The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of bortezomib for relapsed multiple myeloma and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its third meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of bortezomib for relapsed 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 evidence base for this appraisal (the evaluation report) which is 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’ (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: 22 June 2007
Next Appraisal Committee meeting: 4 July 2007

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

Bortezomib monotherapy is recommended as an option for the treatment of progressive multiple myeloma in people who have received at least one prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation under both of the following circumstances.

• The response to bortezomib is measured using serum M-protein after a maximum of four cycles of treatment, and treatment is continued only in people who have a reduction in serum M-protein of 50% or more (that is, a complete or partial response).
• The manufacturer rebates the full cost of bortezomib for people who, after a maximum of four cycles of treatment, have less than a 50% reduction in serum M-protein (that is, less than a partial response).

People currently receiving bortezomib monotherapy who do not meet the criteria in paragraph 1.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Bortezomib treatment is associated with peripheral neuropathy, thrombocytopenia and other side effects. For full details of side effects and contraindications, see the SPC.

The price of bortezomib is £762.38 for a 3.5-mg vial (excluding VAT; ‘British national formulary’, 53rd edition). The cost per patient for a course of three cycles of treatment would be approximately £9000, and for eight cycles would be approximately £25,000. Costs may vary in different settings because of negotiated procurement discounts.

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bortezomib and a review of this submission by the evidence review group (ERG) (appendix B).

The manufacturer’s submission approached the decision problem by comparing the clinical effectiveness of bortezomib with that of high-dose dexamethasone (HDD), based on the results of the APEX (Assessment of Proteasome Inhibition for Extending Remissions) randomised controlled trial (RCT). The population considered was people with multiple myeloma at first or subsequent relapse; however, the manufacturer’s submission placed emphasis on patients at first relapse. The manufacturer considered HDD to be the most appropriate comparator because it is an effective monotherapy for relapsed multiple myeloma that is commonly used in clinical practice in the UK, and its use at first relapse is within its licensed indications. In addition, HDD was the comparator agreed as the basis for regulatory approval of the APEX RCT.

In an interim analysis of the APEX trial (median follow-up of 8.3 months), it was found that people taking bortezomib had a significantly longer median time to disease progression compared with people receiving HDD (6.2 months compared with 3.5 months, hazard ratio 0.55, 95% confidence interval 0.44 to 0.69; p < 0.001); significantly improved overall survival (hazard ratio 0.57, 95% confidence interval 0.40 to 0.81; p = 0.001); and a significantly higher overall (complete or partial) response rate (38% compared with 18%, p < 0.001). Following the predetermined interim analysis, the independent data monitoring committee deemed it unethical to continue with the trial, and recommended that people in the HDD arm should be offered bortezomib. Updated analyses were performed at 15.8 months and 22 months of follow-up.

The manufacturer’s submission provided cost-effectiveness evidence using a semi-Markov state-transition model to compare bortezomib with HDD. The manufacturer did not include other comparators in the model because it contended that there is currently no UK consensus on best practice for the treatment of multiple myeloma at first relapse, because there are no other treatments available that hold a UK marketing authorisation for use at first relapse and because of limitations in the available evidence. Because a high percentage of patients in the HDD arm of the APEX study were allowed to cross over to receive bortezomib, the manufacturer emphasised that the true difference in overall survival between the bortezomib and HDD arms was greater than in the reported results of the APEX study. Because of this, data from the Mayo Observational Study of patients receiving a dexamethasone-containing regimen were used in addition to data from the APEX study in the modelling of both arms of the comparison. The base-case included people at first relapse only, resulting in a point estimate of the incremental cost-effectiveness ratio (ICER) of £31,000 per life year gained.

