Multiple myeloma - bortezomib: Appraisal consultation document
Appraisal Consultation Document
1.Appraisal Committee's preliminary recommendations
3.The manufacturer's submission
4.Consideration of the evidence
6.Proposed recommendations for further research
8.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
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 bortezomib for relapsed and refractory multiple myeloma 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 the representatives nominated by professional/specialist and patient/carer groups. The Committee has developed preliminary recommendations on the use of bortezomib for relapsed and refractory multiple myeloma.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk ). This document should be read in conjunction with the manufacturer’s submission and the evidence review group report, which are available from www.nice.org.uk
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.
The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process (interim process)’ (this document is available on the Institute’s website, www.nice.org.uk).
- The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
- At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
- After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
- Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 14 August 2006
Second Appraisal Committee meeting: 6 September 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|
Bortezomib monotherapy, in its licensed indication, is not recommended for the treatment of patients with multiple myeloma except for use in well-designed clinical studies that focus on the establishment of the position of bortezomib in the pathway of care for people with multiple myeloma in comparison with other agents that are currently used in clinical practice in England and Wales.
|1.2||People currently receiving bortezomib should have the option to continue therapy until they and their clinicians consider it appropriate to stop.|
Bortezomib (Janssen-Cilag Ltd) is an anticancer drug that belongs to a novel class of drugs known as proteasome inhibitors. Bortezomib has a UK marketing authorisation as monotherapy for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation. For further information about the drug, see the ‘Summary of product characteristics’ (SPC).
Bortezomib treatment is associated with peripheral neuropathy, myelosuppression and other side effects. For full details of side effects and contraindications, see the SPC.
The net price of bortezomib is £762.38 for a 3.5-mg vial (excluding VAT; ‘British national formulary’, 51st edition). The cost per patient for a course of six cycles of treatment would be approximately £18,000. Costs may vary in different settings because of negotiated procurement discounts.
|4||Consideration of the evidence|
The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of bortezomib by people with multiple myeloma, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee considered current practice for the treatment of relapsed and refractory multiple myeloma in England and Wales. It noted that a variety of treatment options are currently used, and that the selection of treatment depends in particular on patient-specific factors such as duration of first remission, age and comorbidity. The Committee further noted that there is a lack of consensus on the pathway of care and timing of various treatments for people with multiple myeloma and for relapsed and refractory multiple myeloma in particular. It also noted the substantial amount of ongoing research in this area, including the use of novel therapies, established therapies, and combinations of therapies at various stages of disease. The Committee concluded that the position of bortezomib in the clinical pathway of care for people with multiple myeloma is uncertain at present and that it should be established more clearly by the results of ongoing research.
The Committee considered the framing of the decision problem in the manufacturer’s submission. The Committee discussed the explanation given in the manufacturer’s submission for the selection of HDD as the only relevant comparator. Although the Committee accepted that HDD is an appropriate comparator, it also noted that other agents including thalidomide are commonly used in current UK practice, particularly at first relapse. The Committee did not accept that these alternatives should be rejected as potential comparators on the grounds that some do not currently hold a UK marketing authorisation. Furthermore, the Committee was of the opinion that a lack of standardisation in the current management of multiple myeloma should not preclude efforts to establish the clinical and cost effectiveness of bortezomib within the spectrum of treatment options used in current practice in the NHS in England and Wales.
The Committee heard from clinical specialists that when bortezomib is used in the NHS in England and Wales it is usually given in combination with dexamethasone. Moreover, the manufacturer had presented evidence of the potential additional clinical and cost effectiveness of this combination over bortezomib monotherapy in comparison with HDD. The Committee was, however, mindful that the current UK marketing authorisation for bortezomib is for monotherapy only.
The Committee discussed the outcomes measured in the APEX RCT, of which time to disease progression was the primary endpoint, and overall survival, response rate, adverse events and health-related QoL were secondary endpoints. The Committee accepted that these endpoints were appropriate and relevant to this appraisal.
The Committee considered the evidence for the clinical effectiveness of bortezomib for the treatment of people with multiple myeloma who had received at least one prior therapy and had either undergone, or were considered unsuitable for, bone marrow transplantation. It accepted that the only RCT comparing bortezomib with other therapies that included patients with multiple myeloma at first relapse was the APEX study, which compared bortezomib with HDD. The Committee discussed the results of this study, noting the difficulties in interpreting the results because of the lack of clarity in reporting, the high degree of crossovers and the early termination of the trial. The Committee considered statements from patient experts and clinical specialists that bortezomib provides benefit when other treatment options have not done so or have ceased to do so. It noted that, for some patients, there are significant side effects associated with bortezomib treatment, notably peripheral neuropathy. The Committee concluded that bortezomib has shown clinical benefits compared with HDD, but that there remain uncertainties over its position in the clinical pathway of care for people with multiple myeloma, specifically when compared with alternative treatments currently in use in the NHS in England and Wales.
