Follicular lymphoma - rituximab: appraisal consultation document
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37)
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The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma. This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation . The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the single technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk). The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees. At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process. After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute. Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales. The key dates for this appraisal are: Closing date for comments: 26 October 2007 Second Appraisal Committee meeting: 14 November 2007 Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B. |
| Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Rituximab monotherapy is recommended as an option for the treatment of people with relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma in second or subsequent relapse, when all alternative treatment options have been exhausted (that is, if there is resistance to or intolerance of chemotherapy). |
| 1.2 | Rituximab monotherapy as maintenance therapy, within its marketing authorisation, is recommended as an option for the treatment of relapsed stage III or IV follicular non-Hodgkin's lymphoma in remission induced with chemotherapy only. |
| 1.3 | The Committee is minded not to recommend the use of rituximab in combination with chemotherapy for induction of remission in people with relapsed stage III or IV follicular non-Hodgkin's lymphoma. |
| 1.4 |
The Committee recommends that the Institute requests the manufacturer of rituximab to provide the following further analyses and clarifications as detailed in section 4.14.
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| 2 | The technology |
| 2.1 | Rituximab (MabThera, Roche) is a chimeric (mouse/human) genetically engineered monoclonal antibody. It targets the CD20 surface antigen of mature B-cell lymphocytes. |
| 2.2 |
Rituximab is licensed in relapsed non-Hodgkin's follicular lymphoma as follows.
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| 2.3 |
The Institute sought clarification from the European Medicines Agency and understood that rituximab can be used within its licensed indications as follows:
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| 2.4 | A single dose of rituximab is 375 mg/m2 body surface area. When used as monotherapy, this dose is given every week for 4 weeks. When used in combination with chemotherapy for induction of remission, this dose is given with each cycle of chemotherapy. For maintenance therapy, the same dose is given every 3 months until relapse or for a maximum of 2 years (a total of eight doses). |
| 2.5 | Allergic and skin reactions are the most common side effects of rituximab infusion. Infusion reactions can be complicated by bronchospasm and hypotension and can occasionally be severe or life threatening. Severe reactions are more common in patients with high tumour burden, and the incidence and severity of infusion reactions decrease with successive infusions. Rituximab also causes blood and bone marrow toxicity manifested by neutropenia, leucopenia and infections. In addition rituximab is associated with flu-like symptoms and neurological problems. For full details of side effects and contraindications, see the summary of product characteristics. |
| 2.6 | The cost of one 100-mg vial is £174.63 and one 500-mg vial is £873.15 (excluding VAT; 'British national formulary' [BNF] edition 53). For an average patient (body surface area 1.6-1.87 m2) the cost per dose is £1222. Costs may vary in different settings because of negotiated procurement discounts. |
| 3 | The manufacturer's submission |
| The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B). | |
| 3.1 | The manufacturer identified best supportive care as the comparator for rituximab monotherapy at second and subsequent relapse (the indication appraised in TA 37). No new evidence was provided for this indication. For the use of rituximab with chemotherapy for induction of remission in relapsed follicular lymphoma, the main comparator identified was cyclophosphamide, hydroxydaunomycin, vincristine and prednisone (CHOP) chemotherapy, and fludarabine-containing regimens were also considered appropriate. For the use of rituximab as maintenance therapy, the appropriate comparator was considered to be observation. For the latter two indications the manufacturer identified two trials. |
| 3.2 | The European Organisation for Research and Treatment of Cancer (EORTC) trial was an open-label study conducted in patients with follicular non-Hodgkin's lymphoma, in first and subsequent relapse, who had not previously received rituximab. Patients (N = 465) were randomised to induction with six cycles of CHOP chemotherapy plus rituximab (N = 234) or CHOP without rituximab (N = 231). Those patients in remission after six cycles (N = 334) were subject to a second randomisation; to observation only (N = 167) or eight doses of maintenance therapy with rituximab, given every 3 months for 2 years (N = 167). For induction of remission, there was a statistically significant higher overall response rate following combination therapy with CHOP plus rituximab compared with CHOP alone (85% versus 72%, respectively; p < 0.0001). The median progression-free survival was also statistically significantly longer for patients who received combination