One-way sensitivity analyses of the key parameters identified in the manufacturer’s model resulted in a range of ICERs from £28,000 to £31,000 per life year gained and showed that the duration of treatment effect was the most influential parameter. Three scenario analyses were presented that focused on:

• A stopping rule by which patients whose disease had not responded to treatment (defined as not reaching complete or partial response using the EBMT criteria) after three cycles would not continue treatment. Reductions in both bortezomib costs and survival benefit (resulting from discontinuing treatment under the stopping rule) were included in the model.
• The proportion of patients entering the model at first and second or subsequent relapse.
• The use of bortezomib in combination with HDD.
• These resulted in ICERs ranging from £28,000 to £40,000 per life year gained.

In an additional analysis produced in response to questions raised in the evidence-review phase, the base-case cost per life year gained of £31,000 was estimated to translate to £38,000 per quality-adjusted life year (QALY). The corresponding figure for a scenario with a three-cycle stopping rule with an ICER of £28,000 per life year gained was £33,500 per QALY gained. The QALYs were derived using utilities of 0.81 for the pre-progression state, and 0.644 after progression, which were based on a published study of patients with previously untreated multiple myeloma. The manufacturer requested that due consideration be given to the assertion that it is more appropriate to measure cost effectiveness in terms of cost per life year gained in patients with multiple myeloma. The manufacturer argued that survival gain is the single most important outcome for people with relapsed multiple myeloma, that there is a lack of robust utility data to compute QALYs for people with relapsed multiple myeloma and that the EuroQoL-5D quality of life (QoL) measure is not sensitive to some important facets of multiple myeloma.

The ERG raised a number of key issues about the manufacturer’s submission.

• Concerns were raised over the generalisability of the data from the Mayo Observational Study, which were used in the economic model, to clinical practice in the NHS in England and Wales.
• The model submitted by the manufacturer may have overestimated the true treatment effect by using the data from the Mayo Observational Study to address the crossover in the APEX study.
• Adverse effects were not included in the economic model, in terms of either reduction in quality of life or increased use of resources.
• The ERG’s review of sensitivity analyses indicated a greater variability in cost-effectiveness estimates than was presented in the manufacturer’s submission. The ERG found that the most influential parameters were the hazard ratio for time to disease progression and the cost of bortezomib.
• The ERG stated that, if patients are treated at a later stage of multiple myeloma, the cost per life year gained increases significantly. The ERG found that when all patients were treated at second relapse, the ICER was £77,000 per life year gained; when all patients were treated at third relapse, the ICER was £107,000 per life year gained.

The manufacturer’s response to the original appraisal consultation document (ACD) included clarification of issues related to the APEX study and a revised economic report that included additional scenarios involving vial sharing.

The manufacturer was further requested to provide cost-effectiveness analyses of a stopping rule after three or four cycles for patients after first relapse. It was asked to provide a definition of response and describe how it expected this to be evaluated in practice, and to give details of a response/rebate scheme that had been proposed to the Department of Health. The manufacturer was asked to provide details of any ways in which the modelling of such a scheme differed from the model previously appraised by the Committee.

In the manufacturer’s proposed Velcade Response Scheme (VRS), ‘responders’ would be defined as patients, after first relapse, whose disease reaches a minimal response or better (measured as at least a 25% reduction in initial serum M-protein) after up to four cycles of bortezomib treatment. Therefore, the manufacturer provided the following:

• Information on a four-cycle stopping rule in addition to the three-cycle stopping rule originally proposed (with and without rebate for non-responders).
• Data reflecting the use of initial serum M-protein to measure level of response to treatment, rather than the European Blood and Marrow Transplant (EBMT) criteria that were used in the APEX RCT and the original model (with and without rebate for non-responders).
• Cost effectiveness analysis when minimal response was included in the definition of ‘responder’ used for the stopping rule and rebate scheme. However, the manufacturer stated that because its model was based on time to progression and overall survival taken from the entire cohort in the bortezomib arm, the model did not allow separate estimation of these outcomes for the minimal responder group. The manufacturer further stated that the minimal responder group of first-relapse patients in the APEX trail was too small to allow any meaningful analysis of time to progression and overall survival for this group alone. The model had not been constructed as a responder model, and specifically reflecting the expected health outcomes of minimal response patients would require a differently structured model.
• An adjustment to the economic analysis to reflect the rebate of bortezomib costs that would be paid by the manufacturer for patients whose disease does not reach the required response criteria. This was in addition to the reduction in bortezomib costs and in survival benefit that had been used to calculate the ICER of £33,500 per QALY gained for a three-cycle stopping rule without rebate (see sections 3.4 and 3.5).

