Leukaemia (lymphocytic) - fludarabine (appraisal consultation document)
Fludarabine monotherapy for the first line treatment of chronic lymphocytic leukaemia
Appraisal Consultation Document
Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Implementation
Proposed recommendations for further research
Related guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Appendix C. List of organisations involved in this appraisal
Background
The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of fludarabine for the treatment of chronic lymphocytic leukaemia and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by consultees and by the representatives nominated by healthcare professional and patient/carer groups. The Committee has developed preliminary recommendations on the use of fludarabine in chronic lymphocytic leukaemia.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process. This document should be read in conjunction with the manufacturer’s submission and evidence review group (ERG) report
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.
The process the Institute will follow after the consultation period is summarised below. For further details, see the Guide to the single technology appraisal process.
- The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
- At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
- After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
- Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 07 November 2006
Second Appraisal Committee meeting: 22 November 2006
Details of membership of the Appraisal Committee are given in appendix A, a list of the sources of evidence used in the preparation of this document is given in appendix B, and a list of organisations involved in this appraisal is given in appendix C
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
| 1 | Appraisal Committee's preliminary recommendations |
| This technology appraisal considers the clinical and cost effectiveness of fludarabine only within its licensed indications for the first line treatment of chronic lymphocytic leukemia and therefore no recommendations can be made with respect to fludarabine plus cyclophosphamide combination therapy. | |
| 1.1 | Fludarabine monotherapy within its licensed indications is not recommended for the first-line treatment of chronic lymphocytic leukaemia. |
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| 2 | The technology |
| 2.1 | Fludarabine (Fludara, Schering Health Care Limited) is a deoxyadenosine derivative that inhibits DNA, RNA and protein synthesis, cell replication and growth leading to apoptosis (cell death). Fludarabine has a marketing authorisation for the first-line treatment of symptomatic B-cell chronic lymphocytic leukaemia in patients with sufficient bone marrow reserves and either advanced disease (Binet stage C, Rai stages III/IV) or Binet stage A/B (Rai stages I/II) with disease-related symptoms or evidence of progressive disease. For further information about the drug, see the summary of product characteristics (SPC). |
| 2.2 | Adverse events associated with fludarabine treatment include anaemia, thrombocytopenia and neutropenia, and life-threatening autoimmune haemolytic anaemia. For full details of side effects and contraindications, see the SPC. |
| 2.3 |
The unit cost of proprietary fludarabine is £156 for a 50-mg vial, £279 for a pack of 15 10-mg tablets and £372 for a pack of 20 10-mg tablets (excluding VAT; ‘British national formulary’, edition 51). The cost per patient for a course of six cycles of treatment with fludarabine monotherapy would be approximately £4700. Costs may vary in different settings because of negotiated procurement discounts. |
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| 3 | The manufacturer's submission |
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The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fludarabine and a review of this submission by the Evidence Review Group (appendix B). | |
| 3.1 | The manufacturer’s submission approached the decision problem by comparing fludarabine monotherapy and fludarabine plus cyclophosphamide with chlorambucil. The population under consideration was people with B-cell chronic lymphocytic leukaemia (CLL), who were chemotherapy naïve, had sufficient bone marrow reserves and had advanced symptomatic Binet stage B or C disease or evidence of progressive disease in Binet stage A. The primary outcome measures considered were progression-free survival and health-related quality of life. Secondary outcome measures included treatment response rates, incidence of adverse events and overall survival. |
| 3.2 | The manufacturer’s submission presented evidence on the clinical effectiveness of fludarabine monotherapy and fludarabine plus cyclophosphamide in comparison to that of chlorambucil. Seven randomised controlled trials (RCTs) were identified to be relevant to the decision problem, of which two were published and five were available in abstract form. However, the three-arm CLL4 trial is the only study directly comparing fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil. The CLL4 trial enrolled 777 patients, of whom 194 were randomised to fludarabine monotherapy, 196 to fludarabine plus cyclophosphamide and 387 to chlorambucil. Follow-up of the CLL4 trial is ongoing. Early results of the CLL4 trial published in abstract form and presented in the manufacturer’s submission showed out of 661 patients with available data, overall treatment response rates were 77% for fludarabine monotherapy, 90% for fludarabine plus cyclophosphamide and 69% for chlorambucil (no p values or confidence intervals reported). Early results from the CLL4 trial reported 3-year progression-free survival to be 31% for fludarabine monotherapy, 62% for fludarabine plus cyclophosphamide and 23% for chlorambucil. Analysis of overall survival showed no difference between the three treatment regimens. |
