FDA draft guidance focuses on postapproval trial diversity data

Sponsors can employ several postmarketing strategies to beef up safety and efficacy data on populations that were under-represented in initial clinical trials of drugs and biologics, according to new draft guidance issued by the US Food and Drug Administration (FDA).

The agency’s draft guidance, Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products: Guidance for Industry lays out a number of pathways for obtaining these data after product approval, including single-arm trials, randomized trials, real-world data and meta-analyses that pool data extracted from other studies.

The document indicates FDA’s willingness to work with sponsors on the chronic problem of recruiting a diverse clinical trial population. Women, older adults, racial and ethnic minorities and non-heterosexual subjects are consistently under-represented in both federally and privately sponsored drug trials.

Last year, the FDA published draft guidance recommending that sponsors include a plan to increase diversity when proposing clinical trial designs for investigational products to agency reviewers. But this new guidance acknowledges that this ideal may be difficult to achieve.

“The Agency strongly recommends sponsors obtain information from a diverse, representative patient population early in drug development before initial approval but recognizes that in certain circumstances this information may be limited and must be balanced within the benefit-risk framework, including whether there is unmet medical need and the importance of the product within the overall therapeutic armamentarium … if despite the sponsor’s best efforts, such information could not be obtained prior to initial approval of a drug, this information can be obtained in the postmarketing setting.”

The draft guidance notes that FDA can use two methods to ask for additional diversity data: the postmarketing requirement (PMR) and the postmarketing commitment (PMC).

A PMR is issued if the FDA determines that a sponsor’s adverse event or active risk identification and analysis (ARIA) is insufficient. “For example, FDA may require an applicant to evaluate the incidence rates of certain serious adverse events among U.S. racial and ethnic minorities or older patients when there are data to suggest that those adverse events may occur at a higher rate in these populations but an insufficient number of participants from these populations participated in the pivotal trial to adequately evaluate the signal,” the draft says. “This may include evaluation of a potential serious risk related to reduced effectiveness in a subpopulation of patients (e.g., defined by race, ethnicity, sex or age) compared to the overall populations.”

A PMC, on the other hand, is a written agreement between the agency and the sponsor to conduct postmarketing studies. “FDA may enter into a written agreement with the applicant to collect data from clinical trials, postmarketing studies, or additional data sources to further characterize clinical benefit or safety in those sub-populations under a PMC. For example, if there is a lack of data in a certain subpopulation of patients (e.g., defined by race, ethnicity, sex, age), FDA may enter into a written agreement with the applicant to collect data under a PMC to obtain additional safety and efficacy data in that subpopulation.”

There are several ways to obtain these data, the draft notes.

Single-arm trials can be designed with a sample size calculation to rule out a historical rate of safety or efficacy to provide assurance that the product is safe and effective in a particular subgroup.

These studies can include data on patients from pre-approval studies to hit the required sample size. They can also enroll and analyze the main study’s under-represented subpopulation in a separate cohort as a parallel arm.

“In some cases, the separate cohort can be actively accruing at the time of the new drug application (NDA) or biologics license application (BLA) submission. For example, if the separate cohort is evaluating a group at high risk for toxicity, the cohort may open after the primary analysis portion of the trial to obtain more safety information prior to enrollment of the higher risk population. Alternatively, the separate cohort may remain open after the primary analysis population to allow for enrollment of a larger number of patients from the underrepresented population.”

Randomized trials that are already planned at the time of application can be revised to enrich the population of interest. Ongoing trials can be modified but, the draft notes, “it is important to consider and discuss with the Agency the rationale for the potential changes and any impact on statistical analyses.”

Real-world data (RWD) can also be employed to support these post approval requirements, the draft notes. These sources can include electronic health records and registries. “Sponsors should carefully assess the adequacy of the RWD to appropriately answer the questions relevant to the subpopulation(s) of interest (e.g., ensuring the RWD source is fit for purpose).”

Finally, meta-analyses of pooled data are also a potential supporting data source.

“Pooling data across trials, if methodologically appropriate, may allow for a meaningful evaluation of the drug in patients from different clinically relevant subpopulations if the clinical studies include an adequate number of patients and sufficient data (PK, PD, efficacy, and safety) from each subpopulation.”

It’s important for the sponsor to work proactively with the FDA to achieve these goals, especially since attempts to conduct required diversity studies after approval will still face the same challenges that confronted the initial attempts to enroll diverse populations.

In some cases, the draft says, foreign clinical data might be necessary to meet the goals.

“If a sponsor submits a marketing application comprised of patients enrolled predominantly outside of the United States, data and rationale should be submitted to support applicability to the U.S. population and medical practice. FDA may request or require studies or trials to further characterize the efficacy or safety of the product in subpopulations relevant to the U.S. population.”

The agency will take public comment on the draft guidance through 10 October 2023.

FDA draft guidance focuses on postapproval trial diversity data

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