When no rebate was given, but response-based stopping rules were applied, the new modelling presented by the manufacturer resulted in ICERs of £32,000 to £35,600 per QALY gained for bortezomib compared with HDD.

The modelling of the proposed VRS (four-cycle stopping rule using serum M-protein to measure response and inclusion of minimal responders) resulted in an ICER of £27,400 per QALY gained compared with HDD. ICERs for alternative scenarios (three-cycle stopping rule, use of EBMT to measure response and inclusion of complete and partial responders only) were also provided in order to explain differences between the proposed VRS and the basis of the original modelling. For example, a rebate for non-responders to the original scenario of a three-cycle stopping rule and using EBMT to measure response resulted in an ICER of £26,600 per QALY gained compared with HDD. For the same original scenario but using serum M-protein to assess response and including minimal responders, the ICER was £28,000 per QALY gained compared with HDD.

The manufacturer did not provide an ICER for a scenario using a four-cycle stopping rule, serum M-protein to measure response and including complete and partial responders only (as in the original modelling) with a rebate. However, further analysis of the manufacturer’s revised model showed that such a scenario would result in an ICER of £20,700 compared with HDD, and that all other scenarios resulted in higher costs but no further gain in QALYs. For example, the original scenario (three-cycle stopping rule, EBMT, complete and partial responders only) plus a rebate resulted in estimated additional costs of £2130 and a slight loss in QALYs, while the proposed VRS resulted in estimated additional costs of £4690 and no further gain in QALYs.

The manufacturer provided data showing that with a rebate and using serum M-protein, the four-cycle stopping rule increased the incremental QALYs compared with the three-cycle stopping rule while the incremental costs remained almost unchanged.

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

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence 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 discussed the position of bortezomib in the pathway of care for people with multiple myeloma. The Committee understood that the disease is incurable, and was aware that because of the heterogeneous nature of the disease and its clinical course, the treatment appropriate for each patient at any one time may differ. The Committee understood that there are defined treatment pathways for relapsed multiple myeloma and that choice of therapy for an individual patient is influenced by the initial treatment and the response to it, the inherent characteristics of the disease and the patient’s performance status and preferences. The Committee recognised that many drugs used for the initial treatment of multiple myeloma have a limited evidence base for relapsed multiple myeloma and may also be costly. The Committee understood that bortezomib works through a novel mechanism and that the APEX trial has established bortezomib as an evidence-based treatment for relapsed multiple myeloma. It concluded that bortezomib is considered a clinically important treatment for patients with multiple myeloma at both first and subsequent relapse.

The Committee considered the evidence for the clinical effectiveness of bortezomib monotherapy at both first and subsequent relapse. It understood that the only RCT that included patients at first relapse was the APEX study, which compared bortezomib with HDD, and accepted that HDD was an appropriate comparator. The Committee noted that the APEX study was the largest published RCT of the treatment of relapsed multiple myeloma, and that patients in the bortezomib arm experienced statistically significant improvements in rates of overall response (defined as complete and partial response), time to disease progression and overall survival. The Committee understood that there was a greater frequency of peripheral neuropathy and gastrointestinal adverse effects in the bortezomib arm, but that bortezomib was associated with less bone destruction and fewer infections than HDD. The Committee discussed the methods and results of the APEX study and considered the issues raised about the study in the ERG report. Taking all issues into account the Committee concluded that the APEX study constitutes clear evidence that bortezomib monotherapy is more clinically effective than HDD monotherapy.

