3 The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and a review of this submission by the Evidence Review Group (ERG; appendix B). The Institute and the ERG sought clarification on aspects of the manufacturer submission.
3.1 The manufacturer approached the decision problem by comparing pemetrexed with docetaxel and with best supportive care (BSC). The population under consideration had locally advanced or metastatic NSCLC and had relapsed after previous chemotherapy. The primary outcome measure outlined in the decision problem was overall survival. Secondary outcome measures included time to documented progression of disease, progression-free survival, duration of tumour response, quality of life and the incidence of adverse events.
3.2 The manufacturer's submission presented evidence on the clinical effectiveness of pemetrexed from one open-label randomised controlled trial (RCT) that compared pemetrexed with docetaxel (the JMEI trial). Final analysis showed no significant difference in median overall survival; 8.3 months with pemetrexed versus 7.9 months with docetaxel (p = 0.93 for ITT superiority). The hazard ratio [HR] was 0.99 (95% confidence interval [CI], 0.82 to 1.20) with a non-inferiority p-value of 0.226 for testing HR of <1.11. This means that the non-inferiority criteria were not met using the fixed margin method. Prior to un-blinding of the trial data, another (secondary) non-inferiority criterion was defined in the analysis plan, whereby non-inferiority was defined by HR < 1.21. This 'percentage efficacy method' was used to determine whether pemetrexed retained at least 50% of the assumed efficacy of docetaxel over BSC, using docetaxel efficacy data from an RCT of docetaxel compared with BSC (HR 0.56; 95% CI, 0.35 to 0.88). The estimate of the percentage of survival benefit (docetaxel over BSC) retained by pemetrexed was 102% (95% CI, 52% to 157%) with a non-inferiority p-value of 0.047 for testing 50% retention.
3.3 Regarding adverse effects reported in the RCT, compared with docetaxel, pemetrexed was associated with fewer grade 3 and 4 haematological toxicities; less neutropenia (p < 0.001), febrile neutropenia (p < 0.001) and neutropenia with infection (p = 0.004). There were fewer hospitalisations for neutropenic fever (n= 4 for pemetrexed and n = 35 for docetaxel) (p < 0.001) and reduced use of granulocyte colony-stimulating factor (G-CSF; n = 7 for pemetrexed versus n = 53 for docetaxel p < 0.001) in the pemetrexed group. No differences between the groups were found for anaemia (or number of patients receiving red blood cell transfusions or erythropoietin) or thrombocytopenia. There were also no differences for 10 of the 12 non-haematological toxicities reported, but the docetaxel group had more alopecia (p < 0.001) and a higher percentage of the pemetrexed group had raised levels of alanine transferase, an indicator of impaired liver function (p = 0.028). No statistically significant differences were reported for rate of hospitalisations for any other drug-related adverse event.
3.4 The RCT reported no differences between treatments in disease-specific quality of life, measured using the Lung Cancer Symptom Scale, which includes six symptoms (anorexia, fatigue, cough, dyspnoea, haemoptysis and pain).
3.5 The manufacturer's submission presented an economic analysis based on a Markov model with a 3-year time horizon. The estimates of efficacy used in the economic model were based on an unadjusted indirect comparison of absolute overall survival in which weighted estimates of absolute survival were pooled from single arms of different trials in published literature. The median absolute overall survival was estimated to be 8.3 months for pemetrexed (95% CI, 6.9 to 9.7) based on the results of the JMEI trial, 7.0 months for docetaxel (95% CI, 5.6 to 9.9) based on the pooled results of seven trials, and 4.9 months for BSC (95% CI, 4.2 to 5.5) based on the pooled results of three trials. When these absolute overall survival parameters were put into the economic model, the predicted mean life years gained were estimated to be 11.0 months for pemetrexed, 8.8 months for docetaxel and 7.2 months for BSC. The manufacturer's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £18,672 per additional quality-adjusted life year (QALY) gained for pemetrexed compared with docetaxel and an ICER of £16,458 per additional QALY gained for pemetrexed compared with BSC.
3.6 An adjusted indirect comparison, conducted as a sensitivity analysis, pooled median overall survival from single arms of the trials to estimate hazard rates for each treatment group. The adjusted indirect comparison estimated the life years gained to be 14.4 months for pemetrexed and 12.4 months for docetaxel. This analysis found that the mean ICER of pemetrexed compared with docetaxel was £31,612 per additional QALY gained and the mean ICER of pemetrexed compared with BSC was £10,298 per additional QALY gained.
3.7 The ERG reviewed the evidence submitted for clinical and cost effectiveness. The ERG judged that the open-label RCT had not proved formally the equivalent efficacy of pemetrexed compared to docetaxel, and had not demonstrated that pemetrexed was more efficacious than docetaxel. The ERG's viewpoint on the manufacturer's use of an indirect comparison to generate estimates of efficacy for its model, was that that indirect comparison is only acceptable when direct comparison evidence is not available. The ERG noted that the manufacturer's indirect comparison estimate of mean survival with docetaxel was less than the survival estimate obtained from the head-to-head trial (7.14 compared with 8.74 months, respectively). The ERG considered that the use of an unadjusted indirect comparison for the base-case was not ideal because it was based on pooling of median absolute survival estimates from individual arms of the trials rather than a consideration of the relative treatment effects. The ERG also noted that the estimates of drug acquisition costs used needed adjustment; in particular, the number of chemotherapy cycles should have reflected the number of cycles reported in the head-to-head trial.
3.8 The ERG considered the effect on the ICER of assuming equivalent overall survival for pemetrexed and docetaxel, in place of the manufacturer's assumption of greater survival. In this situation, the ERG estimated that the ICER for pemetrexed versus docetaxel would increase to approximately £458,000 per additional QALY gained. It also noted that if the revised estimates of drug acquisition/administration costs, costs of treating adverse events, and non-treatment-related and palliative care costs were included in the analysis, the ICER for pemetrexed versus docetaxel could be up to £1.8 million per additional QALY gained.
3.9 The ERG evaluated the manufacturer's economic analysis of pemetrexed versus BSC. Based on the manufacturer's estimates of survival and QALYs for the BSC group, but using a survival effect of pemetrexed equivalent to docetaxel, and revised cost estimates, the ERG estimated an ICER of approximately £60,000 per additional QALY gained.