What Do The New FDA Postmarketing Data On Underrepresented Populations Draft Guidelines Mean For Pharmaceutical Companies?
By Life Science Connect Editorial Staff
In April 2022, the FDA released draft guidelines for increasing diversity in clinical trials. These requirements can be challenging for pharmaceutical and biotech companies, who often struggle to recruit enough patients for their trials. When sponsors fail to meet diversity requirements during their clinical trials, they need an alternative option.
Therefore, on Aug. 11, 2023, the FDA released a new set of draft guidelines, Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products. These guidelines create a path forward for companies that need time after approval to thoroughly examine a drug’s efficacy and safety for specific underrepresented patient populations.
How Can Sponsors Use These Guidelines?
Historically, some patient populations have been excluded from clinical trials, and the FDA’s diversity guidelines and these new draft guidelines are both intended to avoid those mistakes in current and future research.
Nevertheless, the FDA recognizes that clinical trials sometimes can’t recruit enough patients from specific groups to meet the new requirements. The FDA doesn’t wish to withhold lifesaving therapeutics from patients who need them, so it designed an alternative approach that allows companies to continue to study their product’s effectiveness on diverse populations after approval. These guidelines explain how the FDA will require or request this data and what design and statistical considerations are necessary.
Why Are These Guidelines Necessary?
Proving safety and efficacy across multiple patient populations is essential to ensuring that the drugs approved for the U.S. population are appropriate for all patients who need them. Demographic factors, such as sex, race, ethnicity, or age, affect a disease’s epidemiology and impact. Likewise, drug toxicity can vary according to demographics for several reasons, including genetics, metabolism, elimination, and physiology.
External factors such as diet, socioeconomic status, culture, environmental exposure, or interactions between various factors also affect how certain patients respond to a given treatment. Yet clinical trials continue to underrepresent particular populations based on race, ethnicity, sex, or age. The FDA has released multiple guidance documents to address this issue and encourage sponsors to make concerted efforts to recruit marginalized groups based on race, ethnicity, sex, age, geographic location, gender identity, socioeconomic status, disability, pregnancy status, lactation status, and comorbidity.
Ideally, these groups would be included early in the drug development process. Early information provides vital insights into pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety that direct future clinical trials and improve drug development overall. However, when sponsors can demonstrate that their drug is unique and urgently needed, the FDA may approve it but require postmarketing data to show its effects on populations not satisfactorily included in the clinical trials.
When Will The FDA Require Postmarketing Data?
Postmarketing data requirements are deemed appropriate when a drug carries a severe known risk or its potential for serious risks needs to be assessed. For example, if there is data to suggest that a drug is more likely to create serious adverse events (SAEs) in specific populations, such as racial or ethnic minorities or older patients, but the clinical trials did not include adequate representation from those groups, then the FDA may require sponsors to conduct further research after approval to evaluate safety and efficacy. The agency outlines two primary methods by which sponsors may be required to provide this data: postapproval studies or clinical trials. Postmarket clinical trials are only recommended if the FDA believes that studies alone are insufficient.
The FDA would require sponsors to conduct one of these options as either a postmarketing requirement (PMR) or may initiate a written agreement as a postmarketing commitment (PMC). Sponsors must also provide any information that the FDA requests in the PMR or PMC, such as timetables for study or clinical trial completion and periodic status reports, including annual reports. If a drug is granted accelerated approval, the FDA requires a confirmatory trial representing the demographics of U.S. patients presumed to take the drug.
How Can Sponsors Design Postmarketing Data Studies?
There are multiple ways to gather postmarketing data, and the FDA has special considerations for each of the following: single-arm trials, randomized trials, real-world data (RWD) sources, and pooled studies.
Single-arm trials can use a sample size calculation that rules out historical safety or efficacy rates to ensure the product is safe and effective for the given subpopulation. Alternatively, they can employ a Bayesian posterior probability model to exclude historical rates at specific levels, such as 90% or higher. Another method is to “borrow” patients from pre-approval studies to gain a larger sample size of a particular subpopulation. Regardless of the methodology, single-arm trials should collect PK and possibly PD information to examine differences in the subpopulation. Also, these trials can create a separate cohort that can be opened or closed simultaneously with the primary cohort or operate independently. This stand-alone cohort can continue running during the NDA or biologics license application (BLA) process or remain open and add more patients after approval to continue studying this subpopulation.
Some sponsors plan postmarket randomized trials at the time of the NDA or BLA submission and can revise them to obtain additional data for the subpopulation of interest. Trials running during NDA or BLA submission may be modified with FDA knowledge and approval. Another option is to stratify based on the subpopulation of interest, such as if effectiveness might vary depending on a person’s race, ethnicity, sex, or age. These stratified studies can focus on the benefits and risks to the underrepresented group. Regardless, the trial must collect PK and possibly PD information to examine the effects of the drug on the subpopulation thoroughly.
RWD sources like EHRs and registries are a rich opportunity for sponsors to gather postmarketing data, but they come with complexities. Before choosing this option, sponsors must carefully assess this data to test whether it can satisfactorily answer the questions relevant to the subpopulation. Also, working with protected health data raises many logistical issues that should be addressed with the FDA in advance to receive feedback and guidance early on.
Sponsors may conduct meta-analyses of randomized trials that are similarly designed to target and examine the subpopulation of interest if the pooled studies’ combined participants represent an adequate sample of the subpopulation of interest. It’s also possible to use pooled studies to evaluate the drug across disparate subpopulations if there are enough patients and data to meet the criteria. When planning this type of study, sponsors should first seek feedback from their relevant review division to determine what defines adequate representation.
What Can Sponsors Do Now?
The FDA advises sponsors to plan for diversity requirements by referring to the guidelines described in Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials. Ideally, sponsors should work with the FDA early in their drug development process to agree on accurate benchmarks for underrepresented populations and submit a diversity plan.
Next, sponsors should create strategies for recruiting enough participants to meet these benchmarks. The FDA published Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry in November 2020 to help sponsors develop strategies for enrolling more diverse patients, including site selection. Sponsors can also use this guidance when designing postmarketing studies. Another option is to use foreign clinical data to examine underrepresented populations. But, if a sponsor uses clinical trial data primarily comprising patients outside of the U.S., they need to demonstrate that their data is relevant to the U.S. population and medical practice. In this instance, the FDA may request additional studies or trials to examine efficacy and safety further.
However, if sponsors’ best efforts to recruit diverse patients fail to meet appropriate benchmarks, they should talk to the FDA about next steps. The FDA may determine that additional postmarketing data is needed and add additional information to drug labeling when deemed necessary.
As with other FDA draft guidelines, these requirements are not legally binding until fully adopted, and sponsors can contact the FDA to discuss alternative approaches to those described in this document. Draft guidelines are intended to alert sponsors to the FDA’s intentions so they can strategically plan to meet new regulatory requirements once they go into effect. Public comments can be submitted to the FDA’s website until Oct. 10, 2023.
References
- Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products | FDA
- Diversity Plans to Improve Enrollment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials; Draft Guidance for Industry; Availability | FDA
- Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry | FDA