The Committee discussed the alternatives to the use of bortezomib monotherapy. It heard from experts that thalidomide is considered an important treatment for multiple myeloma and that it is currently being used without a UK marketing authorisation, both as first-line therapy and for relapsed multiple myeloma. The Committee also heard that bortezomib is likely to have enhanced effectiveness in combination with HDD and/or with cytotoxic drugs, and that a number of trials are either in progress or planned to investigate this. The Committee concluded that this additional research will be important to further establish the position of bortezomib in the pathway of care for multiple myeloma. However, because of the current marketing authorisation for bortezomib, the Committee recognised that it was not in a position to make any recommendations about the use of bortezomib in combination with other drugs, including HDD.

The Committee discussed the manufacturer’s assertion that it is more appropriate to consider cost per life year gained rather than cost per QALY as the measure of cost effectiveness in patients with multiple myeloma. The Committee did not accept the premises for this assertion (see section 3.5), concluding that multiple myeloma and its treatments (including the 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 noted that the additional analysis provided by the manufacturer at the request of the ERG, which estimated the impact of health-related QoL, resulted in a base-case ICER of approximately £38,000 per QALY. However, the Committee was concerned that the utilities assumed for patients with relapsed multiple myeloma may not accurately reflect the significant impairments in QoL that this group of patients can experience. The Committee considered that the manufacturer’s base-case ICER of approximately £38,000 per QALY for bortezomib compared with HDD was therefore likely to be an underestimate.

The Committee discussed the scenario presented in the manufacturer’s response to the original ACD in which vial sharing was proposed as a more cost-efficient use of bortezomib. The Committee was aware that the UK marketing authorisation for bortezomib specifies single use of vials of bortezomib immediately after preparation. Additionally, the Committee expressed a number of concerns over the practice of vial sharing. These included issues related to maintenance of best aseptic practice and the practical constraints of patient numbers and geographical locations of myeloma centres. The latter would limit the possibility of several patients being treated in the same session over several cycles, each of which requires four doses of bortezomib at least 72 hours apart. The Committee was not persuaded that vial sharing could be considered either safe or routinely achievable in practice across the NHS.

The Committee considered the scenario in the economic model in which patients whose disease had not responded after three cycles of bortezomib did not receive further treatment with the drug, whereas those who had achieved a partial or complete response received up to eight cycles of treatment. The Committee considered carefully the adjustments required to the modelling: these were the reduction in bortezomib costs and in survival benefit that resulted from discontinuing treatment in people whose multiple myeloma had not responded after three cycles. In this scenario, the ICER for bortezomib compared with HDD (presented in the manufacturer’s comments on the original ACD) was £33,500 per QALY gained. The Committee further noted that all subsequent analyses presented by the manufacturer that did not include a rebate resulted in ICERs of £32,000 to £35,600 per QALY gained. Because of its concerns described in sections 4.6 and 4.7, the Committee considered that these ICERs were likely to be underestimates. The Committee heard from clinical experts that the response to treatment can be assessed in an appropriate time frame to allow implementation of a stopping rule and that this approach is current practice in the UK. The Committee accepted therefore that such a stopping rule is feasible and that following this approach improves the cost-effectiveness of bortezomib compared with a situation in which no such stopping rule is used.

The Committee discussed the method used to measure response to bortezomib treatment. It understood that the EBMT measurements used in the APEX RCT were considered the ‘gold standard’ for definition of response. However, this full set of measurements is rarely used in clinical practice; instead, the measurement of serum M-protein (which is a component of the EBMT measurements) is routinely used. The Committee heard from the clinical experts that serum M-protein is a specific marker for tumour load in an individual patient and therefore an appropriate measure of disease response in most patients. In addition, serum M-protein showed a strong correlation with the full EBMT criteria used in the APEX RCT. The Committee appreciated that although changes in the concentration of serum M-protein are a good measure of tumour response in an individual patient, they may not be a full surrogate for the effect of treatment on overall life expectancy. The Committee also understood that 10–15% of patients do not have measurable serum M-protein, in which case urinary free light chain (Bence Jones protein) is measured. The Committee accepted that for bortezomib to be used with a stopping rule in the NHS in England and Wales, the appropriate measure for determining response would be serum M-protein, except for a minority of patients for whom urinary free light chain would be the appropriate measure. The Committee noted that the ICER using serum M protein without a rebate would be £32,000 per QALY gained compared with HDD with a three cycle stopping rule, and £32,300 with a four cycle stopping rule. However, after considering the concerns about the modelling (section 4.6. and 4.7), the Committee agreed that this figure was still an underestimate and the use of bortezomib in this situation could not be considered an effective use of NHS resources.