therapy (33 months versus 20 months; p = 0.0003). For patients on rituximab maintenance, the median progression-free survival was 52 months compared with 15 months for patients being observed, and this was statistically significant (p < 0.0001). When CHOP plus rituximab was used for induction, the median progression-free survival for patients who received rituximab maintenance therapy was 52 months compared with 23 months for patients being observed [p = 0.0043]; when CHOP only was used for induction, the corresponding figures were 42 months and 12 months, respectively [p < 0.0001]. Median overall survival could not be calculated as f ewer than half the patients in each group had died at last reported follow up . For patients who received CHOP plus rituximab for induction, the adverse effects reported with a higher incidence (difference ≥ 5%) than in the control group (CHOP only) were skin problems, infections, allergies and neutropenia. During the maintenance phase, patients on rituximab experienced a higher incidence (difference ≥ 5%) of flu-like symptoms, neurological problems, infections, blood and bone marrow problems, pulmonary problems and allergies, than those who were observed. |
| 3.3 | The German Low-Grade Lymphoma Study Group-Fludarabine, Cyclophosphamide, Mitoxantrone (GLSG-FCM) trial was an open-label study conducted in patients with indolent lymphomas. Patients (total N = 137; follicular lymphoma N = 65) were randomised to induction with four cycles of FCM plus rituximab (follicular lymphoma N = 35) or without rituximab (follicular lymphoma N = 30). This randomisation was stopped early when patients in the FCM plus rituximab group had a statistically significant better outcome. In the maintenance period, patients (total N = 176; follicular lymphoma N = 105) were randomised to rituximab therapy of two 4-weekly treatment blocks of rituximab at 3 and 6 months (follicular lymphoma N = 52) or observation only (follicular lymphoma N = 53). For induction of remission in patients with follicular lymphomas, there was a higher complete response rate following combination therapy with FCM plus rituximab compared with FCM alone (40% versus 23%, respectively), but the difference was not statistically significant. For complete and partial response rates in patients with follicular lymphoma, there was a statistically significant higher rate following combination therapy with rituximab (94% versus 70%; p = 0.011). For patients with follicular lymphoma treated with FCM plus rituximab at induction, the median progression-free survival was not reached, whereas median progression-free survival was 21 months in those who received induction with FCM only; this difference was statistically significant (p = 0.0139). Fewer than half the patients in each group had died at last follow up, and there was no statistically significant difference in the proportions surviving to 2 years. For patients with follicular lymphoma who received FCM plus rituximab induction, the median time to progression was 26 months in patients under observation only, but fewer than half of those receiving maintenance rituximab therapy had progressed; this was a statistically significant difference (p = 0.035). Adverse effects with a higher incidence (difference ≥ 5%) in the rituximab maintenance therapy group compared with the observation only group were blood and bone marrow problems, infection, fever, diarrhoea, pulmonary toxicity and liver enzyme elevation. |
| 3.4 | The cost-effectiveness models submitted by the manufacturer were based on the EORTC trial. A two-arm model compared maintenance with observation based on the randomisation of patients who had responded to induction with or without rituximab. The model had three states - progression-free, progressive disease and death. A four-arm model allowed for use of rituximab at induction compared with chemotherapy alone, with the responders in each of these arms being further randomised to rituximab maintenance or observation only. This allowed for comparison of four treatment strategies: rituximab and chemotherapy induction followed by rituximab maintenance (R-CHOP > R); rituximab and chemotherapy induction followed by observation (R-CHOP > O); chemotherapy induction followed by rituximab maintenance (CHOP > R); and chemotherapy induction followed by observation (CHOP > O). The four treatment strategies allowed for the comparison of six pairs. The four-arm model consisted of five states: progression-free in induction setting; progression-free in maintenance setting; progression-free not in induction/maintenance setting; progressive disease; and death. Both models assumed maintenance treatment continued for 2 years or until disease progression. The time horizon for each model was 30 years and each cycle was 1 month. |
