NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

Appraisal consultation document

Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia

1 Appraisal Committee's preliminary recommendations

1.1 Rituximab in combination with fludarabine and cyclophosphamide is recommended as an option for the treatment of relapsed or refractory chronic lymphocytic leukaemia except when the condition:

• is refractory to fludarabine (that is, it has not responded to fludarabine or has relapsed within 6 months of treatment) or
• has previously been treated with rituximab.

1.2 Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the treatment of relapsed or refractory chronic lymphocytic leukaemia.

1.3 People currently receiving rituximab should have the option to continue treatment until they and their clinicians consider it appropriate to stop if they are:

• receiving rituximab in combination with fludarabine and cyclophosphamide but treatment would not be recommended according to section 1.1 or
• receiving rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide.

2 The technology

2.1 Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia. The summary of product characteristics (SPC) states that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or patients refractory to previous rituximab plus chemotherapy. Rituximab is administered intravenously, once every 4 weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24 weeks. Dosing is calculated according to body surface area, with an initial dose of 375 mg/m² followed by 500 mg/m² for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875 mg/m². The SPC states that rituximab should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available.

2.2 The most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the SPC.

2.3 Rituximab is available in 100 mg (10 ml) and 500 mg (50 ml) vials. The cost of a 100 mg vial is £174.63 and of a 500 mg vial is £873.15 (excluding VAT; ‘British national formulary’ [BNF] edition 58). For a person with a body surface area of 1.86 m², the cost of rituximab for the first dose is £1222 and for subsequent doses £1746, including wastage of excess rituximab. The total cost of rituximab is £9954 per course. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer's submission compared rituximab plus fludarabine and cyclophosphamide with fludarabine and cyclophosphamide combination therapy. This comparison was based on the REACH trial, a phase III, multicentre, open-label, randomised controlled trial in people with previously treated chronic lymphocytic leukaemia. People were enrolled if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, a life expectancy greater than 6 months and if they had previously received treatment with single-agent chlorambucil with or without prednisolone, single-agent fludarabine (or other nucleoside analogue), or an alkylator-containing combination therapy (such as cyclophosphamide plus doxorubicin, vincristine and prednisolone, or cyclophosphamide plus vincristine and prednisolone). People were excluded from the trial if they had previously received treatment with fludarabine and cyclophosphamide, either concurrently or sequentially, or with interferon, rituximab or another monoclonal antibody. People were also excluded if they had chronic lymphocytic leukaemia that was refractory to fludarabine (defined as not achieving at least a partial response for a minimum duration of 6 months). A total of 552 people were randomised to receive either rituximab plus fludarabine and cyclophosphamide or fludarabine and cyclophosphamide alone. The median age of people in the trial was 63 years and 67% were men. Most people (90%) had Binet stage B or C disease.

3.2 People in the trial were randomised to six cycles of treatment, with an interim assessment of response after three cycles. At this point, people whose disease showed a partial or complete response continued treatment to six cycles, people with progressive disease discontinued treatment and people with stable disease continued treatment at the investigator’s discretion. Each treatment cycle of 28 days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine [25 mg/m²] and cyclophosphamide [250 mg/m²] on days 1, 2 and 3) with or without rituximab (375 mg/m² on day 0 of cycle 1, 500 mg/m² on day 1 of cycles 2‑6). All treatments were administered intravenously.

3.3 The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality-of-life data were collected in the first year of the trial using the Functional Assessment of Cancer Therapy – General (FACT-G).

3.4 Demographic characteristics and disease characteristics, including Binet stage B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all people in the trial, 59% had Binet stage B disease, 31% had Binet stage C disease, and 10% had Binet stage A disease. The trial enrolled 42 people (8%) with del(17p), a chromosome mutation associated with a poorer prognosis. The manufacturer’s submission states that most people had previously been treated with single-agent chemotherapy (82%), most commonly an alkylating agent (66%) such as chlorambucil or cyclophosphamide. Of the people in the trial 56% were alkylator sensitive, 26% were alkylator refractory, and 16% had previously received fludarabine.