| 3.3 | The manufacturer’s submission presented an economic analysis comparing fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil. The economic analyses were based on a Markov state transition model with a 20-year time horizon. The economic model used patient-level data from the CLL4 trial to inform first-line treatment, with data for second-line and salvage treatments taken from a variety of published sources. The manufacturer submitted revised base-case economic analyses following clarifications requested by the Evidence Review Group (ERG). These showed an incremental cost-effectiveness ratio (ICER) of £26,105 per quality-adjusted life year (QALY) for a comparison of fludarabine monotherapy with chlorambucil, and showed that fludarabine plus cyclophosphamide dominated fludarabine monotherapy. That is, fludarabine plus cyclophosphamide was more effective and less costly than fludarabine monotherapy. |
| 3.4 | The ERG raised a number of issues and uncertainties relating to the clinical and cost effectiveness evidence presented in the manufacturer’s submission. The ERG stated that the clinical effectiveness evidence had to be interpreted with caution because the CLL4 trial results were based on data that were both unpublished and incomplete as trial follow-up is ongoing. The ERG stated that the CLL4 trial data showed more incidents of neutropenia and thrombocytopenia with fludarabine plus cyclophosphamide than with fludarabine monotherapy or chlorambucil. The ERG noted that whilst the manufacturer’s submission stated that progression-free survival was linked to improvements in quality of life in the CLL4 trial, no reference was made to the impact of increased hospitalisations due to infections on the quality of life of patients allocated to the different treatments. |
| 3.5 | The ERG assessed the manufacturer’s economic model and noted that the main drivers of cost-effectiveness ratios were time horizon and rates of response to retreatment with the same chemotherapeutic agent as that used in first-line treatment. The ERG stated that disparities between the ICERs for 5-year, 10-year and 15 year time horizons suggested that extrapolation of model data is likely to be central to the validity of the ICERs presented. The ERG expressed concerns about the assumption of constant transition probabilities over time. The ERG stated that as patient-level data from the CLL4 trial were available, this assumption should have been validated using formal survival analysis. The ERG therefore performed a survival analysis using patient-level data from the CLL4 trial, the results of which showed that the assumption of constant transition probabilities does not hold. However, incorporating the results of the ERG’s survival analysis into the economic model required a major restructuring of the model that was beyond the remit of the ERG. |
| 3.6 | The ERG noted that there were no data available on retreatment response rates for fludarabine plus cyclophosphamide, and that in the manufacturer’s base-case economic analysis, retreatment response rates for fludarabine plus cyclophosphamide were assumed to be equal to the first-line treatment response rates observed in the CLL4 trial. In contrast, retreatment response rates for fludarabine monotherapy and chlorambucil taken from existing literature were lower than the first-line treatment response rates observed in the CLL4 trial. The manufacturer’s submission presented a one-way sensitivity analysis in which retreatment response rates were assumed to be the same as first-line treatment response rates for all the treatment arms in the economic model. The results of this analysis showed that the base-case ICER for fludarabine monotherapy compared with chlorambucil increased from £26,105 to £86,770 per QALY. The ERG did not consider the sensitivity analysis for fludarabine plus cyclophosphamide in particular to be sufficiently robust as the range of values used did not alter the assumption that retreatment response rates were equal to first-line treatment response rates. In an additional analysis, the ERG varied retreatment response rates for fludarabine plus cyclophosphamide within a range of 10–90%. Results of the ERG’s analysis showed that for retreatment response rates less than or equal to 30%, chlorambucil dominated fludarabine plus cyclophosphamide. |
| 3.7 | The ERG expressed concerns that the economic model only considered a limited sequence of treatments and stated that alternative sequences of treatments may be more effective. Different second-line treatments have different response rates and times to disease progression, and the choice of second-line treatments would ultimately affect the additional costs and utilities in the treatment arms of the economic model and hence the ICERs presented in the manufacturer’s submission. The ERG was also concerned that the failure of the manufacturer’s economic model to consider treatment costs of adverse events was likely to have biased the ICERs in favour of fludarabine-containing regimens. |
| 3.8 | Full details of all the evidence are in the manufacturer’s submission and Evidence Review Group report, which are available from www.nice.org.uk/TAxxx |
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| 4 | Consideration of the evidence |
| 4.1 | The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of fludarabine monotherapy for the treatment of chronic lymphocytic leukaemia, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of fludarabine by people with chronic lymphocytic leukaemia, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. |
| Clinical effectiveness | |
| 4.2 | The Committee considered the ERG’s critique of the clinical effectiveness of fludarabine treatments in comparison with chlorambucil. The Committee noted that the manufacturer did not make use of evidence from all relevant RCTs to provide a more precise estimate of the clinical effectiveness of the treatments. The Committee discussed the appropriateness of basing the clinical effectiveness of fludarabine treatment on unpublished results from the CLL4 study with trial follow-up ongoing. The Committee noted the ERG’s view that evidence synthesis using all available sources of direct and indirect clinical data comparing fludarabine with chlorambucil would have been an appropriate approach to reducing the uncertainty over clinical effectiveness. The Committee heard from clinical specialists that patient inclusion criteria in all the relevant RCTs (including the CLL4 study) were substantially the same. The clinical specialists stated that they would expect treatment outcomes to be similar across the trials. |
