrom diagnosis, offer people living with dementia flexible, needs-based palliative care that takes into account how unpredictable dementia progression can be.\n\nFor people living with dementia who are approaching the end of life, use an anticipatory healthcare planning process (see recommendation 1.1.12 on advance care planning). Involve the person and their family members or carers (as appropriate) as far as possible, and use the principles of best-interest decision-making if the person does not have capacity to make decisions about their care.\n\nFor standards and measures on palliative care, see the NICE quality standard on end of life care for adults.\n\nFor guidance on care for people in the last days of life, see the NICE guideline on care of dying adults.\n\nFor guidance on best interests decision-making, see the NICE guideline on decision-making and mental capacity.\n\nEncourage and support people living with dementia to eat and drink, taking into account their nutritional needs.\n\nConsider involving a speech and language therapist if there are concerns about a person's safety when eating and drinking.\n\nDo not routinely use enteral feeding in people living with severe dementia, unless indicated for a potentially reversible comorbidity. NICE has produced a patient decision aid on enteral (tube) feeding for people living with severe dementia.\n\n# Supporting carers\n\nOffer carers of people living with dementia a psychoeducation and skills training intervention that includes:\n\neducation about dementia, its symptoms and the changes to expect as the condition progresses\n\ndeveloping personalised strategies and building carer skills\n\ntraining to help them provide care, including how to understand and respond to changes in behaviour\n\ntraining to help them adapt their communication styles to improve interactions with the person living with dementia\n\nadvice on how to look after their own physical and mental health, and their emotional and spiritual wellbeing\n\nadvice on planning enjoyable and meaningful activities to do with the person they care for\n\ninformation about relevant services (including support services and psychological therapies for carers) and how to access them\n\nadvice on planning for the future.\n\nEnsure that the support provided to carers is:\n\ntailored to their needs and preferences and to what they want it to achieve (for example, providing information on carer's employment rights for carers who work or want to work)\n\ndesigned to help them support people living with dementia\n\navailable at a location they can get to easily\n\nprovided in a format suitable for them (for example individual or group sessions, or online training and support)\n\navailable from diagnosis and as needed after this.\n\nBe aware that carer interventions are likely to be most effective when provided as group sessions.\n\nAdvise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).\n\nBe aware that carers of people living with dementia are at an increased risk of depression. For guidance on identifying and managing depression, see the NICE guideline on depression in adults.\n\n# Moving to different care settings\n\nFor guidance on managing transition between care settings for people living with dementia, see:\n\nthe NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs\n\nthe NICE guideline on transition between inpatient mental health settings and community or care home settings\n\nsection 1.2 of the NICE guideline on medicines optimisation.Follow the principles in these guidelines for transitions between other settings (for example from home to a care home or respite care).\n\nReview the person's needs and wishes (including any care and support plans and advance care and support plans) after every transition.\n\n# Staff training and education\n\nCare and support providers should provide all staff with training in person-centred and outcome-focused care for people living with dementia, which should include:\n\nunderstanding the signs and symptoms of dementia, and the changes to expect as the condition progresses\n\nunderstanding the person as an individual, and their life story\n\nrespecting the person's individual identity, sexuality and culture\n\nunderstanding the needs of the person and their family members or carers\n\nthe principles of the Mental Capacity Act 2005 and the Care Act 2014.\n\nCare providers should provide additional face-to-face training and mentoring to staff who deliver care and support to people living with dementia. This should include:\n\nunderstanding the organisation's model of dementia care and how it provides care\n\nhow to monitor and respond to the lived experience of people living with dementia, including adapting communication styles\n\ninitial training on understanding, reacting to and helping people living with dementia who experience agitation, aggression, pain, or other behaviours indicating distress\n\nfollow-up sessions where staff can receive additional feedback and discuss particular situations\n\nadvice on interventions that reduce the need for antipsychotics and allow doses to be safely reduced\n\npromoting freedom of movement and minimising the use of restraint\n\nif relevant to staff, the specific needs of younger people living with dementia and people who are working or looking for work.\n\nConsider giving carers and/or family members the opportunity to attend and take part in staff dementia training sessions.\n\nConsider training staff to provide multi-sensory stimulation for people with moderate to severe dementia and communication difficulties.\n\nEnsure that all health and social care staff are aware of:\n\nthe extent of their responsibility to protect confidentiality under data protection legislation and\n\nany rights that family members, carers and others have to information about the person's care (see recommendation 1.3.5 on information sharing between different care settings).\n\nHealth and social care professionals advising people living with dementia (including professionals involved in diagnosis) should be trained in starting and holding difficult and emotionally challenging conversations.\n\n# Terms used in this guideline\n\n## Case finding\n\nA strategy of actively assessing people who are at risk for a particular disease, before they present with symptoms and before there is clinical suspicion of the condition. It does not refer to situations such as assessing people for dementia after an acute episode of delirium, where clinical suspicion of dementia is likely to already be raised.\n\n## Cognitive rehabilitation\n\nIdentifying functional goals that are relevant to the person living with dementia, and working with them and their family members or carers to achieve these. The emphasis is on improving or maintaining functioning in everyday life, building on the person's strengths and finding ways to compensate for impairments, and supporting independence. Cognitive rehabilitation does not aim to improve cognition, but addresses the disability resulting from the impact of cognitive impairment on everyday functioning and activity. Rehabilitation is sometimes referred to as 'reablement'.\n\n## Cognitive stimulation\n\nEngaging in a range of activities and discussions (usually in a group) that are aimed at general improvement of cognitive and social functioning.\n\n## Cognitive training\n\nGuided practice on a set of standard tasks that are designed to reflect particular cognitive functions. There may be a range of difficulty levels, to fit the tasks to each person's level of ability.\n\n## Interpersonal therapy\n\nBrief structured attachment-focused therapies for people with mild to moderate depression. These therapies are based on the idea that difficulties interacting with other people can cause psychological symptoms such as depressed mood, which then make the difficulties with interaction worse, causing a cycle. Interpersonal therapies aim to help people interact more effectively with others, and through this improve the psychological symptoms. Therapy typically focuses on relationship issues such as conflict, difficulty starting or maintaining relationships, grief and loss, and life changes.\n\n## Prescribing risperidone and haloperidol\n\nThe marketing authorisation for risperidone only covers short-term treatment (up to 6 weeks) of persistent aggression in people with moderate to severe Alzheimer's disease unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others. The marketing authorisation for haloperidol only covers treatment of persistent aggression and psychotic symptoms in people with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others.\n\n## Refer\n\nA referral to a diagnostic service does not have to involve a clinic appointment. People can be seen in community settings (such as their home or a care home), or advice can be provided to the referrer without a formal appointment being made. The key issue is to ensure that dementia specialists are involved, both for advice on diagnosis and to ensure appropriate access to post-diagnostic support and treatment. Specialists are those with the appropriate knowledge and skills and include secondary care medical specialists (for example psychiatrists, geriatricians and neurologists) and other healthcare professionals (for example GPs, nurse consultants and advanced nurse practitioners) with specialist expertise in assessing and diagnosing dementia.\n\n## Social care terms\n\nFor social care terms see the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Specialist clinician\n\nSpecialist clinicians (for the purpose of starting and monitoring treatment with cholinesterase inhibitors and memantine) are those with the appropriate knowledge and skills and include secondary care medical specialists (for example psychiatrists, geriatricians and neurologists) and other healthcare professionals (for example GPs, nurse consultants and advanced nurse practitioners) with specialist expertise in diagnosing and treating Alzheimer's disease.\n\n## Verbal episodic memory\n\nEpisodic memories include information about recent or past events and experiences (rather than factual knowledge, or habits and skills). They may be recent, or from the distant past (remote or long-term episodic memory). Tests to assess episodic memory may use either verbal or visual material. Examples of verbal episodic memory tests include reading the person a list of words or a short story and asking them to recall this information, both immediately and after a delay.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Case management\n\nWhat is the effectiveness and cost effectiveness of high-intensity case management compared with usual care on quality of life (for the person living with dementia and for their carers) and the timing of entry to long-term care?\n\n## Why this is important\n\nThere is evidence that case management is an effective intervention for people living with dementia. However, the effectiveness and cost effectiveness of high-intensity case management has not been tested in the UK. It has a high upfront cost, but there is some evidence from settings outside the UK that it may reduce the use of other services, leading to cost savings across the whole system. Because of the cost, robust evidence of effectiveness and cost effectiveness from a UK setting is needed.\n\n# Staff training\n\nWhat is the cost effectiveness of using a dementia-specific addition to the Care Certificate for community staff, including dementia-specific elements on managing anxiety, communication, nutritional status and personal care?\n\n## Why this is important\n\nRobust evidence demonstrates the effectiveness of intensive training for staff heavily involved in providing care and support for people living with dementia. However, it is not clear if it is effective to provide basic training to all staff who come into contact with people living with dementia, or how this training should be provided. One possibility is an expanded version of the Care Certificate that includes additional dementia-specific elements. Because this training would need to be given to a large number of staff, there needs to be good evidence of benefits, specifically in improving quality of life for people living with dementia and their carers, to justify the upfront costs.\n\n# Anticholinergic burden\n\nDoes actively reducing anticholinergic burden in people living with dementia improve cognitive outcomes compared with usual care?\n\n## Why this is important\n\nMany people living with dementia are still prescribed medicines with a high anticholinergic burden (which can be caused by individual medicines or by combinations of medicines). It is often unclear if this prescribing is appropriate, or whether actively reducing the number of these medicines would improve cognition. Randomised controlled trials could be conducted, using structured tools to assess anticholinergic burden and actively switching medicines if possible. This would help to identify whether cognition can be improved without adversely affecting the management of the conditions these medicines are prescribed for.\n\n# Managing delirium superimposed on dementia\n\nWhat are the most clinically and cost-effective non-pharmacological interventions for helping the long-term recovery of people with delirium superimposed on dementia?\n\n## Why this is important\n\nThe acute management of delirium superimposed on dementia is likely to be similar to the management of delirium in people without dementia. However, there may be differences in the interventions needed to aid long-term recovery, particularly because people with different severities of dementia will have different baseline cognitive status. Research on the most effective non-pharmacological methods of promoting long-term recovery would help to identify whether alternative approaches are needed for people living with dementia.\n\n# Care and support planning\n\nWhat are the most effective methods of care planning for people who do not have regular contact with an informal carer?\n\n## Why this is important\n\nMany randomised controlled trials of care planning or case management specifically exclude people without an informal carer. Conducting similar studies on case management and care planning for people without an informal carer would fill this gap in the evidence base, and help to identify whether these people have different needs."}
|
https://www.nice.org.uk/guidance/ng97
|
This guideline covers diagnosing and managing dementia (including Alzheimer’s disease). It aims to improve care by making recommendations on training staff and helping carers to support people living with dementia.
|
9a3971baff0365943f4a68822259e6f709ee349d
|
nice
|
Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease
|
Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease
Evidence-based recommendations on donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon) and memantine (Ebixa) for treating Alzheimer's disease in adults.
# Guidance
This guidance has been partially updated by the NICE guideline on dementia. See update information for more information.
The three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer's disease under all of the conditions specified in 1.4 and in recommendation 1.5.5 of the NICE guideline on dementia.
Memantine monotherapy is recommended as an option for managing Alzheimer's disease for people with:
moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or
severe Alzheimer's disease. Treatment should be under the conditions specified in recommendation 1.5.5 in the NICE guideline on dementia.
This recommendation has been updated and replaced by recommendation 1.5.5 in the NICE guideline on dementia.
If prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles.
When using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results and make any adjustments they consider appropriate. Healthcare professionals should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.
When assessing the severity of Alzheimer's disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so. These include:
if the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient's dementia because of the patient's learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or
if it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or
if there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia.In such cases healthcare professionals should determine the need for initiation or continuation of treatment by using another appropriate method of assessment.# Clinical need and practice
Dementia is a chronic progressive mental disorder that adversely affects higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Alzheimer's disease is the most common form of dementia. It is a degenerative cerebral disease with characteristic neuropathological and neurochemical features.
Population data from 2005 indicate that 380,000 people have Alzheimer's disease in England and Wales. The UK incidence of Alzheimer's disease in people over the age of 65 years is estimated to be 4.9 per 1000 person-years. Between 50 and 64% of people with Alzheimer's disease are estimated to have mild to moderately severe disease, and approximately 50% have moderately severe to severe disease.
Alzheimer's disease is usually insidious in onset and develops slowly but steadily over several years. It predominantly affects older people. The median survival for people with Alzheimer's disease from onset has been estimated at 7 years, although survival figures vary and depend on how they are measured, comorbidities, age (median survival decreases with increasing age) and sex.
Progression is characterised by deterioration in cognition (for example, thinking, conceiving and reasoning), functional ability (for example, activities of daily living such as dressing, personal hygiene and handling money), behaviour (for example, agitation, wandering and uncharacteristic aggression) and non-cognitive symptoms including depression, delusions and hallucinations. People with Alzheimer's disease might find it increasingly difficult to do everyday activities, such as shopping, socialising and recognising people and places. Communication may become a problem as people find it more difficult to find words and remember names. In later stages of disease, physical problems can include problems with eating, swallowing, incontinence, and unsettled and unsettling behaviour. Alzheimer's disease may also be associated with loss of confidence and feelings of fear, confusion, apathy, stigma and depression. The effects of Alzheimer's disease are heterogeneous and vary from patient to patient.
Alzheimer's disease has many impacts including physical, mental, nursing, medical and social impacts. Carers (including friends and family) are affected by the progressive deterioration in cognition, function and behaviour of a person with Alzheimer's disease. Behavioural symptoms can have a particular impact on carers, and are often the reason cited for a person with Alzheimer's disease going into full-time residential care. Alzheimer's disease can have a profound and far-reaching effect on family and carers as well as the patient including institutionalisation and a financial impact on family, carers and the state.
The severity of Alzheimer's disease can be assessed using several methods, depending on the setting (for example research or clinical practice) and the outcome being assessed. Clinical practice uses a variety of measures, often along with clinically based assessments such as biographical interview. Severity is frequently defined by Mini Mental State Examination (MMSE) score:
mild Alzheimer's disease: MMSE 21–26
moderate Alzheimer's disease: MMSE 10–20
moderately severe Alzheimer's disease: MMSE 10–14
severe Alzheimer's disease: MMSE less than 10.
The aims of treatment are to promote independence, maintain function and treat symptoms including cognitive, non-cognitive (hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), behavioural and psychological symptoms.
There is no cure for Alzheimer's disease. Current management involves the treatment of cognitive, non-cognitive and behavioural symptoms. AChE inhibitors (donepezil, galantamine and rivastigmine) and memantine are the pharmacological treatments available specifically for Alzheimer's disease. Non-pharmacological treatment includes social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services such as meals-on-wheels, befriending services, day centres, respite care and care homes.# The technologies
# Donepezil
Donepezil (Aricept, Eisai/Pfizer) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission. Donepezil has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe Alzheimer's dementia. It is given initially at 5 mg once daily at bedtime. After 1 month the treatment should be assessed, and the dose can be increased to a maximum of 10 mg once daily if necessary.
Common undesirable effects include diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia. For full details of side effects and contraindications, see the summaries of product characteristics.
Donepezil is available as tablets and orodispersible tablets. Net prices are stated. The cost of tablets is £59.85 (5 mg, 28-tablet pack) and £83.89 (10 mg, 28-tablet pack). The cost of orodispersible tablets is £59.85 (5 mg, 28-tablet pack) and £83.89 (10 mg, 28-tablet pack) ('British national formulary' edition 60). Costs may vary in different settings because of negotiated procurement discounts.
# Galantamine
Galantamine (Reminyl, Shire) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission and also modulates activity at nicotinic receptors. Galantamine has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer's type. The formulation given most frequently is a capsule given initially at 8 mg once daily for 4 weeks and then increased to 16 mg once daily for at least 4 weeks. Maintenance treatment is 16–24 mg once daily depending on assessment of clinical benefit and tolerability. An older tablet formulation and a liquid preparation are also available to be given twice a day, see the summaries of product characteristics for more information.
Common undesirable effects include nausea and vomiting. For full details of side effects and contraindications, see the summaries of product characteristics.
Galantamine is available as tablets, oral solution and capsules. Net prices are stated. The cost of tablets is £68.32 (8 mg, 56-tablet pack) and £84.00 (12 mg, 56-tablet pack). Oral solution (4 mg/ml, 100 ml) costs £120.00. Modified release capsules cost £51.88 (8 mg, 28-capsule pack), £64.90 (16 mg, 28-capsule pack) and £79.80 (24 mg, 28-capsule pack) (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.
# Rivastigmine
Rivastigmine (Exelon, Novartis) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission. Rivastigmine has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe Alzheimer's dementia. The dose is initially 1.5 mg twice daily and may be increased in steps of 1.5 mg twice daily at intervals of at least 2 weeks according to tolerance up to a maximum dose of 6 mg twice daily. Alternatively rivastigmine patches are available, initially using a 4.6-mg patch per day. This can be increased to a 9.5-mg patch per day for at least 4 weeks. See the summary of product characteristics for further information on using patches.
Common undesirable effects are mainly gastrointestinal including nausea and vomiting. For full details of side effects and contraindications, see the summaries of product characteristics.
Rivastigmine is available as capsules, oral solution and patches. Net prices are stated. The cost of 1.5 mg rivastigmine capsules is £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 3 mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 4.5 mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 6 mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack). Oral solution costs £99.14 (2 mg/ml, 120 ml). Patches cost £77.97 (4.6 mg/24 hours, 30 patches) and £77.97 (9.5 mg/24 hours, 30 patches) (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.
# Memantine
Memantine (Ebixa, Lundbeck) is a voltage-dependent, moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction. It has a marketing authorisation in the UK for the treatment of patients with moderate to severe Alzheimer's disease. Memantine is initially given as 5 mg once daily and then increased in steps of 5 mg at weekly intervals to a maximum of 20 mg daily.
Common undesirable effects are dizziness, headache, constipation, somnolence and hypertension. For full details of side effects and contraindications, see the summaries of product characteristics.
Memantine is available as tablets and oral drops. Net prices are stated. 10 mg memantine tablets cost £34.50 (28-tablet pack), £69.01 (56-tablet pack) and £138.01 (112-tablet pack). 20 mg tablets cost £69.01 (28-tablet pack). A treatment initiation pack (7 × 5 mg, 7 × 10 mg, 7 × 15 mg, and 7 × 20 mg tablets) costs £43.13. Oral drops (10 mg/g) cost £61.61 for 50 g and £123.23 for 100 g (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Committee considered evidence from the Assessment Group, submissions from the manufacturers of donepezil, galantamine and memantine, the Alzheimer's Society, the Royal College of Psychiatrists, the British Geriatrics Society, clinical specialists and patient experts.
The Assessment Group conducted a systematic review of randomised controlled trials published since 2004 and those included in 'Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer's disease (amended)' (NICE technology appraisal guidance 111). The Assessment Group reviewed the clinical effectiveness of donepezil, galantamine, rivastigmine and memantine in accordance with their marketing authorisations. For the population with mild Alzheimer's disease (defined as MMSE 21–26) the AChE inhibitors (donepezil, galantamine and rivastigmine) were compared with each other and with best supportive care (that is, without treatment with any AChE inhibitors or memantine). For the population with moderate Alzheimer's disease (MMSE 10–20) the AChE inhibitors and memantine were compared with each other and with best supportive care. For the population with severe Alzheimer's disease (MMSE less than 10) memantine was compared with best supportive care. The Assessment Group considered cognition, function, behaviour, global outcomes, mortality, institutionalisation, health-related quality of life and adverse effects. If possible, new evidence was pooled with the evidence from before 2004 using random effects meta-analysis compared with placebo. The effectiveness of treatments across different outcome measures was also explored in a pooled multiple outcome measure analysis to explore the characteristics of the evidence base. If data were sufficient, the Assessment Group pooled information on all technologies and their comparators in a mixed treatment comparison, using Bayesian Markov Chain Monte-Carlo sampling.
The evidence on clinical effectiveness submitted by the three manufacturers included a wider selection of studies than was included by the definition of randomised controlled trials used by the Assessment Group in its evidence review. The manufacturer of donepezil conducted a systematic review of randomised controlled trials for donepezil since 2004, as well as presenting the evidence already included in NICE technology appraisal guidance 111. It also included a selected review of prospective longitudinal and observational studies. The manufacturer of galantamine submitted new data published since 2004, open-label studies and data from randomised controlled trials already submitted for NICE technology appraisal guidance 111, in 2004 or during the appraisal process. A search strategy with details of the inclusion and exclusion criteria was not submitted. The manufacturer of memantine submitted estimates of clinical effectiveness for the general population with moderate to severe Alzheimer's disease, and a subgroup of patients with agitation, aggression and/or psychotic symptoms. The manufacturer of memantine submitted a meta-analysis of six randomised controlled trials including individual patient data to allow categorisation into patients with moderate to severe disease and the subgroup with agitation, aggression and/or psychotic symptoms. Some of these trials were excluded by the Assessment Group because the trial populations included patients with mild disease, and individual patient data were not publicly available. The other submissions from consultees provided specific references to published literature on clinical effectiveness and were therefore covered by the Assessment Group's systematic review.
## Mild to moderate Alzheimer's disease
The Assessment Group included five new placebo-controlled comparisons of donepezil. The manufacturer of donepezil included new data from three randomised controlled trials, one subanalysis of a randomised controlled trial, two prospective longitudinal studies and three observational studies, six subgroup analyses and four meta-analyses (two systematic reviews and two pooled analyses), in addition to data previously submitted.
For donepezil, the Assessment Group found no new studies reporting the Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-cog) at 12 or 24 weeks or MMSE at 12 weeks. The effectiveness estimates using these scales were therefore based on the studies included in NICE technology appraisal guidance 111. One new study was found that measured the effect of donepezil on cognition at 24 weeks follow-up. The overall pooled benefit using new and old data was significant on all scales (a mean change from baseline versus placebo of 1.165 and 1.206 at 12 and 24 weeks respectively using MMSE score, and −1.969 and −2.895 at 12 and 24 weeks respectively using ADAS-cog score) and the standardised mean difference of pooled outcomes increased with time for ADAS-cog. According to the manufacturer of donepezil, all 12 randomised controlled trials (from NICE technology appraisal guidance 111 and new submissions that reported on cognition using the ADAS-cog, MMSE or Severe Impairment Battery scales) showed a statistically significant difference favouring donepezil versus placebo, with four of these reporting a statistically significant difference on two different cognitive scales.
One randomised controlled trial, described by the Assessment Group as being poorly reported, measured functional outcomes for donepezil. At 12 weeks follow-up, this trial showed a statistically significant benefit from donepezil (5 mg/day) for activities of daily living in an observed cases measured population. The heterogeneous collection of outcome measures prevented any quantitative synthesis of old and new evidence for individual measures since 2004. The pooled multiple outcome measure analysis for functional outcome data from the studies in NICE technology appraisal guidance 111 showed a statistically significant benefit for donepezil at all doses compared with placebo at 24 weeks - a mean change from baseline versus placebo of 0.298 (p < 0.001, no new data available). According to the manufacturer of donepezil, four randomised controlled trials showed a statistically significant difference favouring donepezil versus placebo on at least one scale and three reported non-significant trends in favour of donepezil. Additionally, the manufacturer cited a meta-analysis of seven randomised controlled trials of donepezil reporting a statistically significant benefit favouring donepezil versus placebo.
None of the studies for donepezil newly identified by the Assessment Group provided additional data for behavioural function, so the results were based on studies included in NICE technology appraisal guidance 111, which noted no statistically significant benefit from donepezil compared with placebo at 12 or 24 weeks measured with the neuropsychiatric inventory (NPI). There were mean changes from baseline versus placebo of −2.249 (p = 0.123) and −3.116 (p = 0.226) at 12 and 24 weeks respectively using NPI. According to the manufacturer of donepezil, three randomised controlled trials found a statistically significant difference between donepezil and placebo in NPI score, with a fourth study finding a statistically significant difference for agitation or aggression but not total score. The manufacturer of donepezil also referred to six pooled studies that showed a statistically significant difference in favour of donepezil in NPI total score compared with placebo.
One of the new studies included by the Assessment Group measured global outcomes for donepezil and reported a statistically significant benefit on the clinical dementia rating (CDR). All of the evidence on the Clinician's Interview-Based Impression of Change (CIBIC)-plus was based on NICE technology appraisal guidance 111. A meta-analysis of the effectiveness of donepezil for the CIBIC-plus reported a statistically significant benefit of donepezil 10 mg/day compared with placebo at 12 and 24 weeks. The Assessment Group did not find any new studies that measured global outcomes at 24–26 weeks. The pooled multiple outcome measure analysis for the global outcome data from the studies in NICE technology appraisal guidance 111 showed a statistically significant benefit for donepezil at all doses compared with placebo at 24–26 weeks (a mean change from baseline versus placebo of −0.377 and −0.429 at 12 and 24 weeks respectively using CIBIC-plus score, and −0.263 and −0.568 at 12 and 24 weeks respectively using CDR score). According to the manufacturer of donepezil, global function (CIBIC-plus, CDR sum of boxes or the Gottfries, Brine and Steen scale ) was measured in nine of the studies presented in new and previous submissions with statistically significant results in favour of donepezil in seven of them. A submitted meta-analysis of ten trials also showed significant improvement in global function compared with placebo using the CDR-SB.
According to the Assessment Group, none of the five newly identified studies for donepezil provided data on adverse events observed under randomised conditions except for limited data from one study. The manufacturer also presented safety data. In summary, the manufacturer of donepezil stated that new data since 2004 was consistent with that previously submitted.
The Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with donepezil.
The manufacturer of donepezil included prospective longitudinal and observational studies to support the view that cognitive benefits from donepezil are maintained for up to 3 years. The submission also included new data from a placebo-controlled trial of at least a 2-year duration and a subanalysis of a previous placebo-controlled study of 1 year duration. The manufacturer also presented evidence from randomised and non-randomised controlled trials to demonstrate that benefit was lost when treatment was stopped, the benefits of continuing treatment despite initial decline or stabilisation of MMSE, and the impact of improvement of neuropsychiatric symptoms on caregiver stress and burden.
The manufacturer of donepezil included evidence that patients showing clinical worsening may benefit from treatment compared with those on placebo or who were untreated. The manufacturer also included a responder analysis that showed how results varied depending on the definition of response. The manufacturer used these data to demonstrate the effects of treatment on carers.
A representative from the manufacturer of donepezil informed the Committee that an analysis of a single open-label study found an average of 17.5 months delay in the time to institutionalisation with donepezil treatment. Survival data were not collected in any of the trials because follow-up periods were short and therefore there were few deaths during trials.
The Assessment Group included three new randomised controlled trials of galantamine. The manufacturer of galantamine submitted data from before and after 2004 for six trials and four pooled analyses including mild, moderate and 'advanced moderate' subgroups.
All three studies included by the Assessment Group measured cognition and used ADAS-cog at various points between 6 and 26 weeks and showed improvement with galantamine compared with placebo. When the results of these were added to the results of NICE technology appraisal guidance 111, the pooled estimate demonstrated a statistically significant benefit of galantamine compared with placebo, which increased with time (mean changes from baseline versus placebo of −2.386 and −2.957 at 12–16 and 21–26 weeks respectively using ADAS-cog score). According to the manufacturer of galantamine, established randomised controlled trial data from five placebo-controlled trials in mild to moderate Alzheimer's disease showed statistically significant benefit in ADAS-cog score. This was reflected in the pooled data that included a subgroup of patients with additional cerebrovascular disease from a trial of patients with Alzheimer's disease (other patients in the trial had probable vascular dementia).
The Assessment Group found three new randomised controlled trials measuring functional outcomes for galantamine. The Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) data from the new trials were pooled with those of the studies found in 2004, and the overall pooled estimates showed statistically significant functional benefit from galantamine compared with placebo at 21–26 weeks (mean changes from baseline versus placebo of 1.394 and 2.234 at 12–13 and 21–26 weeks respectively). The results of Disability Assessment for Dementia (DAD) score were pooled at 2126 weeks follow-up. Again this showed a statistically significant benefit of galantamine compared with placebo (mean changes from baseline versus placebo of 3.761 at 21–26 weeks). Two new studies were added to the meta-analysis of combined functional outcome measures at 21–26 weeks. The pooled multiple outcome measure analysis showed a statistically significant functional benefit of galantamine compared with placebo. The manufacturer referred to four established placebo-controlled randomised controlled trials that showed benefits in terms of ADCS-ADL or DAD score, of which some were statistically significant, including the pooled data (which included a subgroup of patients with additional cerebrovascular disease from another trial).
Only one study included by the Assessment Group provided additional data for the effectiveness of galantamine in relieving behavioural symptoms, when compared with placebo. However, this did not show any statistically significant benefit. When the new data were pooled with previous data, at 13 weeks no significant benefit was found, but at 21–26 weeks the overall pooled estimate favoured galantamine significantly (mean changes from baseline versus placebo of −0.746 and −1.455 at 13 and 21–26 weeks respectively using NPI score). The manufacturer of galantamine referred to one study that showed statistically significant benefits in terms of NPI score, and another two placebo-controlled trials that showed non-significant benefits in terms of NPI score. Mixed results were reflected in the pooled data (including the subgroup of patients with additional cerebrovascular disease from another trial).
Two new studies found by the Assessment Group measured global outcomes for galantamine. One found a significant benefit from galantamine measured by the CIBIC-plus compared with placebo at 13–16 weeks. When the new studies' data were pooled with existing evidence, the overall pooled estimates of the CIBIC-plus at 26 weeks showed a statistically significant benefit from galantamine compared with placebo (a mean change from baseline versus placebo of 0.196 at 26 weeks). According to the manufacturer of galantamine, established randomised controlled trial data showed that in four out of five placebo-controlled trials in people with mild to moderate Alzheimer's disease, statistically significant benefits of galantamine were seen with CIBIC-plus. This statistically significant benefit was reflected in the pooled data (including the subgroup of patients with additional cerebrovascular disease from another trial).
The Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with galantamine.
According to the Assessment Group, overall for galantamine in two new studies, there was a high percentage of any adverse event in both studies in treatment and control groups (any adverse events: treatment = 79–84%, placebo = 62–70%). The manufacturer of galantamine did not present any new data on toxicity.
The Assessment Group included a systematic review, including a meta-analysis, that concluded that the AChE inhibitors provided benefits in terms of cognitive function and activities of daily living, and galantamine improved psychological symptoms in mild to moderate dementia.
The Assessment Group included three new randomised placebo-controlled comparisons of rivastigmine. No data were submitted by the manufacturer of rivastigmine.
Three new studies for rivastigmine were identified by the Assessment Group that measured cognition using ADAS-cog and/or MMSE and showed significant benefit (patch and capsule were not differentiated). When the results of these were added to the randomised controlled trials in NICE technology appraisal guidance 111, it demonstrated a statistically significant improvement in cognition with rivastigmine compared with placebo at 24–26 weeks (mean changes from baseline versus placebo of 1.022 using MMSE score and −2.464 using ADAS-cog score).
Two of the three new studies found by the Assessment Group published since 2004 reported statistically significant functional benefit from rivastigmine compared with placebo. These used the Progressive Deterioration Scale (PDS) and ADCS-ADL as outcome measures. The overall pooled estimate using the new and previous data for PDS at 24–26 weeks showed a statistically significant benefit of rivastigmine compared with placebo (a mean change from baseline versus placebo of 3.103 at 24–26 weeks using PDS score). Two new studies were found to add to the pooled multiple outcome measure analysis of functional outcomes at 24–26 weeks, which showed a statistically significant benefit from rivastigmine compared with placebo.
Two new studies were found that measured behavioural outcomes with rivastigmine. One small study found a statistically significant benefit from rivastigmine. The other, much larger, study did not. The Assessment Group stated that the data identified by this review and NICE technology appraisal guidance 111 are sparse and too heterogeneous to permit meaningful quantitative synthesis.
The two new studies in this comparison that reported global outcomes had conflicting results. One found mostly significantly favourable results with the CIBIC-plus and the Global Deterioration Scale (GDS), but the other did not. Data from the new studies were pooled with the existing evidence in a random-effects meta-analysis using the CIBIC-plus and the GDS at 26 weeks. The meta-analysis showed a statistically significant benefit from rivastigmine at 26 weeks (mean changes from baseline versus placebo of 0.420 using CIBIC-plus score and 0.196 using GDS score). The pooled multiple outcome measure analysis showed an overall statistically significant benefit for rivastigmine compared with placebo.
The Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with rivastigmine.
According to the Assessment Group, for rivastigmine, overall there was a high percentage of any adverse events, ranging from 51% to 91% in the treatment groups, and 46% to 76% in control groups. The main adverse events were gastrointestinal. The 9.5 mg/day transdermal patch produced fewer side effects than the capsule (12 mg/day).
The Assessment Group included a Cochrane review that concluded that high doses of rivastigmine offered statistically significant benefits in patients with mild to moderate Alzheimer's disease versus placebo.
The Assessment Group identified four head-to-head randomised controlled trials (two comparing all three AChE inhibitors, one comparing donepezil with rivastigmine and one comparing donepezil with galantamine) but considered only one of the studies to be of sufficiently high quality to inform this review. The included study (which compared donepezil with rivastigmine) noted that over 2 years there was no statistically significant difference between rivastigmine and donepezil for cognitive outcomes (MMSE and SIB). Patients taking rivastigmine had significantly improved outcomes than those taking donepezil in the primary analysis of functional outcomes (p = 0.007–0.047). No significant difference was seen between donepezil and rivastigmine for behavioural outcomes (NPI). The study showed that patients taking rivastigmine did significantly better than those taking donepezil in terms of global outcomes (GDS). However, the manufacturer of donepezil stated that this study did not meet its primary endpoint and showed higher discontinuations and higher rates of some adverse events for rivastigmine compared with donepezil. None of the newly identified, head-to-head, randomised studies investigated quality of life with the technologies under assessment, and no such data were identified in NICE technology appraisal guidance 111. The most common adverse effects reported in the head-to-head studies of the AChE inhibitors were nausea, diarrhoea, vomiting and headache.
If data were sufficient, the Assessment Group pooled information on all technologies and their comparators simultaneously in a mixed treatment comparison, using Bayesian Markov Chain Monte-Carlo sampling, which showed the probability of each treatment being the most clinically effective. The results of the mixed treatment comparison varied depending on the symptom assessed, the instrument used and follow-up time. The Assessment Group included a systematic review, including a meta-analysis, that concluded that the AChE inhibitors provided benefits in terms of cognitive function and activities of daily living, and galantamine improved psychological symptoms in mild to moderate dementia. Another concluded that for the AChE inhibitors and memantine there was a small effect size in mild to moderate Alzheimer's disease.
## Moderate to severe Alzheimer's disease
The Assessment Group found one new randomised controlled trial for memantine monotherapy versus placebo. The manufacturer of memantine submitted estimates of clinical effectiveness for the general population with moderate to severe Alzheimer's disease and a subgroup of patients with agitation, aggression and/or psychotic symptoms. The manufacturer submitted a meta-analysis that had used individual patient data from six 6-month randomised controlled trials. The first three trials were in moderately severe to severe disease and the other three were in mild to moderate disease. The Assessment Group had excluded trials in which at least 20% of the study participants had mild disease because this was outside the marketing authorisation for memantine. The manufacturer included data from patients with moderate disease only in these trials using the individual patient data. In addition, the manufacturer included trials of monotherapy and combination therapy in the pooled results presented in this section whereas the Assessment Group analysed each separately. Evidence from prospective longitudinal and observational studies was also presented.
One new randomised controlled trial of memantine monotherapy included by the Assessment Group showed a statistically significant benefit in a cognitive measure using SIB with memantine compared with placebo. When data from this trial were added to those of NICE technology appraisal guidance 111, a statistically significant benefit was reported at 12 weeks, but this was not maintained at 24–48 weeks (mean changes from baseline versus placebo of 4.147 and 3.254 at 12 and 24–28 weeks using SIB score). Studies included in the manufacturer's meta-analysis for memantine reported a statistically significant benefit in ADAS-cog and SIB compared with placebo at the end of study and at 24 weeks (standardised mean difference = −0.26, p < 0.0001).
The results from the new study included by the Assessment Group showed no significant benefit in functional outcome measured by ADCS-ADL for memantine monotherapy compared with placebo at 12 weeks or when measured with the Functional Assessment Staging (FAST) instrument. The data were synthesised with the existing evidence in random-effects meta-analysis. Two studies provided data for functional effect as measured by ADCS-ADL19 version. The results were not statistically significant at 12 weeks and were only just significant at 24–28 weeks (mean changes from baseline versus placebo of 0.877 and 1.408 at 12 and 2428 weeks respectively using ADCS-ADL score and −0.341 at 24–28 weeks respectively using FAST score). The manufacturer's meta-analysis for memantine in moderate to severe disease showed a statistically significant difference compared with placebo on the ADCS-ADL19 and ADCS-ADL23 (standardised mean difference = −0.18, p < 0.0007).
The study for memantine monotherapy that was published after 2004 and included by the Assessment Group measured behavioural outcomes using NPI and the Behavioural Rating Scale for Geriatric Patients (BGP). Neither measure showed a statistically significant benefit of memantine. The data were pooled with the existing data at 24–28 weeks, which did not show a statistically significant gain from memantine compared with placebo (a mean change from baseline versus placebo of −1.608 (p = 0.314) at 24–28 weeks using NPI score). The results of the meta-analysis by the manufacturer of memantine in moderate to severe disease showed a statistically significant (p = 0.03) benefit in terms of NPI and NPI-Nursing Home version (standardised mean difference = −0.12, p = 0.03).
According to the Assessment Group, one new study for memantine monotherapy measured global outcomes with the CIBIC-plus but the differences found were not statistically significant. When new data were pooled with the existing studies, the overall pooled estimate showed a statistically significant beneficial effect from memantine compared with placebo (a mean change from baseline versus placebo of −0.300 at 24–28 weeks using CIBIC-plus score). Studies included by the manufacturer in the meta-analysis for memantine used CIBIC-plus or the Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC). The standardised mean difference in the manufacturer's meta-analysis for memantine in moderate to severe disease for global outcomes (CIBIC-plus) compared with placebo was statistically significant (standardised mean difference = −0.22, p < 0.0001).
The Assessment Group noted that none of the new randomised studies included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with memantine.
The manufacturer of memantine included an analysis of a subgroup of patients with moderate to severe Alzheimer's disease with agitation, aggression and/or psychotic symptoms to show that memantine offers enhanced benefits in this subgroup in terms of cognition and function. The manufacturer also included an indirect comparison with risperidone, which was not a comparator in the scope and therefore outside the scope of this review. This analysis was not included by the Assessment Group because no subgroup analyses or individual patient data had been published. The MAG-D study was ongoing at the time of writing the assessment report, so was not included by the Assessment Group. In addition, the manufacturer of memantine submitted data from prospective longitudinal and observational studies to support the view that cognitive and functional benefits of memantine are maintained over years, that memantine delays time to institutionalisation, reduces the need for antipsychotic use and that discontinuation of memantine is associated with an increased use of antipsychotics compared with continuous memantine treatment.
According to the Assessment Group, the proportion of any adverse events for memantine in the new study was similar in treatment and control groups (treatment = 74%, control = 73%). The main adverse events in the memantine group were agitation and hypertension, and agitation and falls in the control group. This did not change assumptions about the safety of memantine from technology appraisal guidance 111. The manufacturer highlighted a published meta-analysis of safety data from clinical trials which also showed the most common adverse events with memantine to be agitation and falls. However, it noted that both have a numerically lower incidence than placebo.
The Assessment Group found one new study of memantine in combination with any of the AChE inhibitors. It assessed the clinical effectiveness of memantine combination therapy separately from monotherapy. This was different from the approach taken in NICE technology appraisal guidance 111 and by the manufacturer of memantine. The Assessment Group found one new trial that compared memantine plus a stable dose AChE inhibitor with an AChE inhibitor plus placebo. This trial did not show any benefit from combining memantine with an AChE inhibitor on cognitive, functional, behavioural or global outcomes. A trial that compared memantine plus donepezil with donepezil plus placebo was included in NICE technology appraisal guidance 111. Pooling the new trial with the previous trial of memantine in combination with an AChE inhibitor did not show any additional benefit from combination therapy. The manufacturer of memantine commented that its submitted meta-analysis of six trials showed memantine to be significantly superior to placebo on most outcomes, as adjunct and monotherapy. It also stated that interaction between treatment effect and presence of background treatment was found not to be significant.
The manufacturer of memantine referred to safety reports since 2002, two safety reviews and a meta-analysis. It concluded that memantine was well tolerated when used as monotherapy or as combination therapy.
## Summary
The Assessment Group identified 17 new randomised controlled trials and four systematic reviews of randomised controlled trials. According to the Assessment Group, there was an increase in the amount and precision of available evidence for the clinical effectiveness of the AChE inhibitors and memantine. For the AChE inhibitors, the new studies supported and strengthened the previous evidence of benefit in terms of cognitive outcomes, but results for other outcomes were mixed. For memantine monotherapy, the new evidence did not support evidence of statistically significant benefit compared with placebo for any outcome, but the pooled evidence with previous evidence from before 2004 showed improvement in cognition at 12 weeks and in function at 24–28 weeks.
The Assessment Group concluded that the evidence for monotherapy in the three manufacturer's submissions was broadly consistent with its own, but highlighted that there were differences between the studies included by the manufacturers and its own review. In addition, the Assessment Group analysed monotherapy and combination therapy separately, whereas the manufacturer of memantine combined the two in its submitted meta-analysis.
The Assessment Group considered the quality of the new placebo-controlled studies published since 2004 to be 'disappointing'. Issues included the inappropriate use of last observation carried forward and observed cases analysis instead of intention-to-treat analysis, inadequate reporting of randomisation and allocation, and the small size of studies for donepezil in particular. According to the Assessment Group, the robustness of the new evidence provided by the head-to-head studies was limited by the poor quality of all but one of the studies. Important gaps in the evidence remain.
# Cost effectiveness
The Assessment Group conducted a systematic review of published economic evaluations since 2004. The Assessment Group, the manufacturer of donepezil (Eisai/Pfizer) and the manufacturer of memantine (Lundbeck) submitted new economic models. The Assessment Group's model included all technologies. Because of differences in the marketing authorisations, the base-case cost effectiveness of the AChE inhibitors and memantine were modelled separately in mild to moderate and moderate to severe disease respectively. No new economic models were submitted by the manufacturers of galantamine and rivastigmine. The manufacturer of galantamine highlighted issues with the previous model from NICE technology appraisal guidance 111.
## Mild to moderate Alzheimer's disease
The Assessment Group conducted a systematic review of published economic evaluations since 2004. It identified eight studies of cost effectiveness specifically for donepezil and one that reported on the cost effectiveness of both donepezil and rivastigmine. According to the Assessment Group, these publications generally supported the cost effectiveness of donepezil in the treatment of mild to moderate Alzheimer's disease.
Manufacturer's model for donepezil
The manufacturer of donepezil submitted an economic model that compared the cost effectiveness of donepezil with best supportive care in people with mild to moderate Alzheimer's disease using a discrete event simulation approach over a lifetime. The baseline characteristics of the model population (including age, sex, race, measures of cognition , function , behaviour and concomitant treatments) were based on 221 people with mild disease and 605 people with moderate disease from a pool of three randomised controlled trials. The model used a weighted sampling approach to sample 1000 individuals from the pooled trial populations, and these individuals were then replicated in the model and allocated to donepezil or no AChE inhibitor treatment. Disease progression and treatment effect were measured using cognition (MMSE), activities of daily living (ADL and IADL) and behaviour (NPI). Regression equations were formulated based on data from a US registry (the CERAD study) and seven donepezil clinical trials spanning mild to severe Alzheimer's disease and including data from two open-label extensions of the studies. The updated MMSE score was then used to predict the change in ADL, IADL and NPI. The proportion of people institutionalised depended on severity of Alzheimer's disease.
The effectiveness of donepezil in the manufacturer's model was derived from a meta-analysis of six pooled randomised controlled trials and assumed the same treatment effect for both mild and moderate Alzheimer's disease. The model updated patient characteristics every 3 months. Discontinuation data were taken from 88 patients. Patient utilities were based on a Swedish study using the EQ-5D and carer proxy responses. Carer utilities were estimated using SF-36 scores and the Brazier algorithm from three clinical trials. Carer utility accounted for approximately 10% of the incremental quality-adjusted life years (QALYs) but did not include the impact on carer utility of patients entering an institution. NHS and personal social services costs were included along with costs to the individual and their family. NHS reference costs, list drug prices (including a price reduction effective after the November 2009 Pharmaceutical Price Regulation Scheme, which was later published in the BNF60) and a report by Dementia UK (2007) were used for cost estimates, which were inflated to current prices. Costs included a consultation visit that took place every 6 months during treatment. Cost and benefits were discounted at 3.5%.
The manufacturer's base-case results estimated that donepezil dominated best supportive care because it was less costly and more effective in people with mild, moderate and mild to moderate Alzheimer's disease. The manufacturer reported per patient QALY gains of 0.133 and 0.098 and estimated total per patient cost saving of £3379 and £1889 for groups with mild and moderate disease respectively. When the overall mild to moderate disease population was considered, total cost savings amounted to £2354 and people gained an average of 0.109 QALYs including patient utility alone, and 0.121 including patient and carer utilities. The manufacturer of donepezil estimated a delay to institutionalisation of 2 months.
All but one of the one-way sensitivity analyses conducted by the manufacturer of donepezil in the mild and moderate disease populations (including varying the time horizon, discount rate, MMSE progression, treatment effect, discontinuation, treatment duration, costs of care, costs of nursing home care, patient and carer QALY effect, costs of physician visits, and the 30–50% reduced price of donepezil after loss of patent protection in 2012) resulted in donepezil being dominant. The exception was when nursing home costs were reduced by 50%, which changed the incremental difference in costs from a cost saving of £3379 in the base case to an increased cost of £275, which gave an incremental cost-effectiveness ratio (ICER) of £1866 per QALY gained for mild Alzheimer's disease. When nursing costs were reduced in the moderate disease population, the costs were increased from a cost saving of £1889 in the base case to a cost of £1370, giving an ICER of £7093 per QALY gained. The probabilistic sensitivity analysis reported a 74% and 70% probability of donepezil being cost effective at a threshold of £20,000 per QALY gained in the mild and moderate disease populations respectively (and a 78% and 74% probability respectively at a threshold of £30,000 per QALY).
Issues raised by the Assessment Group included:
the generalisability of the CERAD (US-based) study
potential double counting of improvement in MMSE score in the regression equations for NPI, ADL and IADL
the data for the probability of needing institutionalised care being based on a nursing home population
uncertainty about the quality of inputs, including the link that was made between MMSE and institutionalisation and overestimation of treatment effect
excluding a possible increase in carer utility after institutionalisation
including non-NHS/personal social services costs
including cost and utility inputs based on a cohort approach
uncertainties about the probabilistic sensitivity analysis.
The Assessment Group made several changes to the manufacturer's model, which included corrected MMSE scaling, hazard calculations and life expectancy. These amendments had little impact on the manufacturer's deterministic and probabilistic ICERs, which continued to show that donepezil dominated best supportive care in mild and moderate Alzheimer's disease. The Assessment Group also ran its own assumptions through the model and this also did not change the outcome of dominance.
In response to comments in the assessment report, the representative of the manufacturer of donepezil stated that the improvement in MMSE score had not been double counted in its model. The manufacturer also clarified that a survival effect had not been included.
The Assessment Group conducted a systematic review of published economic evaluations since 2004. It identified one study of cost effectiveness specifically for rivastigmine, two for galantamine, and one that reported on the cost effectiveness of both donepezil and rivastigmine. According to the Assessment Group, these publications generally supported the cost effectiveness of the AChE inhibitors in mild to moderate Alzheimer's disease. Most of the publications applied the existing model of Alzheimer's disease (from NICE technology appraisal guidance 111) to new settings.
The manufacturers of galantamine and rivastigmine did not submit new economic models. The manufacturer of galantamine highlighted issues with the previous model from NICE technology appraisal guidance 111 including:
the need to include long-term efficacy data
recognition of the full impact of decline in untreated patients with mild disease
-verestimation of mortality
the need for current cost data
recognition of 'no change' on global efficacy after 6 months or longer
consideration of costs to the individual, carer time and costs
exploration of responder analyses.
The Assessment Group modelled the cost effectiveness of the AChE inhibitors and memantine separately because of the differences in the marketing authorisations. The base-case model for the AChE inhibitors followed a cohort of 1000 individuals with mild to moderate (MMSE 26–10) Alzheimer's disease for which the comparators were donepezil, rivastigmine (patch and capsule), galantamine and best supportive care. The Assessment Group used a prevalent cohort approach. Differentiation of treatment effect according to severity of disease (that is, mild or moderate) was not included in the base-case model. Populations with mild and moderate disease were assessed individually in the sensitivity analyses.
The Assessment Group's base case for mild to moderate disease evaluated the cost effectiveness of the AChE inhibitors over a lifetime (20-year) time horizon. Memantine was not included in the base case for mild to moderate disease. The Assessment Group constructed a Markov model that estimated the time to institutionalisation, which was defined as 'living in a residential home or a nursing home (not short respite care) or in a hospital on a long-term or permanent basis'. The model included three health states: pre-institutionalisation, institutionalisation and death. Depending on the severity of Alzheimer's disease at the beginning of the model, people could enter the model in the pre-institutionalised or institutionalised health state. Institutionalisation was equivalent to severe Alzheimer's disease (MMSE < 10) at which point treatment with an AChE inhibitor stopped in line with the marketing authorisations. Individual patients' data were used to estimate the proportion of the total cohort in each state at the end of each monthly cycle. An exponential survival regression model was fitted with time to end of pre-institutionalisation (including early death) as the response variable and MMSE, Barthel-ADL and age at start of study as covariates. The model incorporated a gradual increase in costs and gradual reduction in health-related quality of life with time. Cost and benefits were discounted at a rate of 3.5%. A constant rate of 4% discontinuation per monthly cycle for all drugs at all doses was assumed following a review of the included clinical trial evidence. Therefore within 25 months all patients were assumed to have stopped treatment.
Patient characteristics (cognition and function with three subgroups defined by age) were based mainly on individual patients' data from a community-based cohort study of people with untreated Alzheimer's disease by Wolstenholme and colleagues in Oxfordshire (n = 92). People starting in the model had already been diagnosed with Alzheimer's disease for a median of 4.0 years and a mean of 4.9 years. Data from the London and South-East Region Alzheimer's Disease (LASER-AD) study were used to predict the proportion of patients who, at the start of the decision model, were in the institutionalised state (10% for the mild to moderate cohort and 40% for the moderate to severe cohort, based on 5.6% of people with MMSE ≥ 19, 27.1% of people with MMSE 1519 and 59% people with MMSE < 19). In the base-case analysis, it was assumed that treatment delayed time to institutionalisation but not to death. Time to death was predicted by age, cognition (MMSE) and function (ADL) using equations from the Wolstenholme cohort data.
Estimates of treatment effect in the Assessment Group's model (MMSE and ADCS-ADL, in particular) taken from the placebo-controlled randomised controlled trials identified in the systematic review of clinical effectiveness were applied to baseline estimates of best supportive care for time to institutionalisation and death. Estimates of clinical effectiveness were slightly different to those in the clinical effectiveness section of the assessment report in that only randomised controlled trials of licensed doses were considered. Rivastigmine patches were considered separately to capsules. The assessment report noted literature highlighting that patients self-report much higher utilities than those estimated by carers, particularly in people with severe Alzheimer's disease. Therefore, the base-case model included patient utilities based on carer-proxy utility values. Self-reported patient utilities and carer utilities were included in the sensitivity analysis. Carer utility associated with caring for patients with different CDR severities of Alzheimer's disease was mapped onto the MMSE scale. The utility of caring for someone with mild dementia (MMSE 21–26) was 0.87, which was reduced to 0.86 when caring for someone with severe dementia (MMSE of less than 10). The source publication (Jonsson and colleagues) reported only the mean utility values and not the uncertainty in the utility estimates.
The monthly drug costs included in the Assessment Group model, based on the BNF edition 58, were £83 for galantamine, £97 for donepezil, £79 for rivastigmine patches, and £72 for rivastigmine capsules. Additional resource use in the Assessment Group's model was estimated from the Wolstenholme cohort study. The cost of outpatient visits was assumed to be £26 per month and £158 for a 6-monthly assessment. The overall mean monthly cost of institutionalised care was estimated at £2941 (28% of which was assumed to be self-funded) and the cost of pre-institutionalised care depended on the severity of disease and the time to institutionalisation (for example, 1 year before institutionalisation the mean monthly costs for people with mild to moderate Alzheimer's disease was £1938 per month compared with £2427 per month for people with moderate to severe Alzheimer's disease). No adverse events or carer costs were included in the economic model.
After comments from consultees and commentators on the assessment report, the Assessment Group made changes to the modelling of treatment effect based on the equations predicting time to institutionalisation and overall survival using age, cognition and function, and the resulting ICERs quoted in the assessment report. The Committee considered the revised outputs only.
The Assessment Group presented the revised deterministic ICERs and one-way sensitivity analysis (which included an analysis of the robustness of the ICERs to different structural assumptions) and the probabilistic ICERs (which represent the combined effect of some of the parameter uncertainties in the model) for each of the technologies. The deterministic model estimated that treatment with an AChE inhibitor delays time to institutional care by between 1.4 and 1.7 months. The deterministic base-case analyses and the probabilistic sensitivity analysis indicated that all AChE inhibitors dominated best supportive care. Galantamine was associated with the least costs (£69,592 compared with £70,212 for best supportive care) but donepezil was associated with the greatest QALY gains (1.619 compared with 1.584 with best supportive care). The Assessment Group noted that the differences in the costs and QALYs between the AChE inhibitors were very small (total costs ranged from £69,592 to £69,678 and total QALYs ranged from 1.613 to 1.619). The probabilistic sensitivity analysis results did not indicate a particular AChE inhibitor as having a much greater probability of being cost effective compared with any of the other AChE inhibitors. For example, rivastigmine patches had the highest probability (32%) of being cost effective at thresholds of £20,000 and £30,000 per QALY gained, whereas donepezil had a probability of 27% of being the most cost-effective treatment option at a threshold of £20,000 and of 28% at a threshold of £30,000 per QALY.
The Assessment Group conducted one-way sensitivity analyses on the sensitivity of the ICERs to different parameters. The most important parameters were whether a treatment effect on survival was assumed and the rate of discontinuation of drug therapy. Assuming that there was a positive effect of treatment on mortality for all treatments of 1.9 to 2.2 months, it was estimated that treatment with rivastigmine patches provided an additional 0.077 QALYs per patient compared with best supportive care, with additional costs of £2840, leading to an ICER of £37,100 per QALY gained. This was in contrast to rivastigmine patches dominating best supportive care in the base case. In the incremental analysis, when including survival effect as a one-way sensitivity analysis, treatment with galantamine or donepezil provided additional QALYs and additional costs compared with rivastigmine patches. This led to ICERs of £41,800 per QALY gained for galantamine compared with rivastigmine patches, and £51,800 per QALY gained for donepezil compared with galantamine. The Assessment Group explained that this increase in the ICER was expected because when no survival effect was assumed (as per the base case), the delay in time to institutionalisation with treatment resulted in substantial savings in the costs that would have been incurred as a consequence of living in an institution. Assuming that there was also a survival benefit with treatment meant that the costs incurred from living in an institution would be delayed, but not saved. Therefore the incremental difference in costs would be higher and the ICER would increase. Lowering the estimate of the discontinuation rate below 4% resulted in greater treatment and monitoring costs and this led to a negative net benefit for the AChE inhibitors. Higher estimates led to fewer costs and greater net treatment benefit.
The manufacturer of donepezil and the Assessment Group both reported that donepezil treatment dominated best supportive care for both the mild and moderate populations. However, the manufacturer reported per patient QALY gains of 0.133 and estimated total per patient cost savings of £3379 for people with mild disease compared with 0.034 QALY gains and a saving of £551 in the Assessment Group's model. The manufacturer reported per patient QALY gains of 0.098 and estimated total per patient cost savings of £1889 for people with moderate disease compared with 0.035 QALY gains and a saving of £621 in the Assessment Group's model.
Differences between the results of Assessment Group and manufacturer's models may be accounted for by the following:
differences between the models in terms of estimated overall survival (4.6 undiscounted life years for the moderate cohort for the manufacturer compared with 3.6 years for the Assessment Group)
percent of remaining lifetime spent living in the community (40% in the manufacturer model compared with 67% in the Assessment Group's model for the moderate cohort)
assumptions of treatment effect, calculation of pre-institutionalisation cost (MMSE in the donepezil model compared with time to institutionalisation in the Assessment Group's model)
differences in the cost of institutional care (£2801 per month in the donepezil model compared with £2117 in the Assessment Group's model)
inclusion of carer utility
inclusion of non-NHS/personal social services costs (that is, costs to the individual of institutional care).
The Assessment Group also considered the differences in its model compared with the model from NICE technology appraisal guidance 111 (the SHTAC model). The key differences in the Assessment Group's model were that:
the sources used to model disease progression were different
updated estimates of costs and effectiveness were used
costs and utilities were varied according to time before institutionalisation
discontinuation of treatment was accounted for. The SHTAC model used a risk equation to predict time to needing full-time care. This was based on US data (n = 236), in which a number of different domains (ADAS-cog, psychiatric symptoms, extrapyramidal symptoms, age of onset and duration of illness) affected the time to institutionalisation. The Assessment Group's model, in contrast, was based on UK data (n = 92) and assumed that age and MMSE score predicted institutionalisation. The results of the models differed in the time spent in the institutionalised or full-time care states, which consequently affected costs. A longer estimated survival in the SHTAC model compared with the Assessment Group's model (6.5 compared with 3.8 years) led to higher total costs and total QALYs in the SHTAC model. The Assessment Group assumed less of a treatment effect for an AChE inhibitor, which translated to a slightly shorter delay to full-time care or institutionalisation (approximately 2 months in the SHTAC model compared with 1.4 to 1.7 months in the Assessment Group's model). The costs in the pre-institutional state in the Assessment Group's model were varied according to time, which led to lower average costs in the pre-institutional state in the Assessment Group's model. The difference in incremental costs in the Assessment Group model compared with the SHTAC model was a key factor in the different estimates of costs effectiveness (for example, an ICER of over £30,000 per QALY gained in the SHTAC model for donepezil, compared with donepezil dominating best supportive care in the Assessment Group's model). Including discontinuation of treatment in the Assessment Group's model led to fewer costs and greater net benefit associated with the AChE inhibitors, and so when discontinuation of treatment was included in the SHTAC model, this reduced the estimated ICER.
The Assessment Group noted some limitations of its model. These were that:
it assumed a treatment benefit in cognition and function but not in behavioural and psychological symptoms
the expression of treatment effectiveness was mainly based on delay in time to institutionalisation
changes in cost and utility before institutionalisation were assumed to be delayed by the same amount of time as institutionalisation
the generalisability of the Wolstenholme cohort to the UK population was uncertain
full treatment effect at 6 months was assumed. The Assessment Group presented the deterministic ICER for each treatment to provide a comparison with best supportive care so that the data were comparable with those presented in NICE technology appraisal guidance 111.
## Moderate to severe Alzheimer's disease
The Assessment Group's systematic review of literature published since 2004 identified six new cost-effectiveness studies for memantine. According to the Assessment Group, these publications generally supported the cost effectiveness of memantine for the treatment of Alzheimer's disease.
Manufacturer's model for memantine
The manufacturer submitted a Markov cohort model of the cost effectiveness of memantine compared with best supportive care over a 5-year time horizon in people with moderate to severe Alzheimer's disease and a subgroup of people with aggression, agitation and/or psychotic symptoms at baseline based on the NPI scale (at least one domain among agitation/aggression, delusion and hallucination with a score ≥ 3). The model included three states: pre-full-time care; full-time care; and death. Full-time care was defined as either dependent or institutionalised. Transition probabilities, including the baseline probability (on no treatment) of moving from pre-full-time care to full-time care and the probability of death were estimated using data from the LASER-AD UK epidemiological study. Predictors of the length of time to patients entering full-time care included measures of cognition (ADAS-Cog), function (ADCS-ADL), behaviour (NPI) and time in months. The clinical effectiveness of memantine, for which no additional benefit was assumed beyond 6 months, was based on a meta-analysis of six clinical trials of patients with moderate to severe Alzheimer's disease receiving memantine monotherapy or memantine adjunct treatment while on a stable dose of AChE inhibitors. Weighted mean differences were used as predictors in the risk equation estimating monthly probability of entering full-time care to incorporate treatment effect. NHS and personal social services costs were included. Resource use data were taken from the LASER-AD study and the Personal Social Services Research Unit (PSSRU). MIMS March 2010 was used for costs, which were discounted at 3.5%. Indirect costs and quality-of-life effects on relatives and carers were not included. Utility estimates were derived from the LASER-AD study, which involved mapping of three instruments (HSQ-12, Ferm's D test and QoL-AD) onto the EQ-5D. The manufacturer ran the model probabilistically.
The manufacturer found that memantine dominated best supportive care (that is, no pharmacological treatment) because additional QALYs were gained (0.031) at a cost saving of £1711. Memantine treatment was associated with a delay to full-time care of 6 weeks. Additional treatment benefits were reported in the subgroup of patients with aggression, agitation and/or psychotic symptoms in whom the delay to full-time care was prolonged by up to 11 weeks with incremental QALY gains of 0.069 and a cost saving of £4971.
The manufacturer conducted sensitivity analyses. These explored the effect of different treatment effects, discount rates, costs of pre-full-time care, costs of full-time care and alternative sets of utilities on the cost-effectiveness estimates. The results all continued to show that memantine dominated best supportive care for the overall population and subgroups.
The Assessment Group highlighted several issues with the manufacturer of memantine's model. Although the new subgroup was defined differently and based on clinical expertise, the Assessment Group noted that a behavioural subgroup had not previously been accepted by the Appraisal Committee for NICE technology appraisal guidance 111. The manufacturer did not include an AChE inhibitor as a comparator for the population with moderate disease as specified in the scope. There was uncertainty about the risk equation because of lack of clarity over generalisability of the LASER-AD study (many participants in this study had been or were still receiving treatment with AChE inhibitors). The Assessment Group also noted a lack of clarity about the categorisation of 'dependence', inclusion of data from patients with mild disease, poor reporting of statistical analyses and lack of validation from an external source. The manufacturer responded to these criticisms, providing supplementary information in its comments on the assessment report. In addition, because the trials used observed cases with last observation carried forward in the analysis instead of an intention-to-treat analysis, the Assessment Group was concerned that the clinical-effectiveness estimates may have been biased. The manufacturer responded to these comments to confirm that all analyses were performed with an intention-to-treat population using the observed cases approach, with a 'last observation carried forward' analysis to confirm results. There was also uncertainty about the methods used to map one outcome measure to another (mapping one health-related quality-of-life measure onto another, mapping SIB onto the ADAS-cog and rescaling one version of ADCS-ADL to another), pooling data for combination therapy and monotherapy, and using NPI rather than NPI hallucinations as a predictor of time to full-time care. There was also a lack of clarity over the sources of data, inclusion of costs to individuals and retrospective collection of resource data in the LASER-AD study. Benefits to carers were not included in the model, and mapping of health-related quality-of-life data to EQ-5D was poorly described. The Assessment Group queried whether the manufacturer's estimates of at least 90% for the probability of memantine being cost effective at £20,000 and £30,000 thresholds were plausible given the uncertainties about the clinical benefit of memantine.
The cost effectiveness of the AChE inhibitors and memantine were modelled separately by the Assessment Group because of the differences in the marketing authorisations. Memantine was not included in the SHTAC model in NICE technology appraisal guidance 111. The base-case model for memantine followed a cohort of 1000 individuals with moderate to severe (MMSE 200) Alzheimer's disease, for which the comparator was best supportive care. Populations with moderate and severe disease were assessed individually in the sensitivity analyses. The Assessment Group's model is described in sections 4.2.12 to 4.2.16. Different assumptions used in the moderate to severe model were that a higher proportion of people started in institutional care (40% compared with 10% in the mild to moderate model) and treatment with memantine was continued after people entered institutional care (whereas treatment with AChE inhibitors was discontinued when people entered institutional care in the mild to moderate model). The cost of monthly memantine was £71.
The deterministic Assessment Group's model showed that treatment with memantine delayed time to institutional care by about 0.8 months compared with best supportive care. The ICERs were £32,100 per QALY gained (a gain of 0.013 QALYs over a patient's lifetime when treated with memantine compared with best supportive care and the extra cost was £405).
The Assessment Group's probabilistic sensitivity analysis of the cost effectiveness of memantine in the population with moderate to severe Alzheimer's disease estimated a probability of memantine being more cost effective than best supportive care of less than 38% at a threshold of £30,000 per QALY gained and 28% at £20,000 per QALY gained. The mean ICER from the probabilistic sensitivity analysis for memantine compared with best supportive care was £36,900 per QALY gained.
The Assessment Group conducted one-way sensitivity analyses to assess the sensitivity of the ICER to different parameters. When a positive treatment effect on survival was assumed, the ICER of memantine compared with best supportive care increased to £65,619 per QALY gained.
The cost-effectiveness model submitted by the manufacturer of memantine reported that treatment with memantine dominated best supportive care. The Assessment Group's model, however, estimated an ICER of £32,100 per QALY gained. One of the main differences between the manufacturer's model and the Assessment Group's model was that treatment was assumed to continue in institutionalisation by the Assessment Group but not the manufacturer. The estimated overall survival was similar in the two models (3.7 years in the manufacturer's model and 3.5 years in the Assessment Group's model). Another key difference between the models was that the manufacturer's model assumed a greater treatment effect with memantine, which translated to a delay to entering full-time care of 1 month compared with a delay of 0.8 months estimated by the Assessment Group's model. Higher costs were attributed to the full-time care state in the manufacturer's model (£3267 compared with £2117 in the Assessment Group's model). The manufacturer's model also assumed a higher cost of, and a longer time in, pre-institutional care with treatment (1.73 years in the manufacturer's model compared with 1.5 years in the Assessment Group's model).
The Assessment Group ran the manufacturer of memantine's model using its own assumptions. This had a negligible impact on the outputs.
The Assessment Group conducted analyses of the individual mild, moderate and severe populations for the AChE inhibitors, AChE inhibitors and memantine, and memantine respectively (all including best supportive care). Each technology was compared with the next cheapest, non-dominated technology and the ICERs were rounded to the nearest £100. The Assessment Group highlighted that caution should be taken when assessing these results because effectiveness estimates were derived from trials that included populations with varying disease severity. In the subgroup analyses for mild or moderate Alzheimer's disease, all treatments still dominated best supportive care. Memantine had an ICER of £26,500 per QALY gained in severe disease.
## Other key issues
NICE technology appraisal guidance 111 acknowledged the issues in using the MMSE instrument alone as a measure of severity in particular groups. This included people with learning or other disabilities, linguistic or other communication difficulties, or if it is not possible to use the MMSE in a language in which the patient is sufficiently fluent.
Clinical specialists, patient experts and primary care trust commissioners highlighted the need for a wide range of services for people with Alzheimer's disease, and the fact that drugs are just one aspect of this range of care.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of donepezil, galantamine, rivastigmine and memantine having considered evidence on the nature of Alzheimer's disease and the value placed on the benefits of donepezil, galantamine, rivastigmine and memantine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee was aware that there is currently no cure for Alzheimer's disease and that the AChE inhibitors and memantine treat the symptoms of Alzheimer's disease but do not slow the progression of the disease. The Committee was also aware that access to general support services and care for people with Alzheimer's disease is variable and that the availability of pharmacological treatment was relevant to appropriate wider management and support. The Committee considered the current management of Alzheimer's disease under the recommendations of NICE technology appraisal guidance 111, which recommends AChE inhibitors for the treatment of moderate Alzheimer's disease. The Committee was aware of both the importance of early diagnosis and of carers' and clinical views of the advantages of early use of AChE inhibitors in the treatment of Alzheimer's disease. The Committee heard from clinical specialists that there is variation in clinical practice and that AChE inhibitors are also used to treat some patients with an MMSE score of above 20. The clinical specialists also noted that memantine is used in clinical practice. The Committee heard from clinical specialists that antipsychotics are used in clinical practice for people with Alzheimer's disease who have severe behavioural symptoms, but that their use was generally discouraged in people with milder symptoms because of the emerging evidence on increased risk of serious adverse events when used in older people.
The Committee heard from clinical specialists that the MMSE scale was originally developed as a screening tool to aid the diagnosis of Alzheimer's disease. It also heard that NICE technology appraisal guidance 111 had defined the eligibility of people for treatment with AChE inhibitors and when these drugs should be stopped according to MMSE scores (that is, the degree of loss in patient cognition), among other criteria. The Committee noted, as did the Appraisal Committee for NICE technology appraisal guidance 111, that because the MMSE scale is less sensitive to changes in cognition for people at the extreme ends of the scale, clinical judgement is necessary (rather than a rigid adherence to the MMSE alone) to assess the severity of Alzheimer's disease and the suitability of AChE inhibitors on an individual patient basis. In addition, the clinical specialists indicated that a global assessment of the effects of Alzheimer's disease was also important. The Committee was aware of the difficulties of using the MMSE when assessing people with learning difficulties or communication difficulties, or if the person is not fluent in the language of the measurement tool. The Committee also heard from clinical specialists that the use of the MMSE scale alone may not be sensitive enough to assess the severity of Alzheimer's disease in people with a high level of education. The Committee thus recognised the difficulties of using MMSE score alone to assess the severity of Alzheimer's disease and the response to AChE inhibitors. The Committee agreed that cognitive scales alone such as the MMSE are not always appropriate for assessing the severity of dementia. The Committee concluded that if cognitive scales are not appropriate for assessing the need for treatment, or whether to continue treatment, then clinicians should use another appropriate method of assessment.
## Clinical effectiveness
The Committee considered the available evidence on the clinical effectiveness of the AChE inhibitors submitted by the Assessment Group, consultees and commentators. It considered the new evidence available since NICE technology appraisal guidance 111 was published and the impact of the new evidence when combined with the data from NICE technology appraisal guidance 111. The Committee stated that a small amount of new evidence about the clinical effectiveness of the AChE inhibitors from randomised controlled trials had been published since 2004. The Committee recognised the heterogeneity of outcome measures in trials and was aware of the limitations of some of the instruments used in the clinical trials, including cognitive and behavioural scales.
The Committee considered the results from the new placebo-controlled randomised clinical trials, which continued to show the small but definite clinical benefit of the AChE inhibitors in mild and moderate Alzheimer's disease compared with best supportive care. The Committee noted that the evidence was almost exclusively based on 6-month long randomised controlled trials because few of these trials had follow-up of over 6 months. The Committee heard from clinical specialists and patient experts that benefits of treatment appeared to last for 2 to 3 years in some patients in open-label studies. The Committee concluded that the new evidence provided additional support to the conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain owing to mixed results from the available evidence.
The Committee considered whether there was evidence that one of the AChE inhibitors was more clinically effective than any other. The Committee noted that only one good-quality head-to-head randomised controlled trial comparing donepezil and rivastigmine had been published since 2004 and that this did not change the conclusions made in NICE technology appraisal guidance 111. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of clinical effectiveness.
The Committee considered whether there was evidence that AChE inhibitors demonstrated benefits in terms of patient and carer health-related quality of life. The Committee noted that quality of life was not assessed in the majority of randomised controlled trials and that there was no evidence from randomised controlled trials that demonstrated any impact. The Committee considered evidence from patient experts that benefits to people with Alzheimer's disease and their carers were not necessarily those picked up by instruments measuring cognition, function, behaviour or global outcomes. In their experience, relevant benefits included maintaining mood, being able to cope and interact with others, and functional activities that might not be scored on currently used scales, such as being able to pick up the phone or switch on the television. In particular, maintaining aspects of personal identity, such as a naturally methodical person being able to put things in order, was considered important. The Committee concluded that although there was no evidence available on health-related quality of life from a systematic review of randomised controlled clinical trials, there was some anecdotal evidence from clinical practice of benefits to patients and carers from using AChE inhibitors.
The Committee discussed whether there was evidence of a survival benefit associated with the AChE inhibitors. The Committee was aware that these are symptom-treating rather than disease-modifying treatments. In the absence of evidence from randomised controlled trials, the Committee considered the opinion of clinical specialists, who were not aware of a survival effect associated with the AChE inhibitors. The Committee acknowledged that few deaths occurred during randomised controlled trials, which have generally been short with limited follow-up, and that subsequently mortality data were difficult to obtain. The Committee considered the view of clinical specialists who informed the Committee that death was caused by factors such as age, acute infections, comorbidities and complications of Alzheimer's disease rather than the disease itself. The Committee noted that Alzheimer's disease affects predominantly, but not exclusively, people over 65 years of age. The Committee concluded that there was no evidence to suggest that the AChE inhibitors affected survival.
The Committee deliberated whether there was evidence that the AChE inhibitors lead to a delay in institutionalisation. The Committee acknowledged that time to institutionalisation was not generally included as an endpoint in randomised controlled trials and that published data were therefore limited. For example, the AD2000 study collected data on institutionalisation but limited accrual into the trial led to an underpowered conclusion about this outcome. The Committee considered the experiences of clinical specialists and patient experts, who reported that the following were often important factors in the decision to move into institutionalised care: severe behavioural symptoms and the ability of the person with Alzheimer's disease and their family to cope with these, continence issues, and the availability of community support services. Opinion varied between the experts about the degree of impact of the AChE inhibitors on time to institutionalisation. Although one clinical specialist felt that prescribing these drugs has led to a significant delay in people with Alzheimer's disease entering institutions, others thought that this effect was small and many other factors were in operation (such as funding arrangements for state-funded residential care). The Committee was also aware of the individual variability of disease progression, which would influence at what stage a person with Alzheimer's disease would be admitted to an institution. The Committee concluded that although it was clinically plausible that treatment with an AChE inhibitor may delay time to institutionalisation, limited direct evidence was available to assess the size of this effect.
The Committee considered the evidence on adverse effects associated with the AChE inhibitors. The Committee acknowledged the gastrointestinal effects of these technologies. However, it concluded that the adverse effects of these technologies were well documented and that overall evidence since 2004 has not changed the tolerability profile of AChE inhibitors, apart from the fewer side effects noted in patients treated with rivastigmine patches than with oral rivastigmine.
The Committee considered the available evidence on the clinical effectiveness of memantine submitted by the Assessment Group, consultees and commentators. The Committee understood that memantine had a different mode of action from the AChE inhibitors and in practice would be used later in the treatment pathway in people with more severe Alzheimer's disease, this also being at a time when a higher proportion of people develop behavioural symptoms. It considered the new evidence available since the publication of NICE technology appraisal guidance 111, and the impact of the new evidence when it was combined with the data from the previous appraisal. The Committee noted that two of the randomised controlled trials included in the manufacturer's submission were excluded from the Assessment Group's systematic review because at least 20% of each of the trial populations were people with mild Alzheimer's disease, which is not included in the current licensed indication of memantine.
The Committee considered the results of the new randomised controlled trials for memantine and the pooled results in order to estimate the size of clinical effectiveness for memantine compared with placebo or best supportive care. The Committee was aware of the limitations of the instruments used in the clinical trials including cognitive and behavioural scales. The Committee noted that although the new evidence considered by the Assessment Group did not substantially change the estimate of the clinical effectiveness of memantine compared with the review in 2004, the meta-analysis submitted by the manufacturer (which included individual patient data from trials with mixed populations so that the manufacturer was able to exclude data for patients with mild disease) showed significant benefits in the cognitive, functional, global and behavioural domains. The Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.
The Committee considered the evidence in the manufacturer's submission on the clinical effectiveness of memantine in a subgroup of patients with agitation, aggression and/or psychotic symptoms, which are more common in patients with severe Alzheimer's disease. This evidence reported a statistically significant benefit of memantine for cognitive, functional and global outcomes and NPI score on agitation, aggression and/or psychotic symptoms in this subgroup. The Committee concluded, on the basis of the manufacturer's evidence and clinical specialist testimony, that memantine appears to have an effect on these symptoms.
The Committee considered the clinical effectiveness of memantine as an adjunct to AChE inhibitor treatment. The Committee noted evidence that showed no statistically significant benefit for combination treatment with memantine and AChE inhibitors for cognitive, functional, behavioural or global outcomes. The Committee was also made aware of ongoing trials for combination therapy including the DOMINO-AD (donepezil and memantine in moderate to severe Alzheimer's disease) study. The Committee concluded that combination treatment with memantine and AChE inhibitors could not be recommended because of lack of evidence of additional clinical efficacy compared with memantine monotherapy.
The Committee considered the new evidence since 2004 of adverse effects associated with memantine and noted that some patients experience agitation that resolves when the drug is stopped, although agitation was also a main adverse event for those taking placebo. The Committee concluded that the adverse effects of memantine were well documented and that evidence since 2004 has not changed the tolerability profile.
## Cost effectiveness
The Committee reviewed the two economic models submitted by the manufacturers of donepezil and memantine alongside the Assessment Group's model. The Committee considered that the key differences between the models included the selection of cohort data used to model disease progression, model structure (Markov compared with a discrete event simulation), the extent to which the model included the effectiveness of treatment for cognitive, functional and behavioural outcomes, and the measurement of patient utility based on patient or carer proxy values.
The Committee considered the most appropriate cohort data on which to model disease progression. The Committee heard from clinical specialists about the importance of using data from the UK compared with the US because of differences in the healthcare system, and differences in the management of Alzheimer's disease. The Committee also heard from clinical specialists that UK population data such as that found in the Wolstenholme dataset is the best available data on which to model progression of Alzheimer's disease because of the UK location, its long follow-up, the absence of pharmacological treatment for Alzheimer's disease and the availability of individual patient data. The Committee was aware of the limitations of this dataset including the small population, the relatively old data (collected between 1988 and 1999), which might not reflect current rates of and times to institutionalisation, and the fact that the study was based in a semi-rural location. The Committee concluded that although the Wolstenholme dataset that formed the basis of the Assessment Group's model had these limitations it still represented the best available data.
The Committee considered the appropriateness of the structure of the Assessment Group's model, which was based on predicting time to institutionalisation. The Committee was aware that the uncertainty about time to institutionalisation was an issue that affected all submitted models. The Committee recognised the lack of institutionalisation data from randomised controlled trials, the limitations of the AD2000 study which collected institutionalisation data but was underpowered to measure this outcome, and the absence of a systematic review of observational studies available in this area. The Committee discussed the various definitions of institutionalisation. The Committee was aware that in clinical practice, the type of institution would have an impact on time to institutionalisation, as would cost and patient characteristics. The Committee was also aware that the Assessment Group had equated institutionalisation to severe disease, therefore assuming that AChE inhibitors would be stopped on entering an institution. However, the Committee acknowledged that in clinical practice, institutionalisation would not be based on disease severity alone. The Assessment Group used the definition of institutionalisation from the Wolstenholme cohort study, on which disease progression in its model was based.
The Committee considered that only the Assessment Group addressed the decision problem in the scope because it included all of the AChE inhibitors as comparators for mild to moderate Alzheimer's disease, whereas the manufacturer of donepezil's model compared donepezil with best supportive care only. The Committee concluded that there were limitations in constructing an economic model based on time to institutionalisation but that the Assessment Group's model was based on the best currently available and detailed UK evidence to evaluate the cost effectiveness of donepezil, galantamine and rivastigmine.
The Committee discussed the assumption in the Assessment Group's model that age, cognition and function were the key predictors of time to institutionalisation. The Committee was aware of the limitations of scales such as the MMSE in evaluating severity of and change in Alzheimer's disease and also as a proxy for the delay in time to institutionalisation. The Committee also understood that the Wolstenholme study had used a scale of function that had been mapped to another index (the Barthel index), which in turn had been mapped by the Assessment Group to a commonly used index of activities of daily living. The Committee was aware of the potential uncertainties caused by these processes. However, considering all these factors in relation to cognitive and functional scales, the Committee considered it appropriate to use age, cognition and function as key predictors of time to institutionalisation. The Committee considered whether behavioural symptoms should also have been included as a predictor of time to institutionalisation in the Assessment Group's model. The Committee was aware that the Assessment Group's model did not incorporate this because of lack of data. The Committee noted that the clinical specialists and patient experts had emphasised behavioural symptoms being a key factor when deciding when to admit a person with Alzheimer's disease to an institution. The Committee noted that when behaviour was removed from the manufacturer of donepezil's model in sensitivity analyses, it did not have a big impact on the incremental cost-effectiveness results. The Committee concluded that although behaviour was a potential predictor of time to institutionalisation in everyday life, its omission from a model already including cognition and function was unlikely to substantially change the outputs of the model in mild and moderate Alzheimer's disease.
The Committee considered the importance of the assumption that there was no survival effect of treatment. The Committee considered the sensitivity analyses conducted by the Assessment Group, which had assumed a survival effect of 1.9–2.2 months and subsequently raised the ICERs for the AChE inhibitors to over £30,000 per QALY gained. The Committee understood that this increase in ICERs was expected. This was because when no survival effect was assumed (as per the base case), the delay in time to institutionalisation with treatment resulted in substantial savings in the costs that would have been incurred as a consequence of living in an institution. Assuming that there was also a survival benefit with treatment meant that the costs incurred from living in an institution would be delayed, but not saved because people would live for longer. Therefore the incremental difference in costs was higher and the ICER increased. The Committee noted both the lack of randomised evidence measuring the survival effect of treatment with the AChE inhibitors and clinical opinion that mortality was more likely to be influenced by other factors unrelated to treatment. The Committee concluded that the assumption of no survival effect from treatment with the AChE inhibitors in the base-case model was appropriate in light of the lack of evidence of survival effect from randomised controlled trials.
The Committee considered the assumption of a 4% discontinuation rate of treatment in the Assessment Group's model. The Committee was aware that the Assessment Group's model included the ability to allow for discontinuation and this may have been one explanation for the difference in ICERs resulting from this model and the model used in NICE technology appraisal guidance 111 (the SHTAC model). The Committee considered how the Assessment Group had made the assumption of a constant rate of 4% based on the included randomised controlled trial evidence. For all effectiveness estimates it was assumed that an intention-to-treat analysis had been done, so that estimates related to all participants and not only those continuing on treatment. Given that many randomised controlled trials did not report an intention-to-treat analysis, this assumption was likely to over-estimate any treatment effects in the decision model. However, clinical specialists advised that discontinuation in clinical practice is between 2 and 5% per year and considered a 4% discontinuation rate to be appropriate. In addition, the Committee recognised that in sensitivity analyses, variation in the assumed discontinuation rate had the biggest impact on cost-effectiveness estimates. Increasing discontinuation rates led to fewer costs and greater net benefit for the AChE inhibitors and vice versa. The Committee concluded that it was appropriate to include discontinuation rates in the economic model and accepted that the assumption of 4% was plausible.
The Committee considered other inputs to the model, such as assumptions about the costs and QALYs generated in the pre-institutional and institutional health states of the Assessment Group's model. The Committee heard from the Assessment Group that the monthly costs of pre-institutional care and institutional care were higher in its model than in the SHTAC model. When the delay in institutionalisation was taken into account (1.4 to 1.7 months in the Assessment Group's model), donepezil treatment (the example selected by the Assessment Group) in the Assessment Group's model was cost saving compared with best supportive care because the additional costs incurred in pre-institutional care (increased drug costs, monitoring costs and care costs) were outweighed by the cost saving associated with people spending less time in institutional care. In the same way, the QALYs gained by delaying the time to institutionalisation outweighed the QALYs lost in the institutional care health state in the Assessment Group's model.
The Committee was aware that the cost of institutionalisation varied according to institution type and the level of care needed, the availability of institutional care and support services, and that funding arrangements for residential care can result in significant individual contributions by the patient or family. The Committee considered it acceptable to use an average cost for institutional care and accepted the fixed cost of institutionalisation used in the Assessment Group's model. Based on information provided by clinical specialists and patient experts, the Committee also accepted the assumptions in the Assessment Group's model about costs of monitoring the patient every 6 months.
The Committee considered whether assumptions and inputs about health-related quality of life and utilities included in the Assessment Group's model were reasonable. The Committee heard that utility values for health-related quality of life reported by patients themselves and by carers as proxy responses were both relevant. The Committee heard from clinical specialists that in early stages of the disease it would be appropriate for the patient themselves to report their own outcomes, but in more severe stages of the disease a proxy utility provided by the carer would be appropriate. The Committee acknowledged that there were differences in the responses given by patients and those given by carers but that in sensitivity analyses conducted by the Assessment Group, changes to utility values had a small impact on ICERs. The Committee concluded that the assumptions and inputs about utilities in the Assessment Group's model were appropriate.
The Committee also considered the Assessment Group's approach to a variable cost and utility in the pre-institutionalisation health state. The Committee acknowledged that this was a difference between the Assessment Group and SHTAC models, and may have accounted for some of the differences in the ICERs produced by the two models.
The Committee considered whether there were differences in cost effectiveness for particular subgroups of people with Alzheimer's disease. The Committee reviewed the subgroup analyses conducted by the Assessment Group in mild and moderate Alzheimer's disease. The Committee noted that these had been provided as an exploratory analysis by the Assessment Group and that the Assessment Group's model assumed the same treatment effect for patients with mild and moderate disease. The Committee was aware that in NICE technology appraisal guidance 111 a difference in treatment effect between mild and moderate populations was assumed, on the basis of analysis by the Medical Research Council Biostatistics Unit. The Committee was also aware that no subgroup analyses had been identified as part of the systematic review of clinical effectiveness analysis. The Committee also noted that in clinical practice, clinicians found it difficult to differentiate between mild and moderate disease when using the MMSE. The Committee was also aware that many AChE inhibitor trials included patients with both mild and moderate disease.
The Committee considered the merits of the Assessment Group's model compared with the manufacturer of donepezil's model. The Committee considered that both models captured the costs and benefits of treatment with greater accuracy than the SHTAC model used in the previous appraisal and that the manufacturer's discrete event simulation model offered an intuitive description of the disease. The Committee considered the enhancements in the Assessment Group's model compared with the SHTAC model and noted that the individual patient data on which disease progression in the Assessment Group's model was based, combined with the differential utility and costs accrued in the pre-institutional health state, led to a more accurate representation of the costs and outcomes of treatment. The Committee further noted that the discrete event simulation model provided by the manufacturer of donepezil (based on a US cohort) was unable to adequately compare all available treatment options within a full incremental analysis. Overall, the Committee preferred the Assessment Group's model over the discrete event simulation model because the modelling of disease progression (based on UK data from patients who had not received treatment with AChE inhibitors) was most appropriate for the UK clinical setting and the model enabled all of the treatments to be compared in a full incremental analysis. The Committee noted, however, that the manufacturer's model was useful to enable comparisons for specific parts of the decision problem and to test the inputs, assumptions and face validity of the Assessment Group's model. Both models showed donepezil to be cost saving.
The Committee considered the base-case results for the cost effectiveness of the AChE inhibitors compared with best supportive care. The Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation. This assumption led to less time spent in institutional care and subsequent savings to the NHS/personal social services. The Committee considered that, with this assumption, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.
The Committee noted the small difference in absolute costs and benefits between the AChE inhibitors. It also observed that small changes in some of the inputs and assumptions had significant impacts on the incremental estimates of cost effectiveness. The Committee concluded that overall, the AChE inhibitors donepezil, galantamine and rivastigmine had small but demonstrable clinical benefits and were cost-effective treatment options. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). The Committee further accepted that an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions (details of which can be found in the individual summaries of product characteristics) and dosing profiles.
The Committee considered the two models for the cost effectiveness of memantine presented by the manufacturer and the Assessment Group. It noted that although the structures of the models were similar, there were differences in the assumptions underlying the two models. The Committee considered that all the uncertainties about the assumptions and inputs in the Assessment Group's model for the AChE inhibitors also applied to the memantine model. However, the Committee identified additional uncertainties relating to memantine, such as estimates of treatment effect used in the models. The Committee considered the key differences between the Assessment Group's and manufacturer's models to be the selection of cohort data used to model disease progression, assumptions about the proportion of patients who were institutionalised at the start of treatment, the effectiveness estimates used in the model, and whether the model included the effectiveness of treatment on behavioural symptoms.