| 3.5 | The hazard rates were taken from the trial up to 24 months and extrapolated from 24 months to 30 years using a Weibull function. In order to fit the parametric curve to the survival data, data from the clinical trial were limited to 1500 days because this was the point at which the survival curves flattened. The hazard for death and progression for rituximab, that is, the duration of benefit, was assumed to be equivalent to baseline risk after 5 years. Quality of life scores for the health states were derived from a study commissioned by the manufacturer. A quality weight of 0.805 was attached to the progression-free states and of 0.618 to the progressive disease state. Each patient was assumed to relapse every 2 years and undergo further treatment. The cost of post-protocol treatments was based on the average costs observed in the trial. Patients received an average of 5.93 cycles of maintenance rituximab. Administration costs were calculated as being equal to an outpatient visit (£86). Follow-up costs were equal to an outpatient visit every 3 months for the progression-free state and an outpatient visit every month in the progressive disease state. Univariate sensitivity analysis was done for both models using a log-logistic model, changing the duration of treatment benefit to 2 or 30 years, changing the time horizon to 4 or 50 years, changing the frequency of relapse and the cost of its treatment, changing the utility value of each state to that of the other, changing the costs for adverse events, administration and routine management and the discount rate. For the four-arm model, the response rates for induction with rituximab were varied. Probabilistic sensitivity analysis was also conducted. |
| 3.6 | For the two-arm model, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) for rituximab maintenance compared with observation was £7721 per quality-adjusted life year (QALY) gained. These results were sensitive to the assumed duration of treatment benefit; assuming a duration of 2 years, the ICER increased to £18,124 per QALY gained. Reducing the time horizon to 4 years increased the ICER to £15,993 per QALY gained when comparing the same treatment strategies. The model results were not sensitive to changes in the utility values attached to the states. For the four-arm model, the most effective treatment intervention, using rituximab for induction and maintenance (R-CHOP > R), compared with the next most effective, using rituximab for maintenance alone (CHOP > R), gave an ICER of £16,749 per QALY gained. Comparing the use of rituximab for maintenance alone (CHOP > R) with no use of rituximab (CHOP > O) gave an ICER of £9076 per QALY gained. For the four-arm model, decreasing the duration of treatment benefit to 2 years increased the ICER for using rituximab in induction and maintenance (R-CHOP > R) compared with rituximab as maintenance alone (CHOP > R) to £36,497 per QALY gained. Decreasing the time horizon to 4 years increased the ICER for the comparison of the same treatment strategies to £48,116 per QALY gained. The model was not sensitive to the utility values of the health states. |
| 3.7 | The ERG considered that the manufacturer had not adequately described the methods for the systematic review of rituximab as monotherapy for induction at second or subsequent relapse (the indication appraised in TA 37) or explicitly reported on its results. However the ERG was confident that no relevant studies for this or any other indications had been missed. The ERG also confirmed that CHOP and fludarabine-containing regimens were the appropriate comparators for rituximab when used with chemotherapy for induction in relapsed follicular lymphoma. The main clinical trial was conducted in patients who were rituximab-naive. In view of previous NICE guidance (TA 110), patients in routine practice in the NHS can be expected to have received rituximab with first-line chemotherapy. The ERG considered that the effectiveness of rituximab in patients who had previously received the drug was not certain. |
| 3.8 | The ERG considered that the use of only two health states did not adequately represent the differences among patients with follicular lymphoma following different treatment pathways and undergoing different treatments. Furthermore, patients in health states should be homogeneous with respect to all relevant variables, and it was considered unlikely that the response to maintenance rituximab would be the same regardless of its use at induction. The ERG considered that the two-arm model did not differentiate among patients on the basis of the treatment at induction. The four-arm model was therefore considered more appropriate. The models assumed further treatment at relapse with attached costs, but did not assume any health benefits from these treatments despite incurring the costs. The ERG noted that the best way to overcome this deficiency was to limit the gains to the observed period only. |
| 3.9 | The ERG noted that the administration of rituximab was assumed to occur in the outpatient setting and was costed accordingly. Given the duration of infusion it was considered more appropriate for this to occur in the day-case setting and the ERG calculated a cost of £504. The ERG also recalculated post-progression treatment costs by aggregating treatments into a small number of meaningful categories. This avoided the wide variation in treatment costs, some of which are very expensive, skewing the average post-progression treatment costs of individual strategies. The newer categories were 'chemotherapy', the use of which was greater for patients who received rituximab during the trial, 'rituximab' and 'other'. It was assumed that 25% of patients in each treatment strategy would receive other treatments, and 75% would be split between chemotherapy and rituximab treatments according to previous use of rituximab as detailed in table 5-12 on page 68 of the ERG report. The ERG also added an estimated cost of £5000 towards terminal-care costs. |
