Analyzing the FDA’s Approach to Diversity In Clinical Trials

Analyzing the FDA’s Approach to Diversity In Clinical Trials

Certain groups remain underrepresented in clinical research. The FDA has taken steps to address inequities in clinical trials by releasing guidance to sponsors and other regulated entities and included steps on how to address gaps in diversity. Diversity in clinical trials is critical because it helps to ensure that new drugs and medical devices are safe and effective for all populations. 

How did we get here? In 2016, the FDA released their first guidance related to increasing diversity in clinical trials. At this time, sites were only required to ask, “Do you identify as Hispanic or Latino?” the second question being, “Which of the following five racial designations best describes you?” While this is a great start, this still leaves a lot of room to collect much more valuable diversity metrics and data points. 

In November 2020, the FDA released a guidance called ‘Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs’. This document provided approaches on how to increase trial enrollment of underrepresented populations. This guidance provides the foundation for expanding access to clinical trials. 

In April 2022, the FDA also issued a draft guidance called ‘Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials’. This guidance provides recommendations to sponsors developing medical products on the approach for developing a Race and Ethnicity Diversity Plan for their studies. 

First, let’s dive into the November 2020 guidance. In this document, ‘FDA recognizes that some eligibility criteria have become commonly accepted over time or used as a template across trials, sometimes excluding certain populations from trials without strong clinical or scientific justification (e.g., older adults, those at the extremes of the weight range, those with malignancies or certain infections such as HIV, and children).Further, it goes on stating that ‘Unnecessary exclusion of such participants may lead to a failure to discover important safety information about use of the investigational drug in patients who will take the drug after approval. Therefore, broadening eligibility criteria in later stages of drug development for the phase 3 population increases the ability to understand the therapy’s benefit-risk profile across the patient population likely to use the drug in clinical practice.’

There are three key objectives of the guidance: 

1. Broadening eligibility criteria to increase diversity in enrollment 

   • Some patients may be unable to participate without reasonable accommodations (e.g., patients with physical and/or mental disabilities, non-English speakers, patients who work and require evening or weekend hours, and some older adult patients with limited access to transportation).
   • Developing eligibility criteria and improving trial recruitment so that the participants enrolled in trials will better reflect the population most likely to use the drug, if the drug is approved, while maintaining safety and effectiveness standards
   • • Through study design
       • # of visits
       • Flexibility in visit windows
     • Through technology
       • Consideration of Digital Health Technology (DHT) and tools to replace in person participation (where possible) in addition to eConsent.
         • In this document, a digital health technology tool refers to any sensor, device, or component that:
           • Detects and measures a physical or chemical characteristic (e.g., blood pressure).
           • Converts this measurement into an electronic signal.
           • Often transmits the recorded data to remote databases (e.g., ambulatory blood pressure monitors).

2. Study design and conduct considerations for improving enrollment

   • Develop inclusive trial practices
     • Ensure a representative sample of the population – consider eliminating or modifying the criterion. For example, if there are unreasonable risks to participants with advanced heart failure, but enrollment of those with milder disease would be appropriate, the exclusion criteria should specifically define the population of heart failure participants that should be excluded.
     • Change or remove exclusion criteria from phase 2 studies, if possible.
     • Enroll patients who reflect the characteristics of the clinically relevant population:
       • Children (where appropriate)
       • Women
       • Racial and ethnic minorities (Why? Because analyzing data on race and ethnicity may assist in identifying population-specific signals).
   • According to the FDA, here are some avenues that can be explored to lower the burden of participating in a clinical trial:
     • Review who is impacted:
       • Older Adults, children, patients with disabilities or cognitive impaired individuals
       • Patients in rural areas
       • Patients who would suffer financially if participating in a trial (missing shifts at work or having to pay for childcare while visiting a site)
       • Additionally, mistrust of clinical research among certain populations also impacts enrollment

3. Discussing methods for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.

   • Early engagement with patient advocacy groups, experts and patients with the disease to solicit feedback regarding trial design to ensure support from relevant stakeholders – most importantly potential trial participants.
   • Where medically appropriate, consider re-enrollment of participants from early- to later-phase trials.
   • Consider open-label extension studies with broader inclusion criteria after early-phase studies to encourage participation by all participants (including those who have received the placebo during an early phase trial) – and to ultimately, provide access to the investigational treatment to all participants.

Broadening eligibility criteria and using more inclusive enrollment practices as outlined in the 2020 guidance can significantly enhance the quality of studies. This will ultimately lead to: 

• Better Representation: The study population more closely reflects the real-world patients who will use the drug if approved.
• Improved Safety Detection: A wider range of participants allows for the discovery of safety information that might be missed in a more narrow field of participants.<
• Informed Benefit-Risk Analysis: By including a more diverse population, researchers gain a clearer understanding of the therapy’s benefits and risks throughout later development stages (phase 3). This knowledge helps determine if the drug is truly suitable for the intended patient population in clinical practice.

The April 2022 guidance focused more on sponsor initiatives to enhance diversity in clinical trials. Sponsors play a pivotal role in developing and submitting comprehensive Diversity Plans (DP), a cornerstone for fostering inclusivity and enhancing the effectiveness and safety of medical products. The FDA expects sponsors to develop a comprehensive strategy for each medical product to enhance enrollment of underrepresented racial and ethnic groups in clinical studies, as described below through various means.

Understanding the Guidelines:

As per the information from the April 2022 guidance, sponsors are mandated to submit Diversity Plans for all medical products, especially during critical phases such as Investigational New Drug (IND) and Investigational Device Exemption (IDE) applications.

• For IND applications, sponsors must submit the DP as early as possible during drug development or no later than when seeking feedback regarding pivotal trials.
• For IDE applications, the DP should be included as part of the investigational plan submitted.

Key Components of the Diversity Plan:

The Diversity Plan should define enrollment goals for underrepresented racial and ethnic participants, emphasizing early integration into clinical development processes. 

It must review pertinent data indicating any differential safety or effectiveness associated with race or ethnicity concerning the investigational product (IP) itself.For drug development, this means reviewing and analyzing pharmacokinetic (PK), pharmacodynamic (PD), and pharmacogenomic data. Device development necessitates examining factors that may impact device performance across diverse populations, such as phenotypic, anatomical, or biological variations.

Additionally, the plan should describe with great detail strategies for assessing race and ethnicity alongside other covariates. It should facilitate exposure-response analyses, inform dosing regimens for drugs, and evaluate the impact of factors like skin pigmentation on device performance.

• The DP should address continuous monitoring and pediatric studies.In order to ensure ongoing vigilance, sponsors must incorporate mechanisms for continuous data monitoring throughout the product lifecycle to identify any disparities in safety or effectiveness associated with race and ethnicity. Moreover, the plan should encompass pediatric studies integral to the overall product development process.

In setting enrollment goals and devising strategies, sponsors are encouraged to leverage diverse data resources, include published literature, and collaborate with stakeholders to enhance inclusivity and efficacy in clinical trials.

In conclusion, the formulation and submission of a robust Diversity Plan signifies a commitment to equitable healthcare and patient-centric research practices. By prioritizing the inclusion of underrepresented populations and diligently monitoring for disparities, sponsors not only adhere to regulatory mandates but also foster a culture of diversity and inclusivity essential for advancing medical science and improving patient outcomes.

Written By

Hannah Kulkarni, Customer Success Manager III at CRIO

Marc Wartenberger, Sr. Director – Security, Corporate QA and Compliance at CRIO