Halfway there: Novel drug approvals and their supportive clinical trials so far in 2024

Background: New molecular entities (NMEs)

• AgencyIQ reviews drug approvals from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER is the FDA office in charge of reviewing pharmaceuticals and therapeutic biologics. As such, it doesn’t review things like vaccines, blood products or gene therapies – those products are instead reviewed by CBER. All products are received in one of two forms: A New Drug Application (or NDA, for pharmaceuticals) or a Biologics License Application (BLA, for biologics).
• 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 is published throughout the year by both CDER and CBER. 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 over a decade, even despite the widespread disruptions to typical industry and agency activities wrought by the Covid-19 pandemic. While the total number of novel drugs dipped to 37 in 2022, the agency recovered with 55 approvals in 2023, the second highest in a calendar year since 2011. [ For a look at some other trends, see Agency’s Fiscal Year 2023 in Review].

Halfway through 2024: how are novel drug approvals shaping up?

• The following analysis is a deep dive into the 21 NMEs approved by FDA between January 1, 2024, and June 30, 2024. At this halfway mark, the agency appears to be on track to see approval volumes similar to those of recent years.

• AgencyIQ notes that FDA’s NME approval activity has not been consistent across the first six months of 2024. The regulators were off to a slow start, with just three total approvals in the first two months of 2024. However, things picked back up in March, which saw seven total NME approvals.

Most NMEs approved so far this year relied on one pivotal trial.

• Quick background: When seeking approval from the FDA, companies must demonstrate “substantial evidence,” as defined under 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 litigation and the passage of the 1997 FDA Modernization Act (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 due to 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 perspective on foundational issues as well as types of confirmatory evidence.
• In a recent analysis, AgencyIQ found that the majority of NMEs approved each year since 2020 have relied on a single pivotal trial. While the median number of pivotal trials was steady at 2 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.

• In the first half of 2024, over 70% of approved NMEs listed just one pivotal clinical trial in their original labeling. Based on AgencyIQ’s analysis, 15 of 21 NMEs approved relied on just one trial. Of these products, 40% had received Orphan Designation and ~27% were approved via the Accelerated Approved pathway. Just three approvals were based on evidence from two trials, with three more relying on three or more trials.

• As expected, approvals based on single pivotal trails generally enrolled fewer patients than those with more trials. AgencyIQ found that these trials had mean and median enrollments of 331.2 and 179 participants, respectively. On the other hand, the approvals based on multiple trials enrolled between 701 and 3923 participants total, with an average of 1816 participants.

Diversity remains a challenge as policymaking continues.

• At the end of 2022, as part of the 2023 Consolidated Appropriations Act, Congress gave the FDA new authority to require what the law referred to as Diversity Action Plans (DAPs) for certain clinical studies. Section 3601 of the law amended the Federal Food, Drug and Cosmetic (FD&C) Act to expressly grant the FDA the statutory authority to require DAPs for “a new drug that is in a phase 3 study” or “as appropriate, another pivotal study of a new drug.”
• In late June 2024, FDA unveiled long-awaited draft guidance on diversity action plans. In this document, the agency describes how to design a DAP, which should set enrollment goals using data about the incidence and/or prevalence of a disease in the U.S. population. These goals and any adjustments should be explained through a rationale, and a plan must be developed with specific enrollment and retention strategies. Finally, sponsors must articulate a plan to measure progress toward meeting the goals. [ Read AgencyIQ’s deep dive into the DAP guidance here] The comment period for the draft guidance document is currently open until September 25, 2024. Assuming that the comment period is not extended, and FDA meets its statutory timeline to finalize the guidance within nine months of the closing of the comment period, the guidance could theoretically be put into force by late 2025.
• To better understand how many companies might struggle to comply with FDA’s diversity requirements, AgencyIQ assessed how NME approvals this year have enrolled diverse populations. Quick methods note: The data below were collected from the Clinical Studies section of the original labeling for NMEs approved between January 1 and June 30, 2024. Data was pooled for product approvals that relied on multiple studies.
• Labels provide demographic information in a variety of formats. While some included percentages using the 1997 OMB Directive 15 five minimum categories for “race” (American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; White) and ethnicity (Hispanic or Latino; Not Hispanic or Latino), others only reported the percentage of White participants. As a result, the analysis below uses the categories “White” and “Non-White” to enable comparison.
• For context, the 2020 Census studied the racial and ethnic composition and diversity of the U.S. population using the 1997 OMB Directive 15 categories. “The most prevalent racial or ethnic group for the United States was the White alone non-Hispanic population at 57.8%,” stated the Bureau.
• In the first half of 2024, many novel drugs were approved with relatively few non-White participants. Five products were approved based on pivotal studies enrolling more than 90% White participants: Exblifep for complicated urinary tract infections, Ohtuvayre for chronic obstructive pulmonary disease (COPD); Xolremdi for WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis), Iqirvo for primary biliary cholangitis, and Letybo for the appearance of moderate-to-severe glabellar lines.

