The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using rituximab in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE’s final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using rituximab in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 22 March 2011

Second Appraisal Committee meeting: 5 April 2011

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 is not NICE’s final guidance on this technology. The recommendations in section 1 may change after consultation.

1. Appraisal Committee's preliminary recommendations

1.1  The Committee is minded not to recommend rituximab 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.

1.2 The Committee recommends that NICE requests from the manufacturer further clarification, which should be made available for the next Appraisal Committee meeting, as follows:

• A revised cost-effectiveness analysis that incorporates all of the following assumptions:
  • Age at first-line induction: mean age of 62.5 years at the start of treatment.
  • Treatment effect: duration of clinical benefit from first-line rituximab maintenance treatment is 28 months, 36 months or 48 months.
  • Survival modelling: the extent that the benefit of mean progression-free survival from first-line rituximab maintenance treatment translates to mean overall survival gain is 70%, 80% or 90% (undiscounted and not adjusted for health-related quality of life).
• The manufacturer should:
  • report incremental costs and quality-adjusted life years (QALYs) gained
  • provide a revised fully executable economic model amenable to both verification of the above-listed revisions and further exploratory sensitivity analyses.

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 high tumour burdens, and the incidence and severity of infusion reactions decreases with successive infusions. Rituximab treatment can also be associated with blood and bone-marrow toxicity caused by neutropenia, leucopenia and infections. In addition, treatment with rituximab 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 For 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 first-line induction therapy and continue until the disease progresses 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 estimates 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 presented information addressing the decision problem; that is, whether rituximab maintenance offers a clinically‑effective and cost-effective use of NHS resources, compared with standard management without rituximab for people with advanced follicular lymphoma that has responded to first-line induction chemotherapy combined with rituximab. 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 trial, 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 analysed after a median follow-up of 25 months (at the close of the PRIMA trial), but also provided data as academic in confidence 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 that may have been experienced by participants in the PRIMA trial, had the trial gone on longer. The patient population in the EORTC 20981 study was different from the patient population in the PRIMA trial (see section 3.4).

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 or first-line treatment), participants underwent one of three different 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]). People 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 in line with recommendations from regulatory authorities 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 judged that the trial had met its primary objective at the pre-specified interim analysis and recommended closure of the trial. 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. Rather, patients were treated with at least 2 months of single-agent therapy (such as chlorambucil) and/or at least two consecutive cycles of polychemotherapy (such as CVP) or purine analogues. Therefore, they differed from patients in the decision problem in that their disease had progressed after first-line therapy, and they had not been previously treated with R‑CHOP, R-CVP or R-FCM as in the PRIMA trial. Participants were randomised to treatment with R-CHOP or CHOP alone after enrolment. People whose disease responded to second-line 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 relapse) 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 lifetime 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; that is, 4 years beyond the end of the period actually observed in the PRIMA trial. 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 derive 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 costs associated with drug acquisition and administration, supportive care, management of adverse events and monitoring for each health state in the economic model. 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 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 (for example, 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 £20,000 per QALY gained or less was 84.2%, and at £30,000 per QALY gained or less was 99.7%, 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 the PRIMA trial was well-designed and although it was an open-label trial, the results of progression-free survival could be considered 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 randomised to the rituximab maintenance arm and 33.9% (174 of 513) of those randomised to the observation arm of the PRIMA trial had experienced an event (disease progression, relapse or death). The ERG was concerned that follow-up data were not available beyond 4 years and that the manufacturer could not estimate the median time to event by treatment group for the trial population. The ERG cautioned that the data were immature, which might have led to an overestimation of the clinical benefits of rituximab maintenance treatment.

3.17 The ERG noted that treatments administered after participants’ 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 (up to 38 months).

3.19 The ERG noted the low proportion of patients censored (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 had not previously received first-line treatment with rituximab and, compared with participants in the PRIMA trial, had previously had different treatments (the EORTC 20981 study included people if their disease had relapsed after two previous non-anthracycline-containing chemotherapy regimens). 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 progressively declines, the ICER could substantially increase and depends on the time period over which one assumes a difference between the treatment arms (that is, the time until the progression-free survival curves for each arm converge).