The Committee considered the cohort data on which disease progression in each of the models was based. The Committee was aware that the manufacturer's model used LASER-AD data to model disease progression, which had shorter follow-up compared with the cohort study used by the Assessment Group. It was also aware that many of the participants of the LASER-AD study were on active treatment. The Committee concluded that the Wolstenholme data used in the Assessment Group's model were more suitable for assessing disease progression because this study had longer follow-up and the participants were not receiving active therapies.
The Committee considered the assumptions included in the Assessment Group's model. The Committee acknowledged that some of the assumptions may have led to underestimates of the benefits of memantine compared with best supportive care. In the Assessment Group's model, for the 40% of patients with severe Alzheimer's disease who started in institutions or started with a low utility, there was limited opportunity to benefit from treatment, but they nevertheless accrue costs. The Committee therefore concluded that the cost effectiveness of memantine may have been underestimated in the Assessment Group's model for patients with severe Alzheimer's disease, although by how much is uncertain.
The Committee considered the appropriateness of including the impact of memantine on behavioural outcomes. The Committee was aware that the Assessment Group had not included behavioural outcomes as a predictor of time to institutionalisation in its model but the model submitted by the manufacturer of memantine had included behaviour as a predictor of time to full-time care. The Committee noted that the manufacturer's model used LASER-AD data to model disease progression, which included the effectiveness of treatment on behavioural symptoms. The Committee heard from the Assessment Group that when the impact of memantine on behavioural symptoms was removed from the manufacturer's model it had little impact on the cost effectiveness of memantine compared with best supportive care. The Committee was also aware, based on the evidence from the patient experts and clinical specialists, that behavioural outcomes were not well captured by the instruments used in clinical trials. The Committee concluded that although behaviour is a potential predictor of time to institutionalisation, not including it in the Assessment Group's model was unlikely to substantially change its outputs for people with moderate to severe Alzheimer's disease.
The Committee also noted that the manufacturer's submission included a subgroup analysis of the cost effectiveness of memantine in a subgroup of patients with aggression, agitation and/or psychotic symptoms. The Committee heard from clinical specialists and the manufacturer that memantine appears to have cognitive, functional, global and behavioural effects, particularly in people with aggression, agitation and/or psychotic symptoms, which are more common in people with severe Alzheimer's disease. The Committee accepted that memantine may therefore have the potential to reduce the need for antipsychotics but noted that there was no randomised controlled trial evidence supporting this assumption. The Committee accepted on the basis of the evidence in the manufacturer's submission and expert testimony that memantine may offer benefit to people with severe Alzheimer's disease.
The Committee considered the estimates of treatment effect for memantine in the manufacturer's and Assessment Group's models. The Committee noted that estimates of treatment effect were different between the models. The Committee understood that the effectiveness data in the manufacturer's submission were based on a pooled estimate of memantine monotherapy and combination therapy with AChE inhibitors, whereas the Assessment Group's model included effectiveness estimates only for memantine monotherapy. The Committee also noted that the manufacturer's submission was based on analysis of individual patient data of people with moderate Alzheimer's disease taken from two randomised controlled trials that had been submitted to the European Medicines Agency (EMA) in order to gain the license extension for memantine in moderate disease. These data had not been included in the Assessment Group's report because more than 20% of the study population in the trials had mild Alzheimer's disease, and so did not fit with the inclusion criteria of the systematic review based on the licensed indications in the decision problem. As a consequence, the Committee found it difficult to reconcile the lack of statistically significant benefit seen in the meta-analysis from the Assessment Group for cognitive, functional and behavioural outcomes with the significant improvements (particularly for behaviour) in the manufacturer's individual patient data analyses. The Committee was uncertain about how much the difference in clinical effectiveness influenced the differences in cost-effectiveness results between the two models. It was also aware, based on the evidence provided by patient experts and clinical specialists, that behaviour was an important factor when considering institutionalisation. However, published evidence was limited because in trials, institutionalisation was not an outcome measure and instruments had limited capacity to capture behavioural changes. The Committee concluded that because the Assessment Group's model did not include results from some trials in the estimate of treatment effect for which access to individual patient data was needed, it may have underestimated the cost effectiveness of memantine, although by how much is uncertain.
Taking the above factors into account, the Committee considered that, on balance, the Assessment Group's model provided a suitable basis for decision making. This was because the cohort data used to model disease progression were generalisable to the UK, the effectiveness data for memantine monotherapy and combination therapy with AChE inhibitors were not combined, and the cost effectiveness of memantine could be compared with that of the AChE inhibitors in moderate Alzheimer's disease.
The Committee considered that the base-case ICER for memantine of £32,100 per QALY gained compared with best supportive care in moderate to severe Alzheimer's disease was likely to be an overestimate of the true cost per QALY gained, although the size of this overestimation was uncertain. The Committee noted that in moderate disease there were active comparators, whereas only memantine has a marketing authorisation for severe disease.
The Committee considered the subgroups of people with moderate Alzheimer's disease only and severe Alzheimer's disease only. The Committee noted that in the Assessment Group's exploratory analysis, memantine dominated best supportive care for the moderate group, and for the severe group the ICER for memantine compared with best supportive care was £26,500 per QALY gained. The Committee also noted that both subgroup ICERs were lower than the combined base-case ICER of £32,100 per QALY. The Committee heard from the Assessment Group that this may be because of the different assumptions in the subgroup analysis compared with the base case.
The Committee concluded that memantine would not be cost effective compared with the AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost. The Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator. It concluded that in people with moderate Alzheimer's disease memantine should be recommended for people who are intolerant of or have contraindications to AChE inhibitors.
The Committee thought that memantine was likely to have a positive effect on the quality of life of people with severe disease, because they are more likely to experience behavioural symptoms. This was not captured in the Assessment Group's model. Also, even though behavioural benefit did not appear to have a great impact on the results of the manufacturer's model, the Committee had heard from clinical specialists that behavioural effect may not be well captured in the available evidence. The Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the ICER would be less than £26,500 per QALY gained. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.
## Other issues
The Committee considered the criteria for recommending the AChE inhibitors in NICE technology appraisal guidance 111.The Committee acknowledged the importance of people with Alzheimer's disease being assessed by a specialist clinician and heard from clinical specialists that treatment with AChE inhibitors and memantine should always be initiated by a clinical specialist in accordance with the recommendations of NICE technology appraisal guidance 111. However, the Committee acknowledged that for assessing whether treatment should be continued, review by a specialist may be substituted by a shared care arrangement because this may put less pressure on local resources while still ensuring optimal treatment for patients.
The Committee also considered the recommendations of NICE technology appraisal guidance 111 for specific groups of people with Alzheimer's disease, such as those with disabilities (for example, sensory impairments) or linguistic or other communication difficulties. The Committee acknowledged comments from local NHS trusts that use of scales such as the MMSE made prescription monitoring and clinical audit less problematic. However, the Committee confirmed that, as in NICE technology appraisal guidance 111, when using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect the results and make any adjustments they consider appropriate. The Committee noted comments received in consultation that assessment scales such as the MMSE may not capture the severity of disease or benefit of treatment in people with a high level of education. It was aware that this group of people does not fall under the groups protected by equality legislation, but concluded that clinicians should also keep this in mind when assessing patients. Clinicians should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.
The Committee discussed the continuation of treatment and thought it appropriate that treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms. The Committee considered comments received during consultation that a recommendation of 6-monthly reviews for treatment continuation was not evidence based and could be a misuse of NHS resources. The Committee acknowledged that among the submitted data, there was insufficient evidence to define an optimal review time although most clinical-effectiveness evidence was from 6-month trials and the economic models included the costs of 6-monthly monitoring. The Committee also assumed that good clinical practice would be to regularly review patients. The Committee considered that making recommendations on the timings of patient reviews and other implementation issues, such as switching from AChE inhibitors to memantine according to the recommendations, might be better addressed by the clinician. It concluded that patients who continue on the drug should be reviewed regularly using cognitive, global, functional and behavioural assessment and that treatment should be reviewed by an appropriate specialist team, unless there are locally agreed protocols for shared care. The Committee further concluded that carers' views on the patient's condition at follow-up should be sought.
# Summary of the Appraisal Committee's key conclusions
TA217
Appraisal title: Donezepil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of NICE technology appraisal guidance 111)
Section
Key conclusion
The three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine are recommended as options for managing mild to moderate Alzheimer's disease.
The Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation. The Committee considered that, with this assumption, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.
The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost. The Committee further accepted that an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations around adherence, medical comorbidity, possibility of drug interactions and dosing profiles.
Memantine is recommended as an option for managing Alzheimer's disease for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors, or for people with severe Alzheimer's disease.
The Committee concluded that memantine would not be cost effective compared with the AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost. The Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator.
With regard to the severe subgroup analysis, the Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the ICER would be less than £26,500 per QALY gained. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.
Current practice
Clinical need of patients including the availability of alternative treatments
The Committee was aware that there is currently no cure for Alzheimer's disease and that the AChE inhibitors and memantine treat the symptoms of Alzheimer's disease but do not slow the progression of the disease.
The technology
Proposed benefits of the technology
The Committee concluded that new evidence provided additional support to the conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)
The Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of the benefit is uncertain.
What is the position of the treatment in the pathway of care for the condition?
The Committee considered the current management of Alzheimer's disease under the recommendations of NICE technology appraisal guidance 111, which recommends AChE inhibitors for the treatment of moderate Alzheimer's disease. The Committee was aware of both the importance of early diagnosis and carer and clinical views on the advantages of early use of AChE inhibitors in the treatment of Alzheimer's disease. The Committee heard from clinical specialists that there is variation in clinical practice and that AChE inhibitors are also used to treat some patients with an MMSE score of above 20.
Memantine is not recommended by NICE technology appraisal guidance 111 except in the context of clinical trials.
Adverse effects
The Committee stated that the adverse effects of AChE inhibitors and memantine are well documented and that overall evidence since 2004 has not changed the tolerability profile of these treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee stated that a small amount of new evidence about the clinical effectiveness of the AChE inhibitors from randomised controlled trials had been published since 2004.
The Committee considered the results of the new randomised controlled trials for memantine and the pooled results in order to estimate the size of clinical effectiveness for memantine compared with placebo or best supportive care. The Committee noted that although the new evidence considered by the Assessment Group did not substantially change the estimate of the clinical effectiveness of memantine compared with the review in 2004, the meta-analysis submitted by the manufacturer showed significant benefits.
Relevance to general clinical practice in the NHS
The Committee recognised the heterogeneity of outcome measures in trials and was aware of the limitations of some of the instruments used in the clinical trials, including cognitive and behavioural scales.
Uncertainties generated by the evidence
The Committee concluded that AChE inhibitors may offer some behavioural benefits although their nature and extent are uncertain owing to mixed results from available evidence.
The Committee concluded that although there was no evidence available on health-related quality of life from a systematic review of randomised controlled clinical trials, there was some anecdotal evidence from clinical practice of benefits to patients and carers from using AChE inhibitors.
The Committee concluded that there was no evidence to suggest that the AChE inhibitors affected survival.
The Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee considered whether there were differences in cost effectiveness for particular subgroups of people with Alzheimer's disease. The Committee noted that the Assessment Group's model assumed the same treatment effect for patients with mild and moderate disease. The Committee was aware that in NICE technology appraisal guidance 111 a difference in treatment effect between mild and moderate populations was assumed in the amended base case, on the basis of analysis by the Medical Research Council Biostatistics Unit. The Committee was also aware that no subgroup analyses had been identified as part of the systematic review of clinical effectiveness analysis.
The Committee accepted on the basis of the evidence in the manufacturer's submission and expert testimony that memantine may offer benefit to people with severe Alzheimer's disease.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that new evidence provided additional support to the previous conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain owing to mixed results from the available evidence.
The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of clinical effectiveness.
The Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.
The Committee concluded that combination treatment with memantine and AChE inhibitors could not be recommended because there is a lack of evidence of additional clinical efficacy compared with monotherapy.
Evidence for cost effectiveness
Availability and nature of cost effectiveness evidence
The Committee considered economic models from the Assessment Group, the manufacturer of donepezil and the manufacturer of memantine.
The Committee considered that only the Assessment Group addressed the decision problem in the scope because it included all of the AChE inhibitors as comparators for mild to moderate Alzheimer's disease, whereas the manufacturer of donepezil's model compared donepezil with best supportive care only. The Committee concluded that there were limitations in constructing an economic model based on time to institutionalisation but that the Assessment Group's model was based on the best currently available and detailed UK evidence to evaluate the cost effectiveness of donepezil, galantamine and rivastigmine.
The Committee considered that, on balance, the Assessment Group's model provided a suitable basis for decision making. This was because the cohort data used to model disease progression were generalisable to the UK, the effectiveness data for memantine monotherapy and combination therapy with AChE inhibitors were not combined, and the cost effectiveness of memantine could be compared with that of the AChE inhibitors in moderate Alzheimer's disease.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee was aware of the limitations of the Wolstenholme dataset including the small population, the relatively old data (collected between 1988 and 1999), which might not reflect current rates of and times to institutionalisation, and the fact that the study was based in a semi-rural location. The Committee concluded that although the Wolstenholme dataset that formed the basis of the Assessment Group's model had these limitations it still represented the best available data.
The Committee concluded that the assumption of no survival effect from treatment with the AChE inhibitors in the base-case model was appropriate in light of the lack of evidence of survival effect from randomised controlled trials.
The Committee concluded that although behaviour was a potential predictor of time to institutionalisation, not including it in the Assessment Group's model (which already included cognition and function) was unlikely to substantially change the outputs of the model in mild, moderate and severe Alzheimer's disease.
Incorporation of health-related quality-of-life benefits and utility values.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee considered whether assumptions and inputs about health-related quality of life and utilities included in the Assessment Group's model were reasonable. The Committee acknowledged that there were differences in the responses given by patients and those given by carers when reporting outcomes, but that in sensitivity analyses conducted by the Assessment Group, changes to utility values had a small impact on ICERs. The Committee concluded that the assumptions and inputs about utilities in the Assessment Group's model were appropriate.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee did not consider subgroups for AChE inhibitors.
The Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator (that is, for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors).
The Committee concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.
What are the key drivers of cost effectiveness?
The Committee considered the appropriateness of the structure of the Assessment Group's model, which was based on predicting time to institutionalisation.
Considering all the factors in relation to cognitive and functional scales, the Committee considered it appropriate to use age, cognition and function as key predictors of time to institutionalisation. The Committee concluded that although behaviour was a potential predictor of time to institutionalisation in everyday life, its omission from a model already including cognition and function was unlikely to substantially change the outputs of the model in mild and moderate Alzheimer's disease.
The Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered that, with the assumption that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.
The Committee noted the small difference in absolute costs and benefits between the AChE inhibitors. It also observed that small changes in some of the inputs and assumptions had significant impacts on the incremental estimates of cost effectiveness. The Committee concluded that overall, the AChE inhibitors donepezil, galantamine and rivastigmine had small but demonstrable clinical benefits and were cost-effective treatment options. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost.
The Committee considered that the base-case ICER for memantine of £32,100 per QALY gained compared with best supportive care in moderate to severe Alzheimer's disease was likely to be an overestimate of the true cost per QALY gained, although the size of this overestimation was uncertain. The Committee noted that in the Assessment Group's exploratory analysis, memantine dominated best supportive care for the moderate group, and for the severe group the ICER for memantine compared with best supportive care was £26,500 per QALY gained. The Committee concluded that memantine would not be cost effective compared with AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost.
The Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the ICER would be less than £26,500 per QALY gained for severe disease. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.
Additional factors taken into account
Patient access schemes (Pharmaceutical Price Regulation Programme)
Not applicable
End-of-life considerations
Not applicable
Equalities considerations, Social Value Judgement
The Committee confirmed that, as in NICE technology appraisal guidance 111, when using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect the results and make any adjustments they consider appropriate. Clinicians should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.
The Committee recognised the difficulties of using MMSE score alone to assess the severity of Alzheimer's disease and the response to AChE inhibitors. The Committee agreed that cognitive scales alone such as the MMSE are not always appropriate for assessing the severity of dementia. The Committee concluded that if cognitive scales are not appropriate for assessing the need for treatment, or whether to continue treatment, then clinicians should use another appropriate method of assessment.
# Recommendations for further research
Research is needed to generate robust and relevant data on the effects of treating people with Alzheimer's disease on both short-term and long-term outcomes, disease progression through relevant health states, and quality of life.
Research is needed on the impact of treating Alzheimer's disease on mortality and institutionalisation, and to assess the relationship between disease progression and carer utility (quality of life).# Related NICE guidance
Dementia: assessment, management and support for people living with dementia and their carer (2018) NICE guideline NG97# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in April 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMarch 2011
|
{'Guidance': "This guidance has been partially updated by the NICE guideline on dementia. See update information for more information.\n\nThe three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer's disease under all of the conditions specified in 1.4 and in recommendation 1.5.5 of the NICE guideline on dementia.\n\nMemantine monotherapy is recommended as an option for managing Alzheimer's disease for people with:\n\nmoderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or\n\nsevere Alzheimer's disease. Treatment should be under the conditions specified in recommendation 1.5.5 in the NICE guideline on dementia.\n\nThis recommendation has been updated and replaced by recommendation 1.5.5 in the NICE guideline on dementia.\n\nIf prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles.\n\nWhen using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results and make any adjustments they consider appropriate. Healthcare professionals should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.\n\nWhen assessing the severity of Alzheimer's disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so. These include:\n\nif the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient's dementia because of the patient's learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or\n\nif it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or\n\nif there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia.In such cases healthcare professionals should determine the need for initiation or continuation of treatment by using another appropriate method of assessment.", 'Clinical need and practice': "Dementia is a chronic progressive mental disorder that adversely affects higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Alzheimer's disease is the most common form of dementia. It is a degenerative cerebral disease with characteristic neuropathological and neurochemical features.\n\nPopulation data from 2005 indicate that 380,000 people have Alzheimer's disease in England and Wales. The UK incidence of Alzheimer's disease in people over the age of 65 years is estimated to be 4.9 per 1000 person-years. Between 50 and 64% of people with Alzheimer's disease are estimated to have mild to moderately severe disease, and approximately 50% have moderately severe to severe disease.\n\nAlzheimer's disease is usually insidious in onset and develops slowly but steadily over several years. It predominantly affects older people. The median survival for people with Alzheimer's disease from onset has been estimated at 7 years, although survival figures vary and depend on how they are measured, comorbidities, age (median survival decreases with increasing age) and sex.\n\nProgression is characterised by deterioration in cognition (for example, thinking, conceiving and reasoning), functional ability (for example, activities of daily living such as dressing, personal hygiene and handling money), behaviour (for example, agitation, wandering and uncharacteristic aggression) and non-cognitive symptoms including depression, delusions and hallucinations. People with Alzheimer's disease might find it increasingly difficult to do everyday activities, such as shopping, socialising and recognising people and places. Communication may become a problem as people find it more difficult to find words and remember names. In later stages of disease, physical problems can include problems with eating, swallowing, incontinence, and unsettled and unsettling behaviour. Alzheimer's disease may also be associated with loss of confidence and feelings of fear, confusion, apathy, stigma and depression. The effects of Alzheimer's disease are heterogeneous and vary from patient to\xa0patient.\n\nAlzheimer's disease has many impacts including physical, mental, nursing, medical and social impacts. Carers (including friends and family) are affected by the progressive deterioration in cognition, function and behaviour of a person with Alzheimer's disease. Behavioural symptoms can have a particular impact on carers, and are often the reason cited for a person with Alzheimer's disease going into full-time residential care. Alzheimer's disease can have a profound and far-reaching effect on family and carers as well as the patient including institutionalisation and a financial impact on family, carers and the state.\n\nThe severity of Alzheimer's disease can be assessed using several methods, depending on the setting (for example research or clinical practice) and the outcome being assessed. Clinical practice uses a variety of measures, often along with clinically based assessments such as biographical interview. Severity is frequently defined by Mini Mental State Examination (MMSE) score:\n\nmild Alzheimer's disease: MMSE 21–26\n\nmoderate Alzheimer's disease: MMSE 10–20\n\nmoderately severe Alzheimer's disease: MMSE 10–14\n\nsevere Alzheimer's disease: MMSE less than 10.\n\nThe aims of treatment are to promote independence, maintain function and treat symptoms including cognitive, non-cognitive (hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), behavioural and psychological symptoms.\n\nThere is no cure for Alzheimer's disease. Current management involves the treatment of cognitive, non-cognitive and behavioural symptoms. AChE inhibitors (donepezil, galantamine and rivastigmine) and memantine are the pharmacological treatments available specifically for Alzheimer's disease. Non-pharmacological treatment includes social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services such as meals-on-wheels, befriending services, day centres, respite care and care homes.", 'The technologies': "# Donepezil\n\nDonepezil (Aricept, Eisai/Pfizer) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission. Donepezil has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe Alzheimer's dementia. It is given initially at 5\xa0mg once daily at bedtime. After 1 month the treatment should be assessed, and the dose can be increased to a maximum of 10\xa0mg once daily if necessary.\n\nCommon undesirable effects include diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nDonepezil is available as tablets and orodispersible tablets. Net prices are stated. The cost of tablets is £59.85 (5\xa0mg, 28-tablet pack) and £83.89 (10\xa0mg, 28-tablet pack). The cost of orodispersible tablets is £59.85 (5\xa0mg, 28-tablet pack) and £83.89 (10\xa0mg, 28-tablet pack) ('British national formulary' [BNF] edition\xa060). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Galantamine\n\nGalantamine (Reminyl, Shire) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission and also modulates activity at nicotinic receptors. Galantamine has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer's type. The formulation given most frequently is a capsule given initially at 8\xa0mg once daily for 4\xa0weeks and then increased to 16\xa0mg once daily for at least 4\xa0weeks. Maintenance treatment is 16–24\xa0mg once daily depending on assessment of clinical benefit and tolerability. An older tablet formulation and a liquid preparation are also available to be given twice a day, see the summaries of product characteristics for more information.\n\nCommon undesirable effects include nausea and vomiting. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nGalantamine is available as tablets, oral solution and capsules. Net prices are stated. The cost of tablets is £68.32 (8\xa0mg, 56-tablet pack) and £84.00 (12\xa0mg, 56-tablet pack). Oral solution (4\xa0mg/ml, 100 ml) costs £120.00. Modified release capsules cost £51.88 (8\xa0mg, 28-capsule pack), £64.90 (16\xa0mg, 28-capsule pack) and £79.80 (24\xa0mg, 28-capsule pack) (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Rivastigmine\n\nRivastigmine (Exelon, Novartis) is an AChE inhibitor, which works by increasing the concentration of acetylcholine at sites of neurotransmission. Rivastigmine has a marketing authorisation in the UK for the symptomatic treatment of mild to moderately severe Alzheimer's dementia. The dose is initially 1.5\xa0mg twice daily and may be increased in steps of 1.5\xa0mg twice daily at intervals of at least 2\xa0weeks according to tolerance up to a maximum dose of 6\xa0mg twice daily. Alternatively rivastigmine patches are available, initially using a 4.6-mg patch per day. This can be increased to a 9.5-mg patch per day for at least 4\xa0weeks. See the summary of product characteristics for further information on using patches.\n\nCommon undesirable effects are mainly gastrointestinal including nausea and vomiting. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nRivastigmine is available as capsules, oral solution and patches. Net prices are stated. The cost of 1.5\xa0mg rivastigmine capsules is £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 3\xa0mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 4.5\xa0mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack); 6\xa0mg capsules cost £33.25 (28-capsule pack) and £66.51 (56-capsule pack). Oral solution costs £99.14 (2\xa0mg/ml, 120 ml). Patches cost £77.97 (4.6\xa0mg/24 hours, 30 patches) and £77.97 (9.5\xa0mg/24 hours, 30 patches) (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Memantine\n\nMemantine (Ebixa, Lundbeck) is a voltage-dependent, moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction. It has a marketing authorisation in the UK for the treatment of patients with moderate to severe Alzheimer's disease. Memantine is initially given as 5\xa0mg once daily and then increased in steps of 5\xa0mg at weekly intervals to a maximum of 20\xa0mg daily.\n\nCommon undesirable effects are dizziness, headache, constipation, somnolence and hypertension. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nMemantine is available as tablets and oral drops. Net prices are stated. 10\xa0mg memantine tablets cost £34.50 (28-tablet pack), £69.01 (56-tablet pack) and £138.01 (112-tablet pack). 20\xa0mg tablets cost £69.01 (28-tablet pack). A treatment initiation pack (7\xa0×\xa05\xa0mg, 7\xa0×\xa010\xa0mg, 7\xa0×\xa015\xa0mg, and 7\xa0×\xa020\xa0mg tablets) costs £43.13. Oral drops (10\xa0mg/g) cost £61.61 for 50\xa0g and £123.23 for 100\xa0g (BNF edition 60). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Committee considered evidence from the Assessment Group, submissions from the manufacturers of donepezil, galantamine and memantine, the Alzheimer's Society, the Royal College of Psychiatrists, the British Geriatrics Society, clinical specialists and patient experts.\n\nThe Assessment Group conducted a systematic review of randomised controlled trials published since 2004 and those included in 'Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer's disease (amended)' (NICE technology appraisal guidance 111). The Assessment Group reviewed the clinical effectiveness of donepezil, galantamine, rivastigmine and memantine in accordance with their marketing authorisations. For the population with mild Alzheimer's disease (defined as MMSE 21–26) the AChE inhibitors (donepezil, galantamine and rivastigmine) were compared with each other and with best supportive care (that is, without treatment with any AChE inhibitors or memantine). For the population with moderate Alzheimer's disease (MMSE 10–20) the AChE inhibitors and memantine were compared with each other and with best supportive care. For the population with severe Alzheimer's disease (MMSE less than 10) memantine was compared with best supportive care. The Assessment Group considered cognition, function, behaviour, global outcomes, mortality, institutionalisation, health-related quality of life and adverse effects. If possible, new evidence was pooled with the evidence from before 2004 using random effects meta-analysis compared with placebo. The effectiveness of treatments across different outcome measures was also explored in a pooled multiple outcome measure analysis to explore the characteristics of the evidence base. If data were sufficient, the Assessment Group pooled information on all technologies and their comparators in a mixed treatment comparison, using Bayesian Markov Chain Monte-Carlo sampling.\n\nThe evidence on clinical effectiveness submitted by the three manufacturers included a wider selection of studies than was included by the definition of randomised controlled trials used by the Assessment Group in its evidence review. The manufacturer of donepezil conducted a systematic review of randomised controlled trials for donepezil since 2004, as well as presenting the evidence already included in NICE technology appraisal guidance\xa0111. It also included a selected review of prospective longitudinal and observational studies. The manufacturer of galantamine submitted new data published since 2004, open-label studies and data from randomised controlled trials already submitted for NICE technology appraisal guidance 111, in 2004 or during the appraisal process. A search strategy with details of the inclusion and exclusion criteria was not submitted. The manufacturer of memantine submitted estimates of clinical effectiveness for the general population with moderate to severe Alzheimer's disease, and a subgroup of patients with agitation, aggression and/or psychotic symptoms. The manufacturer of memantine submitted a meta-analysis of six randomised controlled trials including individual patient data to allow categorisation into patients with moderate to severe disease and the subgroup with agitation, aggression and/or psychotic symptoms. Some of these trials were excluded by the Assessment Group because the trial populations included patients with mild disease, and individual patient data were not publicly available. The other submissions from consultees provided specific references to published literature on clinical effectiveness and were therefore covered by the Assessment Group's systematic review.\n\n## Mild to moderate Alzheimer's disease\n\nThe Assessment Group included five new placebo-controlled comparisons of donepezil. The manufacturer of donepezil included new data from three randomised controlled trials, one subanalysis of a randomised controlled trial, two prospective longitudinal studies and three observational studies, six subgroup analyses and four meta-analyses (two systematic reviews and two pooled analyses), in addition to data previously submitted.\n\nFor donepezil, the Assessment Group found no new studies reporting the Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-cog) at 12 or 24\xa0weeks or MMSE at 12\xa0weeks. The effectiveness estimates using these scales were therefore based on the studies included in NICE technology appraisal guidance 111. One new study was found that measured the effect of donepezil on cognition at 24\xa0weeks follow-up. The overall pooled benefit using new and old data was significant on all scales (a mean change from baseline versus placebo of 1.165 [p < 0.001] and 1.206 [p\xa0<\xa00.001] at 12 and 24\xa0weeks respectively using MMSE score, and −1.969 [p\xa0=\xa00.006] and −2.895 [p\xa0<\xa00.001] at 12\xa0and 24\xa0weeks respectively using ADAS-cog score) and the standardised mean difference of pooled outcomes increased with time for ADAS-cog. According to the manufacturer of donepezil, all 12\xa0randomised controlled trials (from NICE technology appraisal guidance 111 and new submissions that reported on cognition using the ADAS-cog, MMSE or Severe Impairment Battery [SIB] scales) showed a statistically significant difference favouring donepezil versus placebo, with four of these reporting a statistically significant difference on two different cognitive scales.\n\nOne randomised controlled trial, described by the Assessment Group as being poorly reported, measured functional outcomes for donepezil. At 12\xa0weeks follow-up, this trial showed a statistically significant benefit from donepezil (5\xa0mg/day) for activities of daily living in an observed cases measured population. The heterogeneous collection of outcome measures prevented any quantitative synthesis of old and new evidence for individual measures since 2004. The pooled multiple outcome measure analysis for functional outcome data from the studies in NICE technology appraisal guidance 111 showed a statistically significant benefit for donepezil at all doses compared with placebo at 24\xa0weeks - a mean change from baseline versus placebo of 0.298 (p\xa0<\xa00.001, no new data available). According to the manufacturer of donepezil, four randomised controlled trials showed a statistically significant difference favouring donepezil versus placebo on at least one scale and three reported non-significant trends in favour of donepezil. Additionally, the manufacturer cited a meta-analysis of seven randomised controlled trials of donepezil reporting a statistically significant benefit favouring donepezil versus placebo.\n\nNone of the studies for donepezil newly identified by the Assessment Group provided additional data for behavioural function, so the results were based on studies included in NICE technology appraisal guidance 111, which noted no statistically significant benefit from donepezil compared with placebo at 12 or 24\xa0weeks measured with the neuropsychiatric inventory (NPI). There were mean changes from baseline versus placebo of −2.249 (p\xa0=\xa00.123) and −3.116 (p\xa0=\xa00.226) at 12 and 24\xa0weeks respectively using NPI. According to the manufacturer of donepezil, three randomised controlled trials found a statistically significant difference between donepezil and placebo in NPI score, with a fourth study finding a statistically significant difference for agitation or aggression but not total score. The manufacturer of donepezil also referred to six pooled studies that showed a statistically significant difference in favour of donepezil in NPI total score compared with placebo.\n\nOne of the new studies included by the Assessment Group measured global outcomes for donepezil and reported a statistically significant benefit on the clinical dementia rating (CDR). All of the evidence on the Clinician's Interview-Based Impression of Change (CIBIC)-plus was based on NICE technology appraisal guidance\xa0111. A meta-analysis of the effectiveness of donepezil for the CIBIC-plus reported a statistically significant benefit of donepezil 10\xa0mg/day compared with placebo at 12 and 24\xa0weeks. The Assessment Group did not find any new studies that measured global outcomes at 24–26\xa0weeks. The pooled multiple outcome measure analysis for the global outcome data from the studies in NICE technology appraisal guidance 111 showed a statistically significant benefit for donepezil at all doses compared with placebo at 24–26\xa0weeks (a mean change from baseline versus placebo of −0.377 [p\xa0<\xa00.001] and −0.429 [p\xa0<\xa00.001] at 12 and 24\xa0weeks respectively using CIBIC-plus score, and −0.263 [p\xa0=\xa00.003] and −0.568 [p\xa0<\xa00.001] at 12 and 24\xa0weeks respectively using CDR score). According to the manufacturer of donepezil, global function (CIBIC-plus, CDR sum of boxes [CDR-SB] or the Gottfries, Brine and Steen scale [GBS]) was measured in nine of the studies presented in new and previous submissions with statistically significant results in favour of donepezil in seven of them. A submitted meta-analysis of ten trials also showed significant improvement in global function compared with placebo using the CDR-SB.\n\nAccording to the Assessment Group, none of the five newly identified studies for donepezil provided data on adverse events observed under randomised conditions except for limited data from one study. The manufacturer also presented safety data. In summary, the manufacturer of donepezil stated that new data since 2004 was consistent with that previously submitted.\n\nThe Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with donepezil.\n\nThe manufacturer of donepezil included prospective longitudinal and observational studies to support the view that cognitive benefits from donepezil are maintained for up to 3 years. The submission also included new data from a placebo-controlled trial of at least a 2-year duration and a subanalysis of a previous placebo-controlled study of 1 year duration. The manufacturer also presented evidence from randomised and non-randomised controlled trials to demonstrate that benefit was lost when treatment was stopped, the benefits of continuing treatment despite initial decline or stabilisation of MMSE, and the impact of improvement of neuropsychiatric symptoms on caregiver stress and burden.\n\nThe manufacturer of donepezil included evidence that patients showing clinical worsening may benefit from treatment compared with those on placebo or who were untreated. The manufacturer also included a responder analysis that showed how results varied depending on the definition of response. The manufacturer used these data to demonstrate the effects of treatment on carers.\n\nA representative from the manufacturer of donepezil informed the Committee that an analysis of a single open-label study found an average of 17.5 months delay in the time to institutionalisation with donepezil treatment. Survival data were not collected in any of the trials because follow-up periods were short and therefore there were few deaths during trials.\n\nThe Assessment Group included three new randomised controlled trials of galantamine. The manufacturer of galantamine submitted data from before and after 2004 for six trials and four pooled analyses including mild, moderate and 'advanced moderate' subgroups.\n\nAll three studies included by the Assessment Group measured cognition and used ADAS-cog at various points between 6 and 26\xa0weeks and showed improvement with galantamine compared with placebo. When the results of these were added to the results of NICE technology appraisal guidance 111, the pooled estimate demonstrated a statistically significant benefit of galantamine compared with placebo, which increased with time (mean changes from baseline versus placebo of −2.386 [p\xa0<\xa00.001] and −2.957 [p\xa0<\xa00.001] at 12–16 and 21–26\xa0weeks respectively using ADAS-cog score). According to the manufacturer of galantamine, established randomised controlled trial data from five placebo-controlled trials in mild to moderate Alzheimer's disease showed statistically significant benefit in ADAS-cog score. This was reflected in the pooled data that included a subgroup of patients with additional cerebrovascular disease from a trial of patients with Alzheimer's disease (other patients in the trial had probable vascular dementia).\n\nThe Assessment Group found three new randomised controlled trials measuring functional outcomes for galantamine. The Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) data from the new trials were pooled with those of the studies found in 2004, and the overall pooled estimates showed statistically significant functional benefit from galantamine compared with placebo at 21–26\xa0weeks (mean changes from baseline versus placebo of 1.394 [p\xa0<\xa00.001] and 2.234 [p\xa0<\xa00.001] at 12–13 and 21–26\xa0weeks respectively). The results of Disability Assessment for Dementia (DAD) score were pooled at 21\xad26\xa0weeks follow-up. Again this showed a statistically significant benefit of galantamine compared with placebo (mean changes from baseline versus placebo of 3.761 [p\xa0<\xa00.001] at 21–26\xa0weeks). Two new studies were added to the meta-analysis of combined functional outcome measures at 21–26\xa0weeks. The pooled multiple outcome measure analysis showed a statistically significant functional benefit of galantamine compared with placebo. The manufacturer referred to four established placebo-controlled randomised controlled trials that showed benefits in terms of ADCS-ADL or DAD score, of which some were statistically significant, including the pooled data (which included a subgroup of patients with additional cerebrovascular disease from another trial).\n\nOnly one study included by the Assessment Group provided additional data for the effectiveness of galantamine in relieving behavioural symptoms, when compared with placebo. However, this did not show any statistically significant benefit. When the new data were pooled with previous data, at 13\xa0weeks no significant benefit was found, but at 21–26\xa0weeks the overall pooled estimate favoured galantamine significantly (mean changes from baseline versus placebo of −0.746 [p\xa0=\xa00.179] and −1.455 [p\xa0=\xa00.012] at 13 and 21–26\xa0weeks respectively using NPI score). The manufacturer of galantamine referred to one study that showed statistically significant benefits in terms of NPI score, and another two placebo-controlled trials that showed non-significant benefits in terms of NPI score. Mixed results were reflected in the pooled data (including the subgroup of patients with additional cerebrovascular disease from another trial).\n\nTwo new studies found by the Assessment Group measured global outcomes for galantamine. One found a significant benefit from galantamine measured by the CIBIC-plus compared with placebo at 13–16\xa0weeks. When the new studies' data were pooled with existing evidence, the overall pooled estimates of the CIBIC-plus at 26\xa0weeks showed a statistically significant benefit from galantamine compared with placebo (a mean change from baseline versus placebo of \xad0.196 [p\xa0<\xa00.001] at 26\xa0weeks). According to the manufacturer of galantamine, established randomised controlled trial data showed that in four out of five placebo-controlled trials in people with mild to moderate Alzheimer's disease, statistically significant benefits of galantamine were seen with CIBIC-plus. This statistically significant benefit was reflected in the pooled data (including the subgroup of patients with additional cerebrovascular disease from another trial).\n\nThe Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with galantamine.\n\nAccording to the Assessment Group, overall for galantamine in two new studies, there was a high percentage of any adverse event in both studies in treatment and control groups (any adverse events: treatment = 79–84%, placebo = 62–70%). The manufacturer of galantamine did not present any new data on toxicity.\n\nThe Assessment Group included a systematic review, including a meta-analysis, that concluded that the AChE inhibitors provided benefits in terms of cognitive function and activities of daily living, and galantamine improved psychological symptoms in mild to moderate dementia.\n\nThe Assessment Group included three new randomised placebo-controlled comparisons of rivastigmine. No data were submitted by the manufacturer of rivastigmine.\n\nThree new studies for rivastigmine were identified by the Assessment Group that measured cognition using ADAS-cog and/or MMSE and showed significant benefit (patch and capsule were not differentiated). When the results of these were added to the randomised controlled trials in NICE technology appraisal guidance 111, it demonstrated a statistically significant improvement in cognition with rivastigmine compared with placebo at 24–26\xa0weeks (mean changes from baseline versus placebo of 1.022 [p\xa0<\xa00.001] using MMSE score and −2.464 [p\xa0<\xa00.001] using ADAS-cog score).\n\nTwo of the three new studies found by the Assessment Group published since 2004 reported statistically significant functional benefit from rivastigmine compared with placebo. These used the Progressive Deterioration Scale (PDS) and ADCS-ADL as outcome measures. The overall pooled estimate using the new and previous data for PDS at 24–26\xa0weeks showed a statistically significant benefit of rivastigmine compared with placebo (a mean change from baseline versus placebo of 3.103 [p\xa0<\xa00.001] at 24–26\xa0weeks using PDS score). Two new studies were found to add to the pooled multiple outcome measure analysis of functional outcomes at 24–26\xa0weeks, which showed a statistically significant benefit from rivastigmine compared with placebo.\n\nTwo new studies were found that measured behavioural outcomes with rivastigmine. One small study found a statistically significant benefit from rivastigmine. The other, much larger, study did not. The Assessment Group stated that the data identified by this review and NICE technology appraisal guidance 111 are sparse and too heterogeneous to permit meaningful quantitative synthesis.\n\nThe two new studies in this comparison that reported global outcomes had conflicting results. One found mostly significantly favourable results with the CIBIC-plus and the Global Deterioration Scale (GDS), but the other did not. Data from the new studies were pooled with the existing evidence in a random-effects meta-analysis using the CIBIC-plus and the GDS at 26\xa0weeks. The meta-analysis showed a statistically significant benefit from rivastigmine at 26\xa0weeks (mean changes from baseline versus placebo of 0.420 [p\xa0<\xa00.001] using CIBIC-plus score and 0.196 [p\xa0<\xa00.001] using GDS score). The pooled multiple outcome measure analysis showed an overall statistically significant benefit for rivastigmine compared with placebo.\n\nThe Assessment Group noted that none of the new randomised controlled trials included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with rivastigmine.\n\nAccording to the Assessment Group, for rivastigmine, overall there was a high percentage of any adverse events, ranging from 51% to 91% in the treatment groups, and 46% to 76% in control groups. The main adverse events were gastrointestinal. The 9.5\xa0mg/day transdermal patch produced fewer side effects than the capsule (12\xa0mg/day).\n\nThe Assessment Group included a Cochrane review that concluded that high doses of rivastigmine offered statistically significant benefits in patients with mild to moderate Alzheimer's disease versus placebo.\n\nThe Assessment Group identified four head-to-head randomised controlled trials (two comparing all three AChE inhibitors, one comparing donepezil with rivastigmine and one comparing donepezil with galantamine) but considered only one of the studies to be of sufficiently high quality to inform this review. The included study (which compared donepezil with rivastigmine) noted that over 2 years there was no statistically significant difference between rivastigmine and donepezil for cognitive outcomes (MMSE and SIB). Patients taking rivastigmine had significantly improved outcomes than those taking donepezil in the primary analysis of functional outcomes (p = 0.007–0.047). No significant difference was seen between donepezil and rivastigmine for behavioural outcomes (NPI). The study showed that patients taking rivastigmine did significantly better than those taking donepezil in terms of global outcomes (GDS). However, the manufacturer of donepezil stated that this study did not meet its primary endpoint and showed higher discontinuations and higher rates of some adverse events for rivastigmine compared with donepezil. None of the newly identified, head-to-head, randomised studies investigated quality of life with the technologies under assessment, and no such data were identified in NICE technology appraisal guidance 111. The most common adverse effects reported in the head-to-head studies of the AChE inhibitors were nausea, diarrhoea, vomiting and headache.\n\nIf data were sufficient, the Assessment Group pooled information on all technologies and their comparators simultaneously in a mixed treatment comparison, using Bayesian Markov Chain Monte-Carlo sampling, which showed the probability of each treatment being the most clinically effective. The results of the mixed treatment comparison varied depending on the symptom assessed, the instrument used and follow-up time. The Assessment Group included a systematic review, including a meta-analysis, that concluded that the AChE inhibitors provided benefits in terms of cognitive function and activities of daily living, and galantamine improved psychological symptoms in mild to moderate dementia. Another concluded that for the AChE inhibitors and memantine there was a small effect size in mild to moderate Alzheimer's disease.\n\n## Moderate to severe Alzheimer's disease\n\nThe Assessment Group found one new randomised controlled trial for memantine monotherapy versus placebo. The manufacturer of memantine submitted estimates of clinical effectiveness for the general population with moderate to severe Alzheimer's disease and a subgroup of patients with agitation, aggression and/or psychotic symptoms. The manufacturer submitted a meta-analysis that had used individual patient data from six 6-month randomised controlled trials. The first three trials were in moderately severe to severe disease and the other three were in mild to moderate disease. The Assessment Group had excluded trials in which at least 20% of the study participants had mild disease because this was outside the marketing authorisation for memantine. The manufacturer included data from patients with moderate disease only in these trials using the individual patient data. In addition, the manufacturer included trials of monotherapy and combination therapy in the pooled results presented in this section whereas the Assessment Group analysed each separately. Evidence from prospective longitudinal and observational studies was also presented.\n\nOne new randomised controlled trial of memantine monotherapy included by the Assessment Group showed a statistically significant benefit in a cognitive measure using SIB with memantine compared with placebo. When data from this trial were added to those of NICE technology appraisal guidance 111, a statistically significant benefit was reported at 12\xa0weeks, but this was not maintained at 24–48\xa0weeks (mean changes from baseline versus placebo of 4.147 [p\xa0=\xa00.025] and 3.254 [p\xa0=\xa00.245] at 12 and 24–28\xa0weeks using SIB score). Studies included in the manufacturer's meta-analysis for memantine reported a statistically significant benefit in ADAS-cog and SIB compared with placebo at the end of study and at 24\xa0weeks (standardised mean difference = −0.26, p\xa0<\xa00.0001).\n\nThe results from the new study included by the Assessment Group showed no significant benefit in functional outcome measured by ADCS-ADL for memantine monotherapy compared with placebo at 12\xa0weeks or when measured with the Functional Assessment Staging (FAST) instrument. The data were synthesised with the existing evidence in random-effects meta-analysis. Two studies provided data for functional effect as measured by ADCS-ADL19 version. The results were not statistically significant at 12\xa0weeks and were only just significant at 24–28\xa0weeks (mean changes from baseline versus placebo of 0.877 [p\xa0=\xa00.075] and 1.408 [p\xa0=\xa00.044] at 12 and 24\xad28\xa0weeks respectively using ADCS-ADL score and −0.341 [p\xa0=\xa00.002] at 24–28\xa0weeks respectively using FAST score). The manufacturer's meta-analysis for memantine in moderate to severe disease showed a statistically significant difference compared with placebo on the ADCS-ADL19 and ADCS-ADL23 (standardised mean difference = −0.18, p\xa0<\xa00.0007).\n\nThe study for memantine monotherapy that was published after 2004 and included by the Assessment Group measured behavioural outcomes using NPI and the Behavioural Rating Scale for Geriatric Patients (BGP). Neither measure showed a statistically significant benefit of memantine. The data were pooled with the existing data at 24–28\xa0weeks, which did not show a statistically significant gain from memantine compared with placebo (a mean change from baseline versus placebo of −1.608 (p\xa0=\xa00.314) at 24–28\xa0weeks using NPI score). The results of the meta-analysis by the manufacturer of memantine in moderate to severe disease showed a statistically significant (p = 0.03) benefit in terms of NPI and NPI-Nursing Home version (standardised mean difference\xa0=\xa0−0.12, p\xa0=\xa00.03).\n\nAccording to the Assessment Group, one new study for memantine monotherapy measured global outcomes with the CIBIC-plus but the differences found were not statistically significant. When new data were pooled with the existing studies, the overall pooled estimate showed a statistically significant beneficial effect from memantine compared with placebo (a mean change from baseline versus placebo of −0.300 [p\xa0<\xa00.001] at 24–28\xa0weeks using CIBIC-plus score). Studies included by the manufacturer in the meta-analysis for memantine used CIBIC-plus or the Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC). The standardised mean difference in the manufacturer's meta-analysis for memantine in moderate to severe disease for global outcomes (CIBIC-plus) compared with placebo was statistically significant (standardised mean difference = −0.22, p\xa0<\xa00.0001).\n\nThe Assessment Group noted that none of the new randomised studies included in the assessment report provided any additional data on quality of life, time to institutionalisation or mortality with memantine.\n\nThe manufacturer of memantine included an analysis of a subgroup of patients with moderate to severe Alzheimer's disease with agitation, aggression and/or psychotic symptoms to show that memantine offers enhanced benefits in this subgroup in terms of cognition and function. The manufacturer also included an indirect comparison with risperidone, which was not a comparator in the scope and therefore outside the scope of this review. This analysis was not included by the Assessment Group because no subgroup analyses or individual patient data had been published. The MAG-D study was ongoing at the time of writing the assessment report, so was not included by the Assessment Group. In addition, the manufacturer of memantine submitted data from prospective longitudinal and observational studies to support the view that cognitive and functional benefits of memantine are maintained over years, that memantine delays time to institutionalisation, reduces the need for antipsychotic use and that discontinuation of memantine is associated with an increased use of antipsychotics compared with continuous memantine treatment.\n\nAccording to the Assessment Group, the proportion of any adverse events for memantine in the new study was similar in treatment and control groups (treatment = 74%, control = 73%). The main adverse events in the memantine group were agitation and hypertension, and agitation and falls in the control group. This did not change assumptions about the safety of memantine from technology appraisal guidance 111. The manufacturer highlighted a published meta-analysis of safety data from clinical trials which also showed the most common adverse events with memantine to be agitation and falls. However, it noted that both have a numerically lower incidence than placebo.\n\nThe Assessment Group found one new study of memantine in combination with any of the AChE inhibitors. It assessed the clinical effectiveness of memantine combination therapy separately from monotherapy. This was different from the approach taken in NICE technology appraisal guidance 111 and by the manufacturer of memantine. The Assessment Group found one new trial that compared memantine plus a stable dose AChE inhibitor with an AChE inhibitor plus placebo. This trial did not show any benefit from combining memantine with an AChE inhibitor on cognitive, functional, behavioural or global outcomes. A trial that compared memantine plus donepezil with donepezil plus placebo was included in NICE technology appraisal guidance 111. Pooling the new trial with the previous trial of memantine in combination with an AChE inhibitor did not show any additional benefit from combination therapy. The manufacturer of memantine commented that its submitted meta-analysis of six trials showed memantine to be significantly superior to placebo on most outcomes, as adjunct and monotherapy. It also stated that interaction between treatment effect and presence of background treatment was found not to be significant.\n\nThe manufacturer of memantine referred to safety reports since 2002, two safety reviews and a meta-analysis. It concluded that memantine was well tolerated when used as monotherapy or as combination therapy.\n\n## Summary\n\nThe Assessment Group identified 17 new randomised controlled trials and four systematic reviews of randomised controlled trials. According to the Assessment Group, there was an increase in the amount and precision of available evidence for the clinical effectiveness of the AChE inhibitors and memantine. For the AChE inhibitors, the new studies supported and strengthened the previous evidence of benefit in terms of cognitive outcomes, but results for other outcomes were mixed. For memantine monotherapy, the new evidence did not support evidence of statistically significant benefit compared with placebo for any outcome, but the pooled evidence with previous evidence from before 2004 showed improvement in cognition at 12\xa0weeks and in function at 24–28\xa0weeks.\n\nThe Assessment Group concluded that the evidence for monotherapy in the three manufacturer's submissions was broadly consistent with its own, but highlighted that there were differences between the studies included by the manufacturers and its own review. In addition, the Assessment Group analysed monotherapy and combination therapy separately, whereas the manufacturer of memantine combined the two in its submitted meta-analysis.\n\nThe Assessment Group considered the quality of the new placebo-controlled studies published since 2004 to be 'disappointing'. Issues included the inappropriate use of last observation carried forward and observed cases analysis instead of intention-to-treat analysis, inadequate reporting of randomisation and allocation, and the small size of studies for donepezil in particular. According to the Assessment Group, the robustness of the new evidence provided by the head-to-head studies was limited by the poor quality of all but one of the studies. Important gaps in the evidence remain.\n\n# Cost effectiveness\n\nThe Assessment Group conducted a systematic review of published economic evaluations since 2004. The Assessment Group, the manufacturer of donepezil (Eisai/Pfizer) and the manufacturer of memantine (Lundbeck) submitted new economic models. The Assessment Group's model included all technologies. Because of differences in the marketing authorisations, the base-case cost effectiveness of the AChE inhibitors and memantine were modelled separately in mild to moderate and moderate to severe disease respectively. No new economic models were submitted by the manufacturers of galantamine and rivastigmine. The manufacturer of galantamine highlighted issues with the previous model from NICE technology appraisal guidance 111.\n\n## Mild to moderate Alzheimer's disease\n\nThe Assessment Group conducted a systematic review of published economic evaluations since 2004. It identified eight studies of cost effectiveness specifically for donepezil and one that reported on the cost effectiveness of both donepezil and rivastigmine. According to the Assessment Group, these publications generally supported the cost effectiveness of donepezil in the treatment of mild to moderate Alzheimer's disease.\n\nManufacturer's model for donepezil\n\nThe manufacturer of donepezil submitted an economic model that compared the cost effectiveness of donepezil with best supportive care in people with mild to moderate Alzheimer's disease using a discrete event simulation approach over a lifetime. The baseline characteristics of the model population (including age, sex, race, measures of cognition [MMSE], function [ADL and instrumental ADL (IADL)], behaviour [NPI] and concomitant treatments) were based on 221 people with mild disease and 605 people with moderate disease from a pool of three randomised controlled trials. The model used a weighted sampling approach to sample 1000 individuals from the pooled trial populations, and these individuals were then replicated in the model and allocated to donepezil or no AChE inhibitor treatment. Disease progression and treatment effect were measured using cognition (MMSE), activities of daily living (ADL and IADL) and behaviour (NPI). Regression equations were formulated based on data from a US registry (the CERAD study) and seven donepezil clinical trials spanning mild to severe Alzheimer's disease and including data from two open-label extensions of the studies. The updated MMSE score was then used to predict the change in ADL, IADL and NPI. The proportion of people institutionalised depended on severity of Alzheimer's disease.\n\nThe effectiveness of donepezil in the manufacturer's model was derived from a meta-analysis of six pooled randomised controlled trials and assumed the same treatment effect for both mild and moderate Alzheimer's disease. The model updated patient characteristics every 3 months. Discontinuation data were taken from 88 patients. Patient utilities were based on a Swedish study using the EQ-5D and carer proxy responses. Carer utilities were estimated using SF-36 scores and the Brazier algorithm from three clinical trials. Carer utility accounted for approximately 10% of the incremental quality-adjusted life years (QALYs) but did not include the impact on carer utility of patients entering an institution. NHS and personal social services costs were included along with costs to the individual and their family. NHS reference costs, list drug prices (including a price reduction effective after the November 2009 Pharmaceutical Price Regulation Scheme, which was later published in the BNF60) and a report by Dementia UK (2007) were used for cost estimates, which were inflated to current prices. Costs included a consultation visit that took place every 6 months during treatment. Cost and benefits were discounted at 3.5%.\n\nThe manufacturer's base-case results estimated that donepezil dominated best supportive care because it was less costly and more effective in people with mild, moderate and mild to moderate Alzheimer's disease. The manufacturer reported per patient QALY gains of 0.133 and 0.098 and estimated total per patient cost saving of £3379 and £1889 for groups with mild and moderate disease respectively. When the overall mild to moderate disease population was considered, total cost savings amounted to £2354 and people gained an average of 0.109 QALYs including patient utility alone, and 0.121 including patient and carer utilities. The manufacturer of donepezil estimated a delay to institutionalisation of 2 months.\n\nAll but one of the one-way sensitivity analyses conducted by the manufacturer of donepezil in the mild and moderate disease populations (including varying the time horizon, discount rate, MMSE progression, treatment effect, discontinuation, treatment duration, costs of care, costs of nursing home care, patient and carer QALY effect, costs of physician visits, and the 30–50% reduced price of donepezil after loss of patent protection in 2012) resulted in donepezil being dominant. The exception was when nursing home costs were reduced by 50%, which changed the incremental difference in costs from a cost saving of £3379 in the base case to an increased cost of £275, which gave an incremental cost-effectiveness ratio (ICER) of £1866 per QALY gained for mild Alzheimer's disease. When nursing costs were reduced in the moderate disease population, the costs were increased from a cost saving of £1889 in the base case to a cost of £1370, giving an ICER of £7093 per QALY gained. The probabilistic sensitivity analysis reported a 74% and 70% probability of donepezil being cost effective at a threshold of £20,000 per QALY gained in the mild and moderate disease populations respectively (and a 78% and 74% probability respectively at a threshold of £30,000 per QALY).\n\nIssues raised by the Assessment Group included:\n\nthe generalisability of the CERAD (US-based) study\n\npotential double counting of improvement in MMSE score in the regression equations for NPI, ADL and IADL\n\nthe data for the probability of needing institutionalised care being based on a nursing home population\n\nuncertainty about the quality of inputs, including the link that was made between MMSE and institutionalisation and overestimation of treatment effect\n\nexcluding a possible increase in carer utility after institutionalisation\n\nincluding non-NHS/personal social services costs\n\nincluding cost and utility inputs based on a cohort approach\n\nuncertainties about the probabilistic sensitivity analysis.\n\nThe Assessment Group made several changes to the manufacturer's model, which included corrected MMSE scaling, hazard calculations and life expectancy. These amendments had little impact on the manufacturer's deterministic and probabilistic ICERs, which continued to show that donepezil dominated best supportive care in mild and moderate Alzheimer's disease. The Assessment Group also ran its own assumptions through the model and this also did not change the outcome of dominance.\n\nIn response to comments in the assessment report, the representative of the manufacturer of donepezil stated that the improvement in MMSE score had not been double counted in its model. The manufacturer also clarified that a survival effect had not been included.\n\nThe Assessment Group conducted a systematic review of published economic evaluations since 2004. It identified one study of cost effectiveness specifically for rivastigmine, two for galantamine, and one that reported on the cost effectiveness of both donepezil and rivastigmine. According to the Assessment Group, these publications generally supported the cost effectiveness of the AChE inhibitors in mild to moderate Alzheimer's disease. Most of the publications applied the existing model of Alzheimer's disease (from NICE technology appraisal guidance 111) to new settings.\n\nThe manufacturers of galantamine and rivastigmine did not submit new economic models. The manufacturer of galantamine highlighted issues with the previous model from NICE technology appraisal guidance 111 including:\n\nthe need to include long-term efficacy data\n\nrecognition of the full impact of decline in untreated patients with mild disease\n\noverestimation of mortality\n\nthe need for current cost data\n\nrecognition of 'no change' on global efficacy after 6 months or longer\n\nconsideration of costs to the individual, carer time and costs\n\nexploration of responder analyses.\n\nThe Assessment Group modelled the cost effectiveness of the AChE inhibitors and memantine separately because of the differences in the marketing authorisations. The base-case model for the AChE inhibitors followed a cohort of 1000 individuals with mild to moderate (MMSE 26–10) Alzheimer's disease for which the comparators were donepezil, rivastigmine (patch and capsule), galantamine and best supportive care. The Assessment Group used a prevalent cohort approach. Differentiation of treatment effect according to severity of disease (that is, mild or moderate) was not included in the base-case model. Populations with mild and moderate disease were assessed individually in the sensitivity analyses.\n\nThe Assessment Group's base case for mild to moderate disease evaluated the cost effectiveness of the AChE inhibitors over a lifetime (20-year) time horizon. Memantine was not included in the base case for mild to moderate disease. The Assessment Group constructed a Markov model that estimated the time to institutionalisation, which was defined as 'living in a residential home or a nursing home (not short respite care) or in a hospital on a long-term or permanent basis'. The model included three health states: pre-institutionalisation, institutionalisation and death. Depending on the severity of Alzheimer's disease at the beginning of the model, people could enter the model in the pre-institutionalised or institutionalised health state. Institutionalisation was equivalent to severe Alzheimer's disease (MMSE < 10) at which point treatment with an AChE inhibitor stopped in line with the marketing authorisations. Individual patients' data were used to estimate the proportion of the total cohort in each state at the end of each monthly cycle. An exponential survival regression model was fitted with time to end of pre-institutionalisation (including early death) as the response variable and MMSE, Barthel-ADL and age at start of study as covariates. The model incorporated a gradual increase in costs and gradual reduction in health-related quality of life with time. Cost and benefits were discounted at a rate of 3.5%. A constant rate of 4% discontinuation per monthly cycle for all drugs at all doses was assumed following a review of the included clinical trial evidence. Therefore within 25 months all patients were assumed to have stopped treatment.\n\nPatient characteristics (cognition [MMSE] and function [the Barthel-ADL] with three subgroups defined by age) were based mainly on individual patients' data from a community-based cohort study of people with untreated Alzheimer's disease by Wolstenholme and colleagues in Oxfordshire (n = 92). People starting in the model had already been diagnosed with Alzheimer's disease for a median of 4.0 years and a mean of 4.9\xa0years. Data from the London and South-East Region Alzheimer's Disease (LASER-AD) study were used to predict the proportion of patients who, at the start of the decision model, were in the institutionalised state (10% for the mild to moderate cohort and 40% for the moderate to severe cohort, based on 5.6% of people with MMSE ≥ 19, 27.1% of people with MMSE 15\xad19 and 59% people with MMSE < 19). In the base-case analysis, it was assumed that treatment delayed time to institutionalisation but not to death. Time to death was predicted by age, cognition (MMSE) and function (ADL) using equations from the Wolstenholme cohort data.\n\nEstimates of treatment effect in the Assessment Group's model (MMSE and ADCS-ADL, in particular) taken from the placebo-controlled randomised controlled trials identified in the systematic review of clinical effectiveness were applied to baseline estimates of best supportive care for time to institutionalisation and death. Estimates of clinical effectiveness were slightly different to those in the clinical effectiveness section of the assessment report in that only randomised controlled trials of licensed doses were considered. Rivastigmine patches were considered separately to capsules. The assessment report noted literature highlighting that patients self-report much higher utilities than those estimated by carers, particularly in people with severe Alzheimer's disease. Therefore, the base-case model included patient utilities based on carer-proxy utility values. Self-reported patient utilities and carer utilities were included in the sensitivity analysis. Carer utility associated with caring for patients with different CDR severities of Alzheimer's disease was mapped onto the MMSE scale. The utility of caring for someone with mild dementia (MMSE 21–26) was 0.87, which was reduced to 0.86 when caring for someone with severe dementia (MMSE of less than 10). The source publication (Jonsson and colleagues) reported only the mean utility values and not the uncertainty in the utility estimates.\n\nThe monthly drug costs included in the Assessment Group model, based on the BNF edition 58, were £83 for galantamine, £97 for donepezil, £79 for rivastigmine patches, and £72 for rivastigmine capsules. Additional resource use in the Assessment Group's model was estimated from the Wolstenholme cohort study. The cost of outpatient visits was assumed to be £26 per month and £158 for a 6-monthly assessment. The overall mean monthly cost of institutionalised care was estimated at £2941 (28% of which was assumed to be self-funded) and the cost of pre-institutionalised care depended on the severity of disease and the time to institutionalisation (for example, 1 year before institutionalisation the mean monthly costs for people with mild to moderate Alzheimer's disease was £1938 per month compared with £2427 per month for people with moderate to severe Alzheimer's disease). No adverse events or carer costs were included in the economic model.\n\nAfter comments from consultees and commentators on the assessment report, the Assessment Group made changes to the modelling of treatment effect based on the equations predicting time to institutionalisation and overall survival using age, cognition and function, and the resulting ICERs quoted in the assessment report. The Committee considered the revised outputs only.\n\nThe Assessment Group presented the revised deterministic ICERs and one-way sensitivity analysis (which included an analysis of the robustness of the ICERs to different structural assumptions) and the probabilistic ICERs (which represent the combined effect of some of the parameter uncertainties in the model) for each of the technologies. The deterministic model estimated that treatment with an AChE inhibitor delays time to institutional care by between 1.4\xa0and 1.7 months. The deterministic base-case analyses and the probabilistic sensitivity analysis indicated that all AChE inhibitors dominated best supportive care. Galantamine was associated with the least costs (£69,592 compared with £70,212 for best supportive care) but donepezil was associated with the greatest QALY gains (1.619 compared with 1.584 with best supportive care). The Assessment Group noted that the differences in the costs and QALYs between the AChE inhibitors were very small (total costs ranged from £69,592 to £69,678 and total QALYs ranged from 1.613 to 1.619). The probabilistic sensitivity analysis results did not indicate a particular AChE inhibitor as having a much greater probability of being cost effective compared with any of the other AChE inhibitors. For example, rivastigmine patches had the highest probability (32%) of being cost effective at thresholds of £20,000 and £30,000 per QALY gained, whereas donepezil had a probability of 27% of being the most cost-effective treatment option at a threshold of £20,000 and of 28% at a threshold of £30,000 per QALY.\n\nThe Assessment Group conducted one-way sensitivity analyses on the sensitivity of the ICERs to different parameters. The most important parameters were whether a treatment effect on survival was assumed and the rate of discontinuation of drug therapy. Assuming that there was a positive effect of treatment on mortality for all treatments of 1.9 to 2.2\xa0months, it was estimated that treatment with rivastigmine patches provided an additional 0.077\xa0QALYs per patient compared with best supportive care, with additional costs of £2840, leading to an ICER of £37,100 per QALY gained. This was in contrast to rivastigmine patches dominating best supportive care in the base case. In the incremental analysis, when including survival effect as a one-way sensitivity analysis, treatment with galantamine or donepezil provided additional QALYs and additional costs compared with rivastigmine patches. This led to ICERs of £41,800 per QALY gained for galantamine compared with rivastigmine patches, and £51,800 per QALY gained for donepezil compared with galantamine. The Assessment Group explained that this increase in the ICER was expected because when no survival effect was assumed (as per the base case), the delay in time to institutionalisation with treatment resulted in substantial savings in the costs that would have been incurred as a consequence of living in an institution. Assuming that there was also a survival benefit with treatment meant that the costs incurred from living in an institution would be delayed, but not saved. Therefore the incremental difference in costs would be higher and the ICER would increase. Lowering the estimate of the discontinuation rate below 4% resulted in greater treatment and monitoring costs and this led to a negative net benefit for the AChE inhibitors. Higher estimates led to fewer costs and greater net treatment benefit.\n\nThe manufacturer of donepezil and the Assessment Group both reported that donepezil treatment dominated best supportive care for both the mild and moderate populations. However, the manufacturer reported per patient QALY gains of 0.133 and estimated total per patient cost savings of £3379 for people with mild disease compared with 0.034 QALY gains and a saving of £551 in the Assessment Group's model. The manufacturer reported per patient QALY gains of 0.098 and estimated total per patient cost savings of £1889 for people with moderate disease compared with 0.035 QALY gains and a saving of £621 in the Assessment Group's model.\n\nDifferences between the results of Assessment Group and manufacturer's models may be accounted for by the following:\n\ndifferences between the models in terms of estimated overall survival (4.6\xa0undiscounted life years for the moderate cohort for the manufacturer compared with 3.6 years for the Assessment Group)\n\npercent of remaining lifetime spent living in the community (40% in the manufacturer model compared with 67% in the Assessment Group's model for the moderate cohort)\n\nassumptions of treatment effect, calculation of pre-institutionalisation cost (MMSE in the donepezil model compared with time to institutionalisation in the Assessment Group's model)\n\ndifferences in the cost of institutional care (£2801 per month in the donepezil model compared with £2117 in the Assessment Group's model)\n\ninclusion of carer utility\n\ninclusion of non-NHS/personal social services costs (that is, costs to the individual of institutional care).\n\nThe Assessment Group also considered the differences in its model compared with the model from NICE technology appraisal guidance\xa0111 (the SHTAC model). The key differences in the Assessment Group's model were that:\n\nthe sources used to model disease progression were different\n\nupdated estimates of costs and effectiveness were used\n\ncosts and utilities were varied according to time before institutionalisation\n\ndiscontinuation of treatment was accounted for. The SHTAC model used a risk equation to predict time to needing full-time care. This was based on US data (n\xa0=\xa0236), in which a number of different domains (ADAS-cog, psychiatric symptoms, extrapyramidal symptoms, age of onset and duration of illness) affected the time to institutionalisation. The Assessment Group's model, in contrast, was based on UK data (n\xa0=\xa092) and assumed that age and MMSE score predicted institutionalisation. The results of the models differed in the time spent in the institutionalised or full-time care states, which consequently affected costs. A longer estimated survival in the SHTAC model compared with the Assessment Group's model (6.5 compared with 3.8 years) led to higher total costs and total QALYs in the SHTAC model. The Assessment Group assumed less of a treatment effect for an AChE inhibitor, which translated to a slightly shorter delay to full-time care or institutionalisation (approximately 2 months in the SHTAC model compared with 1.4 to 1.7 months in the Assessment Group's model). The costs in the pre-institutional state in the Assessment Group's model were varied according to time, which led to lower average costs in the pre-institutional state in the Assessment Group's model. The difference in incremental costs in the Assessment Group model compared with the SHTAC model was a key factor in the different estimates of costs effectiveness (for example, an ICER of over £30,000 per QALY gained in the SHTAC model for donepezil, compared with donepezil dominating best supportive care in the Assessment Group's model). Including discontinuation of treatment in the Assessment Group's model led to fewer costs and greater net benefit associated with the AChE inhibitors, and so when discontinuation of treatment was included in the SHTAC model, this reduced the estimated ICER.\n\nThe Assessment Group noted some limitations of its model. These were that:\n\nit assumed a treatment benefit in cognition and function but not in behavioural and psychological symptoms\n\nthe expression of treatment effectiveness was mainly based on delay in time to institutionalisation\n\nchanges in cost and utility before institutionalisation were assumed to be delayed by the same amount of time as institutionalisation\n\nthe generalisability of the Wolstenholme cohort to the UK population was uncertain\n\nfull treatment effect at 6 months was assumed. The Assessment Group presented the deterministic ICER for each treatment to provide a comparison with best supportive care so that the data were comparable with those presented in NICE technology appraisal guidance 111.\n\n## Moderate to severe Alzheimer's disease\n\nThe Assessment Group's systematic review of literature published since 2004 identified six new cost-effectiveness studies for memantine. According to the Assessment Group, these publications generally supported the cost effectiveness of memantine for the treatment of Alzheimer's disease.\n\nManufacturer's model for memantine\n\nThe manufacturer submitted a Markov cohort model of the cost effectiveness of memantine compared with best supportive care over a 5-year time horizon in people with moderate to severe Alzheimer's disease and a subgroup of people with aggression, agitation and/or psychotic symptoms at baseline based on the NPI scale (at least one domain among agitation/aggression, delusion and hallucination with a score ≥ 3). The model included three states: pre-full-time care; full-time care; and death. Full-time care was defined as either dependent or institutionalised. Transition probabilities, including the baseline probability (on no treatment) of moving from pre-full-time care to full-time care and the probability of death were estimated using data from the LASER-AD UK epidemiological study. Predictors of the length of time to patients entering full-time care included measures of cognition (ADAS-Cog), function (ADCS-ADL), behaviour (NPI) and time in months. The clinical effectiveness of memantine, for which no additional benefit was assumed beyond 6 months, was based on a meta-analysis of six clinical trials of patients with moderate to severe Alzheimer's disease receiving memantine monotherapy or memantine adjunct treatment while on a stable dose of AChE inhibitors. Weighted mean differences were used as predictors in the risk equation estimating monthly probability of entering full-time care to incorporate treatment effect. NHS and personal social services costs were included. Resource use data were taken from the LASER-AD study and the Personal Social Services Research Unit (PSSRU). MIMS March 2010 was used for costs, which were discounted at 3.5%. Indirect costs and quality-of-life effects on relatives and carers were not included. Utility estimates were derived from the LASER-AD study, which involved mapping of three instruments (HSQ-12, Ferm's D test and QoL-AD) onto the EQ-5D. The manufacturer ran the model probabilistically.\n\nThe manufacturer found that memantine dominated best supportive care (that is, no pharmacological treatment) because additional QALYs were gained (0.031) at a cost saving of £1711. Memantine treatment was associated with a delay to full-time care of 6\xa0weeks. Additional treatment benefits were reported in the subgroup of patients with aggression, agitation and/or psychotic symptoms in whom the delay to full-time care was prolonged by up to 11\xa0weeks with incremental QALY gains of 0.069 and a cost saving of £4971.\n\nThe manufacturer conducted sensitivity analyses. These explored the effect of different treatment effects, discount rates, costs of pre-full-time care, costs of full-time care and alternative sets of utilities on the cost-effectiveness estimates. The results all continued to show that memantine dominated best supportive care for the overall population and subgroups.\n\nThe Assessment Group highlighted several issues with the manufacturer of memantine's model. Although the new subgroup was defined differently and based on clinical expertise, the Assessment Group noted that a behavioural subgroup had not previously been accepted by the Appraisal Committee for NICE technology appraisal guidance 111. The manufacturer did not include an AChE inhibitor as a comparator for the population with moderate disease as specified in the scope. There was uncertainty about the risk equation because of lack of clarity over generalisability of the LASER-AD study (many participants in this study had been or were still receiving treatment with AChE inhibitors). The Assessment Group also noted a lack of clarity about the categorisation of 'dependence', inclusion of data from patients with mild disease, poor reporting of statistical analyses and lack of validation from an external source. The manufacturer responded to these criticisms, providing supplementary information in its comments on the assessment report. In addition, because the trials used observed cases with last observation carried forward in the analysis instead of an intention-to-treat analysis, the Assessment Group was concerned that the clinical-effectiveness estimates may have been biased. The manufacturer responded to these comments to confirm that all analyses were performed with an intention-to-treat population using the observed cases approach, with a 'last observation carried forward' analysis to confirm results. There was also uncertainty about the methods used to map one outcome measure to another (mapping one health-related quality-of-life measure onto another, mapping SIB onto the ADAS-cog and rescaling one version of ADCS-ADL to another), pooling data for combination therapy and monotherapy, and using NPI rather than NPI hallucinations as a predictor of time to full-time care. There was also a lack of clarity over the sources of data, inclusion of costs to individuals and retrospective collection of resource data in the LASER-AD study. Benefits to carers were not included in the model, and mapping of health-related quality-of-life data to EQ-5D was poorly described. The Assessment Group queried whether the manufacturer's estimates of at least 90% for the probability of memantine being cost effective at £20,000 and £30,000 thresholds were plausible given the uncertainties about the clinical benefit of memantine.\n\nThe cost effectiveness of the AChE inhibitors and memantine were modelled separately by the Assessment Group because of the differences in the marketing authorisations. Memantine was not included in the SHTAC model in NICE technology appraisal guidance 111. The base-case model for memantine followed a cohort of 1000 individuals with moderate to severe (MMSE 20\xad0) Alzheimer's disease, for which the comparator was best supportive care. Populations with moderate and severe disease were assessed individually in the sensitivity analyses. The Assessment Group's model is described in sections 4.2.12 to 4.2.16. Different assumptions used in the moderate to severe model were that a higher proportion of people started in institutional care (40% compared with 10% in the mild to moderate model) and treatment with memantine was continued after people entered institutional care (whereas treatment with AChE inhibitors was discontinued when people entered institutional care in the mild to moderate model). The cost of monthly memantine was £71.\n\nThe deterministic Assessment Group's model showed that treatment with memantine delayed time to institutional care by about 0.8\xa0months compared with best supportive care. The ICERs were £32,100 per QALY gained (a gain of 0.013 QALYs over a patient's lifetime when treated with memantine compared with best supportive care and the extra cost was £405).\n\nThe Assessment Group's probabilistic sensitivity analysis of the cost effectiveness of memantine in the population with moderate to severe Alzheimer's disease estimated a probability of memantine being more cost effective than best supportive care of less than 38% at a threshold of £30,000 per QALY gained and 28% at £20,000 per QALY gained. The mean ICER from the probabilistic sensitivity analysis for memantine compared with best supportive care was £36,900 per QALY gained.\n\nThe Assessment Group conducted one-way sensitivity analyses to assess the sensitivity of the ICER to different parameters. When a positive treatment effect on survival was assumed, the ICER of memantine compared with best supportive care increased to £65,619 per QALY gained.\n\nThe cost-effectiveness model submitted by the manufacturer of memantine reported that treatment with memantine dominated best supportive care. The Assessment Group's model, however, estimated an ICER of £32,100 per QALY gained. One of the main differences between the manufacturer's model and the Assessment Group's model was that treatment was assumed to continue in institutionalisation by the Assessment Group but not the manufacturer. The estimated overall survival was similar in the two models (3.7 years in the manufacturer's model and 3.5 years in the Assessment Group's model). Another key difference between the models was that the manufacturer's model assumed a greater treatment effect with memantine, which translated to a delay to entering full-time care of 1 month compared with a delay of 0.8\xa0months estimated by the Assessment Group's model. Higher costs were attributed to the full-time care state in the manufacturer's model (£3267 compared with £2117 in the Assessment Group's model). The manufacturer's model also assumed a higher cost of, and a longer time in, pre-institutional care with treatment (1.73\xa0years in the manufacturer's model compared with 1.5 years in the Assessment Group's model).\n\nThe Assessment Group ran the manufacturer of memantine's model using its own assumptions. This had a negligible impact on the outputs.\n\nThe Assessment Group conducted analyses of the individual mild, moderate and severe populations for the AChE inhibitors, AChE inhibitors and memantine, and memantine respectively (all including best supportive care). Each technology was compared with the next cheapest, non-dominated technology and the ICERs were rounded to the nearest £100. The Assessment Group highlighted that caution should be taken when assessing these results because effectiveness estimates were derived from trials that included populations with varying disease severity. In the subgroup analyses for mild or moderate Alzheimer's disease, all treatments still dominated best supportive care. Memantine had an ICER of £26,500 per QALY gained in severe disease.\n\n## Other key issues\n\nNICE technology appraisal guidance 111 acknowledged the issues in using the MMSE instrument alone as a measure of severity in particular groups. This included people with learning or other disabilities, linguistic or other communication difficulties, or if it is not possible to use the MMSE in a language in which the patient is sufficiently fluent.\n\nClinical specialists, patient experts and primary care trust commissioners highlighted the need for a wide range of services for people with Alzheimer's disease, and the fact that drugs are just one aspect of this range of care.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of donepezil, galantamine, rivastigmine and memantine having considered evidence on the nature of Alzheimer's disease and the value placed on the benefits of donepezil, galantamine, rivastigmine and memantine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee was aware that there is currently no cure for Alzheimer's disease and that the AChE inhibitors and memantine treat the symptoms of Alzheimer's disease but do not slow the progression of the disease. The Committee was also aware that access to general support services and care for people with Alzheimer's disease is variable and that the availability of pharmacological treatment was relevant to appropriate wider management and support. The Committee considered the current management of Alzheimer's disease under the recommendations of NICE technology appraisal guidance 111, which recommends AChE inhibitors for the treatment of moderate Alzheimer's disease. The Committee was aware of both the importance of early diagnosis and of carers' and clinical views of the advantages of early use of AChE inhibitors in the treatment of Alzheimer's disease. The Committee heard from clinical specialists that there is variation in clinical practice and that AChE inhibitors are also used to treat some patients with an MMSE score of above 20. The clinical specialists also noted that memantine is used in clinical practice. The Committee heard from clinical specialists that antipsychotics are used in clinical practice for people with Alzheimer's disease who have severe behavioural symptoms, but that their use was generally discouraged in people with milder symptoms because of the emerging evidence on increased risk of serious adverse events when used in older people.\n\nThe Committee heard from clinical specialists that the MMSE scale was originally developed as a screening tool to aid the diagnosis of Alzheimer's disease. It also heard that NICE technology appraisal guidance 111 had defined the eligibility of people for treatment with AChE inhibitors and when these drugs should be stopped according to MMSE scores (that is, the degree of loss in patient cognition), among other criteria. The Committee noted, as did the Appraisal Committee for NICE technology appraisal guidance 111, that because the MMSE scale is less sensitive to changes in cognition for people at the extreme ends of the scale, clinical judgement is necessary (rather than a rigid adherence to the MMSE alone) to assess the severity of Alzheimer's disease and the suitability of AChE inhibitors on an individual patient basis. In addition, the clinical specialists indicated that a global assessment of the effects of Alzheimer's disease was also important. The Committee was aware of the difficulties of using the MMSE when assessing people with learning difficulties or communication difficulties, or if the person is not fluent in the language of the measurement tool. The Committee also heard from clinical specialists that the use of the MMSE scale alone may not be sensitive enough to assess the severity of Alzheimer's disease in people with a high level of education. The Committee thus recognised the difficulties of using MMSE score alone to assess the severity of Alzheimer's disease and the response to AChE inhibitors. The Committee agreed that cognitive scales alone such as the MMSE are not always appropriate for assessing the severity of dementia. The Committee concluded that if cognitive scales are not appropriate for assessing the need for treatment, or whether to continue treatment, then clinicians should use another appropriate method of assessment.\n\n## Clinical effectiveness\n\nThe Committee considered the available evidence on the clinical effectiveness of the AChE inhibitors submitted by the Assessment Group, consultees and commentators. It considered the new evidence available since NICE technology appraisal guidance 111 was published and the impact of the new evidence when combined with the data from NICE technology appraisal guidance\xa0111. The Committee stated that a small amount of new evidence about the clinical effectiveness of the AChE inhibitors from randomised controlled trials had been published since 2004. The Committee recognised the heterogeneity of outcome measures in trials and was aware of the limitations of some of the instruments used in the clinical trials, including cognitive and behavioural scales.\n\nThe Committee considered the results from the new placebo-controlled randomised clinical trials, which continued to show the small but definite clinical benefit of the AChE inhibitors in mild and moderate Alzheimer's disease compared with best supportive care. The Committee noted that the evidence was almost exclusively based on 6-month long randomised controlled trials because few of these trials had follow-up of over 6\xa0months. The Committee heard from clinical specialists and patient experts that benefits of treatment appeared to last for 2 to 3 years in some patients in open-label studies. The Committee concluded that the new evidence provided additional support to the conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain owing to mixed results from the available evidence.\n\nThe Committee considered whether there was evidence that one of the AChE inhibitors was more clinically effective than any other. The Committee noted that only one good-quality head-to-head randomised controlled trial comparing donepezil and rivastigmine had been published since 2004 and that this did not change the conclusions made in NICE technology appraisal guidance 111. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of clinical effectiveness.\n\nThe Committee considered whether there was evidence that AChE inhibitors demonstrated benefits in terms of patient and carer health-related quality of life. The Committee noted that quality of life was not assessed in the majority of randomised controlled trials and that there was no evidence from randomised controlled trials that demonstrated any impact. The Committee considered evidence from patient experts that benefits to people with Alzheimer's disease and their carers were not necessarily those picked up by instruments measuring cognition, function, behaviour or global outcomes. In their experience, relevant benefits included maintaining mood, being able to cope and interact with others, and functional activities that might not be scored on currently used scales, such as being able to pick up the phone or switch on the television. In particular, maintaining aspects of personal identity, such as a naturally methodical person being able to put things in order, was considered important. The Committee concluded that although there was no evidence available on health-related quality of life from a systematic review of randomised controlled clinical trials, there was some anecdotal evidence from clinical practice of benefits to patients and carers from using AChE inhibitors.\n\nThe Committee discussed whether there was evidence of a survival benefit associated with the AChE inhibitors. The Committee was aware that these are symptom-treating rather than disease-modifying treatments. In the absence of evidence from randomised controlled trials, the Committee considered the opinion of clinical specialists, who were not aware of a survival effect associated with the AChE inhibitors. The Committee acknowledged that few deaths occurred during randomised controlled trials, which have generally been short with limited follow-up, and that subsequently mortality data were difficult to obtain. The Committee considered the view of clinical specialists who informed the Committee that death was caused by factors such as age, acute infections, comorbidities and complications of Alzheimer's disease rather than the disease itself. The Committee noted that Alzheimer's disease affects predominantly, but not exclusively, people over 65 years of age. The Committee concluded that there was no evidence to suggest that the AChE inhibitors affected survival.\n\nThe Committee deliberated whether there was evidence that the AChE inhibitors lead to a delay in institutionalisation. The Committee acknowledged that time to institutionalisation was not generally included as an endpoint in randomised controlled trials and that published data were therefore limited. For example, the AD2000 study collected data on institutionalisation but limited accrual into the trial led to an underpowered conclusion about this outcome. The Committee considered the experiences of clinical specialists and patient experts, who reported that the following were often important factors in the decision to move into institutionalised care: severe behavioural symptoms and the ability of the person with Alzheimer's disease and their family to cope with these, continence issues, and the availability of community support services. Opinion varied between the experts about the degree of impact of the AChE inhibitors on time to institutionalisation. Although one clinical specialist felt that prescribing these drugs has led to a significant delay in people with Alzheimer's disease entering institutions, others thought that this effect was small and many other factors were in operation (such as funding arrangements for state-funded residential care). The Committee was also aware of the individual variability of disease progression, which would influence at what stage a person with Alzheimer's disease would be admitted to an institution. The Committee concluded that although it was clinically plausible that treatment with an AChE inhibitor may delay time to institutionalisation, limited direct evidence was available to assess the size of this effect.\n\nThe Committee considered the evidence on adverse effects associated with the AChE inhibitors. The Committee acknowledged the gastrointestinal effects of these technologies. However, it concluded that the adverse effects of these technologies were well documented and that overall evidence since 2004 has not changed the tolerability profile of AChE inhibitors, apart from the fewer side effects noted in patients treated with rivastigmine patches than with oral rivastigmine.\n\nThe Committee considered the available evidence on the clinical effectiveness of memantine submitted by the Assessment Group, consultees and commentators. The Committee understood that memantine had a different mode of action from the AChE inhibitors and in practice would be used later in the treatment pathway in people with more severe Alzheimer's disease, this also being at a time when a higher proportion of people develop behavioural symptoms. It considered the new evidence available since the publication of NICE technology appraisal guidance 111, and the impact of the new evidence when it was combined with the data from the previous appraisal. The Committee noted that two of the randomised controlled trials included in the manufacturer's submission were excluded from the Assessment Group's systematic review because at least 20% of each of the trial populations were people with mild Alzheimer's disease, which is not included in the current licensed indication of memantine.\n\nThe Committee considered the results of the new randomised controlled trials for memantine and the pooled results in order to estimate the size of clinical effectiveness for memantine compared with placebo or best supportive care. The Committee was aware of the limitations of the instruments used in the clinical trials including cognitive and behavioural scales. The Committee noted that although the new evidence considered by the Assessment Group did not substantially change the estimate of the clinical effectiveness of memantine compared with the review in 2004, the meta-analysis submitted by the manufacturer (which included individual patient data from trials with mixed populations so that the manufacturer was able to exclude data for patients with mild disease) showed significant benefits in the cognitive, functional, global and behavioural domains. The Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.\n\nThe Committee considered the evidence in the manufacturer's submission on the clinical effectiveness of memantine in a subgroup of patients with agitation, aggression and/or psychotic symptoms, which are more common in patients with severe Alzheimer's disease. This evidence reported a statistically significant benefit of memantine for cognitive, functional and global outcomes and NPI score on agitation, aggression and/or psychotic symptoms in this subgroup. The Committee concluded, on the basis of the manufacturer's evidence and clinical specialist testimony, that memantine appears to have an effect on these symptoms.\n\nThe Committee considered the clinical effectiveness of memantine as an adjunct to AChE inhibitor treatment. The Committee noted evidence that showed no statistically significant benefit for combination treatment with memantine and AChE inhibitors for cognitive, functional, behavioural or global outcomes. The Committee was also made aware of ongoing trials for combination therapy including the DOMINO-AD (donepezil and memantine in moderate to severe Alzheimer's disease) study. The Committee concluded that combination treatment with memantine and AChE inhibitors could not be recommended because of lack of evidence of additional clinical efficacy compared with memantine monotherapy.\n\nThe Committee considered the new evidence since 2004 of adverse effects associated with memantine and noted that some patients experience agitation that resolves when the drug is stopped, although agitation was also a main adverse event for those taking placebo. The Committee concluded that the adverse effects of memantine were well documented and that evidence since 2004 has not changed the tolerability profile.\n\n## Cost effectiveness\n\nThe Committee reviewed the two economic models submitted by the manufacturers of donepezil and memantine alongside the Assessment Group's model. The Committee considered that the key differences between the models included the selection of cohort data used to model disease progression, model structure (Markov compared with a discrete event simulation), the extent to which the model included the effectiveness of treatment for cognitive, functional and behavioural outcomes, and the measurement of patient utility based on patient or carer proxy values.\n\nThe Committee considered the most appropriate cohort data on which to model disease progression. The Committee heard from clinical specialists about the importance of using data from the UK compared with the US because of differences in the healthcare system, and differences in the management of Alzheimer's disease. The Committee also heard from clinical specialists that UK population data such as that found in the Wolstenholme dataset is the best available data on which to model progression of Alzheimer's disease because of the UK location, its long follow-up, the absence of pharmacological treatment for Alzheimer's disease and the availability of individual patient data. The Committee was aware of the limitations of this dataset including the small population, the relatively old data (collected between 1988 and 1999), which might not reflect current rates of and times to institutionalisation, and the fact that the study was based in a semi-rural location. The Committee concluded that although the Wolstenholme dataset that formed the basis of the Assessment Group's model had these limitations it still represented the best available data.\n\nThe Committee considered the appropriateness of the structure of the Assessment Group's model, which was based on predicting time to institutionalisation. The Committee was aware that the uncertainty about time to institutionalisation was an issue that affected all submitted models. The Committee recognised the lack of institutionalisation data from randomised controlled trials, the limitations of the AD2000 study which collected institutionalisation data but was underpowered to measure this outcome, and the absence of a systematic review of observational studies available in this area. The Committee discussed the various definitions of institutionalisation. The Committee was aware that in clinical practice, the type of institution would have an impact on time to institutionalisation, as would cost and patient characteristics. The Committee was also aware that the Assessment Group had equated institutionalisation to severe disease, therefore assuming that AChE inhibitors would be stopped on entering an institution. However, the Committee acknowledged that in clinical practice, institutionalisation would not be based on disease severity alone. The Assessment Group used the definition of institutionalisation from the Wolstenholme cohort study, on which disease progression in its model was based.