1 Appraisal Committee's preliminary recommendations

1.1 Rituximab is recommended as an option for first-line maintenance treatment of people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.

2 The technology

2.1 Rituximab (MabThera, Roche Products) is a chimeric (mouse/human) genetically engineered monoclonal antibody. It targets the CD20 surface antigen of mature B-cell lymphocytes. Rituximab has a marketing authorisation for the ‘treatment of follicular lymphoma patients responding to induction therapy’.

2.2 Allergic and skin reactions are the most common side effects of rituximab infusion. Reactions during infusion can include bronchospasm and hypotension and can occasionally be severe or life threatening. Severe reactions are more common in people with a high tumour burden, and the incidence and severity of infusion reactions decreases with successive infusions. Rituximab treatment can also be associated with blood and bone marrow toxicity manifested by neutropenia, leucopenia and infections. In addition, rituximab treatment may cause flu-like symptoms and has been associated with progressive multifocal leukoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 In people whose previously untreated follicular lymphoma has responded to first-line induction treatment with rituximab and chemotherapy, the recommended dose of rituximab as maintenance treatment is 375 mg/m² body surface area, administered by intravenous infusion once every 2 months. Treatment should start 2 months after the last dose of induction therapy and continue until disease progression or for a maximum period of 2 years. 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 60). The manufacturer estimated that for a person with an average body surface area of 1.8 m², the average cost of rituximab maintenance treatment for 2 years is £14,669 (excluding VAT). 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, a review of this submission by the Evidence Review Group (ERG; appendix B), and statements received from clinical specialists and  patient experts.

3.1 The manufacturer addressed the decision problem for this appraisal by presenting information about whether in people with advanced follicular lymphoma that has responded to first-line chemotherapy combined with rituximab, rituximab maintenance offers a clinically effective and cost-effective use of NHS resources, compared with either standard management without rituximab or ibritumomab tiuxetan. The outcomes defining effectiveness included progression-free survival, overall survival, response rates, adverse effects of treatment and health-related quality of life.

3.2 The manufacturer undertook a systematic literature review and identified only one study, the Primary Rituximab and Maintenance (PRIMA) trial, that met its inclusion criteria. The manufacturer acknowledged in its submission that the final results from the PRIMA trial would not be published until 2011; consequently, much of the information in the manufacturer’s submission was provided as 'academic in confidence'. The manufacturer presented evidence with a median follow-up of 25 months (at the close of the PRIMA study), but also provided data from two post-study observational follow-up periods which had median follow-up periods of 36  and 38 months. In the absence of long-term data from the PRIMA trial, the manufacturer used data from the EORTC 20981 study to model the expected longer term outcomes of people in the PRIMA trial.

3.3 The PRIMA trial was a phase III, open-label, multicentre, randomised trial with two treatment phases. The trial included 1193 people with previously untreated advanced follicular lymphoma with an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and a median age of 57 years. In the first phase (induction phase), participants underwent one of three different induction regimens, all of which included rituximab: R-CVP (rituximab with cyclophosphamide, vincristine and prednisolone [n = 268]), R‑CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone [n = 881]), or R-FCM (rituximab with cyclophosphamide, fludarabine and mitoxantrone [n = 44]). Those whose disease responded (n = 1019) were randomised to the second phase of the trial in which they received either rituximab maintenance treatment (n = 506) or no treatment ('observation', n = 513). People in the  maintenance arm received 375 mg/m² rituximab intravenously: one dose every 8 weeks for 2 years, for a total of 12 doses, or until disease progression, whichever occurred first. The trial was designed initially to estimate event-free survival as the primary outcome. However, during the course of the trial, the manufacturer amended the protocol and changed the primary end point to progression-free survival. Length of follow-up was increased from 5 to 7 years, and the study population was increased from 900 to 1200 participants. Secondary clinical end points included overall survival, event-free survival, time to next anti-lymphoma treatment, overall response rate at the end of maintenance observation phase, the proportion of people with histologic transformation at first progression, quality of life and safety. Quality-of-life data were collected in the trial using Functional Assessment of Cancer Therapy – General (FACT-G) and European Organisation for Research and Treatment of Cancer Quality of life Questionnaire–Core 30 (EORTC QLQ-C30) questionnaires. After a median follow-up of 25 months, a Data and Safety Monitoring Committee (DSMC) judged that the trial had met its primary objective and recommended premature closure of the study. However, investigators continued to follow patients during an observational post-study period to collect longer-term data.