| 4.3 | The Committee discussed the results of the CLL4 trial and were aware that follow-up was ongoing. The Committee accepted that fludarabine treatment showed improved response rates (overall response and complete response) and 3-year progression-free survival compared to chlorambucil. The Committee expressed concerns, however, that improvements in progression-free survival with fludarabine treatment may not lead to improvements in overall survival. The Committee heard from clinical specialists that fludarabine is a more toxic treatment than chlorambucil, and is associated with a higher incidence of adverse events (particularly neutropenia) and potentially higher mortality rates. The clinical specialists also advised that although the incidence of autoimmune haemolytic anaemia (AIHA) was higher in the chlorambucil arm of the CLL4 trial, the form of AIHA triggered by fludarabine treatment is considered to be more severe. |
| 4.4 | The Committee considered current results from the CLL4 study, which showed improvements in response rates and progression-free survival seen with fludarabine treatment did not lead to improvements in overall quality of life. Clinical specialists advised that quality of life in the early stages of treatment may have been adversely affected by the toxicity of fludarabine. However, the clinical specialists stated that they would expect an overall improvement in quality of life for patients who have successfully completed treatment with and responded to fludarabine because of the extended period of progression-free survival it confers during which quality of life would be much better. |
| 4.5 | The Committee considered evidence from clinical specialists that the choice of treatment for CLL and the sequence in which treatments might be used is made on an individual patient basis, taking into account their general health and fitness and clinical measures of disease activity, in particular the rate of disease progression. The Committee heard that on this basis patients with CLL may be divided into those who have a less aggressive form of CLL (with an expected survival of up to 25 years), and those who have a more aggressive form of CLL (with an expected survival of 8 years or less). The Committee heard from clinical specialists that first-line treatment and repeated treatment with chlorambucil may be effective and more appropriate for patients with the less aggressive form of CLL and for those with comorbidities and lower levels of general fitness. On the other hand, first-line treatment with fludarabine-containing regimens may be more appropriate for patients with more aggressive forms of CLL disease and those who are considered fit enough to withstand more challenging treatments. The Committee noted statements from patient experts that CLL patients were cautious about fludarabine treatment as they were aware of its potential toxicity. The patient experts stated that fludarabine might therefore not be suitable for use in all people with CLL. |
| Cost effectiveness | |
| 4.6 | The Committee discussed the disparities in the ICERs for 5-year, 10-year and 15-year time horizons and noted that extrapolation of model data, in particular the assumption of a constant risk of disease progression and death over time, was optimistic given ageing of the population cohort in the economic model over the life time horizon. The Committee further considered the results of the ERG’s survival analysis using patient-level data from the CLL4 trial, which showed over time an increasing risk of disease progression for both responders and non-responders to fludarabine-containing regimens and chlorambucil, and an increasing risk of death for responders to fludarabine-containing regimens and chlorambucil. The Committee noted that the ERG’s survival analysis indicated that extrapolation of the model data may have overestimated the ICERs presented in the manufacturer’s submission. |
| 4.7 | The Committee considered the manufacturer’s one-way sensitivity analysis in which retreatment response rates were assumed to be the same as first-line treatment response rates for fludarabine monotherapy and chlorambucil. The Committee noted the increase in the base-case ICER from £26,105 to £86,770 per QALY. The Committee heard evidence from the clinical specialists that there is currently limited evidence on retreatment response rates for fludarabine monotherapy, and complete follow-up of the CLL4 trial may provide more evidence. The Committee accepted that given the limited evidence on retreatment response rates, the manufacturer’s one-way sensitivity analysis was likely to be a good estimate of the base-case ICER for fludarabine monotherapy in comparison with chlorambucil. |
| 4.8 | The Committee considered the clinical and economic significance of adverse events and noted in particular that the manufacturer’s model did not incorporate the costs of increased hospitalisations and treatment for adverse events associated with fludarabine-containing regimens; for example, the recommended use of prophylaxis against Pneumocystis carinii pneumonia and herpes virus infections. The Committee agreed that failure to consider the number, type, severity and treatment costs of adverse events in the economic model potentially biased cost-effectiveness ratios in favour of fludarabine-containing regimens. |