| 3.10 | The ERG considered that the choice of the Weibull model for the analysis had not been sufficiently justified. In addition the manufacturer had assumed that pairs of patient groups to be compared shared common parameters, estimating only three parameters rather than the four required to fit the curves independently. This approach made a proportional hazard assumption, which was not substantiated by reference to trial data, and assumed that the effect of 2 years of rituximab treatment continued indefinitely. This approach ignored the modifying effects of post-progression treatments. The ERG also noted the lack of an initial period of non-zero hazards for those groups that went on to be randomised at maintenance as these groups would have a protocol-driven event-free period. The ERG repeated the analyses overcoming the problems with model projections by limiting the extrapolation to use of the Kaplan-Meier estimates derived from the data to 1500 days. |
| 3.11 | The reanalyses with changes to costs as suggested by the ERG and with outcomes limited to 1500 days using the Kaplan-Meier estimates gave the following results. The single use of rituximab, as either induction (R-CHOP > O) or maintenance (CHOP > R) when compared with no use (CHOP > O) gave ICERs of £16,488 and £13,122 per QALY gained, respectively. Dual use of rituximab at induction and maintenance (R-CHOP > R) compared with no use (CHOP > O) was associated with an ICER of £25,978 per QALY gained. The dual-use strategy (R-CHOP > R) compared with single-use strategies was associated with ICERs of £42,982 per QALY gained for the use of rituximab at maintenance only (CHOP > R) and £42,192 per QALY gained for the use at induction only (R-CHOP > O). The ERG suggested that a comprehensive probabilistic sensitivity analysis in the form of a combined cost-effectiveness acceptability probability plot would indicate which strategy would have the highest probability of being preferred across a range of willingness to pay thresholds. |
| 3.12 | Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx |
| 4 | Consideration of the evidence |
| 4.1 | The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab for the treatment of recurrent or refractory stage III or IV follicular non-Hodgkin's lymphoma, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with follicular lymphoma, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. |
| Clinical effectiveness | |
| 4.2 | The Committee first considered the use of rituximab as recommended (only in the context of a prospective case series) in the original appraisal (TA 37), that is, as monotherapy for the treatment of patients with relapsed or refractory stage III or IV follicular lymphoma, when all alternative treatment options have been exhausted (if there is resistance to or intolerance of chemotherapy). Resistance was defined as the absence of a response to the last course of chemotherapy following several courses of treatment. The guidance also applies to people who have or are likely to become intolerant of chemotherapy because of adverse effects that severely limit the safety of further treatment. The Committee was concerned that no new evidence for this use of rituximab was made available, particularly because it had been a condition of use that patients only received rituximab if their data were collected as part of a case series. It agreed with the ERG that there was a lack of clarity in the manufacturer's search for relevant new data. The clinical specialists pointed to the diminishing use of rituximab in this way because it has been licensed and recommended for earlier use as first-line therapy (TA 110), and they felt that new evidence would not now be collected at earlier stages of the treatment pathway. They argued that rituximab was still needed as a last line option for frailer patients in whom the use of toxic chemotherapy may not be possible. The Committee agreed that the previous recommendation should be allowed to stand but recognised, for the future, the limitations of treatment recommendations based on the need for future data collection. The Committee concluded that rituximab monotherapy should continue to be recommended as an option for the treatment of patients with relapsed or refractory stage III or IV follicular lymphoma, when all alternative treatment options have been exhausted (if there is resistance to or intolerance of chemotherapy). |
| 4.3 | Secondly, the Committee considered the evidence for the clinical effectiveness of rituximab monotherapy as maintenance therapy, following induction of remission with chemotherapy, with or without rituximab; and thirdly, it considered rituximab as induction therapy in combination with CHOP chemotherapy in relapsed follicular lymphoma. Both these indications were evaluated in the EORTC trial, and in both indications rituximab-treated patients had higher response rates, longer remissions and longer overall survival than control patients. The Committee heard from clinical specialists that rituximab was a valuable treatment and that the possibility of maintaining remission was particularly encouraging. The Committee also heard from the patient representatives of the importance attached by patients to the remission state and the value of maintenance treatment in prolonging it. |