3.5 A pre-planned interim analysis of the trial data was conducted in which response was assessed by an independent panel. However, the trial was continued until the final analysis because the difference in progression-free survival between the treatment groups did not meet the pre-specified level of statistical significance and because all people had completed therapy. The trial results reported in the manufacturer’s submission are based on a median follow-up of 25.3 months. At this point, the median progression-free survival was 30.6 months in the rituximab plus fludarabine and cyclophosphamide group and 20.6 months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.65 (95% CI 0.51 to 0.82, p = 0.0002). The best overall response rate was 69.9% in the rituximab plus fludarabine and cyclophosphamide group and 58% in the fludarabine and cyclophosphamide group (p = 0.0034). The median overall survival was 51.9 months in the fludarabine and cyclophosphamide group and had not been reached in the rituximab plus fludarabine and cyclophosphamide group (hazard ratio 0.83, 95% CI 0.59 to 1.17, p = 0.2871).

3.6 The manufacturer presented a number of subgroup analyses. For people with the del(17p) mutation, the hazard ratio for progression-free survival was 0.75 (95% CI 0.38 to 1.49). The hazard ratio for progression-free survival for people with Binet stage A disease was 0.75 (95% CI 0.33 to 1.72), Binet stage B disease was 0.65 (95% CI 0.47 to 0.88) and Binet stage C disease was 0.61 (95% CI 0.41 to 0.90). The REACH trial was not powered to detect differences between the treatment groups for any of these subgroups.

3.7 In the REACH trial, 80% of people in the rituximab plus fludarabine and cyclophosphamide group experienced a grade 3 or 4 adverse event compared with 74% in the fludarabine and cyclophosphamide group. The most common grade 3 or 4 adverse events, with at least a 2% higher incidence in the rituximab plus fludarabine and cyclophosphamide group, were neutropenia, febrile neutropenia, granulocytopenia and hepatitis B infections. In the rituximab plus fludarabine and cyclophosphamide group, there were 19 treatment-related deaths (7%) and 51% of people had their treatment modified or interrupted for safety reasons. In the fludarabine and cyclophosphamide group, there were 14 treatment-related deaths (5%) and 39% of people had their treatment modified or interrupted for safety reasons.

3.8 The manufacturer provided supporting data from 20 non-comparative studies. These studies examined the efficacy and tolerability of rituximab plus different chemotherapy regimens, and of rituximab-containing regimens in people with fludarabine-refractory chronic lymphocytic leukaemia, and in people previously treated with rituximab (both groups had been excluded from the REACH trial). Of these 20 studies, 19 were uncontrolled, phase II studies and one was a randomised phase II trial of fludarabine, cyclophosphamide and mitoxantrone with or without rituximab in people with previously treated chronic lymphocytic leukaemia (n = 52). However, the small number of people included in each group in the randomised trial did not allow a statistical comparison to be made. Seven of the 20 trials investigated the use of rituximab outside the terms of the marketing authorisation (either rituximab monotherapy or rituximab in combination with non-chemotherapy regimens).

3.9 The largest non-comparative study was a single-arm, open-label, phase II study of 177 people with relapsed or refractory chronic lymphocytic leukaemia (median follow-up 28 months). Of the people in the study, 82% had previously received treatment with fludarabine monotherapy or combination therapy (of whom 108 people were fludarabine sensitive and 37 were fludarabine refractory), 18% had had prior alkylating agents only (of whom 22 people had received rituximab monotherapy or combination therapy). The overall response rate for all people in the study was 73% and the complete response rate was 25%.The overall and complete response rates were 58% and 6% respectively for the group with fludarabine-refractory chronic lymphocytic leukaemia compared with 77% and 33% for the group with fludarabine-sensitive disease. For the group who had previously received rituximab monotherapy or combination therapy, the overall response rate was 64% and the complete response rate was 18%. The manufacturer presented an extended analysis of this study which included results for a total of 284 people. However, data on the subgroups described above were marked as academic in confidence.