3.4 The EORTC 20981 study was a phase III, open-label randomised trial that included people with relapsed or resistant follicular non-Hodgkin’s lymphoma (n = 465) who had not previously been treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP. Participants were randomised to induction treatment with R-CHOP or CHOP alone after enrolment. People whose disease responded to induction therapy (n = 334) were then randomised to either maintenance treatment with 375 mg/m² rituximab (one dose every 8 weeks for 2 years or until disease progression) or observation until relapse.

3.5 The results of the PRIMA trial showed that after 25 months median follow-up, the risk of disease progression was halved in the rituximab maintenance arm compared with the observation arm (hazard ratio (HR) 0.50; 95% CI 0.39 to 0.64; p < 0.0001) as assessed by investigators. This was based on 18.4% of people in the rituximab maintenance arm and 33.9% of people in the observation arm having experienced an event. The estimate of the hazard ratio associated with treatment was slightly higher when assessed by the independent review committee. After 38 months median follow-up, progression-free survival was statistically significantly improved in the group originally randomised during the study period to the rituximab maintenance arm compared with those originally randomised to the observation arm. After 38 months median follow-up, a statistically significant difference in overall survival could not be established between the two arms because of the low number of deaths at that time.

3.6 During induction therapy most people in the PRIMA trial experienced toxicity and 25% experienced a serious adverse event, consistent with the known safety profile of these induction regimens. Following the maintenance phase of the trial the incidence of grade 3 or 4 adverse events was higher in the rituximab maintenance arm compared with the observation arm because of infections (37% in the rituximab arm and 22% in the observation arm).

3.7 In the EORTC 20981 study, maintenance treatment with rituximab significantly improved progression-free survival compared with observation (median 3.7 years versus 1.3 years). Five-year overall survival was not significantly different between the arms (74% in the rituximab maintenance arm and 64% in the observation arm). The authors of the study (van Oers et al. 2010) suggested that this lack of difference may be partly because of the ‘unbalanced use of rituximab in post-protocol salvage treatment’. Maintenance with rituximab was associated with statistically significant increases in grade 3 and 4 infections compared with observation.

3.8 The manufacturer produced a Markov economic model to estimate all life time costs and benefits resulting from the treatment of follicular lymphoma with rituximab compared with observation after first-line induction with different regimens of rituximab and chemotherapy (R-CHOP, R-CVP or R-FCM). Although listed as a comparator in the decision problem for this appraisal, ibritumomab tiuxetan was considered by the manufacturer not to be an appropriate comparator for inclusion in the economic model because of limited evidence available to support its benefits, and because data on local usage suggested that it is seldom prescribed in the UK. The model had four distinct health states: progression-free survival while in the first-line maintenance phase (PF1), progression-free survival after receiving second-line induction treatment with rituximab in combination with chemotherapy (PF2), progressive disease (PD) and death. The manufacturer assumed that all people enter the economic model in the PF1 health state after successful completion of induction treatment (that is, the start of the model reflected the second phase of the PRIMA trial). The model had a cycle of 1 month and a time horizon of 25 years. A half cycle correction was applied to the model.

3.9 Data from the PRIMA trial (after 38 months median follow-up) and the EORTC 20981 study were used by the manufacturer to estimate the transition probabilities between the health states in the economic model. To estimate median progression-free survival, the manufacturer used the Gompertz function to extrapolate progression-free survival data from the PRIMA trial. The manufacturer considered that this function provided a better fit relative to alternative functions. Based on the results from the PRIMA trial, the EORTC 20981 study and expert opinion, the manufacturer assumed that people in the PF1 health state retain a clinical benefit from rituximab maintenance treatment for 6 years. After this time, the risk of disease progression for people in the PF1 health state was assumed to be equal in both the rituximab maintenance and observation arms of the model. Data from the EORTC 20981 study were used to inform the long-term outcomes of people according to the treatment they received after progressing from the PF1 health state.

3.10 In the PRIMA trial, participants did not routinely complete EQ-5D questionnaires. Instead, health-related quality-of-life data were collected in the PRIMA trial using the FACT-G and EORTC      QLQ-C30 questionnaires developed to assess the quality of life of people with cancer. Overall, no differences in health-related quality-of-life data were observed between the rituximab maintenance and observation arms.

