Several drugs approved by the U.S. Food and Drug Administration (FDA) have failed to meet primary efficacy endpoints in pivotal or confirmatory trials, yet many remain on the market or have received full approval. Examples include Biogen’s Qalsody for amyotrophic lateral sclerosis, MacroGenics’ Margenza for breast cancer, and Sarepta’s exon-skipping therapies Vyondys 53 and Amondys 45 for Duchenne muscular dystrophy.
To justify approval or continued marketing, companies often cite supporting evidence such as positive biomarker data, successful secondary endpoints, or real-world evidence of safety and effectiveness. This situation is not uncommon; a study published in JAMA Internal Medicine in 2023 found that out of 210 new drugs approved by the FDA between 2018 and 2021, 21 failed to meet at least one primary efficacy endpoint during pivotal trials.
Joe Ross, professor at Yale School of Medicine and co-author of the study, told BioSpace he was “surprised to find that about 10% of all approvals are made despite the primary efficacy endpoint being null.” He added: “perhaps it isn’t surprising because the FDA has such flexibility in reviewing a marketing application.”
One prominent example is Biogen’s Aduhelm (aducanumab), which was approved under the FDA’s accelerated pathway in June 2021 as an Alzheimer’s treatment targeting amyloid beta plaques. The drug's approval was controversial after its Phase III trials were halted due to lack of success before later analyses suggested some benefit at higher doses. Ultimately, the FDA based its decision on Aduhelm’s ability to reduce amyloid beta plaques rather than direct clinical outcomes.
“It’s a challenging conundrum,” Ross said. “Particularly by the time you reach the pivotal trial phase for a new drug . . . lots of people have invested lots of time and money into bringing that product to market. I think everybody wants it to be a success.” He noted this desire extends beyond companies and patients: “The FDA wants it to be successful. They put out press releases for every new drug they approve, not for every new drug they don’t approve.”
Harpreet Singh, chief medical officer at Precision for Medicine and former division director at the Center for Drug Evaluation and Research (CDER), emphasized lessons learned from Richard Pazdur: “One thing that Rick Pazdur taught us that has really stuck with me over the years is that a failed trial is not a failed drug,” she told BioSpace.
Singh explained there are several reasons why trials might fail. According to the JAMA study referenced earlier, common justifications cited by the FDA when approving drugs despite missed endpoints included success in other pivotal studies (62%), benefits shown by secondary or exploratory endpoints (48%), and post-hoc effectiveness analysis (33%).
For Singh, selecting appropriate endpoints is crucial: “Did we pick the appropriate endpoint for the therapeutic area, for the therapeutic class?” She pointed out immunotherapy as an example where short-term endpoints like response rate may not reflect long-term benefits such as overall survival.
Patient selection can also affect results when moving from small-scale studies to larger randomized trials: “you see a large amount of heterogeneity so the efficacy... sometimes slides a little bit” compared with single-arm settings.
Operational issues may also play a role. Singh said her experience running clinical research organization trials showed these factors could critically impact outcomes.
In cases where pivotal endpoints are missed but other evidence suggests benefit—such as near-significant p-values—the FDA may still consider approval. However, Ross expressed concern when decisions rely solely on biomarkers without statistical significance: “When it’s just a change in a biomarker and even that is not statistically significant, that’s really worrying to me.” He noted longstanding concerns about using markers like response rate or progression-free survival instead of overall survival—a view echoed by recent draft guidance from the agency urging developers to prioritize overall survival as their main endpoint.
Ross observed another finding from his study: only about one-third of drugs missing primary endpoints had confirmatory studies mandated or requested by regulators. While open to considering mixed results initially, he insisted confirmatory trials must ultimately support ongoing market access: regarding Sarepta's Vyondys 53 and Amondys 45 therapies—which did not meet confirmatory trial goals—he stated,“I think that they should be removed from the market.”
“The FDA showed a lot of flexibility...by approving those drugs at the time...with expectation [that] confirmatory studies would be done,” Ross continued.“And I think company should remove them from market...The drugs were not effective.”
Vyondys 53 was approved based on increased dystrophin levels after treatment; Amondys 45 met biological targets related to micro-dystrophin protein expression but neither improved patients’ ability to ascend stairs during longer-term follow-up assessments. Despite this outcome,Sarepta announced plans as recently as November 3rd to discuss converting accelerated approvals into traditional ones with regulators.
Singh argued nuance remains essential:“I don’t think that failed endpoints suggest failed trials,” she reiterated.“I think you really have to unpack what that looks like.” She cited Amgen's Lumakras (sotorasib)—the first KRAS-targeting therapy—as an example where enthusiasm led to complex trial dynamics making interpretation difficult,yet robust response rates justified keeping it available despite inconclusive Phase III data.“I think that's a beautiful example of a failed trial really not representing a failed drug,” she said.
