Analysis: The majority of novel drugs approved by FDA rely on evidence from a single pivotal trial

An analysis by AgencyIQ shows that the FDA is increasingly relying upon evidence obtained from a single pivotal study to demonstrate the safety and efficacy of novel drug products. In calendar year 2024, 66% of all new molecular entities approved by the Center for Drug Evaluation and Research (CDER) relied on evidence from just one clinical trial listed in original labeling.

Background: What makes a drug “new” or “novel” to the FDA?

• Novel drug products are defined as products that have never been approved for any indication. If a drug was previously approved for cancer, but is now approved for a cardiology condition, it would not be considered novel. The FDA also refers to novel products as “new molecular entities,” or NMEs. While the definition of NME has changed over the years, it can sometimes include a combination product consisting of at least one drug that has previously been approved. Data on these novel approvals are published throughout the year by both the Center for Drug Evaluation and Research (CDER). AgencyIQ compiles these data using information in approval letters, labeling and review packages posted to the Drugs@FDA database.
• The overall volume of NMEs approved by the agency has remained relatively stable for the last seven years despite the widespread disruptions to typical industry and agency activities wrought by the Covid-19 pandemic. While the total number of novel drugs approved by CDER dipped to 37 in 2022, the agency recovered with 55 approvals in 2023, the second highest in a calendar year since 2011. The overall number of NMEs approved in 2024 (50) is on par with the volumes of the past decade.

AgencyIQ has identified and tracked a noteworthy trend – industry and FDA’s increasing reliance on a single pivotal trial to support NME approvals

• Quick background: When seeking approval from the FDA, companies must demonstrate “substantial evidence,” as defined in the Federal Food, Drug, and Cosmetics (FD&C) Act, that their product is safe and effective. Traditionally, FDA has interpreted the need for “well-controlled investigations” to mean at least two clinical trials for applications for new drugs or supplemental indications. Over time (with the help of litigation and the passage of the 1997 FDA Modernization Act, or FDAMA), the definition has been updated so that one “adequate and well-controlled investigation” can be sufficient to demonstrate safety and effectiveness if it is supported by “confirmatory evidence.”
• Since the 1990s, the FDA’s acceptance of single pivotal trials has become more common, especially because of the agency’s expanded reviews of products intended to treat, cure or prevent rare diseases or life-threatening conditions for which there is an unmet clinical need. FDA has published and revised guidance offering its perspective on foundational issues and types of confirmatory evidence.
• In a July 2024 analysis, AgencyIQ found that the majority of NMEs approved since 2020 relied on a single pivotal trial. While the median number of pivotal trials was steady at two until 2020, the median has dropped to one trial since. Calendar year 2023 saw the highest number of NMEs approved based on a single pivotal trial, with 35 of 55 products listing just one clinical study in their original labeling.

Data from calendar year 2024 indicate that this trend appears to be the new normal

• Based on AgencyIQ’s latest analysis, 33 of 50 NMEs (66%) approved in 2024 were approved based on one pivotal trial. This percentage aligns with the trend observed since 2020. In 2024, 10 approvals were based on evidence from two trials, with seven more relying on three or more trials.

*The four studies indicated were blinded re-reads of previously conducted randomized controlled trials using various imaging modalities.

• Digging into NME approvals based on a single pivotal trial, about 70% of approvals received orphan drug designation and 20% received accelerated approval. Like 2023 (and years before), most of these products got their stamp of approval from the agency’s Office of Oncologic Diseases (OOD), followed by the Office of Cardiology, Hematology, Endocrinology, and Nephrology (OCHEN). On the other hand, the Office of Neuroscience (ON) seems to have backed off. While 2023 saw nearly a quarter of single trial approvals coming from ON, that office approved only two NMEs in 2024 based on this level of evidence.

Analysis

• The main takeaway: The use of single pivotal trials to support NME approvals appears to be the new normal. As AgencyIQ has noted before, the data indicates that the agency reserves this posture for serious conditions with unmet need, such as orphan designations or oncology indications. That said, the approach continues to be leveraged for a more diverse array of indications. This approach, if considered more widely, could have implications for both the economics of clinical development and the depth of evidence stakeholders have regarding approved products.
• The administration transition and other leadership changes may alter this course, though how remains uncertain. AgencyIQ notes that previous CDER Director PATRIZIA CAVAZZONI retired from the agency in January after 4½ years – a tenure that aligns with the increased acceptance of single pivotal trials. HHS and FDA will usher in new leadership once President DONALD TRUMP’s nominees are confirmed by the Senate. These nominees have supported disruptions to the agency’s status quo.

To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editor of this item, please email Alexander Gaffney (agaffney@agencyiq.com) and Jason Wermers ( jwermers@agencyiq.com)

Key Documents and Dates

• Drugs@FDA Database