3.11 The manufacturer conducted a systematic literature review to identify studies addressing quality of life, but only one study (Pettengel et al. 2008) was considered to meet the inclusion criteria. In this study, 215  adults with follicular lymphoma and an ECOG score of 0−2 completed EQ-5D questionnaires during outpatient appointments across eight sites in the UK. Patients were placed in one of five categories according to the stage of their disease: 'active disease – newly diagnosed', 'active disease - relapsed', 'partial response', 'complete response to therapy (or remission)' and 'disease free (no detectable disease)'. Mean utility values from this study were 0.88 (from 'disease free' category), 0.79 (from 'complete response to therapy' category) and 0.62 (from 'active disease – relapsed' category). These utility values were assigned to the PF1, PF2 and PD health states respectively in the manufacturer’s economic model. The economic model did not include values for the disutility associated with grade 3 and 4 adverse events, or with receiving chemotherapy.

3.12 The manufacturer included for each health state in the economic model costs associated with: drug acquisition and administration, supportive care, management of adverse events, and monitoring. The primary sources of these costs were the BNF (edition 56 was used by the manufacturer, and edition 59 by the ERG), the NHS Reference Cost Schedule 08−09 and the Personal Social Services Research Unit  2009 (unit costs of health and social care). The manufacturer assumed that grade 3 and 4 adverse events incur equivalent costs, as estimated from the PRIMA and EORTC 20981 studies. Costs and benefits were discounted at 3.5% per year.

3.13 In the base-case analysis, which assumed that the clinical benefit of rituximab is sustained over 6 years, the incremental cost-effectiveness ratio (ICER) of rituximab maintenance treatment compared with observation was £15,978 per quality-adjusted life year (QALY) gained (incremental costs: £18,681 and incremental QALYs: 1.169). Sensitivity analyses explored the impact of varying costs of adverse events (±50%), monthly supportive care (±50%), and administering rituximab (e.g. nursing time) (upper = £267, lower = £176). In sensitivity analyses, the manufacturer also tested the impact of varying the time horizon (20 years and 30 years), using other types of parametric functions to extrapolate progression-free survival data from the PRIMA trial, and assuming that people who progress from the PF1 health state die (probability of death was 100%, extreme scenario) rather than experience disease progression. From the analyses, the manufacturer concluded that the model was not sensitive to assumptions around the type of parametric extrapolation fitted to the PRIMA data, or  assumptions around supportive care and administration costs or the time horizon. The model was sensitive to assumptions regarding the duration of treatment effect, which resulted in wider variation in the ICERs; when the manufacturer assumed that the effect of treatment stopped after 47 months (instead of after 72 months as in the base case), the ICER increased to £21,151 per QALY gained. When the manufacturer assumed that all people died after progressing from the PF1 health state (extreme scenario), the ICER decreased to £13,901 per QALY gained.

3.14 The manufacturer conducted probabilistic sensitivity analyses of all major parameters in the model, except age, weight and height. The mean ICER from this analysis was £15,770 per QALY gained, and the manufacturer estimated that the probability of rituximab maintenance treatment being cost effective at thresholds of £20,000 or less and at £30,000 or less was 84.2% and 99.7% respectively compared with observation. The manufacturer concluded that these results demonstrated that the ICER was robust even under a wide range of variation in the model parameters.

3.15 The ERG considered that PRIMA was a well-designed trial. Although it was an open-label trial, the ERG considered that the results of progression-free survival were robust because the trial used a blinded independent review committee. The ERG considered that the rituximab chemotherapy regimens used in the induction phase of the PRIMA trial (that is, R-CHOP, R-CVP and R‑FCM) were appropriate and in line with the rituximab chemotherapy regimens used in UK clinical practice. Overall, the ERG considered the results of the PRIMA trial to be generalisable to the UK setting. In addition, the ERG considered that the manufacturer’s decision not to include ibritumomab tiuxetan as a comparator in the economic analysis was justified.

3.16 The ERG noted that after a median follow-up period of 25 months, only 18.4% (93 of 505) of the participants in the rituximab maintenance arm and 33.9% (174 of 513) of those in the observation arm of the PRIMA trial had experienced an event (disease progression, relapse or death). The ERG was concerned that trial participants were not followed for longer than 4 years (despite a protocol amendment that specified a follow-up of 7 years) and that the manufacturer could not estimate the median time to event by treatment group for the study population. The ERG cautioned that the data were immature and that the early closure of the trial might have led to an overestimation of the clinical benefits of rituximab maintenance treatment.

