![]() ![]() We also investigated the extent to which negative post-approval trials affected recommendations in clinical practice guidelines. 8 We investigated the regulatory consequences for cancer drugs that were previously granted accelerated approval by the FDA but failed to show improvement in the primary efficacy endpoint in post-approval trials. The FDA considers withdrawal of drug approvals to be administratively and socially challenging, 7 as was evident in the case of the revoking of accelerated approval for bevacizumab for metastatic breast cancer. No previous study has examined what regulatory steps are taken with respect to drugs that received accelerated approval when the post-approval trials are conducted and fail to confirm clinical benefit. 5 Among the trials that have been completed, approximately 40% used surrogate measures, including the same surrogate measure that led to accelerated approval. However, post-approval trials are often delayed, with half still underway three years after approval. 4 Central to the accelerated approval concept is the need for these post-approval trials to be conducted in a reasonable timeframe, that the trials use meaningful clinical endpoints, and that the approved indication be withdrawn if a drug fails to show clinical benefit that outweighs its risks. The rationale for such a requirement is to ensure that all drugs granted accelerated approval eventually have their clinical benefit established for the patients relying on them. The law mandates that drugs granted accelerated approval be tested in post-approval trials showing the putative clinical benefit expected from improvement in surrogate measures. These surrogate measures may ultimately be shown to predict meaningful clinical benefit, but this is often not the case. Cancer related surrogate measures include changes in tumour size or time to progression of cancer. The FDA may grant approval to any drug-although it is most often used in cancer-that has shown improvements in surrogate measures in clinical testing that are only reasonably likely to predict actual clinical benefit (that is, improved survival or quality of life). The accelerated approval pathway of the US Food and Drug Administration (FDA) covers this situation. 1 However, measuring clinical endpoints such as improvement in overall survival can take time, and patients may be willing to tolerate uncertainty about such benefits in exchange for early access to promising cancer drugs, particularly for cancers that lack other treatment options. Patients with cancer need timely access to drugs that meaningfully improve how they feel, function, or survive.
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