3.10 The manufacturer submitted an economic analysis comparing rituximab plus fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The manufacturer used a three-state Markov model with a cycle length of 1 month and a 25-year time horizon (to represent a lifetime horizon). The health states in the model were ‘progression-free survival’, ‘progressed’, and ‘death’. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in the REACH trial. For the transition from the progression-free survival to the death health state, trial data were used and supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, people from both groups of the trial were assumed to have equal risk of death. This assumption was based on a non-significant (p = 0.5596) difference in Kaplan-Meier curves for post-progression survival.

3.11 In the model, the drug costs were calculated assuming a body surface area of 1.86 m², which reflects the average body surface area of the people in the REACH trial. The REACH trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide is the same regardless of the route of administration if the dosage is adjusted to ensure equivalent bioavailability. The costs of fludarabine and cyclophosphamide treatment in the model were adjusted to allow for the difference in the route of administration. In the base case, the drug doses and costs were reduced according to the proportion of people expected to progress or die each month. The average undiscounted drug cost for rituximab was £9078 for all six cycles of treatment. The average undiscounted drug costs of fludarabine were £2569 for people in the rituximab plus fludarabine and cyclophosphamide group and £2510 for people in the fludarabine and cyclophosphamide group. The average undiscounted drug costs of cyclophosphamide were calculated as £21 and £20 for each group respectively.

3.12 The model included costs for supportive care. Supportive care consisted of quarterly outpatient consultations, blood transfusions and bone marrow transplants in the progression-free survival health state and monthly outpatient consultations and second-line therapies for the progressed health state. The cost for intravenous administration of rituximab was £307 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £201. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist’s time to prepare the infusion and one consultation with a clinical oncologist.

3.13 The utility values used in the manufacturer’s submission were taken from a health technology assessment report that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility value of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the report from condition-specific health-related quality-of-life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 34 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for the progression-free survival health state was consistent with that used in the manufacturer’s submission. No conclusions could be drawn about the utility value appropriate for the progressed health state because only data for two people were available.

3.14 The manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab plus fludarabine and cyclophosphamide in comparison with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.585 at an incremental cost of £9128, giving an incremental cost-effectiveness ratio (ICER) of £15,593 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab plus fludarabine and cyclophosphamide had a 75% probability of being cost effective at £20,000 and a 94% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide.

3.15 A sensitivity analysis was presented in the manufacturer’s submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows:

• increasing and decreasing adverse event costs by 50%
• increasing and decreasing supportive care costs for the health states by 50%
• assuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1
• assuming upper and lower quartiles for drug administration costs (from reference costs 2007/08)
• assuming differential probabilities of death after progression between treatment arms.

One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including adverse events costs, monthly supportive care costs, and drug administration costs. The results were also not sensitive to the function used to extrapolate progression-free survival. The results were sensitive to assumptions about utilities and assumptions about the probability of death after progression. The highest ICER reported (using both differential mortality rates between treatment arms and adjusting utilities) was £23,790 per QALY gained.

3.16 The manufacturer’s submission also included a scenario analysis to explore the impact on the ICER of combining rituximab with chemotherapy agents other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 45% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained.

3.17 The ERG considered that all the relevant trials had been identified. The ERG noted that the manufacturer’s submission was based on only one clinical trial, and this trial was unpublished. The ERG considered this trial had adequate randomisation and allocation concealment. However, it noted that the trial was open label and therefore assessments might be biased. The ERG stated that there were differences in progression-free survival between the trial groups when assessed by the blinded independent panel and the unblinded trial investigators (independent panel data were provided as academic in confidence). It considered that the trial population was relatively young compared with the UK population who would be eligible for rituximab and 10% of people had mild stage disease (Binet stage A), a stage at which people are not commonly treated in the UK. The ERG also noted that people with fludarabine-refractory chronic lymphocytic leukaemia were excluded from the trial although they could be eligible for rituximab. It considered that the comparator used in the cost-effectiveness analysis (that is, fludarabine and cyclophosphamide) was appropriate.

