Inaccessibility, inadequate engagement, and lack of trust—these are just some of the issues that limit inclusion and lead to a lack of diversity in clinical trials. So, why is diversity in clinical trials important? Diversity is important because there are many examples of drugs that behave differently from one population to another. Failing to understand these differences at the clinical trial stage could leave future patients at risk of a potentially avoidable safety issue or suboptimal efficacy. Put simply, a diverse and inclusive study population helps ensure an adequate understanding of how a drug works and how safe it is across the entire target population.
History of Inclusivity in Clinical Trials
Drug development has had an inconsistent past when it comes to the inclusion of different populations in clinical trials. Historically, there have been two extremes. One extreme was exclusionary, where unless you belonged to a favored group, such as white, adult males, you would not be considered. The other extreme was exploitative, where researchers experimented on vulnerable groups, such as minorities or prisoners, to spare more privileged classes. Ethical and legal safeguards, including the establishment of Good Clinical Practice, have been put in place to ensure the safety of clinical trial participants. Together, these protections have helped to significantly reduce the likelihood of an exploitative clinical trial being conducted. However, despite these successes and despite laws that encourage diversity and inclusivity, clinical trials may still suffer from a lack of inclusion.
Why are Inclusive Clinical Trials Important?
If you were to ask someone off the street to suggest some important characteristics to consider for ensuring a diverse and inclusive population, you would likely hear terms like age, sex, race, and ethnicity. These identifying traits not only provide a framework for how we think about ourselves and others within our society, but they also touch on key considerations that can impact many aspects of our health and wellbeing. Such traits, also known as intrinsic factors, are exceptionally important when it comes to drug development and can meaningfully affect both medical decision making and health outcomes (e.g., who receives what drug and at what dosage based upon predicted safety and effectiveness). There are numerous examples of drugs that behave differently depending upon intrinsic factor variability. For example, individuals of certain races may metabolize a particular drug more quickly than individuals belonging to other races. Likewise, because renal function tends to decline as we get older, a geriatric patient might experience different drug elimination characteristics than a young adult. These variabilities can easily lead to overexposure or underexposure to the drug. Dose adjustments may be required to ensure adequate safety and effectiveness across the entire target population. Given this, it is incumbent upon Sponsors to ensure that their clinical trial designs are appropriately representative of the target population. Equally important are the efforts of regulators to provide the guidance that Sponsors need to accomplish this goal.
Legal Framework to Encourage Inclusive Clinical Trials
Laws promoting diversity and inclusivity in clinical trials were born because regulators understood that there was a lack of diversity in many clinical trials and that drugs were being approved without adequately fulfilling requirements to show that they were safe and effective across the entire target population. FDA has been addressing diversity issues since the 1980s, and there have been several legislative and regulatory efforts over the years to encourage inclusivity in clinical trials, including:
- FDA Guideline for the Format and Content of the Clinical and Statistical Section of New Drug Applications (1988), which called for safety and effectiveness evaluations on subpopulations to gain insight into variabilities associated with intrinsic factors.
- Guideline for the Study of Drugs Likely to be Used in the Elderly (1989), which sought to encourage routine and thorough evaluation of the effects of drugs in elderly populations. This guidance was an important achievement given the potential for key differences in pharmacokinetics and pharmacodynamics (e.g., age-related effects, renal/hepatic impairment) in this population versus younger populations.
- Commitment in 1991 by Dr. David Kessler, newly appointed commissioner of the FDA, to women’s health, including research initiatives and examining the role of women as clinical trial participants. As a result of these efforts and a new statutory requirement in 1998, analysis for sex differences has become a routine part of new drug applications.
- Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (1993), which removed restrictions from a prior (1977) guideline prohibiting women of childbearing potential from participating in clinical studies.
- Establishment of the FDA Office of Women’s Health (1994) to foster more adequate representation of women in clinical trials.
- FDA Guidance for Industry and FDA Staff: Evaluation of Sex-Specific Data in Medical Device Clinical Studies, which provided recommendations for enrollment, analysis, and reporting of sex-specific data in clinical studies.
- National Institutes of Health (NIH) Revitalization Act of 1993, which stated that women and members of minority groups and their subpopulations must be included in all NIH-funded clinical research.
- Pediatric Research Equity Act (PREA; 2003), which was enacted to address the lack of pediatric use information in drug product labeling. PREA requires applications or supplements submitted under section 505 of the Food, Drug, and Cosmetic Act or section 351 of the Public Health Service Act to contain a pediatric assessment (unless waived, deferred, or otherwise excluded from the requirement). Additionally, PREA grants FDA the authority to require holders of approved NDAs and BLAs for marketed drugs and biologics to conduct pediatric studies under certain circumstances.
- Establishment of the FDA Office of Minority Health and Health Equity (2010), which was created under the authority of the Affordable Care Act, to advise FDA on ways to reduce health disparities among racial and ethnic subgroups.
- Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012: Section 907, which directed FDA to investigate how well demographic subgroups (sex, age, race, and ethnicity) are included in clinical trials and if subgroup-specific safety and effectiveness data are available for medical products submitted to FDA for marketing approval. This statute also required FDA to provide Congress with an action plan for 1) improving the collection and quality of data related to demographic subgroups in summaries of product safety and effectiveness and in labeling, 2) determining the inclusion (or not) of these data in product labeling, and 3) improving the public availability of such data.
