National Center for Health Research, August 6, 2019
National Center for Health Research’s Public Comments on
Enhancing the Diversity of Clinical Trial Populations-Eligibility Criteria,
Enrollment Practices, and Trial Designs; Draft Guidance for Industry; Availability
Thank you for the opportunity to express our views on the critical issue of increasing diversity in clinical trials, and how FDA should be addressing this longstanding issue through guidance to its Centers and broadening clinical trial eligibility requirements.
The National Center for Health Research (NCHR) is a non-profit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
For many years, NCHR has been strongly encouraging FDA to expand the diversity of clinical trials for drugs and medical devices to include more elderly patients, women, children, and individuals from a broad variety of racial and ethnic groups. Too frequently, trials of drugs and devices which lead to FDA approval are still conducted mainly on white adults under the age of 65. In some cases, treatments intended for men and women are primarily tested on one or the other, and not analyzed separately by sex. In 2012, Congress passed a law urging the FDA to do a better job of expanding clinical trial participants to take into account the factors of age, race and ethnicity, and sexual differences.
There are reasons why a drug or device may be less safe or less effective for women, children, older patients, or certain ethnic or racial subgroups. These differences in results for under-represented subgroups may not be minor or trivial. According to a review of 167 new molecular entities approved by FDA between 2008 and 2013, approximately 20% had differences in exposure or response across racial or ethnic groups, or both.1
Lack of diversity in clinical trials has real world consequences on the knowledge about the effectiveness and safety of medical products. Our research has identified several products that were less effective for certain subpopulations, which have important implications for clinicians and patients in choosing appropriate care. In addition, the lack of age-related data has enormous consequences for Medicare, which is required to cover substantial costs for medical products that have not been studied on more than a few patients who were over 65. Such lack of meaningful age-related testing results in the waste of many millions of taxpayer dollars on ineffective or even adverse medical outcomes.
In its proposed draft guidance, FDA has recognized the need to broaden eligibility criteria in order to increase diversity in enrollment. However, there has not been sufficient incentive for drug and device sponsors to actively recruit more women, minority patients, children, and older patients. In the past, FDA focused on the need for patient groups to encourage under-represented demographic groups to apply to clinical trials, rather than focusing on what companies should do to recruit under-represented patients to participate. What is needed is an incentive for companies to ensure diversity, and the most effective incentive is if the FDA makes it clear that the agency will not approve medical products for all populations if the product was not tested for safety and efficacy on sufficient numbers of patients representing major demographic subgroups.
Certainly FDA’s draft guidance recommendation to make trial participation less burdensome for participants is a positive step, but that in itself will not result in the recruitment of a broader section of demographic subgroups who have been too often largely excluded in the past. However, advising potential trial participants of possible reimbursement of travel and other trial expenses, as FDA’s draft guidance also recommended, may well help recruit older patients, parents of young children and caretakers of family members, and others who may otherwise lack the financial resources to enable them to participate in clinical trials.
We agree that measures to adopt enrollment and retention practices that enhance inclusiveness as outlined in the draft guidance should have a positive impact on the recruitment of broader demographic subgroups. However, these should be “strongly encouraged” and not simply “considered.” The same is true for the recommendations for trial design and methodological approaches, which are also intended to broaden clinical trial participation. The lack of meaningful incentives for sponsors to broaden clinical trial eligibility and recruitment has been a primary cause of why these various subgroups have remained under-represented for so long.
FDA issued a 1993 guidance for the inclusion of women trial participants in the clinical evaluation of drugs, and that situation has improved although more needs to be done in terms of using the data to restrict labeled indications when appropriate. NCHR was critical of the 2014 FDA Action Plan for efforts to include more elderly patients in clinical trials as lacking in specificity. This latest draft guidance is a chance for the agency to rectify these clearly identified and longstanding shortcomings.
The agency’s work with the Office of Minority Health, the HHS Office for Human Research Protections, and NIH, as well as the FDA Consumer page, indicates progress in improving enrollment diversity practices in clinical trials. But our research indicates that much remains to be done.
We also point out that while this guidance pertains to CDER and CBER, diversity in clinical trials is also essential for medical devices, particularly implants. Our research on devices approved through the PMA pathway following Advisory Committee consideration in 2014-2017 found numerous devices were tested primarily on white patients.2 For devices that included information about race, white participants made up 69%-99% of participants. Most devices did not include information about the number of participants over the age of 65 years and many did not specify the range of ages of participants in trial(s).
In addition, of devices intended for both men and women, 45% (9/20) of devices were approved based on pivotal trials where less than 35% of participants were of the minority gender. The implications of lack of diversity in clinical trials for high-risk medical devices are important. For example, Lutonix, a drug-coated balloon catheter used to open a blocked artery, was found to be beneficial for men but not women; women’s outcomes were better with of the control balloon catheters. A colorectal cancer test, Epi proColon, was, even though it was less accurate for patients older than 69 years of age than for patients less than 60 years old. It was also found to be less accurate for black patients compared to white.
Thank you for the opportunity to comment on this important medical and patient issue.
National Center for Health Research can be reached at firstname.lastname@example.org or at (202) 223-4000.
- Ramamoorthy A, Pacnowski MA, Bull J, Zhang L. Racial/ethnic differences in drug disposition and response: Review of recently-approved drugs. Clinical Pharmacology & Therapeutics. 2015;97(3):263-273. https://www.ncbi.nlm.nih.gov/pubmed/25669658
- Fox-Rawlings SF, Gottschalk L, Doamekpor LA, Zuckerman D. Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients? Milbank Quarterly.2018;96(3):499-529. https://onlinelibrary.wiley.com/doi/abs/10.1111/1468-0009.12344