\n\nThe Committee considered that only the Assessment Group addressed the decision problem in the scope because it included all of the AChE inhibitors as comparators for mild to moderate Alzheimer's disease, whereas the manufacturer of donepezil's model compared donepezil with best supportive care only. The Committee concluded that there were limitations in constructing an economic model based on time to institutionalisation but that the Assessment Group's model was based on the best currently available and detailed UK evidence to evaluate the cost effectiveness of donepezil, galantamine and rivastigmine.\n\nThe Committee discussed the assumption in the Assessment Group's model that age, cognition and function were the key predictors of time to institutionalisation. The Committee was aware of the limitations of scales such as the MMSE in evaluating severity of and change in Alzheimer's disease and also as a proxy for the delay in time to institutionalisation. The Committee also understood that the Wolstenholme study had used a scale of function that had been mapped to another index (the Barthel index), which in turn had been mapped by the Assessment Group to a commonly used index of activities of daily living. The Committee was aware of the potential uncertainties caused by these processes. However, considering all these factors in relation to cognitive and functional scales, the Committee considered it appropriate to use age, cognition and function as key predictors of time to institutionalisation. The Committee considered whether behavioural symptoms should also have been included as a predictor of time to institutionalisation in the Assessment Group's model. The Committee was aware that the Assessment Group's model did not incorporate this because of lack of data. The Committee noted that the clinical specialists and patient experts had emphasised behavioural symptoms being a key factor when deciding when to admit a person with Alzheimer's disease to an institution. The Committee noted that when behaviour was removed from the manufacturer of donepezil's model in sensitivity analyses, it did not have a big impact on the incremental cost-effectiveness results. The Committee concluded that although behaviour was a potential predictor of time to institutionalisation in everyday life, its omission from a model already including cognition and function was unlikely to substantially change the outputs of the model in mild and moderate Alzheimer's disease.\n\nThe Committee considered the importance of the assumption that there was no survival effect of treatment. The Committee considered the sensitivity analyses conducted by the Assessment Group, which had assumed a survival effect of 1.9–2.2 months and subsequently raised the ICERs for the AChE inhibitors to over £30,000 per QALY gained. The Committee understood that this increase in ICERs was expected. This was because when no survival effect was assumed (as per the base case), the delay in time to institutionalisation with treatment resulted in substantial savings in the costs that would have been incurred as a consequence of living in an institution. Assuming that there was also a survival benefit with treatment meant that the costs incurred from living in an institution would be delayed, but not saved because people would live for longer. Therefore the incremental difference in costs was higher and the ICER increased. The Committee noted both the lack of randomised evidence measuring the survival effect of treatment with the AChE inhibitors and clinical opinion that mortality was more likely to be influenced by other factors unrelated to treatment. The Committee concluded that the assumption of no survival effect from treatment with the AChE inhibitors in the base-case model was appropriate in light of the lack of evidence of survival effect from randomised controlled trials.\n\nThe Committee considered the assumption of a 4% discontinuation rate of treatment in the Assessment Group's model. The Committee was aware that the Assessment Group's model included the ability to allow for discontinuation and this may have been one explanation for the difference in ICERs resulting from this model and the model used in NICE technology appraisal guidance 111 (the SHTAC model). The Committee considered how the Assessment Group had made the assumption of a constant rate of 4% based on the included randomised controlled trial evidence. For all effectiveness estimates it was assumed that an intention-to-treat analysis had been done, so that estimates related to all participants and not only those continuing on treatment. Given that many randomised controlled trials did not report an intention-to-treat analysis, this assumption was likely to over-estimate any treatment effects in the decision model. However, clinical specialists advised that discontinuation in clinical practice is between 2 and 5% per year and considered a 4% discontinuation rate to be appropriate. In addition, the Committee recognised that in sensitivity analyses, variation in the assumed discontinuation rate had the biggest impact on cost-effectiveness estimates. Increasing discontinuation rates led to fewer costs and greater net benefit for the AChE inhibitors and vice versa. The Committee concluded that it was appropriate to include discontinuation rates in the economic model and accepted that the assumption of 4% was plausible.\n\nThe Committee considered other inputs to the model, such as assumptions about the costs and QALYs generated in the pre-institutional and institutional health states of the Assessment Group's model. The Committee heard from the Assessment Group that the monthly costs of pre-institutional care and institutional care were higher in its model than in the SHTAC model. When the delay in institutionalisation was taken into account (1.4 to 1.7 months in the Assessment Group's model), donepezil treatment (the example selected by the Assessment Group) in the Assessment Group's model was cost saving compared with best supportive care because the additional costs incurred in pre-institutional care (increased drug costs, monitoring costs and care costs) were outweighed by the cost saving associated with people spending less time in institutional care. In the same way, the QALYs gained by delaying the time to institutionalisation outweighed the QALYs lost in the institutional care health state in the Assessment Group's model.\n\nThe Committee was aware that the cost of institutionalisation varied according to institution type and the level of care needed, the availability of institutional care and support services, and that funding arrangements for residential care can result in significant individual contributions by the patient or family. The Committee considered it acceptable to use an average cost for institutional care and accepted the fixed cost of institutionalisation used in the Assessment Group's model. Based on information provided by clinical specialists and patient experts, the Committee also accepted the assumptions in the Assessment Group's model about costs of monitoring the patient every 6\xa0months.\n\nThe Committee considered whether assumptions and inputs about health-related quality of life and utilities included in the Assessment Group's model were reasonable. The Committee heard that utility values for health-related quality of life reported by patients themselves and by carers as proxy responses were both relevant. The Committee heard from clinical specialists that in early stages of the disease it would be appropriate for the patient themselves to report their own outcomes, but in more severe stages of the disease a proxy utility provided by the carer would be appropriate. The Committee acknowledged that there were differences in the responses given by patients and those given by carers but that in sensitivity analyses conducted by the Assessment Group, changes to utility values had a small impact on ICERs. The Committee concluded that the assumptions and inputs about utilities in the Assessment Group's model were appropriate.\n\nThe Committee also considered the Assessment Group's approach to a variable cost and utility in the pre-institutionalisation health state. The Committee acknowledged that this was a difference between the Assessment Group and SHTAC models, and may have accounted for some of the differences in the ICERs produced by the two models.\n\nThe Committee considered whether there were differences in cost effectiveness for particular subgroups of people with Alzheimer's disease. The Committee reviewed the subgroup analyses conducted by the Assessment Group in mild and moderate Alzheimer's disease. The Committee noted that these had been provided as an exploratory analysis by the Assessment Group and that the Assessment Group's model assumed the same treatment effect for patients with mild and moderate disease. The Committee was aware that in NICE technology appraisal guidance 111 a difference in treatment effect between mild and moderate populations was assumed, on the basis of analysis by the Medical Research Council Biostatistics Unit. The Committee was also aware that no subgroup analyses had been identified as part of the systematic review of clinical effectiveness analysis. The Committee also noted that in clinical practice, clinicians found it difficult to differentiate between mild and moderate disease when using the MMSE. The Committee was also aware that many AChE inhibitor trials included patients with both mild and moderate disease.\n\nThe Committee considered the merits of the Assessment Group's model compared with the manufacturer of donepezil's model. The Committee considered that both models captured the costs and benefits of treatment with greater accuracy than the SHTAC model used in the previous appraisal and that the manufacturer's discrete event simulation model offered an intuitive description of the disease. The Committee considered the enhancements in the Assessment Group's model compared with the SHTAC model and noted that the individual patient data on which disease progression in the Assessment Group's model was based, combined with the differential utility and costs accrued in the pre-institutional health state, led to a more accurate representation of the costs and outcomes of treatment. The Committee further noted that the discrete event simulation model provided by the manufacturer of donepezil (based on a US cohort) was unable to adequately compare all available treatment options within a full incremental analysis. Overall, the Committee preferred the Assessment Group's model over the discrete event simulation model because the modelling of disease progression (based on UK data from patients who had not received treatment with AChE inhibitors) was most appropriate for the UK clinical setting and the model enabled all of the treatments to be compared in a full incremental analysis. The Committee noted, however, that the manufacturer's model was useful to enable comparisons for specific parts of the decision problem and to test the inputs, assumptions and face validity of the Assessment Group's model. Both models showed donepezil to be cost saving.\n\nThe Committee considered the base-case results for the cost effectiveness of the AChE inhibitors compared with best supportive care. The Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation. This assumption led to less time spent in institutional care and subsequent savings to the NHS/personal social services. The Committee considered that, with this assumption, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.\n\nThe Committee noted the small difference in absolute costs and benefits between the AChE inhibitors. It also observed that small changes in some of the inputs and assumptions had significant impacts on the incremental estimates of cost effectiveness. The Committee concluded that overall, the AChE inhibitors donepezil, galantamine and rivastigmine had small but demonstrable clinical benefits and were cost-effective treatment options. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). The Committee further accepted that an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions (details of which can be found in the individual summaries of product characteristics) and dosing profiles.\n\nThe Committee considered the two models for the cost effectiveness of memantine presented by the manufacturer and the Assessment Group. It noted that although the structures of the models were similar, there were differences in the assumptions underlying the two models. The Committee considered that all the uncertainties about the assumptions and inputs in the Assessment Group's model for the AChE inhibitors also applied to the memantine model. However, the Committee identified additional uncertainties relating to memantine, such as estimates of treatment effect used in the models. The Committee considered the key differences between the Assessment Group's and manufacturer's models to be the selection of cohort data used to model disease progression, assumptions about the proportion of patients who were institutionalised at the start of treatment, the effectiveness estimates used in the model, and whether the model included the effectiveness of treatment on behavioural symptoms.\n\nThe Committee considered the cohort data on which disease progression in each of the models was based. The Committee was aware that the manufacturer's model used LASER-AD data to model disease progression, which had shorter follow-up compared with the cohort study used by the Assessment Group. It was also aware that many of the participants of the LASER-AD study were on active treatment. The Committee concluded that the Wolstenholme data used in the Assessment Group's model were more suitable for assessing disease progression because this study had longer follow-up and the participants were not receiving active therapies.\n\nThe Committee considered the assumptions included in the Assessment Group's model. The Committee acknowledged that some of the assumptions may have led to underestimates of the benefits of memantine compared with best supportive care. In the Assessment Group's model, for the 40% of patients with severe Alzheimer's disease who started in institutions or started with a low utility, there was limited opportunity to benefit from treatment, but they nevertheless accrue costs. The Committee therefore concluded that the cost effectiveness of memantine may have been underestimated in the Assessment Group's model for patients with severe Alzheimer's disease, although by how much is uncertain.\n\nThe Committee considered the appropriateness of including the impact of memantine on behavioural outcomes. The Committee was aware that the Assessment Group had not included behavioural outcomes as a predictor of time to institutionalisation in its model but the model submitted by the manufacturer of memantine had included behaviour as a predictor of time to full-time care. The Committee noted that the manufacturer's model used LASER-AD data to model disease progression, which included the effectiveness of treatment on behavioural symptoms. The Committee heard from the Assessment Group that when the impact of memantine on behavioural symptoms was removed from the manufacturer's model it had little impact on the cost effectiveness of memantine compared with best supportive care. The Committee was also aware, based on the evidence from the patient experts and clinical specialists, that behavioural outcomes were not well captured by the instruments used in clinical trials. The Committee concluded that although behaviour is a potential predictor of time to institutionalisation, not including it in the Assessment Group's model was unlikely to substantially change its outputs for people with moderate to severe Alzheimer's disease.\n\nThe Committee also noted that the manufacturer's submission included a subgroup analysis of the cost effectiveness of memantine in a subgroup of patients with aggression, agitation and/or psychotic symptoms. The Committee heard from clinical specialists and the manufacturer that memantine appears to have cognitive, functional, global and behavioural effects, particularly in people with aggression, agitation and/or psychotic symptoms, which are more common in people with severe Alzheimer's disease. The Committee accepted that memantine may therefore have the potential to reduce the need for antipsychotics but noted that there was no randomised controlled trial evidence supporting this assumption. The Committee accepted on the basis of the evidence in the manufacturer's submission and expert testimony that memantine may offer benefit to people with severe Alzheimer's disease.\n\nThe Committee considered the estimates of treatment effect for memantine in the manufacturer's and Assessment Group's models. The Committee noted that estimates of treatment effect were different between the models. The Committee understood that the effectiveness data in the manufacturer's submission were based on a pooled estimate of memantine monotherapy and combination therapy with AChE inhibitors, whereas the Assessment Group's model included effectiveness estimates only for memantine monotherapy. The Committee also noted that the manufacturer's submission was based on analysis of individual patient data of people with moderate Alzheimer's disease taken from two randomised controlled trials that had been submitted to the European Medicines Agency (EMA) in order to gain the license extension for memantine in moderate disease. These data had not been included in the Assessment Group's report because more than 20% of the study population in the trials had mild Alzheimer's disease, and so did not fit with the inclusion criteria of the systematic review based on the licensed indications in the decision problem. As a consequence, the Committee found it difficult to reconcile the lack of statistically significant benefit seen in the meta-analysis from the Assessment Group for cognitive, functional and behavioural outcomes with the significant improvements (particularly for behaviour) in the manufacturer's individual patient data analyses. The Committee was uncertain about how much the difference in clinical effectiveness influenced the differences in cost-effectiveness results between the two models. It was also aware, based on the evidence provided by patient experts and clinical specialists, that behaviour was an important factor when considering institutionalisation. However, published evidence was limited because in trials, institutionalisation was not an outcome measure and instruments had limited capacity to capture behavioural changes. The Committee concluded that because the Assessment Group's model did not include results from some trials in the estimate of treatment effect for which access to individual patient data was needed, it may have underestimated the cost effectiveness of memantine, although by how much is uncertain.\n\nTaking the above factors into account, the Committee considered that, on balance, the Assessment Group's model provided a suitable basis for decision making. This was because the cohort data used to model disease progression were generalisable to the UK, the effectiveness data for memantine monotherapy and combination therapy with AChE inhibitors were not combined, and the cost effectiveness of memantine could be compared with that of the AChE inhibitors in moderate Alzheimer's disease.\n\nThe Committee considered that the base-case ICER for memantine of £32,100 per QALY gained compared with best supportive care in moderate to severe Alzheimer's disease was likely to be an overestimate of the true cost per QALY gained, although the size of this overestimation was uncertain. The Committee noted that in moderate disease there were active comparators, whereas only memantine has a marketing authorisation for severe disease.\n\nThe Committee considered the subgroups of people with moderate Alzheimer's disease only and severe Alzheimer's disease only. The Committee noted that in the Assessment Group's exploratory analysis, memantine dominated best supportive care for the moderate group, and for the severe group the ICER for memantine compared with best supportive care was £26,500 per QALY gained. The Committee also noted that both subgroup ICERs were lower than the combined base-case ICER of £32,100 per QALY. The Committee heard from the Assessment Group that this may be because of the different assumptions in the subgroup analysis compared with the base case.\n\nThe Committee concluded that memantine would not be cost effective compared with the AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost. The Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator. It concluded that in people with moderate Alzheimer's disease memantine should be recommended for people who are intolerant of or have contraindications to AChE inhibitors.\n\nThe Committee thought that memantine was likely to have a positive effect on the quality of life of people with severe disease, because they are more likely to experience behavioural symptoms. This was not captured in the Assessment Group's model. Also, even though behavioural benefit did not appear to have a great impact on the results of the manufacturer's model, the Committee had heard from clinical specialists that behavioural effect may not be well captured in the available evidence. The Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the\xa0ICER would be less than £26,500 per QALY gained. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.\n\n## Other issues\n\nThe Committee considered the criteria for recommending the AChE inhibitors in NICE technology appraisal guidance 111.The Committee acknowledged the importance of people with Alzheimer's disease being assessed by a specialist clinician and heard from clinical specialists that treatment with AChE inhibitors and memantine should always be initiated by a clinical specialist in accordance with the recommendations of NICE technology appraisal guidance 111. However, the Committee acknowledged that for assessing whether treatment should be continued, review by a specialist may be substituted by a shared care arrangement because this may put less pressure on local resources while still ensuring optimal treatment for patients.\n\nThe Committee also considered the recommendations of NICE technology appraisal guidance 111 for specific groups of people with Alzheimer's disease, such as those with disabilities (for example, sensory impairments) or linguistic or other communication difficulties. The Committee acknowledged comments from local NHS trusts that use of scales such as the MMSE made prescription monitoring and clinical audit less problematic. However, the Committee confirmed that, as in NICE technology appraisal guidance 111, when using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect the results and make any adjustments they consider appropriate. The Committee noted comments received in consultation that assessment scales such as the MMSE may not capture the severity of disease or benefit of treatment in people with a high level of education. It was aware that this group of people does not fall under the groups protected by equality legislation, but concluded that clinicians should also keep this in mind when assessing patients. Clinicians should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.\n\nThe Committee discussed the continuation of treatment and thought it appropriate that treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms. The Committee considered comments received during consultation that a recommendation of 6-monthly reviews for treatment continuation was not evidence based and could be a misuse of NHS resources. The Committee acknowledged that among the submitted data, there was insufficient evidence to define an optimal review time although most clinical-effectiveness evidence was from 6-month trials and the economic models included the costs of 6-monthly monitoring. The Committee also assumed that good clinical practice would be to regularly review patients. The Committee considered that making recommendations on the timings of patient reviews and other implementation issues, such as switching from AChE inhibitors to memantine according to the recommendations, might be better addressed by the clinician. It concluded that patients who continue on the drug should be reviewed regularly using cognitive, global, functional and behavioural assessment and that treatment should be reviewed by an appropriate specialist team, unless there are locally agreed protocols for shared care. The Committee further concluded that carers' views on the patient's condition at follow-up should be sought.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA217\n\nAppraisal title: Donezepil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of NICE technology appraisal guidance 111)\n\nSection\n\nKey conclusion\n\n\n\nThe three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine are recommended as options for managing mild to moderate Alzheimer's disease.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation. The Committee considered that, with this assumption, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.\n\n\n\n\n\n\n\nThe Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost. The Committee further accepted that an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations around adherence, medical comorbidity, possibility of drug interactions and dosing profiles.\n\n\n\n\n\n\n\nMemantine is recommended as an option for managing Alzheimer's disease for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors, or for people with severe Alzheimer's disease.\n\n\n\n\n\nThe Committee concluded that memantine would not be cost effective compared with the AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost. The Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator.\n\n\n\n\n\n\n\nWith regard to the severe subgroup analysis, the Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the\xa0ICER would be less than £26,500 per QALY gained. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\nThe Committee was aware that there is currently no cure for Alzheimer's disease and that the AChE inhibitors and memantine treat the symptoms of Alzheimer's disease but do not slow the progression of the disease.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\n\n\nThe Committee concluded that new evidence provided additional support to the conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)\n\nThe Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of the benefit is uncertain.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee considered the current management of Alzheimer's disease under the recommendations of NICE technology appraisal guidance 111, which recommends AChE inhibitors for the treatment of moderate Alzheimer's disease. The Committee was aware of both the importance of early diagnosis and carer and clinical views on the advantages of early use of AChE inhibitors in the treatment of Alzheimer's disease. The Committee heard from clinical specialists that there is variation in clinical practice and that AChE inhibitors are also used to treat some patients with an MMSE score of above 20.\n\n\n\nMemantine is not recommended by NICE technology appraisal guidance 111 except in the context of clinical trials.\n\n\n\nAdverse effects\n\nThe Committee stated that the adverse effects of AChE inhibitors and memantine are well documented and that overall evidence since 2004 has not changed the tolerability profile of these treatments.\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee stated that a small amount of new evidence about the clinical effectiveness of the AChE inhibitors from randomised controlled trials had been published since 2004.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee considered the results of the new randomised controlled trials for memantine and the pooled results in order to estimate the size of clinical effectiveness for memantine compared with placebo or best supportive care. The Committee noted that although the new evidence considered by the Assessment Group did not substantially change the estimate of the clinical effectiveness of memantine compared with the review in 2004, the meta-analysis submitted by the manufacturer showed significant benefits.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee recognised the heterogeneity of outcome measures in trials and was aware of the limitations of some of the instruments used in the clinical trials, including cognitive and behavioural scales.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that AChE inhibitors may offer some behavioural benefits although their nature and extent are uncertain owing to mixed results from available evidence.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that although there was no evidence available on health-related quality of life from a systematic review of randomised controlled clinical trials, there was some anecdotal evidence from clinical practice of benefits to patients and carers from using AChE inhibitors.\n\n\n\n\n\n\n\nThe Committee concluded that there was no evidence to suggest that the AChE inhibitors affected survival.\n\n\n\n\n\n\n\nThe Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered whether there were differences in cost effectiveness for particular subgroups of people with Alzheimer's disease. The Committee noted that the Assessment Group's model assumed the same treatment effect for patients with mild and moderate disease. The Committee was aware that in NICE technology appraisal guidance 111 a difference in treatment effect between mild and moderate populations was assumed in the amended base case, on the basis of analysis by the Medical Research Council Biostatistics Unit. The Committee was also aware that no subgroup analyses had been identified as part of the systematic review of clinical effectiveness analysis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee accepted on the basis of the evidence in the manufacturer's submission and expert testimony that memantine may offer benefit to people with severe Alzheimer's disease.\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that new evidence provided additional support to the previous conclusions from 2004 that each of the AChE inhibitors offers benefits over best supportive care for cognitive, functional and global outcomes, and may offer some benefit in behavioural outcomes, although the nature and extent of behavioural benefits are uncertain owing to mixed results from the available evidence.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of clinical effectiveness.\n\n\n\n\n\n\n\nThe Committee concluded that memantine offers symptomatic benefit in cognitive, functional, global and behavioural outcomes, although the size of this benefit is uncertain.\n\n\n\n\n\n\n\nThe Committee concluded that combination treatment with memantine and AChE inhibitors could not be recommended because there is a lack of evidence of additional clinical efficacy compared with monotherapy.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of cost effectiveness evidence\n\nThe Committee considered economic models from the Assessment Group, the manufacturer of donepezil and the manufacturer of memantine.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee considered that only the Assessment Group addressed the decision problem in the scope because it included all of the AChE inhibitors as comparators for mild to moderate Alzheimer's disease, whereas the manufacturer of donepezil's model compared donepezil with best supportive care only. The Committee concluded that there were limitations in constructing an economic model based on time to institutionalisation but that the Assessment Group's model was based on the best currently available and detailed UK evidence to evaluate the cost effectiveness of donepezil, galantamine and rivastigmine.\n\n\n\n\n\n\n\nThe Committee considered that, on balance, the Assessment Group's model provided a suitable basis for decision making. This was because the cohort data used to model disease progression were generalisable to the UK, the effectiveness data for memantine monotherapy and combination therapy with AChE inhibitors were not combined, and the cost effectiveness of memantine could be compared with that of the AChE inhibitors in moderate Alzheimer's disease.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was aware of the limitations of the Wolstenholme dataset including the small population, the relatively old data (collected between 1988 and 1999), which might not reflect current rates of and times to institutionalisation, and the fact that the study was based in a semi-rural location. The Committee concluded that although the Wolstenholme dataset that formed the basis of the Assessment Group's model had these limitations it still represented the best available data.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that the assumption of no survival effect from treatment with the AChE inhibitors in the base-case model was appropriate in light of the lack of evidence of survival effect from randomised controlled trials.\n\n\n\n\n\n\n\nThe Committee concluded that although behaviour was a potential predictor of time to institutionalisation, not including it in the Assessment Group's model (which already included cognition and function) was unlikely to substantially change the outputs of the model in mild, moderate and severe Alzheimer's disease.\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values.\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee considered whether assumptions and inputs about health-related quality of life and utilities included in the Assessment Group's model were reasonable. The Committee acknowledged that there were differences in the responses given by patients and those given by carers when reporting outcomes, but that in sensitivity analyses conducted by the Assessment Group, changes to utility values had a small impact on ICERs. The Committee concluded that the assumptions and inputs about utilities in the Assessment Group's model were appropriate.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee did not consider subgroups for AChE inhibitors.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the use of memantine in the subgroup with moderate disease would represent a cost-effective use of NHS resources only if best supportive care was the comparator (that is, for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors).\n\n\n\n\n\n\n\nThe Committee concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered the appropriateness of the structure of the Assessment Group's model, which was based on predicting time to institutionalisation.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nConsidering all the factors in relation to cognitive and functional scales, the Committee considered it appropriate to use age, cognition and function as key predictors of time to institutionalisation. The Committee concluded that although behaviour was a potential predictor of time to institutionalisation in everyday life, its omission from a model already including cognition and function was unlikely to substantially change the outputs of the model in mild and moderate Alzheimer's disease.\n\n\n\n\n\n\n\nThe Committee noted that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee considered that, with the assumption that the key driver of cost effectiveness in the Assessment Group's model was treatment leading to delay to institutionalisation, the Assessment Group's model demonstrated that each of the AChE inhibitors was cost saving compared with best supportive care.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted the small difference in absolute costs and benefits between the AChE inhibitors. It also observed that small changes in some of the inputs and assumptions had significant impacts on the incremental estimates of cost effectiveness. The Committee concluded that overall, the AChE inhibitors donepezil, galantamine and rivastigmine had small but demonstrable clinical benefits and were cost-effective treatment options. The Committee concluded that there was insufficient evidence to differentiate between the AChE inhibitors in terms of cost effectiveness and that therefore the best use of NHS resources would be the technology with the lowest acquisition cost.\n\n\n\n\n\n\n\n\n\nThe Committee considered that the base-case ICER for memantine of £32,100 per QALY gained compared with best supportive care in moderate to severe Alzheimer's disease was likely to be an overestimate of the true cost per QALY gained, although the size of this overestimation was uncertain. The Committee noted that in the Assessment Group's exploratory analysis, memantine dominated best supportive care for the moderate group, and for the severe group the ICER for memantine compared with best supportive care was £26,500 per QALY gained. The Committee concluded that memantine would not be cost effective compared with AChE inhibitors in people with moderate disease because it generated fewer QALYs at a higher cost.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee considered that, had it been possible to include the behavioural benefit of memantine in the Assessment Group's model, the\xa0ICER would be less than £26,500 per QALY gained for severe disease. It therefore concluded that treatment with memantine represented a cost-effective use of NHS resources for people with severe Alzheimer's disease.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (Pharmaceutical Price Regulation Programme)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations, Social Value Judgement\n\nThe Committee confirmed that, as in NICE technology appraisal guidance 111, when using assessment scales to determine the severity of Alzheimer's disease, healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect the results and make any adjustments they consider appropriate. Clinicians should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee recognised the difficulties of using MMSE score alone to assess the severity of Alzheimer's disease and the response to AChE inhibitors. The Committee agreed that cognitive scales alone such as the MMSE are not always appropriate for assessing the severity of dementia. The Committee concluded that if cognitive scales are not appropriate for assessing the need for treatment, or whether to continue treatment, then clinicians should use another appropriate method of assessment.\n\n\n\n", 'Recommendations for further research ': "Research is needed to generate robust and relevant data on the effects of treating people with Alzheimer's disease on both short-term and long-term outcomes, disease progression through relevant health states, and quality of life.\n\nResearch is needed on the impact of treating Alzheimer's disease on mortality and institutionalisation, and to assess the relationship between disease progression and carer utility (quality of life).", 'Related NICE guidance': 'Dementia: assessment, management and support for people living with dementia and their carer (2018) NICE guideline NG97', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in April 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMarch 2011'}
|
https://www.nice.org.uk/guidance/ta217
|
Evidence-based recommendations on donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon) and memantine (Ebixa) for treating Alzheimer's disease in adults.
|
450b25757f2705ba80fd3f314ad3e7efd01d84e8
|
nice
|
Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor
|
Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor
Evidence-based recommendations on unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor in adults. This involves applying ultrasound to a specific area on 1 side of the brain (thalamus).
# Recommendations
The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients and their carers understand that this procedure is only done to treat tremor on 1 side of the body, and that the effect of this on the functional ability and quality of life of patients with bilateral disease is uncertain. Patients should be informed about alternative treatments, including those that can be done bilaterally. Provide patients with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor is recommended.
Audit and review clinical outcomes of all patients having unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Patient selection should be done by a multidisciplinary team experienced in managing essential tremor, including clinicians with specific training in the procedure.
Further research, which could include randomised controlled trials, should address patient selection, report on functional improvement and quality of life, and provide long-term follow-up data.# The condition, current treatments and procedure
# The condition
Essential tremor is the most common cause of disabling tremor and is distinct from Parkinson's disease. It typically affects the arms and hands, although it may also involve the head, jaw, tongue and legs. The cause is not known but many patients have a family history of the condition. At first, the tremor may not be present all the time. However, it gradually worsens. Purposeful movement, stress, tiredness, hunger, heightened emotions or extremes in temperature make it worse.
# Current treatments
Treatment for essential tremor includes medications such as beta blockers (for example, propranolol), anti-epileptics (for example, primidone) or sedatives (for example, clonazepam). Rarely, injections of botulinum toxin may be used.
Surgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.
# The procedure
This procedure is carried out with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are kept awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low power (sub-lethal) ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate target tissue. Chilled water is circulated around the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3 hours and symptom relief should be immediate.
The potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sub-lethal doses before ablation. However, it is only done on 1 side.
|
{'Recommendations': "The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand that this procedure is only done to treat tremor on 1\xa0side of the body, and that the effect of this on the functional ability and quality of life of patients with bilateral disease is uncertain. Patients should be informed about alternative treatments, including those that can be done bilaterally. Provide patients with clear written information to support shared decision-making. In addition, the use of NICE's information for the public on unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor is recommended.\n\nAudit and review clinical outcomes of all patients having unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nPatient selection should be done by a multidisciplinary team experienced in managing essential tremor, including clinicians with specific training in the procedure.\n\nFurther research, which could include randomised controlled trials, should address patient selection, report on functional improvement and quality of life, and provide long-term follow-up data.", 'The condition, current treatments and procedure': "# The condition\n\nEssential tremor is the most common cause of disabling tremor and is distinct from Parkinson's disease. It typically affects the arms and hands, although it may also involve the head, jaw, tongue and legs. The cause is not known but many patients have a family history of the condition. At first, the tremor may not be present all the time. However, it gradually worsens. Purposeful movement, stress, tiredness, hunger, heightened emotions or extremes in temperature make it worse.\n\n# Current treatments\n\nTreatment for essential tremor includes medications such as beta blockers (for example, propranolol), anti-epileptics (for example, primidone) or sedatives (for example, clonazepam). Rarely, injections of botulinum toxin may be used.\n\nSurgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.\n\n# The procedure\n\nThis procedure is carried out with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are kept awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low power (sub-lethal) ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate target tissue. Chilled water is circulated around the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3\xa0hours and symptom relief should be immediate.\n\nThe potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sub-lethal doses before ablation. However, it is only done on 1\xa0side."}
|
https://www.nice.org.uk/guidance/ipg617
|
Evidence-based recommendations on unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor in adults. This involves applying ultrasound to a specific area on 1 side of the brain (thalamus).
|
4027c496b75414ea97922cc3d970cd59cb67629f
|
nice
|
Laparoscopic ventral mesh rectopexy for internal rectal prolapse
|
Laparoscopic ventral mesh rectopexy for internal rectal prolapse
Evidence-based recommendations on laparoscopic ventral mesh rectopexy for internal rectal prolapse in adults. This involves using a piece of sterile material (mesh) to attach the rectum to the lower back bone using keyhole surgery.
# Recommendations
Current evidence on the safety of laparoscopic ventral mesh rectopexy for internal rectal prolapse shows there are well‑recognised, serious but infrequent complications. The evidence on efficacy and safety is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do laparoscopic ventral mesh rectopexy for internal rectal prolapse should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and safety and that there are different types of mesh available, which may have different efficacies and complications. Patients should be provided with clear written information. In addition, the use of NICE's information for the public on laparoscopic ventral mesh rectopexy is recommended.
Patient selection should be done by a pelvic floor multidisciplinary team. This should typically include a surgeon, an urogynaecologist, a radiologist, a nurse specialist, a physiotherapist, a pelvic floor physiologist and, when appropriate, a gastroenterologist.
This procedure should only be done by surgeons who are trained and experienced in laparoscopic pelvic floor surgery, who have done their initial procedures with an experienced mentor.
Clinicians should enter details about all patients having laparoscopic ventral mesh rectopexy for internal rectal prolapse onto an appropriate registry (for example, the British Pelvic Floor Society database). The results of the registry should be published.
Clinicians are encouraged to collect data on patient selection, patient‑reported outcomes, mesh‑related complications, the type of mesh used, the attachment method and long‑term follow‑up. NICE may update the guidance on publication of further evidence.
All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.# The condition, current treatments and procedure
# The condition
Internal rectal prolapse is when the lowest part of the bowel (rectum) telescopes on itself. It is more common in women who have had children but also happens in nulliparous women and in men. Factors related to the development of the condition are age, childbirth, constipation and straining. It may be associated with prolapse of other pelvic organs and some people may have a predisposition because of abnormalities in collagen. It is not life threatening but it can be a distressing and demoralising condition, with negative effects on quality of life. Symptoms include discomfort, pain, constipation, difficult evacuation (obstructed defaecation syndrome), faecal incontinence and discharge of mucus or blood. In women it can be associated with vaginal bulge (rectocele), painful intercourse, lower back pain, urinary dysfunction, and vaginal prolapse and enterocele.
# Current treatments
Conservative treatment of internal rectal prolapse may include pelvic floor exercises and advice to improve defaecatory habits, reduce constipation and improve incontinence. These are often termed biofeedback or pelvic floor re‑training. Surgical treatment of internal rectal prolapse is classified into perineal (Delorme's operation) and abdominal procedures. Open abdominal surgery and laparoscopic procedures, with or without robotic assistance, use mesh or direct suturing and may involve resection of the sigmoid colon.
# The procedure
Laparoscopic ventral mesh rectopexy (LVMR) is done under general anaesthesia using keyhole surgery, in which 3 to 4 small incisions are made in the abdomen. The peritoneum over the rectum is dissected, exposing the muscle coat which is mobilised into the rectovaginal septum in females and the level of the seminal vesicles in males. The mesh is secured to the rectum anteriorly, as low as possible in the fascia, using sutures, and fixed to the sacral promontory with permanent sutures or small metal tacks. The peritoneum is closed over the mesh to prevent the bowel becoming trapped or adhering to the mesh. In women, LVMR may help control rectocele or enterocele associated with rectal prolapse.
|
{'Recommendations': "Current evidence on the safety of laparoscopic ventral mesh rectopexy for internal rectal prolapse shows there are well‑recognised, serious but infrequent complications. The evidence on efficacy and safety is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do laparoscopic ventral mesh rectopexy for internal rectal prolapse should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and safety and that there are different types of mesh available, which may have different efficacies and complications. Patients should be provided with clear written information. In addition, the use of NICE's information for the public on laparoscopic ventral mesh rectopexy is recommended.\n\nPatient selection should be done by a pelvic floor multidisciplinary team. This should typically include a surgeon, an urogynaecologist, a radiologist, a nurse specialist, a physiotherapist, a pelvic floor physiologist and, when appropriate, a gastroenterologist.\n\nThis procedure should only be done by surgeons who are trained and experienced in laparoscopic pelvic floor surgery, who have done their initial procedures with an experienced mentor.\n\nClinicians should enter details about all patients having laparoscopic ventral mesh rectopexy for internal rectal prolapse onto an appropriate registry (for example, the British Pelvic Floor Society database). The results of the registry should be published.\n\nClinicians are encouraged to collect data on patient selection, patient‑reported outcomes, mesh‑related complications, the type of mesh used, the attachment method and long‑term follow‑up. NICE may update the guidance on publication of further evidence.\n\nAll adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.", 'The condition, current treatments and procedure': "# The condition\n\nInternal rectal prolapse is when the lowest part of the bowel (rectum) telescopes on itself. It is more common in women who have had children but also happens in nulliparous women and in men. Factors related to the development of the condition are age, childbirth, constipation and straining. It may be associated with prolapse of other pelvic organs and some people may have a predisposition because of abnormalities in collagen. It is not life threatening but it can be a distressing and demoralising condition, with negative effects on quality of life. Symptoms include discomfort, pain, constipation, difficult evacuation (obstructed defaecation syndrome), faecal incontinence and discharge of mucus or blood. In women it can be associated with vaginal bulge (rectocele), painful intercourse, lower back pain, urinary dysfunction, and vaginal prolapse and enterocele.\n\n# Current treatments\n\nConservative treatment of internal rectal prolapse may include pelvic floor exercises and advice to improve defaecatory habits, reduce constipation and improve incontinence. These are often termed biofeedback or pelvic floor re‑training. Surgical treatment of internal rectal prolapse is classified into perineal (Delorme's operation) and abdominal procedures. Open abdominal surgery and laparoscopic procedures, with or without robotic assistance, use mesh or direct suturing and may involve resection of the sigmoid colon.\n\n# The procedure\n\nLaparoscopic ventral mesh rectopexy (LVMR) is done under general anaesthesia using keyhole surgery, in which 3 to 4\xa0small incisions are made in the abdomen. The peritoneum over the rectum is dissected, exposing the muscle coat which is mobilised into the rectovaginal septum in females and the level of the seminal vesicles in males. The mesh is secured to the rectum anteriorly, as low as possible in the fascia, using sutures, and fixed to the sacral promontory with permanent sutures or small metal tacks. The peritoneum is closed over the mesh to prevent the bowel becoming trapped or adhering to the mesh. In women, LVMR may help control rectocele or enterocele associated with rectal prolapse."}
|
https://www.nice.org.uk/guidance/ipg618
|
Evidence-based recommendations on laparoscopic ventral mesh rectopexy for internal rectal prolapse in adults. This involves using a piece of sterile material (mesh) to attach the rectum to the lower back bone using keyhole surgery.
|
8d55ec9f74dc0e4d1891e6437b23b189268367cd
|
nice
|
Intranasal phototherapy for allergic rhinitis
|
Intranasal phototherapy for allergic rhinitis
Evidence-based recommendations on intranasal phototherapy for allergic rhinitis in adults. This involves using light to reduce inflammation inside the nose.
# Recommendations
Current evidence on the efficacy and safety of intranasal phototherapy for allergic rhinitis is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include: details of patient selection including medication use; underlying medical conditions; the intensity, duration and wavelength of light used; patient-reported outcomes; comparison with existing treatments; and the effects of repeated long-term use. NICE may update the guidance if further evidence is published.# The condition, current treatments and procedure
# The condition
Allergic rhinitis is inflammation of the inside of the nose caused by an allergen such as pollen, house dust mites or mould. It causes symptoms such as sneezing, itchiness and a blocked or runny nose. Most people with allergic rhinitis have mild symptoms that can be easily and effectively treated. For some people, however, symptoms can be severe and persistent and have a significant impact on quality of life.
# Current treatments
First-line treatments for allergic rhinitis include medication such as antihistamines and intranasal corticosteroids. For more severe or persistent symptoms that do not respond to medication, immunotherapy (sublingual or subcutaneous) is sometimes used.
# The procedure
Intranasal phototherapy involves using a device with light-emitting probes, which are inserted into the nasal cavity for several minutes at a time. Some devices are designed to be self-administered, whereas others are administered by a clinician. There are different devices available and the duration and dose of treatment varies. The devices use different frequencies of light, ranging from ultraviolet to infrared.
Intranasal phototherapy is claimed to increase local blood flow and suppress inflammation. The aim is to reduce the symptoms of allergic rhinitis.
|
{'Recommendations': 'Current evidence on the efficacy and safety of intranasal phototherapy for allergic rhinitis is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include: details of patient selection including medication use; underlying medical conditions; the intensity, duration and wavelength of light used; patient-reported outcomes; comparison with existing treatments; and the effects of repeated long-term use. NICE may update the guidance if further evidence is published.', 'The condition, current treatments and procedure': '# The condition\n\nAllergic rhinitis is inflammation of the inside of the nose caused by an allergen such as pollen, house dust mites or mould. It causes symptoms such as sneezing, itchiness and a blocked or runny nose. Most people with allergic rhinitis have mild symptoms that can be easily and effectively treated. For some people, however, symptoms can be severe and persistent and have a significant impact on quality of life.\n\n# Current treatments\n\nFirst-line treatments for allergic rhinitis include medication such as antihistamines and intranasal corticosteroids. For more severe or persistent symptoms that do not respond to medication, immunotherapy (sublingual or subcutaneous) is sometimes used.\n\n# The procedure\n\nIntranasal phototherapy involves using a device with light-emitting probes, which are inserted into the nasal cavity for several minutes at a time. Some devices are designed to be self-administered, whereas others are administered by a clinician. There are different devices available and the duration and dose of treatment varies. The devices use different frequencies of light, ranging from ultraviolet to infrared.\n\nIntranasal phototherapy is claimed to increase local blood flow and suppress inflammation. The aim is to reduce the symptoms of allergic rhinitis.'}
|
https://www.nice.org.uk/guidance/ipg616
|
Evidence-based recommendations on intranasal phototherapy for allergic rhinitis in adults. This involves using light to reduce inflammation inside the nose.
|
53f08054078be5e4b2c9bc4c6a8f0448a43a7ba6
|
nice
|
Arsenic trioxide for treating acute promyelocytic leukaemia
|
Arsenic trioxide for treating acute promyelocytic leukaemia
Evidence-based recommendations on arsenic trioxide (Trisenox) for treating acute promyelocytic leukaemia in adults.
# Recommendations
Arsenic trioxide is recommended, within its marketing authorisation, as an option for inducing remission and consolidation in acute promyelocytic leukaemia (characterised by the presence of the t translocation or the PML/RAR-alpha gene) in adults with:
untreated, low-to-intermediate risk disease (defined as a white blood cell count of 10x103 per microlitre or less), when given with all-trans-retinoic acid (ATRA)
relapsed or refractory disease, after a retinoid and chemotherapy.
Why the committee made these recommendations
People with untreated, low-to-intermediate risk acute promyelocytic leukaemia are given ATRA plus chemotherapy (together called AIDA). Clinical trial evidence shows that arsenic trioxide plus ATRA is effective for untreated disease compared with AIDA. Some assumptions in the model, such as the costs of stem cell transplant and the long-term effect of treatment, lead to the cost-effectiveness analyses being uncertain. However, the most plausible cost-effectiveness estimate is likely to be less than £20,000 per quality-adjusted life year gained, so arsenic trioxide plus ATRA is cost effective compared with AIDA in untreated disease.
Arsenic trioxide is already used to treat relapsed or refractory acute promyelocytic leukaemia. The clinical- and cost-effectiveness evidence for arsenic trioxide in relapsed or refractory disease is uncertain, because the clinical trial was small and did not compare arsenic trioxide with AIDA. However, it is likely that arsenic trioxide is clinically effective and represents a cost-effective use of NHS resources in relapsed or refractory disease. Therefore, arsenic trioxide is recommended for both untreated and relapsed or refractory disease.# Information about arsenic trioxide
Marketing authorisation indication
Arsenic trioxide (Trisenox, Teva) is indicated for the induction of remission, and consolidation in adults with:
newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (white blood cell count ≤10x103 per microlitre) in combination with all-trans-retinoic acid (ATRA)
relapsed/refractory acute promyelocytic leukaemia (previous treatment should have included a retinoid and chemotherapy)
characterised by the presence of the t(15;17) translocation and/or the presence of the PML/RAR-alpha gene.
Dosage in the marketing authorisation
For newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia:
mg/kg per day intravenously. In induction, this is given daily until complete remission or for a maximum of 60 days. In consolidation, this is given 5 days per week for 4 weeks on and 4 weeks off, for a total of 4 cycles.
For relapsed and refractory acute promyelocytic leukaemia:
mg/kg per day intravenously. In induction, this is given daily until complete remission or for a maximum of 50 days. Consolidation treatment must begin 3 to 4 weeks after completing induction therapy. In consolidation, treatment is given for 25 doses, 5 days per week, followed by 2 days interruption, repeated for 5 weeks.
Treatment with arsenic trioxide must be temporarily stopped before the scheduled end of therapy if a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed and judged to be possibly related to arsenic trioxide treatment. Treatment may be resumed at 50% of the preceding daily dose after the toxic event is resolved or after recovery to baseline status of the abnormality that prompted the interruption.
Price
£2,920 for 10 ampoules of 10 mg/10 ml concentrate for solution for infusion (excluding VAT; British national formulary online ). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Teva and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with acute promyelocytic leukaemia would welcome a new treatment option
Acute promyelocytic leukaemia is a rapidly progressing form of leukaemia for which treatment must be started quickly. Symptoms include bruising or bleeding (which can sometimes be catastrophic at presentation because of severely disordered blood clotting), fatigue, feeling weak or breathless, bone or joint pain and sleeping problems. A patient group explained that these symptoms affect mobility and daily living such that they may impair education and employment. Current treatments also have high toxicity. For example, the long-term effects of chemotherapy can include a risk of secondary cancers and loss of fertility in younger people. The committee concluded that people with acute promyelocytic leukaemia would welcome an alternative to chemotherapy that could reduce the chance of relapse.
# Clinical management
## Untreated acute promyelocytic leukaemia is treated with ATRA plus chemotherapy
Current treatment for untreated, low-to-intermediate risk acute promyelocytic leukaemia is all-trans-retinoic acid (ATRA) with an anthracycline-based chemotherapy (usually idarubicin, a combination known as AIDA). The committee concluded that, for untreated disease, AIDA is the relevant comparator for arsenic trioxide.
## Relapsed or refractory acute promyelocytic leukaemia is treated with arsenic trioxide plus ATRA
Arsenic trioxide, in combination with ATRA, has been used to treat relapsed or refractory acute promyelocytic leukaemia in NHS clinical practice for over 10 years. The committee understood that the marketing authorisation for arsenic trioxide for relapsed or refractory disease does not include combination treatment with ATRA. The clinical expert explained that arsenic trioxide would not be used to treat relapsed or refractory disease without ATRA in clinical practice in England. The marketing authorisation also states that previous treatment should have included a retinoid and chemotherapy. The company stated that the choice of treatment for relapsed or refractory disease is largely determined by the first treatment used; for example, after treatment with AIDA for untreated disease, current practice is to treat relapsed or refractory disease with arsenic trioxide plus ATRA. The company also stated that if arsenic trioxide were recommended for untreated disease, fewer people would go on to have relapsed or refractory disease so the population eligible for arsenic trioxide would shrink over time. The clinical expert explained that because the risk of relapse is so low after using arsenic trioxide, there is little experience in England of treating relapsed or refractory acute promyelocytic leukaemia after arsenic trioxide. Nevertheless, they added that it would be reasonable to offer AIDA after arsenic trioxide for relapsed or refractory disease. The company stated that stem cell transplant would be used after arsenic trioxide in relapsed or refractory disease, rather than instead of it, so it was not a relevant comparator. The company also stated that best supportive care was not a relevant comparator because it would likely only be used when the disease did not respond to all other treatments, including arsenic trioxide. The committee agreed that, for relapsed or refractory disease, AIDA was the relevant comparator for arsenic trioxide.
# Population
## The relevant population is defined in the marketing authorisation
The marketing authorisation for arsenic trioxide is for use in adults with untreated, low-to-intermediate risk acute promyelocytic leukaemia, and in adults with relapsed or refractory acute promyelocytic leukaemia. The committee understood that arsenic trioxide is currently used to treat relapsed or refractory disease in adults. The clinical expert stated that there was no reason to expect that treatment would be less effective in children. The committee was aware of NHS England's policy on Commissioning Medicines for Children in Specialised Services, which states that NHS England will commission treatments for patients aged less than 18 years if specific commissioning conditions within a NICE technology appraisal are met. The committee noted that the marketing authorisation for arsenic trioxide's use in untreated acute promyelocytic leukaemia did not include high-risk disease. The committee concluded that, in line with NICE policy, it would appraise arsenic trioxide for the population defined in its marketing authorisation.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS clinical practice in England
The evidence for arsenic trioxide in untreated acute promyelocytic leukaemia came from 2 clinical trials: APL0406 (n=266) and AML17 (n=235). Both studies were phase III, randomised, open-label trials; only AML17 included patients from the UK. Both trials compared arsenic trioxide plus ATRA with AIDA. The committee understood that APL0406 used the dosing schedule and population defined in the marketing authorisation for arsenic trioxide, whereas AML17 used a lower dose (about 60% of that in the marketing authorisation) and included people with high-risk disease. The clinical expert confirmed that in England, arsenic trioxide has been used according to the AML17 protocol. However, the committee agreed that it could only appraise arsenic trioxide within its marketing authorisation. The ERG highlighted that the populations in both trials were similar, which suggested that the population in APL0406 may be similar to the population eligible for arsenic trioxide in England. The committee concluded that APL0406 was relevant to NHS clinical practice in England, and that AML17 was relevant as supporting evidence.
## Arsenic trioxide plus ATRA is effective for untreated acute promyelocytic leukaemia
The primary outcome measure in APL0406 was event-free survival at 2 years after diagnosis. An event was defined as no haematological remission after induction, no molecular remission after 3 consolidation courses, haematological or molecular relapse, or death. Although APL0406 was designed as a non-inferiority trial, the investigators were able to demonstrate the superiority of arsenic trioxide plus ATRA compared with AIDA for some outcomes. The results showed that 97.3% of people in the arsenic trioxide plus ATRA group had not had an event after 50 months, compared with 80.0% in the AIDA group. This difference was statistically significant (p<0.001). More people having arsenic trioxide plus ATRA were alive at 50 months compared with people having AIDA (99.2% compared with 92.6%, p=0.007). There was also a statistically significant (p=0.001) lower cumulative incidence of relapse with arsenic trioxide plus ATRA (1.9%), compared with AIDA (13.9%) at 50 months. The primary outcome in AML17 was health-related quality of life. The results did not show a statistically significant difference between arsenic trioxide plus ATRA and AIDA in most health-related quality of life outcomes, but the committee understood that the study may have been underpowered to detect this difference. At 4 years there was a statistically significant difference in event-free survival (91% with arsenic trioxide plus ATRA and 70% with AIDA; p=0.002) but not in overall survival (93% and 89%; p=0.250). The clinical expert highlighted that an effective monitoring and intervention strategy as part of the trial may have led to improved outcomes in the AIDA group. The committee concluded that arsenic trioxide plus ATRA was effective for untreated acute promyelocytic leukaemia.
## The effectiveness of arsenic trioxide for relapsed or refractory disease is uncertain
The company presented results from a very small randomised trial (Raffoux et al., n=20) that compared arsenic trioxide alone with arsenic trioxide plus ATRA for relapsed or refractory acute promyelocytic leukaemia. The results for cumulative percentage of complete remission, overall survival and disease-free survival were similar in both treatment groups. The committee noted that the company had not presented evidence for the effectiveness of arsenic trioxide compared with AIDA for relapsed or refractory disease. The company stated that there was little high-quality evidence in relapsed or refractory disease because acute promyelocytic leukaemia is rare, and only around a third of people will have a relapse. The committee agreed that the effectiveness of arsenic trioxide for relapsed or refractory acute promyelocytic leukaemia is uncertain.
# Adverse events
## The long-term safety of arsenic trioxide remains to be explored
In APL0406, haematological adverse events were generally less common with arsenic trioxide plus ATRA than with AIDA. However, there was a higher incidence of hepatic toxicity in people having arsenic trioxide plus ATRA than people having AIDA, particularly during induction (40% compared with 3% respectively; p<0.001). Some patients taking arsenic trioxide may experience an abnormality of the heart rhythm (QTc prolongation), but the clinical expert indicated that this was uncommon and that the potential toxicity to heart muscle function from idarubicin, an anthracycline, was of greater concern. The committee noted that the European Medicines Agency had recommended a long-term safety study of arsenic trioxide. The company highlighted that adverse events in the trial were mostly managed by temporarily stopping treatment, and that few people permanently stopped treatment. The committee concluded that the long-term safety of arsenic trioxide remains to be explored.
# The company's economic model
## The model structure is appropriate for decision-making
The company presented a single Markov model to assess the cost effectiveness of arsenic trioxide in both untreated and relapsed or refractory acute promyelocytic leukaemia. The model included 14 health states, with additional tunnel states. The first treatment was either arsenic trioxide plus ATRA or AIDA.
After first having AIDA, people with relapsed disease had arsenic trioxide plus ATRA.
After first having arsenic trioxide plus ATRA, people whose disease had been in remission for less than 2 years before relapse had AIDA. People whose disease had been in remission for 2 years or more before relapse had arsenic trioxide plus ATRA again.The committee noted that this retreatment with arsenic trioxide was not in line with the marketing authorisation, which states that treatment for relapsed or refractory disease should follow a retinoid or chemotherapy. However, it was aware that there is little experience in England of treating relapsed or refractory disease after arsenic trioxide because the risk of relapse is low (section 3.3), and that the other treatment pathway in the model for people who first had arsenic trioxide plus ATRA was in line with the marketing authorisation. The committee concluded that the model was appropriate for decision-making.
# Treatment effectiveness in the model
## How treatment effectiveness is implemented in the model leads to uncertainty
In the company's model, the benefit of treatment with arsenic trioxide plus ATRA was maintained for the entire time horizon. For example, the rate of relapse after initial treatment was constant from 2 years after remission until the end of the time horizon. In response to a request from NICE and the ERG at the clarification stage, the company did a scenario analysis in which there were no relapses after 2 years of complete remission following the first treatment. This scenario reduced the cost effectiveness of arsenic trioxide plus ATRA compared with AIDA. The ERG did a further scenario analysis in which it assumed equal relapse probability for both treatment groups after 2 years of complete remission following the first treatment. This scenario also reduced the cost effectiveness of arsenic trioxide plus ATRA compared with AIDA. The committee agreed that it was unlikely that the benefit of treatment with arsenic trioxide plus ATRA would be maintained for the rest of a person's life. It also agreed it was unlikely that the relapse probability would be equal for both treatment groups after 2 years of complete remission following the first treatment, as in the ERG's scenario. However, the committee was reassured that even in this clinically unlikely scenario, the incremental cost-effectiveness ratio (ICER) was within the range that NICE normally considers to be a cost-effective use of NHS resources. The committee concluded that although the implementation of treatment effectiveness in the model led to uncertainty in the cost-effectiveness results, arsenic trioxide plus ATRA was cost effective compared with AIDA.
# Stem cell transplant in the model
## The costs associated with stem cell transplant in the model are uncertain
The committee noted that in the company's base case, the costs of haematopoietic stem cell transplant (HSCT) predicted by the model were £40,681 higher in the AIDA group than in the arsenic trioxide plus ATRA group. This was mainly because more patients in the AIDA group would be expected to have a relapse and subsequently need HSCT. The clinical expert confirmed that in AML17, no patients who had arsenic trioxide plus ATRA had subsequently had a relapse. In the model, the cost of allogeneic HSCT was much higher than the cost of autologous HSCT. There were also substantial yearly costs associated with remission after HSCT, which again were much higher after allogeneic HSCT. The ERG highlighted that in the model, people did not stay in the remission after HSCT health state for more than a few years. The clinical expert stated that costs would realistically be higher for allogeneic HSCT because it is associated with more complications than autologous HSCT, and that the difference in costs predicted by the model seemed reasonable. The committee noted that changing the costs of HSCT in the model had a large effect on the cost-effectiveness results. It considered scenario analyses in which the yearly costs associated with remission after HSCT were set to £5,000 and to £0 per year. The committee agreed it was unlikely that there would be no costs after HSCT, but was reassured that even in these clinically unlikely scenarios, the ICERs were close to, or within, the range that NICE normally considers to be a cost-effective use of NHS resources. It concluded that although there was uncertainty about the most appropriate costs for HSCT and the costs used in the model led to uncertainty in the cost-effectiveness results, arsenic trioxide plus ATRA was cost effective compared with AIDA.
# Cost-effectiveness results
## Arsenic trioxide plus ATRA is less costly and more effective than AIDA for untreated disease in the company's analysis
The company's deterministic base-case results showed that arsenic trioxide plus ATRA was less costly (–£31,270 incremental costs) and more effective (2.62 incremental quality-adjusted life years gained) than AIDA for untreated acute promyelocytic leukaemia.
## Arsenic trioxide plus ATRA remains less costly and more effective than AIDA for untreated disease in the ERG's analysis
The ERG made a number of changes to the company's base case, including:
correcting errors
changing the time horizon from 40 to 56 years
using some alternative utility values
capping utility values so they did not exceed those of the general population
using some alternative remission probabilities.The ERG's base case also showed that arsenic trioxide plus ATRA was less costly (–£23,502 incremental costs) and more effective (2.25 incremental QALYs gained) than AIDA for untreated acute promyelocytic leukaemia. The committee noted that the ERG's scenario analysis assuming equal relapse probability for both treatment groups (section 3.10) showed that arsenic trioxide plus ATRA was not cost saving compared with AIDA, with an ICER of £19,734 per QALY gained. However, the committee acknowledged that even in this unlikely scenario, the ICER was within the range that NICE normally considers to be a cost-effective use of NHS resources.
## The most plausible ICER for untreated disease is less than £20,000 per QALY gained
The committee considered another scenario analysis in which, as well as assuming equal relapse probability for both groups, the costs of remission after HSCT were set to £0. This analysis produced an ICER for arsenic trioxide plus ATRA compared with AIDA of £31,042 per QALY gained. The committee considered that this scenario was clinically implausible but was reassured that even in this scenario the ICER was close to the range that NICE normally considers to be a cost-effective use of NHS resources. The committee was not persuaded that arsenic trioxide plus ATRA was cost saving compared with AIDA, but it agreed that arsenic trioxide plus ATRA was cost effective. The committee concluded that although there was uncertainty in the model, the most plausible ICER for arsenic trioxide plus ATRA compared with AIDA for untreated disease was less than £20,000 per QALY gained.
## The cost effectiveness of arsenic trioxide in relapsed or refractory disease is difficult to establish given the available data
The company presented a scenario analysis to assess the cost effectiveness of arsenic trioxide plus ATRA compared with AIDA for relapsed or refractory disease. This analysis produced an ICER for arsenic trioxide plus ATRA compared with AIDA of £16,733 per QALY gained. The ERG noted that it was unclear how this analysis had been done, and presented another scenario analysis based on its own base-case analysis in which it removed the initial treatment health states. This analysis produced an ICER for arsenic trioxide plus ATRA compared with AIDA of £31,184 per QALY gained. Having raised concerns about the lack of evidence in relapsed or refractory disease (section 3.7), extrapolating treatment effectiveness (section 3.10) and the costs associated with HSCT (section 3.11), the committee agreed that these results were uncertain. It also noted that the model assessed arsenic trioxide plus ATRA, rather than arsenic trioxide alone, as specified in the marketing authorisation for relapsed or refractory disease. It concluded that the cost effectiveness of arsenic trioxide in relapsed or refractory acute promyelocytic leukaemia was difficult to establish given the available data.
## Arsenic trioxide is recommended for untreated low-to-intermediate risk acute promyelocytic leukaemia
The committee agreed that despite uncertainties in the economic model, arsenic trioxide plus ATRA represents a cost-effective use of NHS resources for untreated, low-to-intermediate risk acute promyelocytic leukaemia in adults. The committee was aware that current practice in England is to treat acute promyelocytic leukaemia according to the reduced dosing schedule used in AML17. However, it clarified that its recommendation was to use arsenic trioxide within its marketing authorisation (that is, at the dose specified in the marketing authorisation, and for low-to-intermediate risk disease).
## Arsenic trioxide is also recommended for relapsed or refractory acute promyelocytic leukaemia
The committee acknowledged that there was uncertainty in the evidence for arsenic trioxide for treating relapsed or refractory acute promyelocytic leukaemia. However, arsenic trioxide plus ATRA is current practice in the NHS for treating relapsed or refractory disease. The committee also considered that, because it had recommended arsenic trioxide for use in untreated disease, the number of people eligible for arsenic trioxide for relapsed or refractory disease would fall over time. The committee was reassured by the similar clinical outcomes for arsenic trioxide compared with arsenic trioxide plus ATRA. The committee was also reassured that the ICERs for untreated disease were below the range normally considered to be a cost-effective use of NHS resources, and it considered that arsenic trioxide was likely to be cost effective in relapsed or refractory disease as well. Recognising that its decisions should be constrained to the marketing authorisation (section 3.4), the committee concluded that it could recommend arsenic trioxide as an option, within its marketing authorisation, for treating relapsed or refractory acute promyelocytic leukaemia.
# End of life
## Arsenic trioxide does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The company did not make a case for the end-of-life criteria to apply. The committee noted that after 84 months, median survival was not reached in APL0406, and that the life years predicted in the company's model for people having AIDA were 26.8 years for untreated disease and 10.7 years for relapsed or refractory disease. The committee concluded that arsenic trioxide did not meet the criteria to be considered a life-extending treatment at the end of life.
# Other factors
## There are no equality issues relevant to the recommendations
Stakeholders highlighted that older people or people who are Jehovah's witnesses would be eligible for arsenic trioxide. Because arsenic trioxide is recommended for the whole population in the marketing authorisation, the committee concluded that its recommendations do not have a different impact on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues.
## There are no additional benefits that are not captured in the QALY calculations
The company considered arsenic trioxide to be an innovative treatment, because it is an alternative to chemotherapy. A professional group also considered arsenic trioxide to be innovative because it reduces the risk of relapse and need for HSCT. The committee concluded that arsenic trioxide would be beneficial for patients, but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
|
{'Recommendations': 'Arsenic\xa0trioxide is recommended, within its marketing authorisation, as an option for inducing remission and consolidation in acute promyelocytic leukaemia (characterised by the presence of the t[15;17] translocation or the PML/RAR-alpha gene) in adults with:\n\nuntreated, low-to-intermediate risk disease (defined as a white blood cell count of 10x103 per microlitre or less), when given with all-trans-retinoic acid (ATRA)\n\nrelapsed or refractory disease, after a retinoid and chemotherapy.\n\nWhy the committee made these recommendations\n\nPeople with untreated, low-to-intermediate risk acute promyelocytic leukaemia are given ATRA plus chemotherapy (together called AIDA). Clinical trial evidence shows that arsenic\xa0trioxide plus ATRA is effective for untreated disease compared with AIDA. Some assumptions in the model, such as the costs of stem cell transplant and the long-term effect of treatment, lead to the cost-effectiveness analyses being uncertain. However, the most plausible cost-effectiveness estimate is likely to be less than £20,000 per quality-adjusted life year gained, so arsenic\xa0trioxide plus ATRA is cost effective compared with AIDA in untreated disease.\n\nArsenic\xa0trioxide is already used to treat relapsed or refractory acute promyelocytic leukaemia. The clinical- and cost-effectiveness evidence for arsenic\xa0trioxide in relapsed or refractory disease is uncertain, because the clinical trial was small and did not compare arsenic\xa0trioxide with AIDA. However, it is likely that arsenic\xa0trioxide is clinically effective and represents a cost-effective use of NHS resources in relapsed or refractory disease. Therefore, arsenic\xa0trioxide is recommended for both untreated and relapsed or refractory disease.', 'Information about arsenic\xa0trioxide': 'Marketing authorisation indication\n\nArsenic\xa0trioxide (Trisenox, Teva) is indicated for the induction of remission, and consolidation in adults with:\n\nnewly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (white blood cell count ≤10x103 per microlitre) in combination with all-trans-retinoic acid (ATRA)\n\nrelapsed/refractory acute promyelocytic leukaemia (previous treatment should have included a retinoid and chemotherapy)\n\ncharacterised by the presence of the t(15;17) translocation and/or the presence of the PML/RAR-alpha gene.\n\nDosage in the marketing authorisation\n\nFor newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia:\n\nmg/kg per day intravenously. In induction, this is given daily until complete remission or for a maximum of 60\xa0days. In consolidation, this is given 5\xa0days per week for 4 weeks on and 4 weeks off, for a total of 4 cycles.\n\nFor relapsed and refractory acute promyelocytic leukaemia:\n\nmg/kg per day intravenously. In induction, this is given daily until complete remission or for a maximum of 50\xa0days. Consolidation treatment must begin 3 to 4 weeks after completing induction therapy. In consolidation, treatment is given for 25 doses, 5\xa0days per week, followed by 2\xa0days interruption, repeated for 5 weeks.\n\nTreatment with arsenic\xa0trioxide must be temporarily stopped before the scheduled end of therapy if a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed and judged to be possibly related to arsenic\xa0trioxide treatment. Treatment may be resumed at 50% of the preceding daily dose after the toxic event is resolved or after recovery to baseline status of the abnormality that prompted the interruption.\n\nPrice\n\n£2,920 for 10 ampoules of 10\xa0mg/10\xa0ml concentrate for solution for infusion (excluding VAT; British national formulary [BNF] online [accessed March 2018]). Costs may vary in different settings because of negotiated procurement discounts.', 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Teva and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with acute promyelocytic leukaemia would welcome a new treatment option\n\nAcute promyelocytic leukaemia is a rapidly progressing form of leukaemia for which treatment must be started quickly. Symptoms include bruising or bleeding (which can sometimes be catastrophic at presentation because of severely disordered blood clotting), fatigue, feeling weak or breathless, bone or joint pain and sleeping problems. A patient group explained that these symptoms affect mobility and daily living such that they may impair education and employment. Current treatments also have high toxicity. For example, the long-term effects of chemotherapy can include a risk of secondary cancers and loss of fertility in younger people. The committee concluded that people with acute promyelocytic leukaemia would welcome an alternative to chemotherapy that could reduce the chance of relapse.\n\n# Clinical management\n\n## Untreated acute promyelocytic leukaemia is treated with ATRA plus chemotherapy\n\nCurrent treatment for untreated, low-to-intermediate risk acute promyelocytic leukaemia is all-trans-retinoic acid (ATRA) with an anthracycline-based chemotherapy (usually idarubicin, a combination known as AIDA). The committee concluded that, for untreated disease, AIDA is the relevant comparator for arsenic\xa0trioxide.\n\n## Relapsed or refractory acute promyelocytic leukaemia is treated with arsenic\xa0trioxide plus ATRA\n\nArsenic\xa0trioxide, in combination with ATRA, has been used to treat relapsed or refractory acute promyelocytic leukaemia in NHS clinical practice for over 10\xa0years. The committee understood that the marketing authorisation for arsenic\xa0trioxide for relapsed or refractory disease does not include combination treatment with ATRA. The clinical expert explained that arsenic\xa0trioxide would not be used to treat relapsed or refractory disease without ATRA in clinical practice in England. The marketing authorisation also states that previous treatment should have included a retinoid and chemotherapy. The company stated that the choice of treatment for relapsed or refractory disease is largely determined by the first treatment used; for example, after treatment with AIDA for untreated disease, current practice is to treat relapsed or refractory disease with arsenic\xa0trioxide plus ATRA. The company also stated that if arsenic\xa0trioxide were recommended for untreated disease, fewer people would go on to have relapsed or refractory disease so the population eligible for arsenic\xa0trioxide would shrink over time. The clinical expert explained that because the risk of relapse is so low after using arsenic\xa0trioxide, there is little experience in England of treating relapsed or refractory acute promyelocytic leukaemia after arsenic\xa0trioxide. Nevertheless, they added that it would be reasonable to offer AIDA after arsenic\xa0trioxide for relapsed or refractory disease. The company stated that stem cell transplant would be used after arsenic\xa0trioxide in relapsed or refractory disease, rather than instead of it, so it was not a relevant comparator. The company also stated that best supportive care was not a relevant comparator because it would likely only be used when the disease did not respond to all other treatments, including arsenic\xa0trioxide. The committee agreed that, for relapsed or refractory disease, AIDA was the relevant comparator for arsenic\xa0trioxide.\n\n# Population\n\n## The relevant population is defined in the marketing authorisation\n\nThe marketing authorisation for arsenic\xa0trioxide is for use in adults with untreated, low-to-intermediate risk acute promyelocytic leukaemia, and in adults with relapsed or refractory acute promyelocytic leukaemia. The committee understood that arsenic\xa0trioxide is currently used to treat relapsed or refractory disease in adults. The clinical expert stated that there was no reason to expect that treatment would be less effective in children. The committee was aware of NHS England's policy on Commissioning Medicines for Children in Specialised Services, which states that NHS England will commission treatments for patients aged less than 18\xa0years if specific commissioning conditions within a NICE technology appraisal are met. The committee noted that the marketing authorisation for arsenic\xa0trioxide's use in untreated acute promyelocytic leukaemia did not include high-risk disease. The committee concluded that, in line with NICE policy, it would appraise arsenic\xa0trioxide for the population defined in its marketing authorisation.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS clinical practice in England\n\nThe evidence for arsenic\xa0trioxide in untreated acute promyelocytic leukaemia came from 2 clinical trials: APL0406 (n=266) and AML17 (n=235). Both studies were phase III, randomised, open-label trials; only AML17 included patients from the UK. Both trials compared arsenic\xa0trioxide plus ATRA with AIDA. The committee understood that APL0406 used the dosing schedule and population defined in the marketing authorisation for arsenic\xa0trioxide, whereas AML17 used a lower dose (about 60% of that in the marketing authorisation) and included people with high-risk disease. The clinical expert confirmed that in England, arsenic\xa0trioxide has been used according to the AML17 protocol. However, the committee agreed that it could only appraise arsenic\xa0trioxide within its marketing authorisation. The ERG highlighted that the populations in both trials were similar, which suggested that the population in APL0406 may be similar to the population eligible for arsenic\xa0trioxide in England. The committee concluded that APL0406 was relevant to NHS clinical practice in England, and that AML17 was relevant as supporting evidence.\n\n## Arsenic\xa0trioxide plus ATRA is effective for untreated acute promyelocytic leukaemia\n\nThe primary outcome measure in APL0406 was event-free survival at 2\xa0years after diagnosis. An event was defined as no haematological remission after induction, no molecular remission after 3 consolidation courses, haematological or molecular relapse, or death. Although APL0406 was designed as a non-inferiority trial, the investigators were able to demonstrate the superiority of arsenic\xa0trioxide plus ATRA compared with AIDA for some outcomes. The results showed that 97.3% of people in the arsenic\xa0trioxide plus ATRA group had not had an event after 50\xa0months, compared with 80.0% in the AIDA group. This difference was statistically significant (p<0.001). More people having arsenic\xa0trioxide plus ATRA were alive at 50\xa0months compared with people having AIDA (99.2% compared with 92.6%, p=0.007). There was also a statistically significant (p=0.001) lower cumulative incidence of relapse with arsenic\xa0trioxide plus ATRA (1.9%), compared with AIDA (13.9%) at 50\xa0months. The primary outcome in AML17 was health-related quality of life. The results did not show a statistically significant difference between arsenic\xa0trioxide plus ATRA and AIDA in most health-related quality of life outcomes, but the committee understood that the study may have been underpowered to detect this difference. At 4\xa0years there was a statistically significant difference in event-free survival (91% with arsenic\xa0trioxide plus ATRA and 70% with AIDA; p=0.002) but not in overall survival (93% and 89%; p=0.250). The clinical expert highlighted that an effective monitoring and intervention strategy as part of the trial may have led to improved outcomes in the AIDA group. The committee concluded that arsenic\xa0trioxide plus ATRA was effective for untreated acute promyelocytic leukaemia.\n\n## The effectiveness of arsenic\xa0trioxide for relapsed or refractory disease is uncertain\n\nThe company presented results from a very small randomised trial (Raffoux et al., n=20) that compared arsenic\xa0trioxide alone with arsenic\xa0trioxide plus ATRA for relapsed or refractory acute promyelocytic leukaemia. The results for cumulative percentage of complete remission, overall survival and disease-free survival were similar in both treatment groups. The committee noted that the company had not presented evidence for the effectiveness of arsenic\xa0trioxide compared with AIDA for relapsed or refractory disease. The company stated that there was little high-quality evidence in relapsed or refractory disease because acute promyelocytic leukaemia is rare, and only around a third of people will have a relapse. The committee agreed that the effectiveness of arsenic\xa0trioxide for relapsed or refractory acute promyelocytic leukaemia is uncertain.\n\n# Adverse events\n\n## The long-term safety of arsenic\xa0trioxide remains to be explored\n\nIn APL0406, haematological adverse events were generally less common with arsenic\xa0trioxide plus ATRA than with AIDA. However, there was a higher incidence of hepatic toxicity in people having arsenic\xa0trioxide plus ATRA than people having AIDA, particularly during induction (40% compared with 3% respectively; p<0.001). Some patients taking arsenic\xa0trioxide may experience an abnormality of the heart rhythm (QTc prolongation), but the clinical expert indicated that this was uncommon and that the potential toxicity to heart muscle function from idarubicin, an anthracycline, was of greater concern. The committee noted that the European Medicines Agency had recommended a long-term safety study of arsenic\xa0trioxide. The company highlighted that adverse events in the trial were mostly managed by temporarily stopping treatment, and that few people permanently stopped treatment. The committee concluded that the long-term safety of arsenic\xa0trioxide remains to be explored.\n\n# The company's economic model\n\n## The model structure is appropriate for decision-making\n\nThe company presented a single Markov model to assess the cost effectiveness of arsenic\xa0trioxide in both untreated and relapsed or refractory acute promyelocytic leukaemia. The model included 14 health states, with additional tunnel states. The first treatment was either arsenic\xa0trioxide plus ATRA or AIDA.\n\nAfter first having AIDA, people with relapsed disease had arsenic\xa0trioxide plus ATRA.\n\nAfter first having arsenic\xa0trioxide plus ATRA, people whose disease had been in remission for less than 2\xa0years before relapse had AIDA. People whose disease had been in remission for 2\xa0years or more before relapse had arsenic\xa0trioxide plus ATRA again.The committee noted that this retreatment with arsenic\xa0trioxide was not in line with the marketing authorisation, which states that treatment for relapsed or refractory disease should follow a retinoid or chemotherapy. However, it was aware that there is little experience in England of treating relapsed or refractory disease after arsenic\xa0trioxide because the risk of relapse is low (section 3.3), and that the other treatment pathway in the model for people who first had arsenic\xa0trioxide plus ATRA was in line with the marketing authorisation. The committee concluded that the model was appropriate for decision-making.\n\n# Treatment effectiveness in the model\n\n## How treatment effectiveness is implemented in the model leads to uncertainty\n\nIn the company's model, the benefit of treatment with arsenic\xa0trioxide plus ATRA was maintained for the entire time horizon. For example, the rate of relapse after initial treatment was constant from 2\xa0years after remission until the end of the time horizon. In response to a request from NICE and the ERG at the clarification stage, the company did a scenario analysis in which there were no relapses after 2\xa0years of complete remission following the first treatment. This scenario reduced the cost effectiveness of arsenic\xa0trioxide plus ATRA compared with AIDA. The ERG did a further scenario analysis in which it assumed equal relapse probability for both treatment groups after 2\xa0years of complete remission following the first treatment. This scenario also reduced the cost effectiveness of arsenic\xa0trioxide plus ATRA compared with AIDA. The committee agreed that it was unlikely that the benefit of treatment with arsenic\xa0trioxide plus ATRA would be maintained for the rest of a person's life. It also agreed it was unlikely that the relapse probability would be equal for both treatment groups after 2\xa0years of complete remission following the first treatment, as in the ERG's scenario. However, the committee was reassured that even in this clinically unlikely scenario, the incremental cost-effectiveness ratio (ICER) was within the range that NICE normally considers to be a cost-effective use of NHS resources. The committee concluded that although the implementation of treatment effectiveness in the model led to uncertainty in the cost-effectiveness results, arsenic\xa0trioxide plus ATRA was cost effective compared with AIDA.\n\n# Stem cell transplant in the model\n\n## The costs associated with stem cell transplant in the model are uncertain\n\nThe committee noted that in the company's base case, the costs of haematopoietic stem cell transplant (HSCT) predicted by the model were £40,681 higher in the AIDA group than in the arsenic\xa0trioxide plus ATRA group. This was mainly because more patients in the AIDA group would be expected to have a relapse and subsequently need HSCT. The clinical expert confirmed that in AML17, no patients who had arsenic\xa0trioxide plus ATRA had subsequently had a relapse. In the model, the cost of allogeneic HSCT was much higher than the cost of autologous HSCT. There were also substantial yearly costs associated with remission after HSCT, which again were much higher after allogeneic HSCT. The ERG highlighted that in the model, people did not stay in the remission after HSCT health state for more than a few\xa0years. The clinical expert stated that costs would realistically be higher for allogeneic HSCT because it is associated with more complications than autologous HSCT, and that the difference in costs predicted by the model seemed reasonable. The committee noted that changing the costs of HSCT in the model had a large effect on the cost-effectiveness results. It considered scenario analyses in which the yearly costs associated with remission after HSCT were set to £5,000 and to £0 per year. The committee agreed it was unlikely that there would be no costs after HSCT, but was reassured that even in these clinically unlikely scenarios, the ICERs were close to, or within, the range that NICE normally considers to be a cost-effective use of NHS resources. It concluded that although there was uncertainty about the most appropriate costs for HSCT and the costs used in the model led to uncertainty in the cost-effectiveness results, arsenic\xa0trioxide plus ATRA was cost effective compared with AIDA.\n\n# Cost-effectiveness results\n\n## Arsenic\xa0trioxide plus ATRA is less costly and more effective than AIDA for untreated disease in the company's analysis\n\nThe company's deterministic base-case results showed that arsenic\xa0trioxide plus ATRA was less costly (–£31,270 incremental costs) and more effective (2.62 incremental quality-adjusted life\xa0years [QALYs] gained) than AIDA for untreated acute promyelocytic leukaemia.\n\n## Arsenic\xa0trioxide plus ATRA remains less costly and more effective than AIDA for untreated disease in the ERG's analysis\n\nThe ERG made a number of changes to the company's base case, including:\n\ncorrecting errors\n\nchanging the time horizon from 40 to 56\xa0years\n\nusing some alternative utility values\n\ncapping utility values so they did not exceed those of the general population\n\nusing some alternative remission probabilities.The ERG's base case also showed that arsenic\xa0trioxide plus ATRA was less costly (–£23,502 incremental costs) and more effective (2.25 incremental QALYs gained) than AIDA for untreated acute promyelocytic leukaemia. The committee noted that the ERG's scenario analysis assuming equal relapse probability for both treatment groups (section 3.10) showed that arsenic\xa0trioxide plus ATRA was not cost saving compared with AIDA, with an ICER of £19,734 per QALY gained. However, the committee acknowledged that even in this unlikely scenario, the ICER was within the range that NICE normally considers to be a cost-effective use of NHS resources.\n\n## The most plausible ICER for untreated disease is less than £20,000 per QALY gained\n\nThe committee considered another scenario analysis in which, as well as assuming equal relapse probability for both groups, the costs of remission after HSCT were set to £0. This analysis produced an ICER for arsenic\xa0trioxide plus ATRA compared with AIDA of £31,042 per QALY gained. The committee considered that this scenario was clinically implausible but was reassured that even in this scenario the ICER was close to the range that NICE normally considers to be a cost-effective use of NHS resources. The committee was not persuaded that arsenic\xa0trioxide plus ATRA was cost saving compared with AIDA, but it agreed that arsenic\xa0trioxide plus ATRA was cost effective. The committee concluded that although there was uncertainty in the model, the most plausible ICER for arsenic\xa0trioxide plus ATRA compared with AIDA for untreated disease was less than £20,000 per QALY gained.\n\n## The cost effectiveness of arsenic\xa0trioxide in relapsed or refractory disease is difficult to establish given the available data\n\nThe company presented a scenario analysis to assess the cost effectiveness of arsenic\xa0trioxide plus ATRA compared with AIDA for relapsed or refractory disease. This analysis produced an ICER for arsenic\xa0trioxide plus ATRA compared with AIDA of £16,733 per QALY gained. The ERG noted that it was unclear how this analysis had been done, and presented another scenario analysis based on its own base-case analysis in which it removed the initial treatment health states. This analysis produced an ICER for arsenic\xa0trioxide plus ATRA compared with AIDA of £31,184 per QALY gained. Having raised concerns about the lack of evidence in relapsed or refractory disease (section\xa03.7), extrapolating treatment effectiveness (section\xa03.10) and the costs associated with HSCT (section\xa03.11), the committee agreed that these results were uncertain. It also noted that the model assessed arsenic\xa0trioxide plus ATRA, rather than arsenic\xa0trioxide alone, as specified in the marketing authorisation for relapsed or refractory disease. It concluded that the cost effectiveness of arsenic\xa0trioxide in relapsed or refractory acute promyelocytic leukaemia was difficult to establish given the available data.\n\n## Arsenic\xa0trioxide is recommended for untreated low-to-intermediate risk acute promyelocytic leukaemia\n\nThe committee agreed that despite uncertainties in the economic model, arsenic\xa0trioxide plus ATRA represents a cost-effective use of NHS resources for untreated, low-to-intermediate risk acute promyelocytic leukaemia in adults. The committee was aware that current practice in England is to treat acute promyelocytic leukaemia according to the reduced dosing schedule used in AML17. However, it clarified that its recommendation was to use arsenic\xa0trioxide within its marketing authorisation (that is, at the dose specified in the marketing authorisation, and for low-to-intermediate risk disease).\n\n## Arsenic\xa0trioxide is also recommended for relapsed or refractory acute promyelocytic leukaemia\n\nThe committee acknowledged that there was uncertainty in the evidence for arsenic\xa0trioxide for treating relapsed or refractory acute promyelocytic leukaemia. However, arsenic\xa0trioxide plus ATRA is current practice in the NHS for treating relapsed or refractory disease. The committee also considered that, because it had recommended arsenic\xa0trioxide for use in untreated disease, the number of people eligible for arsenic\xa0trioxide for relapsed or refractory disease would fall over time. The committee was reassured by the similar clinical outcomes for arsenic\xa0trioxide compared with arsenic\xa0trioxide plus ATRA. The committee was also reassured that the ICERs for untreated disease were below the range normally considered to be a cost-effective use of NHS resources, and it considered that arsenic\xa0trioxide was likely to be cost effective in relapsed or refractory disease as well. Recognising that its decisions should be constrained to the marketing authorisation (section 3.4), the committee concluded that it could recommend arsenic\xa0trioxide as an option, within its marketing authorisation, for treating relapsed or refractory acute promyelocytic leukaemia.\n\n# End of life\n\n## Arsenic\xa0trioxide does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The company did not make a case for the end-of-life criteria to apply. The committee noted that after 84\xa0months, median survival was not reached in APL0406, and that the life\xa0years predicted in the company's model for people having AIDA were 26.8\xa0years for untreated disease and 10.7\xa0years for relapsed or refractory disease. The committee concluded that arsenic\xa0trioxide did not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nStakeholders highlighted that older people or people who are Jehovah's witnesses would be eligible for arsenic\xa0trioxide. Because arsenic\xa0trioxide is recommended for the whole population in the marketing authorisation, the committee concluded that its recommendations do not have a different impact on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues.\n\n## There are no additional benefits that are not captured in the QALY calculations\n\nThe company considered arsenic\xa0trioxide to be an innovative treatment, because it is an alternative to chemotherapy. A professional group also considered arsenic\xa0trioxide to be innovative because it reduces the risk of relapse and need for HSCT. The committee concluded that arsenic\xa0trioxide would be beneficial for patients, but that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs."}
|
https://www.nice.org.uk/guidance/ta526
|
Evidence-based recommendations on arsenic trioxide (Trisenox) for treating acute promyelocytic leukaemia in adults.
|
6f3f76cfcdaf66bb2225fa2063dd96246e9f549a
|
nice
|
Guselkumab for treating moderate to severe plaque psoriasis
|
Guselkumab for treating moderate to severe plaque psoriasis
Evidence-based recommendations on guselkumab (Tremfya) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Guselkumab is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet A radiation), or these options are contraindicated or not tolerated and
the company provides the drug according to the commercial arrangement.
Stop guselkumab treatment at 16 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
If patients and their clinicians consider guselkumab to be one of a range of suitable treatments, including ixekizumab and secukinumab, the least costly (taking into account administration costs and commercial arrangements) should be chosen.
This recommendation is not intended to affect treatment with guselkumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Guselkumab is proposed as an alternative to other biological therapies already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials and indirect comparisons show that guselkumab is more effective than TNF‑alpha inhibitors (that is, adalimumab, etanercept and infliximab) and ustekinumab. It also suggests that guselkumab is likely to provide similar health benefits to ixekizumab and secukinumab.
For the cost comparison, it is appropriate to compare guselkumab with ixekizumab and secukinumab. Taking into account how many people continue treatment (which affects the cost to the NHS), guselkumab provides similar health benefits to ixekizumab and secukinumab at a similar or lower cost. It is therefore recommended as an option for treating plaque psoriasis in the NHS.# Information about guselkumab
# Marketing authorisation
Guselkumab (Tremfya, Janssen) is indicated for 'the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.
# Dosage in the marketing authorisation
The recommended dosage of guselkumab is 100 mg by subcutaneous injection at weeks 0 and 4, followed by a 100 mg maintenance dose every 8 weeks. Consideration should be given to stopping treatment in people whose disease has shown no response after 16 weeks of treatment.
# Price
The list price of guselkumab is £2,250 per prefilled syringe (excluding VAT; British national formulary online; accessed March 2018). The company has a commercial arrangement. This makes guselkumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. The company proposed that this technology be considered in a fast track appraisal using cost-comparison methodology.
# Decision problem
## The company's decision problem is relevant to clinical practice
The company proposed that guselkumab should be considered as an alternative to other biological therapies for psoriasis in adults when non-biological systemic treatment or phototherapy is inadequately effective, not tolerated or contraindicated. The committee understood that the company's proposed decision problem was narrower than guselkumab's marketing authorisation. However, it agreed that the proposed population was consistent with previous NICE recommendations for biologicals for psoriasis, and with their use in clinical practice. The committee noted that the company presented comparisons with NICE-recommended biologicals, and considered that this was consistent with the criteria for a cost-comparison appraisal (the appropriateness of specific comparators is discussed in section 3.7). The committee recalled that previous technology appraisal guidance recommendations specified that treatment should stop if there is an inadequate response after induction. An adequate response is defined as:
a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee considered that it would be reasonable to consider a similar approach for this appraisal. It accepted that the company's positioning reflected the likely place of guselkumab in clinical practice, and concluded that the company's decision problem was relevant to clinical practice.
# Clinical effectiveness
## Guselkumab is more effective than adalimumab
Guselkumab has been studied in 3 randomised controlled trials including a total of 2,096 adults with plaque psoriasis. It was directly compared with adalimumab in 2 trials, VOYAGE‑1 and VOYAGE‑2. In these trials, guselkumab was associated with statistically significant improvements compared with adalimumab in primary and secondary outcomes, including PASI response rates. The committee noted, in particular, that patients randomised to guselkumab were statistically significantly more likely to have a PASI 75 response after induction (that is, at week 16) compared with adalimumab (VOYAGE‑1: PASI 75 response rates 91.2% and 73.1% respectively, p<0.001). The committee accepted that the results of the VOYAGE trials showed that guselkumab was more effective than adalimumab.
## The company's network meta-analysis is suitable for decision-making
The company's network meta-analysis compared guselkumab with adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab, using data from 45 trials. It understood that the ERG preferred the analyses based only on comparators specified in the decision problem (termed the 'restricted analyses') because these matched the scope. The committee accepted the ERG's view and concluded that the network meta-analysis provided by the company was suitable for decision-making.
## Guselkumab provides greater benefits than TNF‑alpha inhibitors and ustekinumab, and similar benefits to secukinumab and ixekizumab
The committee noted that the results of the network meta-analysis suggested that guselkumab was statistically significantly more effective, in terms of PASI 75 response, than the TNF‑alpha inhibitors (that is, adalimumab, etanercept and infliximab) and ustekinumab. It considered that guselkumab would provide substantial clinical benefits over adalimumab, etanercept, infliximab and ustekinumab in practice. It also considered that, although guselkumab appeared to be statistically significantly better than secukinumab in terms of PASI 75 response in the network meta-analysis, the difference might not be clinically meaningful. The committee also noted that guselkumab was similarly effective to ixekizumab in this outcome, and that no statistically significant difference was seen. It therefore considered that guselkumab was likely to provide similar benefits to secukinumab and ixekizumab in clinical practice. The committee acknowledged that PASI 75 is a key outcome for informing treatment continuation after induction. However, it also understood that patients are interested in having complete clearance of their psoriasis symptoms so it considered that PASI 100 is also a relevant outcome. The committee appreciated that the company analyses also covered a range of outcomes, and that the results for PASI 100 were broadly consistent with those for PASI 75. The committee noted the safety and tolerability outcomes in the company's network meta-analysis and considered that guselkumab had a similar safety profile to other biologicals, regardless of treatment class. It concluded that guselkumab provides substantially greater clinical benefits compared with adalimumab, etanercept, infliximab and ustekinumab, and is likely to provide similar benefits to secukinumab and ixekizumab.