The Committee discussed the number of cycles of treatment after which a stopping rule could be appropriately implemented. It inferred from a revised model provided by the manufacturer that providing a four-cycle stopping rule would be a cost-effective way of increasing the expected health gains for patients if there were a rebate for non-responders. The Committee also noted that without a rebate the ICER would be £32,300 per QALY gained compared with HDD. The Committee heard that clinicians and patients would value the option to continue treatment for up to four cycles. Furthermore, it understood that implementing a stopping rule after four rather than three cycles might reduce the proportion of people whose disease might otherwise have gone on to respond to more cycles of treatment. The Committee therefore concluded that were a rebate to be given, clinicians and patients should have the option to continue for up to four cycles of bortezomib treatment. At that stage a decision should be made to stop or continue treatment dependant on the serum M-protein response.

The Committee discussed how a ‘responder’ should be defined if a stopping rule were implemented. The Committee noted that overall responders were defined in the APEX RCT as having a 50% or more reduction in serum M-protein from baseline (that is, a complete or partial response) and that the original modelling of a stopping rule was based on continuing treatment beyond three cycles in complete and partial responders only (see section 4.9). The Committee further noted that the VRS proposed by the manufacturer included an additional group of people whose disease demonstrates a minimal response (that is, a 25–49% reduction in serum M-protein). The Committee heard from clinical specialists that a proportion of patients whose disease demonstrates an initial minimal response may go on to have a complete or partial response, and therefore it would be desirable to continue treatment in minimal responders beyond three or four cycles. It further heard from clinical specialists that there is little evidence regarding the association between prognosis (life expectancy) and degree of the initial M-protein response (minimal, partial or complete), but that patients with a complete response tend to have a better prognosis. The Committee was concerned that no evidence was available on outcomes such as time to progression and overall survival in people whose disease demonstrated only minimal response compared with those whose disease demonstrated complete or partial response. The Committee concluded that in the absence of evidence to show that outcomes are comparable for people with different degrees of initial M-protein response a decision to include those in the rebate scheme whose disease demonstrated a minimal response could not be supported.

The Committee considered that the most cost-effective approach was to apply a stopping rule after four cycles, discontinue and rebate treatment in people whose disease has demonstrated less than complete or partial response and continue treatment only in those whose disease responds at least partially. This approach resulted in an ICER of £20,700 per QALY. All other options carried a higher cost and no increase in QALYs and were therefore economically dominated. The Committee agreed that the overall concerns about the modelling methodology were still valid (see 4.6 and 4.7). However, it considered that, even if the ICER of £20,700 per QALY were an underestimate, bortezomib monotherapy when given under these circumstances is likely to be a cost effective use of NHS resources.

The Committee understood that the rebate scheme proposed by the manufacturer included people with complete, partial and minimal response. It noted that this resulted in an ICER compared with HDD of £27,400 per QALY (with a four-cycle stopping rule using serum M-protein to measure response). The Committee did not consider that sufficient clinical evidence was provided for patients whose disease demonstrated a minimal response. Furthermore, the Committee concluded that the ICER for the minimal response group alone was likely to be much higher than for partial or complete responders. The Committee therefore concluded that the modelling data provided by the manufacturer indicated that continuing treatment beyond four cycles for these patients was not likely to approach an acceptable level of cost effectiveness when compared with the scenario in which treatment was only continued in complete or partial responders.