| 4.4 | The Committee accepted that the EORTC trial demonstrated the effectiveness of rituximab for maintenance therapy and (in combination with CHOP) the effectiveness of rituximab for the induction of remission in patients at first and second relapse. However, it was mindful that the results from the EORTC trial were based on rituximab-naive patients. Such patients are a diminishing proportion of patients because of the increased prescribing of rituximab as first-line therapy. The Committee considered that it was necessary to be cautious about the assumption that rituximab is as efficacious in patients who had already received it as in patients who were rituximab-naive. The clinical specialists stated that the evidence indicated that follicular lymphoma could be retreated with rituximab with little or no loss of efficacy. They argued that rituximab delays the progress of the disease such that, at eventual relapse, patients have the same options for treatment that would have been available to them earlier. The Committee noted that rituximab maintenance therapy was associated with similar increases in progression-free survival in patients who had received rituximab at induction as in those who had only chemotherapy for induction. However the Committee was aware that the trial was not powered or designed to evaluate the relative efficacy of rituximab maintenance in patients who had or had not received rituximab at induction. The Committee was therefore unable to draw firm conclusions on the relative efficacy of rituximab maintenance therapy in patients who had and had not received rituximab for induction. |
| 4.5 | The Committee also queried the extent to which induction therapy with CHOP was representative of all the comparator treatments used in the NHS. The clinical specialists stated that CHOP was the main chemotherapy used in follicular lymphoma patients at this stage but that fludarabine-containing regimens are also used to some extent. The Committee was also aware that the GLSG trial, using a fludarabine based regimen, showed a similar magnitude of benefit as the EORTC trial which used CHOP. However the regimen of fludarabine used in the GLSG trial varied from that commonly used in the NHS and the trial population included people with other indolent lymphomas. The Committee considered it appropriate to focus its considerations on CHOP as the most important comparator within the NHS. |
| Cost effectiveness | |
| 4.6 |
The Committee then considered the manufacturer's economic model and the critique of it by the ERG. In particular, it discussed the following issues:
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| 4.7 | The Committee considered the changes to the costs in the manufacturer's model suggested by the ERG. It thought that it was appropriate to calculate costs at progression by aggregating treatments into categories, and it agreed with the ERG's assumptions as to how these would vary across the treatment strategies. It also discussed the hospital costs of delivering the treatment. It heard from clinical and patient specialists that, although the duration of second and subsequent infusions can sometimes be reduced to as little as 2 hours, for the most part, approximately 4 hours are necessary. This would be in addition to the infusion time for any chemotherapy with which rituximab was given. The Committee concluded that it would be more appropriate to cost administration of rituximab as a day-case procedure than as an outpatient visit. The Committee also concurred with the ERG's approach of adding a terminal-care cost to the model and that the amounts assumed were appropriate. |
| 4.8 | The Committee considered the approach to the modelling of survival adopted by the manufacturer. It considered that, although the parametric model fitting Weibull distributions to both treatment arms was one of many possible choices, and although the manufacturer presented data for three alternate distributions, this particular choice had not been sufficiently justified by the manufacturer. It noted that there was no initial zero-hazard period modelled, but there was a protocol-driven event-free period in the data. The Committee agreed that including an event-free period could change the goodness-of-fit of any distribution fitted to trial data and influence the outcome of the cost-effectiveness analysis. |
| 4.9 | The Committee noted that in fitting the Weibull curve to the RCT data the manufacturer had estimated three parameters for each pair of distributions rather than the four required to fit the Weibull distributions independently to each treatment arm. In doing so, the manufacturer had made the assumption of proportional hazards such that the only difference between the fitted distributions was as a result of a treatment effect. The Committee thought that this strong assumption of proportional hazards had not been substantiated by RCT data. In addition, the Committee considered that assuming proportional hazards from data over the RCT follow-up period and then extrapolating parametric models beyond the trial period, would assume that the treatment benefit observed in the trial would persist over the duration of the extrapolation. The Committee concluded that the manufacturer's approach to survival modelling could overestimate the clinical and cost effectiveness of rituximab. |
| 4.10 | The Committee then considered how these concerns might affect the calculated cost effectiveness of rituximab when used as maintenance therapy. When considering rituximab monotherapy as maintenance, it was mindful that the clinical and patient specialists had strongly supported this use based on its potential to prolong remission, and the lack of alternative therapies for doing so. The Committee considered the results of the reanalysis performed by the ERG, which did not use model-based extrapolation but limited the analysis to 1500 days of the Kaplan-Meier estimates and made changes to costs as suggested by the ERG above. The Committee agreed that this approach overcame some of the issues noted in sections 4.8 and 4.9. In the ERG's reanalyses, the use of rituximab as maintenance only (CHOP > R) when compared with no use at all (CHOP > O), was associated with an ICER of £13,100 per QALY gained. The Committee concluded that, despite its concern that the EORTC population (from whom these calculations were derived) was not fully representative of UK patients (section 4.4), and the issues discussed in sections 4.6 to 4.9), the use of rituximab for maintenance therapy following induction with chemotherapy was likely to be a cost-effective use of NHS resources. |
