Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study

Abstract

Objectives To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines. Design Retrospective observational study. Setting FDA and National Comprehensive Cancer Network (NCCN) reports. Included drugs Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials. Main outcome measures Regulatory outcomes, including withdrawal, conversion to regular approval, and no action. Results 18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked. Conclusion Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.

Treatment Access, Health Economics, and the Wave of a Magic Wand

“…With accelerated access through approaches such as “breakthrough therapy” designation, there is always some risk that subsequent trials may fail to confirm that the therapy offers sufficient benefit to justify ongoing access. If this happens, the therapy may be withdrawn from the market after discussion between regulators and the pharmaceutical company, or regulators may unilaterally rescind approval [ 12 ].…”

“…In other cases, a therapy may remain approved despite failure to meet its primary endpoint in subsequent trials [ 12 ]. This can happen if the drug has other benefits that are thought to be useful.…”

Putting patients first in medicines regulation?

“…More than two thirds of expedited drugs do not perform better than existing alternatives 17. Some are later found to be ineffective 1819…”

Medicare Spending on Drugs With Accelerated Approval, 2015-2019

“…Drugs granted accelerated approval must undergo confirmatory studies, but in some cases these studies have not been completed in a timely fashion, 1 and the FDA has had difficulty withdrawing drugs or removing indications even when confirmatory studies fail to demonstrate clinical benefit. 2 Although drugs made available via accelerated approval have no proven clinical benefit, manufacturers still charge high prices. 3 To understand the budgetary implications of high-priced accelerated approval drugs, we estimated Medicare spending on these drugs from 2015 through 2019.…”