The Committee concluded that bortezomib monotherapy for the treatment of relapsed multiple myeloma is clinically effective compared with HDD monotherapy, but that it has not been shown to be cost effective. However, based on the evidence available, the Committee concluded that bortezomib monotherapy can be recommended as an effective use of NHS resources when treatment is continued beyond four cycles only in patients whose disease has demonstrated a complete or partial response, as measured by initial serum M-protein, and if the manufacturer rebates the full cost of bortezomib for patients whose disease has not demonstrated a complete or partial response after four cycles. The Committee further concluded that insufficient evidence had been provided for it to be persuaded of the cost effectiveness of continuing treatment beyond four cycles in patients with a minimal response, as in the VRS proposed by the manufacturer.

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.

'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.

NICE has developed tools to help organisations implement this guidance (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 which support this locally.
• Audit criteria to monitor local practice.

Proposed recommendations for further research

The Committee considered that further research into the effectiveness of bortezomib for the treatment of relapsed multiple myeloma is needed. Such studies should include:

• comparisons with other agents that are currently used in clinical practice in the NHS in England and Wales
• a robust design, adequate sample size and appropriate statistical analysis
• assessment of long-term prognosis, for which observational studies would be appropriate
• measurement of quality of life in patients with relapsed multiple myeloma, including the effect of treatment and adverse events
• a consideration of subgroups of patients in whom bortezomib might be particularly effective.

Related NICE guidance

NICE is in the process of producing the following guidance.

Erythropoietin for anaemia induced by cancer treatment. NICE technology appraisal. (publication date to be confirmed).

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.

It is proposed that the guidance on this technology is considered for review in September 2010. The Institute would particularly welcome comment on this proposed date.

David Barnett
Chair, Appraisal Committee
May 2007

Appendix A. Appraisal Committee members and NICE project team

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 three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and a vice chair. 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.

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Jeff Aronson
Reader in Clinical Pharmacology, Radcliffe Infirmary

Dr Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

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

Professor Stirling Bryan
Director of the Health Economics Facility, University of Birmingham

Mr Brian Buckley
Vice Chairman, InContact

Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine

Professor Mike Campbell
Statistician, University of Sheffield

Dr Mark Chakravarty
Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals (UK)

Dr Peter I Clark
Consultant Medical Oncologist, Clatterbridge Centre for Oncology NHS Trust, Merseyside

Dr Mike Davies
Consultant Physician, University Department of Medicine & Metabolism, Manchester Royal Infirmary

Mr Richard Devereaux-Phillips
Public Affairs Manager, Medtronic

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Professor Christopher Fowler
Professor of Surgical Education, University of London

Dr Fergus Gleeson
Consultant Radiologist, The Churchill Hospital, Oxford

Ms Sally Gooch
Former Director of Nursing & Workforce Development, Mid Essex Hospital Services NHS Trust

Mrs Barbara Greggains
Lay member

Mr Sanjay Gupta
Stroke Services Manager, Basildon and Thurrock University Hospitals
NHS Trust

Professor Philip Home
Professor of Diabetes Medicine, University of Newcastle

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Professor Peter Jones
Professor of Statistics and Dean, Faculty of Natural Sciences, Keele University

Dr Mike Laker
Medical Director, Newcastle Hospitals NHS Trust

Dr George Levvy
Lay member

Ms Rachel Lewis
Nurse Advisor to the Department of Health

Mr Terence Lewis
Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Ruairidh Milne
Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology Assessment , University of Southampton

Dr Neil Milner
General Medical Practitioner, Sheffield

Dr Rubin Minhas
General Practitioner and CHD Clinical Lead, Medway PCT

Dr John Pounsford
Consultant Physician, North Bristol NHS Trust

Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital

Dr Christa Roberts
UK Country Manager, Abbott Vascular

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

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

Professor Mark Sculpher
Professor of Health Economics, University of York

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, Adur, Arun and Worthing PCT

Mr Cliff Snelling
Lay member

Dr Ken Stein
Senior Lecturer in Public Health, Peninsula Medical School, University of Exeter

Professor Andrew Stevens
Professor of Public Health, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter & Plymouth.