3.18 The ERG noted that in the manufacturer’s economic model people in the progressed health state could not move back into the progression-free survival health state. They considered that this did not appropriately reflect the disease process because people with chronic lymphocytic leukaemia receive a series of treatments and therefore they may have periods of progression-free survival after relapse and further treatment. The ERG commented that not all adverse events were assigned costs in the model. In particular, hepatitis B, for which there were six cases in the rituximab plus fludarabine and cyclophosphamide group and no cases in the fludarabine and cyclophosphamide group.

3.19 The ERG completed a series of exploratory analyses. First, it remodelled rituximab costs so that full costs were incurred at the start of each cycle rather than spread throughout the cycle. This amendment increased the base-case analysis from £15,593 to £18,129 per QALY gained. Second, the ERG conducted an analysis using progression-free survival curves based on the independent assessment of progression (from the interim trial analysis) rather than non-blinded, investigator-assessed progression. This increased the base-case ICER to £17,507 per QALY gained. Third, the ERG explored the effect on the ICER of assuming no overall survival benefit of treatment with rituximab plus fludarabine and cyclophosphamide. It used two methods for this; it used the mortality rate from the fludarabine and cyclophosphamide group and applied it to the rituximab plus fludarabine and cyclophosphamide group and vice versa. The resulting ICERs were £40,568 and £42,444 per QALY gained for each method respectively compared with £15,593 per QALY gained in the base case.

3.20 The ERG identified that if it is assumed there is no difference in overall survival between the rituximab plus fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free and the progressed health states. If the difference in utility between the health states is decreased by 0.1 (that is from a difference of 0.2 to 0.1), the ICER increases to between £81,135 and £84,889 per QALY gained.

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

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab, having considered evidence on the nature of relapsed or refractory chronic lymphocytic leukaemia 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.

Clinical effectiveness

4.2 The Appraisal Committee discussed current standard clinical management of relapsed or refractory chronic lymphocytic leukaemia. The Committee heard from clinical specialists that the most frequently used first-line treatments are fludarabine plus cyclophosphamide with or without rituximab, and chlorambucil for people unable to have fludarabine because they have a poor performance status. However, for relapsed or refractory chronic lymphocytic leukaemia there is no single standard treatment option. The choice of treatment depends on a number of factors, including the presence of genetic abnormalities such as del(17p) mutation, previous treatments the person has received, whether a response was achieved from previous treatments, and if so, the duration of response. Experts noted that for these reasons, they considered it important to have a range of treatment options available. The Committee heard that for relapsed disease, treatments used previously may be administered again either with or without the addition of another therapeutic agent, or alternatively a different agent may be used. When additional or different treatments were used, these could include fludarabine and cyclophosphamide with the addition of mitoxantrone, alemtuzumab and stem cell transplantation.

4.3 The Committee noted that the clinical effectiveness evidence was based mainly on a single unpublished randomised controlled trial (the REACH trial). In this trial rituximab plus fludarabine and cyclophosphamide was compared with fludarabine and cyclophosphamide. The Committee heard from clinical specialists that people in the REACH trial were younger and had a better performance status than people with chronic lymphocytic leukaemia seen in routine practice in the NHS in England and Wales. However, the clinical specialists commented that the people in the trial were representative of the people who would be eligible for treatment with fludarabine plus cyclophosphamide. The Committee discussed the inclusion in the trial of people who had Binet stage A chronic lymphocytic leukaemia. It heard from clinical specialists that the decision to treat chronic lymphocytic leukaemia would depend on symptoms and progression of disease rather than specific staging.