- FDA Reauthorization Act of 2017 (FDARA), Section 610(a)(3), which established a mandate for FDA to engage the public and release formal guidance addressing methodological approaches that a manufacturer or Sponsor of an investigation of a new drug may take to 1) broaden eligibility criteria for clinical trials and expanded access to trials, 2) develop eligibility criteria in a way that clinical trials more accurately reflect the patients most likely to receive the drug, and 3) apply these criteria in a manner that is appropriate for drugs intended to treat rare diseases and conditions.
How to Increase Inclusivity & Diversity in Clinical Trials
There are many approaches to address the lack of diversity in clinical trials. As part of their guidance on enhancing the diversity of clinical trials, the FDA has provided several recommendations across the following key focus areas:
Broadening Eligibility Criteria to Increase Diversity in Enrollment
- Carefully examining exclusion criteria to ensure they are necessary to help assure the safety of trial participants and achieve study objectives while not imposing unnecessary limits on study participation
- Characterizing—early in clinical development—drug metabolism and clearance in populations that may metabolize or clear the drug differently (e.g., the elderly and patients with liver or kidney dysfunction), with the goal of avoiding inappropriate exclusions later in development
- Considering adaptive clinical trials, which allow for pre-specified trial design changes during the trial, including altering the trial population
- Considering a pediatric development program early
- Considering enrolling a broader participant group as part of the secondary analyses, even when the primary analysis population is narrowed
- Considering pharmacokinetic sampling in pregnant women when appropriate
Study Design and Conduct Considerations for Improving Enrollment
- Making trial participation less burdensome for participants
- When possible, reducing the frequency of study visits and considering whether flexibility in visit windows or electronic communication tools could be employed
- Offering financial reimbursement for expenses associated with participation in clinical trials (e.g., travel and lodging)
- Adopting enrollment and retention policies that enhance inclusiveness
- Working directly with communities to address participant needs and to involve patients, patient advocates, and caregivers in the design of clinical trial protocols
- Ensuring clinical trial sites include locations with higher concentrations of racial and ethnic minority patients
- Incorporating collaborative strategies for public outreach and education
- Holding recruiting events often and during convenient hours in trusted locations
- Considering expanded access when appropriate
Broadening Eligibility Criteria for Drugs Intended to Treat Rare Diseases or Conditions
- Engaging patient advocacy groups early for suggestions on trial design
- Re-enrolling patients from early-phase trials into later-phase trials when studying the effectiveness of treatments for rare diseases when such an approach would be medically appropriate, avoids selection bias, and presents no unreasonable anticipated safety issues
- Making available an open-label extension study after early-phase studies to encourage participation by ensuring that all study participants will ultimately have access to the investigational treatment
The key to all these recommendations, from a Sponsor’s perspective, is to think deeply about what the study is intended to show and how the study can be designed to ensure that the intended target population is adequately assessed. This also requires Sponsors to recognize and remove any barriers to study participation, including those that might not be blatantly obvious at first glance. For this, it is often helpful to reach out to other drug development experts for unbiased insights on your study design and your clinical program overall. This is one of the many services that Allucent is proud to offer to our clients.
Conclusions
Clinical trials have come a long way over the years in eliminating exploitative practices and promoting inclusivity. These improvements have come from a recognition by lawmakers, regulatory authorities, drug developers, patients, and patient advocates of the importance of diverse clinical trials. Having representative patient populations in clinical trials helps ensure the safety and effectiveness of drugs for everyone. Still, there remains much room for improvement to ensure that all Sponsors are mindful and vigilant about their study designs and any potential barriers to study participation that may limit diversity and inclusion. Ensuring accessibility, encouraging early engagement, and fostering communication and trust with patients benefits all stakeholders and shows a dedication to inclusivity and patient outcomes. Allucent’s experts have extensive experience helping clients design clinical studies that are streamlined, scientifically defensible, and inclusive. Contact us to learn more about Allucent’s approach to study design and our other drug development services.
References and Additional Reading
- FDA Report: Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products (August 2013)
- Strategies Addressing Barriers to Clinical Trial Enrollment of Underrepresented Populations: a Systematic Review (Heller et al., 2014)
- FDA OMHHE Health Equity Lecture Series: Achieving Diversity, Inclusion, and Equity in Clinical Research (9/22/2020; [Recording] [Slides])
- Diversity in Clinical Trial Participation (FDA website)
- Women’s Health Research (FDA website)
- Minority Health and Health Equity (FDA website)
- Minority Health Resources (FDA website)
In addition to the above, FDA released 6 public service announcements, a blog, and an infographic as part of a 2016 outreach campaign to encourage people of diverse races and ethnicities to participate in clinical trials (FDA Office of Minority Health Clinical Trial Diversity Stakeholder Communications Toolkit). More recently, FDA refreshed their guidance on the topic of enhancing the diversity of clinical trial populations and held a webinar on December 16, 2020 to share FDA’s most recent assessment of clinical trial diversity and FDA’s efforts to advance diverse participation in clinical trials.