The Committee considered the evidence provided by the manufacturer on the cost effectiveness of bortezomib. The Committee was mindful that various treatment options are used in current practice, and that the model only provided an indication of cost effectiveness compared with HDD. The Committee considered the base-case and sensitivity analyses of the cost effectiveness of bortezomib compared with HDD. It discussed the issues raised by the ERG about the structure, methods and assumptions of the model as summarised in paragraph 3.5. The Committee concluded that the base-case cost per LYG had been underestimated and that there is greater variability in the cost effectiveness of treatment than presented in the manufacturer’s submission. The Committee therefore concluded that bortezomib had not been shown to be cost effective compared with current practice in the NHS in England and Wales.
The Committee con sidered the scenarios presented in the manufacturer’s submission and ERG report. It was persuaded that bortezomib becomes less cost effective compared with HDD when used at second or later relapse compared with its use at first relapse. The Committee heard from clinical specialists that, in their view, it would be inappropriate to restrict bortezomib to people who had experienced a specific number of relapses. The clinical specialists indicated that selection of treatment is patient and disease specific, and that it is currently unclear how a subgroup of patients who might gain more benefit from bortezomib than others might be defined. The Committee concluded that it could be inappropriate to make any recommendation for bortezomib for a subgroup of patients specified by the number of relapses they had experienced.
The Committee discussed the manufacturer’s assertion that it is more appropriate to consider cost per LYG rather than QALY gained as the measure of cost effectiveness in patients with multiple myeloma. The Committee did not accept the premises for this assertion, concluding that multiple myeloma and its treatments (including adverse effects of treatment) would have significant effects on health-related QoL, that such effects are important to patients, and that sources of information to allow estimation of QALYs gained are available. The Committee reviewed the additional analysis provided by the manufacturer at the request of the ERG, which estimated the impact of health-related QoL on the base-case ICER. The Committee was not persuaded that the utilities assumed for patients with relapsed multiple myeloma were an accurate reflection of the significant impairments in QoL that those in this clinical situation might experience. The Committee considered that the manufacturer’s base-case ICER of approximately £38,000 per QALY was therefore a substantial underestimate.
Summary of the considerations
The Committee was not persuaded that the economic model provided by the manufacturer had shown bortezomib to be cost effective compared with current practice in the NHS in England and Wales.
The Committee considered it important that the position of bortezomib in the clinical management of multiple myeloma should continue to be established by ongoing and planned clinical trials that compare bortezomib with other treatments that are used in the NHS in England and Wales. It also considered it important for data on health-related QoL and long-term effectiveness of bortezomib to be collected.
|4.12||The Committee concluded that bortezomib within its licensed indication should not be recommended for the treatment of people with relapsed or refractory multiple myeloma, except within well-designed clinical trials. The Committee also considered people currently receiving bortezomib and concluded that they should have the option to continue therapy until they and their clinicians consider it appropriate to stop.|
Proposed recommendations for further research
The Committee noted that there are a number of ongoing studies of the treatment of multiple myeloma, some of which compare bortezomib in combination with other therapies with regimens that do not contain bortezomib.
The Committee considered that further research into the effectiveness of bortezomib for the treatment of multiple myeloma is required. Such studies should include:
NICE has issued the following related technology appraisal.
|8||Proposed date for review of guidance|
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 2009. The Institute would particularly welcome comment on this proposed date.|
|Chair, Appraisal Committee|
Appendix A. Appraisal Committee members and NICE project team
A. Appraisal Committee members
The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets 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 Darren Ashcroft
Professor David Barnett (Chair)
Dr Peter Barry
Mr Brian Buckley
Professor John Cairns
Professor Mike Campbell
Professor David Chadwick
Dr Mark Chakravarty
Dr Peter I Clark
Dr Mike Davies
Mr Richard Devereaux-Phillips
Professor Jack Dowie
Dr Fergus Gleeson
Ms Sally Gooch
Mr Sanjay Gupta
Professor Philip Home
Dr Peter Jackson
Professor Peter Jones
Dr Mike Laker
Dr George Levvy
Ms Rachel Lewis
Mr Terence Lewis
Professor Jonathan Michaels
Dr Ruairidh Milne
Dr Neil Milner
Dr Rubin Minhas
Mr Miles Scott
Dr Lindsay Smith
Mr Roderick Smith
Dr Ken Stein
Professor Andrew Stevens
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 advisor and a project manager.
Helen Chung and Ebenezer Tetteh
Appendix B. Sources of evidence considered by the Committee
The following manufacturer/sponsor provided a submission for this appraisal:
The evidence review group report for this appraisal was prepared by Southampton Health Technology Assessment Centre (SHTAC):
C Green, J Bryant, A Takeda, K Cooper, A Clegg, A Smith, and M Stephens, ‘Bortezomib for the treatment of multiple myeloma patients’ , April 2006.
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 bortezomib by providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).
Appendix C. List of organisations involved in this appraisal
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.
Professional/specialist and patient/carer groups:
Commentator organisations (without the right of appeal):
This page was last updated: 30 March 2010