# Cost comparison
## The committee prefers the cost-comparison analysis provided by the ERG
The company presented a cost-comparison analysis that modelled the total costs of guselkumab, adalimumab and ustekinumab treatment over 5 years. It took into account stopping treatment after induction (based on PASI 75 response rates, which was consistent with the stopping rules specified in NICE technology appraisal guidance for the comparators), using an assumption that guselkumab and the comparators were similarly effective (that is, it assumed clinical similarity between treatments). The analysis also took into account the long-term stopping of treatment during maintenance therapy. The committee noted the ERG's view that assuming similar effectiveness was inappropriate because of the statistically significant differences between treatments in clinical effectiveness. Therefore, the ERG presented exploratory analyses either using the company's assumption of clinical similarity, or using different treatment continuation rates for each treatment based on PASI 75 response rates from the network meta-analysis (see section 3.4). These exploratory analyses included all biologicals and used a 10‑year time horizon. The committee appreciated that guselkumab is statistically significantly more effective than some other subcutaneous biological treatments (see section 3.4). It was aware that differences in effectiveness led to differences in the number of people stopping treatment after induction, resulting in differences in treatment duration between therapies and hence differences in costs to the NHS. It considered that treatment duration should be taken into account in a cost-comparison analysis when it is directly affected by clinical effectiveness, and that when there is a difference in effectiveness between guselkumab and a comparator, different continuation rates should be used. The committee therefore concluded that the ERG's cost-comparison analysis was preferable for decision-making.
## Secukinumab and ixekizumab are the relevant comparators for cost comparison
For comparators in its base case, the company focused on adalimumab and ustekinumab. The committee understood that the company chose these because they are the most frequently used biologicals for psoriasis, and accepted this rationale. However, it recalled the statistically and clinically significant increased benefits for guselkumab compared with adalimumab and ustekinumab (see section 3.2), and that such increased benefits affected the cost comparison (see section 3.5). It noted that, in the ERG's analysis, guselkumab was more expensive than adalimumab and ustekinumab. The committee also noted that, when a technology provides greater benefits than a comparator but at a greater cost, it is not possible to reach a conclusion using cost-comparison methods. It therefore concluded that adalimumab and ustekinumab were not acceptable comparators to focus on in a cost-comparison context. Conversely, the committee recognised that, because guselkumab, ixekizumab and secukinumab are likely to provide similar clinical benefits (see section 3.4), it was possible to reach a recommendation using cost-comparison methods by considering the comparison of guselkumab with secukinumab and ixekizumab. It noted that secukinumab has a rapidly growing market share, and that ixekizumab is expected to be used more frequently over time. The committee concluded that ixekizumab and secukinumab, not adalimumab and ustekinumab, were the relevant comparators for the cost-comparison analysis.
## Guselkumab meets the criteria to be recommended using cost comparison
The committee focused on the cost comparison with ixekizumab and secukinumab using the ERG's exploratory analyses (see section 3.5) and taking into account all confidential patient access schemes. In these analyses, the total costs associated with guselkumab were similar to or lower than those associated with ixekizumab and secukinumab (the exact results cannot be reported here because the discounts are confidential). The committee concluded that the criteria for a positive cost comparison were met because:
guselkumab provided similar overall health benefits to ixekizumab and secukinumab and
the total costs associated with guselkumab were similar to or lower than the total costs associated with ixekizumab and secukinumab.The committee therefore recommended guselkumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for guselkumab should be consistent with the company's proposal and the NICE recommendations for ixekizumab and secukinumab, that is:
for people with severe disease (a PASI of 10 or more and a DLQI of more than 10) and
when the disease has not responded to standard systemic therapies or when these treatments are unsuitable
and with consideration given to stopping treatment after induction if the disease does not respond adequately.
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
|
{'Recommendations': 'Guselkumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10\xa0or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet\xa0A radiation), or these options are contraindicated or not tolerated and\n\nthe company provides the drug according to the commercial arrangement.\n\nStop guselkumab treatment at 16\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nIf patients and their clinicians consider guselkumab to be one of a range of suitable treatments, including ixekizumab and secukinumab, the least costly (taking into account administration costs and commercial arrangements) should be chosen.\n\nThis recommendation is not intended to affect treatment with guselkumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nGuselkumab is proposed as an alternative to other biological therapies already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials and indirect comparisons show that guselkumab is more effective than TNF‑alpha inhibitors (that is, adalimumab, etanercept and infliximab) and ustekinumab. It also suggests that guselkumab is likely to provide similar health benefits to ixekizumab and secukinumab.\n\nFor the cost comparison, it is appropriate to compare guselkumab with ixekizumab and secukinumab. Taking into account how many people continue treatment (which affects the cost to the NHS), guselkumab provides similar health benefits to ixekizumab and secukinumab at a similar or lower cost. It is therefore recommended as an option for treating plaque psoriasis in the NHS.', 'Information about guselkumab': "# Marketing authorisation\n\nGuselkumab (Tremfya, Janssen) is indicated for 'the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe recommended dosage of guselkumab is 100\xa0mg by subcutaneous injection at weeks\xa00 and\xa04, followed by a 100\xa0mg maintenance dose every 8\xa0weeks. Consideration should be given to stopping treatment in people whose disease has shown no response after 16\xa0weeks of treatment.\n\n# Price\n\nThe list price of guselkumab is £2,250 per prefilled syringe (excluding VAT; British national formulary online; accessed March 2018). The company has a commercial arrangement. This makes guselkumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. The company proposed that this technology be considered in a fast track appraisal using cost-comparison methodology.\n\n# Decision problem\n\n## The company's decision problem is relevant to clinical practice\n\nThe company proposed that guselkumab should be considered as an alternative to other biological therapies for psoriasis in adults when non-biological systemic treatment or phototherapy is inadequately effective, not tolerated or contraindicated. The committee understood that the company's proposed decision problem was narrower than guselkumab's marketing authorisation. However, it agreed that the proposed population was consistent with previous NICE recommendations for biologicals for psoriasis, and with their use in clinical practice. The committee noted that the company presented comparisons with NICE-recommended biologicals, and considered that this was consistent with the criteria for a cost-comparison appraisal (the appropriateness of specific comparators is discussed in section\xa03.7). The committee recalled that previous technology appraisal guidance recommendations specified that treatment should stop if there is an inadequate response after induction. An adequate response is defined as:\n\na 75% reduction in the Psoriasis Area and Severity Index score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee considered that it would be reasonable to consider a similar approach for this appraisal. It accepted that the company's positioning reflected the likely place of guselkumab in clinical practice, and concluded that the company's decision problem was relevant to clinical practice.\n\n# Clinical effectiveness\n\n## Guselkumab is more effective than adalimumab\n\nGuselkumab has been studied in 3\xa0randomised controlled trials including a total of 2,096\xa0adults with plaque psoriasis. It was directly compared with adalimumab in 2\xa0trials, VOYAGE‑1 and VOYAGE‑2. In these trials, guselkumab was associated with statistically significant improvements compared with adalimumab in primary and secondary outcomes, including PASI response rates. The committee noted, in particular, that patients randomised to guselkumab were statistically significantly more likely to have a PASI\xa075 response after induction (that is, at week\xa016) compared with adalimumab (VOYAGE‑1: PASI\xa075 response rates 91.2% and 73.1% respectively, p<0.001). The committee accepted that the results of the VOYAGE trials showed that guselkumab was more effective than adalimumab.\n\n## The company's network meta-analysis is suitable for decision-making\n\nThe company's network meta-analysis compared guselkumab with adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab, using data from 45\xa0trials. It understood that the ERG preferred the analyses based only on comparators specified in the decision problem (termed the 'restricted analyses') because these matched the scope. The committee accepted the ERG's view and concluded that the network meta-analysis provided by the company was suitable for decision-making.\n\n## Guselkumab provides greater benefits than TNF‑alpha inhibitors and ustekinumab, and similar benefits to secukinumab and ixekizumab\n\nThe committee noted that the results of the network meta-analysis suggested that guselkumab was statistically significantly more effective, in terms of PASI\xa075 response, than the TNF‑alpha inhibitors (that is, adalimumab, etanercept and infliximab) and ustekinumab. It considered that guselkumab would provide substantial clinical benefits over adalimumab, etanercept, infliximab and ustekinumab in practice. It also considered that, although guselkumab appeared to be statistically significantly better than secukinumab in terms of PASI\xa075 response in the network meta-analysis, the difference might not be clinically meaningful. The committee also noted that guselkumab was similarly effective to ixekizumab in this outcome, and that no statistically significant difference was seen. It therefore considered that guselkumab was likely to provide similar benefits to secukinumab and ixekizumab in clinical practice. The committee acknowledged that PASI\xa075 is a key outcome for informing treatment continuation after induction. However, it also understood that patients are interested in having complete clearance of their psoriasis symptoms so it considered that PASI\xa0100 is also a relevant outcome. The committee appreciated that the company analyses also covered a range of outcomes, and that the results for PASI\xa0100 were broadly consistent with those for PASI\xa075. The committee noted the safety and tolerability outcomes in the company's network meta-analysis and considered that guselkumab had a similar safety profile to other biologicals, regardless of treatment class. It concluded that guselkumab provides substantially greater clinical benefits compared with adalimumab, etanercept, infliximab and ustekinumab, and is likely to provide similar benefits to secukinumab and ixekizumab.\n\n# Cost comparison\n\n## The committee prefers the cost-comparison analysis provided by the ERG\n\nThe company presented a cost-comparison analysis that modelled the total costs of guselkumab, adalimumab and ustekinumab treatment over 5\xa0years. It took into account stopping treatment after induction (based on PASI\xa075 response rates, which was consistent with the stopping rules specified in NICE technology appraisal guidance for the comparators), using an assumption that guselkumab and the comparators were similarly effective (that is, it assumed clinical similarity between treatments). The analysis also took into account the long-term stopping of treatment during maintenance therapy. The committee noted the ERG's view that assuming similar effectiveness was inappropriate because of the statistically significant differences between treatments in clinical effectiveness. Therefore, the ERG presented exploratory analyses either using the company's assumption of clinical similarity, or using different treatment continuation rates for each treatment based on PASI\xa075 response rates from the network meta-analysis (see section\xa03.4). These exploratory analyses included all biologicals and used a 10‑year time horizon. The committee appreciated that guselkumab is statistically significantly more effective than some other subcutaneous biological treatments (see section\xa03.4). It was aware that differences in effectiveness led to differences in the number of people stopping treatment after induction, resulting in differences in treatment duration between therapies and hence differences in costs to the NHS. It considered that treatment duration should be taken into account in a cost-comparison analysis when it is directly affected by clinical effectiveness, and that when there is a difference in effectiveness between guselkumab and a comparator, different continuation rates should be used. The committee therefore concluded that the ERG's cost-comparison analysis was preferable for decision-making.\n\n## Secukinumab and ixekizumab are the relevant comparators for cost comparison\n\nFor comparators in its base case, the company focused on adalimumab and ustekinumab. The committee understood that the company chose these because they are the most frequently used biologicals for psoriasis, and accepted this rationale. However, it recalled the statistically and clinically significant increased benefits for guselkumab compared with adalimumab and ustekinumab (see section\xa03.2), and that such increased benefits affected the cost comparison (see section\xa03.5). It noted that, in the ERG's analysis, guselkumab was more expensive than adalimumab and ustekinumab. The committee also noted that, when a technology provides greater benefits than a comparator but at a greater cost, it is not possible to reach a conclusion using cost-comparison methods. It therefore concluded that adalimumab and ustekinumab were not acceptable comparators to focus on in a cost-comparison context. Conversely, the committee recognised that, because guselkumab, ixekizumab and secukinumab are likely to provide similar clinical benefits (see section\xa03.4), it was possible to reach a recommendation using cost-comparison methods by considering the comparison of guselkumab with secukinumab and ixekizumab. It noted that secukinumab has a rapidly growing market share, and that ixekizumab is expected to be used more frequently over time. The committee concluded that ixekizumab and secukinumab, not adalimumab and ustekinumab, were the relevant comparators for the cost-comparison analysis.\n\n## Guselkumab meets the criteria to be recommended using cost comparison\n\nThe committee focused on the cost comparison with ixekizumab and secukinumab using the ERG's exploratory analyses (see section\xa03.5) and taking into account all confidential patient access schemes. In these analyses, the total costs associated with guselkumab were similar to or lower than those associated with ixekizumab and secukinumab (the exact results cannot be reported here because the discounts are confidential). The committee concluded that the criteria for a positive cost comparison were met because:\n\nguselkumab provided similar overall health benefits to ixekizumab and secukinumab and\n\nthe total costs associated with guselkumab were similar to or lower than the total costs associated with ixekizumab and secukinumab.The committee therefore recommended guselkumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for guselkumab should be consistent with the company's proposal and the NICE recommendations for ixekizumab and secukinumab, that is:\n\nfor people with severe disease (a PASI of 10\xa0or more and a DLQI of more than\xa010) and\n\nwhen the disease has not responded to standard systemic therapies or when these treatments are unsuitable\n\nand with consideration given to stopping treatment after induction if the disease does not respond adequately.\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate."}
|
https://www.nice.org.uk/guidance/ta521
|
Evidence-based recommendations on guselkumab (Tremfya) for treating moderate to severe plaque psoriasis in adults.
|
eb051ca254144ba0836b8b160e749381208c4213
|
nice
|
Midostaurin for untreated acute myeloid leukaemia
|
Midostaurin for untreated acute myeloid leukaemia
Evidence-based recommendations on midostaurin (Rydapt) for untreated FLT3-mutation-positive acute myeloid leukaemia in adults.
# Recommendations
Midostaurin is recommended, within its marketing authorisation, as an option in adults for treating newly diagnosed acute FLT3-mutation-positive myeloid leukaemia with standard daunorubicin and cytarabine as induction therapy, with high-dose cytarabine as consolidation therapy, and alone after complete response as maintenance therapy. It is recommended only if the company provides midostaurin with the discount agreed in the patient access scheme.
Why the committee made these recommendations
Treatment for acute myeloid leukaemia is chemotherapy. Evidence from a randomised controlled trial shows that people taking midostaurin with chemotherapy live longer than people taking chemotherapy alone.
There is uncertainty about the cost effectiveness of midostaurin because of problems with the economic model. But with the most plausible model assumptions and the discounted price, the cost-effectiveness estimates of midostaurin plus chemotherapy compared with chemotherapy alone are within the range that NICE normally considers a cost-effective use of NHS resources, so midostaurin is recommended.# Information about midostaurin
# Marketing authorisation indication
Midostaurin (Rydapt, Novartis) is indicated 'in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia who are FLT3 mutation-positive'.
# Dosage in the marketing authorisation
The dose of midostaurin is 50 mg orally twice daily on days 8–21 of induction and consolidation chemotherapy cycles. For patients who have a complete response midostaurin is continued every day as single agent maintenance therapy until relapse, for up to 12 cycles of 28 days each.
# Price
The company stated that the list price of midostaurin is £5,609.94 for 56 capsules. The company has a commercial arrangement. This makes midostaurin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with FLT3-mutation-positive acute myeloid leukaemia would welcome a new treatment option
Acute myeloid leukaemia is a rapidly progressing form of leukaemia, often diagnosed following an emergency admission to hospital. The clinical experts explained that there are 2 main types of FLT3 mutation; ITD and TKD. The FLT3-ITD mutation is associated with poorer outcomes. The committee understood that the marketing authorisation for midostaurin is for adults with any type of FLT3-mutation-positive acute myeloid leukaemia. A patient expert stated that people with the disease have fatigue, weakness or breathlessness, memory loss, bruising, bleeding and frequent infections. Also, the diagnosis has a big emotional impact on them and their families and carers. The clinical experts explained that if the disease progresses, outcomes are likely to be poor. New treatments that could improve the chance of successfully inducing first remission would be welcomed. The committee concluded that people with untreated disease would welcome any new treatment that could improve survival and quality of life and induce remission, especially one that can be taken orally.
# Clinical management
## Treatment for acute myeloid leukaemia is chemotherapy
Current treatment for newly diagnosed acute myeloid leukaemia is intensive chemotherapy, for people who are well enough to have it. The clinical experts explained that the aim of intensive chemotherapy is to induce complete remission, after which people would either have consolidation chemotherapy or a stem cell transplant. The committee understood that midostaurin would be used to treat FLT3-positive acute myeloid leukaemia when given with induction and consolidation chemotherapy, and then as maintenance monotherapy for up to 12 months. The committee concluded that established clinical management is chemotherapy (without midostaurin), and this is the relevant comparator for this appraisal.
# Clinical evidence
## The mean age of people in the trial is lower than in NHS clinical practice in England
The evidence for midostaurin came from RATIFY, a phase 3, multicentre, double-blind, randomised, placebo-controlled trial that included 717 patients with FLT3-positive acute myeloid leukaemia. It compared midostaurin plus intensive chemotherapy (daunorubicin plus cytarabine), followed by midostaurin monotherapy (n=360) with chemotherapy alone (n=357). The ERG noted that RATIFY only included people aged 18 to 60 years, but that a significant proportion of people with acute myeloid leukaemia are over 60. The clinical experts explained that a large proportion of patients aged 60 to 70 are eligible for treatment with intensive chemotherapy, which would increasingly be used for those over 70 as well. A clinical expert said that it would not be unreasonable to assume that the results seen in the trial would be similar for people over 60. The committee understood that the marketing authorisation for midostaurin (see section 2) is not restricted to a particular age group. It concluded that RATIFY was relevant to clinical practice in England, but that the mean age of people likely to have midostaurin in England is higher than the mean age of people in the trial.
# Clinical effectiveness results
## Midostaurin increases overall and event-free survival compared with chemotherapy alone
The primary outcome measure in RATIFY was overall survival. Treatment with midostaurin plus chemotherapy increased median overall survival compared with chemotherapy alone from 25.6 months to 74.7 months (hazard ratio 0.77; 95% confidence interval 0.63 to 0.95, p=0.0078). The increase in mean overall survival was smaller. The committee understood that this was because of the plateau in the Kaplan–Meier curves and the effect of stem cell transplant on survival. Event-free survival was a secondary end point in RATIFY; the company defined an event as not achieving complete remission within 60 days of starting treatment, relapse from complete remission or death from any cause. Treatment with midostaurin plus chemotherapy increased median event-free survival compared with chemotherapy alone from 3.0 months to 8.2 months (HR 0.78; 95% CI 0.66 to 0.93, p=0.002). The committee concluded that midostaurin plus chemotherapy was clinically effective compared with chemotherapy alone.
# Adverse effects
## Midostaurin is well tolerated
The committee noted that, although there was an increase in exfoliative dermatitis in the midostaurin group compared with the standard care group in RATIFY, the numbers of people who had other adverse effects were similar between the 2 groups. It concluded that midostaurin was generally well tolerated.
# The company's economic model
## The model does not reflect clinical practice because people do not move from the relapsed state to remission
The company used a partitioned survival economic model with 5 health states: acute myeloid leukaemia diagnosis and induction, complete remission, relapse, stem cell transplant and death. The complete remission health state was split into 3 further substates (consolidation, monotherapy and complete remission after stopping first-line treatment). The stem cell transplant state was split into 3 tunnel states (treatment, recovery and post-stem cell transplant recovery). The company used RATIFY data in the model, and assumed that after a period equal to the length of the trial, or 80 cycles (about 6.2 years), people surviving would be cured. The ERG noted that the model did not allow for the possibility of relapsed or refractory disease responding to subsequent therapy other than stem cell transplant. People in the relapsed state did not move into the complete remission state, so they either moved into the stem cell transplant state or stayed in the relapsed state for a long time. The ERG noted that after about 10 years in the model, 15% of the people in the midostaurin group were in the relapsed health state, which was associated with high costs (about £60,000 per year) and low quality of life (utility value of 0.53). The clinical experts stated that they would expect about 10% to 15% of people whose disease relapsed to be in complete remission after subsequent therapy. People whose disease did not respond to subsequent therapy were likely to live for only a few months. The committee agreed that in RATIFY, people whose disease relapsed after initial therapy lived for much longer than the clinical experts suggested they would in NHS clinical practice. In its exploratory analysis, the ERG added a new cured health state to the model, in which it assumed the same costs and benefits (utility value of 0.83) as the complete remission after first-line therapy health state. The ERG explored 3 analyses in which all people who were still alive entered the cured state after 80 cycles (about 6.2 years), after 3 years or when they stopped initial therapy. The committee considered that neither the company's base case nor the ERG's exploratory analyses reflected the clinical experts' description of what they would see in clinical practice. The committee concluded that, of the analyses presented by the company and the ERG, surviving patients with relapsed disease entering a cured health state after 3 years was the most appropriate to overcome the model's restriction on people in the relapsed state and to better reflect clinical practice in England.
## The most plausible utility value for the relapsed health state is 0.78
In response to consultation, the company presented evidence from a study by Leunis et al. (2014). The study reported a utility value of 0.78 for people who had a relapse after initial treatment but survived for a long time afterwards. The company argued that the utility value for the relapsed health state should be no more than 0.78, and implemented a utility value of 0.655, as a midpoint between 0.78 and the company's original value of 0.53 (see section 3.6). The committee understood that this health state included people with relapsed or refractory disease and also people whose disease was in remission after subsequent treatment. It agreed that the utility value for this health state should be lower than the utility value for people whose disease was in remission after initial treatment. However, the committee considered that in the long term some people in the relapsed health state would be in remission after subsequent treatment. For example in the committee's preferred model, surviving patients with relapsed disease entered a cured health state, perhaps as a result of salvage treatment, after 3 years (see section 3.6). Therefore it concluded that 0.78 was the most plausible utility value for people in this health state. However, the committee agreed that changing the utility value did not resolve its concerns that the model did not reflect clinical reality in England.
## The costs associated with complete remission after initial therapy and stem cell transplant recovery are implausible
In its base-case model, the company used the same routine care costs as used in the NICE technology appraisal for azacitidine for people in complete remission after first-line therapy and stem cell transplant recovery. The ERG noted that people in the equivalent health states in the azacitidine appraisal had poorer health than the people expected to be in these health states in the current model, and it therefore considered that the costs in the current model (about £8,000 per year) were too high. The ERG explored 3 analyses in which it assumed there were no routine care costs in the first-line therapy and stem cell transplant recovery health states after the cure point (80 cycles or about 6.2 years), after 3 years, or after patients stopped treatment. The clinical experts stated that people whose disease was in complete remission would still need to attend hospital appointments for monitoring. They also stated that the main treatment goal was to enable a stem cell transplant. People whose disease was in complete remission after stem cell transplant were likely to be seen in hospital frequently, although this would lessen over time. The committee noted that in RATIFY, 59.4% of people in the midostaurin group and 55.2% of people in the standard care group had a stem cell transplant. The clinical experts explained that they would expect more people to have a stem cell transplant in clinical practice because its use is increasing with the better health of older patients. The committee agreed that the routine care costs applied in the company's base-case model for people in the complete remission after first-line therapy and stem cell transplant recovery health states were too high. However, it considered that it was implausible that there would be no costs associated with monitoring these groups of people after a certain point, as in the ERG's exploratory analyses. The committee agreed that its preferred model was the ERG's exploratory analysis in which no health state costs were applied after the cure point either for people in complete remission after first-line therapy or for post-stem cell transplant recovery. It concluded that, of the options presented, this was the best one to overcome the model's overestimation of long-term costs following successful treatment and to better reflect clinical practice in England.
## There is uncertainty about the management costs used in the relapsed health state
In the company's original model, the relapsed health state was associated with ongoing management costs of £4,884 per cycle. The committee considered that these costs were too high to be applied for the rest of a person's life in the model. The committee's preferred model structure included surviving patients with relapsed disease entering a cured health state after 3 years (see section 3.6) with the same costs as the complete remission after first-line treatment state (£659 per cycle), and zero costs applied after the cure point (see section 3.8). In response to consultation, the company amended its original base-case model by implementing management costs of £2,000 per cycle for the relapsed health state, for the rest of the person's life in the model. This cost was derived from an economic model for acute myeloid leukaemia by Wang et al. (2014). The committee understood that the relapsed health state included people with relapsed or refractory disease and also people whose disease was in remission after subsequent treatment, and that the proportion of each group would change over time. Therefore it did not agree with applying a constant figure for management costs in the relapsed health state for life. The committee understood that in its preferred model (see section 3.6), the management costs would apply for 3 years for people who had a relapse after initial treatment, until they entered the new cured health state. The committee concluded that it was plausible that management costs would be closer to £2,000 than £4,884 per cycle for the 3 years before people moved into the cured health state. However, it noted that there was uncertainty about the management costs used for the relapsed health state in the model, because the structure of the model, particularly the duration of the relapsed state, did not accurately reflect clinical practice in England.
# Survival after the cure point
## The survival rate after the cure point is lower than in the general population but there is uncertainty about how much lower
In the model, the company assumed that people who were alive after cycle 80 (about 6.2 years) were cured and applied the same mortality rate that would be expected in the general population, adjusted for age and sex. The ERG noted a study by Martin et al. (2011), which suggested that the mortality rate for people who had a stem cell transplant was 4 to 9 times higher than for the general population for at least 25 years after the transplant. The clinical experts stated that they would expect mortality risk to increase following stem cell transplant, but that an overall 4-fold increase in mortality rate seemed high. The committee also noted that some people's disease may be cured by chemotherapy alone and they might be expected to have lower mortality after the cure point than people who have had a stem cell transplant. In response to consultation, the company presented analyses using a 2-fold increase in mortality rate, based on the opinions of 7 clinical experts. The committee was concerned that a standardised mortality rate was difficult for a clinical expert to estimate. This is because they would need to compare survival in people with acute myeloid leukaemia with an age-matched general population, who they may not have direct experience of treating. However, the committee was also aware that a 4-fold increase in mortality rate had been used after stem cell transplant in the NICE appraisal of inotuzumab ozogamicin for a population with a different disease (acute lymphoblastic leukaemia) and in poorer health. The committee agreed that the mortality rate for people whose disease had been 'cured', and especially for people who had a stem cell transplant, would likely be higher than the general population mortality rate. It concluded that although a 2-fold increase in mortality rate after the cure point was plausible, there was uncertainty and the true increase in mortality could be higher.
# Duration of treatment
## The length of treatment in the model should match the RATIFY trial
In the model, the company assumed that the maximum number of cycles of midostaurin monotherapy was 12, which is consistent with the RATIFY protocol and with the marketing authorisation. The ERG noted that a small number of people in RATIFY actually had up to 18 cycles of midostaurin monotherapy. It therefore increased the maximum cycle length in its base case to 18. The committee agreed that the cost data in the model should be consistent with the clinical data. It concluded that the data in the model should be taken from the trial, but noted that because of the small number of people who had more than 12 cycles, increasing the maximum cycle length to 18 had a limited effect on the ICER.
## The company's original calculation of time on treatment is the most appropriate
In response to the ERG's clarification questions, the company changed the way it calculated the time on treatment in the model. This reduced the total amount of midostaurin that people had, and increased the amount of treatment taken in the standard care group. In its exploratory analysis, the ERG used the company's original calculation. At the committee meeting, the company stated that its original calculation was more appropriate. Therefore the committee concluded that this original calculation should be used in the model.
# Utility values in the model
## Age-adjusted utility values are appropriate
The company used utility values from literature sources, because information on health-related quality of life was not collected as part of RATIFY. It used utility values of 0.830 for the complete remission after first-line therapy state and 0.826 for the post-stem cell transplant recovery state. The ERG noted that the company had not adjusted these utility values in the model to account for health-related quality of life decreasing with age. In its base-case model, the ERG adjusted the utility values in these 2 health states for age, which the committee concluded was appropriate. In its response to consultation, the company used a different method of adjusting the utility values for age. The committee concluded that using this different method was appropriate, but it had a limited effect on the ICER.
## Including adverse effects of stem cell transplant in the model is appropriate
The company did not reduce the utility values for adverse effects from initial or subsequent treatment, including stem cell transplant. It suggested that because it had used utility values that were specific to treatment stage, the values would already include the impact of any adverse effects. The clinical experts highlighted that graft versus host disease, a potential adverse effect of stem cell transplant, would have a significant impact on quality of life. In its base case, the ERG reduced the utility values and increased costs to account for the effects of graft versus host disease. The committee concluded that the adverse effects of stem cell transplant should be included in the model.
# Cure point
## The cure point used in the model is uncertain
The ERG noted that the company had used a cure point of about 6.2 years (80 cycles in the model) based on the length of RATIFY, and extrapolated the survival benefit of midostaurin over standard care at this point over a lifetime. The ERG noted that this was an arbitrary assumption and explored analyses in which it changed the cure point to 5 years, resulting in a similar ICER, and 4 and 7 years, which increased the ICER over the 6.2 year base case. The clinical experts stated that they would expect anyone whose disease was still in relapse after 5 years to be cured. The committee considered that it would prefer to use the latest point at which the data showed a levelling out effect because this was more logically a point of 'cure'. However it noted that at 7 years, the trial data were based on a very small number of people and were therefore unreliable. The committee concluded that there was uncertainty about the most plausible choice of cure point, but noted that moving the cure point either earlier or later increased the ICER.
# Mean age of the population in the model
## The mean age of the population eligible for midostaurin is higher than the mean age of the population in the model
The mean age of the population entering the company's model was 45 years based on RATIFY, which excluded people over 60. The clinical experts explained that a large and increasing proportion of people aged 60 to 70 with FLT3-positive acute myeloid leukaemia would be eligible for intensive chemotherapy, and therefore eligible for midostaurin. They also suggested that 40% to 60% of people currently having intensive chemotherapy are over 60. The committee agreed that the mean age of people who would be eligible for midostaurin in NHS practice in England would likely be higher than 45 years. In its base case, the ERG used the mean age of 45. However, it presented 3 exploratory analyses in which it changed the mean age of the population entering the model to 50, 55 and 60. Increasing the mean age significantly increased the ERG's base-case ICER. The ERG pointed out that this change only affected the life expectancy of people in the model and did not change treatment effectiveness. The committee concluded that it was likely the mean age of people eligible for midostaurin in England would be around 60. However, in its response to consultation, the company presented evidence of a lower mean age of people with FLT3-positive acute myeloid leukaemia from the Haematological Malignancy Research Network (HMRN), a large UK registry. The exact figure is academic in confidence and cannot be reported here. The committee considered that this lower mean age was plausible.
## The data in the economic model should be based on RATIFY
In response to the ERG's critique of the mean age of people in RATIFY, the company did a new analysis of a single-arm phase 2 study of midostaurin, which included people with FLT3-positive acute myeloid leukaemia up to the age of 70. In the new analysis, the company used propensity score matching to compare people in the phase 2 study with historical controls. It also selectively used some of the ERG's amendments to the company's original base-case model:
using complete response data uncensored for stem cell transplant
reverting to its original calculation of time on treatment
including adverse effects of stem cell transplant and
using overall survival data from a later data cut.The company claimed the new analysis showed that midostaurin was effective in improving overall survival for people over 60 and incorporated the data into its model. The mean age of the population entering the company's new model was 65. The company applied overall survival data from the propensity score-matched analysis of the phase 2 study to people in the model who were over 60, and overall survival data based on RATIFY to people who were 60 or under. The ERG noted that people in the historical control groups had a shorter life expectancy than people in the RATIFY standard care group. The clinical experts stated that survival rates for people with FLT3-positive acute myeloid leukaemia had improved in recent years. The committee noted that midostaurin appeared more effective in this analysis than in RATIFY, but agreed that this was likely because of the poor survival rates of people in the historical control groups. The committee also noted that this analysis was a non-randomised comparison that could be susceptible to confounding. It concluded that it should not be used in preference to the trial-based economic model with a simple and logical age adjustment.
# Cost-effectiveness results
## The most plausible ICER is below £30,000 per quality-adjusted life year gained
The company presented the results of deterministic analyses, which included error corrections made by the ERG and the company. It included:
a cured health state, which people entered after stopping initial treatment (see section 3.6)
a utility value of 0.655 in the relapsed health state (see section 3.7)
no health state costs after the cure point either for people in complete remission after first-line therapy or for post-stem cell transplant recovery (see section 3.8)
management costs of £2,000 per cycle for people in the relapsed health state after stopping initial treatment and until death (see section 3.9)
a mortality rate 2 times higher than that of the general population after the cure point (see section 3.10)
a maximum of 18 cycles of maintenance therapy with midostaurin (see section 3.11)
the company's original calculation of time on treatment (see section 3.12)
the company's different method of adjusting utility values for age (see section 3.13)
adverse effects of stem cell transplant (see section 3.14)
a mean age of 60 years on entering the model (see section 3.16) and
a patient access scheme discount.Including the agreed patient access scheme discount, the ICER was below £30,000 per QALY gained. The exact ICER is confidential and cannot be reported here to prevent back-calculation of the discount. The company also explored the committee's preferred model assumptions in scenario analyses, incorporating:
a utility value of 0.78 for the relapsed health state (see section 3.7)
the figure from the HMRN registry for the mean age of the population entering the model (see section 3.16) and
a mortality rate 4 times that of the general population after the cure point (see section 3.10).When the company incorporated all of these scenarios, the ICER was also below £30,000 per QALY gained. The committee noted that changing the cure point from 80 cycles to 4 or 7 years, which it agreed was plausible (see section 3.15), did not increase the ICER to above £30,000 per QALY gained. The committee concluded that the ICERs were within the range that NICE usually considers an acceptable use of NHS resources.
# End of life
## Midostaurin does not qualify as a life-extending treatment for people with a short life expectancy
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. This states that a treatment can be considered as a 'life-extending treatment at the end of life' if it is indicated for patients with a short life expectancy, normally less than 24 months, and it offers an extension to life, normally of a mean value of at least an additional 3 months compared with current NHS treatment. The committee noted that the results of RATIFY showed that midostaurin increased life expectancy compared with standard care by more than 3 months. Therefore midostaurin met the criterion of extension to life of at least an additional 3 months. However, it noted that all the estimates of mean overall survival for people with acute myeloid leukaemia from the literature were over 24 months, except those in a study by Marnadie et al. (2013). The committee agreed that this study was not likely to be representative of the UK population because it was based on relatively old registry data from 1995 to 2002, and included people from countries where life expectancy is lower than in the UK. The committee noted that the median overall survival of people in the RATIFY standard care group was 26 months, with a higher mean value, and that this was a more relevant population because it included people with FLT3-positive acute myeloid leukaemia. One of the clinical experts highlighted another study in people with FLT3-positive acute myeloid leukaemia (Knapper et al. 2017), which reported that median overall survival for people in the control group was more than 24 months. In response to consultation, the company presented HMRN registry data. The committee considered the mean and median overall survival for people with newly diagnosed acute myeloid leukaemia, and for the subgroup of people with FLT3-positive acute myeloid leukaemia who had intensive chemotherapy. The exact figures are academic in confidence and cannot be reported here. The committee agreed that the mean overall survival better represented the whole population than the median, and that none of the means presented suggested that overall survival was below 24 months. It also noted that the total number of life years that the company's model predicted for the standard care group suggested that life expectancy was more than 24 months. Therefore midostaurin did not meet the short life expectancy criterion of less than 24 months. The committee concluded that midostaurin did not meet both of NICE's criteria and therefore was not considered a life-extending treatment at the end of life.
# Innovation
## Midostaurin's benefits are captured in the cost-effectiveness analysis
The company considered midostaurin to be an innovative treatment. It highlighted that induction therapy for treating FLT3-positive acute myeloid leukaemia has not changed much in the past 30 years and that midostaurin is the first targeted tyrosine kinase inhibitor that inhibits FLT3 activity. A patient expert and the clinical experts explained that there was an unmet need for a targeted treatment to improve remission rates and overall survival. The committee concluded that midostaurin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# Conclusion
## Midostaurin is recommended for routine use in the NHS
The committee acknowledged that there was uncertainty in the cost-effectiveness model particularly about the mean age of the population, the cure point, the mortality rate after the cure point, and the management costs in the relapsed health state. However it concluded that, with the discount agreed in the patient access scheme, midostaurin is a cost-effective use of NHS resources, and recommended it within its marketing authorisation for treating newly diagnosed FLT3-positive acute myeloid leukaemia.
|
{'Recommendations': 'Midostaurin is recommended, within its marketing authorisation, as an option in adults for treating newly diagnosed acute FLT3-mutation-positive myeloid leukaemia with standard daunorubicin and cytarabine as induction therapy, with high-dose cytarabine as consolidation therapy, and alone after complete response as maintenance therapy. It is recommended only if the company provides midostaurin with the discount agreed in the patient access scheme.\n\nWhy the committee made these recommendations\n\nTreatment for acute myeloid leukaemia is chemotherapy. Evidence from a randomised controlled trial shows that people taking midostaurin with chemotherapy live longer than people taking chemotherapy alone.\n\nThere is uncertainty about the cost effectiveness of midostaurin because of problems with the economic model. But with the most plausible model assumptions and the discounted price, the cost-effectiveness estimates of midostaurin plus chemotherapy compared with chemotherapy alone are within the range that NICE normally considers a cost-effective use of NHS resources, so midostaurin is recommended.', 'Information about midostaurin': "# Marketing authorisation indication\n\nMidostaurin (Rydapt, Novartis) is indicated 'in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia who are FLT3 mutation-positive'.\n\n# Dosage in the marketing authorisation\n\nThe dose of midostaurin is 50\xa0mg orally twice daily on days\xa08–21 of induction and consolidation chemotherapy cycles. For patients who have a complete response midostaurin is continued every day as single agent maintenance therapy until relapse, for up to 12\xa0cycles of 28\xa0days each.\n\n# Price\n\nThe company stated that the list price of midostaurin is £5,609.94 for 56\xa0capsules. The company has a commercial arrangement. This makes midostaurin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with FLT3-mutation-positive acute myeloid leukaemia would welcome a new treatment option\n\nAcute myeloid leukaemia is a rapidly progressing form of leukaemia, often diagnosed following an emergency admission to hospital. The clinical experts explained that there are 2\xa0main types of FLT3 mutation; ITD and TKD. The FLT3-ITD mutation is associated with poorer outcomes. The committee understood that the marketing authorisation for midostaurin is for adults with any type of FLT3-mutation-positive acute myeloid leukaemia. A patient expert stated that people with the disease have fatigue, weakness or breathlessness, memory loss, bruising, bleeding and frequent infections. Also, the diagnosis has a big emotional impact on them and their families and carers. The clinical experts explained that if the disease progresses, outcomes are likely to be poor. New treatments that could improve the chance of successfully inducing first remission would be welcomed. The committee concluded that people with untreated disease would welcome any new treatment that could improve survival and quality of life and induce remission, especially one that can be taken orally.\n\n# Clinical management\n\n## Treatment for acute myeloid leukaemia is chemotherapy\n\nCurrent treatment for newly diagnosed acute myeloid leukaemia is intensive chemotherapy, for people who are well enough to have it. The clinical experts explained that the aim of intensive chemotherapy is to induce complete remission, after which people would either have consolidation chemotherapy or a stem cell transplant. The committee understood that midostaurin would be used to treat FLT3-positive acute myeloid leukaemia when given with induction and consolidation chemotherapy, and then as maintenance monotherapy for up to 12\xa0months. The committee concluded that established clinical management is chemotherapy (without midostaurin), and this is the relevant comparator for this appraisal.\n\n# Clinical evidence\n\n## The mean age of people in the trial is lower than in NHS clinical practice in England\n\nThe evidence for midostaurin came from RATIFY, a phase\xa03, multicentre, double-blind, randomised, placebo-controlled trial that included 717\xa0patients with FLT3-positive acute myeloid leukaemia. It compared midostaurin plus intensive chemotherapy (daunorubicin plus cytarabine), followed by midostaurin monotherapy (n=360) with chemotherapy alone (n=357). The ERG noted that RATIFY only included people aged 18\xa0to\xa060 years, but that a significant proportion of people with acute myeloid leukaemia are over\xa060. The clinical experts explained that a large proportion of patients aged 60\xa0to\xa070 are eligible for treatment with intensive chemotherapy, which would increasingly be used for those over\xa070 as well. A clinical expert said that it would not be unreasonable to assume that the results seen in the trial would be similar for people over\xa060. The committee understood that the marketing authorisation for midostaurin (see section\xa02) is not restricted to a particular age group. It concluded that RATIFY was relevant to clinical practice in England, but that the mean age of people likely to have midostaurin in England is higher than the mean age of people in the trial.\n\n# Clinical effectiveness results\n\n## Midostaurin increases overall and event-free survival compared with chemotherapy alone\n\nThe primary outcome measure in RATIFY was overall survival. Treatment with midostaurin plus chemotherapy increased median overall survival compared with chemotherapy alone from 25.6\xa0months to 74.7\xa0months (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.63 to 0.95, p=0.0078). The increase in mean overall survival was smaller. The committee understood that this was because of the plateau in the Kaplan–Meier curves and the effect of stem cell transplant on survival. Event-free survival was a secondary end point in RATIFY; the company defined an event as not achieving complete remission within 60\xa0days of starting treatment, relapse from complete remission or death from any cause. Treatment with midostaurin plus chemotherapy increased median event-free survival compared with chemotherapy alone from 3.0\xa0months to 8.2\xa0months (HR 0.78; 95% CI 0.66 to 0.93, p=0.002). The committee concluded that midostaurin plus chemotherapy was clinically effective compared with chemotherapy alone.\n\n# Adverse effects\n\n## Midostaurin is well tolerated\n\nThe committee noted that, although there was an increase in exfoliative dermatitis in the midostaurin group compared with the standard care group in RATIFY, the numbers of people who had other adverse effects were similar between the 2\xa0groups. It concluded that midostaurin was generally well tolerated.\n\n# The company's economic model\n\n## The model does not reflect clinical practice because people do not move from the relapsed state to remission\n\nThe company used a partitioned survival economic model with 5\xa0health states: acute myeloid leukaemia diagnosis and induction, complete remission, relapse, stem cell transplant and death. The complete remission health state was split into 3\xa0further substates (consolidation, monotherapy and complete remission after stopping first-line treatment). The stem cell transplant state was split into 3\xa0tunnel states (treatment, recovery and post-stem cell transplant recovery). The company used RATIFY data in the model, and assumed that after a period equal to the length of the trial, or 80\xa0cycles (about 6.2\xa0years), people surviving would be cured. The ERG noted that the model did not allow for the possibility of relapsed or refractory disease responding to subsequent therapy other than stem cell transplant. People in the relapsed state did not move into the complete remission state, so they either moved into the stem cell transplant state or stayed in the relapsed state for a long time. The ERG noted that after about 10\xa0years in the model, 15% of the people in the midostaurin group were in the relapsed health state, which was associated with high costs (about £60,000 per year) and low quality of life (utility value of 0.53). The clinical experts stated that they would expect about 10%\xa0to\xa015% of people whose disease relapsed to be in complete remission after subsequent therapy. People whose disease did not respond to subsequent therapy were likely to live for only a few months. The committee agreed that in RATIFY, people whose disease relapsed after initial therapy lived for much longer than the clinical experts suggested they would in NHS clinical practice. In its exploratory analysis, the ERG added a new cured health state to the model, in which it assumed the same costs and benefits (utility value of 0.83) as the complete remission after first-line therapy health state. The ERG explored 3\xa0analyses in which all people who were still alive entered the cured state after 80\xa0cycles (about 6.2\xa0years), after 3\xa0years or when they stopped initial therapy. The committee considered that neither the company's base case nor the ERG's exploratory analyses reflected the clinical experts' description of what they would see in clinical practice. The committee concluded that, of the analyses presented by the company and the ERG, surviving patients with relapsed disease entering a cured health state after 3\xa0years was the most appropriate to overcome the model's restriction on people in the relapsed state and to better reflect clinical practice in England.\n\n## The most plausible utility value for the relapsed health state is 0.78\n\nIn response to consultation, the company presented evidence from a study by Leunis et al. (2014). The study reported a utility value of 0.78 for people who had a relapse after initial treatment but survived for a long time afterwards. The company argued that the utility value for the relapsed health state should be no more than 0.78, and implemented a utility value of 0.655, as a midpoint between 0.78 and the company's original value of 0.53 (see section\xa03.6). The committee understood that this health state included people with relapsed or refractory disease and also people whose disease was in remission after subsequent treatment. It agreed that the utility value for this health state should be lower than the utility value for people whose disease was in remission after initial treatment. However, the committee considered that in the long term some people in the relapsed health state would be in remission after subsequent treatment. For example in the committee's preferred model, surviving patients with relapsed disease entered a cured health state, perhaps as a result of salvage treatment, after 3\xa0years (see section\xa03.6). Therefore it concluded that 0.78 was the most plausible utility value for people in this health state. However, the committee agreed that changing the utility value did not resolve its concerns that the model did not reflect clinical reality in England.\n\n## The costs associated with complete remission after initial therapy and stem cell transplant recovery are implausible\n\nIn its base-case model, the company used the same routine care costs as used in the NICE technology appraisal for azacitidine for people in complete remission after first-line therapy and stem cell transplant recovery. The ERG noted that people in the equivalent health states in the azacitidine appraisal had poorer health than the people expected to be in these health states in the current model, and it therefore considered that the costs in the current model (about £8,000 per year) were too high. The ERG explored 3\xa0analyses in which it assumed there were no routine care costs in the first-line therapy and stem cell transplant recovery health states after the cure point (80\xa0cycles or about 6.2\xa0years), after 3\xa0years, or after patients stopped treatment. The clinical experts stated that people whose disease was in complete remission would still need to attend hospital appointments for monitoring. They also stated that the main treatment goal was to enable a stem cell transplant. People whose disease was in complete remission after stem cell transplant were likely to be seen in hospital frequently, although this would lessen over time. The committee noted that in RATIFY, 59.4% of people in the midostaurin group and 55.2% of people in the standard care group had a stem cell transplant. The clinical experts explained that they would expect more people to have a stem cell transplant in clinical practice because its use is increasing with the better health of older patients. The committee agreed that the routine care costs applied in the company's base-case model for people in the complete remission after first-line therapy and stem cell transplant recovery health states were too high. However, it considered that it was implausible that there would be no costs associated with monitoring these groups of people after a certain point, as in the ERG's exploratory analyses. The committee agreed that its preferred model was the ERG's exploratory analysis in which no health state costs were applied after the cure point either for people in complete remission after first-line therapy or for post-stem cell transplant recovery. It concluded that, of the options presented, this was the best one to overcome the model's overestimation of long-term costs following successful treatment and to better reflect clinical practice in England.\n\n## There is uncertainty about the management costs used in the relapsed health state\n\nIn the company's original model, the relapsed health state was associated with ongoing management costs of £4,884\xa0per cycle. The committee considered that these costs were too high to be applied for the rest of a person's life in the model. The committee's preferred model structure included surviving patients with relapsed disease entering a cured health state after 3\xa0years (see section\xa03.6) with the same costs as the complete remission after first-line treatment state (£659\xa0per cycle), and zero costs applied after the cure point (see section\xa03.8). In response to consultation, the company amended its original base-case model by implementing management costs of £2,000\xa0per cycle for the relapsed health state, for the rest of the person's life in the model. This cost was derived from an economic model for acute myeloid leukaemia by Wang et al. (2014). The committee understood that the relapsed health state included people with relapsed or refractory disease and also people whose disease was in remission after subsequent treatment, and that the proportion of each group would change over time. Therefore it did not agree with applying a constant figure for management costs in the relapsed health state for life. The committee understood that in its preferred model (see section\xa03.6), the management costs would apply for 3\xa0years for people who had a relapse after initial treatment, until they entered the new cured health state. The committee concluded that it was plausible that management costs would be closer to £2,000 than £4,884\xa0per cycle for the 3\xa0years before people moved into the cured health state. However, it noted that there was uncertainty about the management costs used for the relapsed health state in the model, because the structure of the model, particularly the duration of the relapsed state, did not accurately reflect clinical practice in England.\n\n# Survival after the cure point\n\n## The survival rate after the cure point is lower than in the general population but there is uncertainty about how much lower\n\nIn the model, the company assumed that people who were alive after cycle\xa080 (about 6.2\xa0years) were cured and applied the same mortality rate that would be expected in the general population, adjusted for age and sex. The ERG noted a study by Martin et al. (2011), which suggested that the mortality rate for people who had a stem cell transplant was 4\xa0to\xa09 times higher than for the general population for at least 25\xa0years after the transplant. The clinical experts stated that they would expect mortality risk to increase following stem cell transplant, but that an overall 4-fold increase in mortality rate seemed high. The committee also noted that some people's disease may be cured by chemotherapy alone and they might be expected to have lower mortality after the cure point than people who have had a stem cell transplant. In response to consultation, the company presented analyses using a 2-fold increase in mortality rate, based on the opinions of 7\xa0clinical experts. The committee was concerned that a standardised mortality rate was difficult for a clinical expert to estimate. This is because they would need to compare survival in people with acute myeloid leukaemia with an age-matched general population, who they may not have direct experience of treating. However, the committee was also aware that a 4-fold increase in mortality rate had been used after stem cell transplant in the NICE appraisal of inotuzumab ozogamicin for a population with a different disease (acute lymphoblastic leukaemia) and in poorer health. The committee agreed that the mortality rate for people whose disease had been 'cured', and especially for people who had a stem cell transplant, would likely be higher than the general population mortality rate. It concluded that although a 2-fold increase in mortality rate after the cure point was plausible, there was uncertainty and the true increase in mortality could be higher.\n\n# Duration of treatment\n\n## The length of treatment in the model should match the RATIFY trial\n\nIn the model, the company assumed that the maximum number of cycles of midostaurin monotherapy was\xa012, which is consistent with the RATIFY protocol and with the marketing authorisation. The ERG noted that a small number of people in RATIFY actually had up to 18\xa0cycles of midostaurin monotherapy. It therefore increased the maximum cycle length in its base case to\xa018. The committee agreed that the cost data in the model should be consistent with the clinical data. It concluded that the data in the model should be taken from the trial, but noted that because of the small number of people who had more than 12\xa0cycles, increasing the maximum cycle length to\xa018 had a limited effect on the ICER.\n\n## The company's original calculation of time on treatment is the most appropriate\n\nIn response to the ERG's clarification questions, the company changed the way it calculated the time on treatment in the model. This reduced the total amount of midostaurin that people had, and increased the amount of treatment taken in the standard care group. In its exploratory analysis, the ERG used the company's original calculation. At the committee meeting, the company stated that its original calculation was more appropriate. Therefore the committee concluded that this original calculation should be used in the model.\n\n# Utility values in the model\n\n## Age-adjusted utility values are appropriate\n\nThe company used utility values from literature sources, because information on health-related quality of life was not collected as part of RATIFY. It used utility values of 0.830 for the complete remission after first-line therapy state and 0.826 for the post-stem cell transplant recovery state. The ERG noted that the company had not adjusted these utility values in the model to account for health-related quality of life decreasing with age. In its base-case model, the ERG adjusted the utility values in these 2\xa0health states for age, which the committee concluded was appropriate. In its response to consultation, the company used a different method of adjusting the utility values for age. The committee concluded that using this different method was appropriate, but it had a limited effect on the ICER.\n\n## Including adverse effects of stem cell transplant in the model is appropriate\n\nThe company did not reduce the utility values for adverse effects from initial or subsequent treatment, including stem cell transplant. It suggested that because it had used utility values that were specific to treatment stage, the values would already include the impact of any adverse effects. The clinical experts highlighted that graft versus host disease, a potential adverse effect of stem cell transplant, would have a significant impact on quality of life. In its base case, the ERG reduced the utility values and increased costs to account for the effects of graft versus host disease. The committee concluded that the adverse effects of stem cell transplant should be included in the model.\n\n# Cure point\n\n## The cure point used in the model is uncertain\n\nThe ERG noted that the company had used a cure point of about 6.2\xa0years (80\xa0cycles in the model) based on the length of RATIFY, and extrapolated the survival benefit of midostaurin over standard care at this point over a lifetime. The ERG noted that this was an arbitrary assumption and explored analyses in which it changed the cure point to 5\xa0years, resulting in a similar ICER, and 4 and 7\xa0years, which increased the ICER over the 6.2\xa0year base case. The clinical experts stated that they would expect anyone whose disease was still in relapse after 5\xa0years to be cured. The committee considered that it would prefer to use the latest point at which the data showed a levelling out effect because this was more logically a point of 'cure'. However it noted that at 7\xa0years, the trial data were based on a very small number of people and were therefore unreliable. The committee concluded that there was uncertainty about the most plausible choice of cure point, but noted that moving the cure point either earlier or later increased the ICER.\n\n# Mean age of the population in the model\n\n## The mean age of the population eligible for midostaurin is higher than the mean age of the population in the model\n\nThe mean age of the population entering the company's model was 45\xa0years based on RATIFY, which excluded people over\xa060. The clinical experts explained that a large and increasing proportion of people aged 60\xa0to\xa070 with FLT3-positive acute myeloid leukaemia would be eligible for intensive chemotherapy, and therefore eligible for midostaurin. They also suggested that 40%\xa0to\xa060% of people currently having intensive chemotherapy are over\xa060. The committee agreed that the mean age of people who would be eligible for midostaurin in NHS practice in England would likely be higher than 45\xa0years. In its base case, the ERG used the mean age of\xa045. However, it presented 3\xa0exploratory analyses in which it changed the mean age of the population entering the model to 50, 55 and 60. Increasing the mean age significantly increased the ERG's base-case ICER. The ERG pointed out that this change only affected the life expectancy of people in the model and did not change treatment effectiveness. The committee concluded that it was likely the mean age of people eligible for midostaurin in England would be around\xa060. However, in its response to consultation, the company presented evidence of a lower mean age of people with FLT3-positive acute myeloid leukaemia from the Haematological Malignancy Research Network (HMRN), a large UK registry. The exact figure is academic in confidence and cannot be reported here. The committee considered that this lower mean age was plausible.\n\n## The data in the economic model should be based on RATIFY\n\nIn response to the ERG's critique of the mean age of people in RATIFY, the company did a new analysis of a single-arm phase\xa02 study of midostaurin, which included people with FLT3-positive acute myeloid leukaemia up to the age of\xa070. In the new analysis, the company used propensity score matching to compare people in the phase\xa02 study with historical controls. It also selectively used some of the ERG's amendments to the company's original base-case model:\n\nusing complete response data uncensored for stem cell transplant\n\nreverting to its original calculation of time on treatment\n\nincluding adverse effects of stem cell transplant and\n\nusing overall survival data from a later data cut.The company claimed the new analysis showed that midostaurin was effective in improving overall survival for people over\xa060 and incorporated the data into its model. The mean age of the population entering the company's new model was\xa065. The company applied overall survival data from the propensity score-matched analysis of the phase\xa02 study to people in the model who were over\xa060, and overall survival data based on RATIFY to people who were\xa060 or under. The ERG noted that people in the historical control groups had a shorter life expectancy than people in the RATIFY standard care group. The clinical experts stated that survival rates for people with FLT3-positive acute myeloid leukaemia had improved in recent years. The committee noted that midostaurin appeared more effective in this analysis than in RATIFY, but agreed that this was likely because of the poor survival rates of people in the historical control groups. The committee also noted that this analysis was a non-randomised comparison that could be susceptible to confounding. It concluded that it should not be used in preference to the trial-based economic model with a simple and logical age adjustment.\n\n# Cost-effectiveness results\n\n## The most plausible ICER is below £30,000 per quality-adjusted life year gained\n\nThe company presented the results of deterministic analyses, which included error corrections made by the ERG and the company. It included:\n\na cured health state, which people entered after stopping initial treatment (see section\xa03.6)\n\na utility value of 0.655 in the relapsed health state (see section\xa03.7)\n\nno health state costs after the cure point either for people in complete remission after first-line therapy or for post-stem cell transplant recovery (see section\xa03.8)\n\nmanagement costs of £2,000 per cycle for people in the relapsed health state after stopping initial treatment and until death (see section\xa03.9)\n\na mortality rate 2\xa0times higher than that of the general population after the cure point (see section\xa03.10)\n\na maximum of 18\xa0cycles of maintenance therapy with midostaurin (see section\xa03.11)\n\nthe company's original calculation of time on treatment (see section\xa03.12)\n\nthe company's different method of adjusting utility values for age (see section\xa03.13)\n\nadverse effects of stem cell transplant (see section\xa03.14)\n\na mean age of 60\xa0years on entering the model (see section\xa03.16) and\n\na patient access scheme discount.Including the agreed patient access scheme discount, the ICER was below £30,000 per QALY gained. The exact ICER is confidential and cannot be reported here to prevent back-calculation of the discount. The company also explored the committee's preferred model assumptions in scenario analyses, incorporating:\n\na utility value of 0.78 for the relapsed health state (see section\xa03.7)\n\nthe figure from the HMRN registry for the mean age of the population entering the model (see section\xa03.16) and\n\na mortality rate 4\xa0times that of the general population after the cure point (see section\xa03.10).When the company incorporated all of these scenarios, the ICER was also below £30,000 per QALY gained. The committee noted that changing the cure point from 80\xa0cycles to 4 or 7\xa0years, which it agreed was plausible (see section\xa03.15), did not increase the ICER to above £30,000 per QALY gained. The committee concluded that the ICERs were within the range that NICE usually considers an acceptable use of NHS resources.\n\n# End of life\n\n## Midostaurin does not qualify as a life-extending treatment for people with a short life expectancy\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. This states that a treatment can be considered as a 'life-extending treatment at the end of life' if it is indicated for patients with a short life expectancy, normally less than 24\xa0months, and it offers an extension to life, normally of a mean value of at least an additional 3\xa0months compared with current NHS treatment. The committee noted that the results of RATIFY showed that midostaurin increased life expectancy compared with standard care by more than 3\xa0months. Therefore midostaurin met the criterion of extension to life of at least an additional 3\xa0months. However, it noted that all the estimates of mean overall survival for people with acute myeloid leukaemia from the literature were over 24\xa0months, except those in a study by Marnadie et al. (2013). The committee agreed that this study was not likely to be representative of the UK population because it was based on relatively old registry data from 1995 to 2002, and included people from countries where life expectancy is lower than in the UK. The committee noted that the median overall survival of people in the RATIFY standard care group was 26\xa0months, with a higher mean value, and that this was a more relevant population because it included people with FLT3-positive acute myeloid leukaemia. One of the clinical experts highlighted another study in people with FLT3-positive acute myeloid leukaemia (Knapper et al. 2017), which reported that median overall survival for people in the control group was more than 24\xa0months. In response to consultation, the company presented HMRN registry data. The committee considered the mean and median overall survival for people with newly diagnosed acute myeloid leukaemia, and for the subgroup of people with FLT3-positive acute myeloid leukaemia who had intensive chemotherapy. The exact figures are academic in confidence and cannot be reported here. The committee agreed that the mean overall survival better represented the whole population than the median, and that none of the means presented suggested that overall survival was below 24\xa0months. It also noted that the total number of life years that the company's model predicted for the standard care group suggested that life expectancy was more than 24\xa0months. Therefore midostaurin did not meet the short life expectancy criterion of less than 24\xa0months. The committee concluded that midostaurin did not meet both of NICE's criteria and therefore was not considered a life-extending treatment at the end of life.\n\n# Innovation\n\n## Midostaurin's benefits are captured in the cost-effectiveness analysis\n\nThe company considered midostaurin to be an innovative treatment. It highlighted that induction therapy for treating FLT3-positive acute myeloid leukaemia has not changed much in the past 30\xa0years and that midostaurin is the first targeted tyrosine kinase inhibitor that inhibits FLT3 activity. A patient expert and the clinical experts explained that there was an unmet need for a targeted treatment to improve remission rates and overall survival. The committee concluded that midostaurin would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# Conclusion\n\n## Midostaurin is recommended for routine use in the NHS\n\nThe committee acknowledged that there was uncertainty in the cost-effectiveness model particularly about the mean age of the population, the cure point, the mortality rate after the cure point, and the management costs in the relapsed health state. However it concluded that, with the discount agreed in the patient access scheme, midostaurin is a cost-effective use of NHS resources, and recommended it within its marketing authorisation for treating newly diagnosed FLT3-positive acute myeloid leukaemia."}
|
https://www.nice.org.uk/guidance/ta523
|
Evidence-based recommendations on midostaurin (Rydapt) for untreated FLT3-mutation-positive acute myeloid leukaemia in adults.
|
93ac3888cb6c5dc7ed5d5ab7fa895803a03fd5dd
|
nice
|
Brentuximab vedotin for treating CD30-positive Hodgkin lymphoma
|
Brentuximab vedotin for treating CD30-positive Hodgkin lymphoma
Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating CD30-positive Hodgkin lymphoma in adults.
# Recommendations
Brentuximab vedotin is recommended as an option for treating CD30‑positive Hodgkin lymphoma in adults with relapsed or refractory disease, only if:
they have already had autologous stem cell transplant or
they have already had at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy are not suitable and
the company provides brentuximab vedotin according to the commercial arrangement.
Why the committee made these recommendations (NICE technology appraisal guidance 446)
Hodgkin lymphoma is usually treated with chemotherapy, followed by stem cell transplant. Stem cell transplant gives people the best chance of a cure, so people who cannot have stem cell transplant have a high clinical unmet need. Brentuximab vedotin can be used as a 'bridging' treatment before stem cell transplant and, in some cases, as a curative treatment itself.
NICE technology appraisal guidance 446 recommended brentuximab vedotin as an option for treating adults with relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant. However, it was not recommended for adults who are at increased risk of disease relapse or progression after autologous stem cell transplant because the cost-effectiveness estimates were too high.
For adults with relapsed or refractory disease after at least 2 previous therapies, when autologous stem cell transplant or multi-agent chemotherapy is not suitable, the cost-effectiveness evidence was less clear. So brentuximab vedotin was recommended for use within the Cancer Drugs Fund in this population to collect data on its effectiveness in practice.
Why the committee made these recommendations (Cancer Drugs Fund review of technology appraisal guidance 446)
Data collected through the Cancer Drugs Fund on rates of stem cell transplant after treatment with brentuximab vedotin show that it improved rates of stem cell transplant compared with chemotherapy. Also, the updated cost-effectiveness estimates for brentuximab vedotin are lower than £20,000 per quality-adjusted life year gained. Because of this, brentuximab vedotin is recommended as an option for treating relapsed or refractory CD30‑positive Hodgkin lymphoma in adults, only if they have already had autologous stem cell transplant, or at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy are not suitable.# Information about brentuximab vedotin
# Marketing authorisation indication
Brentuximab vedotin (Adcetris) is indicated for treating relapsed or refractory CD30‑positive Hodgkin lymphoma in adults:
after autologous stem cell transplant or
after at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not a treatment option
at increased risk of relapse or progression after autologous stem cell transplant.
# Dosage in the marketing authorisation
The recommended dose is 1.8 mg/kg administered by intravenous infusion over 30 minutes every 3 weeks.
# Price
The price of brentuximab vedotin is £2,500 for a 50‑mg vial (excluding VAT; British national formulary edition 69). The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.'# Committee discussion
The appraisal committee considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
Sections 3.1 to 3.33 reflect the committee's discussion during NICE technology appraisal 446. These sections are unchanged since the guidance was first published in June 2017.
Sections 3.37 to 3.47 reflect the committee's discussion during the Cancer Drugs Fund review of population 3 from NICE technology appraisal guidance 446.
# The condition (NICE technology appraisal guidance 446)
## Stem cell transplants give people the best chance of a cure for treating Hodgkin lymphoma
The committee noted that there was no NICE technology appraisal guidance on Hodgkin lymphoma. It understood that current first-line treatment is chemotherapy with or without radiotherapy. If this fails to lead to long-term remission, people may have high-dose chemotherapy, followed when possible by autologous stem cell transplant. The committee was aware that there is no standard therapy administered after autologous stem cell transplant to delay disease progression. Up to half the people who have had autologous stem cell transplant develop progressive disease with a life expectancy of less than 3 years. These people may be offered further, usually single-drug, chemotherapy. People whose disease does not respond after 2 previous lines of therapy would also be offered single-agent chemotherapy, but the committee was aware that these patients had a low chance of bridging to stem cell transplantation. Stem cell transplants give people the best chance of a curative treatment; so people who cannot bridge to stem cell transplantation have poor long-term survival prospects and a high clinical unmet need.
## There is a high clinical unmet need for people who cannot have stem cell transplant
The committee understood that allogeneic stem cell transplant was the treatment of choice if there is a suitable donor and a good response to systemic therapy after autologous stem cell transplant has failed. The committee recognised that treatment largely depended on the person's circumstances, including their eligibility for stem cell transplant. The clinical experts advised that autologous stem cell transplant would not generally be recommended for relapsed or refractory Hodgkin lymphoma unless there was an adequate response to previous (salvage) therapy. This normally means at least a partial response, although they noted that the definition of 'adequate response' is uncertain. The committee heard from clinical experts that positron emission tomography (PET) scanning is the preferred method of assessing response to salvage therapy before autologous stem cell transplant, and that this was available in most UK transplant centres. The committee recognised that there were 2 groups who may not have an autologous stem cell transplant: people who are not fit enough for treatment and those for whom salvage therapy did not produce an adequate response. The committee concluded that both of these groups would have a high clinical unmet need.
## Brentuximab vedotin will mainly be used for relapsed or refractory disease after autologous stem cell transplant, or after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option
The committee considered the groups of people with CD30‑positive Hodgkin lymphoma which reflected the marketing authorisation for brentuximab vedotin. These were:
adults with relapsed or refractory disease after autologous stem cell transplant (population 1)
adults with increased risk of disease relapse or progression after autologous stem cell transplant (population 2)
adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option (population 3).The committee heard from clinical experts that the most relevant populations in the UK were the first and third of the groups included in the marketing authorisation. The committee understood that there is currently no NICE guidance for these indications. Brentuximab vedotin is currently available through the Cancer Drugs Fund for populations 1 and 3. The UK marketing authorisation for brentuximab vedotin does not explicitly exclude retreatment as an option, but the company did not focus its submission on retreatment. Retreatment is not permitted through the Cancer Drugs Fund. Brentuximab vedotin offers the chance of a potentially curative stem cell transplant, which the clinical experts considered of great importance. The clinical experts also highlighted that in some instances brentuximab vedotin can be a curative treatment without stem cell transplant. For the second group, the committee heard from clinical experts that it was not routine practice in England to refer patients for transplant who are at increased risk of disease relapse or progression. Most clinicians would aim for PET-negative remission (that is, no signs of disease on the PET scan) before autologous stem cell transplant (see section 3.10). If this is achieved, the risk of subsequent relapse or progression is reduced, and the adverse effects of brentuximab vedotin would likely outweigh its benefit, which is expected to be limited in this situation. If the PET scan is positive, brentuximab vedotin could be used as for the third group (that is, as a possible bridge to autologous stem cell transplant). The committee, however, noted that although the second group does not feature much in current UK clinical practice, it should be appraised for the small subset of patients who may benefit. The committee concluded that based on current clinical practice, brentuximab vedotin would mainly be used for relapsed or refractory disease after autologous stem cell transplant, and for relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option.
## Maximal response is expected after 4 to 5 cycles of brentuximab vedotin rather than 16
The committee asked whether rules for stopping treatment are used in clinical practice. It noted that, at the time of consultation, the Cancer Drugs Fund included brentuximab vedotin for the 2 relapsed or refractory CD30‑positive Hodgkin lymphoma populations, administered once every 3 weeks (see summary of product characteristics) on the condition that treatment is stopped if there is no partial or complete response after 6 treatment cycles. The committee heard from clinical experts that, although there was no robust evidence, maximal response would be expected after 4 to 5 treatment cycles. The committee noted that this was much lower than the maximum number of 16 cycles recommended in the summary of product characteristics.
# Clinical effectiveness (NICE technology appraisal guidance 446)
## The non-randomised evidence provides an immature and limited evidence base
Population 1 is adults with relapsed or refractory disease after autologous stem cell transplant. The committee noted that the trial evidence for this group was from SG035‑0003 (n=102); an open-label, single-arm, phase 2 trial. The key results were:
-verall response rate by independent review (primary outcome): 75% (76/102); complete response rate by independent review: 33% (34/102)
median progression-free survival by investigators: 9.3 months (95% confidence interval 7.1 to 12.2 months)
median overall survival: 40.5 months.
## Comparisons with historical controls are uncertain
The committee noted that the company considered the anti-tumour effect of brentuximab vedotin to compare favourably with historical controls. It was aware that such comparisons are associated with a high risk of bias, not least because they may be based on studies that had found no benefit for the controls. Also, the committee noted that the historical control data came from relatively old studies. It heard from clinical experts that the outcome of chemotherapy was likely to be better than reported in this literature, as shown by the increasing number of people who have allogeneic stem cell transplant. The committee agreed that no definite conclusions about the effect of brentuximab vedotin for this indication could be drawn from comparisons with historical controls.
## The company's intra-patient comparison is a useful indication of the effect of brentuximab vedotin compared with chemotherapy
The committee discussed the company's 'intra-patient' comparison, noting that this was done in a subset of patients (57/102) with relapsed or refractory Hodgkin lymphoma who had 1 or more systemic therapies other than brentuximab vedotin after autologous stem cell transplant. Median progression-free survival (assessed by investigators) after the most recent systemic therapy before brentuximab vedotin was 4.1 months compared with 7.9 months when these same patients then had brentuximab vedotin (hazard ratio 0.40; p<0.001). In its original submission, the company noted that because progression-free intervals are expected to shorten after each successive treatment, the effect of brentuximab vedotin can be considered clinically significant. The committee noted the ERG comment that the intra-patient comparison was only done for patients for whom systemic therapy had failed, excluding those who had a good outcome with chemotherapy. In contrast, the clinical experts considered that patients who had systemic therapies before brentuximab vedotin may be fitter and able to tolerate the adverse effects of chemotherapy. The committee acknowledged that the intra-patient comparison did not provide comparative evidence based on parallel and controlled assignment of patients to different treatment arms; nor did it compare the most effective, as opposed to the most recent, chemotherapy. Nevertheless, the committee concluded that the company's intra-patient comparison gave a useful indication of the effect of brentuximab vedotin compared with chemotherapy.
## Brentuximab vedotin may be more effective than chemotherapy in population 1 but the evidence is uncertain
The committee noted that the company's clinical-effectiveness submission for this group came from non-randomised evidence, which provided an immature and limited evidence base (see section 3.5). The committee also noted that the outcomes presented included the anti-tumour effect of brentuximab vedotin measured as response rate, which is less clinically relevant than progression-free survival and overall survival. Also, the company relied on comparisons with historical controls, the validity of which is questionable. The committee appreciated that it would be difficult to do a randomised controlled trial for brentuximab vedotin in part because Hodgkin lymphoma is rare. It also heard from clinical experts that there was little published evidence for the comparator treatments, preventing a clinically relevant comparison with brentuximab vedotin. Overall the committee concluded there was a large degree of uncertainty in the clinical evidence, but noted comments from clinical experts and positive results from the intra-patient comparison which suggested that brentuximab vedotin was more effective than chemotherapy.
## Clinical-effectiveness evidence for population 2 came from the additional data cut of the AETHERA trial
Population 2 is adults with increased risk of disease relapse or progression after autologous stem cell transplant. The committee noted the evidence base submitted by the company came from AETHERA (n=329); a double-blind, randomised, controlled, phase 3 trial comparing brentuximab vedotin with placebo. The trial collected data between April 2010 and September 2012. The key results were:
median progression-free survival assessed by independent review (primary outcome): 42.9 months for brentuximab vedotin; 24.1 months for placebo (HR 0.57, 95% CI 0.40 to 0.81; p=0.001)
median progression-free survival assessed by investigators: not reached for brentuximab vedotin; 15.8 months for placebo (HR 0.50, 95% CI 0.36 to 0.70)
-verall survival (without adjustment for treatment switching): median not reached for either treatment; HR 1.15 (95% CI 0.67 to 1.97).In response to consultation on the second appraisal consultation document, the company provided a new data cut from the AETHERA trial (ASH 2015) which it used in all of its updated cost-effectiveness analyses for this population.
## The definition of patients at high risk of relapse in the trial is broader than that on which brentuximab vedotin's regulatory approval was based
The committee noted that AETHERA included patients with Hodgkin lymphoma at risk of having residual disease after autologous stem cell transplant, defined as those who have 1 of the following risk factors:
primary refractory Hodgkin lymphoma (as determined by investigators)
relapsed Hodgkin lymphoma with initial remission of less than 12 months
extra-nodal involvement before autologous stem cell transplant.This definition was broader than the one on which brentuximab vedotin's regulatory approval was based, which defined high risk of relapse or progression as the presence of 2 or more of the above risk factors. It was also different from the definition in the final scope, which included a positive PET scan before autologous stem cell transplant as a high-risk factor. In response to consultation on the second appraisal consultation document, the company created 2 definitions of high-risk patients which could be applied to the trial population to identify a subgroup of patients which better reflected the committee's preferences. The committee acknowledged that clinicians considered PET scanning to be valuable in assessing the risk of relapse or progression, and agreed that any definition of high-risk patients should include a positive PET scan result. The committee's preferred patient subgroup was defined as those with a positive PET scan result before autologous stem cell transplant and at least 1 of:
relapsed disease within 12 months or disease refractory to front-line therapy
extra-nodal disease at pre-autologous stem cell transplant relapse
B symptoms at pre-autologous stem cell transplant relapse
at least 2 previous salvage therapies.The company did not present any clinical data for this subset of the trial population in its response to consultation on the second appraisal consultation document. It used the updated data cut and subgroup of patients that met the high-risk definition above in its modelled cost-effectiveness analysis.
## Brentuximab vedotin improves progression-free survival more than placebo in population 2 but the data are uncertain
The committee noted that this was the only population for which randomised controlled trial evidence was available, but that even this was compromised to fit the data to the relevant high-risk group. The committee noted that the median progression-free survival assessed by independent review (primary outcome) for the whole trial population was 42.9 months for brentuximab vedotin and 24.1 months for placebo (HR 0.57, 95% CI 0.40 to 0.81; p=0.001). The committee, however, accepted the company's proposed high-risk patient definition.
## The clinical evidence for population 3 comes from non-randomised studies and is limited
Population 3 is adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option. The committee noted that the original evidence presented by the company came from a group of patients who took part in phase 1 and 2 studies, a study in Japanese patients only (TB-BC010088), and a named patient programme (n=59; 41 patients had the recommended dosage of brentuximab vedotin of 1.8 mg/kg every 3 weeks). The key results were:
-verall response rate: 54% (22/41); complete response rate: 22% (9/41)
patients who became eligible for autologous stem cell transplant: 19% (8/41).
## The company presented additional evidence in this population
In response to the first appraisal consultation document, the company provided additional clinical-effectiveness evidence for this population, from 2 sources:
C25007 (n=60): an ongoing phase 4, single-arm, open-label, multicentre study
a real-world UK observational study (n=78): a retrospective study including multiple centres across England.The company pooled the data from these sources to maximise the target patient population. Table 1 presents the results of the individual studies and the pooled dataset.
Outcome
C25007 study
(n=60)
Observational study (n=78)
Pooled dataset (n=138 for stem cell transplant, n=135 for response)
Overall response rate (%)
(complete response=15, partial response=33)
(complete response=24, partial response=27)
(complete response=20, partial response=30)
Post-brentuximab stem cell transplant rate (%)
Progression-free survival (months)
(95% confidence interval 2.96 to 5.32)
(95% confidence interval 4.21 to 17.05)
Overall survival
% at 24 months (95% confidence interval 58.0 to 84.6)
months
(95% confidence interval 17.8 to not reached)
Mean number of cycles
(95% confidence interval 6.5 to 8.4)
(95% confidence interval 3.7 to 4.6)
(95% confidence interval 5.1 to 6.2)
## Patients in these studies reflected a fitter subset of the population covered in the marketing authorisation
The committee discussed whether the results from these studies were representative of adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option. It considered that in clinical practice, this population could be ineligible for autologous stem cell transplant or multi-agent chemotherapy either because the patient is frail, or because the response to previous treatment does not predict a favourable outcome after autologous stem cell transplant. The committee recognised that the latter group would represent fitter patients for whom brentuximab vedotin could act as a bridge to autologous stem cell transplant, and that it was this group that the pooled dataset reflected more closely. The committee heard from the clinical experts that the most likely treatment option for this population, in the absence of brentuximab vedotin, was single-agent chemotherapy (see section 3.1). The committee concluded that the study populations reflected only a fitter subset of the population under consideration.
## The studies may be not be generalisable to UK clinical practice
The committee recognised that all the data presented, although the best available for this population, was associated with a large amount of uncertainty, as is the case with single-arm studies and retrospective evidence. The committee heard from the ERG that it had a number of concerns about the pooled studies. The first concern was the generalisability of the C25007 data to the UK population. A proportion of patients (18%) in the study only had 1 previous treatment, so did not mirror the marketing authorisation for brentuximab vedotin. Also, 88% of patients in C25007 came from outside the UK, and clinical experts stated that routine clinical practice would be quite different to that of the UK. The ERG highlighted that these differences were seen in the study outcomes of mean treatment cycles and relative rates of allogeneic and autologous stem cell transplant.
## The real-world UK dataset provides the most relevant evidence but any comparison in population 3 is uncertain
The committee noted that the company's clinical-effectiveness submission for this group came from non-randomised evidence which provided a limited evidence base (see sections 3.12 to 3.13). The committee agreed that although the clinical data in the pooled dataset provided an improved evidence base compared with that considered in the first appraisal consultation document, it was still associated with a large amount of uncertainly. The committee also agreed that the real-world UK dataset provided more relevant clinical data to estimate the clinical effectiveness of brentuximab vedotin from an NHS perspective.
# Overall cost effectiveness (NICE technology appraisal guidance 446)
## The cost-effectiveness analyses for populations 1 and 3 are based on clinical-effectiveness evidence that is uncertain
The committee considered the company's amended economic analyses for populations 1 and 3 and the new data cut and subgroup analyses for population 2, all incorporating the updated patient access scheme. It agreed that the uncertainty in the clinical evidence base would be carried over in the economic modelling for populations 1 and 3.
# Cost effectiveness: population 1 (NICE technology appraisal guidance 446)
For this group the committee noted that the cost-effectiveness analysis was sensitive to the progression-free survival extrapolation approach and the mortality benefit of brentuximab vedotin compared with chemotherapy.
## The company's approach to modelling progression-free survival is plausible
The committee noted that to model progression-free survival, the company used the Kaplan–Meier data from SG035‑0003 for brentuximab vedotin and data from the intra-patient comparison for chemotherapy (see sections 3.5 to 3.7). The company and the ERG extrapolated progression-free survival beyond the trial follow-up (6.08 years). They assumed that both brentuximab vedotin and chemotherapy had the same effect on progression-free survival as that measured in another study (Robinson et al. 2009), in which patients had allogeneic stem cell transplant. The committee noted that the ERG estimated progression risk from the entire curve in Robinson et al. (2009), and then applied the mean risk to the extrapolation of progression-free survival. The clinical experts considered it was not appropriate to apply a risk of progression rate estimated from the mean of the entire trial period, as it would incorporate patients with a different prognosis to those who are alive at least 18 months after allogeneic stem cell transplant. The committee agreed that this approach was too pessimistic because the progression-free survival extrapolation dropped too quickly at the end of the trial follow-up. In the original company submission, the company assumed that following the 6.08‑year follow-up from start of treatment, the risk of progression would be equal to that after allogeneic stem cell transplant. The committee heard from the clinical experts that the curve displayed in the company's approach to progression-free survival modelling was a plausible extrapolation of progression-free survival beyond the within trial period. The committee was persuaded that the company's approach to the extrapolation of progression-free survival was plausible and accepted this assumption in its choice of a preferred incremental cost-effectiveness ratio (ICER).
## A mortality benefit of 10% is more plausible than the company's base case of 31%
The committee noted that to estimate overall survival from the model, the company compared brentuximab vedotin patients from SG035‑0003 with chemotherapy patients from an earlier study (Martinez et al. 2010, 2013). The company adjusted the Martinez et al. survival to better reflect the patient characteristics in SG035‑0003. In response to consultation on the second appraisal consultation document, the company provided 2 base-case analyses with different assumptions about mortality benefit and overall survival extrapolation. Base case 1 retained the 31% mortality benefit and reverted to fitting an exponential function to the overall survival data in Martinez et al. Base case 2 assumed a 10% mortality benefit for brentuximab vedotin and fit a lognormal function to the overall survival data in Martinez et al. The company also provided a scenario analysis in which it varied the mortality benefit of brentuximab vedotin between 10% and 40%. The committee heard from clinical experts that the 31% mortality benefit figure was possible and that brentuximab vedotin had served as a curative treatment for some people in this patient population. The committee heard from the ERG that any mortality benefit of brentuximab vedotin in the model was not based on robust evidence, but it incorporated a mortality benefit of 10% for brentuximab vedotin to reflect the committee's preferences as stated in the second appraisal committee document. The committee agreed that the company's modelled benefit of a 31% increase in survival did not reflect robust evidence, but considered that a mortality benefit of at least 10% was likely. The committee concluded that it would be reasonable to incorporate a mortality benefit of 10% for brentuximab vedotin when calculating its preferred ICER.
## The company's approach to treatment dosing and stopping rule is plausible
After consultation on the second appraisal consultation document, the company reverted to the modelling approach from its original submission while incorporating changes to the relative dose intensity for chemotherapy (equal to brentuximab vedotin; that is, 94%) and the stopping rule proposed after consultation on the first appraisal consultation document. The stopping rule applied to patients whose disease did not respond to treatment after 4 or 5 cycles. The committee noted that in response to consultation, both the company's base case and the ERG's modified base case estimated the cost of brentuximab vedotin in the model based on the average number of treatment cycles that patients had in SG035‑0003 (9.7 cycles), which was reduced after accounting for the stopping rule (8.5 cycles). The committee heard from clinical experts that people are likely to have fewer cycles than this because the maximal response to brentuximab vedotin would be expected after only 4 to 5 cycles (see section 3.4). The committee recognised that because brentuximab vedotin is more expensive than chemotherapy, the model was highly sensitive to the drug acquisition cost of brentuximab vedotin. On balance, it considered the company's approach to dosing and the stopping rule a plausible basis for discussion.
## The committee's preferred ICER for population 1 is within the range considered to be cost effective for routine use
The committee agreed that the company and ERG had taken similar approaches in their assessment of cost effectiveness for this population, and that it could accept either if a mortality benefit of 10% was incorporated. The committee noted that with this adjustment, using either the company approach or the ERG approach, its preferred ICER was less than £30,000 per quality-adjusted life year (QALY) gained. The committee concluded that it could recommend brentuximab vedotin as cost effective for routine NHS use in this population.
# Cost effectiveness: population 2 (NICE technology appraisal guidance 446)
## The most plausible mortality benefit is somewhere between the company's and the ERG's estimates
The committee discussed the ERG's concerns about the company's overall approach to the modelling, specifically that the increase in progression-free survival with brentuximab vedotin translated into an equivalent but unproven overall survival gain. To correct this, the ERG rebuilt a partitioned survival model, assuming equal mortality in both treatment arms. The committee heard from the clinical experts that brentuximab vedotin has shown considerable gains in progression-free survival compared with best supportive care, but that overall survival data were not yet available. However, the clinical experts suggested that patients whose disease has not progressed after 2 years are unlikely to relapse, and gains in progression-free survival would be a good predictor of overall survival extensions in this population. The committee agreed that assuming a 1:1 relationship between progression-free survival and overall survival was optimistic, but that it was reasonable to assume that an extension to progression-free survival would lead to some extension in overall survival. The committee concluded that the company's and ERG's assumptions could both be considered extreme, and that the mortality benefit of brentuximab vedotin was likely to lie between the 2 estimates.
## The company's assumptions about long-term health-related quality of life are unrealistic
In response to consultation on the second appraisal consultation document, the company updated the model to assume that 5 years after starting treatment, health-related quality of life for people whose disease did not progress would move back towards the age-adjusted population norm, with a small utility decrement being applied. In the ERG's opinion, this assumption was not justified and contradicted the EQ-5D data collected from AETHERA. The committee concluded that the company's assumption about long-term health-related quality of life remained unrealistic.
## The scenario analysis that incorporates costs for subsequent treatments is not appropriate
In response to consultation on the second appraisal consultation document, the company presented a scenario analysis in which subsequent treatments were included as an additional cost. The company argued that patients on brentuximab vedotin would go on to have fewer subsequent treatments than those on best supportive care, improving the cost effectiveness of brentuximab vedotin. The ERG disagreed with the inclusion of these costs on the grounds that crossover was allowed in the AETHERA trial, meaning that these patients would be unlikely to represent a relevant part of the treatment pathway in UK clinical practice. The committee agreed with the ERG and further considered it unjustified to add the costs of brentuximab vedotin to the comparator arm in the model. It concluded that subsequent therapy costs should not be included in the estimation of the most plausible ICER.
## The committee's preferred ICER for population 2 is over £30,000 per QALY gained and does not have plausible potential to be cost effective through the Cancer Drugs Fund
Overall, the committee noted that it was not currently routine practice in the NHS to refer patients for transplant who are at increased risk of disease relapse or progression. The committee recognised that the clinical data did not reflect the definition of high risk of relapse or progression adopted by the regulator, but accepted the company's subgroup analysis because it included high-risk patients defined as having a positive PET scan plus 1 or more risk factors (see section 3.10). The committee agreed that the ERG's ICERs were generated from an overly pessimistic model which assumed no mortality benefit for brentuximab vedotin, and that the company model was more suitable for estimating its preferred ICER. However, it did not agree with the company model assumption of a 1:1 relationship between progression-free survival and overall survival, and so concluded that the company's cost-effectiveness estimates (an ICER of £35,606 per QALY gained) represented the lower limit of the committee's preferred ICER. The committee agreed that this ICER was higher than the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). It also noted a company comment in response to second consultation requesting brentuximab vedotin to be considered for future use within the Cancer Drugs Fund in this population. The committee considered that its preferred ICER of more than £35,606 per QALY gained did not indicate the plausible potential for satisfying the cost-effectiveness criteria for routine use through data collection. The committee therefore did not recommend brentuximab vedotin as cost effective for routine NHS use in adults with increased risk of disease relapse or progression after autologous stem cell transplant (population 2).
# Cost effectiveness: population 3 (NICE technology appraisal guidance 446)
## The model structure and rates of stem cell transplant after chemotherapy and brentuximab vedotin were key model drivers
The committee noted that the evidence in the pooled dataset was uncertain and agreed that UK observation data was a more suitable source for the economic model (see section 3.16). The committee heard that the relative rate of post-chemotherapy and post-brentuximab stem cell transplants and the economic model structure were key points to consider in the assessment of cost effectiveness for this population.
## The modelled population is not generalisable to the entire population presenting in clinical practice so any results are uncertain
The ERG noted that the modelled population from the pooled brentuximab dataset represented a fitter patient group than described in the indication under consideration. Therefore, the committee considered that the results of the studies were not generalisable to the entire population presenting in clinical practice (see section 3.15). However, the committee noted that the population from the UK observational data were more reflective of patients seen in clinical practice, and agreed that although these data formed a more suitable basis for economic modelling, any conclusions about cost effectiveness based on this evidence should be treated with considerable caution.
## Estimates of overall and progression-free survival are uncertain
The committee noted from the outset that there was a lack of comparative data for this population. The company's base-case analysis compared the brentuximab vedotin single-arm studies with 4 clinical studies of chemotherapy identified from a literature search. The committee recalled that the main limitations of the brentuximab vedotin studies is that they were only generalisable to a subset of the population who would be seen in clinical practice and overall represented a fit population relatively likely to become eligible for stem cell transplant. Furthermore it heard from the ERG that the 4 chemotherapy trials identified were all single-arm studies, published between 1982 and 2000, all of which were poorly reported. The company used response rates as a surrogate for survival outcomes. The committee noted it would have preferred to have seen estimates of progression-free survival and overall survival modelling from people who would have likely become eligible for a stem cell transplant after brentuximab vedotin or after single-agent chemotherapy. It agreed this information would have helped to inform a more accurate economic model structure. It concluded that there would be a high degree of uncertainty in any estimates of relative treatment effectiveness from the presented evidence.