4.4 The Committee discussed the exclusion from the REACH trial of people who were previously treated with fludarabine and cyclophosphamide, people who were previously treated with rituximab and people who had chronic lymphocytic leukaemia that was refractory to fludarabine. It heard from clinical specialists that, if suitable, people often had fludarabine combination therapies as first-line therapy. It also heard that the publication of guidance ‘Rituximab for the first-line treatment of chronic lymphocytic leukaemia’ (NICE technology appraisal guidance 174) recommending rituximab plus fludarabine and cyclophosphamide meant that in the future an increasing number of people with relapsed or refractory disease will have had rituximab and fludarabine combination therapy as a first-line treatment. The Committee considered the exclusion of these groups from the clinical trial was a limitation because it meant that the trial population did not reflect all the people with relapsed or refractory disease who would be eligible for rituximab plus fludarabine and cyclophosphamide.

4.5 The Committee accepted that the REACH trial demonstrated the addition of rituximab to fludarabine and cyclophosphamide improved progression-free survival and complete response rates. The Committee noted there was potential for bias in outcome assessment because of the open-label design of the trial. The Committee discussed the results of an interim analysis of the trial data. This was an independent assessment of response that was provided as academic in confidence. The Committee noted that there was a difference between the investigator and independent assessments but was aware that the interim analysis was conducted 1 year before the investigator assessment. The Committee heard from clinical specialists that assessment of progression-free survival was subjective and could change depending on familiarity with assessment tools. The Committee considered that the differences in these assessments led to uncertainty in estimating the additional benefit of rituximab.

4.6 The Committee noted that in the REACH trial median overall survival had not been reached in the rituximab group, and that survival curves for patients in the two treatment groups hardly diverged until 30 months. The Committee heard expert opinion that it is difficult for studies of chronic lymphocytic leukaemia to demonstrate an effect of treatment on overall survival because of the long natural history of the disease and because people with the disease often receive multiple treatments. It also heard that progression-free survival and response rates are generally accepted as surrogates for overall survival. Furthermore, clinical specialists commented that longer term trial evidence is emerging that demonstrates an overall survival benefit of first-line treatment with rituximab plus fludarabine and cyclophosphamide. On balance, the Committee was persuaded that the improvements observed in progression-free survival and response rates were likely to lead to at least some gain in overall survival, although this gain could not be quantified.

4.7 The Committee noted that in the REACH trial there were slightly more grade 3 or 4 adverse events and treatment-related deaths in the rituximab plus fludarabine and cyclophosphamide group than in the fludarabine and cyclophosphamide group. It heard from specialists that people with chronic lymphocytic leukaemia are aware of the risks of treatments and are willing to accept these risks because of the severity of the condition. The Committee discussed the six cases of hepatitis B seen in the trial in the rituximab plus fludarabine and cyclophosphamide group. However, it heard from clinical specialists that this would be unlikely to happen in the UK because all people with chronic lymphocytic leukaemia are screened for hepatitis B before undergoing treatment, and so hepatitis B reactivation would be rare.

Cost effectiveness

4.8 The Committee reviewed the economic model submitted by the manufacturer and the ERG’s analysis of the model. It was mindful that the model did not allow transition from the progressed health state to the progression-free survival heath state. The Committee considered that this does not appropriately reflect the disease process because people may receive later treatments with further periods of progression-free survival. The Committee was aware that a similar model had been used in the appraisal of rituximab for the first-line treatment of chronic lymphocytic leukaemia (NICE technology appraisal guidance 174). On balance, the Committee agreed that the model could be used as a basis for considering the cost effectiveness of rituximab.