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.

Helen Chung
Technical Lead

Elisabeth George
Technical Adviser

Reetan Patel
Project Manager

The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessment Centre:

• Green C, Bryant J, Takeda A et al. Bortezomib for the treatment of multiple myeloma patients (April 2006)

The following organisations accepted the invitation to participate in this appraisal. 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 gave their expert views on bortezomib monotherapy for relapsed multiple myeloma by providing a written statement to the Committee. Organisations listed in I and II have the opportunity to appeal against the final appraisal determination.

Manufacturer/sponsor:

• Janssen-Cilag

Professional/specialist and patient/carer groups:

• Cancerbackup
• International Myeloma Foundation (UK)
• Leukaemia Care Society
• Long-Term Medical Conditions Alliance
• Macmillan Cancer Relief
• Marie Curie Cancer Care
• National Cancer Alliance
• National Council for Palliative Care
• Tenovus Cancer Information Centre
• Association of Cancer Physicians
• Association of Surgeons of Great Britain and Ireland
• British Association of Surgical Oncology
• British Oncological Association
• British Oncology Pharmacy Association (BOPA)
• British Psychosocial Oncology Society
• British Society for Haematology
• Cancer Research UK
• Community Practitioners' and Health Visitors’ Association
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians of Edinburgh
• Royal College of Physicians' Medical Oncology Joint Special Committee
• Royal College of Radiologists
• Royal College of Surgeons
• Royal Pharmaceutical Society
• UK Myeloma Forum
• Department of Health
• Sedgefield PCT
• Southend PCT
• Welsh Assembly Government

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

• Board of Community Health Councils in Wales
• British National Formulary
• Medicines and Healthcare products Regulatory Agency (MHRA)
• National Public Health Service for Wales
• National Coordinating Centre for Health Technology Assessment (NCCHTA)
• NHS Confederation
• NHS Purchasing and Supplies Agency
• NHS Quality Improvement Scotland
• Baxter Healthcare Ltd (cyclophosphamide)
• Bristol-Myers Squibb Pharmaceuticals (carmustine)
• Clonmel Healthcare Ltd (vincristine)
• GlaxoSmithKline (melphalan)
• Mayne Pharma (doxorubicin, vincristine)
• Medac (UK) (doxorubicin)
• Pfizer (cyclophosphamide, doxorubicin)
• Pharmion (thalidomide)
• Schering-Plough (interferon alfa-2b)
• Teva Pharmaceuticals (doxorubicin)
• National Collaborating Centre for Cancer
• Institute of Cancer Research
• Haemato-oncology Department, King's College Hospital
• Leukaemia Research Fund
• MRC Clinical Trials Unit
• National Cancer Research Institute
• Scottish Medicine Consortium

The following individuals were selected from clinical specialist and patient advocate nominations from non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on bortezomib for the treatment of multiple myeloma by providing written or oral evidence to the Committee. They are invited to comment on the ACD.

• Professor Gareth Morgan, Professor of Haematology and Head of Clinical Unit, nominated by the International Myeloma Foundation and the Institute of Cancer Research – clinical specialist
• Dr Graham Jackson, Consultant Haematologist, nominated by the British Committee for Standards in Haematology – clinical specialist
• Dr Stephen A Schey, Chair, UK Myeloma Forum – clinical specialist (present at the Appraisal Committee meeting on behalf of Dr Graham Jackson, who was unable to attend)
• Mr Brian Jago, nominated by the International Myeloma Foundation – patient expert
• Mr Eric Low, Chief Executive, International Myeloma Foundation (UK) – patient expert
• Dr Jamie Cavenagh, Consultant Haematologist nominated by the British Society for Haematology – clinical specialist (present at FAD meeting)