FDA Faces Growing Dilemma as 10% of Approved Drugs Fail Primary Endpoints in Pivotal Trials
核心洞察
A 2023 JAMA Internal Medicine study revealed that 21 of 210 new drugs approved by the FDA between 2018 and 2021 failed to meet at least one primary efficacy endpoint in pivotal trials.
High-profile failures include Biogen's Qalsody for ALS, MacroGenics' Margenza for breast cancer (搜索), and Sarepta (搜索)'s Vyondys 53 and Amondys 45 for Duchenne muscular dystrophy (搜索), yet most remain on the market.
The FDA's reliance on biomarker evidence and surrogate endpoints for accelerated approvals creates regulatory challenges when confirmatory trials fail to demonstrate clinical benefit.
A growing number of FDA-approved drugs are failing to demonstrate efficacy in pivotal trials, raising critical questions about the agency's approval standards and the use of biomarker evidence in regulatory decision-making. According to a 2023 study published in JAMA Internal Medicine, 21 of the 210 new drugs approved by the FDA between 2018 and 2021 failed to meet at least one primary efficacy endpoint in a pivotal trial—representing approximately 10% of all approvals during this period.
High-Profile Failures Highlight Regulatory Challenges
Several prominent cases illustrate this concerning trend. Biogen's amyotrophic lateral sclerosis (搜索) drug Qalsody, MacroGenics' breast cancer (搜索) drug Margenza, and Sarepta (搜索)'s exon skippers Vyondys 53 and Amondys 45 for Duchenne muscular dystrophy (搜索) have all failed pivotal or confirmatory trials, yet most remain on the market or received full approval.
The most controversial example remains Biogen's Aduhelm (aducanumab), approved under the FDA's accelerated approval pathway in June 2021 as the first Alzheimer's drug to treat the underlying cause of the disease. After Biogen and partner Eisai halted the global Phase III ENGAGE and EMERGE trials in March 2019, the companies later reported that EMERGE had hit the primary endpoint at the highest dose. However, the FDA based its approval on a biomarker—Aduhelm's ability to reduce amyloid beta plaques (搜索) in the brain—leading to the resignation of three prominent FDA reviewers.
The Science Behind Trial Failures
Joe Ross, professor of medicine and public health at Yale School of Medicine and co-author of the JAMA study, expressed surprise at finding "about 10% of all approvals are made despite the primary efficacy endpoint being null." However, he noted that "perhaps it isn't surprising because the FDA has such flexibility in reviewing a marketing application."
According to the 2023 JAMA study, the most common reasons for approval despite failed pivotal trials include "success of other pivotal studies" (62%), "benefit suggested by secondary or exploratory endpoints" (48%), and "post-hoc effectiveness analysis" (33%).
Harpreet Singh, chief medical officer at clinical research organization Precision for Medicine and former division director of oncology under retiring Center for Drug Evaluation and Research head Richard Pazdur, emphasized that "a failed trial is not a failed drug." Singh identified three primary reasons for trial failures: inappropriate endpoint selection, patient selection issues, and operational problems.
The Biomarker Controversy
The reliance on biomarkers for drug approval has become particularly contentious. Ross expressed concern about approvals based solely on biomarker changes, stating, "When it's just a change in a biomarker and even that is not statistically significant, that's really worrying to me." He noted that biomarkers used by the FDA over the years have shown poor correlation with clinical outcomes.
Ross specifically criticized the continued use of response rate and progression-free survival (PFS) in cancer drug development, noting, "We know pretty conclusively that response rate and progression-free survival do not correlate well with patients' symptom or functional status, or overall survival rate, but we continue to use those markers over and over." In response, the FDA issued draft guidance in August emphasizing that drug developers should prioritize using overall survival (OS) as the primary endpoint.
Inconsistent Confirmatory Requirements
A surprising finding from the study was that despite missing primary endpoints in pivotal trials, confirmatory studies were only mandated or requested by the FDA about one-third of the time—for seven of 21 approvals. This inconsistency raises questions about regulatory oversight and the criteria used to determine when additional evidence is necessary.
Case Studies in Regulatory Flexibility
Sarepta (搜索)'s Vyondys 53 and Amondys 45 exemplify the ongoing debate. Vyondys 53 was approved based on data showing increased levels of dystrophin (搜索), a crucial muscle protein lacking in patients with DMD, after 48 weeks. Amondys 45 satisfied the biological endpoint of micro-dystrophin protein expression at 12 weeks post-treatment. However, neither therapy met the confirmatory ESSENCE trial's primary endpoint of an individual's ability to ascend a flight of stairs at 96 weeks. Despite this failure, as of November 3, Sarepta planned to meet with the FDA to discuss converting the accelerated approval to traditional approval.
Ross argued for market withdrawal in such cases, stating, "The FDA showed a lot of flexibility, one might even say leniency, by approving those drugs at the time that they did with the expectation the confirmatory studies would be done. The company at some point should, for lack of a better term, face the music. The drugs were not effective."
The Complexity of Regulatory Decision-Making
Singh defended the nuanced approach to failed trials, citing Amgen's Lumakras (sotorasib) as an example. The first KRAS (搜索)-targeting drug ever authorized by the FDA received accelerated approval based on success in the single-arm Phase II CodeBreak 100 study. However, in October 2023, an advisory committee voted against granting full approval after PFS data from the Phase III confirmatory CodeBreaK 200 study became uninterpretable due to asymmetric dropout in the control arm.
"Essentially, there was so much enthusiasm about the novel drug that there ended up being asymmetric drop out of the control arm... and ultimately rendered the trial results uninterpretable," Singh explained. Despite having the option to withdraw the drug, regulators elected not to due to high unmet need and a "robust response rate" of 36%.
Balancing Access and Scientific Rigor
The ongoing debate reflects the fundamental tension between providing patient access to potentially life-saving treatments and maintaining scientific rigor in drug approval processes. As Ross noted, "It's a challenging conundrum. 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."
This desire for success extends beyond pharmaceutical companies to include patients, healthcare providers, and even the FDA itself, which "puts out press releases for every new drug they approve, not for every new drug they don't approve," according to Ross.
The increasing frequency of approvals despite failed primary endpoints underscores the need for clearer regulatory guidelines and more consistent application of confirmatory study requirements to ensure that approved drugs truly benefit patients while maintaining public trust in the regulatory process.