3.22 The ERG noted that the manufacturer’s model projects future benefits associated with the increased time that a person’s disease remains 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 occurs in the PF1 health state. This implies that the majority (96.6%) of the gains in progression-free survival achieved directly by extending the first-line induction response translate into overall survival gains. The ERG explored how different values of conversion of progression-free survival gain into overall survival gain affect 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 if an extrapolation function other than the Gompertz parametric function was used to convert progression-free survival into overall survival, then the required conversion rate would need to be even higher for the ICER to remain below £30,000 per QALY gained.

3.23 The ERG adjusted the hazard ratio reflecting progression-free survival in the manufacturer’s base case to model the impact of age at first treatment on the ICERs. The results showed that the ICERs increased from £14,214 (for a person aged 50 at first-line 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 because people in both health states 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 dropped by more than 10% and the ICER increased by 11%.

3.25 In response to consultation on the first appraisal consultation document, the manufacturer provided revised cost-effectiveness analyses that modelled the effect on the ICER of difference assumptions including progression-free survival translating into overall survival in a range from 50% to 100%; the clinical benefit from rituximab being either 3 or 4 years; and the age of a patient at induction being between 60 and 65 years. Although requested by the Committee, the manufacturer was unable to also incorporate the potential utility gains associated with delaying the need for chemotherapy after relapse because of limitations with the structure of the model.

3.26 The manufacturer considered that the assumptions in its base-case analysis allowed for a conversion rate of 81.7% from progression‑free survival to overall survival, not 96.6% as reported by the ERG. The manufacturer explained that the conversation rate is not a specific input in the model, and therefore in order to analyse the effect of assuming different conversion rates, other parameters in the model had to be artificially altered. When a conversion factor of 50%, 75% or 100% was assumed in the manufacturer’s revised analysis, the ICERs ranged from £15,978 to £19,339 per QALY gained. The manufacturer questioned the plausibility of these revised analyses because the manufacturer based them on assumptions that it considered worse than those observed in clinical practice and in the clinical trials.

3.27 The majority of the revised analyses from the manufacturer produced ICERs of less than £30,000 per QALY gained for rituximab maintenance compared with observation. Only the analyses which assumed a patient age of 60 or  65 years at induction, 3 years of clinical benefit from rituximab and a conversation rate from progression-free survival to overall survival of 50%, produced  ICERs of more than £36,000 per QALY gained.

3.28 Full details of all the evidence are in the manufacturer’s submission and the ERG report; these and the responses to consultation on the first appraisal consultation document (ACD) from consultees and commentators 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 for 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 advanced follicular non-Hodgkin’s lymphoma and the value placed on the benefits of rituximab by people with the condition, 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 its 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 had not identified  any clinical evidence to support the use of ibritumomab tiuxetan as a maintenance treatment for people who have received first-line treatment with rituximab in combination with chemotherapy, and that ibritumomab tiuxetan is infrequently used in the UK. For these reasons the manufacturer excluded ibritumomab tiuxetan from the list of the comparators originally specified in the decision problem. 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 was aware that NICE technology appraisal guidance 110 recommends R-CVP for the first-line induction treatment of advanced follicular non-Hodgkin’s lymphoma, but that other rituxmab-containing chemotherapeutic regimens (such as R-CHOP and R-FCM) are routinely used, but have not yet been appraised by NICE. 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 current management aims to prolong remission, delay progression (and therefore delay the use of chemotherapy) and improve quality of life. The clinical specialists expressed the view that rituximab maintenance treatment could offer people longer periods of remission and better quality of life if used after first-line induction therapy. The Committee was also aware that rituximab is used in combination with chemotherapy for people whose disease has relapsed or did not respond to treatment, or as monotherapy for maintenance treatment after successful second-line treatment of recurrent or refractory disease (in line with NICE technology appraisal guidance 137). 