4.9 The Committee considered how the costs of rituximab had been incorporated into the economic model. It noted that the ERG considered the assumption in the base-case analysis that costs were incurred throughout the cycle was inappropriate because rituximab was provided on the first day of each cycle. Therefore, the ERG had explored remodelling rituximab costs so that costs were incurred at the start of each treatment cycle. The Committee noted that this had the effect of increasing the ICER from £15,600 per QALY gained in the base case to £18,100. The Committee considered that the costs of rituximab would be incurred at the start of treatment and therefore accepted the amendment proposed by the ERG.

4.10 The Committee discussed whether the modelled gains in overall survival from the economic model appropriately reflected the data from the clinical trial. It noted that the outputs from the manufacturer’s economic analysis modelled a difference in overall survival between treatment groups from the start of treatment that did not reflect the trial data – the overall survival curves from the clinical trial provided by the manufacturer showed no difference in overall survival between the treatment groups before around 30 months, although, beyond this time, the extrapolated curves began to diverge. The Committee considered that there was little evidence from the REACH trial to support the validity of the analysis provided by the manufacturer and that the manufacturer’s base-case analysis was likely to have overestimated the benefits associated with rituximab. However, based on comments from the clinical specialists, the Committee was persuaded that it was appropriate to assume some gain in overall survival in the economic model.

4.11 The Committee discussed the utilities used in the economic model and noted that the evidence base for these estimates did not reflect the NICE reference case; in particular, preference-based methods were not used. It was aware that a utility study was under way in people with chronic lymphocytic leukaemia in the UK but detailed results from this study for people who had progressed following treatment were not yet available. The Committee heard from patient experts that they considered an assumption of only a small difference in utility between the progressed and progression-free survival health states was not realistic. People greatly value being progression free and asymptomatic – it is associated with a marked improvement in quality of life. The Committee considered the lack of appropriate utility data contributed to uncertainty in the economic model. It recognised that when there was no modelled gain in overall survival the results became very sensitive to the difference between the utility values used for the progression-free survival health state and the progressed health state.

4.12 The Committee considered the estimates of cost effectiveness provided by the manufacturer and the additional exploratory analyses performed by the ERG that examined the impact on the ICER of reducing the survival advantage of treatment with rituximab. It noted that using an assumption of no overall survival advantage had the effect of increasing the cost-effectiveness estimates from £15,600 per QALY gained in the base case to £41,000. However, the Committee considered that this assumption represented an extreme case. On balance, the Committee was persuaded that even taking into account the uncertainty about utility values and the uncertainty about a gain in overall survival from treatment with rituximab, the economic model demonstrated that the use of rituximab plus fludarabine and cyclophosphamide was a cost-effective use of NHS resources for the population represented in the REACH trial; that is, people who have not previously received rituximab or fludarabine combination treatment and those whose disease is not refractory to fludarabine monotherapy.

4.13 The Committee discussed the use of rituximab plus fludarabine and cyclophosphamide in people who have previously received treatment with rituximab-containing regimens. The Committee considered the additional evidence from uncontrolled phase II trials reporting the benefits of retreatment with rituximab. The Committee was aware of the methodological limitations of these trials, and heard that the clinical specialists considered there was uncertainty in the degree of benefit of retreatment with rituximab. However, patient experts indicated that there was anecdotal evidence that people retreated with rituximab may have a good response to treatment. The Committee considered that there could be a lower response rate in people who had previously received rituximab. It heard from clinical specialists that people who had received first-line rituximab treatment and had relapsed would not be widely observed in clinical practice for a considerable period of time. It concluded that the relative benefits of retreatment with rituximab were not proven and therefore it could not be recommended as a cost-effective use of NHS resources on the basis of current evidence.