## The company's model is overly optimistic and the ERG's adjustments are overly pessimistic so the preferred cost-effectiveness analysis is between the 2 approaches
The committee agreed with the ERG that there was a structural flaw in the company's original economic model. This was because patients who progressed to stem cell transplant in the model could not then move back to the event-free or post-progression survival states. In consultation on the second appraisal consultation document, the company amended the economic model structure for this population to include a palliative care health state, into which patients would transition 1 year before death. The ERG disagreed with the company that this structural change corrected the underlying model flaw, because including a palliative state was not equivalent to including a post-progression survival state. The committee heard from the ERG that this flaw limited the model's ability to accurately capture the costs and benefits associated with stem cell transplant; this was particularly problematic, in a model in which a change in stem cell transplant eligibility was the key effect of brentuximab vedotin. The model locked in an overly optimistic prognosis for people having stem cell transplant, derived from utility values of non-Hodgkin lymphoma and Hodgkin lymphoma for people having autologous stem cell transplant in van Agthoven et al. (2001), rather than from an originally stem cell transplant-ineligible population. To account for this model flaw, the ERG proposed:
adjusting the utility value for patients who remain in the stem cell transplant state to 0.5 (incorporating any disutility for patients whose disease progressed after stem cell transplant)
reducing the survival rate for patients having stem cell transplant by 20%.The committee noted comments from the clinical experts who disagreed with the ERG's adjustments to account for the model flaw, stating that fewer patients would progress than the ERG had assumed when generating an average utility of 0.5. The committee agreed that the ERG utility adjustments were overly pessimistic. It concluded that the company's updated model structure did not address its concerns because it failed to accurately capture patients who progressed after stem cell transplants. It noted that, any patients transitioning in the model from a stem cell transplant state to a pre-death state should have progressed at a rate which is informed by the literature and fully described. The committee further concluded that the company's updated model was overly optimistic and that the ERG's adjustments were overly pessimistic, and agreed that its preferred cost-effectiveness analysis would lie between the 2 approaches.
## Rates of stem cell transplant after treatment are a source of uncertainty
The committee understood that the relative rate of bridging to stem cell transplant from chemotherapy or brentuximab vedotin was a key driver in the ICER calculations. It was concerned that patients in the model having brentuximab vedotin were relatively fit, but for patients having the comparator the reverse might well be true. The committee heard from clinical experts that having a complete response to treatment is a key factor influencing the decision whether to progress to stem cell transplant, and that available evidence had found more than twice as many patients achieved a complete response on brentuximab vedotin compared with single-agent chemotherapy. Brentuximab vedotin offers these patients a new route to long-term survival because they are responding to treatment for the first time. However, the committee also heard from the clinical experts that the post-chemotherapy stem cell transplant rate estimated from the literature was likely to be an underestimate; in the UK this may be as high as 28.0%, and the post-brentuximab vedotin rate could also be higher at approximately 58.0%. However, the clinical experts would expect a better outcome following a complete response which is much more likely with brentuximab vedotin. The committee noted that the ERG suggested a stem cell transplant rate of 14.3%, taken from Zinzani et al. (2000), in the calculation of its modified base case. Although the company argued that this rate was based on few data points and therefore could not be considered robust, the committee agreed that the relative difference in rates should be smaller than that used in the company's modified base case. The ERG presented a scenario analysis in which it applied a post-chemotherapy stem cell transplant rate of 35.0%, based on clinical expert opinion, although some of the clinical experts said that it was overly optimistic. The committee concluded that post-treatment stem cell transplant rates remained a source of uncertainty, and agreed that the differential in post-treatment rates applied in the economic modelling was too large.
## The committee's preferred ICER for population 3 is around £40,000 per QALY gained
The committee agreed that although the company provided revised modelling to address its concerns about patients who progressed after stem cell transplant, it concluded that there remained a high degree of uncertainty in the cost-effectiveness analysis. The committee accepted that from the scenarios provided, modelling the post-treatment stem cell transplant rates at 14.3% and 53.0%, for chemotherapy and brentuximab vedotin respectively provided the most acceptable stem cell transplant rate differential. The committee considered that, taken together, the company scenario analysis that incorporated the stem cell transplant rates above the lower limit of its preferred ICER of £28,332 per QALY gained and the ERG's modified base case (that also included these stem cell transplant rates and amended assumptions about utility and overall survival to account for the economic model flaw) would represent the upper limit (that is, £53,998 per QALY gained). The committee concluded that because of the uncertainty in the model structure, overall survival and progression-free survival following stem cell transplant, and post-treatment stem cell transplant rates, it was difficult to determine a robust cost-effectiveness estimate. It concluded that its preferred ICER for this population would likely be approximately £40,000 per QALY gained at the mid-point of the range £28,332 and £53,998 per QALY gained, and so it did not recommend brentuximab vedotin as cost effective for routine NHS use in this population.
# End-of-life considerations (NICE technology appraisal guidance 446)
## The company considered that brentuximab vedotin met the end-of-life criteria in populations 1 and 3
The committee considered the advice about life-extending treatments for people with a short life expectancy in the addendum to the NICE process and methods guides. The company made the case that brentuximab vedotin met the criteria for life-extending treatments for people with a short life expectancy for population 1 (relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant) and population 3 (relapsed or refractory CD30‑positive Hodgkin lymphoma after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option). The committee noted that at the first appraisal committee meeting, the company had not considered brentuximab vedotin to meet the criteria for life-extending treatments in population 2.
## Brentuximab vedotin does not meet the end-of-life criteria in any population
The committee discussed whether brentuximab vedotin is indicated for patients with a short life expectancy, normally less than 24 months. It noted that both the company's and ERG's modelling predicted a mean overall survival in the comparator treatment arm of more than 24 months. The committee concluded that its assessment of the short life expectancy criterion should be based on the modelled figures, and therefore this criterion did not apply for any of the 3 populations.The committee also discussed whether there was sufficient evidence to show that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The committee noted that the cost-effectiveness analyses from which the survival benefit of brentuximab vedotin could be inferred were highly uncertain. In both population 1 and population 3, the modelled extension to life surpassed 3 months. In population 1 median overall survival was 40.5 months estimated from trial data, and estimates of median overall survival in population 3 ranged from 3.9 to 4.5 months. The committee concluded that although the modelled benefits demonstrated an extension to life of over 3 months, both criteria would have to have been met for the end-of-life criteria to apply.
## Data collection through the Cancer Drugs Fund in population 3 would be beneficial to improve the accuracy of estimating transplant rates after treatment and to evaluate brentuximab vedotin against the end-of-life criteria
The committee agreed that although the short life expectancy criterion was not met for population 1, it was cost effective for routine NHS use without meeting the end-of-life criteria because the committee's preferred ICER was less than £30,000 per QALY gained. The committee agreed that population 2 did not fulfil the end-of-life criteria, and was not cost effective for routine NHS use with a committee-preferred ICER higher than £35,606 per QALY gained. For population 3, the committee agreed that the available data for life expectancy and overall survival for brentuximab vedotin were promising but it failed to meet the short life expectancy criterion. The committee-preferred ICER was approximately £40,000 per QALY. It concluded that this population would benefit from additional data collection through the Cancer Drugs Fund to improve the accuracy of estimates relating to post-treatment transplant rates; when these are available, brentuximab vedotin will be reviewed against the end-of-life criteria in this population.
# Cancer Drugs Fund considerations (NICE technology appraisal guidance 446)
## Brentuximab vedotin is recommended for use as an option within the Cancer Drugs Fund in population 3
The committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee recommended brentuximab vedotin as cost effective for routine NHS use for population 1 (adults with relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant), so it was not considered for use within the Cancer Drugs Fund. For population 2, the committee did not recommend brentuximab vedotin as cost effective for routine NHS use and therefore considered if brentuximab vedotin could be recommended within the Cancer Drugs Fund. It noted that during the second consultation the company proposed that brentuximab vedotin be considered for future use in the Cancer Drugs Fund in this population. However, it recalled that population 2 was the only population which had randomised controlled trial data, therefore limiting the need for further evidence collection and weakening the case to be considered for the Cancer Drugs Fund. The committee considered its preferred ICER did not have the plausible potential to represent cost effectiveness by the addition of new data collected through the Cancer Drugs Fund for population 2. For these reasons, the committee concluded that brentuximab vedotin should not be included in the Cancer Drugs Fund for population 2 (that is, adults with increased risk of disease relapse or progression after autologous stem cell transplant). Having concluded that it did not recommend brentuximab vedotin as cost effective for routine NHS use in population 3 (that is, adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option), the committee considered if brentuximab vedotin could be recommended within the Cancer Drugs Fund for this population. In population 3, the ICER for brentuximab vedotin was approximately £40,000 per QALY gained (between £28,332 and £53,998 per QALY gained; see section 3.29), and the committee was aware that brentuximab vedotin had already been included in the Cancer Drugs Fund for this population, and gathering more information about post-treatment stem cell transplant rates could help alleviate some of the uncertainty and allow for a more accurate estimation of cost effectiveness in this population. The committee considered that collecting data on overall and progression-free survival would also provide valuable clinical-effectiveness information for this population, but it heard that this could take a long time and would be practically difficult given the low patient numbers in this population. The committee acknowledged that data on post-treatment stem cell transplant rates collected from the drug's use through the Cancer Drugs Fund would offer further insight on the clinical effectiveness of brentuximab vedotin, and provide a robust source of evidence for an influential factor in any further decisions about its cost effectiveness in this population. The committee was aware that NICE, NHS England and the company agreed the data collection arrangements as part of the managed access agreement. The committee concluded that in population 3, brentuximab vedotin met the criteria to be considered for inclusion in the Cancer Drugs Fund, and therefore recommended it as an option for use within the Cancer Drugs Fund for adults with CD30‑positive Hodgkin lymphoma with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option when the conditions of the managed access agreement are followed.
# Cancer Drugs Fund review of technology appraisal guidance 446 for population 3
## The company's revised submission for the Cancer Drugs Fund review of population 3 includes new data and other changes
In technology appraisal guidance 446 the committee concluded that data collected through the Cancer Drugs Fund about stem cell transplant rates after brentuximab vedotin would address some uncertainty and allow for a more accurate estimation of cost effectiveness for population 3. In its revised submission for the Cancer Drugs Fund review, the company included:
data collected through the Cancer Drugs Fund on rates of stem cell transplant after brentuximab vedotin
a new lower rate of stem cell transplant after single-agent chemotherapy
different data to inform overall and progression-free survival rates after stem cell transplant
an updated economic model structure to include a new health state for patients whose disease has progressed after stem cell transplant.
# New data for the Cancer Drugs Fund review of population 3
## The data collection methods are suitable for decision making
The company's evidence on the rate of stem cell transplant after treatment with brentuximab vedotin was collected by Public Health England in a retrospective questionnaire. The questionnaire collected the rates of stem cell transplant in patients who had brentuximab vedotin through the Cancer Drugs Fund between April 2013 and March 2016. Of the 496 questionnaires sent to consultants, 436 (88%) were returned; the committee heard from the Cancer Drugs Fund clinical lead that this response rate was outstandingly high. The clinical experts stated that the data collected through the Cancer Drugs Fund were important for both clinicians and patients, and should address the uncertainties the committee raised in technology appraisal guidance 446 for population 3. The committee concluded that the data collection methods were suitable for its decision making.
Analysis
Stem cell transplant after brentuximab vedotin
Stem cell transplant after brentuximab vedotin and salvage chemotherapy
Main cohort (brentuximab with the intention of bridging to stem cell transplant)
Sensitivity analysis 1 (main cohort plus 60 patients without data)
Sensitivity analysis 2 (main cohort plus patients having brentuximab with no intention of bridging to stem cell transplant)
Sensitivity analysis 3 (main cohort plus all patients in sensitivity analyses 1 and 2)
## Sensitivity analyses 2 and 3 are most relevant to the ICER calculations
The committee was aware that the data had been stratified based on whether brentuximab vedotin was used with the intention of bridging to a stem cell transplant. The data were further divided by patients who had a stem cell transplant after brentuximab vedotin, and those who had a stem cell transplant after both brentuximab vedotin and salvage chemotherapy. The company also presented 3 sensitivity analyses. The company had included the results of sensitivity analysis 2 in its base-case analysis, because it included all patients having brentuximab vedotin (that is, regardless of the intention to bridge to a stem cell transplant) and did not include any effects of salvage chemotherapy. The ERG preferred sensitivity analysis 3, because it also accounted for the missing data of 60 patients and captured the full benefit of brentuximab vedotin (because it included all patients who had a stem cell transplant regardless of whether they had had salvage chemotherapy first). However, the clinical experts and the Cancer Drugs Fund clinical lead disagreed with including the missing patient data. The ERG considered that missing data for 60 patients was a large proportion of the total data, and that it introduced a substantial amount of uncertainty in the estimated stem cell transplant rate. The committee was aware that the economic modelling included the stem cell transplant rates from both sensitivity analyses 2 and 3, so it agreed to consider both estimates in its most plausible ICER considerations.
## The most plausible rate of stem cell transplant after a single-agent chemotherapy is 5.3%
The committee was aware that rates of stem cell transplant after a single-agent chemotherapy had not been collected as part of the Cancer Drugs Fund data collection. In NICE technology appraisal guidance 446, the company's preferred rate was 5.3% based on a pooled estimate of 3 studies; the ERG's preferred rate was 14.0% based on 1 study by Zinzani et al. (2000; see section 3.31). The committee was aware that the published studies were at least 18 years old and unlikely to reflect current clinical practice. It considered the company's clinical expert's opinion that a rate of 5.3% was clinically plausible. This was further supported by the Cancer Drugs Fund clinical lead, who explained that because relevant patients will have had at least 2 chemotherapy regimens and still have relapsed and refractory disease, any responses to single-agent treatment are modest and generally short. The ERG had included both rates (5.3% and 14.0%) in its exploratory analyses but neither had a substantial effect on the results. The committee concluded that in the absence of any robust evidence, and based on clinical expert opinion, the most plausible rate of stem cell transplant after single-agent chemotherapy is 5.3%.
## Rates of overall and progression-free survival after allogenic stem cell transplant taken from Reyal et al. are suitable for decision making
The company presented data from Reyal et al. (2016) to inform rates of overall and progression-free survival after allogenic stem cell transplant. The company explained that the data presented during the development of NICE technology appraisal guidance 446 to inform these outcomes (Sureda et al. 2001) was no longer relevant because they did not include PET-based response-adjusted transplantation strategies. The clinical experts further explained that PET scanning is the preferred method of assessing response to treatment before stem cell transplant. Sureda et al. also included patients that had previously failed an autologous stem cell transplant, which is not a relevant population for this appraisal. In its analysis, the company used a subgroup of the Reyal et al. dataset that excluded patients whose previous autologous stem cell transplant had failed. The results of this analysis were reported as commercial in confidence so cannot be reported here. However, in the full study population (in which 26% of patients had an autologous stem cell transplant that had failed), 4-year overall survival rates after stem cell transplant were 75.0% in people with a complete response and 67.3% in people with a partial response. The ERG considered the Reyal et al. subgroup to be relevant to NHS clinical practice. The committee concluded that the rates of overall and progression-free survival after allogenic stem cell transplant taken from the subgroup of Reyal et al. (that excluded patients whose previous autologous stem cell transplant had failed) were suitable for decision making.
## Rates of overall and progression-free survival after autologous stem cell transplant are less certain
The company presented data from Thomson et al. (2013) to inform overall and progression-free survival rates after autologous stem cell transplant. The ERG commented that the data were relevant to UK clinical practice because they included a PET-response-adjusted transplantation strategy. However, it was concerned with the small sample size (n=28) and noted that the data are very immature and suffer from substantial censoring, which makes any extrapolation of the data highly uncertain. Because of these limitations, the ERG preferred to use data from Reyal et al. (2016). It also commented that this would result in more conservative estimates of overall and progression-free survival. However, the clinical experts noted that patients having an allogenic stem cell transplant are not as healthy as those having autologous stem cell transplants so this assumption may not be valid. Furthermore, the clinical experts stated that the overall survival extrapolations using data from Thomson et al. were clinically plausible, and that the 2 years of overall survival after stem cell transplant would be similar to the general population. The committee acknowledged the ERG's concerns about Thomson et al., and was aware that the ERG had included the outcomes from Reyal et al. in its exploratory analyses. It therefore concluded to explore both sources of data in the economic modelling.
# Updated cost effectiveness for the Cancer Drugs Fund review of population 3
## The company's updated model and the ERG's exploratory analyses (using the company's original model) are both suitable for decision making
In technology appraisal guidance 446, the committee raised concerns about the omission of a post-stem cell transplant disease progression state in the company's original model (see section 3.30). For the Cancer Drugs Fund review, the company included this health state as well as tunnel states to correct errors it identified in the way transitions between health states had been calculated. The committee heard from the ERG that it had serious concerns with the company's use of tunnel states in the updated model: it could not properly validate the model because of the volume of code and model running time. The ERG commented that the use of tunnel states was also inappropriate, because the change in the risk of death after a stem cell transplant is accounted for in the underlying hazard of the best fitting survival curve. The committee accepted the company's reasons for updating its model. It was also aware that the company had included a sensitivity analysis using the original model. The ERG had also presented exploratory analyses using the company's original model. The committee therefore concluded to consider both the results from the company's updated model, including sensitivity analyses, and the ERG's exploratory analyses (using the company's original model) in its decision making.
## The company's base-case ICER for brentuximab vedotin is less than £17,000 per QALY gained
The committee considered the results of the company's updated economic analyses, which incorporated the same patient access scheme for brentuximab vedotin that was considered during the development of technology appraisal guidance 446. It noted that the company had included:
additional model health states for stem cell transplant after disease progression and tunnel states to correct errors in transition probability calculations (see section 3.43)
a 25% stem cell transplant rate after treatment with brentuximab vedotin from sensitivity analysis 2 of Cancer Drugs Fund data collection, and 41% in a scenario analysis (see section 3.38)
a 5.3% stem cell transplant rate after treatment with single-agent chemotherapy (see section 3.40)
data from Thomson et al. (2013) and Reyal et al. (2016) to inform overall and progression-free survival after stem cell transplant (see sections 3.41 and 3.42).The company's base-case ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population was £16,535 per QALY gained. Using a stem cell transplant rate of 41% (which includes patients who need salvage chemotherapy after brentuximab vedotin), the ICER fell to £13,503 per QALY gained.
## The ERG's exploratory ICER for brentuximab vedotin is less than £18,000 per QALY gained
The committee considered the ERG's exploratory analyses, which were based on the company's original model and included:
using a stem cell transplant rate after brentuximab vedotin of 34%, taken from sensitivity analysis 3 (see section 3.38)
using a stem cell transplant rate after single-agent chemotherapy of 5.3%, and 14.0% in a scenario analyses (see section 3.40)
using data from Reyal et al. (2016) to inform overall and progression-free survival rates after stem cell transplant (see sections 3.41 and 3.42).With these changes, the ERG's exploratory ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population was £17,885 per QALY gained. Using a stem cell transplant rate after single-agent chemotherapy of 14.0% increased the ICER to £21,339 per QALY gained.
## The most plausible ICER is between £16,000 and £18,000 per QALY gained for population 3
The committee concluded that data on stem cell transplant rates after brentuximab vedotin collected through the Cancer Drugs Fund addressed some of the uncertainty and allowed a more accurate estimation of cost effectiveness for population 3. However, the committee was aware of the limitations with both the company's models. It noted that the main driver in the model were the rates of overall and progression-free survival after stem cell transplant, and that the rate of stem cell transplant after brentuximab vedotin had only a modest effect on the results. The committee therefore considered the most plausible ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population to be between £16,535 (using data from Thomson et al. and Reyal) and £17,885 (using data from Reyal) per QALY gained. Because the ICER is within the range normally considered to be a cost-effective use of NHS resources, the committee concluded that brentuximab vedotin can be recommended for routine use to treat CD30‑positive Hodgkin lymphoma in adults with relapsed or refractory disease, after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not suitable.
# Updated end-of-life considerations for the Cancer Drugs Fund review of population 3
## Brentuximab vedotin does not meet the end-of-life criteria
The committee recalled that during the development of technology appraisal guidance 446, it agreed to review brentuximab vedotin against the end-of-life criteria in population 3 (that is, adults with relapsed or refractory disease, after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not suitable) once data collection in the Cancer Drugs Fund had ended (see section 3.32). The committee discussed whether brentuximab vedotin in this population is indicated for patients with a short life expectancy, normally less than 24 months. It noted that in technology appraisal guidance 446, both the company's and ERG's modelling predicted a mean overall survival in the comparator treatment arm of more than 24 months. For this Cancer Drugs Fund review, the modelled mean overall survival in the comparator treatment arm was more than 24 months. The committee therefore concluded that because it did not meet the short life expectancy criterion, it did not need to conclude on the life extension criterion. It agreed that brentuximab vedotin does not meet the end-of-life criteria for people with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is suitable.
|
{'Recommendations': "Brentuximab vedotin is recommended as an option for treating CD30‑positive Hodgkin lymphoma in adults with relapsed or refractory disease, only if:\n\nthey have already had autologous stem cell transplant or\n\nthey have already had at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy are not suitable and\n\nthe company provides brentuximab vedotin according to the commercial arrangement.\n\nWhy the committee made these recommendations (NICE technology appraisal guidance 446)\n\nHodgkin lymphoma is usually treated with chemotherapy, followed by stem cell transplant. Stem cell transplant gives people the best chance of a cure, so people who cannot have stem cell transplant have a high clinical unmet need. Brentuximab vedotin can be used as a 'bridging' treatment before stem cell transplant and, in some cases, as a curative treatment itself.\n\nNICE technology appraisal guidance 446 recommended brentuximab vedotin as an option for treating adults with relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant. However, it was not recommended for adults who are at increased risk of disease relapse or progression after autologous stem cell transplant because the cost-effectiveness estimates were too high.\n\nFor adults with relapsed or refractory disease after at least 2\xa0previous therapies, when autologous stem cell transplant or multi-agent chemotherapy is not suitable, the cost-effectiveness evidence was less clear. So brentuximab vedotin was recommended for use within the Cancer Drugs Fund in this population to collect data on its effectiveness in practice.\n\nWhy the committee made these recommendations (Cancer Drugs Fund review of technology appraisal guidance 446)\n\nData collected through the Cancer Drugs Fund on rates of stem cell transplant after treatment with brentuximab vedotin show that it improved rates of stem cell transplant compared with chemotherapy. Also, the updated cost-effectiveness estimates for brentuximab vedotin are lower than £20,000 per quality-adjusted life year gained. Because of this, brentuximab vedotin is recommended as an option for treating relapsed or refractory CD30‑positive Hodgkin lymphoma in adults, only if they have already had autologous stem cell transplant, or at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy are not suitable.", 'Information about brentuximab vedotin': "# Marketing authorisation indication\n\nBrentuximab vedotin (Adcetris) is indicated for treating relapsed or refractory CD30‑positive Hodgkin lymphoma in adults:\n\nafter autologous stem cell transplant or\n\nafter at least 2\xa0prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not a treatment option\n\nat increased risk of relapse or progression after autologous stem cell transplant.\n\n# Dosage in the marketing authorisation\n\nThe recommended dose is 1.8\xa0mg/kg administered by intravenous infusion over 30\xa0minutes every 3\xa0weeks.\n\n# Price\n\nThe price of brentuximab vedotin is £2,500 for a 50‑mg vial (excluding VAT; British national formulary edition 69). The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.'", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\nSections 3.1 to 3.33 reflect the committee's discussion during NICE technology appraisal 446. These sections are unchanged since the guidance was first published in June 2017.\n\nSections 3.37 to 3.47 reflect the committee's discussion during the Cancer Drugs Fund review of population\xa03 from NICE technology appraisal guidance 446.\n\n# The condition (NICE technology appraisal guidance 446)\n\n## Stem cell transplants give people the best chance of a cure for treating Hodgkin lymphoma\n\nThe committee noted that there was no NICE technology appraisal guidance on Hodgkin lymphoma. It understood that current first-line treatment is chemotherapy with or without radiotherapy. If this fails to lead to long-term remission, people may have high-dose chemotherapy, followed when possible by autologous stem cell transplant. The committee was aware that there is no standard therapy administered after autologous stem cell transplant to delay disease progression. Up to half the people who have had autologous stem cell transplant develop progressive disease with a life expectancy of less than 3\xa0years. These people may be offered further, usually single-drug, chemotherapy. People whose disease does not respond after 2\xa0previous lines of therapy would also be offered single-agent chemotherapy, but the committee was aware that these patients had a low chance of bridging to stem cell transplantation. Stem cell transplants give people the best chance of a curative treatment; so people who cannot bridge to stem cell transplantation have poor long-term survival prospects and a high clinical unmet need.\n\n## There is a high clinical unmet need for people who cannot have stem cell transplant\n\nThe committee understood that allogeneic stem cell transplant was the treatment of choice if there is a suitable donor and a good response to systemic therapy after autologous stem cell transplant has failed. The committee recognised that treatment largely depended on the person's circumstances, including their eligibility for stem cell transplant. The clinical experts advised that autologous stem cell transplant would not generally be recommended for relapsed or refractory Hodgkin lymphoma unless there was an adequate response to previous (salvage) therapy. This normally means at least a partial response, although they noted that the definition of 'adequate response' is uncertain. The committee heard from clinical experts that positron emission tomography (PET) scanning is the preferred method of assessing response to salvage therapy before autologous stem cell transplant, and that this was available in most UK transplant centres. The committee recognised that there were 2\xa0groups who may not have an autologous stem cell transplant: people who are not fit enough for treatment and those for whom salvage therapy did not produce an adequate response. The committee concluded that both of these groups would have a high clinical unmet need.\n\n## Brentuximab vedotin will mainly be used for relapsed or refractory disease after autologous stem cell transplant, or after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option\n\nThe committee considered the groups of people with CD30‑positive Hodgkin lymphoma which reflected the marketing authorisation for brentuximab vedotin. These were:\n\nadults with relapsed or refractory disease after autologous stem cell transplant (population\xa01)\n\nadults with increased risk of disease relapse or progression after autologous stem cell transplant (population\xa02)\n\nadults with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option (population\xa03).The committee heard from clinical experts that the most relevant populations in the UK were the first and third of the groups included in the marketing authorisation. The committee understood that there is currently no NICE guidance for these indications. Brentuximab vedotin is currently available through the Cancer Drugs Fund for populations\xa01 and\xa03. The UK marketing authorisation for brentuximab vedotin does not explicitly exclude retreatment as an option, but the company did not focus its submission on retreatment. Retreatment is not permitted through the Cancer Drugs Fund. Brentuximab vedotin offers the chance of a potentially curative stem cell transplant, which the clinical experts considered of great importance. The clinical experts also highlighted that in some instances brentuximab vedotin can be a curative treatment without stem cell transplant. For the second group, the committee heard from clinical experts that it was not routine practice in England to refer patients for transplant who are at increased risk of disease relapse or progression. Most clinicians would aim for PET-negative remission (that is, no signs of disease on the PET scan) before autologous stem cell transplant (see section\xa03.10). If this is achieved, the risk of subsequent relapse or progression is reduced, and the adverse effects of brentuximab vedotin would likely outweigh its benefit, which is expected to be limited in this situation. If the PET scan is positive, brentuximab vedotin could be used as for the third group (that is, as a possible bridge to autologous stem cell transplant). The committee, however, noted that although the second group does not feature much in current UK clinical practice, it should be appraised for the small subset of patients who may benefit. The committee concluded that based on current clinical practice, brentuximab vedotin would mainly be used for relapsed or refractory disease after autologous stem cell transplant, and for relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option.\n\n## Maximal response is expected after 4\xa0to 5\xa0cycles of brentuximab vedotin rather than\xa016\n\nThe committee asked whether rules for stopping treatment are used in clinical practice. It noted that, at the time of consultation, the Cancer Drugs Fund included brentuximab vedotin for the 2\xa0relapsed or refractory CD30‑positive Hodgkin lymphoma populations, administered once every 3\xa0weeks (see summary of product characteristics) on the condition that treatment is stopped if there is no partial or complete response after 6\xa0treatment cycles. The committee heard from clinical experts that, although there was no robust evidence, maximal response would be expected after 4 to 5\xa0treatment cycles. The committee noted that this was much lower than the maximum number of 16\xa0cycles recommended in the summary of product characteristics.\n\n# Clinical effectiveness (NICE technology appraisal guidance 446)\n\n## The non-randomised evidence provides an immature and limited evidence base\n\nPopulation 1 is adults with relapsed or refractory disease after autologous stem cell transplant. The committee noted that the trial evidence for this group was from SG035‑0003 (n=102); an open-label, single-arm, phase\xa02 trial. The key results were:\n\noverall response rate by independent review (primary outcome): 75% (76/102); complete response rate by independent review: 33% (34/102)\n\nmedian progression-free survival by investigators: 9.3\xa0months (95% confidence interval [CI] 7.1 to 12.2\xa0months)\n\nmedian overall survival: 40.5\xa0months.\n\n## Comparisons with historical controls are uncertain\n\nThe committee noted that the company considered the anti-tumour effect of brentuximab vedotin to compare favourably with historical controls. It was aware that such comparisons are associated with a high risk of bias, not least because they may be based on studies that had found no benefit for the controls. Also, the committee noted that the historical control data came from relatively old studies. It heard from clinical experts that the outcome of chemotherapy was likely to be better than reported in this literature, as shown by the increasing number of people who have allogeneic stem cell transplant. The committee agreed that no definite conclusions about the effect of brentuximab vedotin for this indication could be drawn from comparisons with historical controls.\n\n## The company's intra-patient comparison is a useful indication of the effect of brentuximab vedotin compared with chemotherapy\n\nThe committee discussed the company's 'intra-patient' comparison, noting that this was done in a subset of patients (57/102) with relapsed or refractory Hodgkin lymphoma who had 1\xa0or more systemic therapies other than brentuximab vedotin after autologous stem cell transplant. Median progression-free survival (assessed by investigators) after the most recent systemic therapy before brentuximab vedotin was 4.1\xa0months compared with 7.9\xa0months when these same patients then had brentuximab vedotin (hazard ratio [HR] 0.40; p<0.001). In its original submission, the company noted that because progression-free intervals are expected to shorten after each successive treatment, the effect of brentuximab vedotin can be considered clinically significant. The committee noted the ERG comment that the intra-patient comparison was only done for patients for whom systemic therapy had failed, excluding those who had a good outcome with chemotherapy. In contrast, the clinical experts considered that patients who had systemic therapies before brentuximab vedotin may be fitter and able to tolerate the adverse effects of chemotherapy. The committee acknowledged that the intra-patient comparison did not provide comparative evidence based on parallel and controlled assignment of patients to different treatment arms; nor did it compare the most effective, as opposed to the most recent, chemotherapy. Nevertheless, the committee concluded that the company's intra-patient comparison gave a useful indication of the effect of brentuximab vedotin compared with chemotherapy.\n\n## Brentuximab vedotin may be more effective than chemotherapy in population\xa01 but the evidence is uncertain\n\nThe committee noted that the company's clinical-effectiveness submission for this group came from non-randomised evidence, which provided an immature and limited evidence base (see section\xa03.5). The committee also noted that the outcomes presented included the anti-tumour effect of brentuximab vedotin measured as response rate, which is less clinically relevant than progression-free survival and overall survival. Also, the company relied on comparisons with historical controls, the validity of which is questionable. The committee appreciated that it would be difficult to do a randomised controlled trial for brentuximab vedotin in part because Hodgkin lymphoma is rare. It also heard from clinical experts that there was little published evidence for the comparator treatments, preventing a clinically relevant comparison with brentuximab vedotin. Overall the committee concluded there was a large degree of uncertainty in the clinical evidence, but noted comments from clinical experts and positive results from the intra-patient comparison which suggested that brentuximab vedotin was more effective than chemotherapy.\n\n## Clinical-effectiveness evidence for population\xa02 came from the additional data cut of the AETHERA trial\n\nPopulation 2 is adults with increased risk of disease relapse or progression after autologous stem cell transplant. The committee noted the evidence base submitted by the company came from AETHERA (n=329); a double-blind, randomised, controlled, phase\xa03 trial comparing brentuximab vedotin with placebo. The trial collected data between April 2010 and September 2012. The key results were:\n\nmedian progression-free survival assessed by independent review (primary outcome): 42.9\xa0months for brentuximab vedotin; 24.1\xa0months for placebo (HR\xa00.57, 95% CI\xa00.40 to 0.81; p=0.001)\n\nmedian progression-free survival assessed by investigators: not reached for brentuximab vedotin; 15.8\xa0months for placebo (HR\xa00.50, 95% CI\xa00.36 to 0.70)\n\noverall survival (without adjustment for treatment switching): median not reached for either treatment; HR\xa01.15 (95% CI\xa00.67 to 1.97).In response to consultation on the second appraisal consultation document, the company provided a new data cut from the AETHERA trial (ASH 2015) which it used in all of its updated cost-effectiveness analyses for this population.\n\n## The definition of patients at high risk of relapse in the trial is broader than that on which brentuximab vedotin's regulatory approval was based\n\nThe committee noted that AETHERA included patients with Hodgkin lymphoma at risk of having residual disease after autologous stem cell transplant, defined as those who have 1\xa0of the following risk factors:\n\nprimary refractory Hodgkin lymphoma (as determined by investigators)\n\nrelapsed Hodgkin lymphoma with initial remission of less than 12\xa0months\n\nextra-nodal involvement before autologous stem cell transplant.This definition was broader than the one on which brentuximab vedotin's regulatory approval was based, which defined high risk of relapse or progression as the presence of 2\xa0or more of the above risk factors. It was also different from the definition in the final scope, which included a positive PET scan before autologous stem cell transplant as a high-risk factor. In response to consultation on the second appraisal consultation document, the company created 2\xa0definitions of high-risk patients which could be applied to the trial population to identify a subgroup of patients which better reflected the committee's preferences. The committee acknowledged that clinicians considered PET scanning to be valuable in assessing the risk of relapse or progression, and agreed that any definition of high-risk patients should include a positive PET scan result. The committee's preferred patient subgroup was defined as those with a positive PET scan result before autologous stem cell transplant and at least 1\xa0of:\n\nrelapsed disease within 12\xa0months or disease refractory to front-line therapy\n\nextra-nodal disease at pre-autologous stem cell transplant relapse\n\nB symptoms at pre-autologous stem cell transplant relapse\n\nat least 2 previous salvage therapies.The company did not present any clinical data for this subset of the trial population in its response to consultation on the second appraisal consultation document. It used the updated data cut and subgroup of patients that met the high-risk definition above in its modelled cost-effectiveness analysis.\n\n## Brentuximab vedotin improves progression-free survival more than placebo in population\xa02 but the data are uncertain\n\nThe committee noted that this was the only population for which randomised controlled trial evidence was available, but that even this was compromised to fit the data to the relevant high-risk group. The committee noted that the median progression-free survival assessed by independent review (primary outcome) for the whole trial population was 42.9\xa0months for brentuximab vedotin and 24.1\xa0months for placebo (HR\xa00.57, 95% CI\xa00.40 to 0.81; p=0.001). The committee, however, accepted the company's proposed high-risk patient definition.\n\n## The clinical evidence for population\xa03 comes from non-randomised studies and is limited\n\nPopulation 3 is adults with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option. The committee noted that the original evidence presented by the company came from a group of patients who took part in phase\xa01 and\xa02 studies, a study in Japanese patients only (TB-BC010088), and a named patient programme (n=59; 41\xa0patients had the recommended dosage of brentuximab vedotin of 1.8\xa0mg/kg every 3\xa0weeks). The key results were:\n\noverall response rate: 54% (22/41); complete response rate: 22% (9/41)\n\npatients who became eligible for autologous stem cell transplant: 19% (8/41).\n\n## The company presented additional evidence in this population\n\nIn response to the first appraisal consultation document, the company provided additional clinical-effectiveness evidence for this population, from 2\xa0sources:\n\nC25007 (n=60): an ongoing phase\xa04, single-arm, open-label, multicentre study\n\na real-world UK observational study (n=78): a retrospective study including multiple centres across England.The company pooled the data from these sources to maximise the target patient population. Table\xa01 presents the results of the individual studies and the pooled dataset.\n\nOutcome\n\nC25007 study\n\n(n=60)\n\nObservational study (n=78)\n\nPooled dataset (n=138 for stem cell transplant, n=135 for response)\n\nOverall response rate (%)\n\n(complete response=15, partial response=33)\n\n(complete response=24, partial response=27)\n\n(complete response=20, partial response=30)\n\nPost-brentuximab stem cell transplant rate (%)\n\n\n\n\n\n\n\nProgression-free survival (months)\n\n\n\n(95% confidence interval 2.96 to 5.32)\n\n\n\n(95% confidence interval 4.21 to 17.05)\n\n–\n\nOverall survival\n\n% at 24\xa0months (95% confidence interval 58.0 to 84.6)\n\nmonths\n\n(95% confidence interval 17.8 to not reached)\n\n–\n\nMean number of cycles\n\n\n\n(95% confidence interval 6.5 to 8.4)\n\n\n\n(95% confidence interval 3.7 to 4.6)\n\n\n\n(95% confidence interval 5.1 to 6.2)\n\n## Patients in these studies reflected a fitter subset of the population covered in the marketing authorisation\n\nThe committee discussed whether the results from these studies were representative of adults with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option. It considered that in clinical practice, this population could be ineligible for autologous stem cell transplant or multi-agent chemotherapy either because the patient is frail, or because the response to previous treatment does not predict a favourable outcome after autologous stem cell transplant. The committee recognised that the latter group would represent fitter patients for whom brentuximab vedotin could act as a bridge to autologous stem cell transplant, and that it was this group that the pooled dataset reflected more closely. The committee heard from the clinical experts that the most likely treatment option for this population, in the absence of brentuximab vedotin, was single-agent chemotherapy (see section\xa03.1). The committee concluded that the study populations reflected only a fitter subset of the population under consideration.\n\n## The studies may be not be generalisable to UK clinical practice\n\nThe committee recognised that all the data presented, although the best available for this population, was associated with a large amount of uncertainty, as is the case with single-arm studies and retrospective evidence. The committee heard from the ERG that it had a number of concerns about the pooled studies. The first concern was the generalisability of the C25007 data to the UK population. A proportion of patients (18%) in the study only had 1\xa0previous treatment, so did not mirror the marketing authorisation for brentuximab vedotin. Also, 88% of patients in C25007 came from outside the UK, and clinical experts stated that routine clinical practice would be quite different to that of the UK. The ERG highlighted that these differences were seen in the study outcomes of mean treatment cycles and relative rates of allogeneic and autologous stem cell transplant.\n\n## The real-world UK dataset provides the most relevant evidence but any comparison in population\xa03 is uncertain\n\nThe committee noted that the company's clinical-effectiveness submission for this group came from non-randomised evidence which provided a limited evidence base (see sections\xa03.12 to\xa03.13). The committee agreed that although the clinical data in the pooled dataset provided an improved evidence base compared with that considered in the first appraisal consultation document, it was still associated with a large amount of uncertainly. The committee also agreed that the real-world UK dataset provided more relevant clinical data to estimate the clinical effectiveness of brentuximab vedotin from an NHS perspective.\n\n# Overall cost effectiveness (NICE technology appraisal guidance 446)\n\n## The cost-effectiveness analyses for populations\xa01 and\xa03 are based on clinical-effectiveness evidence that is uncertain\n\nThe committee considered the company's amended economic analyses for populations\xa01 and\xa03 and the new data cut and subgroup analyses for population\xa02, all incorporating the updated patient access scheme. It agreed that the uncertainty in the clinical evidence base would be carried over in the economic modelling for populations\xa01 and 3.\n\n# Cost effectiveness: population\xa01 (NICE technology appraisal guidance 446)\n\nFor this group the committee noted that the cost-effectiveness analysis was sensitive to the progression-free survival extrapolation approach and the mortality benefit of brentuximab vedotin compared with chemotherapy.\n\n## The company's approach to modelling progression-free survival is plausible\n\nThe committee noted that to model progression-free survival, the company used the Kaplan–Meier data from SG035‑0003 for brentuximab vedotin and data from the intra-patient comparison for chemotherapy (see sections 3.5 to 3.7). The company and the ERG extrapolated progression-free survival beyond the trial follow-up (6.08\xa0years). They assumed that both brentuximab vedotin and chemotherapy had the same effect on progression-free survival as that measured in another study (Robinson et\xa0al. 2009), in which patients had allogeneic stem cell transplant. The committee noted that the ERG estimated progression risk from the entire curve in Robinson et\xa0al. (2009), and then applied the mean risk to the extrapolation of progression-free survival. The clinical experts considered it was not appropriate to apply a risk of progression rate estimated from the mean of the entire trial period, as it would incorporate patients with a different prognosis to those who are alive at least 18\xa0months after allogeneic stem cell transplant. The committee agreed that this approach was too pessimistic because the progression-free survival extrapolation dropped too quickly at the end of the trial follow-up. In the original company submission, the company assumed that following the 6.08‑year follow-up from start of treatment, the risk of progression would be equal to that after allogeneic stem cell transplant. The committee heard from the clinical experts that the curve displayed in the company's approach to progression-free survival modelling was a plausible extrapolation of progression-free survival beyond the within trial period. The committee was persuaded that the company's approach to the extrapolation of progression-free survival was plausible and accepted this assumption in its choice of a preferred incremental cost-effectiveness ratio (ICER).\n\n## A mortality benefit of 10% is more plausible than the company's base case of 31%\n\nThe committee noted that to estimate overall survival from the model, the company compared brentuximab vedotin patients from SG035‑0003 with chemotherapy patients from an earlier study (Martinez\xa0et\xa0al. 2010, 2013). The company adjusted the Martinez\xa0et\xa0al. survival to better reflect the patient characteristics in SG035‑0003. In response to consultation on the second appraisal consultation document, the company provided 2 base-case analyses with different assumptions about mortality benefit and overall survival extrapolation. Base case\xa01 retained the 31% mortality benefit and reverted to fitting an exponential function to the overall survival data in Martinez\xa0et\xa0al. Base case\xa02 assumed a 10% mortality benefit for brentuximab vedotin and fit a lognormal function to the overall survival data in Martinez\xa0et\xa0al. The company also provided a scenario analysis in which it varied the mortality benefit of brentuximab vedotin between 10% and 40%. The committee heard from clinical experts that the 31% mortality benefit figure was possible and that brentuximab vedotin had served as a curative treatment for some people in this patient population. The committee heard from the ERG that any mortality benefit of brentuximab vedotin in the model was not based on robust evidence, but it incorporated a mortality benefit of 10% for brentuximab vedotin to reflect the committee's preferences as stated in the second appraisal committee document. The committee agreed that the company's modelled benefit of a 31% increase in survival did not reflect robust evidence, but considered that a mortality benefit of at least 10% was likely. The committee concluded that it would be reasonable to incorporate a mortality benefit of 10% for brentuximab vedotin when calculating its preferred ICER.\n\n## The company's approach to treatment dosing and stopping rule is plausible\n\nAfter consultation on the second appraisal consultation document, the company reverted to the modelling approach from its original submission while incorporating changes to the relative dose intensity for chemotherapy (equal to brentuximab vedotin; that is, 94%) and the stopping rule proposed after consultation on the first appraisal consultation document. The stopping rule applied to patients whose disease did not respond to treatment after 4\xa0or 5\xa0cycles. The committee noted that in response to consultation, both the company's base case and the ERG's modified base case estimated the cost of brentuximab vedotin in the model based on the average number of treatment cycles that patients had in SG035‑0003 (9.7\xa0cycles), which was reduced after accounting for the stopping rule (8.5\xa0cycles). The committee heard from clinical experts that people are likely to have fewer cycles than this because the maximal response to brentuximab vedotin would be expected after only 4 to 5\xa0cycles (see section\xa03.4). The committee recognised that because brentuximab vedotin is more expensive than chemotherapy, the model was highly sensitive to the drug acquisition cost of brentuximab vedotin. On balance, it considered the company's approach to dosing and the stopping rule a plausible basis for discussion.\n\n## The committee's preferred ICER for population\xa01 is within the range considered to be cost effective for routine use\n\nThe committee agreed that the company and ERG had taken similar approaches in their assessment of cost effectiveness for this population, and that it could accept either if a mortality benefit of 10% was incorporated. The committee noted that with this adjustment, using either the company approach or the ERG approach, its preferred ICER was less than £30,000\xa0per\xa0quality-adjusted life year (QALY) gained. The committee concluded that it could recommend brentuximab vedotin as cost effective for routine NHS use in this population.\n\n# Cost effectiveness: population\xa02 (NICE technology appraisal guidance 446)\n\n## The most plausible mortality benefit is somewhere between the company's and the ERG's estimates\n\nThe committee discussed the ERG's concerns about the company's overall approach to the modelling, specifically that the increase in progression-free survival with brentuximab vedotin translated into an equivalent but unproven overall survival gain. To correct this, the ERG rebuilt a partitioned survival model, assuming equal mortality in both treatment arms. The committee heard from the clinical experts that brentuximab vedotin has shown considerable gains in progression-free survival compared with best supportive care, but that overall survival data were not yet available. However, the clinical experts suggested that patients whose disease has not progressed after 2\xa0years are unlikely to relapse, and gains in progression-free survival would be a good predictor of overall survival extensions in this population. The committee agreed that assuming a 1:1 relationship between progression-free survival and overall survival was optimistic, but that it was reasonable to assume that an extension to progression-free survival would lead to some extension in overall survival. The committee concluded that the company's and ERG's assumptions could both be considered extreme, and that the mortality benefit of brentuximab vedotin was likely to lie between the 2\xa0estimates.\n\n## The company's assumptions about long-term health-related quality of life are unrealistic\n\nIn response to consultation on the second appraisal consultation document, the company updated the model to assume that 5\xa0years after starting treatment, health-related quality of life for people whose disease did not progress would move back towards the age-adjusted population norm, with a small utility decrement being applied. In the ERG's opinion, this assumption was not justified and contradicted the EQ-5D data collected from AETHERA. The committee concluded that the company's assumption about long-term health-related quality of life remained unrealistic.\n\n## The scenario analysis that incorporates costs for subsequent treatments is not appropriate\n\nIn response to consultation on the second appraisal consultation document, the company presented a scenario analysis in which subsequent treatments were included as an additional cost. The company argued that patients on brentuximab vedotin would go on to have fewer subsequent treatments than those on best supportive care, improving the cost effectiveness of brentuximab vedotin. The ERG disagreed with the inclusion of these costs on the grounds that crossover was allowed in the AETHERA trial, meaning that these patients would be unlikely to represent a relevant part of the treatment pathway in UK clinical practice. The committee agreed with the ERG and further considered it unjustified to add the costs of brentuximab vedotin to the comparator arm in the model. It concluded that subsequent therapy costs should not be included in the estimation of the most plausible ICER.\n\n## The committee's preferred ICER for population\xa02 is over £30,000 per QALY gained and does not have plausible potential to be cost effective through the Cancer Drugs Fund\n\nOverall, the committee noted that it was not currently routine practice in the NHS to refer patients for transplant who are at increased risk of disease relapse or progression. The committee recognised that the clinical data did not reflect the definition of high risk of relapse or progression adopted by the regulator, but accepted the company's subgroup analysis because it included high-risk patients defined as having a positive PET scan plus 1\xa0or more risk factors (see section\xa03.10). The committee agreed that the ERG's ICERs were generated from an overly pessimistic model which assumed no mortality benefit for brentuximab vedotin, and that the company model was more suitable for estimating its preferred ICER. However, it did not agree with the company model assumption of a 1:1 relationship between progression-free survival and overall survival, and so concluded that the company's cost-effectiveness estimates (an ICER of £35,606 per QALY gained) represented the lower limit of the committee's preferred ICER. The committee agreed that this ICER was higher than the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). It also noted a company comment in response to second consultation requesting brentuximab vedotin to be considered for future use within the Cancer Drugs Fund in this population. The committee considered that its preferred ICER of more than £35,606 per QALY gained did not indicate the plausible potential for satisfying the cost-effectiveness criteria for routine use through data collection. The committee therefore did not recommend brentuximab vedotin as cost effective for routine NHS use in adults with increased risk of disease relapse or progression after autologous stem cell transplant (population\xa02).\n\n# Cost effectiveness: population\xa03 (NICE technology appraisal guidance 446)\n\n## The model structure and rates of stem cell transplant after chemotherapy and brentuximab vedotin were key model drivers\n\nThe committee noted that the evidence in the pooled dataset was uncertain and agreed that UK observation data was a more suitable source for the economic model (see section\xa03.16). The committee heard that the relative rate of post-chemotherapy and post-brentuximab stem cell transplants and the economic model structure were key points to consider in the assessment of cost effectiveness for this population.\n\n## The modelled population is not generalisable to the entire population presenting in clinical practice so any results are uncertain\n\nThe ERG noted that the modelled population from the pooled brentuximab dataset represented a fitter patient group than described in the indication under consideration. Therefore, the committee considered that the results of the studies were not generalisable to the entire population presenting in clinical practice (see section\xa03.15). However, the committee noted that the population from the UK observational data were more reflective of patients seen in clinical practice, and agreed that although these data formed a more suitable basis for economic modelling, any conclusions about cost effectiveness based on this evidence should be treated with considerable caution.\n\n## Estimates of overall and progression-free survival are uncertain\n\nThe committee noted from the outset that there was a lack of comparative data for this population. The company's base-case analysis compared the brentuximab vedotin single-arm studies with 4\xa0clinical studies of chemotherapy identified from a literature search. The committee recalled that the main limitations of the brentuximab vedotin studies is that they were only generalisable to a subset of the population who would be seen in clinical practice and overall represented a fit population relatively likely to become eligible for stem cell transplant. Furthermore it heard from the ERG that the 4\xa0chemotherapy trials identified were all single-arm studies, published between 1982 and 2000, all of which were poorly reported. The company used response rates as a surrogate for survival outcomes. The committee noted it would have preferred to have seen estimates of progression-free survival and overall survival modelling from people who would have likely become eligible for a stem cell transplant after brentuximab vedotin or after single-agent chemotherapy. It agreed this information would have helped to inform a more accurate economic model structure. It concluded that there would be a high degree of uncertainty in any estimates of relative treatment effectiveness from the presented evidence.\n\n## The company's model is overly optimistic and the ERG's adjustments are overly pessimistic so the preferred cost-effectiveness analysis is between the 2\xa0approaches\n\nThe committee agreed with the ERG that there was a structural flaw in the company's original economic model. This was because patients who progressed to stem cell transplant in the model could not then move back to the event-free or post-progression survival states. In consultation on the second appraisal consultation document, the company amended the economic model structure for this population to include a palliative care health state, into which patients would transition 1\xa0year before death. The ERG disagreed with the company that this structural change corrected the underlying model flaw, because including a palliative state was not equivalent to including a post-progression survival state. The committee heard from the ERG that this flaw limited the model's ability to accurately capture the costs and benefits associated with stem cell transplant; this was particularly problematic, in a model in which a change in stem cell transplant eligibility was the key effect of brentuximab vedotin. The model locked in an overly optimistic prognosis for people having stem cell transplant, derived from utility values of non-Hodgkin lymphoma and Hodgkin lymphoma for people having autologous stem cell transplant in van Agthoven\xa0et\xa0al. (2001), rather than from an originally stem cell transplant-ineligible population. To account for this model flaw, the ERG proposed:\n\nadjusting the utility value for patients who remain in the stem cell transplant state to 0.5 (incorporating any disutility for patients whose disease progressed after stem cell transplant)\n\nreducing the survival rate for patients having stem cell transplant by 20%.The committee noted comments from the clinical experts who disagreed with the ERG's adjustments to account for the model flaw, stating that fewer patients would progress than the ERG had assumed when generating an average utility of 0.5. The committee agreed that the ERG utility adjustments were overly pessimistic. It concluded that the company's updated model structure did not address its concerns because it failed to accurately capture patients who progressed after stem cell transplants. It noted that, any patients transitioning in the model from a stem cell transplant state to a pre-death state should have progressed at a rate which is informed by the literature and fully described. The committee further concluded that the company's updated model was overly optimistic and that the ERG's adjustments were overly pessimistic, and agreed that its preferred cost-effectiveness analysis would lie between the 2\xa0approaches.\n\n## Rates of stem cell transplant after treatment are a source of uncertainty\n\nThe committee understood that the relative rate of bridging to stem cell transplant from chemotherapy or brentuximab vedotin was a key driver in the ICER calculations. It was concerned that patients in the model having brentuximab vedotin were relatively fit, but for patients having the comparator the reverse might well be true. The committee heard from clinical experts that having a complete response to treatment is a key factor influencing the decision whether to progress to stem cell transplant, and that available evidence had found more than twice as many patients achieved a complete response on brentuximab vedotin compared with single-agent chemotherapy. Brentuximab vedotin offers these patients a new route to long-term survival because they are responding to treatment for the first time. However, the committee also heard from the clinical experts that the post-chemotherapy stem cell transplant rate estimated from the literature was likely to be an underestimate; in the UK this may be as high as 28.0%, and the post-brentuximab vedotin rate could also be higher at approximately 58.0%. However, the clinical experts would expect a better outcome following a complete response which is much more likely with brentuximab vedotin. The committee noted that the ERG suggested a stem cell transplant rate of 14.3%, taken from Zinzani\xa0et\xa0al. (2000), in the calculation of its modified base case. Although the company argued that this rate was based on few data points and therefore could not be considered robust, the committee agreed that the relative difference in rates should be smaller than that used in the company's modified base case. The ERG presented a scenario analysis in which it applied a post-chemotherapy stem cell transplant rate of 35.0%, based on clinical expert opinion, although some of the clinical experts said that it was overly optimistic. The committee concluded that post-treatment stem cell transplant rates remained a source of uncertainty, and agreed that the differential in post-treatment rates applied in the economic modelling was too large.\n\n## The committee's preferred ICER for population\xa03 is around £40,000 per QALY gained\n\nThe committee agreed that although the company provided revised modelling to address its concerns about patients who progressed after stem cell transplant, it concluded that there remained a high degree of uncertainty in the cost-effectiveness analysis. The committee accepted that from the scenarios provided, modelling the post-treatment stem cell transplant rates at 14.3% and 53.0%, for chemotherapy and brentuximab vedotin respectively provided the most acceptable stem cell transplant rate differential. The committee considered that, taken together, the company scenario analysis that incorporated the stem cell transplant rates above the lower limit of its preferred ICER of £28,332 per QALY gained and the ERG's modified base case (that also included these stem cell transplant rates and amended assumptions about utility and overall survival to account for the economic model flaw) would represent the upper limit (that is, £53,998 per QALY gained). The committee concluded that because of the uncertainty in the model structure, overall survival and progression-free survival following stem cell transplant, and post-treatment stem cell transplant rates, it was difficult to determine a robust cost-effectiveness estimate. It concluded that its preferred ICER for this population would likely be approximately £40,000 per QALY gained at the mid-point of the range £28,332 and £53,998 per QALY gained, and so it did not recommend brentuximab vedotin as cost effective for routine NHS use in this population.\n\n# End-of-life considerations (NICE technology appraisal guidance 446)\n\n## The company considered that brentuximab vedotin met the end-of-life criteria in populations\xa01 and 3\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in the addendum to the NICE process and methods guides. The company made the case that brentuximab vedotin met the criteria for life-extending treatments for people with a short life expectancy for population\xa01 (relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant) and population\xa03 (relapsed or refractory CD30‑positive Hodgkin lymphoma after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option). The committee noted that at the first appraisal committee meeting, the company had not considered brentuximab vedotin to meet the criteria for life-extending treatments in population\xa02.\n\n## Brentuximab vedotin does not meet the end-of-life criteria in any population\n\nThe committee discussed whether brentuximab vedotin is indicated for patients with a short life expectancy, normally less than 24\xa0months. It noted that both the company's and ERG's modelling predicted a mean overall survival in the comparator treatment arm of more than 24\xa0months. The committee concluded that its assessment of the short life expectancy criterion should be based on the modelled figures, and therefore this criterion did not apply for any of the 3 populations.The committee also discussed whether there was sufficient evidence to show that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment. The committee noted that the cost-effectiveness analyses from which the survival benefit of brentuximab vedotin could be inferred were highly uncertain. In both population\xa01 and population\xa03, the modelled extension to life surpassed 3\xa0months. In population\xa01 median overall survival was 40.5\xa0months estimated from trial data, and estimates of median overall survival in population\xa03 ranged from 3.9\xa0to 4.5\xa0months. The committee concluded that although the modelled benefits demonstrated an extension to life of over 3\xa0months, both criteria would have to have been met for the end-of-life criteria to apply.\n\n## Data collection through the Cancer Drugs Fund in population\xa03 would be beneficial to improve the accuracy of estimating transplant rates after treatment and to evaluate brentuximab vedotin against the end-of-life criteria\n\nThe committee agreed that although the short life expectancy criterion was not met for population\xa01, it was cost effective for routine NHS use without meeting the end-of-life criteria because the committee's preferred ICER was less than £30,000 per QALY gained. The committee agreed that population\xa02 did not fulfil the end-of-life criteria, and was not cost effective for routine NHS use with a committee-preferred ICER higher than £35,606 per QALY gained. For population\xa03, the committee agreed that the available data for life expectancy and overall survival for brentuximab vedotin were promising but it failed to meet the short life expectancy criterion. The committee-preferred ICER was approximately £40,000 per QALY. It concluded that this population would benefit from additional data collection through the Cancer Drugs Fund to improve the accuracy of estimates relating to post-treatment transplant rates; when these are available, brentuximab vedotin will be reviewed against the end-of-life criteria in this population.\n\n# Cancer Drugs Fund considerations (NICE technology appraisal guidance 446)\n\n## Brentuximab vedotin is recommended for use as an option within the Cancer Drugs Fund in population\xa03\n\nThe committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee recommended brentuximab vedotin as cost effective for routine NHS use for population\xa01 (adults with relapsed or refractory CD30‑positive Hodgkin lymphoma after autologous stem cell transplant), so it was not considered for use within the Cancer Drugs Fund. For population\xa02, the committee did not recommend brentuximab vedotin as cost effective for routine NHS use and therefore considered if brentuximab vedotin could be recommended within the Cancer Drugs Fund. It noted that during the second consultation the company proposed that brentuximab vedotin be considered for future use in the Cancer Drugs Fund in this population. However, it recalled that population\xa02 was the only population which had randomised controlled trial data, therefore limiting the need for further evidence collection and weakening the case to be considered for the Cancer Drugs Fund. The committee considered its preferred ICER did not have the plausible potential to represent cost effectiveness by the addition of new data collected through the Cancer Drugs Fund for population\xa02. For these reasons, the committee concluded that brentuximab vedotin should not be included in the Cancer Drugs Fund for population\xa02 (that is, adults with increased risk of disease relapse or progression after autologous stem cell transplant). Having concluded that it did not recommend brentuximab vedotin as cost effective for routine NHS use in population\xa03 (that is, adults with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option), the committee considered if brentuximab vedotin could be recommended within the Cancer Drugs Fund for this population. In population\xa03, the ICER for brentuximab vedotin was approximately £40,000 per QALY gained (between £28,332 and £53,998 per QALY gained; see section\xa03.29), and the committee was aware that brentuximab vedotin had already been included in the Cancer Drugs Fund for this population, and gathering more information about post-treatment stem cell transplant rates could help alleviate some of the uncertainty and allow for a more accurate estimation of cost effectiveness in this population. The committee considered that collecting data on overall and progression-free survival would also provide valuable clinical-effectiveness information for this population, but it heard that this could take a long time and would be practically difficult given the low patient numbers in this population. The committee acknowledged that data on post-treatment stem cell transplant rates collected from the drug's use through the Cancer Drugs Fund would offer further insight on the clinical effectiveness of brentuximab vedotin, and provide a robust source of evidence for an influential factor in any further decisions about its cost effectiveness in this population. The committee was aware that NICE, NHS England and the company agreed the data collection arrangements as part of the managed access agreement. The committee concluded that in population\xa03, brentuximab vedotin met the criteria to be considered for inclusion in the Cancer Drugs Fund, and therefore recommended it as an option for use within the Cancer Drugs Fund for adults with CD30‑positive Hodgkin lymphoma with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option when the conditions of the managed access agreement are followed.\n\n# Cancer Drugs Fund review of technology appraisal guidance 446 for population\xa03\n\n## The company's revised submission for the Cancer Drugs Fund review of population\xa03 includes new data and other changes\n\nIn technology appraisal guidance 446 the committee concluded that data collected through the Cancer Drugs Fund about stem cell transplant rates after brentuximab vedotin would address some uncertainty and allow for a more accurate estimation of cost effectiveness for population\xa03. In its revised submission for the Cancer Drugs Fund review, the company included:\n\ndata collected through the Cancer Drugs Fund on rates of stem cell transplant after brentuximab vedotin\n\na new lower rate of stem cell transplant after single-agent chemotherapy\n\ndifferent data to inform overall and progression-free survival rates after stem cell transplant\n\nan updated economic model structure to include a new health state for patients whose disease has progressed after stem cell transplant.\n\n# New data for the Cancer Drugs Fund review of population\xa03\n\n## The data collection methods are suitable for decision making\n\nThe company's evidence on the rate of stem cell transplant after treatment with brentuximab vedotin was collected by Public Health England in a retrospective questionnaire. The questionnaire collected the rates of stem cell transplant in patients who had brentuximab vedotin through the Cancer Drugs Fund between April 2013 and March 2016. Of the 496 questionnaires sent to consultants, 436 (88%) were returned; the committee heard from the Cancer Drugs Fund clinical lead that this response rate was outstandingly high. The clinical experts stated that the data collected through the Cancer Drugs Fund were important for both clinicians and patients, and should address the uncertainties the committee raised in technology appraisal guidance 446 for population\xa03. The committee concluded that the data collection methods were suitable for its decision making.\n\nAnalysis\n\nStem cell transplant after brentuximab vedotin\n\n\n\nStem cell transplant after brentuximab vedotin and salvage chemotherapy\n\nMain cohort (brentuximab with the intention of bridging to stem cell transplant)\n\n/219 (36%)\n\n/219 (58%)\n\nSensitivity analysis 1 (main cohort plus 60 patients without data)\n\n/279 (28%)\n\n/279 (46%)\n\nSensitivity analysis 2 (main cohort plus patients having brentuximab with no intention of bridging to stem cell transplant)\n\n/312 (25%)\n\n/312 (41%)\n\nSensitivity analysis 3 (main cohort plus all patients in sensitivity analyses 1 and 2)\n\n/372 (21%)\n\n/372 (34%)\n\n## Sensitivity analyses 2 and 3 are most relevant to the ICER calculations\n\nThe committee was aware that the data had been stratified based on whether brentuximab vedotin was used with the intention of bridging to a stem cell transplant. The data were further divided by patients who had a stem cell transplant after brentuximab vedotin, and those who had a stem cell transplant after both brentuximab vedotin and salvage chemotherapy. The company also presented 3\xa0sensitivity analyses. The company had included the results of sensitivity analysis\xa02 in its base-case analysis, because it included all patients having brentuximab vedotin (that is, regardless of the intention to bridge to a stem cell transplant) and did not include any effects of salvage chemotherapy. The ERG preferred sensitivity analysis 3, because it also accounted for the missing data of 60\xa0patients and captured the full benefit of brentuximab vedotin (because it included all patients who had a stem cell transplant regardless of whether they had had salvage chemotherapy first). However, the clinical experts and the Cancer Drugs Fund clinical lead disagreed with including the missing patient data. The ERG considered that missing data for 60\xa0patients was a large proportion of the total data, and that it introduced a substantial amount of uncertainty in the estimated stem cell transplant rate. The committee was aware that the economic modelling included the stem cell transplant rates from both sensitivity analyses 2 and 3, so it agreed to consider both estimates in its most plausible ICER considerations.\n\n## The most plausible rate of stem cell transplant after a single-agent chemotherapy is 5.3%\n\nThe committee was aware that rates of stem cell transplant after a single-agent chemotherapy had not been collected as part of the Cancer Drugs Fund data collection. In NICE technology appraisal guidance 446, the company's preferred rate was 5.3% based on a pooled estimate of 3 studies; the ERG's preferred rate was 14.0% based on 1 study by Zinzani\xa0et\xa0al. (2000; see section\xa03.31). The committee was aware that the published studies were at least 18\xa0years old and unlikely to reflect current clinical practice. It considered the company's clinical expert's opinion that a rate of 5.3% was clinically plausible. This was further supported by the Cancer Drugs Fund clinical lead, who explained that because relevant patients will have had at least 2 chemotherapy regimens and still have relapsed and refractory disease, any responses to single-agent treatment are modest and generally short. The ERG had included both rates (5.3% and 14.0%) in its exploratory analyses but neither had a substantial effect on the results. The committee concluded that in the absence of any robust evidence, and based on clinical expert opinion, the most plausible rate of stem cell transplant after single-agent chemotherapy is 5.3%.\n\n## Rates of overall and progression-free survival after allogenic stem cell transplant taken from Reyal\xa0et\xa0al. are suitable for decision making\n\nThe company presented data from Reyal\xa0et\xa0al. (2016) to inform rates of overall and progression-free survival after allogenic stem cell transplant. The company explained that the data presented during the development of NICE technology appraisal guidance 446 to inform these outcomes (Sureda\xa0et\xa0al. 2001) was no longer relevant because they did not include PET-based response-adjusted transplantation strategies. The clinical experts further explained that PET scanning is the preferred method of assessing response to treatment before stem cell transplant. Sureda\xa0et\xa0al. also included patients that had previously failed an autologous stem cell transplant, which is not a relevant population for this appraisal. In its analysis, the company used a subgroup of the Reyal\xa0et\xa0al. dataset that excluded patients whose previous autologous stem cell transplant had failed. The results of this analysis were reported as commercial in confidence so cannot be reported here. However, in the full study population (in which 26% of patients had an autologous stem cell transplant that had failed), 4-year overall survival rates after stem cell transplant were 75.0% in people with a complete response and 67.3% in people with a partial response. The ERG considered the Reyal\xa0et\xa0al. subgroup to be relevant to NHS clinical practice. The committee concluded that the rates of overall and progression-free survival after allogenic stem cell transplant taken from the subgroup of Reyal\xa0et\xa0al. (that excluded patients whose previous autologous stem cell transplant had failed) were suitable for decision making.\n\n## Rates of overall and progression-free survival after autologous stem cell transplant are less certain\n\nThe company presented data from Thomson\xa0et\xa0al. (2013) to inform overall and progression-free survival rates after autologous stem cell transplant. The ERG commented that the data were relevant to UK clinical practice because they included a PET-response-adjusted transplantation strategy. However, it was concerned with the small sample size (n=28) and noted that the data are very immature and suffer from substantial censoring, which makes any extrapolation of the data highly uncertain. Because of these limitations, the ERG preferred to use data from Reyal\xa0et\xa0al. (2016). It also commented that this would result in more conservative estimates of overall and progression-free survival. However, the clinical experts noted that patients having an allogenic stem cell transplant are not as healthy as those having autologous stem cell transplants so this assumption may not be valid. Furthermore, the clinical experts stated that the overall survival extrapolations using data from Thomson\xa0et\xa0al. were clinically plausible, and that the 2\xa0years of overall survival after stem cell transplant would be similar to the general population. The committee acknowledged the ERG's concerns about Thomson\xa0et\xa0al., and was aware that the ERG had included the outcomes from Reyal\xa0et\xa0al. in its exploratory analyses. It therefore concluded to explore both sources of data in the economic modelling.\n\n# Updated cost effectiveness for the Cancer Drugs Fund review of population\xa03\n\n## The company's updated model and the ERG's exploratory analyses (using the company's original model) are both suitable for decision making\n\nIn technology appraisal guidance 446, the committee raised concerns about the omission of a post-stem cell transplant disease progression state in the company's original model (see section\xa03.30). For the Cancer Drugs Fund review, the company included this health state as well as tunnel states to correct errors it identified in the way transitions between health states had been calculated. The committee heard from the ERG that it had serious concerns with the company's use of tunnel states in the updated model: it could not properly validate the model because of the volume of code and model running time. The ERG commented that the use of tunnel states was also inappropriate, because the change in the risk of death after a stem cell transplant is accounted for in the underlying hazard of the best fitting survival curve. The committee accepted the company's reasons for updating its model. It was also aware that the company had included a sensitivity analysis using the original model. The ERG had also presented exploratory analyses using the company's original model. The committee therefore concluded to consider both the results from the company's updated model, including sensitivity analyses, and the ERG's exploratory analyses (using the company's original model) in its decision making.\n\n## The company's base-case ICER for brentuximab vedotin is less than £17,000 per QALY gained\n\nThe committee considered the results of the company's updated economic analyses, which incorporated the same patient access scheme for brentuximab vedotin that was considered during the development of technology appraisal guidance 446. It noted that the company had included:\n\nadditional model health states for stem cell transplant after disease progression and tunnel states to correct errors in transition probability calculations (see section\xa03.43)\n\na 25% stem cell transplant rate after treatment with brentuximab vedotin from sensitivity analysis\xa02 of Cancer Drugs Fund data collection, and 41% in a scenario analysis (see section\xa03.38)\n\na 5.3% stem cell transplant rate after treatment with single-agent chemotherapy (see section\xa03.40)\n\ndata from Thomson\xa0et\xa0al. (2013) and Reyal\xa0et\xa0al. (2016) to inform overall and progression-free survival after stem cell transplant (see sections\xa03.41 and\xa03.42).The company's base-case ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population was £16,535 per QALY gained. Using a stem cell transplant rate of 41% (which includes patients who need salvage chemotherapy after brentuximab vedotin), the ICER fell to £13,503 per QALY gained.\n\n## The ERG's exploratory ICER for brentuximab vedotin is less than £18,000 per QALY gained\n\nThe committee considered the ERG's exploratory analyses, which were based on the company's original model and included:\n\nusing a stem cell transplant rate after brentuximab vedotin of 34%, taken from sensitivity analysis\xa03 (see section\xa03.38)\n\nusing a stem cell transplant rate after single-agent chemotherapy of 5.3%, and 14.0% in a scenario analyses (see section\xa03.40)\n\nusing data from Reyal\xa0et\xa0al. (2016) to inform overall and progression-free survival rates after stem cell transplant (see sections\xa03.41 and\xa03.42).With these changes, the ERG's exploratory ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population was £17,885 per QALY gained. Using a stem cell transplant rate after single-agent chemotherapy of 14.0% increased the ICER to £21,339 per QALY gained.\n\n## The most plausible ICER is between £16,000 and £18,000 per QALY gained for population\xa03\n\nThe committee concluded that data on stem cell transplant rates after brentuximab vedotin collected through the Cancer Drugs Fund addressed some of the uncertainty and allowed a more accurate estimation of cost effectiveness for population\xa03. However, the committee was aware of the limitations with both the company's models. It noted that the main driver in the model were the rates of overall and progression-free survival after stem cell transplant, and that the rate of stem cell transplant after brentuximab vedotin had only a modest effect on the results. The committee therefore considered the most plausible ICER for brentuximab vedotin compared with single-agent chemotherapy in the relevant population to be between £16,535 (using data from Thomson\xa0et\xa0al. and Reyal) and £17,885 (using data from Reyal) per QALY gained. Because the ICER is within the range normally considered to be a cost-effective use of NHS resources, the committee concluded that brentuximab vedotin can be recommended for routine use to treat CD30‑positive Hodgkin lymphoma in adults with relapsed or refractory disease, after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not suitable.\n\n# Updated end-of-life considerations for the Cancer Drugs Fund review of population\xa03\n\n## Brentuximab vedotin does not meet the end-of-life criteria\n\nThe committee recalled that during the development of technology appraisal guidance 446, it agreed to review brentuximab vedotin against the end-of-life criteria in population\xa03 (that is, adults with relapsed or refractory disease, after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not suitable) once data collection in the Cancer Drugs Fund had ended (see section\xa03.32). The committee discussed whether brentuximab vedotin in this population is indicated for patients with a short life expectancy, normally less than 24\xa0months. It noted that in technology appraisal guidance 446, both the company's and ERG's modelling predicted a mean overall survival in the comparator treatment arm of more than 24\xa0months. For this Cancer Drugs Fund review, the modelled mean overall survival in the comparator treatment arm was more than 24\xa0months. The committee therefore concluded that because it did not meet the short life expectancy criterion, it did not need to conclude on the life extension criterion. It agreed that brentuximab vedotin does not meet the end-of-life criteria for people with relapsed or refractory disease after at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is suitable."}
|
https://www.nice.org.uk/guidance/ta524
|
Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating CD30-positive Hodgkin lymphoma in adults.
|
9c43149c20be700fae98d0e00f508d01c61d8204
|
nice
|
Atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy
|
Atezolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy
Evidence-based recommendations on atezolizumab (Tecentriq) for previously treated locally advanced or metastatic urothelial carcinoma in adults.
# Recommendations
Atezolizumab is recommended as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, only if:
atezolizumab is stopped at 2 years of uninterrupted treatment or earlier if the disease progresses and
the company provides atezolizumab with the discount agreed in the patient access scheme.
This recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
These recommendations only cover people with locally advanced or metastatic urothelial carcinoma who have had platinum-containing chemotherapy. There is separate guidance on atezolizumab for untreated disease for people who cannot have cisplatin.
Treatment options for people whose disease has progressed after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care.
Evidence from 2 clinical trials, one of which compares atezolizumab directly with chemotherapy, suggests that atezolizumab is an effective treatment. According to clinical experts, the trial results compare favourably with their experience of current treatments for the disease.
Atezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life.
Although there are uncertainties in the economic model, the most plausible cost-effectiveness estimates for atezolizumab compared with taxanes are within the range NICE considers an acceptable use of NHS resources. Therefore, atezolizumab can be recommended as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.# Information about atezolizumab
Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) has a marketing authorisation for 'the treatment of adult patients with locally advanced or metastatic urothelial carcinoma after prior platinum-containing chemotherapy or who are considered cisplatin ineligible'.
Dosage in the marketing authorisation
,200 mg by intravenous infusion every 3 weeks.
Price
A 1,200 mg vial costs £3,807.69 excluding VAT (company submission).
The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. This guidance only includes recommendations on atezolizumab for urothelial carcinoma after platinum-containing chemotherapy; there is separate guidance on atezolizumab for untreated disease when cisplatin-containing chemotherapy is unsuitable.
# The condition
## Metastatic urothelial carcinoma substantially decreases quality of life
Urothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial effect on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and places people at a greater risk of infection. The committee was aware that many people with locally advanced or metastatic urothelial carcinoma are older and may have comorbidities, which can affect treatment decisions. The committee recognised that locally advanced or metastatic urothelial carcinoma has a substantial effect on quality of life.
# Current treatments
## There is unmet need for effective treatment options
Treatment options for people whose disease has progressed after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care. The clinical experts explained that none of the current treatments offer lasting benefit and the prognosis is poor. The patient experts explained that the side effects of chemotherapy can have a major negative effect on quality of life and regular hospital visits for treatment disrupt usual activities. The clinical experts noted that there have been no new treatments for locally advanced or metastatic urothelial carcinoma for a number of years and that, unlike for other cancers, there is no targeted or personalised treatment after platinum-containing chemotherapy. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial carcinoma.
# Comparators
## The comparison with taxanes is sufficient for decision-making, but the committee would have liked to see a comparison with best supportive care
The company submitted analyses comparing atezolizumab with taxanes (docetaxel and paclitaxel). The committee understood that docetaxel and paclitaxel are considered to be similarly effective and represent the standard of care in the NHS. It concluded that the comparison with taxanes was adequate for decision-making in this appraisal. The committee recalled that best supportive care is included as a comparator in the NICE scope. It would have preferred to also see a comparison with best supportive care, but acknowledged that a lack of data would have made this difficult.
# Clinical evidence
## Atezolizumab is an effective treatment option
The company's clinical effectiveness evidence for atezolizumab came from 2 sources:
IMvigor 210, a phase 2, single-arm trial that included 310 patients whose disease progressed after at least 1 platinum-containing chemotherapy regimen (cohort 2).
IMvigor 211, a phase 3, open-label trial that included 931 patients randomised to atezolizumab or chemotherapy (docetaxel, paclitaxel or vinflunine).The objective response rate in IMvigor 210 was 15.8% at 20 months (95% confidence interval 11.9 to 20.4) and median overall survival was 7.9 months (95% CI 6.7 to 9.3) for atezolizumab. The clinical experts explained that the response rates and overall survival data from IMvigor 210 match their clinical experience with atezolizumab; some people whose disease initially responds well to treatment sustain a lasting response. Moreover, people whose disease responds to treatment can have a good quality of life and some patients survive for a significant period of time. The clinical experts noted that this was something they had not seen with chemotherapy and as such atezolizumab represents a major change in clinical practice. The primary outcome of IMvigor 211 was overall survival in the group with the highest level of PD-L1 expression (5% or more, n=234). In this group, median overall survival was not statistically significantly higher with atezolizumab (11.1 months) than with chemotherapy (10.6 months, hazard ratio 0.87; 95% CI 0.63 to 1.21). The company argued that because overall survival was longer than expected in the comparator arm, not enough patients were included in the analysis to be able to detect whether the difference was statistically significant. Median overall survival for the overall population was 8.6 months with atezolizumab and 8.0 months with chemotherapy, resulting in a similar hazard ratio, 0.85 (95% CI 0.73 to 0.99). The company argued that because the overall population is larger (n=931) this analysis has more power to detect whether the difference is statistically significant, and so these results are more meaningful. However, the committee was concerned that because the overall survival Kaplan‒Meier curves cross, the hazards are unlikely to be proportional and so the hazard ratios may not adequately represent the effectiveness of atezolizumab. Median progression-free survival for the overall population was shorter with atezolizumab than with chemotherapy (2.1 months compared with 4.0 months), but the duration of response was longer. The committee accepted that the evidence from the overall population was relevant for decision-making, and concluded that atezolizumab is an effective treatment option compared with chemotherapy.
## The comparison with taxanes in IMvigor 211 is relevant for decision-making
The company also presented evidence from IMvigor 211 according to whether the patients in the comparator arm had vinflunine (n=242) or taxanes (docetaxel or paclitaxel, n=214). The company stated that because vinflunine is not used in the NHS and is not a comparator in the scope for this appraisal, exploratory analyses comparing atezolizumab with taxanes are more relevant than analyses including vinflunine. In this comparison, median overall survival was 8.3 months with atezolizumab and 7.5 months with taxanes, resulting in a hazard ratio of 0.73 (95% CI 0.58 to 0.92). Progression-free survival was shorter with atezolizumab (2.1 months) than with taxanes (3.7 months). The committee noted that the overall survival hazard ratio is lower when the comparison does not include patients taking vinflunine. The committee was again concerned that the hazard ratios may not adequately represent the effectiveness of atezolizumab, because the overall survival Kaplan–Meier curves cross (see section 3.4). The committee concluded that the comparison with taxanes was relevant to decision-making.
# Adverse events
## Atezolizumab is well tolerated in clinical practice
Fewer patients in the atezolizumab arm of IMvigor 211 had grade 3 or 4 treatment-related adverse events than in the comparator arm (20% compared with 43%) or stopped treatment because of adverse events (7% compared with 18%). The clinical experts explained that in their experience of using atezolizumab, it is well tolerated and associated with fewer severe adverse events than chemotherapy. The committee understood that atezolizumab is still associated with some unpleasant and potentially serious adverse events, but it heard from the clinical experts that they are actively working on ways to identify and manage the adverse events of immunotherapies. The committee concluded that atezolizumab is a well-tolerated treatment option.
# Assumptions used in the economic model
## The taxane progression-free survival data are mature and do not need to be extrapolated
The company used the Kaplan–Meier curves for progression-free survival and extrapolated the tails using a generalised gamma distribution from the point when 10% of patients had disease that had not progressed. The ERG explained that the company's choice of distribution was appropriate, but because almost all patients in the taxane arm (99.5%) had progressed disease by the end of the trial, the Kaplan–Meier curve alone could be used, effectively without extrapolation. The committee agreed that because the taxane progression-free survival data are mature, there was no need to extrapolate the tail of the Kaplan–Meier curve. The committee noted that this has a marginal effect on the cost-effectiveness results.
## Kaplan–Meier curves for overall survival extrapolated with a log-logistic distribution produce more plausible estimates for taxanes
The company used a generalised gamma distribution to model overall survival for atezolizumab and the taxanes in its base case, because it had the best statistical fit to the observed data. It also presented scenario analyses using alternative parametric distributions. The ERG noted that the company's base-case approach predicted that at 5 years, 0.4% of patients in the taxane arm would be alive. However, the committee recalled that it had heard from clinical experts that about 2 to 3% of people taking taxanes would be alive at 5 years. The ERG suggested an alternative approach, using the Kaplan–Meier curves with the tails extrapolated from the point when 20% of patients are still alive, using a log-logistic distribution for both atezolizumab and the taxanes. The log-logistic distribution had a similar statistical fit to the taxane data as the generalised gamma distribution, but this approach predicted that 2.4% of people in the taxane arm would be alive at 5 years. The committee considered that this was more in line with what clinicians would expect. For atezolizumab, the ERG's curve had a similar visual fit to the company's base-case choice of generalised gamma distribution and predicted a similar proportion of people alive at 5 years (7.3% compared with 7.6% in the company's base case). The committee noted that the choice of distribution had a large effect on the cost-effectiveness results, and each of the company's scenario analyses increased the incremental cost-effectiveness ratio (ICER). It concluded that modelling overall survival using Kaplan–Meier curves with the tails extrapolated with a log-logistic distribution (the ERG's approach) was more appropriate than the company's approach, because it produced more plausible estimates for the taxanes.
## The log-logistic distribution should be used to extrapolate atezolizumab time to treatment discontinuation, because it fits the data best
The company extrapolated time to treatment discontinuation because some people were still taking atezolizumab at the end of the trial. It used the Kaplan–Meier curves with the tails extrapolated using a generalised gamma distribution. This distribution fitted the taxane data best, but was the second-best fit to the atezolizumab data, for which the log-logistic distribution was the best fit. The company argued that it was inappropriate to use the log-logistic distribution, because for the atezolizumab arm, the resulting extrapolation curve meets the extrapolated overall survival curve at 13 years, which is not plausible. The ERG presented an alternative approach. It noted that nearly all of the patients in the taxane arm had stopped treatment by the end of the trial, so it used the taxane Kaplan–Meier data alone, effectively without extrapolating the tail. For atezolizumab, it extrapolated the tail of the Kaplan–Meier curve using the log-logistic distribution, because it fitted the data best. The extrapolated atezolizumab time to treatment discontinuation curve and overall survival curve did not meet or cross when the log-logistic distribution was used for both (the committee's preferred approach to extrapolating overall survival used the log-logistic distribution, see section 3.8). The committee noted that the choice of extrapolation for atezolizumab time to treatment discontinuation had a large effect on the cost-effectiveness results. This is because more people remain on treatment in later years when the log-logistic distribution is used than when the generalised gamma is used (4% at year 5 compared with 1.2%) and this increases costs. The committee considered that 4% of patients could plausibly still be having atezolizumab at year 5. This is because some tumours have a very long response to atezolizumab and people can remain on treatment as long as there is clinical benefit. The committee concluded that the ERG's approach to extrapolating time to treatment discontinuation was more appropriate.
# Duration of treatment
## Some people will continue to take atezolizumab when their disease progresses
In the IMvigor 210 and IMvigor 211 trials, patients continued to take atezolizumab until unmanageable toxicity or lack of clinical efficacy. This means that some people continued to take atezolizumab after their disease progressed. The committee was concerned that there was no standard definition of loss of clinical efficacy. The clinical experts explained that the symptoms associated with locally advanced or metastatic urothelial carcinoma can be very unpleasant, so it is possible to use the severity of a person's symptoms, alongside radiological scans and blood tests, to assess whether the drug is benefitting them despite their disease progression. The committee concluded that some people who have had previous chemotherapy and for whom atezolizumab remains beneficial would continue treatment after their disease progresses.
# Stopping rule
## The committee prefers a 2-year stopping rule in the model
The committee understood that for other immunotherapies in the same class as atezolizumab, consideration has been given to stopping treatment after a defined period of time (a 'stopping rule'). In its additional evidence, the company included a 2‑year treatment stopping rule in its revised economic analysis. The committee noted that the evidence for atezolizumab and its summary of product characteristics did not include a stopping rule. The company considered that there is a lack of clinical evidence to show that imposing a stopping rule is of benefit to patients in the long term. However, the committee recognised that in previous NICE technology appraisals clinicians have highlighted growing concern about using immunotherapies beyond 2 years. The Cancer Drugs Fund clinical lead clarified that a 2-year stopping rule is acceptable to both patients and clinicians, and would be implementable. The committee also recognised that NICE guidance for other immunotherapies for metastatic urothelial carcinoma and other cancers include 2-year stopping rules. The committee concluded that it is appropriate to include a 2-year stopping rule in the economic model.
## A lifetime treatment effect for atezolizumab after stopping is implausible
The committee noted that, in previous technology appraisals, it has been highlighted that atezolizumab's mechanism of action suggests its effects would continue after treatment stopped. However, there was limited evidence to support this. It understood that the duration of any continued treatment effect was uncertain and is an area of ongoing research. Alongside the analyses including a stopping rule, the company provided scenario analyses in which the treatment effect for atezolizumab was capped at 3 or 5 years after stopping atezolizumab. It highlighted that this was consistent with committees' considerations in other technology appraisals of immunotherapies which have included a stopping rule. The committee agreed that it was implausible that the treatment effect for atezolizumab would continue life long after stopping treatment. It acknowledged that previous guidance took into account analyses using a 3-year treatment effect cap after stopping treatment, but noted that there was not enough evidence to support a specific duration of benefit. It concluded that, although the duration of continued treatment effect after stopping atezolizumab remains uncertain, a lifetime treatment effect is implausible. The committee agreed that it should take into account in its decision-making the analysis including a treatment effect cap at 3 years after stopping.
# Cost-effectiveness estimates
## The company's updated analyses include the committee's preferred assumptions
The company's base-case ICER using the list price for atezolizumab (excluding the 2-year stopping rule and capped duration of treatment effect) was £100,844 per quality-adjusted life year (QALY) gained compared with the taxanes, but the ERG's ICER was £154,282 per QALY gained. The company agreed a confidential patient access scheme discount with the Department of Health and Social Care and the committee considered analyses incorporating the discount. However, the results of these analyses cannot be reported here because they are considered confidential by the company. The committee considered that its preferred assumptions were:
taxane progression-free survival based on the Kaplan–Meier curve alone (see section 3.7)
-verall survival based on the Kaplan–Meier curves with the tails extrapolated from the point when 20% of patients are still alive, using the log-logistic distribution (see section 3.8)
duration of atezolizumab treatment based on the Kaplan–Meier curve with the tail extrapolated using the log-logistic distribution (see section 3.9)
applying a 2-year stopping rule (see section 3.11).The committee also took into account the analyses assuming that the effects of atezolizumab last for up to 3 or 5 years after stopping treatment (see section 3.12). In response to consultation, the company did not challenge the committee's preferred assumptions about extrapolating progression-free survival and time to treatment discontinuation. However, it argued that the committee's preferred approach to extrapolating overall survival disregards the IMvigor 211 data and relies only on expert validation of predicted survival at 5 years; the generalised gamma distribution used in the company's base case is more appropriate. The committee reiterated that the company's approach underestimates 5-year survival for people taking taxanes but the ERG's approach produces plausible estimates for both the taxanes and atezolizumab (see section 3.8). It also noted that the company had highlighted that if overall survival and time to treatment discontinuation are extrapolated with a generalised gamma and log-logistic distribution respectively (the approach implied in the company's consultation response), the atezolizumab curves meet, which is implausible (see section 3.9). The committee considered that the company's updated analyses including a 2-year stopping rule reflected its preferred assumptions, and noted the effect on the ICER of the 3-year cap on the duration of treatment effect after stopping. The most plausible ICER, including the patient access scheme discount and the committee's preferred assumptions, was confidential so cannot be reported here.
# PD-L1 subgroups
## The committee cannot make recommendations for subgroups based on PD‑L1 expression because no substantial differences in survival were identified and cost-effectiveness analyses were not provided
The committee was aware that atezolizumab works by inhibiting the PD-L1 protein and that for other immunotherapies with similar mechanisms of action greater effectiveness was reported in patients with higher levels of PD-L1 expression. The committee considered that it was therefore possible that atezolizumab might be more cost effective for some groups. The company presented clinical results from IMvigor 210 and 211 based on different PD-L1 expression levels. These showed that the objective response rate was higher for patients with higher levels of PD-L1 expression. However, the committee could not identify substantial differences in progression-free or overall survival based on PD-L1 expression. It noted that the company had not provided cost-effectiveness analyses based on PD-L1 subgroup data. The committee was unable to make recommendations for any subgroups based on PD-L1 expression.
