4 Consideration of the evidence
4.1 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.
4.2 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 it was aware that because of the heterogeneous nature of the disease and its clinical course, the treatment appropriate for each patient at different times during the course of the disease may vary. 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 has a novel mechanism of action 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.
4.3 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. The Committee accepted that HDD was an appropriate comparator. It 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 time to disease progression and overall survival. The Committee also noted that 'overall response' was defined in the APEX trial as either complete or partial response and that patients in the bortezomib arm experienced statistically significant improvements in rates of overall response. The Committee understood from the clinical specialists 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 for the treatment of relapsed multiple myeloma.
4.4 The Committee discussed the alternatives to the use of bortezomib monotherapy for the treatment of relapsed multiple myeloma. It heard from clinical specialists 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 establish further the position of bortezomib in the pathway of care for multiple myeloma. However, because the current marketing authorisation for bortezomib is for its use as monotherapy, 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.
4.5 The Committee considered the cost effectiveness of bortezomib compared with HDD. The Committee understood that it was difficult to include other comparators in the model because of lack of evidence. However, it acknowledged that this contributed to the uncertainty in the assessment of cost effectiveness. The Committee discussed the base case and the sensitivity and scenario analyses of the manufacturer's economic model. It noted that clinical specialists have suggested several approaches for using bortezomib more cost effectively in the treatment of relapsed multiple myeloma, including its use at first relapse only. The Committee noted that the base case presented in the manufacturer's model, which included patients at first relapse only, resulted in an ICER of £31,000 per life year gained. It further noted from the ERG report that treating patients at second relapse only or at third relapse only would result in markedly increased ICERs of £77,000 and £107,000 per life year gained, respectively. The Committee therefore accepted that bortezomib monotherapy is not cost effective when used at second or subsequent relapse.
4.6 The Committee discussed the manufacturer's view 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 this view (see section 3.5). It concluded 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. The Committee was concerned that the utilities assumed for patients with relapsed multiple myeloma may not accurately reflect the significant impairments in QoL that these patients can experience. Therefore, the Committee considered that the manufacturer's base-case ICER of approximately £38,000 per QALY for bortezomib compared with HDD was likely to be an underestimate.
4.7 The Committee considered the ERG's evaluation of the way in which survival was modelled in the manufacturer's submission. The Committee agreed that because of the degree of crossover that occurred between the arms of the APEX trial it was necessary and justified to adjust the APEX data. However, the Committee was concerned that there was uncertainty about the impact of using data from the Mayo Observational Study to make these adjustments in the model and that the modelling approach may have overestimated the effect of bortezomib treatment in the long term (see section 3.6). The Committee concurred with the ERG that the data used may predict a more severe disease progression profile than would be expected in a hypothetical cohort of patients treated with HDD at first relapse. It noted the manufacturer's assertion that the inclusion of the Mayo Observational Study data affected only post-progression survival. However, it did not agree with this view because the Mayo data had been used throughout the model and would therefore influence the modelling of both time to progression and overall survival for both bortezomib and HDD arms. Therefore, the Committee concluded that there was a high probability that manufacturer's base-case ICER for bortezomib compared with HDD was an underestimate.
4.8 The Committee discussed the scenario presented in the manufacturer's response to the first appraisal consultation document issued for this technology appraisal 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 the 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.
4.9 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 noted the adjustments required to the modelling, namely 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. The Committee heard from clinical specialists 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 therefore accepted 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 definition and evaluation of response, the number of treatment cycles used in the stopping rule, and the corresponding estimates of cost effectiveness.
4.10 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 specialists that serum M protein is a specific marker for tumour load in an individual patient, so it is 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 fully reflect 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, the appropriate measure for determining response would be serum M protein, except for those patients in whom M protein is not measurable and for whom a complete or partial response could be defined as a reduction of at least 90% in urinary free light chains.
4.11 The Committee discussed how a 'responder' should be defined if a stopping rule were implemented. The Committee noted that overall a response was defined in the APEX RCT as a reduction in serum M protein of 50% or more from baseline (that is, a complete or partial response). It also noted 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 noted that the Velcade Response Scheme proposed by the manufacturer included an additional group of people whose disease demonstrated 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 demonstrated an initial minimal response may go on to have a complete or partial response, so it would be desirable to continue treatment in minimal responders beyond three or four cycles. The Committee was concerned that minimal responders would not experience outcomes similar to complete or partial responders. The manufacturer provided the Committee with confidential time-to-progression data for minimal responders separately from non-responders and from complete and partial responders according to levels of response at the fourth cycle of treatment. The Committee considered that the variability in this analysis was such that the true clinical outcomes experienced by minimal responders were uncertain.
