Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
Six of 18 cancer drugs that initially received accelerated approval have indications that remain on the labeling and are recommended in clinical guidelines despite no improvement in the primary endpoint in post-approval trials. These findings reflect the lack of fulfillment of the compromise between speed and evidence that underpins the accelerated approval pathway. A recent flurry of regulatory action suggests that the FDA has paid greater attention to these situations in the past two years, although additional guidance and reforms of the accelerated approval pathway are needed to assure that all FDA approved drugs are shown to be safe and effective for patients.
All confirmatory trials that failed to show improvement in the primary endpoint had used overall survival as the primary endpoint. Accelerated approval is not always withdrawn, even when the confirmatory trial results are negative. Clinical guidelines continue to recommend cancer drugs for indications for which the confirmatory trials have failed to show clinical benefit, sometimes despite the withdrawal of approval.
Patients with cancer need timely access to drugs that meaningfully improve how they feel, function, or survive. 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.
The accelerated approval pathway of the US Food and Drug Administration (FDA) covers this situation. 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). Cancer related surrogate measures include changes in tumor size or time to progression of cancer. These surrogate measures may ultimately be shown to predict meaningful clinical benefit, but this is often not the case...
Click for Source
