Reputation and Precedent in the Bevacizumab Decision. Part 2
Ultimately, data from confirmatory studies should either permit conversion to regular approval or lead to withdrawal of the indication in question. Hence, accelerated approval is provisional — a medium-term stopover en route to full approval or market withdrawal. There should be a clear end point and, after a reasonable period for confirmatory trials, the sponsor should provide evidence that meets the standard for regular approval. If such evidence emerges, the FDA must convert the drug’s status to regular approval. Otherwise, the FDA must rescind approval. Without a genuine option to withdraw accelerated approval in light of either inadequate or unfavorable confirmatory data, the FDA would have few tools to ensure that companies provide the new, rigorous data they promised to obtain.
Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions. A central question in the bevacizumab dispute concerns whether the standard for conversion of accelerated to regular approval has been met. Genentech argues that progressionfree survival is an acceptable measure of direct clinical benefit in metastatic breast cancer and that confirmatory trials demonstrate that bevacizumab prolongs progression-free survival. Yet the progression-free– survival benefit in confirmatory trials, while statistically significant, was considerably smaller than that seen in E2100. In addition, safety concerns — both new and previously described — have arisen from the recent clinical trials. Genentech further claims that the FDA has switched approval standards for bevacizumab. The agency, however, has consistently maintained that progression-free survival is “not statistically validated as surrogate for survival in all settings” and is “not precisely measured.”4 Therefore, the FDA has full authority to respond to adverse safety and efficacy data by changing medication labeling. Genentech’s second claim, that the possibility of heterogeneity in the treatment effect should justify continued approval, suffers from an absence of data identifying which patient characteristics are associated with clinical benefit. As the FDA’s decision memorandum notes, the mere prospect of efficacy in subgroups of patients, without the ability to identify those subgroups in advance, is inadequate as a rationale for continued approval.
Genentech’s philosophical claim that “conflicting interpretations of data should be resolved in favor of retaining access and choice” represents a departure from federal statute and a bold challenge to the FDA’s mission. In a democratic republic, access and choice represent two among many values. The FDA must also protect scientific rigor, the integrity and legitimacy of federal regulations and guidance, and the public’s health. The agency’s reputation for using science to guide regulatory decisions in the public interest is its most critical institutional asset.