4.12 The Committee discussed the number of cycles of treatment after which it would be appropriate to apply a stopping rule. The Committee understood that implementing a stopping rule after four rather than three cycles might reduce the proportion of people in whom treatment would be stopped but whose disease might otherwise have gone on to respond after further treatment. It therefore understood that clinicians and patients would value the option to continue treatment for up to four cycles. However, the Committee noted that the analysis in the manufacturer's submission showed that no reduction in risk of progression was observed after three cycles. The Committee agreed in principle that it might be desirable that clinicians and patients have the option to continue bortezomib treatment for up to four cycles. However, it concluded that the number of cycles prior to a stopping rule would need to be determined by considering the incremental cost effectiveness of adding an additional treatment cycles beyond three cycles.
4.13 The Committee discussed the ICERs for the use of bortezomib at first relapse if a stopping rule were implemented. It noted that the ICER for bortezomib compared with HDD ranged from £32,000 to £35,600 per QALY. The Committee noted that moving from three to four cycles or adding the minimal responders increased the ICERs. However, when initial M protein – rather than EBMT criteria – was used as the method of assessing responders, the ICERs decreased. The Committee noted that the manufacturer did not provide ICERs for a scenario in which serum M protein was used and only complete and partial responders were included (as in the original modelling). However, it noted that these ICERs could be established from the manufacturer's revised model and were in the range £26,500 to £29,000 per QALY gained for a three- and four‑cycle stopping rule, respectively. The Committee was concerned that all these ICERs may be underestimates of the most plausible ICER. For the original analysis, the Committee was provided with additional confidential data by the manufacturer that estimated the ICER without adjustment for the crossover effect in the APEX trial. Although the Committee accepted that cross-over should be accounted for in the modelling, this analysis indicated the likely upper boundary in the cost effectiveness. The Committee considered the innovative nature of bortezomib and the severity of disease and the alternative treatment options for people at this stage of the disease. However, it concluded that, on the basis of the evidence currently available, it was not in a position to recommend bortezomib without a rebate scheme.
4.14 The Committee considered the scenario in which the manufacturer would rebate the cost of bortezomib for patients whose disease had not responded after a specified number cycles of bortezomib. The Committee noted the additional adjustment required to the modelling, namely the additional reduction in bortezomib costs achieved by the rebate. The Committee noted the concerns expressed by some consultees about the implementation of a rebate scheme, in particular that the administration of the scheme could be time and resource-intensive. It noted that the incremental cost to the NHS of implementing the scheme, including the staff time required to complete even a simple claim form, had not been included in the economic modelling. In considering these concerns, the Committee took account of the advice from the Department of Health that it considered that the scheme would not impose a disproportionate organisational burden on NHS organisations in England. The Committee took the view that the costs likely to be associated with the capture of the simple data needed to trigger an application to the manufacturer for a rebate, for the numbers of patients involved, would be substantially outweighed by the value of the rebate, and do not alter its conclusion on cost effectiveness.
4.15 The Committee noted that the most cost-effective approach to using bortezomib was to treat patients at first relapse, to measure serum M protein after four cycles, to discontinue and rebate treatment in people whose disease had responded less than partially, and to continue treatment only in those whose disease had responded at least partially. This approach resulted in an ICER of £20,700 per QALY. All other options, particularly the addition of continuing treatment in the minimal responder group (as in the manufacturer's original Velcade Response scheme), carried a higher cost and no increase in QALYs. This implied that the incremental cost per QALY gained for the addition of the minimal responder group would be very high. The Committee reflected upon its overall concerns about the modelling methodology (see sections 4.6 and 4.7) and about the administration costs of the rebate scheme (see section 4.14). However, it agreed that, even if the ICER of £20,700 per QALY were an underestimate, it was likely that bortezomib monotherapy when given under these circumstances would be a cost-effective use of NHS resources within the range that the Committee had previously accepted.