In the FDA’s push to grant accelerated approvals to treatments that can help patients in need, the agency has become increasingly reliant on the use of surrogate markers (or “proxies”), which can foreshadow clinical outcomes. While it can take several years for a drugmaker to conduct a clinical trial to prove the worth of a medicine, proxies can be generated quickly and suggest that a product is ready to help cure diseases and save lives.
But there is much debate—internal and external—about how much the U.S. regulator should depend on surrogate data.
Adding fuel to the fire is a recent report from the Yale School of Medicine and Emory University which shows that there is little evidence backing the use of surrogate markers to determine if a medicine is fit for approval.
Because a 2022 report, which limited its analysis to cancer approvals, came to a similar conclusion, the Yale and Emory researchers limited their study to non-cancer treatments that have been approved by the FDA.
There was a “real paucity of evidence” that surrogates are valid markers of a good disease outcome, according to Joseph Ross, M.D., a professor of medicine and public health at Yale and the author of the study.
“Even though the FDA has indicated the level of evidence needed to support use of a surrogate and feel good about its reliability, we weren’t able to find that evidence,” Ross told the Yale School of Public Health.
The FDA has said that meta-analysis studies, which compile data from several different trials in a particular indication, act as a guide to determine which surrogate markers are associated with positive outcomes for patients.
But Yale and Emory researchers, who analyzed 37 surrogate markers for 32 different diseases, said meta-analyses existed for only 40%. And of these, there was a lack of “high-strength evidence of associations with clinical outcomes."
Once the FDA approves a drug based on biomarker data, other companies are free to pursue nods for their treatments through the same pathway. Last month, an FDA panel voted unanimously to allow a surrogate endpoint to support multiple myeloma approvals.
Over the last decade, FDA experts have not been in unison on the value of surrogate markers. In 2016, for example, there was much debate on whether to approve Sarepta’s Duchenne muscular dystrophy (DMD) drug Exondys 51 based on biomarker data. The regulator approved the treatment despite getting a thumbs down from its own reviewers and from an independent panel of experts. The disagreement was such that there were some high-profile departures from the agency.
In 2020, amid a similar debate, the FDA signed off on NS Pharma’s DMD drug Viltepso based on its ability to produce the protein dystrophin. Earlier this week, the company reported that Viltepso flunked a confirmatory trial.