Contributed Commentary by Sheila N. Bello-Irizarry and Lauren Neighbours

August 15, 2017 | In January of this year, FDA released a snapshot report showing the diversity of clinical trial participants in studies conducted in 2015 and 2016. Out of over 31,000 patients who participated in clinical trials for novel products in 2016, 48% of the study participants were women, an increase from 40% in 2015. African American participation in clinical trials increased from 5% in 2015 to 7% in 2016. However, Asian participation in clinical studies decreased from 12% to 11% between 2015 and 2016. The trend toward increasing the diversity of clinical trial participants is encouraging, but continued efforts are needed to keep moving in the right direction.

FDA expects sponsors to enroll study participants who reflect the demographics of clinically relevant populations for their product with regard to age, sex, race, and ethnicity. In reality, however, current clinical trial populations do not reflect the true demographics and disease prevalence in the United States.

Adjusting To New Expectations

In October 2016, FDA released an updated guidance for the collection of race and ethnicity data in clinical trials. The guidance describes FDA’s expectations for and recommendations on the use of a standardized approach for collecting and analyzing race and ethnicity data in studies conducted in the US and abroad that will be used to support marketing application submissions for FDA-regulated products. Using standardized terminology for age, sex, race, and ethnicity helps ensure subpopulation data are collected consistently. Additionally, this guidance recommends collection of race and ethnicity clinical trial data in Study Data Tabulation Model (SDTM) format as specified in FDA’s Guidance on providing regulatory submissions in electronic format. 

The updated guidance provides direction on how sponsors can meet the requirements outlined in the 1998 final rule regarding presentation of demographic data for INDs and NDAs (known as the “Demographic Rule”) and collection of race and ethnicity data in biologics license applications (BLAs) and medical device applications. It also addresses compliance with the FDA Safety and Innovation Act (FDASIA), Section 907 Action Plan to improve the quality of demographic subgroup data.

The recommendations are summarized as follows:

1. Two-question format: one for ethnicity and one for race
2. Self-reporting: trial participants self-report race and ethnicity information and those individuals are permitted to designate a multiracial identity
3. Ethnicity: choice of “Hispanic or Latino” with recommended definition and “Not Hispanic or Latino”
4. Race: a minimum of 5 choices according to Office of Management and Budget (OMB) Directive 15
5. Use of more detailed racial and ethnic categories when appropriate: recommended for studies in certain geographic regions

For INDs, NDAs, and BLAs, FDA recommends the submission of tabulated demographic data based on the Demographic Rule using the characterizations of race and ethnicity described in the International Conference on Harmonisation (ICH) guidances for benefit-risk information and multi-regional clinical trials. The updated FDA guidance focuses on recommendations that apply to clinical trials conducted in the US, and it is advisable to consult with all regulatory authorities involved when planning clinical trials globally.  

Another consideration is the historically inconsistent use of subgroup classifications, which leads to potentially confusing and inaccurate collection and analysis of data. For example, the terms sex and gender have been interchangeably used in some FDA and NIH documents. However, according to a 2001 consensus report from the Institute of Medicine, the terms have distinct definitions that should be used consistently to describe research results.

Sex refers to the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement. Gender refers to a person’s self-representation as male or female, or how that person is responded to by social institutions based on the individual’s gender presentation.

Likewise, race is associated with biology, whereas ethnicity is associated with culture. According to LiveScience, races are genetically distinct populations within the same species. Ethnicity is the term for the culture of people in each geographic region, including heritage, nationality, language, and customs. 

In terms of subgroup analyses, a clearer understanding of potential differences in subpopulations will occur when more pharmacogenetic data are available and included in clinical studies to correlate disease burden and responses to medical products with genetic makeup. This will help in the overall understanding of variations in drug responses based on genetic, clinical, and environmental factors; and to target treatment appropriately.

It is important to consider the collection and analyses of subpopulation data early during clinical development planning. Disease prevalence, regulatory strategy and approval pathway, protocol development, and operational considerations are all important factors to consider for clinical trials to ensure demographic subgroup populations are fairly represented.  

Sheila N. Bello-Irizarry, PhD, RAC is Integrated Product Development Associate at Rho. She is actively involved in product development in the areas of protocol development, clinical feasibility, regulatory submissions and authoring including INDs, NDAs/BLAs modules, orphan-drug designation applications, among others. Dr. Bello‑Irizarry was part of the Global Community Advisory Board for the NIH funded HIV Vaccine Trials Network, AIDS Clinical Trials Group, and the Pediatric HIV Program for 8 years. At the local Community Advisory Board in Rochester, NY, she was part of the Outreach Committee contributing to community education and encouraging minorities to participate in clinical trials. She can be reached at sheila_bello-irizarry@rhoworld.com