3.17 The ERG noted that treatments administered after a person’s disease had progressed may have affected the rate of overall survival. Although the post-progression treatments considered in the manufacturer’s submission were in line with those used in UK clinical practice, the ERG was unclear from the data provided whether the time at which these treatments were offered in the trial reflected the time that they would be offered in routine practice.

3.18 Although the ERG identified a number of problems with the structure and implementation of the manufacturer’s model, the ERG considered most of them to be minor and did not expect them to impact on the cost-effectiveness results. The ERG noted that the manufacturer did not model the disutilities associated with grade 3 and 4 adverse events. The ERG considered that this omission would favour the rituximab maintenance arm because people are more likely to experience adverse events with rituximab compared with observation. The ERG was concerned that the manufacturer may have underestimated the costs of adverse events experienced in the PF2 health state because most of the people in the PRIMA trial had not progressed beyond the first-line maintenance or observation phase at the time of data analysis.

3.19 The ERG noted the low proportion of censored patients (less than 3%) during the first 800 days of the PRIMA trial, and also noted that this proportion increased greatly (70% for rituximab maintenance and 50% for observation) by 1600 days. Consequently, the ERG believed that the Kaplan–Meier estimate of progression-free survival becomes uncertain after 800 days. The ERG had concerns about the use of long-term modelling to inform the duration of treatment benefit estimated in the economic model. The ERG noted that the manufacturer used the Gompertz parametric function, which generated the highest overall estimate compared with other algorithms, to model progression-free survival.

3.20 The ERG was concerned about the manufacturer’s approach of using data from the EORTC 20981 study to inform the economic model. The ERG noted that the participants in this study were rituximab-naive and had different treatment histories (people were included in the trial if their disease had relapsed following two previous non-anthracycline-containing chemotherapy regimens) than participants in the PRIMA trial. Therefore, the ERG questioned whether the manufacturer could reliably use the outcomes from the EORTC 20981 study to predict future outcomes for participants in the PRIMA trial.

3.21 The ERG noted that, in the base case, the manufacturer assumed rituximab maintenance treatment had a clinical benefit for 6 years (that is, the hazard ratio from the PRIMA trial was applied for 6 years). However, if one assumed that the clinical benefit of rituximab was sustained only for 3 or 4 years the ICERs were £26,079 or £21,151 per QALY gained respectively.  If one assumed that the clinical benefit lasted only for 26 months (800 days), the ICER more than doubled to £32,230 per QALY gained. In addition, the ERG noted that in the base case model more than 72% of the gain in progression-free survival arises beyond 4 years. Therefore, the ERG cautioned that if the gain in progression-free survival is progressively lost, the ICER could substantially increase depending on the time period over which a difference between the treatment arms is still assumed (that is, the time until the progression-free survival curves for each arm are assumed to converge).

3.22 The ERG noted that the manufacturer’s model projects future benefits in terms of the increased time that a person’s disease is progression free. The model estimated that the mean time before a person’s disease progresses is 8.64 years for the observation arm and 10.65 years for people who receive rituximab maintenance therapy; a gain of 2.01 years. The ERG noted that the manufacturer’s analysis assumed that almost all of this gain in progression free survival is generated in the PF1 health state. This implies that gains in progression-free survival achieved directly by extending the first-line induction response are translated almost entirely (96.6%) into overall survival gains. The ERG explored how different values of conversion of progression-free survival gain into overall survival gain impact on the estimated ICER, and predicted that at least 50% of progression-free survival gain would need to be converted into overall survival gain to achieve an ICER below £30,000 per QALY gained. The ERG further noted that the required conversion from progression-free survival into overall survival would probably need to be higher than 50% to achieve similar ICERs if an extrapolation function other than the Gompertz parametric function were used.

3.23 The ERG adjusted the hazard ratio of progression-free survival in the manufacturer’s base case to model the impact on the ICERs of age at first treatment. The results showed that the ICERs increased from £14,214 (for a person aged 50  at induction) to £43,306 (for a person aged 80  at induction). When the mean age is 60 or 65 years at induction (in line with the average age at the start of treatment in UK practice) the ICERs increased to £18,055 and £21,099 per QALY gained respectively.

