Nearly half of the 253 drugs authorized via FDA's accelerated approval pathway since 1992 have never been confirmed as clinically effective—leading some experts to suggest the approval process has been "exploited, to the detriment of patients … and of taxpayers," Elizabeth Mahase writes for The BMJ.
What The BMJ found about the accelerated approval pathway
The approval pathway allows certain drugs to enter the U.S. market prior to proving clinical efficacy if they treat serious conditions and fill an unmet medical need "based on a surrogate endpoint," according to FDA.
As FDA explains, "A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit." This approach can "considerably shorten the time required prior to receiving FDA approval," the agency says.
However, accelerated approvals carry the condition that, post-approval, manufacturers must conduct so-called Phase IV studies to ensure they actually provide a clinical benefit. And according to The BMJ, 112 of the 253 drugs approved through the pathway thus far still haven't been confirmed as clinically effective in post-approval studies—including 24 drugs that have been on the market for more than five years.
To learn more, The BMJ contacted the manufacturers of those 24 drugs to determine the status of the required Phase IV trials. According to Mahase, 6 of those drugs had been withdrawn, approved, or postponed; 6 manufacturers provided relevant confirmatory trial information; and 11 companies (representing the remaining 12 drugs) did not respond to The BMJ's request.
Why some experts have raised about accelerated approval
According to Mahase, the BMJ investigation follows prior research conducted by the Government Accountability Office, which in 2015 determined that "'data on post-market safety issues and studies were found to be incomplete, outdated, (and) to contain inaccuracies.'"
Similarly, the Institute for Clinical and Economic Review (ICER) in April of this year said a lack of "credible threats" to withdraw approval without confirmatory trials has provided little incentive for—or pressure on—manufacturers to complete the trials. According to Mahase, only 16 drugs approved through the accelerated pathway have ever been withdrawn.
Moreover, ICER found that FDA, "barring safety concerns, … has generally preferred to steer clear of withdrawing approval, even when post-marketing trials do not support a treatment effect on the primary clinical endpoint."
According to Mahase, in light of these findings, some medical leaders believe FDA's standards for evidence are too low. "Sometimes we just don't really know how well the surrogate outcome correlates with future patient outcomes," Steven Pearson, ICER president and a lecturer at Harvard Medical School, said.
Recommendations for improvement
Mahase writes that, even though several experts consulted by The BMJ were concerned about the current use of the accelerated approval pathway, they agreed it remains a "useful" and potentially "beneficial" way to getting drugs to market safety. They highlighted several potential reforms, including:
- Requiring that companies design, agree to, and potentially start confirmatory trials as part of the accelerated approval process
- Strengthening the selection of surrogate endpoints
- Regulating the price of accelerated drugs
- Regularly re-reviewing and renewing the approval
"We could move the needle and get the true goal of accelerated approval, which is still a very viable one, (but) get it done in a way that really is more beneficial for patients in the long run," Pearson said.
Separately, an FDA spokesperson told The BMJ that the agency is "committed to working with sponsors to ensure that confirmatory studies are completed in a timely manner. … We expect sponsors to commit all resources needed to move trials forward as effectively as possible, with the aim of completing trials as soon as is feasible, while assuring the quality of the data and the robustness of the results." (Mahase, The BMJ, 7/30)