4 Consideration of the evidence
4.1 The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of gemcitabine for the treatment of metastatic breast cancer, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of gemcitabine by people with metastatic breast cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee considered current clinical practice in the treatment of metastatic breast cancer following relapse after anthracycline-based regimens in adjuvant and neo-adjuvant settings. The Committee heard from the clinical specialists that gemcitabine plus paclitaxel would be valued as an option in a group of patients who required a higher level of efficacy than would be achieved with a single agent taxane (for example, in patients with visceral metastasis) and who were also considered fit enough to receive combination therapy. The Committee heard from the clinical specialists that gemcitabine plus paclitaxel would probably be used as an alternative option to the combination of docetaxel plus capecitabine because it is considered to be equally effective but less toxic. Finally, the Committee heard from the clinical specialists that because capecitabine is an important option in later lines of therapy for metastatic breast cancer, the use of docetaxel plus capecitabine as a first-line choice would reduce the possibility of using capecitabine in later lines of therapy. The patient representatives confirmed that for patients whose condition required an alternative to single agent taxanes, gemcitabine plus paclitaxel was a useful option because of its efficacy and low level of toxicity.
4.3 The Committee considered the evidence on the clinical effectiveness of gemcitabine plus paclitaxel for the treatment of metastatic breast cancer. The Committee noted that the JHQG trial is the only RCT comparing gemcitabine plus paclitaxel with paclitaxel monotherapy, and the final results of the trial have not yet been published in a peer-reviewed journal. The Committee considered the uncertainty surrounding the clinical effectiveness data relating to the borderline statistical significance of median overall survival, the fact that the 95% confidence interval for the hazard ratio for median overall survival included 1.00, and the possibility that the four-fold greater use of gemcitabine as second-line treatment in the paclitaxel arm of the trial may have influenced the results. The Committee considered evidence from post hoc analyses of the JHQG trial provided by the manufacturer that showed that 95% confidence intervals of the hazard ratio for median overall survival did not include 1.00. The Committee was mindful that repeated post hoc statistical tests increase the likelihood of generating apparently statistically significant results, and agreed that the preplanned primary analysis of median overall survival was the most reliable analysis of the JHQG trial. Based on the primary analysis of the JHQG trial, the Committee concluded that gemcitabine plus paclitaxel is likely to be more clinically effective than paclitaxel monotherapy, but recognised substantial uncertainty concerning the size of the treatment effect.
4.4 The Committee considered the evidence on the cost effectiveness of gemcitabine plus paclitaxel when compared with all relevant UK comparators as presented in the manufacturer's submission. The Committee noted that the manufacturer provided estimates of the cost effectiveness of gemcitabine plus paclitaxel versus paclitaxel monotherapy using only data from the indirect comparisons. The Committee also noted the ERG's view that using the actual data from the trial that directly compared gemcitabine plus paclitaxel with paclitaxel monotherapy provided an ICER of £42,800 per QALY.
4.5 The Committee understood that, given the lack of head-to-head trials, indirect comparison methods are necessary in order to compare gemcitabine plus paclitaxel with docetaxel monotherapy or docetaxel plus capecitabine. The Committee discussed the indirect comparisons method used by the manufacturer, and expressed concerns about the pooling of treatment outcome data from single arms of different trials. The Committee noted that recent medical statistical literature has concluded that the approach to indirect comparisons used by the manufacturer is flawed and tends to produce inconsistencies between direct and indirect estimates of treatment effects. The Committee noted that a mixed treatment comparison meta‑analysis that maintains the benefits of randomisation and requires a connected network of RCTs could have been carried out to indirectly compare all of the treatments simultaneously.
4.6 The Committee noted that the manufacturer's economic analysis suggested that the ICER for gemcitabine plus paclitaxel was lower when compared with docetaxel monotherapy than with paclitaxel monotherapy. The Committee noted that the survival estimates from the manufacturer's indirect comparisons appeared to contradict the results from a study that directly compared docetaxel monotherapy with paclitaxel monotherapy. The indirect comparison suggested that overall survival with paclitaxel monotherapy was superior to docetaxel monotherapy, but the clinical study suggested the opposite. Given that overall survival is a key driver of cost effectiveness in the manufacturer's economic model, the manufacturer's indirect survival estimates have the effect of producing cost-effectiveness ratios in favour of gemcitabine plus paclitaxel when compared with docetaxel monotherapy.