• That said, some of these approvals could have satisfied a DAP under the recent draft guidance based on the treatment population’s demographic makeup. This analysis is limited because it does not account for the epidemiology of the disease the products are intended to treat.
• One product was approved despite ample missing demographic data. According to the original label for Day One Biopharma’s Ojemda for pediatric low-grade glioma (LGG), race was not reported for 26% of the 76-person efficacy population.
• This was briefly acknowledged in the review package section on exploratory efficacy analyses, where the agency states, “Due to the limited subgroup sizes (and unavailability of adequate information on race and ethnicity for a high fraction of the patient population) these results should be interpreted with caution.” Upon approval, the sponsor was tasked with a dozen Post-Marketing Requirements (PMRs) and Commitments (PMCs), notably including a confirmatory study for accelerated approval. That said, these requirements and commitments do not specifically request more complete collection of demographic data.
• This is somewhat surprising given that FDA begun using PMRs as a method to address trial diversity concerns for some oncology products in recent years, as AgencyIQ has previously discussed. This type of requirement was given to several accelerated approval confirmatory studies for oncology drugs in 2023, who were instructed to enroll a study population that sufficiently reflects the racial and ethnic diversity of the U.S. patient population with the disease (See Jaypirca (pirtobrutinib) approval letter and Lunsumio (mosunetuzumab-axgb) approval letter). The FDA recently articulated its thoughts on how to collect post-approval data from underrepresented groups in an August 2023 draft guidance, suggesting that this language may seep into more approval letters [ Read AgencyIQ analysis of the draft guidance here.]. AgencyIQ wrote at that time that this is something oncology sponsors should prepare for, especially if the pivotal study relied on a small or homogenous population. Nonetheless, the Ojemda case provides some evidence that the FDA is not using this approach in all cases.

Analysis

• The data indicate a continued trend toward the use of single pivotal trials to support approval by sponsors. According to AgencyIQ’s analysis, this trend began in earnest in 2020, and has only accelerated single that time. In CY 2023, more than 60% of all NMEs approved by CDER were approved on the basis of a single pivotal trial. In H1 2024, more than 70% of all NMEs were approved on the basis of a single pivotal trial. While it’s too early to tell if this trend will hold for the rest of 2024, if it does, it would represent the highest percentage of approvals based on single pivotal trials in FDA history.
• FDA’s apparently increasing openness to single pivotal trials to support the approval of novel drugs represents a huge change in the clinical trial enterprise. While the data indicate that the agency continues to reserve this posture for serious conditions with unmet need (i.e., orphan designations and priority review), recent approvals show that the approach is being leveraged for a more diverse array of indications, especially in the field of neurology. This approach, if considered more widely, could lower the costs of drug development by allowing companies to obtain approval using fewer clinical studies, which are generally costly to companies.
• The data also show that some companies have apparently not moved to diversity their trials despite impending regulatory changes imposed through FDA’s diversity action plan guidance. While these requirements aren’t yet in effect, and likely won’t be until next year at the earliest, the latest approval data indicate that some companies are still falling far short of diverse enrollment expectations.

Featuring previous research by Laura DiAngelo.
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)

Key Documents and Dates

• Drugs@FDA Database