3.24 The ERG noted that the manufacturer’s model included utility values of  0.88 and 0.79 for the PF1 and PF2 health states respectively. The ERG considered that the same utility value should be used in both health states because people either are in remission or have a full response. The ERG conducted a sensitivity analysis assuming that both health states have a utility value of  0.79 and noted that the QALY gain associated with maintenance treatment with rituximab was reduced by more than 10% and the ICER was increased by 11%.

3.25 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab maintenance treatment of people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with follicular non-Hodgkin’s lymphoma, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee noted that the decision problem for this topic defines the population as ‘adults with advanced follicular lymphoma that has responded to first-line chemotherapy’, and that the population considered by the manufacturer was 'adults with advanced follicular lymphoma that has responded to first-line treatment with rituximab plus chemotherapy'. The manufacturer indicated that the population in their analysis was restricted to those who had received first-line treatment with rituximab plus chemotherapy because this reflected standard first-line treatment used in UK clinical practice. The Committee also noted that the manufacturer excluded one of the comparators originally specified in the decision problem, ibritumomab tiuxetan, because it considered that no clinical evidence was available to support the benefits of ibritumomab tiuxetan as a maintenance treatment for people who have received first-line treatment with rituximab in combination with chemotherapy, and that it is infrequently used in the UK. The Committee accepted the manufacturer’s justifications for the changes to the decision problem.

4.3 The Committee was aware that rituximab in combination with chemotherapy is currently the standard of care in the UK for first-line induction therapy of people with advanced follicular non-Hodgkin's lymphoma. The Committee noted that 'watchful waiting' (observation) is the current standard treatment for people with advanced follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy. The Committee heard from the clinical specialists that the aim of current management is to prolong remission, delay progression (and therefore delay the use of chemotherapy) and improve quality of life. The clinical specialists considered that rituximab maintenance treatment could offer people longer periods of remission and therefore better quality of life if used after first-line induction therapy.

4.4 The Committee heard from patient experts that chemotherapy is considered to be more toxic than rituximab and may cause symptoms that are worse than those caused by follicular lymphoma itself, and that it has a substantial impact on an individual’s quality of life. The patient experts stated that while being on chemotherapy they experienced symptoms of weakness and fatigue and were not able to do simple routine tasks without the support of their family and carers. However, they were aware that people who were treated with rituximab in the PRIMA trial did not have the symptoms that may occur with chemotherapy and were able to continue with their normal daily routine. The patient experts expressed the view that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of disease.

 Clinical effectiveness

4.5 The Committee considered the data presented by the manufacturer on the clinical effectiveness of rituximab maintenance treatment after first-line induction with rituximab plus chemotherapy. The Committee noted that the manufacturer derived efficacy data primarily from the PRIMA trial that compared rituximab maintenance with observation (watchful waiting) in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this study were available from the post-study observational follow-up period, which had a median follow-up of 38 months and indicated that progression-free survival was statistically significantly improved with rituximab maintenance treatment compared with observation. However, the Committee noted that beause of the small number of deaths during this period, overall survival associated with rituximab maintenance treatment could not be estimated. The Committee heard from the ERG that the immature results of the study meant that the clinical benefit of rituximab may have been overestimated. However, the Committee heard from the clinical specialists that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected their observations from clinical practice. The Committee concluded that the available evidence shows that rituximab maintenance treatment improves progression-free survival compared with observation, but that the size of any survival benefit from first-line maintenance treatment with rituximab is uncertain.  

4.6 The Committee considered the adverse event profile of rituximab. It noted that the incidence of adverse events was higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial. This difference was attributed to infections observed in the rituximab maintenance arm. However, the Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment was generally well tolerated and that adverse events were easily managed. In addition, the patient experts highlighted that the side effects associated with rituximab were considered to be less severe than those experienced while receiving chemotherapy. The Committee concluded that, overall, most adverse events associated with rituximab treatment are not severe, and that its use to extend remission may delay the need for chemotherapy.

