BMJ Study: Accelerated Approval Drugs Retain Status Despite Lack of Benefit

Sept. 20, 2021 – Six out of 18 cancer drugs that initially received accelerated approval from the FDA have indications that remain on the labeling and continue to be recommended in clinical guidelines despite post-approval trials demonstrating no improvement in the primary endpoint, according to a retrospective observational study published Sept. 9 by BMJ.

“The accelerated approval pathway provides the FDA with a valuable tool to encourage innovation in certain cancers, rare disorders, and other serious illnesses,” said Coalition for Healthcare Communication Executive Director Jon Bigelow. “But this study reaffirms the need for tighter monitoring and enforcement of the requirements for post-marketing studies to maintain the integrity of the process.”

“These findings reflect the lack of fulfilment of the compromise between speed and evidence that underpins the accelerated approval pathway,” the study abstract states. “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.”

“Greater attention” from the FDA includes the recent meeting of the FDA Oncologic Drugs Advisory Committee, which voted in late April that specific uses of two of six cancer drugs being reviewed – Keytruda for stomach cancer and Opdivo for certain types of liver cancer – which were approved under the accelerated approval process, should be withdrawn.

The study also comes on the heels of the FDA’s controversial accelerated approval of Biogen’s Aduhelm for Alzheimer’s disease based on meeting the surrogate endpoint of reducing amyloid in the brain. That decision – which an FDA advisory committee nearly unanimously rejected – has been criticized amid calls for investigations into how the FDA approved the drug, which bears an annual cost of $56,000, not including physician, infusion center and imaging costs. [Note: Acting FDA Commissioner Dr. Janet Woodcock has called for an independent Office of the Inspector General investigation of FDA/Biogen interactions prior to the Aduhelm approval.]

The FDA’s accelerated approval program was established in 1992 to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint. According to the agency, drug companies are still required to conduct Phase 4 clinical trials to confirm the anticipated clinical benefit.

Under the program parameters, approval of a drug may be withdrawn or the labeled indication of the drug changed “if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).”

Critics of the program argue that post-accelerated approval evaluations lag far behind the approvals and that the process for withdrawing drugs that have failed to deliver on the primary efficacy endpoint is too slow.

Indeed, the BMJ study found that for the 18 cancer drugs examined, the time from accelerated approval to regulatory outcome, “which included withdrawal, revocation, conversion to regular approval or the end of the study time period on 31 May 2021,” ranged from 1.7 years to 11.5 years, with a median of 3.9 years, and that post-approval  trials “are often delayed, with half still underway three years after approval.”

Additionally, the BMJ abstract notes that clinical guidelines, such as those issued by the National Comprehensive Cancer Center (NCCN), trail behind the science, with NCCN endorsements continuing for accelerated approval drugs “that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.”

The BMJ analysis states that although drugs that receive accelerated approval may offer promise and surrogate measures “may ultimately be shown to predict meaningful clinical benefit … this is often not the case.”