4.4 The Committee heard from patient experts that chemotherapy is associated with more adverse events than rituximab, that it may cause symptoms worse than those caused by follicular non-Hodgkin’s lymphoma itself, and that chemotherapy therefore has a substantial negative 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 family and carers. However, they were aware that people who were treated with rituximab in the PRIMA trial did not have the same adverse effects associated 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 the 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 appreciated that following closure of the PRIMA trial progression-free survival could be estimated only with considerable uncertainty, and that overall survival could not be estimated at all. The Committee understood that the manufacturer estimated progression-free survival from the period after the end of the trial, during which time the patients may have received other therapies that could  have affected the chance of disease progression. The Committee noted that the most recent data from this trial 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 in people who had been  randomised to rituximab maintenance treatment compared with people who had been  randomised to observation. The Committee also noted that despite following patients beyond the end of the trial, the manufacturer could not estimate the overall survival associated with rituximab maintenance treatment because of the small number of deaths during this period. The Committee was aware that the trial stopped on advice from the trial’s statisticians, but heard from the ERG that there is evidence suggesting that studies with immature data often overestimate  the clinical benefit. However, the Committee heard from the clinical specialists that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians’ observations from clinical practice. The Committee concluded that the available evidence shows that first-line maintenance treatment with rituximab improves progression-free survival compared with observation, but that the size of any overall survival benefit could not be determined.

4.6 The Committee was aware that the PRIMA trial was the only trial that directly addressed the decision problem, and included the relevant population, intervention, comparison and outcomes. The Committee learned from the manufacturer that another trial (ECOG 1496) demonstrated that rituximab maintenance led to longer progression-free survival compared with observation, but that this trial had been conducted in people who had not previously had first-line treatment with rituximab-containing chemotherapy. The Committee understood that  another trial (SAKK 35/98) had also observed a longer progression-free survival for people randomised to rituximab maintenance compared with those who had been randomised to no treatment (observation), but that the participants of this trial had either not been treated at all or had only had first-line treatment with rituximab monotherapy, but not combined with chemotherapy.

4.7 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 is generally well tolerated and that adverse events are easily managed. The patient experts also highlighted that they consider the side effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy, which may become a necessary treatment once the disease relapses. 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 and in turn delay the adverse events associated with it.

Cost effectiveness

4.8 The Committee reviewed the original and revised economic analyses provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that they identified inconsistencies and errors in the manufacturer’s model, but that revising them was unlikely to have a large effect on the manufacturer’s base-case results. The Committee was cautioned by the ERG that it considers the base-case ICER of £16,000 per QALY gained  from the manufacturer’s economic model to be too greatly affected by extensive and unquantifiable uncertainty around the clinical benefit of rituximab for the results to be useful for making decisions. The Committee noted that the manufacturer had assumed in the base case of its original model that the clinical benefit of rituximab maintenance would last for 6 years, which is 4 years beyond the end of the observed data in the PRIMA trial. The Committee heard from the ERG that the manufacturer’s extrapolation of the clinical benefit of rituximab beyond the observed period in the PRIMA trial assumed a proportional (linear) increase in survival with time, which may not reflect the true survival effect. The Committee heard from the ERG that the only long-term patient-level data for rituximab maintenance treatment from the PRIMA trial indicate that the duration of effect is about 28 months. The Committee heard from the clinical specialists that the period over which the benefit of rituximab is sustained is probably 3 to 4 years, and that assuming a duration of benefit of 6 years in the base case was not realistic. The Committee noted from the revised analyses by the manufacturer that when the clinical benefit of rituximab is assumed to be sustained only for 3 to 4 years, the ICERs ranged from £21,000 to £26,000 per QALY gained. The Committee considered that the duration of clinical benefit of rituximab maintenance was a key driver of cost effectiveness and therefore chose to seek revised analyses from the manufacturer in which the duration of benefit is assumed to be 28 months, 36 months or 48 months in line with clinical opinion and available data.

