Study: FDA offers flexibility, expedited review to first-in-class drugs more often than EMA

Editor's note: This article has been updated with comment from one of the study authors.

The US Food and Drug Administration (FDA) is more likely to offer regulatory flexibility and grant expedited review to first-in-class drugs than the European Medicines Agency (EMA), according to recent research published in Health Affairs.
 
Jihye Han and Aaron Kesselheim, of Brigham and Women’s Hospital and Harvard University, examined 186 first-in-class drugs approved by FDA between 2013 and 2023 as well as 121 drugs approved by FDA and EMA between 2013 and 2022. The researchers assessed the duration of review at each agency, whether the drug was granted expedited review, the therapeutic area associated with the drug, and the characteristics of pivotal trials that led to the drug’s approval.
                         
The most common drug types approved by FDA were related to cancer, with 45 drugs approved by FDA alone (24.1%) and 33 drugs approved by both FDA and EMA (27.2%). Overall, the review duration for FDA alone was a median of 8.17 months, while the median review duration for first-in-class drugs approved by both FDA and EMA was 8.13 months for FDA compared to 10 months for EMA.
 
Of the 186 FDA-approved drugs, 150 drugs (80.6%) had been granted one or more expedited review such as priority review (75.2%), fast track designation (45.6%), breakthrough therapy (40.8%), or accelerated approval (18.2%). For the group of 121 drugs approved by both FDA and EMA, 83.4% of drugs were granted expedited review compared to the use of an EMA expedited regulatory program (29.7%) such as accelerated assessment (12.3%), conditional approval (10.7%), or exceptional circumstances (8.2%).
 
When analyzing 185 first-in-class drugs approved by FDA alone that were approved based on clinical trials in humans, the researchers identified 314 pivotal trials; of these, 109 drugs (58.9%) had one pivotal trial, 61 drugs (32.9%) had trials that used surrogate measures, 46 drugs (24.8%) had clinical evidence from trials with external controls, and 45 drugs (24.3%) had no phase 3 pivotal trials supporting their approval. The article notes that the smallpox treatment Tpoxx (tecovirimat) was approved under the Animal Rule because it was not feasible to test the treatment in humans at the time.
 
“Our findings underscore the need for regulators to carefully balance regulatory incentives with rigorous ongoing assessments of evidence supporting drug innovations,” Han and Kesselheim concluded.
 
Accountability for manufacturers
 
Commenting on the study, Joseph Ross, professor of medicine and public health at Yale School of Medicine, who was not involved with the study, said the results highlight the challenges patients and clinicians are experiencing as regulatory systems move towards using expedited pathways more often for product approvals. “It is not surprising that first-in-class drugs are more likely to receive expedited review—the FDA’s increased use of expedited programs has been well established,” Ross told Focus.
 
There are two important consequences to this, Ross noted. The first is the potential for faster clinical trial testing, drug development, and regulatory review, which may help bring a drug to market faster. However, there is also greater uncertainty at approval due to the use of one clinical trial rather than two and may use surrogate markers rather than clinical outcomes.
 
“The ‘bargain’ we are making as a society is that, in return for bringing drugs to market more quickly, but with less certainty, is that manufacturers need to confirm benefits, and the FDA needs to hold the manufacturers accountable for completing the clinical trials that confirm benefits,” Ross said. “This is not consistently happening. “
 
There has been progress for first-in-class drugs granted accelerated approval, but “this is less true” of breakthrough-designed first-in-class drugs, Ross explained.
 
“My hope is that studies like the one just published by Han and Kesselheim continue to bring attention to these issues, and the challenges we continue to face with this trade-off, so that we can be sure that robust and rigorous evidence is consistently generated for the critical drug and biological treatments patients rely on for their care each day,” Ross said.

Han, one of the study authors, told Focus there are two points at which regulatory scrutiny can be applied to drugs -- during the premarket review and during the postmarketing stage.

"Since first-in-class drugs introduce technological advancements into clinical settings, they necessarily carry uncertainty in their clinical outcomes," Han said. "It is important that regulatory standard ensure only drugs with substantial evidence of efficacy and sufficient safety are approved for routine clinical use. Our findings showed that the FDA has exerted a high degree of regulatory flexibility in approving 186 first-in-class drugs in the US, and drug developers should expect the same or even greater flexibility in future cases, making it unlikely that evidentiary requirements will become more stringent unless the FDA takes deliberate action to tighten oversight through clearer guidelines and rulemaking."

Han added that once approved, "the burden of remaining uncertainty in the drug’s outcomes is borne by patients and the health care system. The most effective way to mitigate the risks of ineffective or unsafe drugs would be through clear post-marketing oversight. Confirming whether a drug is effective and safe as expected is imperative. If it does not, further measures—such as updating safety warnings, restricting indications, or withdrawing approval—should be implemented to promote its appropriate use. However, it is well known that there are limitations in the FDA’s ability to withdraw accelerated approval drugs from the market, even when the post-marketing trials are delayed or fail to confirm effectiveness and safety. Strengthening post-marketing oversight is therefore critical to ensure the thoughtful introduction of first-in-class drugs."
 
Health Affairs Han et al.