4.7 The Committee also discussed survival estimates calculated by the ERG, using an indirect comparison method that was based on relative treatment efficacy data that maintained the randomised structure of clinical trials. The Committee considered the ICER of £45,800 per QALY obtained using the ERG's indirect estimates for a comparison of gemcitabine plus paclitaxel with docetaxel monotherapy. Although the ERG's analyses were indicative and for illustrative purposes only, the ERG's indirect survival estimates were more consistent with, and closer to, the results from the head-to-head trial between docetaxel monotherapy and paclitaxel monotherapy. Furthermore, the Committee accepted that the manufacturer's indirect estimates were inconsistent with published evidence, and subject to substantial uncertainty.
4.8 The Committee noted that both the manufacturer and clinical experts positioned gemcitabine plus paclitaxel for the treatment of patients for whom combination chemotherapy would be most appropriate. The Committee discussed the clinical experts' view that docetaxel plus capecitabine was likely to be as clinically effective as gemcitabine plus paclitaxel but more toxic. The Committee concluded that the clinical evidence before it did not clearly indicate whether gemcitabine plus paclitaxel was more or less clinically effective than docetaxel plus capecitabine, but it was persuaded that docetaxel plus capecitabine was likely to be more toxic than gemcitabine plus paclitaxel. The Committee further concluded that gemcitabine plus paclitaxel was likely to be as clinically effective as docetaxel monotherapy. On this basis the Committee agreed that gemcitabine plus paclitaxel could be a useful alternative when docetaxel monotherapy or docetaxel plus capecitabine were being considered in an individual patient. However, the Committee noted that the ERG had not provided an estimate of the ICER for a comparison between gemcitabine plus paclitaxel and docetaxel plus capecitabine. Taking into consideration the inconsistencies of the manufacturer's indirect estimates of treatment effects, the Committee concluded that the ICER presented in the manufacturer's submission for gemcitabine plus paclitaxel compared with docetaxel plus capecitabine was likely to be a substantial underestimate.
4.9 The Committee heard from the NHS Purchasing and Supply Agency (PASA) and Welsh Health Supplies (WHS) that the discounts on non-proprietary paclitaxel referred to in the manufacturer's submission are available throughout England and Wales. The Committee considered the impact and relevance of the discounts on non-proprietary paclitaxel for the economic analyses, and accepted that using the discounted non-proprietary paclitaxel prices could substantially lower the ICERs for gemcitabine plus paclitaxel (when compared with docetaxel monotherapy or docetaxel plus capecitabine) to levels of cost effectiveness previously considered to be an efficient use of NHS resources. The Committee considered that uncertainties remain over the economic evidence presented by the manufacturer, but having had confirmation that discounts on non-proprietary paclitaxel are available throughout England and Wales, the Committee agreed that the ICERs for gemcitabine plus paclitaxel in comparison with docetaxel monotherapy and docetaxel plus capecitabine are likely to fall within acceptable levels of cost effectiveness. The Committee considered, however, that even with discounted non-proprietary paclitaxel, the ICER for a comparison of gemcitabine plus paclitaxel with paclitaxel would not fall within acceptable levels of cost effectiveness.
4.10 The Committee considered that the evidence presented by the manufacturer of the clinical and cost effectiveness of gemcitabine plus paclitaxel compared with the other licensed taxane-based treatments was subject to considerable uncertainties. The Committee concluded that the ERG's critique of the manufacturer's methods was valid and that the alternative approaches and resulting ICERs suggested by the ERG were more appropriate. The Committee accepted the confirmation from the NHS PASA and WHS of the availability of discounts on non-proprietary paclitaxel. The Committee considered the effect that the discounts would have on the economic analyses and results reported by both the manufacturer and the ERG. The Committee accepted that it was likely that the ICERs for gemcitabine plus paclitaxel compared with docetaxel monotherapy or docetaxel plus capecitabine would fall within acceptable levels of cost effectiveness. The Committee concluded gemcitabine plus paclitaxel, within its licensed indication, should be recommended as an option for the treatment of metastatic breast cancer in the NHS when docetaxel monotherapy or docetaxel plus capecitabine are considered appropriate.