| 4.11 | Having accepted that rituximab maintenance therapy following induction with chemotherapy was likely to be a cost-effective use of NHS resources, the Committee then considered the use of rituximab as induction with chemotherapy. It discussed that, although a possible theoretical approach could be to consider this indication separately from maintenance with rituximab, it was clinically inappropriate to do so. Given that patient experts and clinical specialists identified maintenance therapy as the clinical priority and that this is cost effective when compared with current standard treatment, the cost effectiveness of rituximab at induction was considered as an additional strategy over its use as maintenance alone. In other words, it is expected that rituximab maintenance will become standard therapy following this appraisal, and the Committee agreed that the appropriate comparator for the dual-use strategy was the next best use of resources ? which would be single use of rituximab as maintenance therapy as opposed to no use of rituximab. |
| 4.12 | The ICER of dual-use strategy (R-CHOP > R) compared with single-use rituximab maintenance only (CHOP > R) was estimated in the ERG reanalysis to be £43,000 per QALY gained. The Committee thought this high ICER could indicate that this strategy is not cost effective, but was aware that the limited availability of data for the ERG's probabilistic sensitivity analysis comparing the cost effectiveness of multiple strategies made this analysis uncertain. Therefore the Committee felt that it was not in a position to recommend rituximab for use at both induction and maintenance without further robust analysis and that this should be requested from the manufacturer. |
| 4.13 | The Committee accepted that limiting the analysis to the 1500 days of the Kaplan-Meier estimates from the RCT could also underestimate the true health gain from rituximab, noting that a longer time horizon would be in keeping with standard NICE recommended methodology for calculating cost effectiveness. It suggested that the trial data be extrapolated using an appropriate parametric model with distributions fitted independently for each treatment group and taking into account an initial event-free period. If a proportional hazard assumption was made, this would need to be justified from RCT data. In view of the uncertainty of health benefits from treatment at progression and the inappropriateness of assuming proportional hazards over the entire duration of the extrapolation, the Committee concluded that further analysis to address these concerns should be requested from the manufacturer. |
| 4.14 |
The Committee discussed the need for clarification and further analyses, and concluded that these should include the following.
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| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare Standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 |
NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]
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| 6 | Related NICE guidance |
| 6.1 |
The following related NICE guidance is available.
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| 7 | Proposed date for review of guidance |
| 7.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 7.2 | It is proposed that the guidance on this technology is considered for review in September 2010. The Institute would particularly welcome comment on this proposed date. |
| Andrew Stevens Chair, Appraisal Committee September 2007 |
| Appendix A. Appraisal Committee members and NICE project team | |
| A | Appraisal Committee members |
| The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches. | |
| Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. | |
| The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. | |
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| B | NICE project team |
| Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager. | |
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Elangovan Gajraj Helen Chung Chris Feinmann |
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| Appendix B. Sources of evidence considered by the Committee | |
| A |
The Evidence Review Group (ERG) report for this appraisal was prepared by Liverpool Reviews and Implementation Group:
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| B | The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II gave their expert views on rituximab by providing a written statement to the Committee. Organisations listed in I and II have the opportunity to appeal against the final appraisal determination. |
| I |
Professional/specialist and patient/carer groups:
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| II |
Commentator organisations (did not provide written evidence and without the right of appeal):
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| C |
The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on rituximab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.
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