4.9 The Committee noted that the manufacturer assumed that most of the progression-free survival benefit translates to an overall survival gain in its model. The Committee heard from the clinical specialists that it is not possible to verify the specific conversion factor from  progression-free survival to overall survival from the literature or clinical experience, but that they would expect a conversion factor closer to 70%. The Committee acknowledged that if a conversion factor of 70% was assumed, the base-case ICER (which was driven by a conversion factor of more than 80%) would increase. The Committee considered that the manufacturer should have sought data from patient registries or observational data 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 heard from the manufacturer that the conversion factor was not an actual input in the model and could only be adjusted by artificially modifying other parameters. As such, the manufacturer was concerned that its revised analyses, which were requested by the Committee, were driven by implausible assumptions. The Committee considered analyses from the manufacturer with a conversion factor of 50%, 75% or 100%, and noted that the ICERs ranged from £16,600 to £19,400 per QALY gained. The Committee considered that rituximab maintenance was likely to be associated with a conversion factor of at least 70% and therefore concluded that it was reasonable to request additional analyses from the manufacturer that assume that the extent to which progression-free survival translates to overall survival gain is 70%, 80% or 90%.

4.10 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 first-line 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 the mean age at first-line treatment was assumed to be 60 years and 65 years respectively. In light of these analyses, the Committee was concerned that the manufacturer had underestimated the true ICER. In response to consultation on the first appraisal consultation document, the manufacturer provided analyses that assumed the age at induction was between 60 and 65 years. The Committee noted that this assumption did not have a significant impact on the ICERs, but requested that the manufacturer assumes in any additional analyses it provides, that the mean age of a patient at the start of treatment is 62.5 years, to better reflect clinical practice in the UK.

4.11 The Committee discussed the utility values used in the economic model. The Committee appreciated that no differences in health‑related quality of life were observed between the arms of the PRIMA trial. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the model had a marginal effect on the base-case ICER, and was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival.  

4.12 The Committee was aware that the economic model did not include the utility associated with delaying chemotherapy, however if it was included, it would likely decrease the ICER (that is, improve the cost effectiveness). The Committee noted that the ICERs for rituximab maintenance compared with observation in the manufacturer’s submission were less than £30,000 per QALY gained for most scenarios. However, the Committee was mindful that some consultees had strongly disagreed with the preliminary advice to recommend the use of rituximab maintenance treatment because of considerable uncertainty around the effect of rituximab maintenance on survival and improved quality of life. In addition, a number of consultees questioned the assumption of a sustained clinical benefit of rituximab so far beyond that which was observed in the PRIMA trial (the period of randomisation), and whether therapies given beyond the end of the trial, but during the period of follow-up, may have affected the rates of disease progression observed during this time. In addition, the Committee was concerned that the economic model contained a number of assumptions that it did not consider plausible. It concluded that the ICERs presented by the manufacturer were associated with a great deal of uncertainty, some of which further analysis may reduce. Therefore, the Committee was minded not to recommend rituximab for the first‑line maintenance treatment of people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction treatment with rituximab in combination with chemotherapy as a cost-effective use of NHS resources. The Committee recommends that NICE requests from the manufacturer further clarification, which should be made available for the next Appraisal Committee meeting (see section 1.2).

