First-in-Class Drugs Offered Greater Regulatory Flexibility in the US vs Europe
Between 2013 and 2023, 81% of first-in-class drugs were approved under one of the FDA’s expedited programs.
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First-in-class drugs are often considered a signifier of innovation in drug discovery; however, they can also carry substantial uncertainty. A new comparison of approval data for first-in-class drugs approved by the US Food and Drug Administration (FDA) and those approved by the European Medicines Agency (EMA) revealed that the FDA is more likely to offer regulatory flexibility and designate first-in-class drugs for expedited review.
The results of the research, published in Health Affairs, highlight variations in review durations by therapeutic area, high rates of expedited program use and substantial flexibilities in clinical evidence at the time of approval.
The researchers state that these findings underscore the need for regulators to carefully balance regulatory incentives with rigorous continual assessments of evidence supporting new drug approvals.
Regulatory treatment for first-in-class drugs in the US vs Europe
Drugs that use a new and unique mechanism of action to treat a particular medical condition are awarded the first-in-class designation. These drugs are often cited as representing important scientific advancements in drug development. However, as they work via new mechanisms, there is no prior clinical experience to hint at how they will perform in routine clinical use.
“From a regulatory and policy standpoint, studying first-in-class drugs allows us to assess the extent of regulatory flexibility granted to products considered highly innovative despite uncertainties about their safety and efficacy,” Dr. Jihye Han, research specialist at Brigham and Women’s Hospital and Harvard Medical School, told Technology Networks.
“We wanted to better understand how much regulatory flexibility has been applied and what level of uncertainty has been introduced into the market by first-in-class drugs with novel mechanisms of action in recent years.”
To understand how such drugs advance through development to market, Han and colleagues examined 186 first-in-class drugs approved by the FDA between 2013 and 2023 and data for 121 drugs approved by both the FDA and the EMA between 2013 and 2022.
“Alongside review duration at each agency, we assessed regulatory flexibility in two key areas: the use of expedited programs and the design of pivotal trials,” said Han.
Between 2013 and 2023, 81% of first-in-class drugs were approved under at least one of the FDA’s expedited programs (priority review, accelerated approval, fast track and breakthrough therapy), compared to 30% of those approved by the EMA.
Regarding trial design, the researchers found that 50% of trials lacked clinical endpoints and relied on surrogate measures, and 30% lacked blinding and comparator drugs in the pivotal trials.
“The degree of regulatory flexibility – particularly in terms of the methodological rigor of clinical trials supporting first-in-class drugs – was striking,” Han said.
“While we did not separately examine the trials submitted to the EMA, earlier studies have reported a high degree of overlap, about 80%, in the clinical trials submitted to both agencies. Therefore, the level of clinical uncertainty we identified is likely relevant to both the FDA and EMA.”
These findings aren’t entirely unexpected; “The FDA’s broad use of expedited programs is well documented,” Han stated. “As cited in our recent publication, the increasing use of these pathways for new drug approvals has been widely studied.”
A previous study found that around 80% of first-in-class drugs approved between 1987 and 2014 received at least one expedited designation, consistent with the researcher's findings for the more recent period.
Concerns over less rigorous pivotal trial design are also not new in the context of regulatory flexibility. “Other researchers have shown that the FDA increasingly allows flexibility in trial design, especially when drugs are reviewed under expedited pathways,” explained Han.
Regulatory flexibility should be taken with a side of caution, experts warn
“[The] FDA’s accelerated approval pathway allows drugs to be approved based on surrogate measures that are only reasonably likely to predict clinical benefit, with the expectation that post-market confirmatory trials will later verify their actual impact on patient outcomes,” said Han. “However, those surrogate measures have received increasing attention because many drugs approved through accelerated approval have delayed or failed to confirm clinical benefits in post-marketing trials.”
While regulatory flexibility can help bring novel treatments to patients more quickly, it can also increase uncertainty about their safety and effectiveness, the researchers argue.
“A drug is clinically innovative only if it leads to meaningful improvements in patient outcomes, not just because it has the potential to do so. That’s why it is critical to monitor real-world performance, especially when approval is based on surrogate endpoints and less rigorous trial designs. Regulatory flexibility should not come at the cost of patient safety and efficacy,” Han said.
Of the drug types approved, drugs for cancer came out on top at 27% of the drugs approved by both the FDA and EMA between 2012 and 2022. For the first-in-class drugs treating cancer in the study cohort, about 90% were based on surrogate measures of efficacy.
These findings are consistent with prior research showing that faster review and surrogate endpoints are commonly used in oncology trials. “The urgency of treating life-threatening cancers has led to federal initiatives like the 21st Century Cures Act, which introduced the Real-Time Oncology Review program to speed up [the] approval process,” explained Han. “There are also strong financial incentives for manufacturers to accelerate the approval process for oncology drugs, given the high price tag of oncology drugs. Reflecting these, cancer drugs made up the largest share of first-in-class approvals in our cohort.”
The study findings suggest there is already a high degree of regulatory flexibility applied to first-in-class drugs, and the researchers suggest that regulators may need to consider the precedent this sets.
“When a drug is approved based on limited clinical evidence, such as surrogate measures used under accelerated approval, clear post-marketing oversight is essential to confirm whether the drug is effective and safe as expected,” Han said.
“However, previous experience has shown that there are limitations in the FDA’s ability to withdraw accelerated approval drugs from the market, even when post-marketing trials are delayed or fail to confirm effectiveness and safety. Therefore, strengthening post-marketing oversight would be an important focus in shaping the future regulatory landscape to ensure the thoughtful introduction of first-in-class drugs,” Han concluded.
Reference: Han J, Kesselheim AS. First-in-class drugs experienced different regulatory treatment in the US And Europe. Health Aff. 2025;44(3):265-273. doi: 10.1377/hlthaff.2024.01072
About the interviewee
Dr. Jihye Han, MPH, is a research specialist within the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School. Her research focuses on drug regulation and pricing policy to ensure safe, affordable access to medicines.
