The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pazopanib, having considered evidence on the nature of advanced renal cell carcinoma and the value placed on the benefits of pazopanib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the patient experts and clinical specialists that advanced renal cell carcinoma is a relatively rare cancer and noted the views of patient experts and clinical specialists on the severity of the disease. The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE (see NICE's technology appraisal guidance on sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma). The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity. These include hypertension, fatigue, diarrhoea and hand-foot syndrome. The patient experts highlighted that hand-foot syndrome is frequently intolerable. The clinical specialists stated that patients receiving treatment with sunitinib require a 2-week rest period as part of the treatment cycle, because patients are not able to tolerate sunitinib after 4 weeks. In addition, for a number of patients the dose of sunitinib has to be adjusted to maintain tolerability. The clinical specialists considered that the 2-week rest period and dose adjustment may reduce the benefits gained from sunitinib. The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib.
The Committee considered the evidence on the clinical effectiveness of pazopanib presented in the manufacturer's submission and the ERG report. The Committee noted that the VEG105192 trial compared pazopanib with placebo and the trial was generally of acceptable quality. It was aware of the ERG's concerns that the trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales. The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8 months (10.8 versus 2.9 months [Independent Review Committee assessment, HR 0.36, 95% CI 0.24 to 0.55]).
The Committee then discussed the estimates of overall survival gain obtained from the VEG105192 trial. The Committee acknowledged that the estimates of overall survival for pazopanib versus placebo according to the intention-to-treat analysis (22.9 versus 23.5 months; HR 1.01, 95% CI 0.72 to 1.42) had been confounded by crossover and that 51% of patients who had received placebo crossed over to receive pazopanib after disease progression. The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.
The Committee discussed the manufacturer's approach to estimating overall survival, adjusting for crossover. It acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available to adjust for crossover, including an analysis of survival in patients who did not receive post-study cancer therapy. The Committee noted the hazard ratios for overall survival varied from 0.30, based on patients who did not receive post-study cancer therapy, to 0.642, based on the IPCW method, and that these had wide confidence intervals. The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee noted the ERG's comments suggesting that this approach was reasonable and it accepted the use of this hazard ratio in the indirect comparison. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. The Committee noted that the pazopanib trial was only conducted with patients who had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care.
The Committee then discussed the manufacturer's indirect comparison, used to estimate progression-free survival and overall survival for pazopanib compared with sunitinib, interferon-alpha and best supportive care. It noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-alpha (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009; 11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643). The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon-alpha or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide. The Committee heard from the clinical specialists that, in their opinion, the estimates obtained for progression-free survival (with no need for adjustment for crossover) supported the overall survival estimates. The Committee noted that the results of a direct comparison would be available in 2012 when an ongoing head-to-head study of pazopanib versus sunitinib (the COMPARZ trial) was complete, but until then it was reasonable to consider that pazopanib was as clinically effective as sunitinib. The Committee concluded that pazopanib is likely to be more clinically effective than interferon-alpha and is probably comparable in its effectiveness to sunitinib.
The Committee heard from the clinical specialists that the evidence presented by the manufacturer suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome. It noted that in the VEG105192 trial, 1.9% of patients receiving pazopanib had hand-foot syndrome (all grades) compared with 0% receiving placebo, while in the study by Motzer et al. (2009), 29% of patients receiving sunitinib) experienced hand-foot syndrome (all grades) compared with 3% of patients receiving interferon-alpha. The Committee noted that grade 3 or 4 hand-foot syndrome occurred in 0% of patients receiving either pazopanib or placebo in the VEG105192 study, while 9% of patients receiving sunitinib in the study by Motzer et al. (2009) had grade 3 or 4 hand-foot syndrome compared with 1% of patients receiving interferon-alpha. The Committee discussed the evidence provided by the manufacturer on the adverse events associated with pazopanib. The Committee noted that the numbers of grade 3 and 4 adverse events were similar between the pazopanib and placebo groups in the VEG105192 trial. The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.
The Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model.
The Committee discussed the cost-effectiveness data submitted by the manufacturer for pazopanib compared with sunitinib, interferon-alpha and best supportive care. The Committee discussed the key parameters used in the model. It agreed that the cost-effectiveness estimates derived from the hazard ratio estimate for overall survival for pazopanib versus placebo, obtained using the unadjusted weighted RPSFT analysis (hazard ratio 0.501), were reasonable (see section 4.6). The Committee then considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee noted that these utility values were lower than those used in NICE's technology appraisal guidance on sunitinib but that the difference of 0.11 between these values was greater. The Committee agreed that this difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer.
The Committee was aware that a 2-part patient access scheme has been agreed by the Department of Health (see section 2.3). The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme. The Committee noted that when the manufacturer had presented cost-effectiveness estimates for part A of the patient access scheme, it had also provided additional cost-effectiveness results that used alternative methods of adjusting for crossover in the VEG105192 trial. It acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-alpha, and from £1,790 to £5,330 per QALY gained for pazopanib versus sunitinib. Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib compared with best supportive care, interferon-alpha and sunitinib of £33,000, £38,900 and £1,790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.
The Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon-alpha when applying the supplementary advice on appraising life extending, end of life treatments. The Committee was aware that only the ICERs for pazopanib compared with best supportive care and interferon-alpha in relation to part A of the patient access scheme were higher than the range normally considered a cost-effective use of NHS resources.
The Committee next considered whether pazopanib fulfilled the criteria for an end of life treatment in the context of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
When taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee was aware from discussion with the clinical specialists that in England and Wales the total number of people that would be eligible for treatment with pazopanib was less than 4000. The Committee heard from the clinical specialist that the life expectancy for people with advanced renal cell carcinoma receiving best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 5 months. The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased overall survival by more than 3 months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-alpha. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.
The Committee considered the central estimate of the ICER (£38,900 per QALY gained) and the robustness and uncertainty of the ICER. The Committee was aware of exploratory net benefit analyses carried out by the ERG which indicated that pazopanib would be considered cost effective at willingness to pay thresholds between £35,000 and £50,000 per QALY gained. The Committee considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was within the range considered acceptable for an end of life treatment. Therefore, the Committee concluded that pazopanib should be recommended as a first-line treatment option for patients with advanced renal cell carcinoma who have not received prior cytokine therapy and have an ECOG performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5% discount on the list price.
The Committee considered part B of the patient access scheme which linked a specific future rebate to the outcome of the COMPARZ trial. The Committee accepted that the approach taken in part B of the patient access scheme, the details of which are provided 'commercially in confidence', was reasonable and that the ICERs were acceptable. The Committee concluded that pazopanib should be recommended as indicated above (see section 4.14) and if the manufacturer provides a future rebate linked to the outcome of the COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.
The Committee considered whether its recommendation was associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.