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
The Committee is minded not to recommend rituximab 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 recommends that NICE requests from the manufacturer further clarification, which should be made available for the next Appraisal Committee meeting.			1.1, 1.2, 4.12
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the clinical specialists that current management aims 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 expressed the view 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 the disease. They also suggested that chemotherapy is associated with more adverse events than rituximab.	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 is generally well tolerated and that adverse events are easily managed. The patient experts also highlighted that they consider the side effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy, which may be given once the disease relapses.	4.7
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 trialwere 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 was aware that the trial stopped on advice from the trial’s statisticians, but heard from the ERG that there is evidence suggesting that studies with immature results overestimate the clinical benefit. However, the Committee heard from the clinical specialists that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians’ observations from clinical practice. The Committee concluded that the available evidence shows that first-line maintenance treatment with rituximab improves progression-free survival compared with observation, but that the size of any overall survival benefit could not be determined.	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 first-line 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 it assumed that the mean age at first treatment was 60 years and 65 years respectively. In response to consultation on the first appraisal consultation document, the manufacturer provided analyses that assumed the age at induction was between 60 and 65 years. The Committee noted that this assumption did not have a significant impact on the ICERs, but requested that the manufacturer assumes a mean age of 62.5 years in any additional analyses it provides, to better reflect clinical practice in the UK.	4.10
Uncertainties generated by the evidence		The Committee noted that because of the small number of deaths during the trialperiod, overall survival associated with rituximab maintenance treatment could not be estimated. A number of consultees questioned the assumption of a sustained clinical benefit of rituximab so far beyond that which was observed in the PRIMA trial (the period of randomisation), and whether therapies given beyond the end of the trial, but during the period of follow-up, may have affected the rates of disease progression observed during this time.	4.5 4.12
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 first-line maintenance treatment with rituximab improves progression-free survival compared with observation, but that the size of any overall survival benefit could not be determined.	4.5
Evidence for cost effectiveness
Availability and nature of evidence		The Committee reviewed the original and revised economic analyses provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that although they identified inconsistencies and errors in the manufacturer’s model, revising them was unlikely to have a large effect on the manufacturer’s base-case results. The Committee was cautioned by the ERG that it considers the results from the manufacturer’s economic model to be too greatly affected by extensive and unquantifiable uncertainty around the clinical benefit of rituximab for the results to be useful for making decisions.	4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model		In the base-case, the manufacturer assumed that the clinical benefit of rituximab maintenance 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 3 to 4 years, and that assuming a duration of benefit of 6 years in the base case was not realistic. The Committee noted from the revised analyses by the manufacturer that when the clinical benefit of rituximab is assumed to be sustained only for 3 to 4 years, the ICERs ranged from £21,000 to £26,000 per QALY gained. The Committee heard from the ERG that the only long-term patient-level data for rituximab maintenance treatment from the PRIMA trial show the duration of effect is about 28 months. The Committee considered that the duration of clinical benefit of rituximab maintenance was a key driver of cost effectiveness and therefore chose to seek revised analyses from the manufacturer in which the duration of benefit is assumed to be 28 months, 36 months or 48 months. The Committee noted that the manufacturer assumed that most progression-free survival translates to an overall survival gain in its model. 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 factor closer to 70%. The Committee acknowledged that if a conversion factor of 70% was assumed, the base-case ICER (which was driven by a conversion factor of more than 80%) would increase. The Committee considered analyses from the manufacturer in which a conversion factor of 50%, 75% or 100% was assumed, and noted that the ICERs ranged from £16,600 to £19,400 per QALY gained. The Committee considered that rituximab maintenance was likely to have a conversion factor of at least 70% and therefore concluded that it was reasonable to request additional analyses from the manufacturer that assume that the extent to which progression-free survival translates to overall survival gain would be 70%, 80% or 90%.	4.8    4.9
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 after receiving second-line induction treatment with rituximab in combination with chemotherapy’) health states respectively. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the model had marginal effect on the base-case ICER, and was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival. The Committee was aware that the model did not include the utility associated with delaying chemotherapy, however if it was included, it would likely decrease the ICER (that is, improve the cost effectiveness).	3.24, 4.11, 4.12
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 maintenance, the conversion rate 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 that incorporates all of the following assumptions: - mean age of 62.5 years at the start of treatment - duration of clinical benefit from rituximab maintenance treatment is 28 months, 36 months or 48 months - the extent that the benefit of mean progression-free survival translates to mean overall survival gain is 70%, 80% or 90% (undiscounted and not adjusted for health-related quality of life).	1.2, 4.8, 4.9, 4.10
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that the ICERs presented by the manufacturer were associated with a great deal of uncertainty, some of which further analysis may reduce. Therefore, the Committee was minded not to recommend rituximab for the first-line maintenance treatment of people with advanced follicular non-Hodgkin’s lymphoma that has responded to first-line induction treatment with rituximab in combination with chemotherapy as a cost-effective use of NHS resources. The Committee requested from the manufacturer further clarification, which should be made available for the next Appraisal Committee meeting.	4.12
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
February 2011

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. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once 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

Professor 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

Professor 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

Professor 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

Mr 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