4.14 The Committee considered the use of rituximab plus fludarabine and cyclophosphamide in people whose disease had previously responded to first-line treatment with fludarabine plus cyclophosphamide (that is, fludarabine-sensitive chronic lymphocytic leukaemia). It heard from clinical specialists that for people with relapsed disease in whom there had been a period of progression-free survival of at least 6-12 months after first-line treatment, treatments used previously may be administered again because a good response was likely. The Committee discussed evidence from the REACH trial. It recognised that although the trial excluded people previously treated with fludarabine plus cyclophosphamide, it included people who had had fludarabine monotherapy and whose disease was considered to be fludarabine sensitive. On balance, the Committee concluded that rituximab plus fludarabine and cyclophosphamide could be considered a cost-effective use of NHS resources in people who had previously had a response lasting at least 6 months to treatment with fludarabine and cyclophosphamide.

4.15 The Committee also discussed the use of rituximab plus fludarabine and cyclophosphamide in people who have chronic lymphocytic leukaemia that is refractory to fludarabine. The Committee discussed the additional evidence provided by the manufacturer on people with chronic lymphocytic leukaemia that is refractory to fludarabine and noted the methodological limitations of these non-comparative trials. The Committee discussed the results from the largest trial reported by the manufacturer. It considered that the results showed a lower response to treatment with rituximab plus fludarabine and cyclophosphamide in chronic lymphocytic leukaemia that was refractory to fludarabine than in disease that was sensitive to fludarabine. On this basis the Committee considered that the use of rituximab plus fludarabine and cyclophosphamide for the treatment of people who had already had fludarabine could only be considered a cost-effective use of NHS resources when the chronic lymphocytic leukaemia remained fludarabine sensitive and not when it was fludarabine refractory.

4.16 The Committee recognised that the marketing authorisation for rituximab allowed its use with any chemotherapy regimen. The Committee discussed the additional evidence on using rituximab plus chemotherapy regimens other than fludarabine and cyclophosphamide. The Committee considered that there was considerable uncertainty about the relative clinical benefit associated with adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide for the treatment of relapsed or refractory chronic lymphocytic leukaemia. The Committee was not persuaded that the relative treatment effect for rituximab plus fludarabine and cyclophosphamide could be generalised to other chemotherapy combinations. It concluded that the use of rituximab with chemotherapy regimens other than fludarabine and cyclophosphamide had not been demonstrated to represent a cost-effective use of NHS resources.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must 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. The NHS is not required to fund treatments that are not recommended by NICE.

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/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the 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 first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 174 (2009). Available from www.nice.org.uk/TA174
• Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007). Available from www.nice.org.uk/TA119
• Improving outcomes in haematological cancers. NICE cancer service guidance (2003). Available from www.nice.org.uk/CSGHO

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 October 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
October 2009

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A. Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. There are four Appraisal Committees, each with a chair and vice chair. Each Committee considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Kathryn Abel
Reader and Consultant Psychiatrist/Director of Centre for Women's Mental Health, University of Manchester

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Professor Mike Campbell
Statistician, Institute of Primary Care and General Practice, University of Sheffield

Mr David Chandler
Lay member

Ms Mary Cooke
Lecturer School of Nursing, Midwifery & Social Work, University of Manchester

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Mr Stephen Greep
Chief Executive of Hull and East Yorkshire Hospitals NHS Trust 

Dr Wasim Hanif
Consultant Physician & Honorary Senior Lecturer, University Hospital Birmingham

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Dr Catherine Jackson
Professor of Primary Care Medicine, University of St Andrews

Professor Gary McVeigh (Vice Chair)
Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority

Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Mrs Ruth Oliver-Williams
Head of Nursing/Quality Improvement Lead Surgical Services, Royal Derby Hospital

Dr Katherine Payne
Health Economics Research Fellow, University of Manchester

Dr Danielle Preedy
Lay member

Dr Martin J Price
Head of Outcomes Research, Janssen-Cilag

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Mr Miles Scott
Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

John Stevens
Director, Centre for Bayesian Statistics in Health Economics University of Sheffield

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle
Lay member

C. 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.

Sally Gallaugher
Technical Lead

Zoe Garrett
Technical Adviser

Laura Malone
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 West Midlands Health Technology Assessment Collaboration:

• Dretzke J et al., Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia, 14 September 2009

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 and II also have the opportunity to appeal against the final appraisal determination.