 Cost effectiveness

4.7 The Committee reviewed the economic analysis provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that although inconsistencies and errors in the manufacturer’s model were identified, their revision was unlikely to substantially impact the manufacturer’s base case results. The Committee was therefore persuaded that the manufacturer’s model was acceptable to address the decision problem for  this appraisal. The Committee noted that the manufacturer had assumed in the base case that the clinical benefit of rituximab therapy would last for 6 years. The Committee heard from the clinical specialists that the period over which the benefit of rituximab is sustained is probably around 3 to 4 years, and that assuming a duration of benefit of 6 years was unrealistic. The Committee noted from the sensitivity analysis conducted by the ERG that when the clinical benefit of rituximab is assumed to be sustained only for the first 3 to 4 years the ICERs ranged from £21,000 to £26,000 per QALY gained.

4.8 The Committee noted that the manufacturer assumed a 96.6% conversion of progression-free survival to overall survival. The Committee heard from the clinical specialists that it is not possible to verify the specific conversion factor from the literature or clinical experience, but that they would expect a conversion closer to 70%. The Committee acknowledged that if a conversion factor of  70% was assumed, the base case ICER would increase. The Committee considered that the manufacturer should have sought data from patient registries to validate the conversion factor assumed for the base case estimate, and to confirm the degree to which rituximab maintenance treatment might prolong life. The Committee also noted that in the PRIMA trial the median age at randomisation was 57 years. However, it heard from the clinical specialists that the mean age at the start of treatment in the UK is between 60 and 65 years. Although the Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, it noted from sensitivity analyses conducted by the ERG that the manufacturer’s base case ICER increased to £18,100 and £21,100 per QALY gained when one assumed that the mean age at first treatment was 60 years and 65 years respectively. In light of these analyses, the Committee was concerned that the manufacturer’s base case underestimated the true ICER.

4.9 The Committee discussed the utility values used in the economic model. It noted that in sensitivity analyses when the ERG reduced the values for the utility gains in the PF1 (progression-free survival while in the first-line maintenance phase) and PF2 (progression-free survival while in the second-line maintenance phase) health states by more than 10%, the ICER increased by approximately 11% only. From these analyses, the Committee was persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival. The Committee considered that the model underestimated the utility associated with delaying chemotherapy treatment and that if it was included, it would likely decrease the ICER (that is, improve the cost-effectiveness estimate).

4.10 In summary, the Committee agreed that the results from the PRIMA trial and clinical opinion suggested that rituximab maintenance treatment confers clinical benefit and delays the need for further chemotherapy. The Committee also considered  that rituximab maintenance treatment was likely to prolong survival in people with follicular lymphoma, but that the extent of this survival  was uncertain. The Committee concluded that the current clinical-effectiveness evidence indicates that a positive recommendation is justified for the use of rituximab as first-line maintenance treatment in people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction treatment with rituximab in combination with chemotherapy. The Committee concluded that it was difficult to establish the most plausible ICER for this treatment because sensitivity analyses to capture all preferred assumptions were not available. However, the Committee concluded that the ICER may be within the range that is consistent with an appropriate use of NHS resources. Therefore, because of these uncertainties, the Committee expects the manufacturer to respond to this appraisal consultation document by addressing the remaining uncertainties and by providing a revised cost-effectiveness analysis:

• for people who are 60 to 65 years at the start of treatment, and
• in which the duration of clinical benefit from rituximab maintenance treatment is 3 to 4 years, and
• in which the extent that progression-free survival translates into overall survival gain is informed by the best available evidence, which could include patient registries and prospective observational data. Analyses should be presented for a range of plausible values, from 50% to 100%, and
• in which utility gains associated with delaying the need for chemotherapy after relapse are included.