| 4.9 | The Committee discussed the manufacturer’s ‘conservative’ assumption that overall survival is the same for the fludarabine-containing regimens and chlorambucil. The Committee noted that the way the manufacturer’s economic model implemented survival equalisation meant that people in the fludarabine arms spent less time in the salvage treatment state, which is associated with lower utilities and additional costs. The Committee accepted that the structure of the economic model potentially biases cost-effectiveness ratios in favour of the fludarabine-containing regimens. The Committee further considered that the manufacturer’s survival equalisation approach may not be conservative given that the CLL4 trial showed higher mortality rates with fludarabine-containing regimens than chlorambucil (although this was not statistically significant). |
| 4.10 | The Committee noted that all the uncertainties and issues surrounding clinical and economic evidence on fludarabine monotherapy applied equally to fludarabine plus cyclophosphamide. The Committee accepted the ERG’s view that structural uncertainties in the economic model made it difficult to estimate the precise ICERs for the fludarabine-containing regimens. The Committee, however, were unable to make any recommendations on the use of fludarabine plus cyclophosphamide in the absence of a UK marketing authorisation. |
| Summary of the considerations | |
| 4.11 | In summary, the Committee noted that although additional evidence could help to clarify the uncertainties surrounding the ICERs obtained for a comparison of fludarabine monotherapy and chlorambucil, it was unlikely that such evidence would bring the ICERs for fludarabine monotherapy within the range of cost effectiveness considered acceptable by the Committee. The Committee was therefore unable to recommend fludarabine monotherapy for first line treatment of chronic lymphocytic leukaemia as a cost effective use of NHS resources. |
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| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 | NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued] |
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| 6 |
Proposed recommendations for further research |
| 6.1 | Further evidence should be gathered on the retreatment response rates for the fludarabine-containing regimens and chlorambucil, and on the incidence and severity of adverse effects of the fludarabine-containing regimens. |
| 6.2 | The Committee recommended evidence synthesis using data from all clinical trials comparing fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil to provide definitive information on treatment effects including retreatment response rates and overall survival outcomes. |
| 6.3 | The Committee recommended further research to identify prognostic markers that would allow better characterisation of subgroups of patients who will benefit the most from fludarabine. |
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| 7 |
Related guidance |
| 7.1 | NICE has issued the following related technology appraisal and cancer service guidance. |
| Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia. NICE technology appraisal guidance no. 29 (September 2001). Available from: www.nice.org.uk/TA029 | |
| Guidance on the use of imatinib for chronic myeloid leukaemia. NICE technology appraisal guidance no. 70 (October 2003). Available from: www.nice.org.uk/TA070 | |
| Improving outcomes in haematological cancers. NICE cancer service guidance (October 2003). Available from: www.nice.org.uk/csgho | |
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| 8 | Proposed date for review of guidance |
| 8.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 8.2 | It is proposed that the guidance on this technology is considered for review in October 2009. The Institute would particularly welcome comment on this proposed date. |
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David Barnett
Chair, Appraisal Committee
October 2006
Appendix A. Appraisal Committee members and NICE project team |
A. Appraisal Committee members |
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The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches. Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. Dr Jane Adam Professor A E Ades Dr Amanda Adler Dr Tom Aslan Professor David Barnett (Chair) Mrs Elizabeth Brain Dr Karl Claxton Dr Richard Cookson Mrs Fiona Duncan Dr Paul Ewings Professor John Geddes Mr John Goulston Ms Linda Hands Dr Elizabeth Haxby Dr Rowan Hillson Dr Catherine Jackson Professor Richard Lilford Dr Simon Mitchell Ms Judith Paget Dr Katherine Payne Dr Ann Richardson Dr Stephen Saltissi Mr Mike Spencer Dr Debbie Stephenson Professor Andrew Stevens (Vice Chair) Dr Cathryn Thomas Dr Simon Thomas Dr Norman Vetter Professor Mary Watkins Dr Paul Watson
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B. NICE Project Team |
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Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal) and a project manager. Ebenezer Tetteh and Eleanor Donegan Christopher Feinmann |
Appendix B. Sources of evidence considered by the Committee | |
| A |
The following manufacturer provided a submission for this appraisal:
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| B | The Evidence Review Group (ERG) report for this appraisal was prepared by the Centre for Health Economics, University of York (Walker S, Palmer S) and the NHS Northern and Yorkshire Regional Drug and Therapeutics Centre (Erhorn S, Brent S, Dyker A et al.), August 2006. Fludarabine phosphate for the first-line treatment of chronic lymphocytic leukaemia. |
| C |
The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on fludarabine by providing written and oral evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).
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Appendix C. List of organisations involved in this appraisal |
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The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the Appraisal Consultation Document (ACD) and supporting evidence. Consultee organisations have the opportunity to appeal against the Final Appraisal Determination. I Professional/specialist and patient/carer groups:
II Other consultee organisations:
III Commentator organisations (without the right of appeal):
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This page was last updated: 30 March 2010