I. Manufacturer/sponsor:

• Roche Products

II. Professional/specialist and patient/carer groups:

• Association of Cancer Physicians
• British Association for Services to the Elderly
• British Geriatrics Society
• British Oncological Association
• British Psychosocial Oncology Society
• British Society for Haematology
• Cancer Networks Pharmacists Forum
• Cancer Research UK
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• Royal College of Radiologists
• Royal Society of Medicine – Intellectual Disabilities Forum
• United Kingdom Clinical Pharmacy Association
• United Kingdom CLL Forum
• United Kingdom Oncology Nursing Society
• Afiya Trust
• African Caribbean Leukaemia Trust (ACLT)
• Age Concern & Help the Aged
• Anthony Nolan Trust
• Black Health Agency
• CancerACTIVE
• Cancer Black Care
• Cancer Equality
• Chinese National Healthy Living Centre
• Chronic Lymphocytic Leukaemia Support Association (CLLSA)
• Confederation of Indian Organisations
• Counsel and Care
• Equalities National Council
• Helen Rollason Heal Cancer Charity
• Leukaemia CARE
• Leukaemia Society (UK)
• Macmillan Cancer Support
• Maggie’s Centres
• Muslim Council of Great Britain
• Muslim Health Network
• National Cancer Alliance
• National Council for Palliative Care
• South Asian Health Foundation
• Specialised Healthcare Alliance
• Sue Ryder Care
• Tenovus Cancer Information Centre
• Transplant Support Network
• UK Transplant

III. Other consultees:

• Department of Health
• Knowsley PCT
• Surrey PCT
• Welsh Assembly Government

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

• Board of Community Health Councils in Wales
• British National Formulary
• Cancer Care Cymru
• Department of Health, Social Services and Public Safety for Northern Ireland
• Medicines and Healthcare products Regulatory Agency
• National Association of Primary Care
• National Public Health Service for Wales
• NHS Alliance
• NHS Confederation
• NHS Purchasing and Supply Agency
• NHS Quality Improvement Scotland
• Scottish Medicines Consortium
• Alliance Pharmaceuticals (prednisolone)
• Baxter Healthcare (cyclophosphamide)
• Bayer (fludarabine)
• Cephalon (doxorubicin)
• Eli Lilly and Company (vincristine)
• GlaxoSmithKline (chlorambucil)
• Hospira UK (doxorubicin) (vincristine)
• Medac UK (doxorubicin)
• Pfizer (cyclophosphamide, prednisolone, doxorubicin)
• Schering-Plough (doxorubicin)
• Sovereign Medical (prednisolone)
• Teva UK (doxorubicin), (vincristine)
• Winthrop Pharmaceuticals UK (prednisolone)
• Wockhardt UK (doxorubicin)
• Institute of Cancer Research
• Leukaemia Research Fund
• MRC Clinical Trials Unit
• National Cancer Research Institute
• National Cancer Research Network
• National Institute of Health Research
• Policy Research Institute on Ageing and Ethnicity
• National Institute for Health Research Health Technology Assessment Programme
• West Midlands Health Technology Assessment Collaboration (WMHTAC)
• National Collaborating Centre for Cancer

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 for the treatment of relapsed or refractory chronic lymphocytic leukaemia by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Chris Fegan, Consultant Haematologist, nominated by Royal College of Physicians – clinical specialist
• Professor Andrew Pettitt, Division of Haematology nominated by Royal College of Pathologists – clinical specialist
• Ms Jacquelyn Williams Durkin, Trustee of Chronic Lymphocytic Leukaemia Support Association, nominated by Chronic Lymphocytic Leukaemia Support Association ‑ patient expert
• Ms Jane Barnard, Chairman of Chronic Lymphocytic Leukaemia Support Association, nominated by Chronic Lymphocytic Leukaemia Support Association – patient expert