Summary of Appraisal Committee's key conclusions

TAXXX (STA)	Appraisal title: Rituximab for the first-line maintenance treatment of follicular non-Hodgkin’s lymphoma		Section
Key conclusion
Rituximab is recommended as an option for first-line maintenance treatment of people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy The Committee agreed that the results from the PRIMA trial and clinical opinion suggested that rituximab maintenance treatment confers clinical benefit and delays the need for further chemotherapy. The Committee also considered  that rituximab maintenance treatment was likely to prolong survival in people with follicular lymphoma, but that the extent of this survival was uncertain.The Committee concluded that it was difficult to establish the most plausible ICER for this treatment because sensitivity analyses to capture all preferred assumptions were not available. However, the Committee concluded that the ICER may be within the range that is consistent with an appropriate use of NHS resources. The Committee expects that the manufacturer responds to this appraisal consultation document by addressing the remaining uncertainties and by providing a revised cost-effectiveness analysis.			1.1 4.10
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the clinical specialists that the aim of current management is to prolong remission, delay progression (and therefore delay the use of chemotherapy), and improve quality of life. ‘Watchful waiting’ (observation) is the current standard treatment for people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy.	4.3
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 clinical specialists considered that rituximab maintenance treatment could offer people longer periods of remission and therefore better quality of life if used after first-line induction therapy. Patient experts expressed the view that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of disease. They were also  aware that people who were treated with rituximab in the PRIMA trial did not have the symptoms that may occur with chemotherapy and were able to continue with their normal daily routine.	4.3 4.4
What is the position of the treatment in the pathway of care for the condition?		Rituximab has a UK marketing authorisation for the ‘treatment of follicular lymphoma patients responding to induction therapy’.	2.1
Adverse effects		The incidence of adverse events was higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial. This difference was attributed to infections observed in the rituximab maintenance arm. The Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment was generally well tolerated and that adverse events were easily managed. The patient experts also highlighted that the side effects associated with rituximab were considered to be less severe than those experienced while receiving chemotherapy.	4.6
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The manufacturer derived efficacy data primarily from the PRIMA trial that compared rituximab maintenance with observation (watchful waiting) in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this study were available from the post-study observational follow-up period, which had a median follow-up of 38 months (data provided academic in confidence). The Committee heard from the ERG that the immature results of the study meant that the clinical benefit of rituximab may have been overestimated. However, the Committee heard from clinical specialists that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected their observations from clinical practice.	4.5
Relevance to general clinical practice in the NHS		The Committee noted that in the PRIMA trial the median age at randomisation was 57 years. However, it heard from the clinical specialists that the mean age at the start of treatment in the UK is between 60 and 65 years. Although the Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, it noted from sensitivity analyses conducted by the ERG that the manufacturer’s base case ICER increased to £18,100 and £21,100 per QALY gained when one assumed that the mean age at first treatment was 60 years and 65 years respectively.	4.8
Uncertainties generated by the evidence		The Committee noted that beause of the small number of deaths during the study period, overall survival associated with rituximab maintenance treatment could not be estimated.	4.5
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 Committee concluded that the available evidence shows that rituximab maintenance treatment improves progression-free survival compared with observation, but that the size of any survival benefit from first-line maintenance treatment with rituximab was uncertain.	4.5
Evidence for cost effectiveness
Availability and nature of evidence		The Committee reviewed the economic analysis provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that although inconsistencies and errors in the manufacturer’s model were identified, their revision was unlikely to substantially impact the manufacturer’s base case results. The Committee was therefore persuaded that the manufacturer’s model was acceptable to address the decision problem for this appraisal.	4.7
Uncertainties around and plausibility of assumptions and inputs in the economic model		In the base case the manufactuer assumed that the clinical benefit of rituximab therapy would be sustained for 6 years. The Committee heard from the clinical specialists that the period over which the benefit of rituximab is sustained is probably around 3 to 4 years, and that assuming a duration of benefit of 6 years was unrealistic. The Committee noted from the sensitivity analysis conducted by the ERG that when the clinical benefit of rituximab is assumed to be sustained only for the first 3 to 4 years the ICERs ranged from £21,000 to £26,000 per QALY gained. The manufacturer assumed a 96.6% conversion of progression-free survival to overall survival. The Committee heard from the clinical specialists that it is not possible to verify the specific conversion factor from the literature or clinical experience, but that they would expect a conversion closer to 70%. The Committee acknowledged that if a conversion factor of 70% was assumed, the base-case ICER would increase. In light of these analyses, the Committee was concerned that the manufacturer’s base-case underestimated the true ICER.	4.7 4.8
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 manufacturer’s model included utility values of  0.88 and 0.79 for the PF1 (progression-free survival while in the first-line maintenance phase) and PF2 (progression-free survival while in the second-line maintenance phase) health states respectively. The Committee noted that when assumed utility gains in PF1 and PF2 health states were reduced by more than 10% in a sensitivity analysis conducted by the ERG, the ICER increased by approximately 11% only. From these analyses, the Committee was persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival. The Committee considered that the model underestimated the utility associated with delaying chemotherapy treatment and that if it was included, it would likely decrease the ICER (that is, improve the cost-effectiveness estimate).	3.24, 4.9
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		The key drivers of cost effectiveness were assumptions about the duration of clinical benefit of rituximab therapy, the conversion of progression-free survival to overall survival and the  underestimation in the economic model of the utility associated with delaying chemotherapy treatment. Therefore, the Committee expects the manufacturer to respond to this appraisal  consultation document by addressing the remaining uncertainties and by providing a revised cost-effectiveness analysis: for people who are 60 to 65 years at the start of treatment, and in which the duration of clinical benefit from rituximab maintenance treatment is 3 to 4 years, and in which the extent that progression-free survival translates into overall survival gain is informed by the best available evidence, which could include patient registries and prospective observational data. Analyses should be presented for a range of plausible values, from 50% to 100%, and in which utility gains associated with delaying the need for chemotherapy after relapse are included.	4.8 – 4.10
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that it was difficult to establish the most plausible ICER for this treatment because sensitivity analyses to capture preferred assumptions were not available. However, the Committee concluded that the ICER may bewithin the range that is consistent with an appropriate use of NHS resources.	4.10
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		No equalities issues were raised during the scoping exercise or during the course of the appraisal.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma (review of technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008). Available from www.nice.org.uk/guidance/TA137
• Rituximab for the treatment of follicular lymphoma. NICE technology appraisal guidance 110 (2006). Available from www.nice.org.uk/guidance/TA110
• Improving outcomes in haematological cancers – the manual. NICE cancer service guidance haemato-oncology (2003). Available from www.nice.org.uk/guidance/CSGHO