# End of life
## Atezolizumab meets the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. Data from the company's and the ERG's models showed that mean overall survival is much less than 24 months (around 12 months) for people having treatment with taxanes. The clinical experts also agreed that they would expect people with locally advanced or metastatic urothelial carcinoma to live for less than 24 months. Both the company's and the ERG's models predict that atezolizumab extends life by a mean of around 8 months compared with taxanes. The committee concluded that atezolizumab meets the end-of-life criteria.
# Conclusion
## Atezolizumab is cost effective for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy
The committee concluded that the most plausible ICER with the patient access scheme was within the range considered cost effective for end-of-life treatments. It recommended atezolizumab for routine use in the NHS for people with previously treated locally advanced or metastatic urothelial carcinoma who have had platinum-containing chemotherapy, only if atezolizumab is stopped at 2 years (or earlier if the disease progresses).
# Other factors
No equality issues were identified.
The company did not highlight any additional benefits that had not been captured in the QALY.
|
{'Recommendations': "Atezolizumab is recommended as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, only if:\n\natezolizumab is stopped at 2\xa0years of uninterrupted treatment or earlier if the disease progresses and\n\nthe company provides atezolizumab with the discount agreed in the patient access scheme.\n\nThis recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThese recommendations only cover people with locally advanced or metastatic urothelial carcinoma who have had platinum-containing chemotherapy. There is separate guidance on atezolizumab for untreated disease for people who cannot have cisplatin.\n\nTreatment options for people whose disease has progressed after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care.\n\nEvidence from 2\xa0clinical trials, one of which compares atezolizumab directly with chemotherapy, suggests that atezolizumab is an effective treatment. According to clinical experts, the trial results compare favourably with their experience of current treatments for the disease.\n\nAtezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life.\n\nAlthough there are uncertainties in the economic model, the most plausible cost-effectiveness estimates for atezolizumab compared with taxanes are within the range NICE considers an acceptable use of NHS resources. Therefore, atezolizumab can be recommended as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy.", 'Information about atezolizumab': "Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) has a marketing authorisation for 'the treatment of adult patients with locally advanced or metastatic urothelial carcinoma after prior platinum-containing chemotherapy or who are considered cisplatin ineligible'.\n\nDosage in the marketing authorisation\n\n,200\xa0mg by intravenous infusion every 3\xa0weeks.\n\nPrice\n\nA 1,200\xa0mg vial costs £3,807.69 excluding VAT (company submission).\n\nThe company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. This guidance only includes recommendations on atezolizumab for urothelial carcinoma after platinum-containing chemotherapy; there is separate guidance on atezolizumab for untreated disease when cisplatin-containing chemotherapy is unsuitable.\n\n# The condition\n\n## Metastatic urothelial carcinoma substantially decreases quality of life\n\nUrothelial carcinoma causes a number of symptoms, including haematuria (blood in the urine) and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial effect on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as fatigue, nausea and vomiting and places people at a greater risk of infection. The committee was aware that many people with locally advanced or metastatic urothelial carcinoma are older and may have comorbidities, which can affect treatment decisions. The committee recognised that locally advanced or metastatic urothelial carcinoma has a substantial effect on quality of life.\n\n# Current treatments\n\n## There is unmet need for effective treatment options\n\nTreatment options for people whose disease has progressed after platinum-containing chemotherapy include docetaxel, paclitaxel or best supportive care. The clinical experts explained that none of the current treatments offer lasting benefit and the prognosis is poor. The patient experts explained that the side effects of chemotherapy can have a major negative effect on quality of life and regular hospital visits for treatment disrupt usual activities. The clinical experts noted that there have been no new treatments for locally advanced or metastatic urothelial carcinoma for a number of years and that, unlike for other cancers, there is no targeted or personalised treatment after platinum-containing chemotherapy. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial carcinoma.\n\n# Comparators\n\n## The comparison with taxanes is sufficient for decision-making, but the committee would have liked to see a comparison with best supportive care\n\nThe company submitted analyses comparing atezolizumab with taxanes (docetaxel and paclitaxel). The committee understood that docetaxel and paclitaxel are considered to be similarly effective and represent the standard of care in the NHS. It concluded that the comparison with taxanes was adequate for decision-making in this appraisal. The committee recalled that best supportive care is included as a comparator in the NICE scope. It would have preferred to also see a comparison with best supportive care, but acknowledged that a lack of data would have made this difficult.\n\n# Clinical evidence\n\n## Atezolizumab is an effective treatment option\n\nThe company's clinical effectiveness evidence for atezolizumab came from 2\xa0sources:\n\nIMvigor\xa0210, a phase\xa02, single-arm trial that included 310\xa0patients whose disease progressed after at least 1\xa0platinum-containing chemotherapy regimen (cohort\xa02).\n\nIMvigor\xa0211, a phase\xa03, open-label trial that included 931\xa0patients randomised to atezolizumab or chemotherapy (docetaxel, paclitaxel or vinflunine).The objective response rate in IMvigor\xa0210 was 15.8% at 20\xa0months (95% confidence interval [CI] 11.9 to 20.4) and median overall survival was 7.9\xa0months (95% CI 6.7 to 9.3) for atezolizumab. The clinical experts explained that the response rates and overall survival data from IMvigor\xa0210 match their clinical experience with atezolizumab; some people whose disease initially responds well to treatment sustain a lasting response. Moreover, people whose disease responds to treatment can have a good quality of life and some patients survive for a significant period of time. The clinical experts noted that this was something they had not seen with chemotherapy and as such atezolizumab represents a major change in clinical practice. The primary outcome of IMvigor\xa0211 was overall survival in the group with the highest level of PD-L1 expression (5% or more, n=234). In this group, median overall survival was not statistically significantly higher with atezolizumab (11.1\xa0months) than with chemotherapy (10.6\xa0months, hazard ratio 0.87; 95% CI 0.63 to 1.21). The company argued that because overall survival was longer than expected in the comparator arm, not enough patients were included in the analysis to be able to detect whether the difference was statistically significant. Median overall survival for the overall population was 8.6\xa0months with atezolizumab and 8.0\xa0months with chemotherapy, resulting in a similar hazard ratio, 0.85 (95% CI 0.73 to 0.99). The company argued that because the overall population is larger (n=931) this analysis has more power to detect whether the difference is statistically significant, and so these results are more meaningful. However, the committee was concerned that because the overall survival Kaplan‒Meier curves cross, the hazards are unlikely to be proportional and so the hazard ratios may not adequately represent the effectiveness of atezolizumab. Median progression-free survival for the overall population was shorter with atezolizumab than with chemotherapy (2.1\xa0months compared with 4.0\xa0months), but the duration of response was longer. The committee accepted that the evidence from the overall population was relevant for decision-making, and concluded that atezolizumab is an effective treatment option compared with chemotherapy.\n\n## The comparison with taxanes in IMvigor\xa0211 is relevant for decision-making\n\nThe company also presented evidence from IMvigor\xa0211 according to whether the patients in the comparator arm had vinflunine (n=242) or taxanes (docetaxel or paclitaxel, n=214). The company stated that because vinflunine is not used in the NHS and is not a comparator in the scope for this appraisal, exploratory analyses comparing atezolizumab with taxanes are more relevant than analyses including vinflunine. In this comparison, median overall survival was 8.3\xa0months with atezolizumab and 7.5\xa0months with taxanes, resulting in a hazard ratio of 0.73 (95% CI 0.58 to 0.92). Progression-free survival was shorter with atezolizumab (2.1\xa0months) than with taxanes (3.7\xa0months). The committee noted that the overall survival hazard ratio is lower when the comparison does not include patients taking vinflunine. The committee was again concerned that the hazard ratios may not adequately represent the effectiveness of atezolizumab, because the overall survival Kaplan–Meier curves cross (see section\xa03.4). The committee concluded that the comparison with taxanes was relevant to decision-making.\n\n# Adverse events\n\n## Atezolizumab is well tolerated in clinical practice\n\nFewer patients in the atezolizumab arm of IMvigor\xa0211 had grade 3\xa0or\xa04 treatment-related adverse events than in the comparator arm (20% compared with 43%) or stopped treatment because of adverse events (7% compared with 18%). The clinical experts explained that in their experience of using atezolizumab, it is well tolerated and associated with fewer severe adverse events than chemotherapy. The committee understood that atezolizumab is still associated with some unpleasant and potentially serious adverse events, but it heard from the clinical experts that they are actively working on ways to identify and manage the adverse events of immunotherapies. The committee concluded that atezolizumab is a well-tolerated treatment option.\n\n# Assumptions used in the economic model\n\n## The taxane progression-free survival data are mature and do not need to be extrapolated\n\nThe company used the Kaplan–Meier curves for progression-free survival and extrapolated the tails using a generalised gamma distribution from the point when 10% of patients had disease that had not progressed. The ERG explained that the company's choice of distribution was appropriate, but because almost all patients in the taxane arm (99.5%) had progressed disease by the end of the trial, the Kaplan–Meier curve alone could be used, effectively without extrapolation. The committee agreed that because the taxane progression-free survival data are mature, there was no need to extrapolate the tail of the Kaplan–Meier curve. The committee noted that this has a marginal effect on the cost-effectiveness results.\n\n## Kaplan–Meier curves for overall survival extrapolated with a log-logistic distribution produce more plausible estimates for taxanes\n\nThe company used a generalised gamma distribution to model overall survival for atezolizumab and the taxanes in its base case, because it had the best statistical fit to the observed data. It also presented scenario analyses using alternative parametric distributions. The ERG noted that the company's base-case approach predicted that at 5\xa0years, 0.4% of patients in the taxane arm would be alive. However, the committee recalled that it had heard from clinical experts that about 2 to 3% of people taking taxanes would be alive at 5\xa0years. The ERG suggested an alternative approach, using the Kaplan–Meier curves with the tails extrapolated from the point when 20% of patients are still alive, using a log-logistic distribution for both atezolizumab and the taxanes. The log-logistic distribution had a similar statistical fit to the taxane data as the generalised gamma distribution, but this approach predicted that 2.4% of people in the taxane arm would be alive at 5\xa0years. The committee considered that this was more in line with what clinicians would expect. For atezolizumab, the ERG's curve had a similar visual fit to the company's base-case choice of generalised gamma distribution and predicted a similar proportion of people alive at 5\xa0years (7.3% compared with 7.6% in the company's base case). The committee noted that the choice of distribution had a large effect on the cost-effectiveness results, and each of the company's scenario analyses increased the incremental cost-effectiveness ratio (ICER). It concluded that modelling overall survival using Kaplan–Meier curves with the tails extrapolated with a log-logistic distribution (the ERG's approach) was more appropriate than the company's approach, because it produced more plausible estimates for the taxanes.\n\n## The log-logistic distribution should be used to extrapolate atezolizumab time to treatment discontinuation, because it fits the data best\n\nThe company extrapolated time to treatment discontinuation because some people were still taking atezolizumab at the end of the trial. It used the Kaplan–Meier curves with the tails extrapolated using a generalised gamma distribution. This distribution fitted the taxane data best, but was the second-best fit to the atezolizumab data, for which the log-logistic distribution was the best fit. The company argued that it was inappropriate to use the log-logistic distribution, because for the atezolizumab arm, the resulting extrapolation curve meets the extrapolated overall survival curve at 13\xa0years, which is not plausible. The ERG presented an alternative approach. It noted that nearly all of the patients in the taxane arm had stopped treatment by the end of the trial, so it used the taxane Kaplan–Meier data alone, effectively without extrapolating the tail. For atezolizumab, it extrapolated the tail of the Kaplan–Meier curve using the log-logistic distribution, because it fitted the data best. The extrapolated atezolizumab time to treatment discontinuation curve and overall survival curve did not meet or cross when the log-logistic distribution was used for both (the committee's preferred approach to extrapolating overall survival used the log-logistic distribution, see section\xa03.8). The committee noted that the choice of extrapolation for atezolizumab time to treatment discontinuation had a large effect on the cost-effectiveness results. This is because more people remain on treatment in later years when the log-logistic distribution is used than when the generalised gamma is used (4% at year\xa05 compared with 1.2%) and this increases costs. The committee considered that 4% of patients could plausibly still be having atezolizumab at year\xa05. This is because some tumours have a very long response to atezolizumab and people can remain on treatment as long as there is clinical benefit. The committee concluded that the ERG's approach to extrapolating time to treatment discontinuation was more appropriate.\n\n# Duration of treatment\n\n## Some people will continue to take atezolizumab when their disease progresses\n\nIn the IMvigor\xa0210 and IMvigor\xa0211 trials, patients continued to take atezolizumab until unmanageable toxicity or lack of clinical efficacy. This means that some people continued to take atezolizumab after their disease progressed. The committee was concerned that there was no standard definition of loss of clinical efficacy. The clinical experts explained that the symptoms associated with locally advanced or metastatic urothelial carcinoma can be very unpleasant, so it is possible to use the severity of a person's symptoms, alongside radiological scans and blood tests, to assess whether the drug is benefitting them despite their disease progression. The committee concluded that some people who have had previous chemotherapy and for whom atezolizumab remains beneficial would continue treatment after their disease progresses.\n\n# Stopping rule\n\n## The committee prefers a 2-year stopping rule in the model\n\nThe committee understood that for other immunotherapies in the same class as atezolizumab, consideration has been given to stopping treatment after a defined period of time (a 'stopping rule'). In its additional evidence, the company included a 2‑year treatment stopping rule in its revised economic analysis. The committee noted that the evidence for atezolizumab and its summary of product characteristics did not include a stopping rule. The company considered that there is a lack of clinical evidence to show that imposing a stopping rule is of benefit to patients in the long term. However, the committee recognised that in previous NICE technology appraisals clinicians have highlighted growing concern about using immunotherapies beyond 2\xa0years. The Cancer Drugs Fund clinical lead clarified that a 2-year stopping rule is acceptable to both patients and clinicians, and would be implementable. The committee also recognised that NICE guidance for other immunotherapies for metastatic urothelial carcinoma and other cancers include 2-year stopping rules. The committee concluded that it is appropriate to include a 2-year stopping rule in the economic model.\n\n## A lifetime treatment effect for atezolizumab after stopping is implausible\n\nThe committee noted that, in previous technology appraisals, it has been highlighted that atezolizumab's mechanism of action suggests its effects would continue after treatment stopped. However, there was limited evidence to support this. It understood that the duration of any continued treatment effect was uncertain and is an area of ongoing research. Alongside the analyses including a stopping rule, the company provided scenario analyses in which the treatment effect for atezolizumab was capped at 3 or 5\xa0years after stopping atezolizumab. It highlighted that this was consistent with committees' considerations in other technology appraisals of immunotherapies which have included a stopping rule. The committee agreed that it was implausible that the treatment effect for atezolizumab would continue life long after stopping treatment. It acknowledged that previous guidance took into account analyses using a 3-year treatment effect cap after stopping treatment, but noted that there was not enough evidence to support a specific duration of benefit. It concluded that, although the duration of continued treatment effect after stopping atezolizumab remains uncertain, a lifetime treatment effect is implausible. The committee agreed that it should take into account in its decision-making the analysis including a treatment effect cap at 3\xa0years after stopping.\n\n# Cost-effectiveness estimates\n\n## The company's updated analyses include the committee's preferred assumptions\n\nThe company's base-case ICER using the list price for atezolizumab (excluding the 2-year stopping rule and capped duration of treatment effect) was £100,844 per quality-adjusted life year (QALY) gained compared with the taxanes, but the ERG's ICER was £154,282 per QALY gained. The company agreed a confidential patient access scheme discount with the Department of Health and Social Care and the committee considered analyses incorporating the discount. However, the results of these analyses cannot be reported here because they are considered confidential by the company. The committee considered that its preferred assumptions were:\n\ntaxane progression-free survival based on the Kaplan–Meier curve alone (see section\xa03.7)\n\noverall survival based on the Kaplan–Meier curves with the tails extrapolated from the point when 20% of patients are still alive, using the log-logistic distribution (see section\xa03.8)\n\nduration of atezolizumab treatment based on the Kaplan–Meier curve with the tail extrapolated using the log-logistic distribution (see section\xa03.9)\n\napplying a 2-year stopping rule (see section\xa03.11).The committee also took into account the analyses assuming that the effects of atezolizumab last for up to 3 or 5\xa0years after stopping treatment (see section\xa03.12). In response to consultation, the company did not challenge the committee's preferred assumptions about extrapolating progression-free survival and time to treatment discontinuation. However, it argued that the committee's preferred approach to extrapolating overall survival disregards the IMvigor\xa0211 data and relies only on expert validation of predicted survival at 5\xa0years; the generalised gamma distribution used in the company's base case is more appropriate. The committee reiterated that the company's approach underestimates 5-year survival for people taking taxanes but the ERG's approach produces plausible estimates for both the taxanes and atezolizumab (see section\xa03.8). It also noted that the company had highlighted that if overall survival and time to treatment discontinuation are extrapolated with a generalised gamma and log-logistic distribution respectively (the approach implied in the company's consultation response), the atezolizumab curves meet, which is implausible (see section\xa03.9). The committee considered that the company's updated analyses including a 2-year stopping rule reflected its preferred assumptions, and noted the effect on the ICER of the 3-year cap on the duration of treatment effect after stopping. The most plausible ICER, including the patient access scheme discount and the committee's preferred assumptions, was confidential so cannot be reported here.\n\n# PD-L1 subgroups\n\n## The committee cannot make recommendations for subgroups based on PD‑L1 expression because no substantial differences in survival were identified and cost-effectiveness analyses were not provided\n\nThe committee was aware that atezolizumab works by inhibiting the PD-L1 protein and that for other immunotherapies with similar mechanisms of action greater effectiveness was reported in patients with higher levels of PD-L1 expression. The committee considered that it was therefore possible that atezolizumab might be more cost effective for some groups. The company presented clinical results from IMvigor\xa0210 and\xa0211 based on different PD-L1 expression levels. These showed that the objective response rate was higher for patients with higher levels of PD-L1 expression. However, the committee could not identify substantial differences in progression-free or overall survival based on PD-L1 expression. It noted that the company had not provided cost-effectiveness analyses based on PD-L1 subgroup data. The committee was unable to make recommendations for any subgroups based on PD-L1 expression.\n\n# End of life\n\n## Atezolizumab meets the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. Data from the company's and the ERG's models showed that mean overall survival is much less than 24\xa0months (around 12\xa0months) for people having treatment with taxanes. The clinical experts also agreed that they would expect people with locally advanced or metastatic urothelial carcinoma to live for less than 24\xa0months. Both the company's and the ERG's models predict that atezolizumab extends life by a mean of around 8\xa0months compared with taxanes. The committee concluded that atezolizumab meets the end-of-life criteria.\n\n# Conclusion\n\n## Atezolizumab is cost effective for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy\n\nThe committee concluded that the most plausible ICER with the patient access scheme was within the range considered cost effective for end-of-life treatments. It recommended atezolizumab for routine use in the NHS for people with previously treated locally advanced or metastatic urothelial carcinoma who have had platinum-containing chemotherapy, only if atezolizumab is stopped at 2\xa0years (or earlier if the disease progresses).\n\n# Other factors\n\nNo equality issues were identified.\n\nThe company did not highlight any additional benefits that had not been captured in the QALY."}
|
https://www.nice.org.uk/guidance/ta525
|
Evidence-based recommendations on atezolizumab (Tecentriq) for previously treated locally advanced or metastatic urothelial carcinoma in adults.
|
0dace7eee5a40bfd250173ec80f611edf4d79f49
|
nice
|
Cancer of the upper aerodigestive tract: assessment and management in people aged 16 and over
|
Cancer of the upper aerodigestive tract: assessment and management in people aged 16 and over
This guideline covers assessing and managing cancers of the upper aerodigestive tract in people aged 16 and over. These are cancers of the airways of the head and neck, including the mouth, throat, larynx (voicebox) and sinuses. It aims to reduce variation in practice and improve survival.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Stages of upper aerodigestive tract cancer
The stages of upper aerodigestive tract cancer referred to in this guideline are based on the TNM classification 7th Edition:
T0: this means there is no primary tumour, but there may be abnormal cells that are precancerous.
T1 to T4: this refers to the increasing size and/or extent of the primary tumour, with 1 being smallest and 4 largest.
N0: no lymph nodes contain cancer cells.
N1 and upwards: increasing involvement of lymph nodes by cancer cells.
# Information and support
## Information needs
For people with cancer of the upper aerodigestive tract and their carers:
provide consistent information and support at diagnosis
review their needs throughout the care pathway including at the end of treatment
tailor information and support to the person's needs (including the benefits and side effects of treatment, psychosocial and long‑term functional issues).
Give people contact details for their allocated key worker, in line with NICE's cancer service guidance on improving outcomes in head and neck cancer and recommendations of the National Peer Review Programme.
Give people details of peer support services that can help them throughout their care pathway.
Offer information about human papillomavirus (HPV) to people with HPV‑related cancer of the upper aerodigestive tract.
## Smoking cessation
Inform patients and carers at the point of diagnosis about how continuing to smoke adversely affects outcomes such as:
treatment‑related side effects
risk of recurrence
risk of second primary cancers.
Offer help to people to stop smoking, in line with NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence.
# Investigation
## Assessment of neck lumps
Consider adding ultrasound‑guidance to fine‑needle aspiration cytology or core biopsy for people with a neck lump that is suspected of being cancer of the upper aerodigestive tract.
Consider having a cytopathologist or biomedical scientist assess the cytology sample adequacy when the procedure is carried out.
## Identifying the occult primary
Consider a fluorodeoxyglucose positron emission tomography (FDG PET)‑CT scan as the first investigation to detect the primary site in people with metastatic nodal squamous cell carcinoma of unknown origin that is thought to arise from the upper aerodigestive tract.
Consider using narrow‑band imaging endoscopy to identify a possible primary site when it has not been possible to do so using FDG PET‑CT.
Offer a biopsy to confirm a possible primary site.
Offer surgical diagnostic assessment if FDG PET‑CT does not identify a possible primary site. This may include:
guided biopsies
tonsillectomy
tongue base mucosectomy.
Consider an MRI or CT scan before diagnostic surgery to help with radiotherapy treatment planning.
## Clinical staging – who and how?
Offer systemic staging (see recommendations 1.2.9–1.2.11) to all people with cancer of the upper aerodigestive tract except those with T1N0 or T2N0 disease.
Offer FDG PET‑CT to people with T4 cancer of the hypopharynx or nasopharynx.
Offer FDG PET‑CT to people with N3 cancer of the upper aerodigestive tract.
Offer conventional imaging (for example, chest CT) to people with cancer of the upper aerodigestive tract who require systemic staging (see recommendation 1.2.8) but FDG PET‑CT is not indicated for them.
# Treatment of early stage disease
## Squamous cell carcinoma of the larynx
Offer transoral laser microsurgery to people with newly‑diagnosed T1a squamous cell carcinoma of the glottic larynx.
Offer a choice of transoral laser microsurgery or radiotherapy to people with newly‑diagnosed T1b–T2 squamous cell carcinoma of the glottic larynx.
Offer a choice of transoral surgery or radiotherapy to people with newly‑diagnosed T1–T2 squamous cell carcinoma of the supraglottic larynx.
## Management of the N0 neck in T1–2 squamous cell carcinoma of the oral cavity
Offer surgical management of the neck to all people with early oral cavity cancer (T1–T2, N0).
Offer sentinel lymph node biopsy instead of elective neck dissection to people with early oral cavity cancer (T1–T2, N0), unless they need cervical access at the same time (for example, free‑flap reconstruction).
## Squamous cell carcinoma of the oropharynx (T1–2, N0)
Offer people the choice of transoral surgical resection or primary radiotherapy for T1–2 N0 tumours of the oropharynx.
Consider postoperative radiotherapy, with or without concomitant chemotherapy, for T1–2 N0 tumours of the oropharynx if pathologically adverse risk factors have been identified.
# Treatment of advanced disease
## Squamous cell carcinoma of the larynx
Offer people with T3 squamous cell carcinoma of the larynx a choice of:
radiotherapy with concomitant chemotherapy or
surgery with adjuvant radiotherapy, with or without concomitant chemotherapy.
Discuss the following with people with T3 squamous cell carcinoma of the larynx and their carers, to inform their choice of treatment:
the potential advantages of laryngeal preservation
the risk of needing salvage laryngectomy (and its associated complications)
the benefits of primary surgery in people with existing compromised swallowing and airway function
likely voice and swallowing function after treatment (including the need for a long‑term feeding tube).
For people with T4a squamous cell carcinoma of the larynx consider surgery with adjuvant radiotherapy, with or without concomitant chemotherapy.
## Squamous cell carcinoma of the hypopharynx
Offer larynx‑preserving treatment to people with locally‑advanced squamous cell carcinoma of the hypopharynx if radiation and neo‑adjuvant and/or concomitant chemotherapy would be suitable for them and they do not have:
tumour‑related dysphagia needing a feeding tube
a compromised airway
recurrent aspiration pneumonias.
Offer radiotherapy with neo‑adjuvant and/or concomitant chemotherapy if larynx‑preserving treatment is suitable for the person.
Offer primary surgery followed by adjuvant radiotherapy to people if chemotherapy is not a suitable treatment for them.
Offer adjuvant radiotherapy to people having surgery as their primary treatment. Add concomitant chemotherapy if appropriate.
## Palliation of breathing difficulties
Identify people at risk of airways obstruction for whom intervention is appropriate. Think about:
their performance status
treatment side effects and length of hospital stay
involving the palliative care team and other specialists when appropriate.
Consider endoluminal debulking in preference to tracheostomy.
Establish a management plan if surgical intervention is not appropriate, in conjunction with the person, carers and clinical staff.
Assess and treat other causes of breathlessness in people with incurable upper aerodigestive tract cancer.
## Genomic biomarker-based treatment
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.
# Response assessment after chemoradiotherapy
Offer FDG PET-CT to guide management for people treated with radical chemoradiotherapy who have:
an oropharyngeal primary cancer site and
-r more positive nodes in the neck, all of which are less than 6 cm across. The term 'radical chemoradiotherapy' refers to treatment aiming to cure cancer rather than to relieve symptoms (palliative treatment). It is used here to reflect the evidence that these recommendations are based on.
Consider FDG PET-CT to guide management for people treated with radical chemoradiotherapy who have:
an oropharyngeal primary site with 1 positive node in the neck that is less than 6 cm across or
an oropharyngeal primary site with 1 or more positive nodes larger than 6 cm across in the neck or
a hypopharyngeal or laryngeal primary site with 1 or more positive nodes in the neck.
For people having an FDG PET-CT scan after chemoradiotherapy, perform the scan 3 to 6 months after chemoradiotherapy has finished.
Do not offer neck dissection to people with no abnormal FDG uptake or residual soft tissue mass on an FDG PET-CT scan.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on response assessment after chemoradiotherapy .
Full details of the evidence and the committee's discussion are in evidence review A: evidence reviews for treatment of advanced disease
Loading. Please wait.
# HPV‑related disease
## HPV testing
Test all squamous cell carcinomas of the oropharynx using p16 immunohistochemistry. Regard the p16 test result as positive only if there is strong nuclear and cytoplasmic staining in more than 70% of tumour cells.
Consider high‑risk HPV DNA or RNA in‑situ hybridisation in all p16‑positive cancers of the oropharynx to confirm HPV status.
## De‑intensification of treatment
Do not offer de‑intensification of curative treatment to people with HPV‑positive cancer of the oropharynx, unless it is part of a clinical trial.
# Less common upper aerodigestive tract cancers
## Carcinoma of the nasopharynx
Offer intensity‑modulated radiation therapy with concomitant chemotherapy to people with locally‑advanced (stage II and above) nasopharyngeal cancer.
Consider adjuvant or neo‑adjuvant chemotherapy for people with locally‑advanced (stage II and above) nasopharyngeal cancer.
## Carcinoma of the paranasal sinuses
Offer surgery as the first treatment for carcinoma of the paranasal sinuses if complete resection is possible.
Consider radiotherapy with or without concomitant chemotherapy before planned surgical resection of the paranasal sinuses if complete resection is not initially possible.
## Unknown primary of presumed upper aerodigestive tract origin
Offer people with squamous cell carcinoma in the cervical lymph nodes with an unknown primary the choice of:
neck dissection and adjuvant radiation with or without chemotherapy or
primary radiation with or without chemotherapy, with surgery for persistent disease.
Consider no further treatment as an option in people with pN1 disease without extracapsular spread after neck dissection.
Consider including potential primary tumour sites when selecting the volume to be treated with radiotherapy.
## Mucosal melanoma
Consider surgery and adjuvant radiotherapy for people with newly‑diagnosed upper aerodigestive tract mucosal melanoma without systemic metastases.
## Genomic biomarker-based treatment
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.
# Optimising rehabilitation and function
## Enteral nutrition support
Assess people's need for enteral nutrition at diagnosis, including prophylactic tube placement. The multidisciplinary team should take into account:
performance status and social factors
nutritional status (weight loss, high or low BMI, ability to meet estimated nutritional needs)
tumour stage
tumour site
pre‑existing dysphagia
impact of planned treatment (such as radiation treatment volume and dose‑fractionation, concomitant chemotherapy, and extent and site of surgery).
Follow the recommendations in NICE's guideline on nutrition support for adults for people aged 18 years and over.
## Speech and language therapy interventions
Consider swallowing‑exercise programmes for people having radiotherapy.
Consider mouth‑opening exercises for people having radiotherapy who are at risk of reduced mouth opening.
Consider voice therapy for people whose voice has changed because of their treatment.
## Shoulder rehabilitation
Consider progressive resistance training for people with impaired shoulder function, as soon as possible after neck dissection.
# Follow‑up of people with cancer of the upper aerodigestive tract and management of osteoradionecrosis
## Follow‑up
Ensure people with cancer of the upper aerodigestive tract and their carers have tailored information about the symptoms of recurrence and late effects of treatment at the end of curative therapy.
Consider structured, risk‑adapted follow‑up using locally‑agreed protocols for people who have had curative treatment for cancer of the upper aerodigestive tract. Use the follow‑up protocols to:
help improve quality of life, including discussing psychosocial issues
detect disease recurrence or second primary cancer, possibly including narrow‑band imaging to improve detection.
## Management of osteoradionecrosis
Consider surgery to remove necrotic bone and to establish soft tissue coverage in people with osteoradionecrosis.
Only consider hyperbaric oxygen therapy or medical management for treating osteoradionecrosis as part of a clinical trial. # Recommendations for research
The 2016 guideline committee made the following recommendations for research, marked . The guideline committee's full set of research recommendations is detailed in the full version of the guideline. As part of the 2018 update, the standing committee further research recommendations, marked . Full details of these can be found in evidence review A.
# Indeterminate FDG PET-CT after radical chemoradiotherapy: long-term outcomes
What are the long-term outcomes for people with an indeterminate fluorodeoxyglucose positron emission tomography (FDG PET)-CT scan result (a residual mass with no abnormal FDG uptake) after radical chemoradiotherapy?
## Why this is important
People with indeterminate FDG PET-CT results receive neck dissection surgery according to current practice in the UK. However, there is no standardised practice on long-term follow-up for people with negative disease and persistent nodes on FDG PET-CT scan. Research to investigate long-term outcomes could improve clinical outcomes and efficient use of resources. Randomised controlled trials or prospective cohort studies would be used to answer this research question. Outcomes of interest include recurrence rates, overall survival, quality of life, surgical complications, and adverse events.
# Indeterminate FDG PET-CT after radical chemoradiotherapy: investigations
What are the most appropriate investigations for people with an indeterminate FDG PET-CT scan result (a residual mass with no abnormal FDG uptakes) after radical chemoradiotherapy?
## Why this is important
People with indeterminate FDG PET-CT results receive neck dissection surgery according to current practice in the UK. However, there is no standardised practice on long-term follow-up for people with negative disease and persistent nodes on FDG PET-CT scan. Research to investigate appropriate investigations could improve clinical outcomes and efficient use of resources. Randomised controlled trials or prospective cohort studies would be used to answer this research question. Investigations include interval FDG PET-CT, ultrasound with or without biopsy, multi-parametric MRI, and serial imaging.
# Management of nodal metastasis in nasopharynx cancer after chemoradiotherapy
What is the optimal management strategy of nodal metastasis in nasopharynx cancer after chemoradiotherapy?
## Why this is important
There is evidence that FDG PET-CT is cost-saving, prevents unnecessary surgeries and reduces recurrence and overall mortality compared with neck dissection surgery in people who have received chemoradiotherapy. However, the evidence is only for people with oropharyngeal, laryngeal and hypopharyngeal cancer and there is no evidence on people with nasopharynx cancer. Natural history and response to treatment of cervical nodal metastases from nasopharynx primary sites are different, in terms of their impact on prognosis (TNM 7 cancer staging manual), and nasopharynx cancer is highly sensitive to radiotherapy and should not be treated by neck dissection (PET-NECK NIHR report). Research to investigate the optimal management of nodal metastasis in people with primary nasopharynx cancer after chemoradiotherapy could improve clinical outcomes and the use of resources. Outcomes of interest include recurrence rates, overall survival, quality of life, surgical complications, and adverse events.
# Effectiveness of FDG PET-CT to guide follow-up
What is the effectiveness and cost-effectiveness of using FDG PET-CT to guide follow-up after treatment for people with head and neck cancer?
## Why this is important
There is evidence that FDG PET-CT is cost-saving, prevents unnecessary surgeries and has similar results for recurrence and overall mortality compared with neck dissection surgery in people with oropharyngeal, laryngeal and hypopharyngeal cancer who have received chemoradiotherapy. However, there is no evidence on FDG PET-CT for follow-up after other head and neck cancer treatments. Research to investigate the effectiveness of FDG PET-CT to guide follow-up could improve clinical outcomes and the use of resources. Outcomes of interest include recurrence rates, overall survival, and quality of life.
# Systemic imaging – who and why?
What factors determine the risk of a person presenting with cancer of the upper aerodigestive tract having metastasis or a second primary cancer?
## Why this is important
Outcomes of interest include prevalence, predictive value and how the abnormalities identified influence patient management. The presence of metastasis or a synchronous second primary cancer at presentation is rare in patients with cancer of the upper aerodigestive tract. Subgroups of patients have been identified in whom the risk is clearly elevated. However, it is not clear at which level of risk detailed staging investigations are justified and the impact the results of these would have on decision making by the clinicians and the patient. Health economic modelling is needed to inform this process.
# HPV testing
What is the comparative effectiveness of single‑step laboratory diagnostic tests to identify human papillomavirus (HPV) against current diagnostic test algorithms and reference standards in people with cancer of the oropharynx?
## Why this is important
Outcomes of interest are sensitivity, specificity and resource use. HPV testing is currently recommended in cancer of the oropharynx because it has significant prognostic implication. Current methods use a 2‑step procedure that is not widely available in all treatment centres. A single‑step test is likely to be more widely adopted and could have significant budgetary implications for the NHS. The study should also consider the prognostic value and the economic benefits of novel tests.
# Unknown primary of presumed upper aerodigestive tract origin
In people with cancer of the upper aerodigestive tract of unknown primary, can radiotherapy target volumes be selected based on clinical and pathological factors?
## Why this is important
Outcomes of interest include local control, progression‑free survival, overall survival, and treatment‑related morbidity and mortality. In a very small percentage of patients with squamous carcinoma involving a cervical lymph node the primary site remains occult despite intensive investigations. The optimum treatment for these patients is uncertain. Some clinical teams will treat the neck disease alone and others will treat some or all potential primary sites with the radiotherapy with or without chemotherapy. The latter strategy is associated with a high level of side effects that may have lifelong consequences, for example xerostomia. A better understanding of the clinic‑pathological factors associated with treatment outcomes would improve treatment selection with the potential to reduce these side effects.
# Enteral nutrition support
What specific clinical and non‑clinical factors allow risk stratification when selecting which people with cancer of the upper aerodigestive tract would benefit from short‑ or long‑term enteral nutrition?
## Why this is important
Outcomes of interest include resource use, morbidity of tube placement, duration of enteral feeding and nutritional status. There are no nationally agreed selection criteria for the type of feeding tube placed at diagnosis for people who need enteral nutrition support during curative treatment. Variation across the UK exists as a result of clinician‑led practices and local policy. The systematic review by NICE in 2015 found some evidence but no specific list was identified because of limitations with study design, and inability to stratify clinical and non‑clinical factors meaningfully. These factors included restricted populations for tumour staging, patient demographics, treatment plan and intent, definitions of malnutrition, timing and method of tube placement, and duration of enteral nutrition.
# Follow‑up
What is the optimal method, frequency and duration of follow‑up for people who are disease‑free after treatment for cancer of the upper aerodigestive tract?
## Why this is important
Outcomes of interest include quality of life, local control and overall survival. The optimal methods, frequency, and duration of follow‑up in people who are clinically disease‑free and who have undergone treatment for squamous cell cancer of the upper aerodigestive tract with curative intent are not known. Considerable resources are expended throughout the country on the follow‑up of people who have completed potentially curative treatment. Local follow‑up protocols are based more on historical practice than evidence and are often disease‑ rather than patient‑centred. Research to investigate how and when follow‑up should optimally be carried out could improve clinical outcomes and the use of resources. # Rationale and impact
# Response assessment after chemoradiotherapy
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
Overall, the evidence showed that recurrence rates and overall mortality for fluorodeoxyglucose positron emission tomography (FDG PET)-CT-guided management after radical chemoradiotherapy were similar to those for neck dissection. In addition, the evidence showed that FDG PET-CT was cost-saving compared with neck dissection, and would prevent unnecessary surgeries, surgical complications, and adverse events.
The committee agreed to make recommendations only for people with oropharyngeal, laryngeal and hypopharyngeal primary sites, because these were the main focus of the evidence. Most of the people in the study had an oropharyngeal primary site and more than 1 positive node under 6 cm across in the neck, and the evidence was strongest for this population. Therefore, the committee agreed that they should be offered an FDG PET-CT scan.
The evidence was weaker for people with:
an oropharyngeal primary site and 'N2a' stage disease (only 1 positive node of more than 3 cm but no more than 6 cm across)
an oropharyngeal primary site and higher 'N' stage disease (1 or more positive node larger than 6 cm across in the neck)
laryngeal or hypopharyngeal primary sites.
To reflect this, FDG PET-CT scanning could be considered for these groups.
The evidence did not include people with an oropharyngeal primary site and 'N1' stage disease (only 1 positive node of less than 3 cm across). However, the committee agreed that it is particularly important that FDG PET-CT scans are considered for this population to avoid unnecessary surgery. These people are likely to be at a lower risk of recurrence and so the benefits of neck dissection are lower.
The committee noted that new classifications for head and neck cancer (TNM classification of malignant tumours, 8th edition) have been introduced, which are different from those used in the evidence. They decided to describe the stage of cancer for these recommendations in terms of the number and size of positive nodes to avoid confusion.
The timing of FDG PET-CT scans (3 to 6 months after completion of radical chemoradiotherapy) is in line with current Royal College of Radiologists guidelines on the use of PET-CT. Scans earlier than 3 months are more likely to give a false-positive result, due to the residual effects of treatment.
The committee decided to be specific that neck dissection should not be offered to people with no abnormal FDG uptake or residual soft tissue mass, to give clear advice about how to interpret a 'negative' FDG PET-CT result.
The committee noted several areas in which future research would be helpful, such as management for people with indeterminate test results (see research recommendations 1 and 2), the role of FDG PET-CT for people with nasopharyngeal cancer (see research recommendation 3) and the effectiveness of FDG PET-CT to guide follow-up (see research recommendation 4).
## How the recommendations might affect practice
There may an increase in the number of FDG PET-CT scans performed and a reduction in surgical procedures. However, the evidence showed that the amount of money saved from unnecessary surgery is likely to be considerably higher than the cost of the additional scans.
Full details of the evidence and the committee's discussion are in evidence review A: evidence reviews for treatment of advanced disease.# Context
Upper aerodigestive tract cancers are found at various sites in the airways of the head and neck: the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx and nasal sinuses. The majority are squamous cell cancers. The major risk factors for upper aerodigestive tract squamous cell cancer in the UK are tobacco smoking and alcohol consumption.
There is currently variation or uncertainty in the investigations used to assess neck lumps; who needs systemic staging, the most effective treatment for early stage and advanced disease, how to best identify HPV‑positive disease, how to optimise function and rehabilitation, the most effective follow‑up and the management of osteoradionecrosis of the jaw. This guideline aims to make recommendations that address these areas of variation or uncertainty.
This guideline will cover adults and young people (16 years and older):
referred from primary care with suspected cancer of the upper aerodigestive tract
with newly‑diagnosed or recurrent cancer of the upper aerodigestive tract.
It will not cover:
adults and young people with cancers of the thyroid, orbit, middle ear, cutaneous lip, skull base or salivary gland
adults and young people with sarcoma or lymphoma
children and young people under 16 years.
Since publication, new evidence was identified on the use of fluorodeoxyglucose positron emission tomography (FDG PET)-CT scanning to inform decisions about surgery for nodal metastases after radical chemoradiotherapy. This less invasive approach to management has the potential to reduce unnecessary surgery for people with locally advanced head and neck cancer. In 2018 we reviewed this evidence and added new recommendations.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nStages of upper aerodigestive tract cancer\n\nThe stages of upper aerodigestive tract cancer referred to in this guideline are based on the TNM classification 7th Edition:\n\nT0: this means there is no primary tumour, but there may be abnormal cells that are precancerous.\n\nT1 to T4: this refers to the increasing size and/or extent of the primary tumour, with 1 being smallest and 4 largest.\n\nN0: no lymph nodes contain cancer cells.\n\nN1 and upwards: increasing involvement of lymph nodes by cancer cells.\n\n# Information and support\n\n## Information needs\n\nFor people with cancer of the upper aerodigestive tract and their carers:\n\nprovide consistent information and support at diagnosis\n\nreview their needs throughout the care pathway including at the end of treatment\n\ntailor information and support to the person's needs (including the benefits and side effects of treatment, psychosocial and long‑term functional issues). \n\nGive people contact details for their allocated key worker, in line with NICE's cancer service guidance on improving outcomes in head and neck cancer and recommendations of the National Peer Review Programme. \n\nGive people details of peer support services that can help them throughout their care pathway. \n\nOffer information about human papillomavirus (HPV) to people with HPV‑related cancer of the upper aerodigestive tract. \n\n## Smoking cessation\n\nInform patients and carers at the point of diagnosis about how continuing to smoke adversely affects outcomes such as:\n\ntreatment‑related side effects\n\nrisk of recurrence\n\nrisk of second primary cancers. \n\nOffer help to people to stop smoking, in line with NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence. \n\n# Investigation\n\n## Assessment of neck lumps\n\nConsider adding ultrasound‑guidance to fine‑needle aspiration cytology or core biopsy for people with a neck lump that is suspected of being cancer of the upper aerodigestive tract. \n\nConsider having a cytopathologist or biomedical scientist assess the cytology sample adequacy when the procedure is carried out. \n\n## Identifying the occult primary\n\nConsider a fluorodeoxyglucose positron emission tomography (FDG\xa0PET)‑CT scan as the first investigation to detect the primary site in people with metastatic nodal squamous cell carcinoma of unknown origin that is thought to arise from the upper aerodigestive tract. \n\nConsider using narrow‑band imaging endoscopy to identify a possible primary site when it has not been possible to do so using FDG\xa0PET‑CT. \n\nOffer a biopsy to confirm a possible primary site. \n\nOffer surgical diagnostic assessment if FDG\xa0PET‑CT does not identify a possible primary site. This may include:\n\nguided biopsies\n\ntonsillectomy\n\ntongue base mucosectomy. \n\nConsider an MRI or CT\xa0scan before diagnostic surgery to help with radiotherapy treatment planning. \n\n## Clinical staging – who and how?\n\nOffer systemic staging (see recommendations 1.2.9–1.2.11) to all people with cancer of the upper aerodigestive tract except those with T1N0 or T2N0 disease. \n\nOffer FDG\xa0PET‑CT to people with T4 cancer of the hypopharynx or nasopharynx. \n\nOffer FDG\xa0PET‑CT to people with N3 cancer of the upper aerodigestive tract. \n\nOffer conventional imaging (for example, chest CT) to people with cancer of the upper aerodigestive tract who require systemic staging (see recommendation 1.2.8) but FDG\xa0PET‑CT is not indicated for them. \n\n# Treatment of early stage disease\n\n## Squamous cell carcinoma of the larynx\n\nOffer transoral laser microsurgery to people with newly‑diagnosed T1a squamous cell carcinoma of the glottic larynx. \n\nOffer a choice of transoral laser microsurgery or radiotherapy to people with newly‑diagnosed T1b–T2 squamous cell carcinoma of the glottic larynx. \n\nOffer a choice of transoral surgery or radiotherapy to people with newly‑diagnosed T1–T2 squamous cell carcinoma of the supraglottic larynx. \n\n## Management of the N0 neck in T1–2 squamous cell carcinoma of the oral cavity\n\nOffer surgical management of the neck to all people with early oral cavity cancer (T1–T2, N0). \n\nOffer sentinel lymph node biopsy instead of elective neck dissection to people with early oral cavity cancer (T1–T2, N0), unless they need cervical access at the same time (for example, free‑flap reconstruction). \n\n## Squamous cell carcinoma of the oropharynx (T1–2, N0)\n\nOffer people the choice of transoral surgical resection or primary radiotherapy for T1–2 N0 tumours of the oropharynx. \n\nConsider postoperative radiotherapy, with or without concomitant chemotherapy, for T1–2 N0 tumours of the oropharynx if pathologically adverse risk factors have been identified. \n\n# Treatment of advanced disease\n\n## Squamous cell carcinoma of the larynx\n\nOffer people with T3 squamous cell carcinoma of the larynx a choice of:\n\nradiotherapy with concomitant chemotherapy or\n\nsurgery with adjuvant radiotherapy, with or without concomitant chemotherapy. \n\nDiscuss the following with people with T3 squamous cell carcinoma of the larynx and their carers, to inform their choice of treatment:\n\nthe potential advantages of laryngeal preservation\n\nthe risk of needing salvage laryngectomy (and its associated complications)\n\nthe benefits of primary surgery in people with existing compromised swallowing and airway function\n\nlikely voice and swallowing function after treatment (including the need for a long‑term feeding tube). \n\nFor people with T4a squamous cell carcinoma of the larynx consider surgery with adjuvant radiotherapy, with or without concomitant chemotherapy. \n\n## Squamous cell carcinoma of the hypopharynx\n\nOffer larynx‑preserving treatment to people with locally‑advanced squamous cell carcinoma of the hypopharynx if radiation and neo‑adjuvant and/or concomitant chemotherapy would be suitable for them and they do not have:\n\ntumour‑related dysphagia needing a feeding tube\n\na compromised airway\n\nrecurrent aspiration pneumonias. \n\nOffer radiotherapy with neo‑adjuvant and/or concomitant chemotherapy if larynx‑preserving treatment is suitable for the person. \n\nOffer primary surgery followed by adjuvant radiotherapy to people if chemotherapy is not a suitable treatment for them. \n\nOffer adjuvant radiotherapy to people having surgery as their primary treatment. Add concomitant chemotherapy if appropriate. \n\n## Palliation of breathing difficulties\n\nIdentify people at risk of airways obstruction for whom intervention is appropriate. Think about:\n\ntheir performance status\n\ntreatment side effects and length of hospital stay\n\ninvolving the palliative care team and other specialists when appropriate. \n\nConsider endoluminal debulking in preference to tracheostomy. \n\nEstablish a management plan if surgical intervention is not appropriate, in conjunction with the person, carers and clinical staff. \n\nAssess and treat other causes of breathlessness in people with incurable upper aerodigestive tract cancer. \n\n## Genomic biomarker-based treatment\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.\n\n# Response assessment after chemoradiotherapy\n\nOffer FDG PET-CT to guide management for people treated with radical chemoradiotherapy who have:\n\nan oropharyngeal primary cancer site and\n\nor more positive nodes in the neck, all of which are less than 6\xa0cm across. The term 'radical chemoradiotherapy' refers to treatment aiming to cure cancer rather than to relieve symptoms (palliative treatment). It is used here to reflect the evidence that these recommendations are based on. \n\nConsider FDG\xa0PET-CT to guide management for people treated with radical chemoradiotherapy who have:\n\nan oropharyngeal primary site with 1 positive node in the neck that is less than 6\xa0cm across or\n\nan oropharyngeal primary site with 1 or more positive nodes larger than 6\xa0cm across in the neck or\n\na hypopharyngeal or laryngeal primary site with 1 or more positive nodes in the neck. \n\nFor people having an FDG\xa0PET-CT scan after chemoradiotherapy, perform the scan 3 to 6\xa0months after chemoradiotherapy has finished. \n\nDo not offer neck dissection to people with no abnormal FDG uptake or residual soft tissue mass on an FDG PET-CT scan. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on response assessment after chemoradiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: evidence reviews for treatment of advanced disease\n\nLoading. Please wait.\n\n# HPV‑related disease\n\n## HPV testing\n\nTest all squamous cell carcinomas of the oropharynx using p16 immunohistochemistry. Regard the p16 test result as positive only if there is strong nuclear and cytoplasmic staining in more than 70% of tumour cells. \n\nConsider high‑risk HPV DNA or RNA in‑situ hybridisation in all p16‑positive cancers of the oropharynx to confirm HPV status. \n\n## De‑intensification of treatment\n\nDo not offer de‑intensification of curative treatment to people with HPV‑positive cancer of the oropharynx, unless it is part of a clinical trial. \n\n# Less common upper aerodigestive tract cancers\n\n## Carcinoma of the nasopharynx\n\nOffer intensity‑modulated radiation therapy with concomitant chemotherapy to people with locally‑advanced (stage II and above) nasopharyngeal cancer. \n\nConsider adjuvant or neo‑adjuvant chemotherapy for people with locally‑advanced (stage II and above) nasopharyngeal cancer. \n\n## Carcinoma of the paranasal sinuses\n\nOffer surgery as the first treatment for carcinoma of the paranasal sinuses if complete resection is possible. \n\nConsider radiotherapy with or without concomitant chemotherapy before planned surgical resection of the paranasal sinuses if complete resection is not initially possible. \n\n## Unknown primary of presumed upper aerodigestive tract origin\n\nOffer people with squamous cell carcinoma in the cervical lymph nodes with an unknown primary the choice of:\n\nneck dissection and adjuvant radiation with or without chemotherapy or\n\nprimary radiation with or without chemotherapy, with surgery for persistent disease. \n\nConsider no further treatment as an option in people with pN1\xa0disease without extracapsular spread after neck dissection. \n\nConsider including potential primary tumour sites when selecting the volume to be treated with radiotherapy. \n\n## Mucosal melanoma\n\nConsider surgery and adjuvant radiotherapy for people with newly‑diagnosed upper aerodigestive tract mucosal melanoma without systemic metastases. \n\n## Genomic biomarker-based treatment\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.\n\n# Optimising rehabilitation and function\n\n## Enteral nutrition support\n\nAssess people's need for enteral nutrition at diagnosis, including prophylactic tube placement. The multidisciplinary team should take into account:\n\nperformance status and social factors\n\nnutritional status (weight loss, high or low BMI, ability to meet estimated nutritional needs)\n\ntumour stage\n\ntumour site\n\npre‑existing dysphagia\n\nimpact of planned treatment (such as radiation treatment volume and dose‑fractionation, concomitant chemotherapy, and extent and site of surgery). \n\nFollow the recommendations in NICE's guideline on nutrition support for adults for people aged 18\xa0years and over. \n\n## Speech and language therapy interventions\n\nConsider swallowing‑exercise programmes for people having radiotherapy. \n\nConsider mouth‑opening exercises for people having radiotherapy who are at risk of reduced mouth opening. \n\nConsider voice therapy for people whose voice has changed because of their treatment. \n\n## Shoulder rehabilitation\n\nConsider progressive resistance training for people with impaired shoulder function, as soon as possible after neck dissection. \n\n# Follow‑up of people with cancer of the upper aerodigestive tract and management of osteoradionecrosis\n\n## Follow‑up\n\nEnsure people with cancer of the upper aerodigestive tract and their carers have tailored information about the symptoms of recurrence and late effects of treatment at the end of curative therapy. \n\nConsider structured, risk‑adapted follow‑up using locally‑agreed protocols for people who have had curative treatment for cancer of the upper aerodigestive tract. Use the follow‑up protocols to:\n\nhelp improve quality of life, including discussing psychosocial issues\n\ndetect disease recurrence or second primary cancer, possibly including narrow‑band imaging to improve detection. \n\n## Management of osteoradionecrosis\n\nConsider surgery to remove necrotic bone and to establish soft tissue coverage in people with osteoradionecrosis. \n\nOnly consider hyperbaric oxygen therapy or medical management for treating osteoradionecrosis as part of a clinical trial. ", 'Recommendations for research': "The 2016 guideline committee made the following recommendations for research, marked . The guideline committee's full set of research recommendations is detailed in the full version of the guideline. As part of the 2018 update, the standing committee further research recommendations, marked . Full details of these can be found in evidence review A.\n\n# Indeterminate FDG PET-CT after radical chemoradiotherapy: long-term outcomes\n\nWhat are the long-term outcomes for people with an indeterminate fluorodeoxyglucose positron emission tomography (FDG\xa0PET)-CT scan result (a residual mass with no abnormal FDG uptake) after radical chemoradiotherapy?\n\n## Why this is important\n\nPeople with indeterminate FDG\xa0PET-CT results receive neck dissection surgery according to current practice in the UK. However, there is no standardised practice on long-term follow-up for people with negative disease and persistent nodes on FDG\xa0PET-CT scan. Research to investigate long-term outcomes could improve clinical outcomes and efficient use of resources. Randomised controlled trials or prospective cohort studies would be used to answer this research question. Outcomes of interest include recurrence rates, overall survival, quality of life, surgical complications, and adverse events. \n\n# Indeterminate FDG PET-CT after radical chemoradiotherapy: investigations\n\nWhat are the most appropriate investigations for people with an indeterminate FDG PET-CT scan result (a residual mass with no abnormal FDG uptakes) after radical chemoradiotherapy?\n\n## Why this is important\n\nPeople with indeterminate FDG\xa0PET-CT results receive neck dissection surgery according to current practice in the UK. However, there is no standardised practice on long-term follow-up for people with negative disease and persistent nodes on FDG\xa0PET-CT scan. Research to investigate appropriate investigations could improve clinical outcomes and efficient use of resources. Randomised controlled trials or prospective cohort studies would be used to answer this research question. Investigations include interval FDG\xa0PET-CT, ultrasound with or without biopsy, multi-parametric MRI, and serial imaging. \n\n# Management of nodal metastasis in nasopharynx cancer after chemoradiotherapy\n\nWhat is the optimal management strategy of nodal metastasis in nasopharynx cancer after chemoradiotherapy?\n\n## Why this is important\n\nThere is evidence that FDG\xa0PET-CT is cost-saving, prevents unnecessary surgeries and reduces recurrence and overall mortality compared with neck dissection surgery in people who have received chemoradiotherapy. However, the evidence is only for people with oropharyngeal, laryngeal and hypopharyngeal cancer and there is no evidence on people with nasopharynx cancer. Natural history and response to treatment of cervical nodal metastases from nasopharynx primary sites are different, in terms of their impact on prognosis (TNM\xa07 cancer staging manual), and nasopharynx cancer is highly sensitive to radiotherapy and should not be treated by neck dissection (PET-NECK NIHR report). Research to investigate the optimal management of nodal metastasis in people with primary nasopharynx cancer after chemoradiotherapy could improve clinical outcomes and the use of resources. Outcomes of interest include recurrence rates, overall survival, quality of life, surgical complications, and adverse events. \n\n# Effectiveness of FDG PET-CT to guide follow-up\n\nWhat is the effectiveness and cost-effectiveness of using FDG\xa0PET-CT to guide follow-up after treatment for people with head and neck cancer?\n\n## Why this is important\n\nThere is evidence that FDG\xa0PET-CT is cost-saving, prevents unnecessary surgeries and has similar results for recurrence and overall mortality compared with neck dissection surgery in people with oropharyngeal, laryngeal and hypopharyngeal cancer who have received chemoradiotherapy. However, there is no evidence on FDG\xa0PET-CT for follow-up after other head and neck cancer treatments. Research to investigate the effectiveness of FDG\xa0PET-CT to guide follow-up could improve clinical outcomes and the use of resources. Outcomes of interest include recurrence rates, overall survival, and quality of life. \n\n# Systemic imaging – who and why?\n\nWhat factors determine the risk of a person presenting with cancer of the upper aerodigestive tract having metastasis or a second primary cancer?\n\n## Why this is important\n\nOutcomes of interest include prevalence, predictive value and how the abnormalities identified influence patient management. The presence of metastasis or a synchronous second primary cancer at presentation is rare in patients with cancer of the upper aerodigestive tract. Subgroups of patients have been identified in whom the risk is clearly elevated. However, it is not clear at which level of risk detailed staging investigations are justified and the impact the results of these would have on decision making by the clinicians and the patient. Health economic modelling is needed to inform this process. \n\n# HPV testing\n\nWhat is the comparative effectiveness of single‑step laboratory diagnostic tests to identify human papillomavirus (HPV) against current diagnostic test algorithms and reference standards in people with cancer of the oropharynx?\n\n## Why this is important\n\nOutcomes of interest are sensitivity, specificity and resource use. HPV testing is currently recommended in cancer of the oropharynx because it has significant prognostic implication. Current methods use a 2‑step procedure that is not widely available in all treatment centres. A single‑step test is likely to be more widely adopted and could have significant budgetary implications for the NHS. The study should also consider the prognostic value and the economic benefits of novel tests. \n\n# Unknown primary of presumed upper aerodigestive tract origin\n\nIn people with cancer of the upper aerodigestive tract of unknown primary, can radiotherapy target volumes be selected based on clinical and pathological factors?\n\n## Why this is important\n\nOutcomes of interest include local control, progression‑free survival, overall survival, and treatment‑related morbidity and mortality. In a very small percentage of patients with squamous carcinoma involving a cervical lymph node the primary site remains occult despite intensive investigations. The optimum treatment for these patients is uncertain. Some clinical teams will treat the neck disease alone and others will treat some or all potential primary sites with the radiotherapy with or without chemotherapy. The latter strategy is associated with a high level of side effects that may have lifelong consequences, for example xerostomia. A better understanding of the clinic‑pathological factors associated with treatment outcomes would improve treatment selection with the potential to reduce these side effects. \n\n# Enteral nutrition support\n\nWhat specific clinical and non‑clinical factors allow risk stratification when selecting which people with cancer of the upper aerodigestive tract would benefit from short‑ or long‑term enteral nutrition?\n\n## Why this is important\n\nOutcomes of interest include resource use, morbidity of tube placement, duration of enteral feeding and nutritional status. There are no nationally agreed selection criteria for the type of feeding tube placed at diagnosis for people who need enteral nutrition support during curative treatment. Variation across the UK exists as a result of clinician‑led practices and local policy. The systematic review by NICE in 2015 found some evidence but no specific list was identified because of limitations with study design, and inability to stratify clinical and non‑clinical factors meaningfully. These factors included restricted populations for tumour staging, patient demographics, treatment plan and intent, definitions of malnutrition, timing and method of tube placement, and duration of enteral nutrition. \n\n# Follow‑up\n\nWhat is the optimal method, frequency and duration of follow‑up for people who are disease‑free after treatment for cancer of the upper aerodigestive tract?\n\n## Why this is important\n\nOutcomes of interest include quality of life, local control and overall survival. The optimal methods, frequency, and duration of follow‑up in people who are clinically disease‑free and who have undergone treatment for squamous cell cancer of the upper aerodigestive tract with curative intent are not known. Considerable resources are expended throughout the country on the follow‑up of people who have completed potentially curative treatment. Local follow‑up protocols are based more on historical practice than evidence and are often disease‑ rather than patient‑centred. Research to investigate how and when follow‑up should optimally be carried out could improve clinical outcomes and the use of resources. ", 'Rationale and impact': "# Response assessment after chemoradiotherapy\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nOverall, the evidence showed that recurrence rates and overall mortality for fluorodeoxyglucose positron emission tomography (FDG\xa0PET)-CT-guided management after radical chemoradiotherapy were similar to those for neck dissection. In addition, the evidence showed that FDG\xa0PET-CT was cost-saving compared with neck dissection, and would prevent unnecessary surgeries, surgical complications, and adverse events.\n\nThe committee agreed to make recommendations only for people with oropharyngeal, laryngeal and hypopharyngeal primary sites, because these were the main focus of the evidence. Most of the people in the study had an oropharyngeal primary site and more than 1 positive node under 6\xa0cm across in the neck, and the evidence was strongest for this population. Therefore, the committee agreed that they should be offered an FDG\xa0PET-CT scan.\n\nThe evidence was weaker for people with:\n\nan oropharyngeal primary site and 'N2a' stage disease (only 1 positive node of more than 3\xa0cm but no more than 6\xa0cm across)\n\nan oropharyngeal primary site and higher 'N' stage disease (1 or more positive node larger than 6\xa0cm across in the neck)\n\nlaryngeal or hypopharyngeal primary sites.\n\nTo reflect this, FDG\xa0PET-CT scanning could be considered for these groups.\n\nThe evidence did not include people with an oropharyngeal primary site and 'N1' stage disease (only 1 positive node of less than 3\xa0cm across). However, the committee agreed that it is particularly important that FDG\xa0PET-CT scans are considered for this population to avoid unnecessary surgery. These people are likely to be at a lower risk of recurrence and so the benefits of neck dissection are lower.\n\nThe committee noted that new classifications for head and neck cancer (TNM classification of malignant tumours, 8th edition) have been introduced, which are different from those used in the evidence. They decided to describe the stage of cancer for these recommendations in terms of the number and size of positive nodes to avoid confusion.\n\nThe timing of FDG\xa0PET-CT scans (3 to 6\xa0months after completion of radical chemoradiotherapy) is in line with current Royal College of Radiologists guidelines on the use of PET-CT. Scans earlier than 3\xa0months are more likely to give a false-positive result, due to the residual effects of treatment.\n\nThe committee decided to be specific that neck dissection should not be offered to people with no abnormal FDG uptake or residual soft tissue mass, to give clear advice about how to interpret a 'negative' FDG\xa0PET-CT result.\n\nThe committee noted several areas in which future research would be helpful, such as management for people with indeterminate test results (see research recommendations 1 and 2), the role of FDG\xa0PET-CT for people with nasopharyngeal cancer (see research recommendation 3) and the effectiveness of FDG\xa0PET-CT to guide follow-up (see research recommendation 4).\n\n## How the recommendations might affect practice\n\nThere may an increase in the number of FDG\xa0PET-CT scans performed and a reduction in surgical procedures. However, the evidence showed that the amount of money saved from unnecessary surgery is likely to be considerably higher than the cost of the additional scans.\n\nFull details of the evidence and the committee's discussion are in evidence review A: evidence reviews for treatment of advanced disease.", 'Context': 'Upper aerodigestive tract cancers are found at various sites in the airways of the head and neck: the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx and nasal sinuses. The majority are squamous cell cancers. The major risk factors for upper aerodigestive tract squamous cell cancer in the UK are tobacco smoking and alcohol consumption.\n\nThere is currently variation or uncertainty in the investigations used to assess neck lumps; who needs systemic staging, the most effective treatment for early stage and advanced disease, how to best identify HPV‑positive disease, how to optimise function and rehabilitation, the most effective follow‑up and the management of osteoradionecrosis of the jaw. This guideline aims to make recommendations that address these areas of variation or uncertainty.\n\nThis guideline will cover adults and young people (16\xa0years and older):\n\nreferred from primary care with suspected cancer of the upper aerodigestive tract\n\nwith newly‑diagnosed or recurrent cancer of the upper aerodigestive tract.\n\nIt will not cover:\n\nadults and young people with cancers of the thyroid, orbit, middle ear, cutaneous lip, skull base or salivary gland\n\nadults and young people with sarcoma or lymphoma\n\nchildren and young people under 16\xa0years.\n\nSince publication, new evidence was identified on the use of fluorodeoxyglucose positron emission tomography (FDG\xa0PET)-CT scanning to inform decisions about surgery for nodal metastases after radical chemoradiotherapy. This less invasive approach to management has the potential to reduce unnecessary surgery for people with locally advanced head and neck cancer. In 2018 we reviewed this evidence and added new recommendations.'}
|
https://www.nice.org.uk/guidance/ng36
|
This guideline covers assessing and managing cancers of the upper aerodigestive tract in people aged 16 and over. These are cancers of the airways of the head and neck, including the mouth, throat, larynx (voicebox) and sinuses. It aims to reduce variation in practice and improve survival.
|
a124ca3339961c95f9e8d57cf62e33cec9ddd3d5
|
nice
|
Endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer
|
Endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer
Evidence-based recommendations on endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer in adults. This involves using heat energy both to clear blockage in the bile ducts before inserting stents and to clear blocked stents.
# Recommendations
Current evidence on endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer shows there are serious but well recognised safety concerns. Evidence on efficacy is limited in quality and quantity. Therefore, this procedure should only be used in the context of research, which should include randomised controlled trials. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should address: patient selection, relief of biliary obstruction, quality of life and survival.# The condition, current treatments and procedure
# The condition
Biliary obstruction caused by cancers such as cholangiocarcinoma or pancreatic adenocarcinoma causes symptoms including jaundice, nausea, bloating and abdominal pain. Surgical resection is often not possible.
# Current treatments
Current management of unresectable cholangiocarcinoma or pancreatic cancer includes biliary stenting during endoscopic retrograde cholangiopancreatography, chemotherapy, biological therapies (for example, monoclonal antibodies), radiation therapy and photodynamic therapy, which involves using a light-sensitive drug and a light source to destroy abnormal cells. Stents often need to be replaced because of blockage by tumour ingrowth.
# The procedure
Endoscopic bipolar radiofrequency ablation uses heat energy to ablate malignant tissue that is obstructing the bile or pancreatic ducts. This may be done before inserting stents or to clear obstructed stents.
The procedure is done with the patient under sedation. Endoscopic retrograde cholangiopancreatography with fluoroscopic guidance is used to establish the length, diameter and position of the stricture. Under endoscopic visualisation, a bipolar endoscopic radiofrequency ablation catheter is deployed over a guide wire across the stricture. Controlled pulses of radiofrequency energy are applied to obstructing tumour tissue to ablate it, and to allow insertion of a stent or clear the lumen of a previously placed stent. Sequential applications are applied throughout the length of the stricture to achieve recanalisation. Repeat treatments may be used if obstruction recurs.
|
{'Recommendations': 'Current evidence on endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer shows there are serious but well recognised safety concerns. Evidence on efficacy is limited in quality and quantity. Therefore, this procedure should only be used in the context of research, which should include randomised controlled trials. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should address: patient selection, relief of biliary obstruction, quality of life and survival.', 'The condition, current treatments and procedure': '# The condition\n\nBiliary obstruction caused by cancers such as cholangiocarcinoma or pancreatic adenocarcinoma causes symptoms including jaundice, nausea, bloating and abdominal pain. Surgical resection is often not possible.\n\n# Current treatments\n\nCurrent management of unresectable cholangiocarcinoma or pancreatic cancer includes biliary stenting during endoscopic retrograde cholangiopancreatography, chemotherapy, biological therapies (for example, monoclonal antibodies), radiation therapy and photodynamic therapy, which involves using a light-sensitive drug and a light source to destroy abnormal cells. Stents often need to be replaced because of blockage by tumour ingrowth.\n\n# The procedure\n\nEndoscopic bipolar radiofrequency ablation uses heat energy to ablate malignant tissue that is obstructing the bile or pancreatic ducts. This may be done before inserting stents or to clear obstructed stents.\n\nThe procedure is done with the patient under sedation. Endoscopic retrograde cholangiopancreatography with fluoroscopic guidance is used to establish the length, diameter and position of the stricture. Under endoscopic visualisation, a bipolar endoscopic radiofrequency ablation catheter is deployed over a guide wire across the stricture. Controlled pulses of radiofrequency energy are applied to obstructing tumour tissue to ablate it, and to allow insertion of a stent or clear the lumen of a previously placed stent. Sequential applications are applied throughout the length of the stricture to achieve recanalisation. Repeat treatments may be used if obstruction recurs.'}
|
https://www.nice.org.uk/guidance/ipg614
|
Evidence-based recommendations on endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cancer in adults. This involves using heat energy both to clear blockage in the bile ducts before inserting stents and to clear blocked stents.
|
6d42c9bca328911b42ec3ec6812f627bd63e0fb9
|
nice
|
Low-level laser therapy for preventing or treating oral mucositis caused by radiotherapy or chemotherapy
|
Low-level laser therapy for preventing or treating oral mucositis caused by radiotherapy or chemotherapy
Evidence-based recommendations on low-level laser therapy for preventing or treating oral mucositis caused by radiotherapy or chemotherapy. This involves applying low-energy lasers to the affected tissue.
# Recommendations
Current evidence on the safety of low-level laser therapy for oral mucositis shows no major safety concerns. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
Oral mucositis (OM) is a common side effect of chemotherapy or radiotherapy used for treating head and neck cancer or before bone marrow transplantation. Symptoms usually start 5 to 10 days after chemotherapy or 14 days after radiotherapy and include dryness, halitosis, pain, inflammation and oral mucosa ulceration. Chemotherapy-associated OM can resolve within a few days after completion of chemotherapy, but radiotherapy-associated OM can last for weeks. OM can affect nutritional status (which may need enteral or parental nutrition) and quality of life, and can increase hospital stay. It can also require interruptions or dose reductions in chemotherapy or radiotherapy treatment.
# Current treatments
Comprehensive oral hygiene, good hydration, a bland soft diet and avoiding alcohol and tobacco may increase the person's comfort. Ice, water-based moisturisers, painkillers and non-steroidal anti-inflammatory drugs can help reduce symptoms. Drugs such as palifermin are sometimes used to prevent or treat OM. Antibiotics may be needed to treat infectious complications.
# The procedure
Low-level laser therapy aims to treat or prevent OM by promoting healing, reducing inflammation and increasing cell metabolism. A hand-held probe is used to deliver light in the red or near-infrared spectrum to the oral mucosa. It can be delivered intra-orally or extra-orally, or as a combination of both approaches. During intra-oral treatment the probe, which is about the size of a dental curing light, is introduced into the mouth. For extra-oral treatment the probe is positioned close to the cheek. The procedure typically takes 20 to 30 minutes, and is delivered 2 to 5 times a week for the duration of the oncology treatment. The procedure may be started before treatment with chemotherapy or radiotherapy begins, with the intention of preventing OM.
|
{'Recommendations': 'Current evidence on the safety of low-level laser therapy for oral mucositis shows no major safety concerns. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': "# The condition\n\nOral mucositis (OM) is a common side effect of chemotherapy or radiotherapy used for treating head and neck cancer or before bone marrow transplantation. Symptoms usually start 5\xa0to 10\xa0days after chemotherapy or 14\xa0days after radiotherapy and include dryness, halitosis, pain, inflammation and oral mucosa ulceration. Chemotherapy-associated OM can resolve within a few days after completion of chemotherapy, but radiotherapy-associated OM can last for weeks. OM can affect nutritional status (which may need enteral or parental nutrition) and quality of life, and can increase hospital stay. It can also require interruptions or dose reductions in chemotherapy or radiotherapy treatment.\n\n# Current treatments\n\nComprehensive oral hygiene, good hydration, a bland soft diet and avoiding alcohol and tobacco may increase the person's comfort. Ice, water-based moisturisers, painkillers and non-steroidal anti-inflammatory drugs can help reduce symptoms. Drugs such as palifermin are sometimes used to prevent or treat OM. Antibiotics may be needed to treat infectious complications.\n\n# The procedure\n\nLow-level laser therapy aims to treat or prevent OM by promoting healing, reducing inflammation and increasing cell metabolism. A hand-held probe is used to deliver light in the red or near-infrared spectrum to the oral mucosa. It can be delivered intra-orally or extra-orally, or as a combination of both approaches. During intra-oral treatment the probe, which is about the size of a dental curing light, is introduced into the mouth. For extra-oral treatment the probe is positioned close to the cheek. The procedure typically takes 20\xa0to 30\xa0minutes, and is delivered 2\xa0to\xa05\xa0times a week for the duration of the oncology treatment. The procedure may be started before treatment with chemotherapy or radiotherapy begins, with the intention of preventing OM."}
|
https://www.nice.org.uk/guidance/ipg615
|
Evidence-based recommendations on low-level laser therapy for preventing or treating oral mucositis caused by radiotherapy or chemotherapy. This involves applying low-energy lasers to the affected tissue.
|
278ddef80219f10819dc8d2e2fb4a28027e799b7
|
nice
|
Atezolizumab for treating locally advanced or metastatic non-small-cell lung cancer after chemotherapy
|
Atezolizumab for treating locally advanced or metastatic non-small-cell lung cancer after chemotherapy
Evidence-based recommendations on atezolizumab (Tecentriq) for locally advanced or metastatic non-small-cell lung cancer after chemotherapy in adults.
# Recommendations
Atezolizumab is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults who have had chemotherapy (and targeted treatment if they have an EGFR- or ALK‑positive tumour), only if:
atezolizumab is stopped at 2 years of uninterrupted treatment or earlier if the disease progresses and
the company provides atezolizumab with the discount agreed in the patient access scheme.
This recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatments for NSCLC after chemotherapy include docetaxel alone, pembrolizumab (for tumours expressing the PD‑L1 protein) and nintedanib plus docetaxel for adenocarcinoma.
Clinical trial evidence shows that people having atezolizumab live longer than those having docetaxel alone. There is no evidence directly comparing atezolizumab with pembrolizumab. But indirect analyses show that for people with PD‑L1‑positive disease, there may be no difference in survival benefit for atezolizumab compared with pembrolizumab.
Atezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life compared with docetaxel alone, but not compared with pembrolizumab.
The most plausible cost-effectiveness estimates for atezolizumab, compared with docetaxel (for PD‑L1‑negative disease) and with pembrolizumab (for PD‑L1‑positive disease), are within the range NICE considers an acceptable use of NHS resources. Therefore it can be recommended after chemotherapy for locally advanced or metastatic NSCLC.# Information about atezolizumab
# Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) has a marketing authorisation in the UK for 'adult patients with locally advanced or metastatic non‑small cell lung cancer after prior chemotherapy. Patients with EGFR-activating mutations or ALK‑positive tumour mutations should also have received targeted therapy before receiving atezolizumab'.
# Dosage in the marketing authorisation
1,200 mg every 3 weeks by intravenous infusion. The company submission states that patients should have treatment until loss of clinical benefit or unmanageable toxicity.
# Price
A 1,200 mg vial costs £3,807.69 excluding VAT (company submission). The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition
## Atezolizumab is a potentially important option for locally advanced or metastatic NSCLC after chemotherapy
Locally advanced or metastatic non-small-cell lung cancer (NSCLC) that has progressed after chemotherapy is often diagnosed late in life and has a poor prognosis. It is a debilitating condition with many distressing symptoms. The current outlook for people with NSCLC whose disease has relapsed after chemotherapy is poor. The clinical experts stated that people with this disease have limited treatment options, which are all associated with high toxicity. The committee noted that improving quality of life and even small extensions to life are of considerable importance to this patient group. The committee concluded that atezolizumab is a potentially important treatment option for people with locally advanced or metastatic NSCLC after chemotherapy.
# Current treatments
## Options for NSCLC after chemotherapy include docetaxel, nintedanib plus docetaxel, and pembrolizumab
Platinum-based chemotherapy is given as a first treatment for NSCLC in people whose tumours are not epidermal growth factor receptor (EGFR)‑positive, followed by docetaxel, or nintedanib plus docetaxel for people with adenocarcinoma. For people with EGFR‑positive tumours, treatment starts with a tyrosine kinase inhibitor followed by platinum-based therapy. For people with anaplastic lymphoma kinase (ALK)‑positive tumours, standard treatment is ALK inhibitors followed by platinum-based chemotherapy. NICE technology appraisal guidance recommends pembrolizumab for treating PD‑L1‑positive NSCLC after chemotherapy; NICE also recommends pembrolizumab as an option for untreated PD‑L1‑positive NSCLC if the tumour expresses at least a 50% tumour proportion score (see the NICE technology appraisal guidance on pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy and pembrolizumab for untreated PD-L1-positive metastatic NSCLC). The clinical experts stated that since publication of this guidance the use of pembrolizumab has been increasing and PD‑L1 testing at diagnosis has become part of standard care for this population. The committee understood that, after chemotherapy, most patients would have active treatment such as pembrolizumab, docetaxel or nintedanib plus docetaxel. But for a small proportion of patients who decline docetaxel, or cannot not tolerate it, best supportive care may be the only option. The committee concluded that atezolizumab could be a treatment option for people who have had previous chemotherapy and for people with EGFR-activating mutations or ALK‑positive mutations who have had a targeted therapy instead of docetaxel, nintedanib plus docetaxel (for adenocarcinoma), or pembrolizumab (for PD‑L1‑positive NSCLC).
# Comparators
## Docetaxel (for PD‑L1‑negative disease) and pembrolizumab (for PD‑L1‑positive disease) are relevant comparators
For both second- and third-line treatment, the comparators would be docetaxel alone, nintedanib plus docetaxel (for people with adenocarcinoma), pembrolizumab (for PD‑L1‑positive NSCLC), and best supportive care when docetaxel is not suitable. The company had included both docetaxel and nintedanib plus docetaxel as comparators in the submission. At the third committee meeting, the Cancer Drugs Fund clinical lead and the clinical expert explained that docetaxel and nintedanib plus docetaxel (for the adenocarcinoma population only) are considered relevant treatments only for PD‑L1‑negative disease. Comments received at consultation suggested that nintedanib plus docetaxel is used only for a small number of people in clinical practice, which the committee accepted. The company had not considered nivolumab and best supportive care, which were included in the final scope. The committee considered that excluding best supportive care was reasonable because patients eligible to have atezolizumab would be well enough to have other treatment, and it noted that nivolumab is not recommended for routine commissioning. The committee concluded that for the populations under consideration, the relevant comparators for atezolizumab were:
docetaxel alone (for PD‑L1‑negative disease)
pembrolizumab (for PD‑L1‑positive disease).
# Clinical evidence
## Atezolizumab offers a gain in survival compared with docetaxel alone
The main clinical trial evidence for atezolizumab compared with docetaxel came from the OAK trial. This was an open-label, phase 3 randomised controlled trial in adults with locally advanced or metastatic NSCLC, whose disease had progressed during or after 1 platinum-containing chemotherapy regimen. The data used by the company in its clinical and cost-effectiveness analyses were from a primary population (n=850), and the study had recruited more patients in total (n=1,225) by the time the company made its original submission. The results of the primary analysis showed a statistically significant median overall survival gain for atezolizumab (13.8 months; 95% confidence interval 11.8 to 15.7) compared with docetaxel (9.6 months; 95% CI 8.6 to 11.2). In response to the second consultation, the company submitted the results from the full trial population (n=1,225). The committee noted that the results from the larger population supported the results from the primary analysis, and concluded that atezolizumab offers a gain in survival compared with docetaxel alone.
## Using the unadjusted trial data to account for treatment switching is appropriate
In the primary analysis of the OAK trial, 5% of patients having atezolizumab and 17% of patients having docetaxel went on to have subsequent therapy, mostly nivolumab. In response to the first consultation, the company provided analyses that adjusted for this subsequent treatment. These analyses used the rank-preserving structural failure time method, which the ERG stated was not suitable for adjusting for subsequent therapies (it is normally used to adjust for treatment crossover). The committee was aware that in the NICE technology appraisal of pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy, the preferred method of adjusting for crossover was the 2-stage adjustment method. The company did not provide this analysis, noting that it could not be implemented for the OAK dataset because it would need new baseline values of previously selected variables to be defined at the time of the switch. Therefore the committee agreed that it would use the estimates from the unadjusted trial data. The committee concluded that the unadjusted data in the company's original submission should be considered for decision-making.
# PD‑L1 expression
## Results from the full trial population are not suitable for decision-making
The marketing authorisation for atezolizumab is for adults with locally advanced or metastatic NSCLC after chemotherapy, and after chemotherapy and targeted treatment in people with EGFR- or ALK‑positive tumours; it does not specify treatment based on PD‑L1 expression. The committee noted that the trial results suggested that higher levels of PD‑L1 expression led to greater clinical response in people with locally advanced or metastatic NSCLC after previous chemotherapy (see table 1). The committee was aware that 54% of patients recruited in the OAK trial had PD‑L1‑positive disease. In this population, pembrolizumab is the appropriate comparator. Comments from the first and second consultation noted that it was inappropriate for the committee to make a recommendation based on PD‑L1 expression, because PD‑L1 is not a perfect biomarker and atezolizumab has shown benefit regardless of PD‑L1 expression. The committee agreed that the OAK trial showed atezolizumab to be more effective than docetaxel alone, regardless of PD‑L1 expression, but it did not include the appropriate comparator for most patients recruited. The committee concluded that the results from the full trial population were not suitable for its decision-making.
## The company's PD‑L1 subgroup analyses are suitable for decision-making
The company noted that overall survival with atezolizumab was better compared with docetaxel alone regardless of PD‑L1 expression, so it had positioned atezolizumab as a treatment for the full population. The company did not initially provide analyses by PD‑L1 expression because the trials for atezolizumab (OAK) and pembrolizumab (KEYNOTE-010) used different PD‑L1 tests. A clinical expert commented that data presented at the European Society for Medical Oncology conference suggested that there is some consistency between the Ventana SP142 and the Dako 22C3 immunohistochemistry assays. They noted that in clinical practice it was likely that tumours identified by the 2 tests would be treated in a similar way, and there would be considerable overlap in the patients identified by the different tests as having PD‑L1‑positive NSCLC. Also, following the adoption of pembrolizumab in NHS practice, PD‑L1 testing is already routinely done and, if needed, existing tests such as the Dako 22C3 could be used to inform treatment with atezolizumab. The Cancer Drugs Fund clinical lead noted that there were studies ongoing to assess the test accuracy of 4 PD‑L1 assays. The committee concluded that a comparison in people with PD‑L1‑positive NSCLC as defined by the tests would be appropriate, given that there was likely overlap in the patients identified. In response to the second consultation, the company provided separate clinical effectiveness analyses (see table 1) and cost-effectiveness analyses for:
atezolizumab compared with docetaxel alone (using data from the OAK primary analysis for people with PD‑L1‑negative disease)
atezolizumab compared with pembrolizumab (using data from the OAK primary analysis for people with PD‑L1‑positive disease).The committee concluded that the company's analyses by PD‑L1 expression were appropriate for its decision-making.
Population
Number (%)
Median overall survival (months) for atezolizumab
Median overall survival (months) for docetaxel
Hazard ratio (95% confidence interval)
Intention to treat
(0.62 to 0.87)
TC3 or IC3
(0.27 to 0.64)
TC2/3 or IC2/3
(0.49 to 0.90)
TC1/2/3 or IC1/2/3
(0.58 to 0.93)
TC0 and IC0
(0.59 to 0.96)
# Indirect treatment comparisons
## All indirect treatment comparisons are associated with uncertainty
In response to the first consultation, the company updated the indirect treatment comparison analyses using a smaller network of comparators:
atezolizumab (in the full population)
docetaxel (in the full population)
nintedanib plus docetaxel (in people with adenocarcinoma)
pembrolizumab (in people with PD‑L1‑positive disease ).The original network had included more comparators: atezolizumab, docetaxel, nintedanib plus docetaxel, erlotinib, pemetrexed, afatinib, gefitinib, paclitaxel and dacomitinib. The ERG stated that the results of both indirect comparisons were not robust; there was statistical heterogeneity that was influenced by a range of factors, including the choice of comparators included in the network, the populations used, use of fixed effects or random effects models, and the type of fractional polynomial model chosen. The committee agreed to use the company's updated networks, but noted the uncertainty associated with all the indirect analyses.
## The second updated indirect treatment comparison shows no difference in overall survival between atezolizumab and pembrolizumab
In response to the second consultation, the company further updated the indirect treatment comparison analyses using a smaller network of comparators and including only people with PD‑L1‑positive disease (1% expression or more). The comparators in the second updated indirect treatment comparison were:
atezolizumab
docetaxel
pembrolizumab.The updated results showed no statistically significant difference in overall survival for atezolizumab compared with pembrolizumab (−0.18 months ) using the unadjusted OAK data. The ERG reiterated that in the updated analysis there was statistical heterogeneity that was influenced by a range of factors. At the third appraisal committee meeting, the ERG provided a comparative analysis of overall survival and progression-free survival in the PD‑L1‑positive population of OAK with data from KEYNOTE-010 (the pivotal trial used in the NICE technology appraisal of pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). The results suggested that overall survival was higher with atezolizumab than with pembrolizumab, but median overall survival was lower in the docetaxel arm of KEYNOTE-010. The rates of treatment-related adverse events in each trial were similar. The committee agreed to use the company's second updated network in its decision-making, but noted the uncertainty associated with all the indirect analyses. It concluded that atezolizumab may be clinically equivalent to pembrolizumab, but uncertainty remains.
# The company's economic model
## The committee accepted the company's updated economic model
In response to the first consultation, the company updated the model, incorporating the ERG's corrections for:
applying a different discount rate for the intervention (discount from week 1) than for the comparators (discount from year 2)
not applying an age-related utility decrement
applying an inappropriate half cycle correction.In response to the second consultation, the company updated the patient access scheme and cost-effectiveness analyses for atezolizumab:
compared with docetaxel alone in the full trial population
compared with pembrolizumab in people with PD‑L1‑positive disease
compared with docetaxel alone in people with PD‑L1‑negative disease.The committee accepted the company's updated economic model.
# Continued treatment effect
## A lifetime treatment effect for atezolizumab is implausible
The company explained that atezolizumab's mechanism of action suggests that its effects on tumours would continue after treatment stopped. The committee considered this assumption to be biologically plausible, but it was concerned about the lack of evidence to support this. In response to the first consultation, the company provided updated data from the OAK trial which showed that the median length of treatment effect had increased from 16.3 months to 23.9 months. It also provided scenario analyses using various cut-offs for treatment effect, including a waning effect and spanning 5 to 20 years after stopping atezolizumab. The committee considered that the treatment effect was unlikely to last more than 5 years after treatment had stopped. It concluded that although it was biologically plausible for the treatment effect to continue after stopping treatment, the length of any continued effect was uncertain.
# Extrapolating overall survival
## Using Kaplan–Meier data plus a log-logistic model produces clinically plausible survival assumptions at 5 years
To estimate overall survival for atezolizumab in the full population, the company used data from OAK in which the median length of overall survival follow-up was 21.4 months for atezolizumab. In response to the first consultation, the company used Kaplan–Meier data up to 23.3 and 16.3 months for atezolizumab and docetaxel, respectively and extrapolated the data using a log-logistic curve based on best statistical fit for both atezolizumab and docetaxel. The ERG's preferred method was to use Kaplan–Meier data up to 19 months and then extrapolate using an exponential curve in both arms, which was the best fit visually for the trial data after 19 months. In response to the second consultation the committee considered comments from the clinical expert, Cancer Drugs Fund clinical lead and the company. These suggested that the ERG's preferred method (Kaplan–Meier plus exponential overall survival extrapolation; 4% alive at 5 years) underestimated 5‑year survival, and that the company's preferred overall survival extrapolation (Kaplan–Meier plus log-logistic curve; 10% alive at 5 years) was more appropriate. The company provided a range of survival estimates from other immunotherapy trials which supported this. The committee accepted that overall survival at 5 years was likely to be similar to that predicted for other immunotherapies, and concluded that using the Kaplan–Meier data with a log-logistic curve was appropriate for its decision-making.
