On May 11, 2012, the UK National Institute for Health and Clinical Excellence (NICE) published guidance on cabazitaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.
Cabazitaxel was not considered a cost-effective use of National Health Service (NHS) resources. Cabazitaxel was appraised under the Single Technology Appraisal process.
The manufacturer (Sanofi) submitted clinical evidence and a health economic model, 2 which was critiqued by an independent Evidence Review Group (ERG), based at the School of Health and Related Research (University of Sheffield, Sheffield, UK).
An independent Appraisal Committee consisting of NHS health professionals, lay members, industry representatives, health economists and statisticians met twice to develop guidance on cabazitaxel. Clinicians and patient experts attended the first meeting, and the manufacturer attended both meetings.
The clinical evidence was based on one randomised controlled trial (TROPIC) in which patients were randomised to receive either cabazitaxel or mitoxantrone, in addition to prednisone or prednisolone. 4 TROPIC enrolled 755 men from 26 countries.
The published analysis reported a statistically significant improvement in median overall survival with cabazitaxel compared with mitoxantrone (15·1 months vs 12·7 months; pCabazitaxel was associated with a statistically significant improvement in median progressionfree survival (with progression defined as a rise in prostate-specific antigen concentration, tumour progression, pain progression, or death; 2·8 months with cabazitaxel, 1·4 months with mitoxantrone. The most common adverse events associated with cabazitaxel were neutropenia, its complications, and gastrointestinal toxicity.
The manufacturer submitted a cohort Markov model that included three health states: stable disease, progressive disease, and death.
The perspective was that of the NHS and personal social services. For the base-case analysis, the manufacturer used survival data from a post-hoc subgroup of TROPIC consisting of European patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had previously received 225 mg/m2 or more of docetaxel.
The manufacturer calculated transition probabilities from stable to progressive disease using progression-free survival, and from stable or progressive disease to death using data for overall survival, both estimated from Kaplan-Meier curves from TROPIC up to the point at which a small number of patients remained in the trial. The manufacturer defined this point as the time when no patient had an event over four consecutive cycles of treatment. After this time point, the manufacturer calculated transition probabilities from fitted parametric curves.
Data for health-related quality of life were not collected in TROPIC. In the model, the manufacturer incorporated a utility value for stable disease from an interim analysis of an ongoing single-arm study collecting EQ-5D data from UK patients receiving cabazitaxel for metastatic prostate cancer. The utility of the progressive disease state was calculated by decreasing the utility value of stable disease by 0·07 (derived from Sullivan and colleagues).
The manufacturer’s base-case model estimated an incremental cost-effectiveness ratio (ICER) of £74900 per quality-adjusted life-year (QALY) gained. The ERG considered that the manufacturer’s choice of the basecase population was not appropriate because there was no reason why results from patients recruited at TROPIC’s European centres would differ from those recruited elsewhere. The ERG considered that the appropriate population for this appraisal should include all patients who received 225 mg/m2 or more of docetaxel and who had an ECOG performance score of 0 or 1.
The ERG was not convinced by the manufacturer’s modelling of Kaplan–Meier data, because it was specific to the trial population and less generalisable to other populations. The ERG preferred parametric models, which assume an underlying trend and minimise the effect of chance observations that could occur in a specific clinical trial. Using survival data specific to its preferred population, using parametric curves, and making other minor amendments, the ERG estimated an ICER of £89476 per QALY gained.
The key drivers of the cost-effectiveness analysis were the utility values used for stable and progressive disease. The Committee had concerns about the manufacturer’s base-case population, the methods used for extrapolating survival data, and the utility value used for the stable disease state, which was similar to that observed in the age-matched general population and which the Committee agreed was implausible.
The Committee concluded that a difference in utility of 0·07 between stable and progressive disease underestimated the difference in quality of life because patients with progressive disease generally feel less well and have a worse quality of life than do those with stable disease. The Committee considered the ICERs in the context of NICE’s supplementary advice for the appraisal of treatments that might give patients with a short life expectancy at least 3 more months of life, and for which the licensed indications affect a small proportion of patients.
The Committee agreed that because people in trials of metastatic prostate cancer randomly assigned to best supportive care have a life expectancy of less than 15 months, and because fewer than 2000 people are estimated to receive second-line chemotherapy, two of the criteria were fulfilled. In relation to the modelled gain in survival, the Committee noted that it was dependent on the method of extrapolation, which was uncertain.
The Committee concluded at its first meeting that, in view of this uncertainty, it could not consider all end-of-life criteria to be met. On the basis of evidence reviewed at its first meeting, in September, 2011, the Appraisal Committee concluded that cabazitaxel would not be a costeffective use of NHS resources and issued an appraisal consultation document. During the subsequent consultation period, the manufacturer presented a revised base-case model that included an updated utility value for the stable disease state from a second interim analysis of its ongoing single arm study and that, using the Committee’s preferred population, estimated an ICER of £86008 per QALY gained.
The manufacturer also used a number of different mathematical approaches to extrapolate trial data to model the gain in overall survival, all of which resulted in an extension of life of 3 months or greater.
At its second meeting, in November, 2011, the Appraisal Committee considered all responses to its preliminary guidance 7 received from the manufacturer, clinical organisations, and patient groups, as well as additional exploratory analyses of overall survival data submitted by the manufacturer.
The Committee agreed that a mean improvement of more than 3 months in overall survival had been shown robustly and that all end-of-life criteria were met. The Committee concluded that of the manufacturer’s proposed methods of extrapolating survival data, the piecewise analysis was the most appropriate, which resulted in an ICER of £87 518 per QALY gained for the Committee’s preferred population.
The Committee agreed that changes to the model that would likely further increase the ICER included: a lower utility value for stable disease, a larger difference in quality of life between stable and progressive disease, costs for hospital admission in all patients with febrile neutropenia, and fitting of the curve for mitoxantrone using a piecewise approach. The Committee agreed that cabazitaxel was an effective, lifeextending treatment, but that the most plausible ICER exceeded £87 500 per QALY gained.
Although the appraisal met the end-of-life criteria, the Committee considered that the additional weight needed to bring the ICER into the range regarded as a costeffective use of NHS resources was too great, and that cabazitaxel could not be recommended as an appropriate use of NHS resources.
The manufacturer appealed against the final appraisal determination. 8 The appeal points related to the Committee’s understanding and interpretation of the utility values provided by the manufacturer.
The Appeal Panel considered all appeal points at a hearing in March, 2012, and concluded that the process by which the Committee involves manufacturers at the meetings was followed correctly, and that the Appraisal Committee had not failed to understand the nature of interim data.
The Appeal Panel concluded that the recommendations were not affected by a difference of opinion between the Appraisal Committee and manufacturer and dismissed the appeal on all grounds.
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