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Rituximab for the treatment of follicular lymphoma. Review of NICE technology appraisal guidance 110 (publication expected December 2011).

 7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in March 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.

Amanda Adler
Chair, Appraisal Committee
November 2010

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. 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. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Dr Mark Chakravarty
External Relations Director, Pharmaceuticals and Personal Health, Oral Care Europe

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Mrs Eleanor Grey
Lay member

Dr Neil Iosson
General Practitioner

Dr Rosa Legood
Lecturer, London School of Hygiene and Tropical Medicine

Mr Terence Lewis
Lay member

Dr Ruairidh Milne
Director of Strategy and Development, and Director for Public Health Research, NIHR Evaluation, Trials and Studies Coordinating Centre, University of Southampton

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Mr Stephen Palmer
Senior Research Fellow, Centre for Health Economics, University of York

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Casey Quinn
Lecturer in Health Economics, Division of Primary Care, University of Nottingham

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Mr Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Dr Florian Alexander Ruths
Consultant Psychiatrist and Cognitive Therapist, Maudsley Hospital, London

Mr Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Colin Watts
Consultant Neurosurgeon, Addenbrookes Hospital

Mr Tom Wilson
Director of Contracting and Performance, NHS Tameside and Glossop

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.

Panagiota Vrouchou
Technical Lead

Fiona Rinaldi
Technical Adviser

Jeremy Powell
Project Manager

 Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by the Liverpool Reviews and Implementation Group:

• Bagust A, Boland A, Blundell M, et al. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin’s lymphoma, October, 2010

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. 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 and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Roche Products

II Professional/specialist and patient/carer groups:

• British Society for Haematology
• Cancer Networks Pharmacists Forum
• Cancer Research UK
• Leukaemia CARE
• Lymphoma Association
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• United Kingdom Oncology Nursing Society

III Other consultees:

• Department of Health
• NHS Camden
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Leukaemia & Lymphoma Research
• Medicines and Healthcare products Regulatory Agency
• NHS Quality Improvement Scotland

C The following individuals were selected from clinical specialist and patient expert 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.

• Professor Peter Johnson, Professor of Medical Oncology, nominated by National Cancer Research Institute/Royal College of Physicians/Royal College of Radiologists/Association of Cancer Physicians/Joint Collegiate Council for Oncology – clinical specialist
• Dr Helen McCarthy, Consultant Haematologist, nominated by the Royal College of Pathologists – clinical specialist
• Dr Robert Marcus, Consultant Haematologist, nominated by National Cancer Research Institute/Royal College of Physicians/Royal College of Radiologists/Association of Cancer Physicians/Joint Collegiate Council for Oncology – clinical specialist
• Mandy Childs, nominated by Lymphoma CARE – patient expert
• Elizabeth Nelson, nominated by the Lymphoma Association – patient expert

D Representatives from the following manufacturer/sponsor attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Roche Products