# Stopping rule
## The committee prefers a 2‑year stopping rule in the model
The company explained that the evidence for immunotherapies such as atezolizumab was immature. There are no clear data on the effect of stopping treatment in the absence of disease progression. The company and the clinical expert explained that in a trial investigating the effect of 1‑year nivolumab treatment, patients who stopped therapy after 1 year had statistically significantly worse progression-free survival than those who continued therapy until they no longer benefitted clinically. The committee noted that the mean length of therapy in the OAK trial was less than 11 cycles (about 33 weeks), and that there was no maximum length of treatment (that is, a stopping rule). The Cancer Drugs Fund clinical lead said that the long-term consequences of stopping treatment are unknown, but clinical experience of immunotherapies in other indications suggests that significant treatment-related toxicities may occur while the disease is still responding. There is growing concern among clinicians about the use of immunotherapies beyond 2 years. The clinical experts explained that the best length of treatment with immunotherapies such as atezolizumab is uncertain, with clinicians stopping treatment anywhere between 6 months and 2 years. The committee considered that sometimes treatment may continue beyond 2 years, but it acknowledged that there was very limited evidence to support this. In response to the second consultation, the company included a 2‑year stopping rule in its sensitivity analyses (but reiterated that applying it was unreasonable given the potential harm to patients in stopping treatment early). The committee was aware that the summary of product characteristics does not include a 2‑year stopping rule and it queried whether clinicians would follow such a rule, especially if the patient was still benefitting from treatment. The Cancer Drugs Fund clinical lead clarified that a 2‑year stopping rule is acceptable to both patients and clinicians, and would be implementable. The committee further noted that NICE guidance for other immunotherapies for previously treated NSCLC (pembrolizumab and nivolumab) include 2‑year stopping rules. It concluded that it would prefer a 2‑year stopping rule in the economic model.
# Cost-effectiveness estimates
## The company's updated analyses include the committee's preferred assumptions
The committee considered the company's amended economic analyses, which incorporated the updated patient access scheme. It recalled that because the data for the full trial population did not include the appropriate comparator for PD‑L1‑positive disease, the company's cost-effectiveness estimates using these data were not suitable for decision-making. It noted that, responding to a request from NICE, the company had provided sensitivity analyses that included the committee's preferred assumptions, specifically:
extrapolating overall survival using Kaplan–Meier data plus a log-logistic curve (section 3.12)
applying a 2‑year stopping rule (section 3.13)
assuming that the effects of atezolizumab last for up to 3 years after stopping treatment (section 3.11)
not adjusting for subsequent treatment switching.
# End of life
## People with NSCLC have a life expectancy of less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether life expectancy without atezolizumab would be less than 24 months. It noted the company's evidence, which showed that people with NSCLC have an average life expectancy of less than 24 months (median survival has been reported as 7.5 months for stage 3b and 3.4 months for stage 4 NSCLC, which was supported by trial data and estimates from the economic model). The committee concluded that the short life expectancy criterion was met.
## Atezolizumab compared with docetaxel meets NICE's end-of-life criteria
The committee discussed whether a survival benefit of over 3 months can be expected for atezolizumab compared with docetaxel. The committee heard that in the full trial population the mean number of months of life gained with atezolizumab, as estimated by the company's economic model, was over 3 months compared with docetaxel. It further noted that for people with PD‑L1‑negative disease, the estimated difference in mean overall survival with atezolizumab was 7.1 months compared with docetaxel. The committee considered it reasonable to assume that the benefit is likely to exceed 3 months and concluded that atezolizumab met the end-of-life criteria for this population.
## Atezolizumab compared with pembrolizumab does not meet NICE's end-of-life criteria
The results of the company's indirect treatment comparison showed no statistically significant difference in overall survival between atezolizumab and pembrolizumab in people with PD‑L1‑positive disease. The committee concluded that atezolizumab compared with pembrolizumab for PD‑L1‑positive disease did not offer a proven extension to life of more than 3 months.
## Atezolizumab is cost effective for PD‑L1‑positive NSCLC if treatment is stopped at 2 years
The committee considered the company's cost-effectiveness analysis for PD‑L1‑positive disease, submitted in response to the second consultation, including the sensitivity analyses. The incremental cost-effectiveness ratios (ICERs) for atezolizumab compared with pembrolizumab for PD‑L1‑positive disease included an updated patient access scheme for atezolizumab and a confidential commercial access agreement for pembrolizumab which was incorporated by the ERG, so the exact values cannot be reported here. However, atezolizumab had similar total costs and quality-adjusted life years (QALYs) to pembrolizumab. In response to the second consultation, the company provided an updated cost-minimisation analyses using the OAK trial data for people with PD‑L1‑positive disease. The results supported the conclusions from the cost-effectiveness analyses. The committee concluded that because the ICER is within the range normally considered to be a cost-effective use of NHS resources, atezolizumab can be recommended for routine use to treat PD‑L1‑positive NSCLC in adults, only if treatment is stopped at 2 years.
## Atezolizumab is cost effective for PD‑L1‑negative NSCLC if treatment is stopped at 2 years
The committee considered the company's updated cost-effectiveness analysis for PD‑L1‑negative disease, submitted in response to the second consultation, including the committee's preferred assumptions. It was aware that for extrapolating overall survival, the company had used a Kaplan–Meier plus log-logistic curve for the atezolizumab arm and a Kaplan–Meier plus log-normal curve for the docetaxel arm. The results (which cannot be reported here because they include an updated patient access scheme for atezolizumab) showed that the ICER was within the range normally considered a cost-effective use of NHS resources. The committee concluded that atezolizumab is cost effective for PD‑L1‑negative NSCLC in adults, only if treatment is stopped at 2 years.
# Conclusion
## Atezolizumab is recommended for people with previously treated NSCLC
The committee recalled its earlier conclusion that because the company's full trial population data did not include the appropriate comparator for people with PD‑L1‑positive disease, it preferred the company's subgroup analyses by PD‑L1 status. It concluded that the most plausible ICER for atezolizumab compared with pembrolizumab for PD‑L1‑positive disease was within the range usually considered a cost-effective use of NHS resources. For PD‑L1‑negative disease the committee noted that atezolizumab met NICE's end-of-life criteria compared with docetaxel. It concluded that the most plausible ICER for atezolizumab compared with docetaxel was also within the range usually considered a cost-effective use of NHS resources. The committee recalled its conclusion that a 2‑year stopping rule for treatment with atezolizumab is preferred because the best length of treatment with immunotherapies is uncertain. The committee therefore recommended atezolizumab as an option for treating locally advanced or metastatic NSCLC in adults who have had chemotherapy (and targeted treatment if they have an EGFR- or ALK‑positive tumour), only if:
atezolizumab is stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses and
the company provides atezolizumab with the discount agreed in the patient access scheme.
|
{'Recommendations': "Atezolizumab is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults who have had chemotherapy (and targeted treatment if they have an EGFR- or ALK‑positive tumour), only if:\n\natezolizumab is stopped at 2\xa0years of uninterrupted treatment or earlier if the disease progresses and\n\nthe company provides atezolizumab with the discount agreed in the patient access scheme.\n\nThis recommendation is not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatments for NSCLC after chemotherapy include docetaxel alone, pembrolizumab (for tumours expressing the PD‑L1\xa0protein) and nintedanib plus docetaxel for adenocarcinoma.\n\nClinical trial evidence shows that people having atezolizumab live longer than those having docetaxel alone. There is no evidence directly comparing atezolizumab with pembrolizumab. But indirect analyses show that for people with PD‑L1‑positive disease, there may be no difference in survival benefit for atezolizumab compared with pembrolizumab.\n\nAtezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life compared with docetaxel alone, but not compared with pembrolizumab.\n\nThe most plausible cost-effectiveness estimates for atezolizumab, compared with docetaxel (for PD‑L1‑negative disease) and with pembrolizumab (for PD‑L1‑positive disease), are within the range NICE considers an acceptable use of NHS resources. Therefore it can be recommended after chemotherapy for locally advanced or metastatic NSCLC.", 'Information about atezolizumab': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) has a marketing authorisation in the UK for 'adult patients with locally advanced or metastatic non‑small cell lung cancer after prior chemotherapy. Patients with EGFR-activating mutations or ALK‑positive tumour mutations should also have received targeted therapy before receiving atezolizumab'.\n\n# Dosage in the marketing authorisation\n\n1,200\xa0mg every 3\xa0weeks by intravenous infusion. The company submission states that patients should have treatment until loss of clinical benefit or unmanageable toxicity.\n\n# Price\n\nA 1,200\xa0mg vial costs £3,807.69 excluding VAT (company submission). The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition\n\n## Atezolizumab is a potentially important option for locally advanced or metastatic NSCLC after chemotherapy\n\nLocally advanced or metastatic non-small-cell lung cancer (NSCLC) that has progressed after chemotherapy is often diagnosed late in life and has a poor prognosis. It is a debilitating condition with many distressing symptoms. The current outlook for people with NSCLC whose disease has relapsed after chemotherapy is poor. The clinical experts stated that people with this disease have limited treatment options, which are all associated with high toxicity. The committee noted that improving quality of life and even small extensions to life are of considerable importance to this patient group. The committee concluded that atezolizumab is a potentially important treatment option for people with locally advanced or metastatic NSCLC after chemotherapy.\n\n# Current treatments\n\n## Options for NSCLC after chemotherapy include docetaxel, nintedanib plus docetaxel, and pembrolizumab\n\nPlatinum-based chemotherapy is given as a first treatment for NSCLC in people whose tumours are not epidermal growth factor receptor (EGFR)‑positive, followed by docetaxel, or nintedanib plus docetaxel for people with adenocarcinoma. For people with EGFR‑positive tumours, treatment starts with a tyrosine kinase inhibitor followed by platinum-based therapy. For people with anaplastic lymphoma kinase (ALK)‑positive tumours, standard treatment is ALK inhibitors followed by platinum-based chemotherapy. NICE technology appraisal guidance recommends pembrolizumab for treating PD‑L1‑positive NSCLC after chemotherapy; NICE also recommends pembrolizumab as an option for untreated PD‑L1‑positive NSCLC if the tumour expresses at least a 50% tumour proportion score (see the NICE technology appraisal guidance on pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy and pembrolizumab for untreated PD-L1-positive metastatic NSCLC). The clinical experts stated that since publication of this guidance the use of pembrolizumab has been increasing and PD‑L1\xa0testing at diagnosis has become part of standard care for this population. The committee understood that, after chemotherapy, most patients would have active treatment such as pembrolizumab, docetaxel or nintedanib plus docetaxel. But for a small proportion of patients who decline docetaxel, or cannot not tolerate it, best supportive care may be the only option. The committee concluded that atezolizumab could be a treatment option for people who have had previous chemotherapy and for people with EGFR-activating mutations or ALK‑positive mutations who have had a targeted therapy instead of docetaxel, nintedanib plus docetaxel (for adenocarcinoma), or pembrolizumab (for PD‑L1‑positive NSCLC).\n\n# Comparators\n\n## Docetaxel (for PD‑L1‑negative disease) and pembrolizumab (for PD‑L1‑positive disease) are relevant comparators\n\nFor both second- and third-line treatment, the comparators would be docetaxel alone, nintedanib plus docetaxel (for people with adenocarcinoma), pembrolizumab (for PD‑L1‑positive NSCLC), and best supportive care when docetaxel is not suitable. The company had included both docetaxel and nintedanib plus docetaxel as comparators in the submission. At the third committee meeting, the Cancer Drugs Fund clinical lead and the clinical expert explained that docetaxel and nintedanib plus docetaxel (for the adenocarcinoma population only) are considered relevant treatments only for PD‑L1‑negative disease. Comments received at consultation suggested that nintedanib plus docetaxel is used only for a small number of people in clinical practice, which the committee accepted. The company had not considered nivolumab and best supportive care, which were included in the final scope. The committee considered that excluding best supportive care was reasonable because patients eligible to have atezolizumab would be well enough to have other treatment, and it noted that nivolumab is not recommended for routine commissioning. The committee concluded that for the populations under consideration, the relevant comparators for atezolizumab were:\n\ndocetaxel alone (for PD‑L1‑negative disease)\n\npembrolizumab (for PD‑L1‑positive disease).\n\n# Clinical evidence\n\n## Atezolizumab offers a gain in survival compared with docetaxel alone\n\nThe main clinical trial evidence for atezolizumab compared with docetaxel came from the OAK trial. This was an open-label, phase\xa03 randomised controlled trial in adults with locally advanced or metastatic NSCLC, whose disease had progressed during or after 1\xa0platinum-containing chemotherapy regimen. The data used by the company in its clinical and cost-effectiveness analyses were from a primary population (n=850), and the study had recruited more patients in total (n=1,225) by the time the company made its original submission. The results of the primary analysis showed a statistically significant median overall survival gain for atezolizumab (13.8\xa0months; 95% confidence interval [CI] 11.8 to 15.7) compared with docetaxel (9.6\xa0months; 95% CI 8.6 to 11.2). In response to the second consultation, the company submitted the results from the full trial population (n=1,225). The committee noted that the results from the larger population supported the results from the primary analysis, and concluded that atezolizumab offers a gain in survival compared with docetaxel alone.\n\n## Using the unadjusted trial data to account for treatment switching is appropriate\n\nIn the primary analysis of the OAK trial, 5% of patients having atezolizumab and 17% of patients having docetaxel went on to have subsequent therapy, mostly nivolumab. In response to the first consultation, the company provided analyses that adjusted for this subsequent treatment. These analyses used the rank-preserving structural failure time method, which the ERG stated was not suitable for adjusting for subsequent therapies (it is normally used to adjust for treatment crossover). The committee was aware that in the NICE technology appraisal of pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy, the preferred method of adjusting for crossover was the 2-stage adjustment method. The company did not provide this analysis, noting that it could not be implemented for the OAK dataset because it would need new baseline values of previously selected variables to be defined at the time of the switch. Therefore the committee agreed that it would use the estimates from the unadjusted trial data. The committee concluded that the unadjusted data in the company's original submission should be considered for decision-making.\n\n# PD‑L1\xa0expression\n\n## Results from the full trial population are not suitable for decision-making\n\nThe marketing authorisation for atezolizumab is for adults with locally advanced or metastatic NSCLC after chemotherapy, and after chemotherapy and targeted treatment in people with EGFR- or ALK‑positive tumours; it does not specify treatment based on PD‑L1\xa0expression. The committee noted that the trial results suggested that higher levels of PD‑L1\xa0expression led to greater clinical response in people with locally advanced or metastatic NSCLC after previous chemotherapy (see table\xa01). The committee was aware that 54% of patients recruited in the OAK trial had PD‑L1‑positive disease. In this population, pembrolizumab is the appropriate comparator. Comments from the first and second consultation noted that it was inappropriate for the committee to make a recommendation based on PD‑L1\xa0expression, because PD‑L1\xa0is not a perfect biomarker and atezolizumab has shown benefit regardless of PD‑L1\xa0expression. The committee agreed that the OAK trial showed atezolizumab to be more effective than docetaxel alone, regardless of PD‑L1\xa0expression, but it did not include the appropriate comparator for most patients recruited. The committee concluded that the results from the full trial population were not suitable for its decision-making.\n\n## The company's PD‑L1\xa0subgroup analyses are suitable for decision-making\n\nThe company noted that overall survival with atezolizumab was better compared with docetaxel alone regardless of PD‑L1\xa0expression, so it had positioned atezolizumab as a treatment for the full population. The company did not initially provide analyses by PD‑L1\xa0expression because the trials for atezolizumab (OAK) and pembrolizumab (KEYNOTE-010) used different PD‑L1\xa0tests. A clinical expert commented that data presented at the European Society for Medical Oncology conference suggested that there is some consistency between the Ventana SP142 and the Dako 22C3 immunohistochemistry assays. They noted that in clinical practice it was likely that tumours identified by the 2\xa0tests would be treated in a similar way, and there would be considerable overlap in the patients identified by the different tests as having PD‑L1‑positive NSCLC. Also, following the adoption of pembrolizumab in NHS practice, PD‑L1\xa0testing is already routinely done and, if needed, existing tests such as the Dako 22C3 could be used to inform treatment with atezolizumab. The Cancer Drugs Fund clinical lead noted that there were studies ongoing to assess the test accuracy of 4\xa0PD‑L1\xa0assays. The committee concluded that a comparison in people with PD‑L1‑positive NSCLC as defined by the tests would be appropriate, given that there was likely overlap in the patients identified. In response to the second consultation, the company provided separate clinical effectiveness analyses (see table\xa01) and cost-effectiveness analyses for:\n\natezolizumab compared with docetaxel alone (using data from the OAK primary analysis for people with PD‑L1‑negative [tumour cell or infiltrating cell; TC0 or IC0] disease)\n\natezolizumab compared with pembrolizumab (using data from the OAK primary analysis for people with PD‑L1‑positive [TC1/2/3 or IC1/2/3] disease).The committee concluded that the company's analyses by PD‑L1\xa0expression were appropriate for its decision-making.\n\nPopulation\n\nNumber (%)\n\nMedian overall survival (months) for atezolizumab\n\nMedian overall survival (months) for docetaxel\n\nHazard ratio (95% confidence interval)\n\nIntention to treat\n\n(100)\n\n\n\n\n\n(0.62 to 0.87)\n\nTC3 or IC3\n\n(16)\n\n\n\n\n\n(0.27 to 0.64)\n\nTC2/3 or IC2/3\n\n(31)\n\n\n\n\n\n(0.49 to 0.90)\n\nTC1/2/3 or IC1/2/3\n\n(54)\n\n\n\n\n\n(0.58 to 0.93)\n\nTC0 and IC0\n\n(45)\n\n\n\n\n\n(0.59 to 0.96)\n\n# Indirect treatment comparisons\n\n## All indirect treatment comparisons are associated with uncertainty\n\nIn response to the first consultation, the company updated the indirect treatment comparison analyses using a smaller network of comparators:\n\natezolizumab (in the full population)\n\ndocetaxel (in the full population)\n\nnintedanib plus docetaxel (in people with adenocarcinoma)\n\npembrolizumab (in people with PD‑L1‑positive disease [1% expression or more]).The original network had included more comparators: atezolizumab, docetaxel, nintedanib plus docetaxel, erlotinib, pemetrexed, afatinib, gefitinib, paclitaxel and dacomitinib. The ERG stated that the results of both indirect comparisons were not robust; there was statistical heterogeneity that was influenced by a range of factors, including the choice of comparators included in the network, the populations used, use of fixed effects or random effects models, and the type of fractional polynomial model chosen. The committee agreed to use the company's updated networks, but noted the uncertainty associated with all the indirect analyses.\n\n## The second updated indirect treatment comparison shows no difference in overall survival between atezolizumab and pembrolizumab\n\nIn response to the second consultation, the company further updated the indirect treatment comparison analyses using a smaller network of comparators and including only people with PD‑L1‑positive disease (1% expression or more). The comparators in the second updated indirect treatment comparison were:\n\natezolizumab\n\ndocetaxel\n\npembrolizumab.The updated results showed no statistically significant difference in overall survival for atezolizumab compared with pembrolizumab (−0.18\xa0months [95% CI −5.58 to 4.60]) using the unadjusted OAK data. The ERG reiterated that in the updated analysis there was statistical heterogeneity that was influenced by a range of factors. At the third appraisal committee meeting, the ERG provided a comparative analysis of overall survival and progression-free survival in the PD‑L1‑positive population of OAK with data from KEYNOTE-010 (the pivotal trial used in the NICE technology appraisal of pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). The results suggested that overall survival was higher with atezolizumab than with pembrolizumab, but median overall survival was lower in the docetaxel arm of KEYNOTE-010. The rates of treatment-related adverse events in each trial were similar. The committee agreed to use the company's second updated network in its decision-making, but noted the uncertainty associated with all the indirect analyses. It concluded that atezolizumab may be clinically equivalent to pembrolizumab, but uncertainty remains.\n\n# The company's economic model\n\n## The committee accepted the company's updated economic model\n\nIn response to the first consultation, the company updated the model, incorporating the ERG's corrections for:\n\napplying a different discount rate for the intervention (discount from week\xa01) than for the comparators (discount from year\xa02)\n\nnot applying an age-related utility decrement\n\napplying an inappropriate half cycle correction.In response to the second consultation, the company updated the patient access scheme and cost-effectiveness analyses for atezolizumab:\n\ncompared with docetaxel alone in the full trial population\n\ncompared with pembrolizumab in people with PD‑L1‑positive disease\n\ncompared with docetaxel alone in people with PD‑L1‑negative disease.The committee accepted the company's updated economic model.\n\n# Continued treatment effect\n\n## A lifetime treatment effect for atezolizumab is implausible\n\nThe company explained that atezolizumab's mechanism of action suggests that its effects on tumours would continue after treatment stopped. The committee considered this assumption to be biologically plausible, but it was concerned about the lack of evidence to support this. In response to the first consultation, the company provided updated data from the OAK trial which showed that the median length of treatment effect had increased from 16.3\xa0months to 23.9\xa0months. It also provided scenario analyses using various cut-offs for treatment effect, including a waning effect and spanning 5\xa0to\xa020\xa0years after stopping atezolizumab. The committee considered that the treatment effect was unlikely to last more than 5\xa0years after treatment had stopped. It concluded that although it was biologically plausible for the treatment effect to continue after stopping treatment, the length of any continued effect was uncertain.\n\n# Extrapolating overall survival\n\n## Using Kaplan–Meier data plus a log-logistic model produces clinically plausible survival assumptions at 5\xa0years\n\nTo estimate overall survival for atezolizumab in the full population, the company used data from OAK in which the median length of overall survival follow-up was 21.4\xa0months for atezolizumab. In response to the first consultation, the company used Kaplan–Meier data up to 23.3 and 16.3\xa0months for atezolizumab and docetaxel, respectively and extrapolated the data using a log-logistic curve based on best statistical fit for both atezolizumab and docetaxel. The ERG's preferred method was to use Kaplan–Meier data up to 19\xa0months and then extrapolate using an exponential curve in both arms, which was the best fit visually for the trial data after 19\xa0months. In response to the second consultation the committee considered comments from the clinical expert, Cancer Drugs Fund clinical lead and the company. These suggested that the ERG's preferred method (Kaplan–Meier plus exponential overall survival extrapolation; 4% alive at 5\xa0years) underestimated 5‑year survival, and that the company's preferred overall survival extrapolation (Kaplan–Meier plus log-logistic curve; 10% alive at 5\xa0years) was more appropriate. The company provided a range of survival estimates from other immunotherapy trials which supported this. The committee accepted that overall survival at 5\xa0years was likely to be similar to that predicted for other immunotherapies, and concluded that using the Kaplan–Meier data with a log-logistic curve was appropriate for its decision-making.\n\n# Stopping rule\n\n## The committee prefers a 2‑year stopping rule in the model\n\nThe company explained that the evidence for immunotherapies such as atezolizumab was immature. There are no clear data on the effect of stopping treatment in the absence of disease progression. The company and the clinical expert explained that in a trial investigating the effect of 1‑year nivolumab treatment, patients who stopped therapy after 1\xa0year had statistically significantly worse progression-free survival than those who continued therapy until they no longer benefitted clinically. The committee noted that the mean length of therapy in the OAK trial was less than 11\xa0cycles (about 33\xa0weeks), and that there was no maximum length of treatment (that is, a stopping rule). The Cancer Drugs Fund clinical lead said that the long-term consequences of stopping treatment are unknown, but clinical experience of immunotherapies in other indications suggests that significant treatment-related toxicities may occur while the disease is still responding. There is growing concern among clinicians about the use of immunotherapies beyond 2\xa0years. The clinical experts explained that the best length of treatment with immunotherapies such as atezolizumab is uncertain, with clinicians stopping treatment anywhere between 6\xa0months and 2\xa0years. The committee considered that sometimes treatment may continue beyond 2\xa0years, but it acknowledged that there was very limited evidence to support this. In response to the second consultation, the company included a 2‑year stopping rule in its sensitivity analyses (but reiterated that applying it was unreasonable given the potential harm to patients in stopping treatment early). The committee was aware that the summary of product characteristics does not include a 2‑year stopping rule and it queried whether clinicians would follow such a rule, especially if the patient was still benefitting from treatment. The Cancer Drugs Fund clinical lead clarified that a 2‑year stopping rule is acceptable to both patients and clinicians, and would be implementable. The committee further noted that NICE guidance for other immunotherapies for previously treated NSCLC (pembrolizumab and nivolumab) include 2‑year stopping rules. It concluded that it would prefer a 2‑year stopping rule in the economic model.\n\n# Cost-effectiveness estimates\n\n## The company's updated analyses include the committee's preferred assumptions\n\nThe committee considered the company's amended economic analyses, which incorporated the updated patient access scheme. It recalled that because the data for the full trial population did not include the appropriate comparator for PD‑L1‑positive disease, the company's cost-effectiveness estimates using these data were not suitable for decision-making. It noted that, responding to a request from NICE, the company had provided sensitivity analyses that included the committee's preferred assumptions, specifically:\n\nextrapolating overall survival using Kaplan–Meier data plus a log-logistic curve (section\xa03.12)\n\napplying a 2‑year stopping rule (section\xa03.13)\n\nassuming that the effects of atezolizumab last for up to 3\xa0years after stopping treatment (section\xa03.11)\n\nnot adjusting for subsequent treatment switching.\n\n# End of life\n\n## People with NSCLC have a life expectancy of less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether life expectancy without atezolizumab would be less than 24\xa0months. It noted the company's evidence, which showed that people with NSCLC have an average life expectancy of less than 24\xa0months (median survival has been reported as 7.5\xa0months for stage\xa03b and 3.4\xa0months for stage\xa04 NSCLC, which was supported by trial data and estimates from the economic model). The committee concluded that the short life expectancy criterion was met.\n\n## Atezolizumab compared with docetaxel meets NICE's end-of-life criteria\n\nThe committee discussed whether a survival benefit of over 3\xa0months can be expected for atezolizumab compared with docetaxel. The committee heard that in the full trial population the mean number of\xa0months of life gained with atezolizumab, as estimated by the company's economic model, was over 3\xa0months compared with docetaxel. It further noted that for people with PD‑L1‑negative disease, the estimated difference in mean overall survival with atezolizumab was 7.1\xa0months compared with docetaxel. The committee considered it reasonable to assume that the benefit is likely to exceed 3\xa0months and concluded that atezolizumab met the end-of-life criteria for this population.\n\n## Atezolizumab compared with pembrolizumab does not meet NICE's end-of-life criteria\n\nThe results of the company's indirect treatment comparison showed no statistically significant difference in overall survival between atezolizumab and pembrolizumab in people with PD‑L1‑positive disease. The committee concluded that atezolizumab compared with pembrolizumab for PD‑L1‑positive disease did not offer a proven extension to life of more than 3\xa0months.\n\n## Atezolizumab is cost effective for PD‑L1‑positive NSCLC if treatment is stopped at 2\xa0years\n\nThe committee considered the company's cost-effectiveness analysis for PD‑L1‑positive disease, submitted in response to the second consultation, including the sensitivity analyses. The incremental cost-effectiveness ratios (ICERs) for atezolizumab compared with pembrolizumab for PD‑L1‑positive disease included an updated patient access scheme for atezolizumab and a confidential commercial access agreement for pembrolizumab which was incorporated by the ERG, so the exact values cannot be reported here. However, atezolizumab had similar total costs and quality-adjusted life\xa0years (QALYs) to pembrolizumab. In response to the second consultation, the company provided an updated cost-minimisation analyses using the OAK trial data for people with PD‑L1‑positive disease. The results supported the conclusions from the cost-effectiveness analyses. The committee concluded that because the ICER is within the range normally considered to be a cost-effective use of NHS resources, atezolizumab can be recommended for routine use to treat PD‑L1‑positive NSCLC in adults, only if treatment is stopped at 2\xa0years.\n\n## Atezolizumab is cost effective for PD‑L1‑negative NSCLC if treatment is stopped at 2\xa0years\n\nThe committee considered the company's updated cost-effectiveness analysis for PD‑L1‑negative disease, submitted in response to the second consultation, including the committee's preferred assumptions. It was aware that for extrapolating overall survival, the company had used a Kaplan–Meier plus log-logistic curve for the atezolizumab arm and a Kaplan–Meier plus log-normal curve for the docetaxel arm. The results (which cannot be reported here because they include an updated patient access scheme for atezolizumab) showed that the ICER was within the range normally considered a cost-effective use of NHS resources. The committee concluded that atezolizumab is cost effective for PD‑L1‑negative NSCLC in adults, only if treatment is stopped at 2\xa0years.\n\n# Conclusion\n\n## Atezolizumab is recommended for people with previously treated NSCLC\n\nThe committee recalled its earlier conclusion that because the company's full trial population data did not include the appropriate comparator for people with PD‑L1‑positive disease, it preferred the company's subgroup analyses by PD‑L1\xa0status. It concluded that the most plausible ICER for atezolizumab compared with pembrolizumab for PD‑L1‑positive disease was within the range usually considered a cost-effective use of NHS resources. For PD‑L1‑negative disease the committee noted that atezolizumab met NICE's end-of-life criteria compared with docetaxel. It concluded that the most plausible ICER for atezolizumab compared with docetaxel was also within the range usually considered a cost-effective use of NHS resources. The committee recalled its conclusion that a 2‑year stopping rule for treatment with atezolizumab is preferred because the best length of treatment with immunotherapies is uncertain. The committee therefore recommended atezolizumab as an option for treating locally advanced or metastatic NSCLC in adults who have had chemotherapy (and targeted treatment if they have an EGFR- or ALK‑positive tumour), only if:\n\natezolizumab is stopped at 2\xa0years of uninterrupted treatment, or earlier if the disease progresses and\n\nthe company provides atezolizumab with the discount agreed in the patient access scheme."}
|
https://www.nice.org.uk/guidance/ta520
|
Evidence-based recommendations on atezolizumab (Tecentriq) for locally advanced or metastatic non-small-cell lung cancer after chemotherapy in adults.
|
3a878920e075e719a4c6acc0790139da77ccc36b
|
nice
|
Percutaneous balloon valvuloplasty for fetal critical aortic stenosis
|
Percutaneous balloon valvuloplasty for fetal critical aortic stenosis
Evidence-based recommendations on percutaneous balloon valvuloplasty for fetal critical aortic stenosis. This involves placing a catheter into the baby’s heart, while the baby is still in the womb. The aim is to help the heart develop properly.
# Recommendations
Current evidence on the safety and efficacy of percutaneous balloon valvuloplasty for fetal critical aortic stenosis is limited in quantity and the results are inconsistent. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
NICE encourages the peer-reviewed publication of all further research. Further research could be in the form of controlled trials, analysis of registry data or other observational studies. It should address patient selection, timing of the intervention and the natural history of the disease.# The condition, current treatments and procedure
# The condition
Congenital heart defects are the most common type of birth defect and include aortic valve stenosis. Aortic valve stenosis ranges from mild to severe, known as critical aortic stenosis. Critical stenosis is rare but carries a high rate of postnatal morbidity and mortality.
Critical aortic stenosis in early fetal life causes left ventricular dysfunction; the increased pressure in the heart initially produces left ventricular dilatation and then myocardial damage. Myocardial damage can lead to hypoplastic left heart syndrome (HLHS), which can be associated with underdevelopment of the mitral valve and the aortic arch. The high pressure in the left side of the heart can increase further if the foramen ovale closes before birth, causing fibrosis of the myocardium and pulmonary venous hypertension with arterialisation of the pulmonary veins. This is known as aortic stenosis with restrictive interatrial communication and it has a very poor prognosis.
Many fetuses with critical aortic stenosis will survive until birth. However, about 10% will die before birth either from hydrops associated with restrictive interatrial communication or from a chromosomal abnormality.
# Current treatments
At birth, some babies with critical aortic stenosis will not be able to have biventricular heart repair and about 50% of babies will die during the first year of life, despite surgical treatment. This prognosis can lead parents to ask for a termination of pregnancy.
For babies born with an adequate biventricular heart and aortic valve disease, postnatal balloon valvuloplasty is the initial preferred option to encourage remodelling and growth of the left ventricle. Further balloon valvuloplasty is often needed, with later valve replacement.
Staged reconstruction to create a single ventricle circulation can improve survival for babies with HLHS. This takes multiple operations over several years and involves complex high-risk open-heart surgery.
Fetal aortic balloon valvuloplasty may be considered when there is a high risk of fetal deterioration before delivery and an increased likelihood of postnatal mortality and morbidity. Improvements in imaging have helped identify fetuses for whom this procedure is suitable.
The aim of fetal aortic balloon valvuloplasty is to prevent progressive damage to the ventricle. This may allow postnatal surgical intervention to have more chance of success.
# The procedure
Fetal aortic balloon valvuloplasty is done at 21 to 32 weeks' gestation. Under maternal local anaesthesia (with or without sedation), a needle is inserted through the mother's abdominal wall into the uterine cavity with ultrasound guidance. Analgesia is injected into the fetus before advancing the needle through the fetal chest wall into the left ventricle. A guidewire is inserted through the needle and across the aortic valve. A balloon catheter is then inserted and inflated to dilate the stenotic valve. The catheter and needle are then withdrawn.
Fetal positioning is critical for the success of the procedure.
|
{'Recommendations': 'Current evidence on the safety and efficacy of percutaneous balloon valvuloplasty for fetal critical aortic stenosis is limited in quantity and the results are inconsistent. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nNICE encourages the peer-reviewed publication of all further research. Further research could be in the form of controlled trials, analysis of registry data or other observational studies. It should address patient selection, timing of the intervention and the natural history of the disease.', 'The condition, current treatments and procedure': "# The condition\n\nCongenital heart defects are the most common type of birth defect and include aortic valve stenosis. Aortic valve stenosis ranges from mild to severe, known as critical aortic stenosis. Critical stenosis is rare but carries a high rate of postnatal morbidity and mortality.\n\nCritical aortic stenosis in early fetal life causes left ventricular dysfunction; the increased pressure in the heart initially produces left ventricular dilatation and then myocardial damage. Myocardial damage can lead to hypoplastic left heart syndrome (HLHS), which can be associated with underdevelopment of the mitral valve and the aortic arch. The high pressure in the left side of the heart can increase further if the foramen ovale closes before birth, causing fibrosis of the myocardium and pulmonary venous hypertension with arterialisation of the pulmonary veins. This is known as aortic stenosis with restrictive interatrial communication and it has a very poor prognosis.\n\nMany fetuses with critical aortic stenosis will survive until birth. However, about 10% will die before birth either from hydrops associated with restrictive interatrial communication or from a chromosomal abnormality.\n\n# Current treatments\n\nAt birth, some babies with critical aortic stenosis will not be able to have biventricular heart repair and about 50% of babies will die during the first year of life, despite surgical treatment. This prognosis can lead parents to ask for a termination of pregnancy.\n\nFor babies born with an adequate biventricular heart and aortic valve disease, postnatal balloon valvuloplasty is the initial preferred option to encourage remodelling and growth of the left ventricle. Further balloon valvuloplasty is often needed, with later valve replacement.\n\nStaged reconstruction to create a single ventricle circulation can improve survival for babies with HLHS. This takes multiple operations over several years and involves complex high-risk open-heart surgery.\n\nFetal aortic balloon valvuloplasty may be considered when there is a high risk of fetal deterioration before delivery and an increased likelihood of postnatal mortality and morbidity. Improvements in imaging have helped identify fetuses for whom this procedure is suitable.\n\nThe aim of fetal aortic balloon valvuloplasty is to prevent progressive damage to the ventricle. This may allow postnatal surgical intervention to have more chance of success.\n\n# The procedure\n\nFetal aortic balloon valvuloplasty is done at 21 to 32\xa0weeks' gestation. Under maternal local anaesthesia (with or without sedation), a needle is inserted through the mother's abdominal wall into the uterine cavity with ultrasound guidance. Analgesia is injected into the fetus before advancing the needle through the fetal chest wall into the left ventricle. A guidewire is inserted through the needle and across the aortic valve. A balloon catheter is then inserted and inflated to dilate the stenotic valve. The catheter and needle are then withdrawn.\n\nFetal positioning is critical for the success of the procedure."}
|
https://www.nice.org.uk/guidance/ipg613
|
Evidence-based recommendations on percutaneous balloon valvuloplasty for fetal critical aortic stenosis. This involves placing a catheter into the baby’s heart, while the baby is still in the womb. The aim is to help the heart develop properly.
|
b9b6240b5f69d63fded9ff6206538d2f24d45941
|
nice
|
Adjunctive colposcopy technologies for assessing suspected cervical abnormalities: the DYSIS colposcope with DYSISmap and the ZedScan I
|
Adjunctive colposcopy technologies for assessing suspected cervical abnormalities: the DYSIS colposcope with DYSISmap and the ZedScan I
Evidence-based recommendations on 2 adjunctive colposcopy technologies (the DYSIS colposcope with DYSISmap and the ZedScan I) for assessing suspected cervical abnormalities in people having colposcopy.
# Recommendations
The Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap shows promise and is recommended for assessing suspected cervical abnormalities in people having colposcopy. Centres using the technology should audit their outcomes (see section 5.16).
Further research is recommended on the effects of using the DYSIS colposcope with DYSISmap on clinical and patient outcomes in a human papilloma virus primary screening setting, and on patient experience (see sections 6.1 to 6.3).
The ZedScan I shows promise in assessing suspected cervical abnormalities, but there is currently not enough evidence to recommend its routine adoption. Further research on the effects of using the technology on clinical and patient outcomes is recommended (see sections 6.1 to 6.3). Colposcopy services that implemented the ZedScan I before this guidance was published are encouraged to take part in studies that address these research recommendations.# Clinical need and practice
# The problem addressed
The Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap and the ZedScan I adjunctive colposcopy technologies are intended to be used with colposcopy to help identify cervical intraepithelial neoplasia (CIN) during a colposcopy examination. CIN is a term used to describe precancerous changes in cells in the surface layer of the cervix (the cervical epithelium). Most changes arise in the transformation zone, where the endocervical canal (the internal canal of the cervix) meets the external part of the cervix. This is the area examined during standard colposcopy, and from where a sample is taken for cervical screening. Less often, abnormalities occur on the inside of the cervical canal instead of the surface. These changes are known as cervical glandular intraepithelial neoplasia.
Standard colposcopy is subjective and can be associated with both inter- and intra-observer variability, particularly with lower-grade abnormalities. It is usually done using a binocular colposcope, unless the clinic has a DYSIS colposcope that incorporates a digital (video) colposcope. The adjunctive colposcopy technologies aim to evaluate cellular changes objectively, using optical or electrical impedance spectroscopy to assess the characteristics of cervical cells.
The results provided by the technologies can help a colposcopist to decide whether further treatment or biopsies are needed, by guiding them to areas that are most likely to be abnormal. If the results do not suggest any areas of abnormality, and standard colposcopy is normal, the colposcopist can be more confident that high-grade disease is unlikely to be present. It is claimed that using the devices may result in more accurate detection of cervical abnormalities and identification of the correct sites for biopsy.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of the DYSIS colposcope with DYSISmap and the ZedScan I. It is a full update of NICE's diagnostics guidance on the DYSIS colposcope with DYSISmap and the Niris Imaging System, which was published in 2012. NICE's original guidance concluded that DYSIS was a clinically and cost-effective option compared with standard colposcopy. Since the guidance was published there have been changes to the care pathway (see sections 2.9 and 2.10) and changes to the CE-marked products. Also, the Niris Imaging System is no longer available.
# The condition
## Cervical intraepithelial neoplasia and cervical cancer
Cervical cancer is one of the less common cancers in the UK, largely because of the NHS cervical screening programme (NHSCSP). In 2013 there were 3,200 cases of cervical cancer in the UK (Cancer Research UK), which accounted for less than 1% of all new cases of cancer. In 2014 there were 890 deaths from cervical cancer in the UK (Cancer Research UK). The main cause of cervical cancer is persistent infection with high-risk genotypes of human papilloma virus (HPV; hereafter referred to as high-risk HPV), which causes changes in the cervical cells that can progress to cervical cancer if not treated.
CIN is classified based on the depth of abnormal cells in the surface layer of the cervix seen on a diagnostic or excisional (treatment) biopsy:
CIN 1: one third of the thickness of the surface layer is affected
CIN 2: two thirds of the thickness of the surface layer is affected
CIN 3: the full thickness of the surface layer is affected.Grades 2 and 3, often referred to as high-grade, are usually treated to prevent possible progression to cervical cancer. But expert advice suggests that CIN 2 may be managed more conservatively in people who have smaller lesions and who have not completed their family.
# The diagnostic and care pathways
## Diagnosis
Precancerous changes to cells in the cervix are detected by cervical screening. People are invited, through the NHSCSP, to have cervical screening every 3 years for those aged 25 to 49 and every 5 years for those aged 50 to 64. It involves taking a sample of cells from the cervix, usually the transformation zone (see section 2.1), using a specially designed brush. The cells are preserved using liquid-based cytology kits and are sent to a cytology laboratory where they are examined under a microscope.
The criteria for reporting cervical cytology and the management protocols for results are outlined in the NHSCSP's achievable standards, benchmarks for reporting, and criteria for evaluating cervical cytopathology (commonly known as ABC3; 2013). Samples are graded depending on the degree of abnormality, known as dyskaryosis (changes to the nucleus of a cell), seen under the microscope. Finding dyskaryotic cells suggests the presence of CIN.
The current management protocols for cervical cytology are described in the third edition of the NHSCSP's colposcopy and programme management guidelines (2016). Currently, people with samples that show high-grade dyskaryosis or worse are referred for colposcopy. If low-grade dyskaryosis is seen, the residual cells collected during the cervical screen are used for high-risk HPV testing to determine whether a colposcopy referral is needed. This is part of the management protocol referred to as HPV triage. The HPV test helps to identify people who are at the greatest risk of having abnormalities that may need further investigation and treatment. If low-grade dyskaryosis is seen but HPV is not detected, the risk of having underlying abnormalities is low and the cellular changes are likely to resolve without further investigation or treatment.
In July 2016, the Department of Health announced its decision to begin HPV primary screening through the NHSCSP. In HPV primary screening, the sample is tested for high-risk HPV first. If the results are positive, a cytology test is routinely done on the residual sample. People with either low- or high-grade abnormalities are referred for colposcopy. Those whose cytology results are negative are asked to come back in 12 months. HPV primary screening has now been adopted as the standard of care in several sites in England where it was piloted. Full roll out of this pathway is expected by 2019.
## Treatment
Treatment for CIN aims to remove the cells either by excision or ablation. Treatment for cervical glandular intraepithelial neoplasia often needs deeper excisions than for CIN.
The management protocols for colposcopy services in England are described in the NHSCSP's colposcopy and programme management guidelines (2016). Of the 188,179 people referred for colposcopy in England between 2015 and 2016, 61% had a treatment or procedure at their first appointment. The most common procedure was diagnostic biopsy (47%), followed by an excision (12%). The most common excision was a large-loop excision of the transformation zone (LLETZ; NHS Digital 2016).
Management is guided by a colposcopist's opinion of the extent of any abnormalities seen during colposcopy. If an abnormality is found, the colposcopist may take a diagnostic biopsy (punch biopsy). Or they may opt to treat an abnormality during the first clinic appointment ('see and treat') by excising the area of abnormal cells if they believe that high-grade changes are present. The NHSCSP's colposcopy and programme management guidelines (2016) recommend that treatment should not be offered at a person's first visit to a colposcopy clinic after referral for borderline or low-grade dyskaryosis. Ablative treatments should only be done after a diagnostic punch biopsy has been taken and the results have been checked.
Biopsies are examined by a histopathologist and the results are used to help the colposcopist decide whether treatment is needed. Typically, areas of CIN 2 or worse (known as CIN 2+) would need treatment. This can be done either by excising the area of abnormal cells or by destroying them in situ (ablation). During excision, cells are usually removed using a thin electrically-heated looped wire in the LLETZ procedure. The excised tissue is sent to histopathology to confirm the extent of the abnormality and to guide further management. LLETZ is usually done in the colposcopy clinic using local anaesthetic.
Unlike excisional treatment, cells removed by ablative treatment cannot be examined by a histopathologist because they are destroyed in situ. Ablative treatments include laser ablation, cryocautery and cold coagulation.
If cervical cancer is identified, depending on the stage, conservative treatment could be offered. Treatment options for cervical cancer include cone biopsy for very early stage disease, trachelectomy, hysterectomy, radiotherapy and chemotherapy. The treatment and management of cervical cancer is described in more detail in the NICE interactive flowchart on cervical cancer and in the SIGN guideline on the management of cervical cancer.# The diagnostic tests
Two interventions and 1 comparator were included in this assessment.
# The interventions
## Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap (DYSIS Medical)
The DYSIS colposcope is a CE-marked digital video colposcope. It uses spectral imaging technology and an inbuilt algorithm to produce an adjunctive map of the cervical epithelium, known as the DYSISmap (or pseudo-colour imaging). The DYSISmap is intended to be used with colposcopy to help detect cervical intraepithelial neoplasia (CIN).
The system comprises:
a high-resolution digital colposcope, which incorporates an inbuilt display console and monitor for the clinician
an optional additional monitor that allows the patient to see the images
single-use or reusable specula
an acetic acid applicator
software
a patient database (the patient management system) that stores images and videos from a colposcopy examination and records biopsy sites.
The device can be used as a standard digital video colposcope, but the spectral imaging technology used by the DYSIS colposcope also measures the speed, intensity and duration of aceto-whitening. These parameters are used to produce dynamic curves that plot intensity against time and an inbuilt algorithm assigns each area of the cervix a colour on the DYSISmap.
The DYSISmap is displayed on the screen, overlaid on a live image of the cervix, and can be used by the colposcopist to select areas for biopsy. The colour spectrum shown on the DYSISmap ranges from cyan, which represents weak aceto-whitening, to white, which represents intense aceto-whitening. The greater the intensity of the measured aceto-whitening reaction, the greater the likelihood of an abnormality. Imaging takes 3 minutes, but the colposcopist can stop it manually. However the company recommends that the system needs at least 125 seconds of imaging to allow it to calculate and display the DYSISmap.
## ZedScan I
The ZedScan I is a CE-marked electrical impedance spectroscopy (EIS) system, which is designed to be used with colposcopy to help detect high-grade CIN. The system comprises:
a portable handset, which takes EIS readings and displays the results to the user on an inbuilt interface
a docking station
single-use EIS sensors that are placed over the snout of the handset
a software application, which incorporates a database to store results and can be installed onto a personal computer.
The device uses EIS to differentiate normal, precancerous and cancerous tissue by measuring the electrical properties of the cervical epithelial cells. Electrical impedance is measured at 14 different frequencies and a spectrum is produced, which varies according to the structure and properties of the tissue. The device can be used in scanning mode or in single-point mode. During scanning mode, and after acetic acid has been applied, the single-use EIS sensors take readings from between 10 and 12 sites on the cervical transformation zone. The readings are processed by the handset using an inbuilt algorithm, which quantifies the degree of abnormality (dysplasia) at each site and compares it with a reference value to give the user a semi-quantitative result. Results are displayed to the colposcopist on the inbuilt user interface. The results show the likelihood of high-grade CIN being present at each of the scanned sites.
The results provided by the device are intended to be used to guide a colposcopist to areas that need to be biopsied, when used with standard colposcopy. It is estimated that the device takes 2 to 3 minutes to scan the cervix and display the results. The results from the ZedScan I handset are automatically uploaded to the system's database through the docking station.
# The comparator
## Colposcopy
During colposcopy the cervix is assessed by a colposcopist using a colposcope, which is a low-powered microscope. The aim of colposcopy in the NHS cervical screening programme (NHSCSP) is to confirm whether a potential abnormality found by cervical screening is present, and if so, to assess the likely extent and grade of the abnormal cells. Binocular colposcopy is most often used in the NHS.
The NHSCSP's colposcopy and management guidelines (2016) state that when an adequate colposcopy has been done, that is when the transformation zone has been fully visualised, the colposcopic diagnosis should have a positive predictive value of 65% for a high-grade lesion (CIN 2 or worse ).# Evidence
The diagnostics advisory committee (section 8) considered evidence on the DYSIS colposcope with DYSISmap (hereafter referred to as DYSIS) and the ZedScan I for detecting cervical intraepithelial neoplasia (CIN) from several sources. Full details of all the evidence are in the committee papers.
For the diagnostic accuracy review, studies were included if a prospective cohort had the index test or their prototypes (DYSIS or ZedScan I done in addition to colposcopy) and reference standard (histopathology) done independently, and contained enough data to allow diagnostic accuracy estimates to be calculated. For the effectiveness and implementation reviews, observational or experimental studies were included if DYSIS or ZedScan I, or their prototypes, were used in addition to colposcopy. All studies included in the diagnostic accuracy review were appraised using the QUADAS-2 tool. Studies in the implementation review were appraised using guidance from Burns et al. (2008) and the Centre for Evidence Based Management (2014).
In total, 12 studies were included: 11 in the diagnostic accuracy review, 3 in the review of clinical outcomes, and 5 in the implementation review. Some studies included outcomes that were relevant to more than 1 review. Most studies were reported in more than 1 paper or abstract.
# Diagnostic accuracy
Of the 11 studies included in the diagnostic accuracy review, 9 included data for DYSIS and 2 included data for ZedScan (1 for ZedScan I and 1 for a prototype). All studies were done in hospital-based colposcopy clinics, and 6 were multicentre studies. Five studies included at least 1 centre in England (both ZedScan studies and 3 DYSIS studies). Most of the people in the studies were referred for colposcopy because of an abnormal screening result.
Of the 9 DYSIS studies, 1 was considered to be at low risk of bias and the other 8 at high risk of bias. Both ZedScan studies were considered to be at a high risk of bias. The main source of bias in the studies was verification bias. This was because biopsies were not taken to confirm the absence of disease when the colposcopist did not identify any abnormalities because this is not generally considered to be good clinical practice. Concerns about the generalisability of the results of the ZedScan studies were highlighted because most of the people in the studies were examined at a single centre.
Meta-analyses were done for the diagnostic accuracy of DYSIS, which included 6 studies. Two studies were excluded because they only reported data for subgroups and 1 was included in a narrative analysis only. The analyses assume that DYSIS video colposcopy (without the DYSISmap), the comparator in the DYSIS studies, is equivalent in diagnostic accuracy to binocular colposcopy (used in the ZedScan studies and in routine NHS practice). The threshold used to determine a positive result was CIN 2 or worse (CIN 2+). No meta-analysis was done for the ZedScan studies.
## DYSIS
The pooled results from the meta-analyses are summarised in table 1. The pooled positive predictive value of colposcopy was 55.78% (95% confidence interval 47.54% to 64.03%) and of DYSISmap with colposcopy was 43.60% (95% CI 33.12% to 54.07%). The corresponding negative predictive value of colposcopy was 86.70% (95% CI 80.17% to 93.22%) and of DYSISmap with colposcopy was 92.20% (95% CI 88.06% to 96.34%). A sensitivity analysis was done with a logistic regression model. Roensbo et al. (2015) was excluded because this study did not assess DYSIS with colposcopy directly but recorded whether a colposcopist agreed or disagreed with the DYSISmap. To examine the effect of verification bias, results were stratified by the number of biopsies taken in the studies when both DYSIS and colposcopy did not identify any areas of abnormality.
The results of the meta-analyses suggest that compared with colposcopy alone, DYSIS with colposcopy improves sensitivity for detecting CIN 2+, although this is associated with a reduction in specificity. However, the results of the logistic regression model show a statistically significant difference in specificity between DYSIS and colposcopy (difference in log odds 1.33, p<0.0001), but no significant difference in diagnostic odds ratio (difference in log odds 0.04; p=0.84). This suggests that DYSIS increases the number of people suspected of having CIN 2+ and may therefore increase the number of biopsies taken. But it may not improve the ability to discriminate between lesions with and without CIN 2+ when compared with colposcopy. The results of the sensitivity analyses designed to explore verification bias in people with negative DYSIS and colposcopy examinations suggested that sensitivity and specificity estimates decline as the number of random biopsies taken increases.
An additional 5 studies were included in a separate narrative analysis. This confirmed the results of the meta-analyses; DYSIS improves sensitivity but reduces specificity when compared with colposcopy.
## Table 1 Diagnostic accuracy of DYSIS
Analysis
Technology
(number of studies)
Summary estimates
Sensitivity %
(95% CI)
Specificity %
(95%CI)
Forest plots of diagnostic accuracy
Colposcopy(6 studies)a
(50.31 to 66.50)
(81.26 to 91.66)
DYSISmap alone(3 studies)b
(33.10 to 85.26)
(71.25 to 92.04)
DYSISmap plus colposcopy(6 studies)a
(77.35 to 85.07)
(60.31 to 79.82)
Hierarchical bivariate analysis
Colposcopy (6 studies)a
(49.7 to 63.4)
(79.7 to 92.4)
DYSISmap plus colposcopy(6 studies)a
(76.0 to 85.1)
(60.8 to 79.3)
Logistic regression model
Colposcopy (6 studies)a
(47.2 to 67.9)
(81.7 to 91.5)
DYSISmap plus colposcopy (6 studies)a
(72.2 to 87.9)
(59.4 to 79.5)
Sensitivity analyses
Logistic regression model (excluding Roensbo et al. 2015)
Colposcopy(5 studies)c
(47.5 to 64.9)
(86.3 to 93.1)
DYSISmap plus colposcopy(5 studies)c
(75.0 to 88.7)
(63.3 to 80.7)
Studies with no biopsies in negative examinations
Colposcopy(3 studies)d
(40.89 to 83.33)
(90.23 to 94.13)
DYSISmap plus colposcopy(3 studies)d
(79.6 to 92.7)
(50.0 to 97.2)
Studies with 1 random biopsy in negative examinations
Colposcopy(Louwers et al. 2011, Soutter et al. 2009)
(43.0 to 57.5)
(79.1 to 93.3)
DYSISmap plus colposcopy(Louwers et al. 2011, Soutter et al. 2009)
(72.6 to 85.6)
(57.9 to 82.2)
Studies with multiple random biopsies in negative examinations
Colposcopy(Roensbo et al. 2015)
(56.5 to 78.8)
(60.2 to 74.3)
DYSISmap plus colposcopy(Roensbo et al. 2015)
(64.7 to 85.3)
(49.9 to 64.7)
Abbreviations: 95% CI, 95% confidence interval; NPV, negative predictive value; PPV, positive predictive value.
References:
a Budithi et al. (in press), Coronado et al. (2016), Louwers et al. (2011), Roensbo et al. (2015), Salter et al. (2016) and Soutter et al. (2009).
b Coronado et al. (2016), Louwers et al. (2011) and Roensbo et al. (2015).
c Budithi et al. (in press), Coronado et al. (2016), Louwers et al. (2011), Salter et al. (2016) and Soutter et al. (2009).
d Budithi et al. (in press), Coronado et al. (2016) and Salter et al. (2016).
## ZedScan I
Two studies were included in a narrative analysis; 1 included the current version (ZedScan I) and the other a third-generation prototype. The results are shown in table 2. Tidy et al. (in press) includes results for the current version of the device in a human papilloma virus (HPV) primary screening setting, but none for colposcopy alone. The results of the studies suggest that using ZedScan with colposcopy may have better sensitivity or specificity than colposcopy alone depending on the threshold used (which is set by the manufacturer). But when a regression model was fitted to the results from Tidy et al. (2013), the improvement in diagnostic accuracy was not quite statistically significant (difference in log diagnostic accuracy 0.488, p=0.078). However, only 1 study was available for analysis and the EAG commented that this is a conservative approach which should be considered as exploratory only.
## Table 2 Diagnostic accuracy of ZedScan
Study
Colposcopy
cut-off
Colposcopy alone
ZedScan cut-off
ZedScan plus colposcopy
Sensitivity % (95% CI)
Specificity % (95% CI)
Sensitivity % (95% CI)
Specificity % (95% CI)
Tidy et al. (in press)
ZedScan I
Not reported
Not reported
Multiple
(96.6 to 99.2)
(55.1 to 62.1)
Tidy et al. (2013) prototype device
Colposcopic impression
(64.3 to 82.8)
(76.5 to 90.5)
(64.3 to 82.8)
(85.4 to 96.2)
(69.5 to 86.8)
(76.5 to 90.5)
(51.9 to 72.3)
(91.5 to 99.3)
Disease present
(81.8 to 95.2)
(29.4 to 47.7)
(81.8 to 95.2)
(56.2 to 74.1)
(92.7 to 100)
(29.4 to 47.7)
(86.2 to 97.7)
(42 to 60.8)
Disease present: colposcopy was considered positive if at least 1 measurement point was suggested for biopsy; colposcopic impression: colposcopy was considered positive if it was judged that high-grade CIN was present.
Abbreviations: CI, confidence interval; CIN, cervical intraepithelial neoplasia.
Further data on ZedScan I were available in 2 substudies of Tidy et al. (in press). In a conference abstract Tidy et al. (2016) reported that the performance of the technology varied across colposcopy clinics in England, Ireland and Germany, with sensitivity ranging from 73.1% to 100% and specificity from 25.7% to 58.1%. McDonald et al. (2017) evaluated the accuracy of ZedScan I in people with known high-risk HPV genotypes and compared its performance among those with HPV 16 and those with other high-risk genotypes. The sensitivity of ZedScan I was high (100%) regardless of genotype but the sensitivity of standard colposcopy was higher in the HPV 16 group (86.9%) than in the other high-risk genotypes group (79.7%).
A study including 91 people (Muszynski et al. 2017) was submitted during consultation. In 1 French hospital, using ZedScan I with colposcopy increased detection of people with high-grade lesions by 47.3%. The rate at which biopsies were taken also increased when making decisions using results from both ZedScan I and colposcopy, compared with using colposcopy alone. The reported sensitivity of ZedScan I with colposcopy was 93.3% compared with 61.3% for colposcopy alone. The reported specificity of ZedScan I with colposcopy was 34.4% compared with 80.0% for colposcopy alone.
## Test positive rates
Test positive rates ranged from 21.22% to 55.51% for DYSIS and from 13.77% to 42.68% for colposcopy alone in 6 DYSIS studies (Budithi et al. in press, Coronado et al. 2016, Louwers et al. 2011, Roensbo et al. 2015, Salter et al. 2016 and Soutter et al. 2009). In each study the test positive rate was always higher for DYSIS than for colposcopy alone.
Test positive rates ranged from 30.20% to 77.04% for ZedScan, depending on the cut-off used in the 2 studies (Tidy et al. 2013, Tidy et al. in press). Test positive rates for colposcopy were 41.84% when colposcopic impression was used as a cut-off and 73.47% when disease present was used as a cut-off (Tidy et al. 2013).
## Test failure rates
Test failure rates (including failures not related to the technology) with DYSIS were reported in 6 studies and ranged from 2.9% to 31.4%. The highest failure rate was reported by Soutter et al. (2009), which included a prototype version of the system that had problems with unsatisfactory view and faulty acetic acid applicators. Failure rates for ZedScan (including failures not related to the technology) were reported in 2 studies. They were 5.6% (Zedscan I) and 13.6% (prototype; Tidy et al. in press and Tidy et al. 2013).
## Biopsy rates
All diagnostic accuracy studies included in the external assessment group's (EAG) analysis included some data on the number of diagnostic and treatment biopsies taken, but there were not enough details to assess whether the adjunctive technologies had a substantial effect on this.
Two prepublication manuscripts by Cholkeri-Singh et al. (2018) and DeNardis et al. (2017), which included additional data from the IMPROVE-COLPO trial, were submitted during consultation. Diagnostic accuracy data from this study had been included in the EAG's analysis. IMPROVE-COLPO was an observational study done in 39 colposcopy clinics in the US.
Cholkeri-Singh et al. (2018) reported results of a 2-arm observational study in which people who were prospectively assessed using DYSIS were compared with historical controls (people assessed with standard colposcopy by the same colposcopists). The yield of CIN 2+ (defined as the proportion of people with at least 1 biopsy showing CIN 2+) was higher in the DYSIS group (9.48% compared with 7.21%; p=0.014). The yield of CIN 3+ was also higher in this group (3.23% compared with 2.07%; p=0.031). The number of people having biopsies between the groups was similar (71.6% compared with 71.5%), but the average number of biopsies per person was higher for the DYSIS group (1.26 compared with 1.03).
DeNardis et al. (2017) reported results of a cross-sectional observational study in which DYSISmap was used after an initial assessment with DYSIS video colposcopy to identify further sites for biopsy. DYSIS video colposcopy-directed biopsies identified 78 people with CIN 2+; DYSISmap-assisted biopsies identified a further 34 people with CIN 2+. Also, DYSIS video colposcopy-directed biopsies identified 30 people with CIN 3+ and DYSISmap-assisted biopsies identified a further 15 people with CIN 3+. The positive predictive value of DYSIS video colposcopy-directed biopsies was 13.24% compared with 16.16% for DYSISmap-assisted biopsies.
## Subgroup analyses
Data on referrals for low-grade and high-grade cytology suggested that colposcopy was less sensitive for detecting CIN 2+ in low-grade cytology referrals. No differences in sensitivity were seen for DYSIS and ZedScan I.
There were not enough data to determine whether the accuracy of any of the technologies differed between people with and without high-risk HPV.
Founta et al. (unpublished) reported data from a test of cure population for whom the EAG calculated 95% confidence intervals. This showed a sensitivity of 0% (95% CI 0% to 53%) and a specificity of 94.0% (95% CI 89.35% to 98.65%) for colposcopy, and a sensitivity of 80.0% (95% CI 44.94% to 100%) and a specificity of 64.0% (95% CI 54.59% to 73.41%) for DYSIS in a test of cure population. The accuracy of colposcopy was substantially different in this study compared with the summary estimates provided in the meta-analyses for all colposcopy referrals.
# Clinical effectiveness
Data on adverse events were reported in 5 studies. In a ZedScan prototype study, 1 person felt unwell after the examination and 2 people had issues with bleeding after biopsies were taken. It is uncertain whether these events were related to using the ZedScan. No adverse events were reported in 4 DYSIS studies.
No data were found for morbidity and mortality associated with treatment and biopsy during colposcopy, or for health-related quality of life. There were insufficient data to determine whether the increased detection of CIN 2+ was associated with a reduction in cervical cancer.
Two systematic reviews of adverse outcomes of CIN treatment were found. Kyrgiou et al. (2015) focused on fertility and early pregnancy outcomes (less than 24 weeks' gestation). People who had treatment for CIN were at increased risk of miscarriage in the second trimester of pregnancy (relative risk 2.60, 95% CI 1.45 to 4.67). Kyrgiou et al. (2016) focused on obstetric (more than 24 weeks' gestation) and neonatal outcomes. People who had large-loop excision of the transformation zone (LLETZ) were at increased risk of giving birth prematurely (relative risk 1.56, 95% CI 1.36 to 1.79). The risk increased as the depth of the excision increased.
# Implementation
Five studies were included in the implementation review. Of these, 3 were done in the UK (Lowe et al. 2016, Palmer et al. 2016 and Budithi et al. in press), 1 in Spain (Coronado et al. 2014) and 1 in the Netherlands (Louwers et al. 2015). None of the studies used validated questionnaires.
## Patient and clinician satisfaction
Lowe et al. (2016) surveyed 763 patients in 4 NHS hospitals that were using DYSIS. Two questionnaires were used: 1 for people having their first colposcopy and 1 for people who had previously had a colposcopy. The number of respondents per questionnaire was not reported in the conference abstract available to the EAG. Participants reported that DYSIS did not take longer than their previous smear test or colposcopy and that anxiety was reduced during and after examinations compared with previous examinations.
Louwers et al. (2015) gave a patient satisfaction questionnaire to 239 people who had a DYSIS examination. Results showed that 93.9% of people agreed or strongly agreed to have colposcopy with DYSIS if it helped locate CIN; 29.5% agreed or strongly agreed that DYSIS was less comfortable than a cervical smear; 16.5% reported that DYSIS made them feel nervous during the examination, and 6.5% thought that an examination with DYSIS took too long.
Budithi et al. (2017) gave questionnaires to both patients and colposcopists in 5 colposcopy clinics in Wales; 68 patients responded and 45 colposcopist responses were received (the number of colposcopists was not reported in the abstract). Results from patients showed that 86% agreed or strongly agreed that the DYSIS images helped their understanding and were reassuring; 52% believed DYSIS to be more accurate than their previous colposcopy; 4% thought that DYSIS lasted too long compared with previous colposcopies and 13% found it less comfortable. Of the responses received from colposcopists, 96% agreed or strongly agreed that they were confident about colposcopy and their decision-making in selecting biopsy sites. But only 48% went on to agree that DYSISmap affected their selection of biopsy sites; 58% said they were able to identify additional sites with DYSISmap and 55% agreed or strongly agreed that DYSISmap improved their colposcopic examination.
## Colposcopist experience
Coronado et al. (2014) surveyed 63 colposcopists with different levels of experience. A retrospective review of 50 colposcopy and DYSISmap images was also done. The study found that the correct diagnosis (either normal, low-grade lesion, high-grade lesion or cancer) was made more frequently with DYSIS than with standard colposcopy for colposcopists with low and medium levels of experience. There was no difference for highly experienced colposcopists. All groups agreed that DYSIS is better at directing diagnosis and provides more information than standard colposcopy. The survey also reported that using DYSISmap improved detection of CIN 2+ by colposcopists of all experience levels. However, the EAG noted that this was based on a small subgroup analysis of the retrospective review of stored images.
# Cost effectiveness
## Review of economic evidence
Two relevant economic evaluations were identified; 1 for DYSIS compared with colposcopy over a lifetime time horizon (Wade et al. 2013) and another for a ZedScan prototype compared with colposcopy over a 3‑year time horizon (Whyte et al. 2013). Wade et al. was produced for NICE's diagnostics guidance 4 on adjunctive colposcopy technologies and found that DYSIS dominated colposcopy (that is, DYSIS cost less and was more effective than colposcopy). Whyte et al. reported lower costs associated with the use of a prototype ZedScan device per person with CIN 2 or 3 treated, because it reduced both rates of overtreatment and the number of follow-up appointments needed for people with CIN 1. However, this was associated with a reduction in the number of CIN 2 or 3 lesions treated and a consequent reduction in the number of cancers detected. Neither study fully addressed the decision problem.
## Modelling approach
The EAG developed a de novo economic model designed to assess the cost effectiveness of DYSIS and ZedScan I, used with colposcopy, in both an HPV triage and an HPV primary screening setting. The analyses took the perspective of the NHS and personal social services and had a 60‑year (lifetime) time horizon. All costs and effects were discounted at 3.5%.
A patient-level state-transition model with a 6‑month cycle time was constructed using TreeAge Pro (2016) software. The model included 500,000 simulations to ensure that first-order uncertainty was adequately captured, that is, variability in the simulated experiences between identical patients. The model incorporated both screening and treatment pathways: 1 submodel simulated the natural history of CIN and cervical cancer, and another submodel simulated adverse obstetric outcomes for people who had treatment for CIN. The adverse obstetric outcome model captured the costs and quality-adjusted life year (QALY) decrements associated with initial management and the increased probability of neonatal mortality and QALY decrements associated with higher risks of disability among infants born preterm. The natural history model was adapted from Kulasingam et al. (2013) with invasive cancer parameters taken from Campos et al. (2014).
At the beginning of the first cycle each person is referred for colposcopy and has treatment if needed, before entering the natural history model. In subsequent cycles, the person can follow 1 of 4 screening and treatment pathways: no screening, colposcopy referral, routine screening, or a follow-up pathway for those who have had previous treatment, unless they died in the previous cycle. Every pathway ends with the person entering the natural history model.
The model was implemented using a random walk and for each person it simulated the following uncertain events occurring: disease progression, diagnostic results or treatment outcomes. The characteristics that determined the associated events and transitions for each person in the model were:
age
health state (clear, HPV, CIN 1, CIN 2 or 3, cancer)
reason for referral for colposcopy (high-grade or low-grade cytology)
next scheduled screening (routine call, 6‑month cytology, 6‑month colposcopy, test of cure, CIN 1 follow-up)
time elapsed since last screening
type of clinic visited ('see and treat' or 'watchful waiting').Identical patients were run through each treatment strategy and random numbers were maintained across all runs of the model.
Two base cases were modelled: HPV triage and HPV primary screening. The modelled pathways for HPV triage were based on those outlined in the NHS cervical screening programme's (NHSCSP) colposcopy and programme management guidelines (2016). For HPV primary screening the modelled pathways were based on the testing algorithms used in the NHSCSP's pilot sites.
The diagnostic accuracy estimates used in the model are shown in table 3.
## Table 3 Accuracy estimates used in the model
Technology
(source)
Sensitivity % (95% CI)
Specificity % (95%CI)
Colposcopy alone
(regression model)
(47.2 to 67.9)
(81.7 to 91.5)
DYSIS
(regression model)
(72.2 to 87.9)
(59.4 to 79.5)
ZedScan I
(Tidy et al. )
(96.5 to 99.2)
(55.1 to 62.1)
Abbreviation: CI, confidence interval.
The performance of cytology in both the HPV triage and HPV primary screening scenarios was modelled using data from Hadwin et al. (2008) and from the NHSCSP statistical bulletin (2015/16). The diagnostic accuracy of HPV testing in HPV triage was modelled using data from the TOMBOLA study (Cotton et al. 2010) and in HPV primary screening from the ARTISTIC study (Kitchener et al. 2014).
In the model, people referred for colposcopy have 2 initial characteristics; a true underlying health state (clear, HPV, CIN 1, CIN 2 or 3, or cancer) and a reason for referral (low-grade or high-grade lesions). These joint distributions were taken from the NHSCSP statistical bulletin (2015/16) for HPV triage and unpublished data provided by the NHSCSP pilot sites for HPV primary screening, and were influenced by disease prevalence and the accuracy of screening.
Heterogeneity in treatment decisions after a positive colposcopy was modelled using 2 different types of clinic; a 'watchful waiting' clinic or a 'see and treat' clinic. The probability of treatment failure after an excisional biopsy was taken from Ghaem-Maghami et al. (2011) and ranged from 4.9% for CIN 1 to 10.3% for CIN 3. The probability of adverse obstetric outcomes after treatment was estimated by applying the relative risk of preterm birth (1.56) from Kyrgiou et al. (2016) to the probability of preterm birth for people with untreated lesions as reported in NICE's guideline on preterm labour and birth (7.3%). This gave an excess risk of 4.09% for preterm birth after LLETZ treatment.
The average cost per person of using the technologies was calculated using information from companies and clinical experts. The costs include the capital cost of the technologies (spread over 15 years for a colposcope and over 5 years for DYSIS and ZedScan I), annual maintenance costs and consumable costs. To calculate the average cost per procedure, and to be consistent with Wade et al. (2013), it was assumed that 1,229 people per year were seen. The following costs per person were assumed:
colposcopy: £3.75
DYSIS: £9.24
ZedScan I: £30.52.
Biopsy and treatment costs were taken from NHS reference costs. The cost of a cytology and HPV test were taken from the TOMBOLA study and inflated to 2016 prices. The values used in the model for screening events are shown in table 4.
## Table 4 Costs of screening events
Treatment
Device
Cost per treatment
Colposcopy examination only
Colposcopy
DYSIS
ZedScan I
Diagnostic biopsy
LLETZ
Cytology test
HPV test
Abbreviations: HPV, human papilloma virus; LLETZ, large-loop excision of the transformation zone.
Cancer treatment costs were taken from Martin-Hirsch et al. (2007). Costs associated with adverse obstetric outcomes were taken from Lomas et al. (2016) and inflated to 2016 prices. It was assumed that a preterm birth costs £24,610, which takes into account initial inpatient neonatal care and ongoing costs for the first 18 years of life.
Health-related quality-of-life estimates were taken from the published literature. The disutilities associated with screening, diagnosing and treating CIN were taken from Simonella and Canfell (2014) and are shown in table 5. Age- and gender-specific utilities from Kind et al. (1999) were applied to the HPV, CIN 1 and CIN 2 or 3 asymptomatic health states. Disutilities associated with cervical cancer were taken from Goldie et al. (2004) and a QALY decrement of 1.3 was applied for preterm birth (Lomas et al. 2016).
## Table 5 Disutilities for screening, diagnosis and treatment of CIN
Screening event
QALY decrement
Negative cytology or HPV
False positive referral for colposcopy
Diagnosed CIN 1
Treatment of CIN
Abbreviations: CIN, cervical intraepithelial neoplasia; HPV, human papilloma virus; QALY, quality-adjusted life year.
## Base-case results
The following assumptions were applied in the base-case analysis:
Diagnostic accuracy estimates for both colposcopy and the adjunctive technologies were based on a cut-off of CIN 2+.
The probability of a positive colposcopy result was:
identical for people with clear, HPV or CIN 1 results
identical for people with CIN 2 or 3 or invasive cancer.
The choice between a 'see and treat' clinic and a 'watchful waiting' clinic was independent of diagnostic accuracy.
Biopsy and histopathology (the reference standard) were 100% accurate.
Excision at the first colposcopy appointment was only possible for referrals for high-grade lesions with a positive colposcopy result.
For low-grade lesion referrals, CIN 2+ was confirmed by diagnostic biopsy before treatment.
CIN 1 lesions were not treated and people had a 12‑month follow-up screening in the community.
People whose lesions were treated for CIN remained at risk of preterm birth (before 37 weeks' gestation) for each year after treatment up to the age of 45.
When cancer was detected, treatment was offered appropriate to the stage. An excess risk of mortality was applied for 5 years and decreased according to time since diagnosis.
DYSIS or ZedScan I examinations were the same length as a standard colposcopy examination.
ZedScan I was used for diagnostic colposcopies only.
There were 2 base cases: 1 for HPV triage and 1 for HPV primary screening. In a 'see and treat' clinic, treatment was done at the first visit for people who had a referral for a high-grade lesion according to cytology and a colposcopy examination graded as CIN 2+. In a 'watchful waiting' clinic, treatment was done at the second visit when the results of any diagnostic biopsies showed CIN 2+.
The results of the HPV triage base case showed that both technologies dominated standard colposcopy in 'see and treat' clinics (that is, they cost less and are more effective). In 'watchful waiting' clinics, DYSIS dominated standard colposcopy for low-grade lesion referrals and for all referrals combined, but had an incremental cost-effectiveness ratio (ICER) of £675 per QALY gained for high-grade lesion referrals compared with standard colposcopy. ZedScan I had an ICER of £272 per QALY gained for low-grade lesion referrals and £4,070 per QALY gained for high-grade lesion referrals. For all referrals, it had an ICER of £418 per QALY gained. Indirect comparisons suggest that ZedScan I always costs more but is more effective than DYSIS in both 'see and treat' and 'watchful waiting' clinics. The results of the HPV primary screening base case were similar to the HPV triage base case. The EAG highlighted that because the diagnostic accuracy of DYSIS and ZedScan I have not been compared directly, these results should be considered exploratory.
The number of treatments, biopsies and missed disease in each base case is shown in table 6. This table shows the cumulative occurrence of events over the lifetime of the modelled cohort, therefore an event can occur more than once per person. Because of their increased sensitivity, the adjunctive technologies are associated with less missed disease and so less cancers. However, they also have reduced specificity and result in more unnecessary diagnostic biopsies and treatments (except in 'watchful waiting' clinics).
## Table 6 Secondary outcomes per 1,000 people referred for colposcopy (60‑year time horizon)
Clinic
Strategy
Missed CIN 2+*
Cancers
LLETZ
UnnecessaryLLETZ
Unnecessary diagnostic biopsy
HPV triage
'See and treat'
Colposcopy
DYSIS
ZedScan I
'Watchful waiting'
Colposcopy
DYSIS
ZedScan I
HPV primary screening
'See and treat'
Colposcopy
DYSIS
ZedScan I
'Watchful waiting'
Colposcopy
DYSIS
ZedScan I
- Missed CIN 2+ refers to the number of CIN 2+ cases not detected by the technologies (colposcopy, DYSIS, ZedScan I) rather than cases not detected following referral for colposcopy. In the model people with high-grade cytology referrals have a diagnostic biopsy and are identified as CIN 2+ even if a colposcopic examination is incorrectly negative.
Abbreviations: CIN 2+, cervical intraepithelial neoplasia grade 2 or worse; HPV, human papilloma virus; LLETZ, large-loop excision of the transformation zone.
## Scenario analyses
The following scenario analyses were done to explore the effect of alternative structural assumptions:
time horizon restricted to 1 screening interval (3 years)
adverse obstetric outcomes excluded
ZedScan I used in both diagnostic and treatment colposcopies.
When the time horizon was restricted to 3 years, colposcopy dominated (that is, it cost less and was more effective) both DYSIS and ZedScan I in most scenarios except for high-grade lesion referrals in HPV triage 'see and treat' clinics. In this scenario, DYSIS had an ICER of £236,692 saved per QALY lost and ZedScan I had an ICER of £84,045 saved per QALY lost. For HPV primary screening, the respective ICERs were £250,587 saved per QALY lost for DYSIS and £110,371 saved per QALY lost for ZedScan I. Colposcopy generally dominated because its higher specificity resulted in fewer treatments, and because people with untreated CIN (false negatives) did not go on to develop cancer within the 3‑year time horizon. The results of the model did not change substantially in the other scenario analyses.
## Sensitivity analyses
The following inputs were changed in sensitivity analyses to explore the effect of parameter uncertainty:
diagnostic accuracy
costs of the technologies
costs of treatment and biopsies
characteristics of the population referred for colposcopy in HPV primary screening.
When the accuracy of colposcopy relative to ZedScan I was taken from Tidy et al. (2013), the incremental costs associated with ZedScan I compared with colposcopy increased, whereas the QALYs decreased. Under these assumptions ZedScan I became less cost effective than in the base case and it no longer dominated colposcopy in 'see and treat' clinics. Its highest ICER was £24,686 per QALY gained for high-grade lesion referrals in HPV primary screening 'watchful waiting' clinics.
The DYSIS results were sensitive to assumptions around reduced throughput and a consequent increase in cost per test because of its higher purchase price. When it was assumed that only 614 people per year were seen, it no longer dominated colposcopy in HPV primary screening 'watchful waiting' clinics and had an ICER of £270 per QALY gained for all referrals. None of the other sensitivity analyses changed the results substantially.
The ZedScan I results were sensitive to changes in the cost of diagnostic and treatment biopsies because of its increased sensitivity and lower specificity than colposcopy. When the cost of a diagnostic biopsy was increased to £102.72 and a treatment biopsy (LLETZ) to £490.89, ZedScan I no longer dominated colposcopy for low-grade lesion referrals and all referrals combined. Under these assumptions, its highest ICER was £6,709 for high-grade referrals to an HPV primary screening 'watchful waiting' clinic. None of the other sensitivity analyses changed the results substantially.# Committee discussion
# Current practice
The committee discussed current practice for assessing suspected cervical abnormalities in a colposcopy clinic. The clinical experts explained that NHS clinics most often use binocular colposcopy, which allows a colposcopist to examine a cervix and take both diagnostic and treatment biopsies under direct visualisation. Acetic acid is used to highlight areas of abnormality. The committee noted that colposcopy is associated with both intra- and inter-observer variability because it is a visual examination that is highly dependent on the colposcopist's expertise. The committee considered the role of the adjunctive colposcopy technologies and was advised by the clinical experts that the technologies could provide less subjective results and help colposcopists select areas for biopsy. The clinical experts also explained that the technologies could help identify high-grade lesions in people referred for colposcopy because of low-grade cytology.
The committee noted that a series of changes are being made to the screening pathways used in the NHS cervical screening programme (NHSCSP). Human papilloma virus (HPV) triage was fully implemented in England in April 2014. HPV primary screening is currently being done in several pilot sites, with full implementation in England expected in 2019. These changes could affect referrals to colposcopy clinics and consequently the prevalence of high-grade disease, particularly when people with a HPV-positive cytology-negative screening result are seen in colposcopy. The committee concluded that there had been substantial changes to the care pathways since NICE's first diagnostics assessment of the DYSIS colposcope with DYSISmap in 2012.
# Diagnostic accuracy and clinical effectiveness
The committee discussed the external assessment group's (EAG) critical appraisal of the included diagnostic accuracy studies. It noted that the greatest risk of bias in the studies occurred because not all patients had the reference standard test (colposcopically directed biopsies and histopathology). In most studies, people who had a negative colposcopy did not have biopsies taken. The clinical experts explained that it was not considered good clinical practice to take biopsies when there was no clinical indication. But the committee noted that the EAG's sensitivity analyses on the effect of verification bias showed that the more random biopsies taken, the lower the estimates of both sensitivity and specificity. The committee concluded that the diagnostic accuracy estimates provided by the included studies were likely to have been influenced by verification bias, and highlighted that future studies should aim to minimise this when possible.
The committee considered the applicability of the diagnostic accuracy studies that were done outside the UK. The clinical experts explained that the quality assurance measures for colposcopy done outside the UK are different to those in the UK, and that this was likely to influence the accuracy of colposcopy. The committee noted that the NHSCSP recommends that a satisfactory colposcopy should have a 65% positive predictive value for CIN 2+. It considered that although positive predictive value was likely to be influenced by several confounding factors, video colposcopy in the DYSIS studies did not achieve this benchmark, with a pooled positive predictive value of 55.78%. However, the committee noted that because this value depends on disease prevalence, the use of positive predictive value to assess the generalisability of studies to UK practice is problematic. The clinical experts also noted that the pooled sensitivity of colposcopy in the DYSIS studies was lower than they would expect to see in the UK. They also noted that in the ZedScan I study, which was done in the UK and used binocular colposcopy, a higher sensitivity for colposcopy was reported. The committee concluded that because of differences in colposcopy practice, such as fewer quality assurance measures and the use of video colposcopy, the accuracy data from non-UK studies may not be generalisable to the NHSCSP.
The committee considered the potential for the adjunctive colposcopy technologies to reduce both intra- and inter-observer variability. The companies explained that the technologies are designed to reduce the subjectivity of colposcopy by providing more objective results, but noted that no data on the reproducibility of the tests had been presented for the assessment. However, the committee noted published data suggesting that clinicians felt that the DYSISmap improved their confidence when selecting biopsy sites. It concluded that the technologies had the potential to help standardise colposcopy examinations, but that insufficient data were available to determine whether this benefit would be realised in NHS clinical practice.
The committee discussed the results of the diagnostic accuracy analyses for the DYSIS colposcope with DYSISmap and the ZedScan I. It noted that although the accuracy estimates for colposcopy alone in the DYSIS and ZedScan studies varied considerably, the estimates suggested that the technologies were more sensitive but less specific than colposcopy alone. It considered that in practice this would result in a reduced false negative rate with more people being diagnosed with CIN 2 or worse (CIN 2+). But this could be at the expense of a higher false positive rate with more people having unnecessary diagnostic biopsies and treatment. The committee further noted that the diagnostic odds ratios, which had been calculated by the EAG for the DYSIS colposcope with DYSISmap studies, suggested that there was no difference between the accuracy of DYSIS colposcopy alone and DYSIS colposcopy with DYSISmap. The committee concluded that the results of the diagnostic accuracy studies suggest that it is plausible that the adjunctive colposcopy technologies may change the test threshold so that more people have biopsies, but without improving colposcopists' ability to differentiate between high- and low-grade disease.
The committee discussed the Cholkeri-Singh et al. (2018) and DeNardis et al. (2017) studies, submitted as prepublication manuscripts during consultation. These provided data from the IMPROVE-COLPO study. It acknowledged that these studies provide real world outcome data on the number of biopsies taken and supplement the diagnostic accuracy data in the EAG's systematic review. The committee noted that the results of the Cholkeri-Singh et al. study show that DYSIS with DYSISmap detects additional cases of both CIN 2 and CIN 3, relative to standard colposcopy, without increasing the number of people having biopsies. The committee considered the design of this study and noted a lack of detail on the methods used to ensure that controls in the retrospective arm were comparable with the people in the prospective arm. However, the committee heard from the EAG that the people in the 2 study arms appear to be comparable for key baseline characteristics. The committee also considered analyses provided at consultation based on KC65 data (from the NHSCSP in England between 2012/13 and 2015/16). It noted that the data generally showed no increase in biopsy rates in centres adopting DYSIS, but it acknowledged that DYSIS may not be used for every colposcopy in these centres. The committee concluded that despite these papers having methodological limitations, combined with the KC65 data they provided some reassurance that the increase in biopsies implied by the results of the diagnostic accuracy studies alone may not be realised in practice in centres using DYSIS colposcopy with DYSISmap.
A patient expert explained that referral for colposcopy can often cause substantial anxiety, which may not reduce even when the colposcopy is normal. People having a colposcopy may be anxious because of the examination itself and because they have already had a screening result informing them that an abnormality has been detected. The clinical experts explained that it can often be difficult to reduce anxiety in people who have a negative colposcopy, but who were referred with an HPV-positive result, because no treatment can be offered. The committee noted evidence from the systematic review and also anecdotal evidence from clinical and patient experts, which suggested that the adjunctive colposcopy technologies could reduce anxiety because people can be shown objective information to explain that no abnormality has been detected. The committee concluded that although the additional information provided by the adjunctive colposcopy technologies has the potential to help clinicians reassure people and reduce their anxiety, there are currently insufficient data to conclude that they have a significant effect on this (see section 6.3).
# Cost effectiveness
The committee discussed the assumption made in the cost-effectiveness model that video colposcopy and binocular colposcopy are equivalent in terms of diagnostic accuracy. The clinical experts explained that there was no consensus among experts about their equivalence and that the sensitivity estimates for video colposcopy obtained in the DYSIS studies were lower than would be expected for binocular colposcopy in the NHS. Also, the clinical experts noted that the estimates for the sensitivity of binocular colposcopy in the ZedScan studies were higher, and more representative of NHS practice. But the committee noted that the estimates used in the cost-effectiveness model for colposcopy alone were taken from the meta-analyses of DYSIS colposcopy. Therefore, the committee concluded that the relative benefits of the adjunctive colposcopy technologies could have been overestimated in the modelling.
The committee discussed both modelled base cases and noted that the increased sensitivity of the adjunctive colposcopy technologies led to less cervical cancers developing over the 60‑year time horizon. The clinical experts explained that the additional high-grade lesions detected using the adjunctive colposcopy technologies could in fact be low-volume CIN 2 disease, which could regress without treatment. The committee questioned whether data were available that explained the natural history of low-volume CIN 2 but heard that these were not available. Anecdotal evidence, and results of a British Society for Colposcopy and Cervical Pathology survey, suggest that some clinicians are now using either ablative techniques or 'watchful waiting' management strategies for low-volume CIN 2 in some circumstances. The committee also noted that when the time horizon of the model was reduced to 3 years, and the longer-term outcomes associated with increased sensitivity were removed, colposcopy alone dominated; that is, it was more effective and less expensive than the adjunctive colposcopy technologies. The committee concluded that, without clinical outcome data, or data on the natural history of low-volume CIN 2, there was uncertainty about the longer-term outcomes associated with the increased sensitivity of the adjunctive colposcopy technologies. It wished to encourage further data collection to resolve this (see section 6.4).
The committee discussed the effect of the lower specificity associated with the adjunctive colposcopy technologies on longer-term outcomes in the model. In the shorter term, the model showed that reduced specificity is associated with an increase in unnecessary biopsies and treatments. The committee questioned whether this would be realised in practice. The EAG advised that the assumptions made in the model about when biopsies would be taken were based on the NHSCSP's colposcopy and programme management guidelines (2016; publication number 20). The clinical experts explained that these guidelines may not always be followed, and colposcopists may take biopsies for reassurance that high-grade disease is not present. The committee noted that there is considerable variation in clinical practice between colposcopists, and that there were no data to show how the adjunctive colposcopy technologies affect clinical decision-making in the UK. The committee also noted its previous conclusion (see section 5.7) that results from the prepublication version of Cholkeri-Singh et al. (2018) study and the KC65 data (from the NHSCSP in England between 2012/13 and 2015/16) showed no increase in biopsy rates in centres adopting DYSIS. It also noted that Cholkeri-Singh et al. reported that using DYSIS was associated with an increased yield of CIN 2+ which, combined with the data on biopsy rates, suggests that DYSIS helps colposcopists target the areas chosen for biopsy. The committee concluded that there is some real world evidence suggesting that DYSIS does not increase the biopsy rate to the extent predicted by the model, and noted that equivalent data were not yet available for ZedScan I.
The committee discussed whether reduced specificity is associated with an increased risk of adverse obstetric outcomes in the longer term. The clinical experts explained that the relationship between biopsies, treatment and adverse obstetric outcomes was not well understood, but it was generally acknowledged that the smaller the excisional treatment the lower the risk of adverse outcomes. The committee noted that the base case assumed an excess risk of preterm delivery of 0.04, which was reduced to 0 in a scenario analysis with no substantial effect on the results. The committee concluded that although they were an important clinical consideration in practice, the longer-term effects of reduced specificity did not seem to be a key driver in the model.
The committee questioned the cost savings of the adjunctive colposcopy technologies in the model. The EAG explained that the model's cost savings were driven by increased sensitivity, which led to a reduction in costs associated with both cancer treatment and follow-up appointments. The clinical experts noted that technologies that improve the negative predictive value of colposcopy may become more important after HPV primary screening is fully rolled out and people with HPV-positive, cytology-negative results are referred for colposcopy. The committee noted that the base case for HPV primary screening was based on preliminary data only, but acknowledged that improvements in sensitivity may become increasingly important in the future. The committee concluded that because there were no data on the natural history of low-volume disease, it was uncertain whether the adjunctive colposcopy technologies would increase the detection of disease that would progress to cancer if not treated. Therefore, the cost savings in the model may not be robust.
