Time for a level playing field: inequalities in regulatory/approval processes—the example of bevacizumab in epithelial ovarian cancer.

Abstract

As outsiders, we do not have access to the deliberations of the regulatory bodies. The NICE reasons are in the public domain. The Health Canada queries that led to Roche withdrawing their application are not known. Therefore, the following are possible explanations for this inconsistency. One possible reason that might be given for nonapproval: The clinical benefit is too small (Fig 1). This statement is incorrect. The PFS benefit that was obtained, as demonstrated by hazard ratios, ranged from 0.48 to 0.73 in EOC (superior in the recurrent setting). In comparison, hazard ratios for colorectal cancer were 0.50 to 0.89 and for lung cancer were 0.66 to 0.75. More relevantly, the absolute differences in median PFS were 3.3 to 5.5 months, 2 to 4.4 months, and 0.4 to 1.7 months, respectively, in these three cancer types. Is it that regulatory bodies need more than improvements in medians alone? This would be ideal but, unfortunately, is rarely the case because financial imperatives usually result in relatively immature data being submitted, leading to reliance on the medians. Even if longer term outcomes had been used as part of the decision making, they would not have had an adverse impact, given that the increases in survival at 1 and 2 years were clinically meaningful. Overall survival (OS) benefits were much less impressive. Hazard ratios again were 0.64 to 0.88, 0.66 to 0.94, and 0.79 to 0.93 in ovary, colorectal, and lung cancers. Absolute OS differences were 3.2 to 7.8 months, 0.4 to 4.4 months, and 0.5 to 2 months, respectively. These ovarian and colorectal outcomes are similar. Oncologists are convinced of bevacizumab’s utility. Bevacizumab is part of standard therapy in metastatic colorectal cancer. These outcomes in EOC are also regarded as worthwhile by Canadian oncologists. Support for use of bevacizumab was unanimous at a recent meeting of Gynecologic Oncology Canada (a pan-Canadian not-for-profit organization that represents physicians and nurses who specialize in gynecologic malignancies). Bevacizumab’s use is included in the National Comprehensive Cancer Network ovary guidelines in the platinum resistant/refractory setting in combination or as monotherapy. 21 The EMA, who approved it, found that there was “robust evidence for clinically significant effect.” 22(p47) However, some agencies were less enthusiastic. Documented reasons are available from NICE in the United Kingdom. 23,24 Lack of clinical benefit was not the only reason. The reasoning in the first-line setting was that,