The committee questioned the effect of not having a probabilistic sensitivity analysis to quantify the overall uncertainty in the model. The EAG explained that it could not do this analysis because of the length of time needed to run each simulation. The EAG also explained that although the mean ICER may be different from the deterministic analyses if the model was run probabilistically, there was unlikely to be a substantial difference that would change the modelling conclusions. The committee noted that the model results had been robust to changes in many parameter estimates and assumptions in the deterministic sensitivity and scenario analyses, but that the results were likely to be confounded by the lack of clinical outcome data. The committee concluded that on this occasion the lack of a probabilistic sensitivity analysis was not critical.
The committee considered whether the adjunctive colposcopy technologies should be recommended for routine adoption. It noted its conclusions on the applicability of data from non-UK studies where the accuracy of colposcopy may differ (see section 5.4), the lack of data on the natural history of low-volume CIN 2 (see section 5.10) and the uncertainty about whether the adjunctive colposcopy technologies would reduce cervical cancer over the longer term (see section 5.13). Taking these factors into account, the committee considered that there was uncertainty about the clinical and cost effectiveness of the adjunctive colposcopy technologies because only diagnostic accuracy data were available. It noted, however, that further data (prepublication versions of Cholkeri-Singh et al. 2018 and DeNardis et al. 2017) provided at consultation showed that DYSIS was able to detect more CIN 3 lesions than standard colposcopy, without increasing the number of people having biopsies. Therefore, the committee concluded that there was enough evidence that colposcopy using DYSIS with DYSISmap detects more clinically important lesions than colposcopy alone to recommend its continued adoption. It also noted that the additional data provided at consultation were from a US study. The committee wished to encourage centres using DYSIS to audit their outcomes and confirm that the expected benefits are achieved in the NHS (see section 5.16). Also, the committee concluded that although the ZedScan I shows promise, there was too much uncertainty over clinical and cost effectiveness to recommend its routine adoption at present, and recommended that further research was needed (see section 5.17).
# Research considerations
The committee recalled that the available clinical outcome data that support using DYSIS with DYSISmap were from a US study (see section 5.15). It therefore recommended that centres using this technology should audit their clinical outcomes and confirm that the expected benefits are achieved in the NHS. Outcomes that should be audited include, but are not limited to, rates of CIN 2+ detection, CIN 3+ detection and biopsy.
The committee considered the amount of evidence available for both adjunctive technologies. It noted that more data were available for the DYSIS system, and that evidence for ZedScan I was limited to a small number of diagnostic accuracy studies. The committee considered that ZedScan I shows promise but further studies are needed, in particular to compare the accuracy and the clinical effectiveness of the technology with standard colposcopy.
The clinical experts explained that all colposcopy clinics complete a quarterly data return for Public Health England, the KC65. This is used to compare and assess their data against the standards outlined in NHSCSP's colposcopy and programme management guidelines (2016). The committee considered whether these data could be studied to see if biopsy and detection rates of CIN 2+ had increased in centres that had already adopted DYSIS colposcopy with DYSISmap or the ZedScan I. The clinical experts explained that the device used in each colposcopy is not currently recorded and it is not known whether centres with an adjunctive colposcopy technology use it routinely. The committee acknowledged that making the necessary changes to the KC65 to collect these data would be difficult. However, it wished to encourage the owners of the KC65 dataset to consider whether it could be adapted in the future and used to support further data collection for the adjunctive colposcopy technologies, and whether papers based on the data could be published and used for updates of this guidance. The committee also suggested that, if it is not possible to use the KC65 to collect these data nationally, then local audits should be used to collect these data from services that have adopted the adjunctive technologies.
The committee identified that different thresholds had been used to assess the accuracy of colposcopy in the studies. Some used colposcopic impression that high-grade disease was present (that is, what the colposcopist thought). In other studies colposcopy was considered positive if at least 1 measurement point was suggested for biopsy (that is, what action was taken). Some studies used both. This made comparison of the relative cost effectiveness of the adjunctive technologies difficult. The committee considered that a more consistent approach to assessing and reporting colposcopic accuracy in studies would help future comparisons of adjunctive technologies. The clinical experts stated that work on producing standards for reporting colposcopic accuracy in the NHSCSP is being done.
The committee noted the assumption made in the cost-effectiveness model that video colposcopy and binocular colposcopy are equivalent in terms of diagnostic accuracy (see section 5.9). The clinical experts explained that there is limited evidence to support this assumption. Future assessments of adjunctive technologies would benefit from research assessing the equivalence of different types of colposcope (digital, video and binocular).# Recommendations for further research
The committee noted that human papilloma virus (HPV) primary screening is being implemented across England (see section 5.2) and that the base-case economic modelling for HPV primary screening in this assessment was based on preliminary data only (see section 5.13). The committee recommended that further studies should be done in a HPV primary screening setting. These studies should incorporate clinical outcome data and be designed to minimise verification bias. Future studies should consider measuring variability and should also take into account HPV genotyping status when possible, so that the difference in accuracy in a population vaccinated against HPV types 16 and 18 can be better understood.
The committee noted that there were no data to show how the adjunctive colposcopy technologies affect UK clinical decision-making, when all colposcopy is done by accredited colposcopists (see section 5.11). It therefore recommended that data should be collected to show how the results of the technologies affect decision-making, including biopsy decisions and decisions to discharge people with a negative colposcopy examination back to routine screening.
The committee considered that the adjunctive colposcopy technologies had the potential to improve patient experience and reduce anxiety (see section 5.8). Further research is needed to understand the effect of having the additional information provided by the adjunctive colposcopy technologies on anxiety for people having a colposcopy, when this information is shown to a person during the examination.
The committee recommended that further research is needed to better understand the natural history of low-volume cervical intraepithelial neoplasia (CIN) 2 lesions. It noted that this is not captured in the current versions of the natural history models for CIN and cervical cancer (see section 5.10), but is likely to become increasingly important for colposcopy services as HPV primary screening is rolled out and vaccinated groups enter the screening programme.
|
{'Recommendations': 'The Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap shows promise and is recommended for assessing suspected cervical abnormalities in people having colposcopy. Centres using the technology should audit their outcomes (see section\xa05.16).\n\nFurther research is recommended on the effects of using the DYSIS colposcope with DYSISmap on clinical and patient outcomes in a human papilloma virus primary screening setting, and on patient experience (see sections\xa06.1 to\xa06.3).\n\nThe ZedScan\xa0I shows promise in assessing suspected cervical abnormalities, but there is currently not enough evidence to recommend its routine adoption. Further research on the effects of using the technology on clinical and patient outcomes is recommended (see sections\xa06.1 to\xa06.3). Colposcopy services that implemented the ZedScan\xa0I before this guidance was published are encouraged to take part in studies that address these research recommendations.', 'Clinical need and practice': "# The problem addressed\n\nThe Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap and the ZedScan\xa0I adjunctive colposcopy technologies are intended to be used with colposcopy to help identify cervical intraepithelial neoplasia (CIN) during a colposcopy examination. CIN is a term used to describe precancerous changes in cells in the surface layer of the cervix (the cervical epithelium). Most changes arise in the transformation zone, where the endocervical canal (the internal canal of the cervix) meets the external part of the cervix. This is the area examined during standard colposcopy, and from where a sample is taken for cervical screening. Less often, abnormalities occur on the inside of the cervical canal instead of the surface. These changes are known as cervical glandular intraepithelial neoplasia.\n\nStandard colposcopy is subjective and can be associated with both inter- and intra-observer variability, particularly with lower-grade abnormalities. It is usually done using a binocular colposcope, unless the clinic has a DYSIS colposcope that incorporates a digital (video) colposcope. The adjunctive colposcopy technologies aim to evaluate cellular changes objectively, using optical or electrical impedance spectroscopy to assess the characteristics of cervical cells.\n\nThe results provided by the technologies can help a colposcopist to decide whether further treatment or biopsies are needed, by guiding them to areas that are most likely to be abnormal. If the results do not suggest any areas of abnormality, and standard colposcopy is normal, the colposcopist can be more confident that high-grade disease is unlikely to be present. It is claimed that using the devices may result in more accurate detection of cervical abnormalities and identification of the correct sites for biopsy.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of the DYSIS colposcope with DYSISmap and the ZedScan\xa0I. It is a full update of NICE's diagnostics guidance on the DYSIS colposcope with DYSISmap and the Niris Imaging System, which was published in 2012. NICE's original guidance concluded that DYSIS was a clinically and cost-effective option compared with standard colposcopy. Since the guidance was published there have been changes to the care pathway (see sections\xa02.9 and\xa02.10) and changes to the CE-marked products. Also, the Niris Imaging System is no longer available.\n\n# The condition\n\n## Cervical intraepithelial neoplasia and cervical cancer\n\nCervical cancer is one of the less common cancers in the UK, largely because of the NHS cervical screening programme (NHSCSP). In 2013 there were 3,200\xa0cases of cervical cancer in the UK (Cancer Research UK), which accounted for less than 1% of all new cases of cancer. In 2014 there were 890\xa0deaths from cervical cancer in the UK (Cancer Research UK). The main cause of cervical cancer is persistent infection with high-risk genotypes of human papilloma virus (HPV; hereafter referred to as high-risk HPV), which causes changes in the cervical cells that can progress to cervical cancer if not treated.\n\nCIN is classified based on the depth of abnormal cells in the surface layer of the cervix seen on a diagnostic or excisional (treatment) biopsy:\n\nCIN\xa01: one third of the thickness of the surface layer is affected\n\nCIN\xa02: two thirds of the thickness of the surface layer is affected\n\nCIN\xa03: the full thickness of the surface layer is affected.Grades\xa02 and\xa03, often referred to as high-grade, are usually treated to prevent possible progression to cervical cancer. But expert advice suggests that CIN\xa02 may be managed more conservatively in people who have smaller lesions and who have not completed their family.\n\n# The diagnostic and care pathways\n\n## Diagnosis\n\nPrecancerous changes to cells in the cervix are detected by cervical screening. People are invited, through the NHSCSP, to have cervical screening every 3\xa0years for those aged 25 to 49 and every 5\xa0years for those aged 50 to 64. It involves taking a sample of cells from the cervix, usually the transformation zone (see section\xa02.1), using a specially designed brush. The cells are preserved using liquid-based cytology kits and are sent to a cytology laboratory where they are examined under a microscope.\n\nThe criteria for reporting cervical cytology and the management protocols for results are outlined in the NHSCSP's achievable standards, benchmarks for reporting, and criteria for evaluating cervical cytopathology (commonly known as ABC3; 2013). Samples are graded depending on the degree of abnormality, known as dyskaryosis (changes to the nucleus of a cell), seen under the microscope. Finding dyskaryotic cells suggests the presence of CIN.\n\nThe current management protocols for cervical cytology are described in the third edition of the NHSCSP's colposcopy and programme management guidelines (2016). Currently, people with samples that show high-grade dyskaryosis or worse are referred for colposcopy. If low-grade dyskaryosis is seen, the residual cells collected during the cervical screen are used for high-risk HPV testing to determine whether a colposcopy referral is needed. This is part of the management protocol referred to as HPV triage. The HPV test helps to identify people who are at the greatest risk of having abnormalities that may need further investigation and treatment. If low-grade dyskaryosis is seen but HPV is not detected, the risk of having underlying abnormalities is low and the cellular changes are likely to resolve without further investigation or treatment.\n\nIn July 2016, the Department of Health announced its decision to begin HPV primary screening through the NHSCSP. In HPV primary screening, the sample is tested for high-risk HPV first. If the results are positive, a cytology test is routinely done on the residual sample. People with either low- or high-grade abnormalities are referred for colposcopy. Those whose cytology results are negative are asked to come back in 12\xa0months. HPV primary screening has now been adopted as the standard of care in several sites in England where it was piloted. Full roll out of this pathway is expected by 2019.\n\n## Treatment\n\nTreatment for CIN aims to remove the cells either by excision or ablation. Treatment for cervical glandular intraepithelial neoplasia often needs deeper excisions than for CIN.\n\nThe management protocols for colposcopy services in England are described in the NHSCSP's colposcopy and programme management guidelines (2016). Of the 188,179\xa0people referred for colposcopy in England between 2015 and 2016, 61% had a treatment or procedure at their first appointment. The most common procedure was diagnostic biopsy (47%), followed by an excision (12%). The most common excision was a large-loop excision of the transformation zone (LLETZ; NHS Digital 2016).\n\nManagement is guided by a colposcopist's opinion of the extent of any abnormalities seen during colposcopy. If an abnormality is found, the colposcopist may take a diagnostic biopsy (punch biopsy). Or they may opt to treat an abnormality during the first clinic appointment ('see and treat') by excising the area of abnormal cells if they believe that high-grade changes are present. The NHSCSP's colposcopy and programme management guidelines (2016) recommend that treatment should not be offered at a person's first visit to a colposcopy clinic after referral for borderline or low-grade dyskaryosis. Ablative treatments should only be done after a diagnostic punch biopsy has been taken and the results have been checked.\n\nBiopsies are examined by a histopathologist and the results are used to help the colposcopist decide whether treatment is needed. Typically, areas of CIN\xa02 or worse (known as CIN\xa02+) would need treatment. This can be done either by excising the area of abnormal cells or by destroying them in situ (ablation). During excision, cells are usually removed using a thin electrically-heated looped wire in the LLETZ procedure. The excised tissue is sent to histopathology to confirm the extent of the abnormality and to guide further management. LLETZ is usually done in the colposcopy clinic using local anaesthetic.\n\nUnlike excisional treatment, cells removed by ablative treatment cannot be examined by a histopathologist because they are destroyed in situ. Ablative treatments include laser ablation, cryocautery and cold coagulation.\n\nIf cervical cancer is identified, depending on the stage, conservative treatment could be offered. Treatment options for cervical cancer include cone biopsy for very early stage disease, trachelectomy, hysterectomy, radiotherapy and chemotherapy. The treatment and management of cervical cancer is described in more detail in the NICE interactive flowchart on cervical cancer and in the SIGN guideline on the management of cervical cancer.", 'The diagnostic tests': "Two interventions and 1\xa0comparator were included in this assessment.\n\n# The interventions\n\n## Dynamic Spectral Imaging System (DYSIS) colposcope with DYSISmap (DYSIS Medical)\n\nThe DYSIS colposcope is a CE-marked digital video colposcope. It uses spectral imaging technology and an inbuilt algorithm to produce an adjunctive map of the cervical epithelium, known as the DYSISmap (or pseudo-colour imaging). The DYSISmap is intended to be used with colposcopy to help detect cervical intraepithelial neoplasia (CIN).\n\nThe system comprises:\n\na high-resolution digital colposcope, which incorporates an inbuilt display console and monitor for the clinician\n\nan optional additional monitor that allows the patient to see the images\n\nsingle-use or reusable specula\n\nan acetic acid applicator\n\nsoftware\n\na patient database (the patient management system) that stores images and videos from a colposcopy examination and records biopsy sites.\n\nThe device can be used as a standard digital video colposcope, but the spectral imaging technology used by the DYSIS colposcope also measures the speed, intensity and duration of aceto-whitening. These parameters are used to produce dynamic curves that plot intensity against time and an inbuilt algorithm assigns each area of the cervix a colour on the DYSISmap.\n\nThe DYSISmap is displayed on the screen, overlaid on a live image of the cervix, and can be used by the colposcopist to select areas for biopsy. The colour spectrum shown on the DYSISmap ranges from cyan, which represents weak aceto-whitening, to white, which represents intense aceto-whitening. The greater the intensity of the measured aceto-whitening reaction, the greater the likelihood of an abnormality. Imaging takes 3\xa0minutes, but the colposcopist can stop it manually. However the company recommends that the system needs at least 125\xa0seconds of imaging to allow it to calculate and display the DYSISmap.\n\n## ZedScan\xa0I\n\nThe ZedScan\xa0I is a CE-marked electrical impedance spectroscopy (EIS) system, which is designed to be used with colposcopy to help detect high-grade CIN. The system comprises:\n\na portable handset, which takes EIS readings and displays the results to the user on an inbuilt interface\n\na docking station\n\nsingle-use EIS sensors that are placed over the snout of the handset\n\na software application, which incorporates a database to store results and can be installed onto a personal computer.\n\nThe device uses EIS to differentiate normal, precancerous and cancerous tissue by measuring the electrical properties of the cervical epithelial cells. Electrical impedance is measured at 14\xa0different frequencies and a spectrum is produced, which varies according to the structure and properties of the tissue. The device can be used in scanning mode or in single-point mode. During scanning mode, and after acetic acid has been applied, the single-use EIS sensors take readings from between 10\xa0and 12\xa0sites on the cervical transformation zone. The readings are processed by the handset using an inbuilt algorithm, which quantifies the degree of abnormality (dysplasia) at each site and compares it with a reference value to give the user a semi-quantitative result. Results are displayed to the colposcopist on the inbuilt user interface. The results show the likelihood of high-grade CIN being present at each of the scanned sites.\n\nThe results provided by the device are intended to be used to guide a colposcopist to areas that need to be biopsied, when used with standard colposcopy. It is estimated that the device takes 2\xa0to 3\xa0minutes to scan the cervix and display the results. The results from the ZedScan\xa0I handset are automatically uploaded to the system's database through the docking station.\n\n# The comparator\n\n## Colposcopy\n\nDuring colposcopy the cervix is assessed by a colposcopist using a colposcope, which is a low-powered microscope. The aim of colposcopy in the NHS cervical screening programme (NHSCSP) is to confirm whether a potential abnormality found by cervical screening is present, and if so, to assess the likely extent and grade of the abnormal cells. Binocular colposcopy is most often used in the NHS.\n\nThe NHSCSP's colposcopy and management guidelines (2016) state that when an adequate colposcopy has been done, that is when the transformation zone has been fully visualised, the colposcopic diagnosis should have a positive predictive value of 65% for a high-grade lesion (CIN\xa02 or worse [CIN\xa02+]).", 'Evidence': "The diagnostics advisory committee (section\xa08) considered evidence on the DYSIS colposcope with DYSISmap (hereafter referred to as DYSIS) and the ZedScan\xa0I for detecting cervical intraepithelial neoplasia (CIN) from several sources. Full details of all the evidence are in the committee papers.\n\nFor the diagnostic accuracy review, studies were included if a prospective cohort had the index test or their prototypes (DYSIS or ZedScan\xa0I done in addition to colposcopy) and reference standard (histopathology) done independently, and contained enough data to allow diagnostic accuracy estimates to be calculated. For the effectiveness and implementation reviews, observational or experimental studies were included if DYSIS or ZedScan\xa0I, or their prototypes, were used in addition to colposcopy. All studies included in the diagnostic accuracy review were appraised using the QUADAS-2 tool. Studies in the implementation review were appraised using guidance from Burns et al. (2008) and the Centre for Evidence Based Management (2014).\n\nIn total, 12\xa0studies were included: 11 in the diagnostic accuracy review, 3 in the review of clinical outcomes, and 5 in the implementation review. Some studies included outcomes that were relevant to more than 1\xa0review. Most studies were reported in more than 1\xa0paper or abstract.\n\n# Diagnostic accuracy\n\nOf the 11\xa0studies included in the diagnostic accuracy review, 9\xa0included data for DYSIS and 2\xa0included data for ZedScan (1\xa0for ZedScan\xa0I and 1\xa0for a prototype). All studies were done in hospital-based colposcopy clinics, and 6 were multicentre studies. Five studies included at least 1\xa0centre in England (both ZedScan studies and 3\xa0DYSIS studies). Most of the people in the studies were referred for colposcopy because of an abnormal screening result.\n\nOf the 9\xa0DYSIS studies, 1\xa0was considered to be at low risk of bias and the other 8\xa0at high risk of bias. Both ZedScan studies were considered to be at a high risk of bias. The main source of bias in the studies was verification bias. This was because biopsies were not taken to confirm the absence of disease when the colposcopist did not identify any abnormalities because this is not generally considered to be good clinical practice. Concerns about the generalisability of the results of the ZedScan studies were highlighted because most of the people in the studies were examined at a single centre.\n\nMeta-analyses were done for the diagnostic accuracy of DYSIS, which included 6\xa0studies. Two studies were excluded because they only reported data for subgroups and 1\xa0was included in a narrative analysis only. The analyses assume that DYSIS video colposcopy (without the DYSISmap), the comparator in the DYSIS studies, is equivalent in diagnostic accuracy to binocular colposcopy (used in the ZedScan studies and in routine NHS practice). The threshold used to determine a positive result was CIN\xa02 or worse (CIN\xa02+). No meta-analysis was done for the ZedScan studies.\n\n## DYSIS\n\nThe pooled results from the meta-analyses are summarised in table\xa01. The pooled positive predictive value of colposcopy was 55.78% (95% confidence interval [CI] 47.54% to 64.03%) and of DYSISmap with colposcopy was 43.60% (95% CI 33.12% to 54.07%). The corresponding negative predictive value of colposcopy was 86.70% (95% CI 80.17% to 93.22%) and of DYSISmap with colposcopy was 92.20% (95% CI 88.06% to 96.34%). A sensitivity analysis was done with a logistic regression model. Roensbo et al. (2015) was excluded because this study did not assess DYSIS with colposcopy directly but recorded whether a colposcopist agreed or disagreed with the DYSISmap. To examine the effect of verification bias, results were stratified by the number of biopsies taken in the studies when both DYSIS and colposcopy did not identify any areas of abnormality.\n\nThe results of the meta-analyses suggest that compared with colposcopy alone, DYSIS with colposcopy improves sensitivity for detecting CIN\xa02+, although this is associated with a reduction in specificity. However, the results of the logistic regression model show a statistically significant difference in specificity between DYSIS and colposcopy (difference in log odds\xa01.33, p<0.0001), but no significant difference in diagnostic odds ratio (difference in log odds\xa00.04; p=0.84). This suggests that DYSIS increases the number of people suspected of having CIN\xa02+ and may therefore increase the number of biopsies taken. But it may not improve the ability to discriminate between lesions with and without CIN\xa02+ when compared with colposcopy. The results of the sensitivity analyses designed to explore verification bias in people with negative DYSIS and colposcopy examinations suggested that sensitivity and specificity estimates decline as the number of random biopsies taken increases.\n\nAn additional 5\xa0studies were included in a separate narrative analysis. This confirmed the results of the meta-analyses; DYSIS improves sensitivity but reduces specificity when compared with colposcopy.\n\n## Table 1 Diagnostic accuracy of DYSIS\n\nAnalysis\n\nTechnology\n\n(number of studies)\n\nSummary estimates\n\nSensitivity %\n\n(95% CI)\n\nSpecificity %\n\n(95%CI)\n\nForest plots of diagnostic accuracy\n\nColposcopy(6 studies)a\n\n(50.31 to 66.50)\n\n\n\n(81.26 to 91.66)\n\nDYSISmap alone(3 studies)b\n\n(33.10 to 85.26)\n\n(71.25 to 92.04)\n\nDYSISmap plus colposcopy(6 studies)a\n\n(77.35 to 85.07)\n\n(60.31 to 79.82)\n\nHierarchical bivariate analysis\n\nColposcopy (6 studies)a\n\n(49.7 to 63.4)\n\n(79.7 to 92.4)\n\nDYSISmap plus colposcopy(6 studies)a\n\n(76.0 to 85.1)\n\n(60.8 to 79.3)\n\nLogistic regression model\n\nColposcopy (6 studies)a\n\n(47.2 to 67.9)\n\n(81.7 to 91.5)\n\nDYSISmap plus colposcopy (6 studies)a\n\n(72.2 to 87.9)\n\n(59.4 to 79.5)\n\nSensitivity analyses\n\nLogistic regression model (excluding Roensbo et al. 2015)\n\nColposcopy(5 studies)c\n\n(47.5 to 64.9)\n\n(86.3 to 93.1)\n\nDYSISmap plus colposcopy(5 studies)c\n\n(75.0 to 88.7)\n\n(63.3 to 80.7)\n\nStudies with no biopsies in negative examinations\n\nColposcopy(3 studies)d\n\n(40.89 to 83.33)\n\n(90.23 to 94.13)\n\nDYSISmap plus colposcopy(3 studies)d\n\n(79.6 to 92.7)\n\n(50.0 to 97.2)\n\nStudies with 1 random biopsy in negative examinations\n\nColposcopy(Louwers et al. 2011, Soutter et al. 2009)\n\n(43.0 to 57.5)\n\n(79.1 to 93.3)\n\nDYSISmap plus colposcopy(Louwers et al. 2011, Soutter et al. 2009)\n\n(72.6 to 85.6)\n\n(57.9 to 82.2)\n\nStudies with multiple random biopsies in negative examinations\n\nColposcopy(Roensbo et al. 2015)\n\n(56.5 to 78.8)\n\n(60.2 to 74.3)\n\nDYSISmap plus colposcopy(Roensbo et al. 2015)\n\n(64.7 to 85.3)\n\n(49.9 to 64.7)\n\nAbbreviations: 95% CI, 95% confidence interval; NPV, negative predictive value; PPV, positive predictive value.\n\nReferences:\n\na Budithi et al. (in press), Coronado et al. (2016), Louwers et al. (2011), Roensbo et al. (2015), Salter et al. (2016) and Soutter et al. (2009).\n\nb Coronado et al. (2016), Louwers et al. (2011) and Roensbo et al. (2015).\n\nc Budithi et al. (in press), Coronado et al. (2016), Louwers et al. (2011), Salter et al. (2016) and Soutter et al. (2009).\n\nd Budithi et al. (in press), Coronado et al. (2016) and Salter et al. (2016).\n\n## ZedScan\xa0I\n\nTwo studies were included in a narrative analysis; 1\xa0included the current version (ZedScan\xa0I) and the other a third-generation prototype. The results are shown in table\xa02. Tidy et al. (in press) includes results for the current version of the device in a human papilloma virus (HPV) primary screening setting, but none for colposcopy alone. The results of the studies suggest that using ZedScan with colposcopy may have better sensitivity or specificity than colposcopy alone depending on the threshold used (which is set by the manufacturer). But when a regression model was fitted to the results from Tidy et al. (2013), the improvement in diagnostic accuracy was not quite statistically significant (difference in log diagnostic accuracy\xa00.488, p=0.078). However, only 1\xa0study was available for analysis and the EAG commented that this is a conservative approach which should be considered as exploratory only.\n\n## Table 2 Diagnostic accuracy of ZedScan\n\nStudy\n\nColposcopy\n\ncut-off\n\nColposcopy alone\n\nZedScan cut-off\n\nZedScan plus colposcopy\n\nSensitivity % (95% CI)\n\nSpecificity % (95% CI)\n\nSensitivity % (95% CI)\n\nSpecificity % (95% CI)\n\nTidy et al. (in press)\n\nZedScan I\n\n–\n\nNot reported\n\nNot reported\n\nMultiple\n\n(96.6 to 99.2)\n\n(55.1 to 62.1)\n\nTidy et al. (2013) prototype device\n\nColposcopic impression\n\n(64.3 to 82.8)\n\n(76.5 to 90.5)\n\n\n\n(64.3 to 82.8)\n\n(85.4 to 96.2)\n\n\n\n(69.5 to 86.8)\n\n(76.5 to 90.5)\n\n\n\n(51.9 to 72.3)\n\n(91.5 to 99.3)\n\nDisease present\n\n(81.8 to 95.2)\n\n(29.4 to 47.7)\n\n\n\n(81.8 to 95.2)\n\n(56.2 to 74.1)\n\n\n\n(92.7 to 100)\n\n(29.4 to 47.7)\n\n\n\n(86.2 to 97.7)\n\n(42 to 60.8)\n\nDisease present: colposcopy was considered positive if at least 1 measurement point was suggested for biopsy; colposcopic impression: colposcopy was considered positive if it was judged that high-grade CIN was present.\n\nAbbreviations: CI, confidence interval; CIN, cervical intraepithelial neoplasia.\n\nFurther data on ZedScan\xa0I were available in 2\xa0substudies of Tidy et al. (in press). In a conference abstract Tidy et al. (2016) reported that the performance of the technology varied across colposcopy clinics in England, Ireland and Germany, with sensitivity ranging from 73.1% to 100% and specificity from 25.7% to 58.1%. McDonald et al. (2017) evaluated the accuracy of ZedScan\xa0I in people with known high-risk HPV genotypes and compared its performance among those with HPV\xa016 and those with other high-risk genotypes. The sensitivity of ZedScan\xa0I was high (100%) regardless of genotype but the sensitivity of standard colposcopy was higher in the HPV\xa016 group (86.9%) than in the other high-risk genotypes group (79.7%).\n\nA study including 91\xa0people (Muszynski et al. 2017) was submitted during consultation. In 1\xa0French hospital, using ZedScan\xa0I with colposcopy increased detection of people with high-grade lesions by 47.3%. The rate at which biopsies were taken also increased when making decisions using results from both ZedScan\xa0I and colposcopy, compared with using colposcopy alone. The reported sensitivity of ZedScan\xa0I with colposcopy was 93.3% compared with 61.3% for colposcopy alone. The reported specificity of ZedScan\xa0I with colposcopy was 34.4% compared with 80.0% for colposcopy alone.\n\n## Test positive rates\n\nTest positive rates ranged from 21.22% to 55.51% for DYSIS and from 13.77% to 42.68% for colposcopy alone in 6\xa0DYSIS studies (Budithi et al. in press, Coronado et al. 2016, Louwers et al. 2011, Roensbo et al. 2015, Salter et al. 2016 and Soutter et al. 2009). In each study the test positive rate was always higher for DYSIS than for colposcopy alone.\n\nTest positive rates ranged from 30.20% to 77.04% for ZedScan, depending on the cut-off used in the 2\xa0studies (Tidy et al. 2013, Tidy et al. in press). Test positive rates for colposcopy were 41.84% when colposcopic impression was used as a cut-off and 73.47% when disease present was used as a cut-off (Tidy et al. 2013).\n\n## Test failure rates\n\nTest failure rates (including failures not related to the technology) with DYSIS were reported in 6\xa0studies and ranged from 2.9% to 31.4%. The highest failure rate was reported by Soutter et al. (2009), which included a prototype version of the system that had problems with unsatisfactory view and faulty acetic acid applicators. Failure rates for ZedScan (including failures not related to the technology) were reported in 2\xa0studies. They were 5.6% (Zedscan\xa0I) and 13.6% (prototype; Tidy et al. in press and Tidy et al. 2013).\n\n## Biopsy rates\n\nAll diagnostic accuracy studies included in the external assessment group's (EAG) analysis included some data on the number of diagnostic and treatment biopsies taken, but there were not enough details to assess whether the adjunctive technologies had a substantial effect on this.\n\nTwo prepublication manuscripts by Cholkeri-Singh et al. (2018) and DeNardis et al. (2017), which included additional data from the IMPROVE-COLPO trial, were submitted during consultation. Diagnostic accuracy data from this study had been included in the EAG's analysis. IMPROVE-COLPO was an observational study done in 39\xa0colposcopy clinics in the US.\n\nCholkeri-Singh et al. (2018) reported results of a 2-arm observational study in which people who were prospectively assessed using DYSIS were compared with historical controls (people assessed with standard colposcopy by the same colposcopists). The yield of CIN\xa02+ (defined as the proportion of people with at least 1\xa0biopsy showing CIN\xa02+) was higher in the DYSIS group (9.48% compared with 7.21%; p=0.014). The yield of CIN\xa03+ was also higher in this group (3.23% compared with 2.07%; p=0.031). The number of people having biopsies between the groups was similar (71.6% compared with 71.5%), but the average number of biopsies per person was higher for the DYSIS group (1.26 compared with 1.03).\n\nDeNardis et al. (2017) reported results of a cross-sectional observational study in which DYSISmap was used after an initial assessment with DYSIS video colposcopy to identify further sites for biopsy. DYSIS video colposcopy-directed biopsies identified 78\xa0people with CIN\xa02+; DYSISmap-assisted biopsies identified a further 34\xa0people with CIN\xa02+. Also, DYSIS video colposcopy-directed biopsies identified 30\xa0people with CIN\xa03+ and DYSISmap-assisted biopsies identified a further 15\xa0people with CIN\xa03+. The positive predictive value of DYSIS video colposcopy-directed biopsies was 13.24% compared with 16.16% for DYSISmap-assisted biopsies.\n\n## Subgroup analyses\n\nData on referrals for low-grade and high-grade cytology suggested that colposcopy was less sensitive for detecting CIN\xa02+ in low-grade cytology referrals. No differences in sensitivity were seen for DYSIS and ZedScan\xa0I.\n\nThere were not enough data to determine whether the accuracy of any of the technologies differed between people with and without high-risk HPV.\n\nFounta et al. (unpublished) reported data from a test of cure population for whom the EAG calculated 95% confidence intervals. This showed a sensitivity of 0% (95% CI 0% to 53%) and a specificity of 94.0% (95% CI 89.35% to 98.65%) for colposcopy, and a sensitivity of 80.0% (95% CI 44.94% to 100%) and a specificity of 64.0% (95% CI 54.59% to 73.41%) for DYSIS in a test of cure population. The accuracy of colposcopy was substantially different in this study compared with the summary estimates provided in the meta-analyses for all colposcopy referrals.\n\n# Clinical effectiveness\n\nData on adverse events were reported in 5\xa0studies. In a ZedScan prototype study, 1\xa0person felt unwell after the examination and 2\xa0people had issues with bleeding after biopsies were taken. It is uncertain whether these events were related to using the ZedScan. No adverse events were reported in 4\xa0DYSIS studies.\n\nNo data were found for morbidity and mortality associated with treatment and biopsy during colposcopy, or for health-related quality of life. There were insufficient data to determine whether the increased detection of CIN\xa02+ was associated with a reduction in cervical cancer.\n\nTwo systematic reviews of adverse outcomes of CIN treatment were found. Kyrgiou et al. (2015) focused on fertility and early pregnancy outcomes (less than 24\xa0weeks' gestation). People who had treatment for CIN were at increased risk of miscarriage in the second trimester of pregnancy (relative risk\xa02.60, 95% CI 1.45 to 4.67). Kyrgiou et al. (2016) focused on obstetric (more than 24\xa0weeks' gestation) and neonatal outcomes. People who had large-loop excision of the transformation zone (LLETZ) were at increased risk of giving birth prematurely (relative risk\xa01.56, 95% CI 1.36 to 1.79). The risk increased as the depth of the excision increased.\n\n# Implementation\n\nFive studies were included in the implementation review. Of these, 3\xa0were done in the UK (Lowe et al. 2016, Palmer et al. 2016 and Budithi et al. in press), 1 in Spain (Coronado et al. 2014) and 1 in the Netherlands (Louwers et al. 2015). None of the studies used validated questionnaires.\n\n## Patient and clinician satisfaction\n\nLowe et al. (2016) surveyed 763\xa0patients in 4\xa0NHS hospitals that were using DYSIS. Two questionnaires were used: 1 for people having their first colposcopy and 1 for people who had previously had a colposcopy. The number of respondents per questionnaire was not reported in the conference abstract available to the EAG. Participants reported that DYSIS did not take longer than their previous smear test or colposcopy and that anxiety was reduced during and after examinations compared with previous examinations.\n\nLouwers et al. (2015) gave a patient satisfaction questionnaire to 239\xa0people who had a DYSIS examination. Results showed that 93.9% of people agreed or strongly agreed to have colposcopy with DYSIS if it helped locate CIN; 29.5% agreed or strongly agreed that DYSIS was less comfortable than a cervical smear; 16.5% reported that DYSIS made them feel nervous during the examination, and 6.5% thought that an examination with DYSIS took too long.\n\nBudithi et al. (2017) gave questionnaires to both patients and colposcopists in 5\xa0colposcopy clinics in Wales; 68\xa0patients responded and 45\xa0colposcopist responses were received (the number of colposcopists was not reported in the abstract). Results from patients showed that 86% agreed or strongly agreed that the DYSIS images helped their understanding and were reassuring; 52% believed DYSIS to be more accurate than their previous colposcopy; 4% thought that DYSIS lasted too long compared with previous colposcopies and 13% found it less comfortable. Of the responses received from colposcopists, 96% agreed or strongly agreed that they were confident about colposcopy and their decision-making in selecting biopsy sites. But only 48% went on to agree that DYSISmap affected their selection of biopsy sites; 58% said they were able to identify additional sites with DYSISmap and 55% agreed or strongly agreed that DYSISmap improved their colposcopic examination.\n\n## Colposcopist experience\n\nCoronado et al. (2014) surveyed 63\xa0colposcopists with different levels of experience. A retrospective review of 50\xa0colposcopy and DYSISmap images was also done. The study found that the correct diagnosis (either normal, low-grade lesion, high-grade lesion or cancer) was made more frequently with DYSIS than with standard colposcopy for colposcopists with low and medium levels of experience. There was no difference for highly experienced colposcopists. All groups agreed that DYSIS is better at directing diagnosis and provides more information than standard colposcopy. The survey also reported that using DYSISmap improved detection of CIN\xa02+ by colposcopists of all experience levels. However, the EAG noted that this was based on a small subgroup analysis of the retrospective review of stored images.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nTwo relevant economic evaluations were identified; 1 for DYSIS compared with colposcopy over a lifetime time horizon (Wade et al. 2013) and another for a ZedScan prototype compared with colposcopy over a 3‑year time horizon (Whyte et al. 2013). Wade et al. was produced for NICE's diagnostics guidance\xa04 on adjunctive colposcopy technologies and found that DYSIS dominated colposcopy (that is, DYSIS cost less and was more effective than colposcopy). Whyte et al. reported lower costs associated with the use of a prototype ZedScan device per person with CIN\xa02 or 3\xa0treated, because it reduced both rates of overtreatment and the number of follow-up appointments needed for people with CIN\xa01. However, this was associated with a reduction in the number of CIN\xa02 or\xa03 lesions treated and a consequent reduction in the number of cancers detected. Neither study fully addressed the decision problem.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model designed to assess the cost effectiveness of DYSIS and ZedScan\xa0I, used with colposcopy, in both an HPV triage and an HPV primary screening setting. The analyses took the perspective of the NHS and personal social services and had a 60‑year (lifetime) time horizon. All costs and effects were discounted at 3.5%.\n\nA patient-level state-transition model with a 6‑month cycle time was constructed using TreeAge Pro (2016) software. The model included 500,000\xa0simulations to ensure that first-order uncertainty was adequately captured, that is, variability in the simulated experiences between identical patients. The model incorporated both screening and treatment pathways: 1\xa0submodel simulated the natural history of CIN and cervical cancer, and another submodel simulated adverse obstetric outcomes for people who had treatment for CIN. The adverse obstetric outcome model captured the costs and quality-adjusted life year (QALY) decrements associated with initial management and the increased probability of neonatal mortality and QALY decrements associated with higher risks of disability among infants born preterm. The natural history model was adapted from Kulasingam et al. (2013) with invasive cancer parameters taken from Campos et al. (2014).\n\nAt the beginning of the first cycle each person is referred for colposcopy and has treatment if needed, before entering the natural history model. In subsequent cycles, the person can follow 1\xa0of 4\xa0screening and treatment pathways: no screening, colposcopy referral, routine screening, or a follow-up pathway for those who have had previous treatment, unless they died in the previous cycle. Every pathway ends with the person entering the natural history model.\n\nThe model was implemented using a random walk and for each person it simulated the following uncertain events occurring: disease progression, diagnostic results or treatment outcomes. The characteristics that determined the associated events and transitions for each person in the model were:\n\nage\n\nhealth state (clear, HPV, CIN\xa01, CIN\xa02 or\xa03, cancer)\n\nreason for referral for colposcopy (high-grade or low-grade cytology)\n\nnext scheduled screening (routine call, 6‑month cytology, 6‑month colposcopy, test of cure, CIN\xa01 follow-up)\n\ntime elapsed since last screening\n\ntype of clinic visited ('see and treat' or 'watchful waiting').Identical patients were run through each treatment strategy and random numbers were maintained across all runs of the model.\n\nTwo base cases were modelled: HPV triage and HPV primary screening. The modelled pathways for HPV triage were based on those outlined in the NHS cervical screening programme's (NHSCSP) colposcopy and programme management guidelines (2016). For HPV primary screening the modelled pathways were based on the testing algorithms used in the NHSCSP's pilot sites.\n\nThe diagnostic accuracy estimates used in the model are shown in table\xa03.\n\n## Table 3 Accuracy estimates used in the model\n\nTechnology\n\n(source)\n\nSensitivity % (95% CI)\n\nSpecificity % (95%CI)\n\nColposcopy alone\n\n(regression model)\n\n(47.2 to 67.9)\n\n(81.7 to 91.5)\n\nDYSIS\n\n(regression model)\n\n(72.2 to 87.9)\n\n(59.4 to 79.5)\n\nZedScan\xa0I\n\n(Tidy et al. [in press])\n\n(96.5 to 99.2)\n\n(55.1 to 62.1)\n\nAbbreviation: CI, confidence interval.\n\nThe performance of cytology in both the HPV triage and HPV primary screening scenarios was modelled using data from Hadwin et al. (2008) and from the NHSCSP statistical bulletin (2015/16). The diagnostic accuracy of HPV testing in HPV triage was modelled using data from the TOMBOLA study (Cotton et al. 2010) and in HPV primary screening from the ARTISTIC study (Kitchener et al. 2014).\n\nIn the model, people referred for colposcopy have 2\xa0initial characteristics; a true underlying health state (clear, HPV, CIN\xa01, CIN\xa02 or\xa03, or cancer) and a reason for referral (low-grade or high-grade lesions). These joint distributions were taken from the NHSCSP statistical bulletin (2015/16) for HPV triage and unpublished data provided by the NHSCSP pilot sites for HPV primary screening, and were influenced by disease prevalence and the accuracy of screening.\n\nHeterogeneity in treatment decisions after a positive colposcopy was modelled using 2\xa0different types of clinic; a 'watchful waiting' clinic or a 'see and treat' clinic. The probability of treatment failure after an excisional biopsy was taken from Ghaem-Maghami et al. (2011) and ranged from 4.9% for CIN\xa01 to 10.3% for CIN\xa03. The probability of adverse obstetric outcomes after treatment was estimated by applying the relative risk of preterm birth (1.56) from Kyrgiou et al. (2016) to the probability of preterm birth for people with untreated lesions as reported in NICE's guideline on preterm labour and birth (7.3%). This gave an excess risk of 4.09% for preterm birth after LLETZ treatment.\n\nThe average cost per person of using the technologies was calculated using information from companies and clinical experts. The costs include the capital cost of the technologies (spread over 15\xa0years for a colposcope and over 5\xa0years for DYSIS and ZedScan\xa0I), annual maintenance costs and consumable costs. To calculate the average cost per procedure, and to be consistent with Wade et al. (2013), it was assumed that 1,229\xa0people per year were seen. The following costs per person were assumed:\n\ncolposcopy: £3.75\n\nDYSIS: £9.24\n\nZedScan\xa0I: £30.52.\n\nBiopsy and treatment costs were taken from NHS reference costs. The cost of a cytology and HPV test were taken from the TOMBOLA study and inflated to 2016 prices. The values used in the model for screening events are shown in table\xa04.\n\n## Table 4 Costs of screening events\n\nTreatment\n\nDevice\n\nCost per treatment\n\nColposcopy examination only\n\nColposcopy\n\n£175\n\nDYSIS\n\n£180.49\n\nZedScan I\n\n£205.52\n\nDiagnostic biopsy\n\n£47\n\nLLETZ\n\n£63\n\nCytology test\n\n£37.19\n\nHPV test\n\n£29.66\n\nAbbreviations: HPV, human papilloma virus; LLETZ, large-loop excision of the transformation zone.\n\nCancer treatment costs were taken from Martin-Hirsch et al. (2007). Costs associated with adverse obstetric outcomes were taken from Lomas et al. (2016) and inflated to 2016 prices. It was assumed that a preterm birth costs £24,610, which takes into account initial inpatient neonatal care and ongoing costs for the first 18\xa0years of life.\n\nHealth-related quality-of-life estimates were taken from the published literature. The disutilities associated with screening, diagnosing and treating CIN were taken from Simonella and Canfell (2014) and are shown in table\xa05. Age- and gender-specific utilities from Kind et al. (1999) were applied to the HPV, CIN\xa01 and CIN\xa02 or\xa03 asymptomatic health states. Disutilities associated with cervical cancer were taken from Goldie et al. (2004) and a QALY decrement of 1.3 was applied for preterm birth (Lomas et al. 2016).\n\n## Table 5 Disutilities for screening, diagnosis and treatment of CIN\n\nScreening event\n\nQALY decrement\n\nNegative cytology or HPV\n\n\n\nFalse positive referral for colposcopy\n\n\n\nDiagnosed CIN 1\n\n\n\nTreatment of CIN\n\n\n\nAbbreviations: CIN, cervical intraepithelial neoplasia; HPV, human papilloma virus; QALY, quality-adjusted life year.\n\n## Base-case results\n\nThe following assumptions were applied in the base-case analysis:\n\nDiagnostic accuracy estimates for both colposcopy and the adjunctive technologies were based on a cut-off of CIN\xa02+.\n\nThe probability of a positive colposcopy result was:\n\n\n\nidentical for people with clear, HPV or CIN\xa01 results\n\nidentical for people with CIN\xa02 or\xa03 or invasive cancer.\n\n\n\nThe choice between a 'see and treat' clinic and a 'watchful waiting' clinic was independent of diagnostic accuracy.\n\nBiopsy and histopathology (the reference standard) were 100% accurate.\n\nExcision at the first colposcopy appointment was only possible for referrals for high-grade lesions with a positive colposcopy result.\n\nFor low-grade lesion referrals, CIN\xa02+ was confirmed by diagnostic biopsy before treatment.\n\nCIN\xa01 lesions were not treated and people had a 12‑month follow-up screening in the community.\n\nPeople whose lesions were treated for CIN remained at risk of preterm birth (before 37\xa0weeks' gestation) for each year after treatment up to the age of 45.\n\nWhen cancer was detected, treatment was offered appropriate to the stage. An excess risk of mortality was applied for 5\xa0years and decreased according to time since diagnosis.\n\nDYSIS or ZedScan\xa0I examinations were the same length as a standard colposcopy examination.\n\nZedScan\xa0I was used for diagnostic colposcopies only.\n\nThere were 2 base cases: 1 for HPV triage and 1 for HPV primary screening. In a 'see and treat' clinic, treatment was done at the first visit for people who had a referral for a high-grade lesion according to cytology and a colposcopy examination graded as CIN\xa02+. In a 'watchful waiting' clinic, treatment was done at the second visit when the results of any diagnostic biopsies showed CIN\xa02+.\n\nThe results of the HPV triage base case showed that both technologies dominated standard colposcopy in 'see and treat' clinics (that is, they cost less and are more effective). In 'watchful waiting' clinics, DYSIS dominated standard colposcopy for low-grade lesion referrals and for all referrals combined, but had an incremental cost-effectiveness ratio (ICER) of £675 per QALY gained for high-grade lesion referrals compared with standard colposcopy. ZedScan\xa0I had an ICER of £272 per QALY gained for low-grade lesion referrals and £4,070 per QALY gained for high-grade lesion referrals. For all referrals, it had an ICER of £418 per QALY gained. Indirect comparisons suggest that ZedScan\xa0I always costs more but is more effective than DYSIS in both 'see and treat' and 'watchful waiting' clinics. The results of the HPV primary screening base case were similar to the HPV triage base case. The EAG highlighted that because the diagnostic accuracy of DYSIS and ZedScan\xa0I have not been compared directly, these results should be considered exploratory.\n\nThe number of treatments, biopsies and missed disease in each base case is shown in table\xa06. This table shows the cumulative occurrence of events over the lifetime of the modelled cohort, therefore an event can occur more than once per person. Because of their increased sensitivity, the adjunctive technologies are associated with less missed disease and so less cancers. However, they also have reduced specificity and result in more unnecessary diagnostic biopsies and treatments (except in 'watchful waiting' clinics).\n\n## Table 6 Secondary outcomes per 1,000\xa0people referred for colposcopy (60‑year time horizon)\n\nClinic\n\nStrategy\n\nMissed CIN 2+*\n\nCancers\n\nLLETZ\n\nUnnecessaryLLETZ\n\nUnnecessary diagnostic biopsy\n\nHPV triage\n\n'See and treat'\n\nColposcopy\n\n\n\n\n\n\n\n\n\n\n\nDYSIS\n\n\n\n\n\n\n\n\n\n\n\nZedScan\xa0I\n\n\n\n\n\n\n\n\n\n\n\n'Watchful waiting'\n\nColposcopy\n\n\n\n\n\n\n\n\n\n\n\nDYSIS\n\n\n\n\n\n\n\n\n\n\n\nZedScan\xa0I\n\n\n\n\n\n\n\n\n\n\n\nHPV primary screening\n\n'See and treat'\n\nColposcopy\n\n\n\n\n\n\n\n\n\n\n\nDYSIS\n\n\n\n\n\n\n\n\n\n\n\nZedScan\xa0I\n\n\n\n\n\n\n\n\n\n\n\n'Watchful waiting'\n\nColposcopy\n\n\n\n\n\n\n\n\n\n\n\nDYSIS\n\n\n\n\n\n\n\n\n\n\n\nZedScan\xa0I\n\n\n\n\n\n\n\n\n\n\n\n* Missed CIN\xa02+ refers to the number of CIN\xa02+ cases not detected by the technologies (colposcopy, DYSIS, ZedScan I) rather than cases not detected following referral for colposcopy. In the model people with high-grade cytology referrals have a diagnostic biopsy and are identified as CIN\xa02+ even if a colposcopic examination is incorrectly negative.\n\nAbbreviations: CIN\xa02+, cervical intraepithelial neoplasia grade\xa02 or worse; HPV, human papilloma virus; LLETZ, large-loop excision of the transformation zone.\n\n## Scenario analyses\n\nThe following scenario analyses were done to explore the effect of alternative structural assumptions:\n\ntime horizon restricted to 1\xa0screening interval (3\xa0years)\n\nadverse obstetric outcomes excluded\n\nZedScan\xa0I used in both diagnostic and treatment colposcopies.\n\nWhen the time horizon was restricted to 3\xa0years, colposcopy dominated (that is, it cost less and was more effective) both DYSIS and ZedScan\xa0I in most scenarios except for high-grade lesion referrals in HPV triage 'see and treat' clinics. In this scenario, DYSIS had an ICER of £236,692 saved per QALY lost and ZedScan\xa0I had an ICER of £84,045 saved per QALY lost. For HPV primary screening, the respective ICERs were £250,587 saved per QALY lost for DYSIS and £110,371 saved per QALY lost for ZedScan\xa0I. Colposcopy generally dominated because its higher specificity resulted in fewer treatments, and because people with untreated CIN (false negatives) did not go on to develop cancer within the 3‑year time horizon. The results of the model did not change substantially in the other scenario analyses.\n\n## Sensitivity analyses\n\nThe following inputs were changed in sensitivity analyses to explore the effect of parameter uncertainty:\n\ndiagnostic accuracy\n\ncosts of the technologies\n\ncosts of treatment and biopsies\n\ncharacteristics of the population referred for colposcopy in HPV primary screening.\n\nWhen the accuracy of colposcopy relative to ZedScan\xa0I was taken from Tidy et al. (2013), the incremental costs associated with ZedScan\xa0I compared with colposcopy increased, whereas the QALYs decreased. Under these assumptions ZedScan\xa0I became less cost effective than in the base case and it no longer dominated colposcopy in 'see and treat' clinics. Its highest ICER was £24,686 per QALY gained for high-grade lesion referrals in HPV primary screening 'watchful waiting' clinics.\n\nThe DYSIS results were sensitive to assumptions around reduced throughput and a consequent increase in cost per test because of its higher purchase price. When it was assumed that only 614\xa0people per year were seen, it no longer dominated colposcopy in HPV primary screening 'watchful waiting' clinics and had an ICER of £270 per QALY gained for all referrals. None of the other sensitivity analyses changed the results substantially.\n\nThe ZedScan\xa0I results were sensitive to changes in the cost of diagnostic and treatment biopsies because of its increased sensitivity and lower specificity than colposcopy. When the cost of a diagnostic biopsy was increased to £102.72 and a treatment biopsy (LLETZ) to £490.89, ZedScan\xa0I no longer dominated colposcopy for low-grade lesion referrals and all referrals combined. Under these assumptions, its highest ICER was £6,709 for high-grade referrals to an HPV primary screening 'watchful waiting' clinic. None of the other sensitivity analyses changed the results substantially.", 'Committee discussion': "# Current practice\n\nThe committee discussed current practice for assessing suspected cervical abnormalities in a colposcopy clinic. The clinical experts explained that NHS clinics most often use binocular colposcopy, which allows a colposcopist to examine a cervix and take both diagnostic and treatment biopsies under direct visualisation. Acetic acid is used to highlight areas of abnormality. The committee noted that colposcopy is associated with both intra- and inter-observer variability because it is a visual examination that is highly dependent on the colposcopist's expertise. The committee considered the role of the adjunctive colposcopy technologies and was advised by the clinical experts that the technologies could provide less subjective results and help colposcopists select areas for biopsy. The clinical experts also explained that the technologies could help identify high-grade lesions in people referred for colposcopy because of low-grade cytology.\n\nThe committee noted that a series of changes are being made to the screening pathways used in the NHS cervical screening programme (NHSCSP). Human papilloma virus (HPV) triage was fully implemented in England in April 2014. HPV primary screening is currently being done in several pilot sites, with full implementation in England expected in 2019. These changes could affect referrals to colposcopy clinics and consequently the prevalence of high-grade disease, particularly when people with a HPV-positive cytology-negative screening result are seen in colposcopy. The committee concluded that there had been substantial changes to the care pathways since NICE's first diagnostics assessment of the DYSIS colposcope with DYSISmap in 2012.\n\n# Diagnostic accuracy and clinical effectiveness\n\nThe committee discussed the external assessment group's (EAG) critical appraisal of the included diagnostic accuracy studies. It noted that the greatest risk of bias in the studies occurred because not all patients had the reference standard test (colposcopically directed biopsies and histopathology). In most studies, people who had a negative colposcopy did not have biopsies taken. The clinical experts explained that it was not considered good clinical practice to take biopsies when there was no clinical indication. But the committee noted that the EAG's sensitivity analyses on the effect of verification bias showed that the more random biopsies taken, the lower the estimates of both sensitivity and specificity. The committee concluded that the diagnostic accuracy estimates provided by the included studies were likely to have been influenced by verification bias, and highlighted that future studies should aim to minimise this when possible.\n\nThe committee considered the applicability of the diagnostic accuracy studies that were done outside the UK. The clinical experts explained that the quality assurance measures for colposcopy done outside the UK are different to those in the UK, and that this was likely to influence the accuracy of colposcopy. The committee noted that the NHSCSP recommends that a satisfactory colposcopy should have a 65% positive predictive value for CIN\xa02+. It considered that although positive predictive value was likely to be influenced by several confounding factors, video colposcopy in the DYSIS studies did not achieve this benchmark, with a pooled positive predictive value of 55.78%. However, the committee noted that because this value depends on disease prevalence, the use of positive predictive value to assess the generalisability of studies to UK practice is problematic. The clinical experts also noted that the pooled sensitivity of colposcopy in the DYSIS studies was lower than they would expect to see in the UK. They also noted that in the ZedScan\xa0I study, which was done in the UK and used binocular colposcopy, a higher sensitivity for colposcopy was reported. The committee concluded that because of differences in colposcopy practice, such as fewer quality assurance measures and the use of video colposcopy, the accuracy data from non-UK studies may not be generalisable to the NHSCSP.\n\nThe committee considered the potential for the adjunctive colposcopy technologies to reduce both intra- and inter-observer variability. The companies explained that the technologies are designed to reduce the subjectivity of colposcopy by providing more objective results, but noted that no data on the reproducibility of the tests had been presented for the assessment. However, the committee noted published data suggesting that clinicians felt that the DYSISmap improved their confidence when selecting biopsy sites. It concluded that the technologies had the potential to help standardise colposcopy examinations, but that insufficient data were available to determine whether this benefit would be realised in NHS clinical practice.\n\nThe committee discussed the results of the diagnostic accuracy analyses for the DYSIS colposcope with DYSISmap and the ZedScan\xa0I. It noted that although the accuracy estimates for colposcopy alone in the DYSIS and ZedScan studies varied considerably, the estimates suggested that the technologies were more sensitive but less specific than colposcopy alone. It considered that in practice this would result in a reduced false negative rate with more people being diagnosed with CIN\xa02 or worse (CIN\xa02+). But this could be at the expense of a higher false positive rate with more people having unnecessary diagnostic biopsies and treatment. The committee further noted that the diagnostic odds ratios, which had been calculated by the EAG for the DYSIS colposcope with DYSISmap studies, suggested that there was no difference between the accuracy of DYSIS colposcopy alone and DYSIS colposcopy with DYSISmap. The committee concluded that the results of the diagnostic accuracy studies suggest that it is plausible that the adjunctive colposcopy technologies may change the test threshold so that more people have biopsies, but without improving colposcopists' ability to differentiate between high- and low-grade disease.\n\nThe committee discussed the Cholkeri-Singh et al. (2018) and DeNardis et al. (2017) studies, submitted as prepublication manuscripts during consultation. These provided data from the IMPROVE-COLPO study. It acknowledged that these studies provide real world outcome data on the number of biopsies taken and supplement the diagnostic accuracy data in the EAG's systematic review. The committee noted that the results of the Cholkeri-Singh et al. study show that DYSIS with DYSISmap detects additional cases of both CIN\xa02 and CIN\xa03, relative to standard colposcopy, without increasing the number of people having biopsies. The committee considered the design of this study and noted a lack of detail on the methods used to ensure that controls in the retrospective arm were comparable with the people in the prospective arm. However, the committee heard from the EAG that the people in the 2\xa0study arms appear to be comparable for key baseline characteristics. The committee also considered analyses provided at consultation based on KC65 data (from the NHSCSP in England between 2012/13 and 2015/16). It noted that the data generally showed no increase in biopsy rates in centres adopting DYSIS, but it acknowledged that DYSIS may not be used for every colposcopy in these centres. The committee concluded that despite these papers having methodological limitations, combined with the KC65 data they provided some reassurance that the increase in biopsies implied by the results of the diagnostic accuracy studies alone may not be realised in practice in centres using DYSIS colposcopy with DYSISmap.\n\nA patient expert explained that referral for colposcopy can often cause substantial anxiety, which may not reduce even when the colposcopy is normal. People having a colposcopy may be anxious because of the examination itself and because they have already had a screening result informing them that an abnormality has been detected. The clinical experts explained that it can often be difficult to reduce anxiety in people who have a negative colposcopy, but who were referred with an HPV-positive result, because no treatment can be offered. The committee noted evidence from the systematic review and also anecdotal evidence from clinical and patient experts, which suggested that the adjunctive colposcopy technologies could reduce anxiety because people can be shown objective information to explain that no abnormality has been detected. The committee concluded that although the additional information provided by the adjunctive colposcopy technologies has the potential to help clinicians reassure people and reduce their anxiety, there are currently insufficient data to conclude that they have a significant effect on this (see section\xa06.3).\n\n# Cost effectiveness\n\nThe committee discussed the assumption made in the cost-effectiveness model that video colposcopy and binocular colposcopy are equivalent in terms of diagnostic accuracy. The clinical experts explained that there was no consensus among experts about their equivalence and that the sensitivity estimates for video colposcopy obtained in the DYSIS studies were lower than would be expected for binocular colposcopy in the NHS. Also, the clinical experts noted that the estimates for the sensitivity of binocular colposcopy in the ZedScan studies were higher, and more representative of NHS practice. But the committee noted that the estimates used in the cost-effectiveness model for colposcopy alone were taken from the meta-analyses of DYSIS colposcopy. Therefore, the committee concluded that the relative benefits of the adjunctive colposcopy technologies could have been overestimated in the modelling.\n\nThe committee discussed both modelled base cases and noted that the increased sensitivity of the adjunctive colposcopy technologies led to less cervical cancers developing over the 60‑year time horizon. The clinical experts explained that the additional high-grade lesions detected using the adjunctive colposcopy technologies could in fact be low-volume CIN\xa02 disease, which could regress without treatment. The committee questioned whether data were available that explained the natural history of low-volume CIN\xa02 but heard that these were not available. Anecdotal evidence, and results of a British Society for Colposcopy and Cervical Pathology survey, suggest that some clinicians are now using either ablative techniques or 'watchful waiting' management strategies for low-volume CIN\xa02 in some circumstances. The committee also noted that when the time horizon of the model was reduced to 3\xa0years, and the longer-term outcomes associated with increased sensitivity were removed, colposcopy alone dominated; that is, it was more effective and less expensive than the adjunctive colposcopy technologies. The committee concluded that, without clinical outcome data, or data on the natural history of low-volume CIN\xa02, there was uncertainty about the longer-term outcomes associated with the increased sensitivity of the adjunctive colposcopy technologies. It wished to encourage further data collection to resolve this (see section\xa06.4).\n\nThe committee discussed the effect of the lower specificity associated with the adjunctive colposcopy technologies on longer-term outcomes in the model. In the shorter term, the model showed that reduced specificity is associated with an increase in unnecessary biopsies and treatments. The committee questioned whether this would be realised in practice. The EAG advised that the assumptions made in the model about when biopsies would be taken were based on the NHSCSP's colposcopy and programme management guidelines (2016; publication number 20). The clinical experts explained that these guidelines may not always be followed, and colposcopists may take biopsies for reassurance that high-grade disease is not present. The committee noted that there is considerable variation in clinical practice between colposcopists, and that there were no data to show how the adjunctive colposcopy technologies affect clinical decision-making in the UK. The committee also noted its previous conclusion (see section\xa05.7) that results from the prepublication version of Cholkeri-Singh et al. (2018) study and the KC65 data (from the NHSCSP in England between 2012/13 and 2015/16) showed no increase in biopsy rates in centres adopting DYSIS. It also noted that Cholkeri-Singh et al. reported that using DYSIS was associated with an increased yield of CIN\xa02+ which, combined with the data on biopsy rates, suggests that DYSIS helps colposcopists target the areas chosen for biopsy. The committee concluded that there is some real world evidence suggesting that DYSIS does not increase the biopsy rate to the extent predicted by the model, and noted that equivalent data were not yet available for ZedScan I.\n\nThe committee discussed whether reduced specificity is associated with an increased risk of adverse obstetric outcomes in the longer term. The clinical experts explained that the relationship between biopsies, treatment and adverse obstetric outcomes was not well understood, but it was generally acknowledged that the smaller the excisional treatment the lower the risk of adverse outcomes. The committee noted that the base case assumed an excess risk of preterm delivery of 0.04, which was reduced to\xa00 in a scenario analysis with no substantial effect on the results. The committee concluded that although they were an important clinical consideration in practice, the longer-term effects of reduced specificity did not seem to be a key driver in the model.\n\nThe committee questioned the cost savings of the adjunctive colposcopy technologies in the model. The EAG explained that the model's cost savings were driven by increased sensitivity, which led to a reduction in costs associated with both cancer treatment and follow-up appointments. The clinical experts noted that technologies that improve the negative predictive value of colposcopy may become more important after HPV primary screening is fully rolled out and people with HPV-positive, cytology-negative results are referred for colposcopy. The committee noted that the base case for HPV primary screening was based on preliminary data only, but acknowledged that improvements in sensitivity may become increasingly important in the future. The committee concluded that because there were no data on the natural history of low-volume disease, it was uncertain whether the adjunctive colposcopy technologies would increase the detection of disease that would progress to cancer if not treated. Therefore, the cost savings in the model may not be robust.\n\nThe committee questioned the effect of not having a probabilistic sensitivity analysis to quantify the overall uncertainty in the model. The EAG explained that it could not do this analysis because of the length of time needed to run each simulation. The EAG also explained that although the mean ICER may be different from the deterministic analyses if the model was run probabilistically, there was unlikely to be a substantial difference that would change the modelling conclusions. The committee noted that the model results had been robust to changes in many parameter estimates and assumptions in the deterministic sensitivity and scenario analyses, but that the results were likely to be confounded by the lack of clinical outcome data. The committee concluded that on this occasion the lack of a probabilistic sensitivity analysis was not critical.\n\nThe committee considered whether the adjunctive colposcopy technologies should be recommended for routine adoption. It noted its conclusions on the applicability of data from non-UK studies where the accuracy of colposcopy may differ (see section\xa05.4), the lack of data on the natural history of low-volume CIN\xa02 (see section\xa05.10) and the uncertainty about whether the adjunctive colposcopy technologies would reduce cervical cancer over the longer term (see section\xa05.13). Taking these factors into account, the committee considered that there was uncertainty about the clinical and cost effectiveness of the adjunctive colposcopy technologies because only diagnostic accuracy data were available. It noted, however, that further data (prepublication versions of Cholkeri-Singh et al. 2018 and DeNardis et al. 2017) provided at consultation showed that DYSIS was able to detect more CIN\xa03 lesions than standard colposcopy, without increasing the number of people having biopsies. Therefore, the committee concluded that there was enough evidence that colposcopy using DYSIS with DYSISmap detects more clinically important lesions than colposcopy alone to recommend its continued adoption. It also noted that the additional data provided at consultation were from a US study. The committee wished to encourage centres using DYSIS to audit their outcomes and confirm that the expected benefits are achieved in the NHS (see section\xa05.16). Also, the committee concluded that although the ZedScan I shows promise, there was too much uncertainty over clinical and cost effectiveness to recommend its routine adoption at present, and recommended that further research was needed (see section\xa05.17).\n\n# Research considerations\n\nThe committee recalled that the available clinical outcome data that support using DYSIS with DYSISmap were from a US study (see section\xa05.15). It therefore recommended that centres using this technology should audit their clinical outcomes and confirm that the expected benefits are achieved in the NHS. Outcomes that should be audited include, but are not limited to, rates of CIN\xa02+ detection, CIN\xa03+ detection and biopsy.\n\nThe committee considered the amount of evidence available for both adjunctive technologies. It noted that more data were available for the DYSIS system, and that evidence for ZedScan\xa0I was limited to a small number of diagnostic accuracy studies. The committee considered that ZedScan\xa0I shows promise but further studies are needed, in particular to compare the accuracy and the clinical effectiveness of the technology with standard colposcopy.\n\nThe clinical experts explained that all colposcopy clinics complete a quarterly data return for Public Health England, the KC65. This is used to compare and assess their data against the standards outlined in NHSCSP's colposcopy and programme management guidelines (2016). The committee considered whether these data could be studied to see if biopsy and detection rates of CIN\xa02+ had increased in centres that had already adopted DYSIS colposcopy with DYSISmap or the ZedScan\xa0I. The clinical experts explained that the device used in each colposcopy is not currently recorded and it is not known whether centres with an adjunctive colposcopy technology use it routinely. The committee acknowledged that making the necessary changes to the KC65 to collect these data would be difficult. However, it wished to encourage the owners of the KC65 dataset to consider whether it could be adapted in the future and used to support further data collection for the adjunctive colposcopy technologies, and whether papers based on the data could be published and used for updates of this guidance. The committee also suggested that, if it is not possible to use the KC65 to collect these data nationally, then local audits should be used to collect these data from services that have adopted the adjunctive technologies.\n\nThe committee identified that different thresholds had been used to assess the accuracy of colposcopy in the studies. Some used colposcopic impression that high-grade disease was present (that is, what the colposcopist thought). In other studies colposcopy was considered positive if at least 1\xa0measurement point was suggested for biopsy (that is, what action was taken). Some studies used both. This made comparison of the relative cost effectiveness of the adjunctive technologies difficult. The committee considered that a more consistent approach to assessing and reporting colposcopic accuracy in studies would help future comparisons of adjunctive technologies. The clinical experts stated that work on producing standards for reporting colposcopic accuracy in the NHSCSP is being done.\n\nThe committee noted the assumption made in the cost-effectiveness model that video colposcopy and binocular colposcopy are equivalent in terms of diagnostic accuracy (see section\xa05.9). The clinical experts explained that there is limited evidence to support this assumption. Future assessments of adjunctive technologies would benefit from research assessing the equivalence of different types of colposcope (digital, video and binocular).", 'Recommendations for further research': 'The committee noted that human papilloma virus (HPV) primary screening is being implemented across England (see section\xa05.2) and that the base-case economic modelling for HPV primary screening in this assessment was based on preliminary data only (see section\xa05.13). The committee recommended that further studies should be done in a HPV primary screening setting. These studies should incorporate clinical outcome data and be designed to minimise verification bias. Future studies should consider measuring variability and should also take into account HPV genotyping status when possible, so that the difference in accuracy in a population vaccinated against HPV types\xa016 and\xa018 can be better understood.\n\nThe committee noted that there were no data to show how the adjunctive colposcopy technologies affect UK clinical decision-making, when all colposcopy is done by accredited colposcopists (see section\xa05.11). It therefore recommended that data should be collected to show how the results of the technologies affect decision-making, including biopsy decisions and decisions to discharge people with a negative colposcopy examination back to routine screening.\n\nThe committee considered that the adjunctive colposcopy technologies had the potential to improve patient experience and reduce anxiety (see section\xa05.8). Further research is needed to understand the effect of having the additional information provided by the adjunctive colposcopy technologies on anxiety for people having a colposcopy, when this information is shown to a person during the examination.\n\nThe committee recommended that further research is needed to better understand the natural history of low-volume cervical intraepithelial neoplasia (CIN)\xa02 lesions. It noted that this is not captured in the current versions of the natural history models for CIN and cervical cancer (see section\xa05.10), but is likely to become increasingly important for colposcopy services as HPV primary screening is rolled out and vaccinated groups enter the screening programme.'}
|
https://www.nice.org.uk/guidance/dg32
|
Evidence-based recommendations on 2 adjunctive colposcopy technologies (the DYSIS colposcope with DYSISmap and the ZedScan I) for assessing suspected cervical abnormalities in people having colposcopy.
|
91251f44db8618478b7cd77751c219b85331389a
|
nice
|
Robot-assisted kidney transplant
|
Robot-assisted kidney transplant
Evidence-based recommendations on robot-assisted kidney transplant in adults. This involves the surgeon using a robot to help with a kidney transplant.
# Recommendations
Current evidence on the safety and efficacy of robot-assisted kidney transplant is limited in quantity and quality. For patients with obesity who would not otherwise be able to have a kidney transplant without an unacceptable risk of morbidity, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. In patients for whom open kidney transplant surgery is suitable, this procedure should only be used in the context of research. Find out what special arrangements and only in research mean on the NICE interventional procedures guidance page.
Clinicians wishing to do robot-assisted kidney transplant in people with obesity who would not otherwise be able to have a kidney transplant without an unacceptable risk of morbidity should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.
Report details about all patients having robot-assisted kidney transplantation to NHS Blood and Transplant and review clinical outcomes locally. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Further research should include studies comparing robot-assisted kidney transplant with open surgery. This should collect data on patient selection, warm ischaemia times, the need for conversion to open surgery, graft function, and long-term graft and patient survival.
The procedure should only be done by teams of surgeons with experience in both transplant surgery and robotic surgery.# The condition, current treatments and procedure
# The condition
End-stage renal disease happens when kidney function is insufficient to maintain health without either dialysis or a kidney transplant. This is typically when the glomerular filtration rate is less than 15 ml/min/1.73 m2. End-stage renal disease may be caused by a number of conditions, most commonly diabetes.
# Current treatments
The treatments for end-stage renal disease include conservative treatment, dialysis and kidney transplant. Kidney transplant is considered the treatment of choice for many patients but is not always possible.
Kidney transplant, using a kidney from either a deceased or living donor, is usually done by open surgery through an incision in the left or right lower abdomen providing a retroperitoneal approach to the iliac fossa.
# The procedure
Robot-assisted kidney transplants may result in decreased blood loss, shorter recovery time, fewer wound complications and improved cosmetic results compared with conventional open surgery.
With the patient under general anaesthesia and placed in a supine position, a periumbilical incision of about 7 cm is made to insert a hand-assist device. Then, 4 or 5 small incisions (0.5 cm to 1 cm) are made to insert robotic arms and instruments into the abdomen. After the ports and the hand-assist device are in place, the patient is usually moved to the Trendelenburg position. The external iliac vessels are prepared and the bladder is filled with normal saline to facilitate its dissection. The graft kidney is put into the peritoneum, and the renal vein and artery are anastomosed to the external iliac vessels using the robot. After completion of vascular anastomoses, an ureteroneocystostomy is done robotically. The patient's wounds are then sutured. Intra-operative Doppler imaging may be used to assess graft vascular flow.
Modifications of the techniques used for robot-assisted kidney transplant have been described.
|
{'Recommendations': "Current evidence on the safety and efficacy of robot-assisted kidney transplant is limited in quantity and quality. For patients with obesity who would not otherwise be able to have a kidney transplant without an unacceptable risk of morbidity, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. In patients for whom open kidney transplant surgery is suitable, this procedure should only be used in the context of research. Find out what special arrangements and only in research mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do robot-assisted kidney transplant in people with obesity who would not otherwise be able to have a kidney transplant without an unacceptable risk of morbidity should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.\n\nReport details about all patients having robot-assisted kidney transplantation to NHS Blood and Transplant and review clinical outcomes locally. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nFurther research should include studies comparing robot-assisted kidney transplant with open surgery. This should collect data on patient selection, warm ischaemia times, the need for conversion to open surgery, graft function, and long-term graft and patient survival.\n\nThe procedure should only be done by teams of surgeons with experience in both transplant surgery and robotic surgery.", 'The condition, current treatments and procedure': "# The condition\n\nEnd-stage renal disease happens when kidney function is insufficient to maintain health without either dialysis or a kidney transplant. This is typically when the glomerular filtration rate is less than 15\xa0ml/min/1.73\xa0m2. End-stage renal disease may be caused by a number of conditions, most commonly diabetes.\n\n# Current treatments\n\nThe treatments for end-stage renal disease include conservative treatment, dialysis and kidney transplant. Kidney transplant is considered the treatment of choice for many patients but is not always possible.\n\nKidney transplant, using a kidney from either a deceased or living donor, is usually done by open surgery through an incision in the left or right lower abdomen providing a retroperitoneal approach to the iliac fossa.\n\n# The procedure\n\nRobot-assisted kidney transplants may result in decreased blood loss, shorter recovery time, fewer wound complications and improved cosmetic results compared with conventional open surgery.\n\nWith the patient under general anaesthesia and placed in a supine position, a periumbilical incision of about 7\xa0cm is made to insert a hand-assist device. Then, 4 or 5\xa0small incisions (0.5\xa0cm to 1\xa0cm) are made to insert robotic arms and instruments into the abdomen. After the ports and the hand-assist device are in place, the patient is usually moved to the Trendelenburg position. The external iliac vessels are prepared and the bladder is filled with normal saline to facilitate its dissection. The graft kidney is put into the peritoneum, and the renal vein and artery are anastomosed to the external iliac vessels using the robot. After completion of vascular anastomoses, an ureteroneocystostomy is done robotically. The patient's wounds are then sutured. Intra-operative Doppler imaging may be used to assess graft vascular flow.\n\nModifications of the techniques used for robot-assisted kidney transplant have been described."}
|
https://www.nice.org.uk/guidance/ipg609
|
Evidence-based recommendations on robot-assisted kidney transplant in adults. This involves the surgeon using a robot to help with a kidney transplant.
|
4402942e68e4e0fab3801383a7201eaefd0ecb13
|
nice
|
Prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia
|
Prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia
Evidence-based recommendations on prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves blocking the blood vessels supplying the prostate with tiny plastic particles.
# Recommendations
Current evidence on the safety and efficacy of prostate artery embolisation for benign prostatic hyperplasia is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a urologist and an interventional radiologist.
This technically demanding procedure should only be done by an interventional radiologist with specific training and expertise in prostatic artery embolisation.# The condition, current treatments and procedure
# The condition
Benign prostatic hyperplasia is common in older men. Stromal and epithelial cells increase in number, causing the prostate to increase in size. It often occurs in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.
# Current treatments
Mild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5‑alpha-reductase inhibitors. If other treatments have not worked, then surgical options include transurethral resection of the prostate, transurethral vaporisation of the prostate, holmium laser enucleation of the prostate or prostatectomy (see the NICE clinical guideline on lower urinary tract symptoms in men). Insertion of prostatic urethral lift implants has been introduced more recently as an alternative treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Potential complications of surgical procedures include bleeding, infection, strictures, incontinence and sexual dysfunction.
# The procedure
Prostate artery embolisation for benign prostate hyperplasia is usually done using local anaesthesia. Under X‑ray guidance, the prostate is approached through the left or right femoral artery. Super-selective catheterisation of the small prostatic arteries is done using fine microcatheters through the pelvic arteries. Embolisation involves the introduction of microparticles to completely block the prostatic vessels. Embolisation agents include polyvinyl alcohol (PVA) and other newer synthetic biocompatible materials.
The aim of prostate artery embolisation is to reduce the prostate's blood supply, causing some of it to undergo necrosis and shrink. It is common for patients to experience pelvic pain during and after the procedure. This does not usually last more than 1 to 3 days. The potential benefits of prostate artery embolisation compared with surgery include fewer complications, avoiding a general anaesthetic and it may be done as a day case procedure.
|
{'Recommendations': 'Current evidence on the safety and efficacy of prostate artery embolisation for benign prostatic hyperplasia is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a urologist and an interventional radiologist.\n\nThis technically demanding procedure should only be done by an interventional radiologist with specific training and expertise in prostatic artery embolisation.', 'The condition, current treatments and procedure': "# The condition\n\nBenign prostatic hyperplasia is common in older men. Stromal and epithelial cells increase in number, causing the prostate to increase in size. It often occurs in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.\n\n# Current treatments\n\nMild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5‑alpha-reductase inhibitors. If other treatments have not worked, then surgical options include transurethral resection of the prostate, transurethral vaporisation of the prostate, holmium laser enucleation of the prostate or prostatectomy (see the NICE clinical guideline on lower urinary tract symptoms in men). Insertion of prostatic urethral lift implants has been introduced more recently as an alternative treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Potential complications of surgical procedures include bleeding, infection, strictures, incontinence and sexual dysfunction.\n\n# The procedure\n\nProstate artery embolisation for benign prostate hyperplasia is usually done using local anaesthesia. Under X‑ray guidance, the prostate is approached through the left or right femoral artery. Super-selective catheterisation of the small prostatic arteries is done using fine microcatheters through the pelvic arteries. Embolisation involves the introduction of microparticles to completely block the prostatic vessels. Embolisation agents include polyvinyl alcohol (PVA) and other newer synthetic biocompatible materials.\n\nThe aim of prostate artery embolisation is to reduce the prostate's blood supply, causing some of it to undergo necrosis and shrink. It is common for patients to experience pelvic pain during and after the procedure. This does not usually last more than 1\xa0to 3\xa0days. The potential benefits of prostate artery embolisation compared with surgery include fewer complications, avoiding a general anaesthetic and it may be done as a day case procedure."}
|
https://www.nice.org.uk/guidance/ipg611
|
Evidence-based recommendations on prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia in adults. This involves blocking the blood vessels supplying the prostate with tiny plastic particles.
|
3ed91db4c116d6dfb79be68641af7f97c541fc08
|
nice
|
Microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma
|
Microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma
Evidence-based recommendations on microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma in adults. This involves putting a tiny gelatin tube (stent) under the skin at the base of the eye to create a new drainage channel for excess fluid.
# Recommendations
Evidence on the safety and efficacy of microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.
NICE encourages further research into microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma, including randomised studies. Further research should include details of patient selection and long-term outcomes.# The condition, current treatments and procedure
# The condition
Open-angle glaucoma is a chronic condition associated with increased intraocular pressure, which leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.
# Current treatments
Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, inserting drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.
# The procedure
Microinvasive insertion of a trans-scleral gelatin stent via the ab interno approach (placed surgically from the anterior chamber, outwards to the subconjunctival space) for treating open-angle glaucoma is a minimally invasive procedure. It involves implanting a gelatin stent, a collagen-derived drainage device, to reduce intraocular pressure. The collagen is derived from animal sources. The procedure creates an artificial bypass channel and drainage pathway from the anterior chamber into the non-dissected tissue of the subconjunctival space to improve drainage and outflow of aqueous humor.
This procedure can be done at the same time as phacoemulsification and intraocular lens insertion for treating cataracts.
Under local or topical anaesthesia, a small incision is made in the cornea, and the anterior chamber is filled with viscoelastic. A preloaded implant injector is then advanced through the same corneal incision and directed towards the scleral spur. The injector needle is directed through the sclera to emerge under the conjunctiva, approximately 2 mm to 3 mm behind the limbus. The soft and permanent gelatin stent is then injected, to traverse the anterior chamber, sclera and conjunctival space. After placement is checked (using a gonioscopy mirror) the viscoelastic is exchanged for a balanced salt solution and the injector is withdrawn. The corneal incision is usually self-sealing but is sometimes sutured. Subconjunctival injection of mitomycin‑C may be done during the procedure.
|
{'Recommendations': "Evidence on the safety and efficacy of microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.\n\nNICE encourages further research into microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma, including randomised studies. Further research should include details of patient selection and long-term outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nOpen-angle glaucoma is a chronic condition associated with increased intraocular pressure, which leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.\n\n# Current treatments\n\nTreatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, inserting drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.\n\n# The procedure\n\nMicroinvasive insertion of a trans-scleral gelatin stent via the ab interno approach (placed surgically from the anterior chamber, outwards to the subconjunctival space) for treating open-angle glaucoma is a minimally invasive procedure. It involves implanting a gelatin stent, a collagen-derived drainage device, to reduce intraocular pressure. The collagen is derived from animal sources. The procedure creates an artificial bypass channel and drainage pathway from the anterior chamber into the non-dissected tissue of the subconjunctival space to improve drainage and outflow of aqueous humor.\n\nThis procedure can be done at the same time as phacoemulsification and intraocular lens insertion for treating cataracts.\n\nUnder local or topical anaesthesia, a small incision is made in the cornea, and the anterior chamber is filled with viscoelastic. A preloaded implant injector is then advanced through the same corneal incision and directed towards the scleral spur. The injector needle is directed through the sclera to emerge under the conjunctiva, approximately 2\xa0mm to 3\xa0mm behind the limbus. The soft and permanent gelatin stent is then injected, to traverse the anterior chamber, sclera and conjunctival space. After placement is checked (using a gonioscopy mirror) the viscoelastic is exchanged for a balanced salt solution and the injector is withdrawn. The corneal incision is usually self-sealing but is sometimes sutured. Subconjunctival injection of mitomycin‑C may be done during the procedure.'}
|
https://www.nice.org.uk/guidance/ipg612
|
Evidence-based recommendations on microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma in adults. This involves putting a tiny gelatin tube (stent) under the skin at the base of the eye to create a new drainage channel for excess fluid.
|
07f74c8bb14fbb5ddb3a4a965cd8479355388dd4
|
nice
|
Nerve transfer to partially restore upper limb function in tetraplegia
|
Nerve transfer to partially restore upper limb function in tetraplegia
Evidence-based recommendations on nerve transfer to partially restore upper limb function in people with tetraplegia. This involves connecting an undamaged, functioning, but non-essential nerve near the injury to the damaged essential nerve.
# Recommendations
The evidence on efficacy of nerve transfer to partially restore upper limb function in tetraplegia is limited in quantity. There are no major safety concerns. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do nerve transfer to partially restore upper limb function in tetraplegia should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having nerve transfer to partially restore upper limb function in tetraplegia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.
Patient selection and treatment should be done by a multidisciplinary team with expertise in managing spinal cord injury, and nerve and tendon transfers. This team should typically include a surgeon with experience in the surgical management of tetraplegia and nerve transfer, an occupational therapist, a physiotherapist with experience in spinal injury rehabilitation, a spinal injuries consultant and a neurophysiologist.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Tetraplegia is typically caused by cervical spinal cord injuries, with associated complete or incomplete loss of muscle strength in all 4 extremities. The exact symptoms depend on the location and extent of injury. The most common neurological level of injury is the fifth cervical vertebra. This results in loss of upper limb function and the inability to carry out activities of daily living.
# Current treatments
Restoring upper limb function is an important rehabilitation aim in people with tetraplegia. Conservative treatment options include a comprehensive program of physical and occupational therapy, including orthoses and functional electrical stimulation. Surgical techniques to restore function of the upper limb (elbow, thumb and finger extension, wrist movement, hand opening and closing, and pinch and grip) include neuroprostheses, tendon transfer, nerve transfers, reconstructive surgeries or a combination of these procedures.
# The procedure
In this procedure, the nearest functional undamaged and non-essential nerve is used as the donor nerve.
Under general anaesthesia, with the patient in a supine position and with their arms on a board, the non-functioning nerve is exposed and the degree of paralysis is defined neurophysiologically. The closest functional donor nerve is identified. It is then isolated, divided, transferred and joined to the selected damaged nerve while avoiding tension in the donor nerve. The aim is to re‑innervate the target muscles and improve limb function.
Post-operatively, the patient needs nerve and muscle rehabilitation training to recover the strength of the re‑innervated muscles and improve activities of daily living.
Nerve transfers may sometimes be combined with tendon transfers.
|
{'Recommendations': "The evidence on efficacy of nerve transfer to partially restore upper limb function in tetraplegia is limited in quantity. There are no major safety concerns. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do nerve transfer to partially restore upper limb function in tetraplegia should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having nerve transfer to partially restore upper limb function in tetraplegia. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool.\n\nPatient selection and treatment should be done by a multidisciplinary team with expertise in managing spinal cord injury, and nerve and tendon transfers. This team should typically include a surgeon with experience in the surgical management of tetraplegia and nerve transfer, an occupational therapist, a physiotherapist with experience in spinal injury rehabilitation, a spinal injuries consultant and a neurophysiologist.\n\nNICE may update the guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nTetraplegia is typically caused by cervical spinal cord injuries, with associated complete or incomplete loss of muscle strength in all 4\xa0extremities. The exact symptoms depend on the location and extent of injury. The most common neurological level of injury is the fifth cervical vertebra. This results in loss of upper limb function and the inability to carry out activities of daily living.\n\n# Current treatments\n\nRestoring upper limb function is an important rehabilitation aim in people with tetraplegia. Conservative treatment options include a comprehensive program of physical and occupational therapy, including orthoses and functional electrical stimulation. Surgical techniques to restore function of the upper limb (elbow, thumb and finger extension, wrist movement, hand opening and closing, and pinch and grip) include neuroprostheses, tendon transfer, nerve transfers, reconstructive surgeries or a combination of these procedures.\n\n# The procedure\n\nIn this procedure, the nearest functional undamaged and non-essential nerve is used as the donor nerve.\n\nUnder general anaesthesia, with the patient in a supine position and with their arms on a board, the non-functioning nerve is exposed and the degree of paralysis is defined neurophysiologically. The closest functional donor nerve is identified. It is then isolated, divided, transferred and joined to the selected damaged nerve while avoiding tension in the donor nerve. The aim is to re‑innervate the target muscles and improve limb function.\n\nPost-operatively, the patient needs nerve and muscle rehabilitation training to recover the strength of the re‑innervated muscles and improve activities of daily living.\n\nNerve transfers may sometimes be combined with tendon transfers.'}
|
https://www.nice.org.uk/guidance/ipg610
|
Evidence-based recommendations on nerve transfer to partially restore upper limb function in people with tetraplegia. This involves connecting an undamaged, functioning, but non-essential nerve near the injury to the damaged essential nerve.
|
Subsets and Splits
Count and Percentage of 'None'
The query reveals the frequency of 'none' values in raw and clean text fields, their percentage in the dataset, and average text length differences, providing valuable insights for data cleaning and quality assessment.
Text Length Statistics
Provides the minimum and maximum lengths of both cleaned and raw text, offering basic insights into text length variation.
Count None Values in Text Columns
Counts the occurrences and percentages of rows where 'raw_text' or 'clean_text' is 'none', providing a basic overview of missing or placeholder data.
Top 100 Longest Clean Texts
Retrieves the 100 longest cleaned text entries along with their raw text versions, offering basic insight into text length differences.
Longest Clean Text Entries
Returns the 100 longest clean texts in the dataset, which could help identify unusually long entries for quality review.
Longest Clean Text Entries
Returns the 100 longest cleaned text entries by id and title, providing basic information about the longest entries without significant analytical insight.