FDA Requirements for Diversity of Subjects in Clinical Trials

Subject diversity is critical to improving the representativeness of clinical trials, because different groups may respond differently to a drug or treatment. Since 1993, the FDA has issued regulations and guidance to increase the diversity of clinical trial populations, and the FDA encourages investigators to enroll a diverse group of subjects, including different races, genders, ages, and socioeconomic backgrounds.

Determine Needs and Criteria

Two-Question Format

FDA recommends that sponsors use the Two-Question Format to consider diversity from both an ethnicity and a race perspective.

Ethnicity

• Hispanic or Latino: Includes Cubans, Mexicans, Puerto Ricans, South or Central Americans, or other persons of Hispanic culture or ancestry, regardless of race.
• Not Hispanic or Latino

Race

• American Indian or Alaska Native: Native or Indigenous ancestry from North and South America (including Central America)
• Asian: Southeast or South Asian (e.g., Cambodian, Chinese, Indian, Japanese, Korean, Malaysian, Pakistani, Filipino, Thai, and Vietnamese) ancestry
• Black or African American: descent from any black racial group in Africa
• Native Hawaiian or Other Pacific Islander: Hawaiian, Guam, Samoan, or other Pacific Islander ancestry
• White: European, Middle Eastern and North African ancestry

Support from Other Sectors

In addition to the efforts required of sponsors, the diversity of clinical trials requires the understanding and support of the community, including regulatory agencies, industry, institutional review boards (IRBs), academia and patient organizations.

The FDA has also taken actions in the area of patient outreach and education, such as Drug Trials Snapshots (DTS). This program provides consumers and health care professionals with concise information about who is participating in key clinical trials used to support drug marketing approval, making trial demographics more accessible to the public and communication with the public more open and transparent.

Drug Trials Snapshots information includes:

• Trial design
• Demographic characteristics (gender, race, age and ethnicity)
• Overall assessment of benefits and risks for subgroups of the population

In addition, the FDA may require pharmaceutical companies to conduct specific subgroup analyses before and after a drug is marketed to assess the safety and efficacy of the drug in different populations.

Relevant Regulations and Guidance

01. Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, July 1993

Prior to 1993, most female patients were excluded from clinical trials, primarily because in 1977 the FDA recommended that anyone who might become pregnant be excluded from early studies of a drug to minimize the potential risk to the fetus.

It was not until September 1993, when the FDA issued that guidance, that the phenomenon began to improve.

One month prior to the FDA's issuance of the guidance (August 1993), the NIH Revitalization Act was passed, which explicitly mandated the inclusion of women and minorities in NIH-funded biomedical research in order to increase the representation of women and minorities in clinical trials.

02. ICH E7: Studies in Support of Special Populations: Geriatrics, Aug 1994

As societies age, the use of medications for the elderly requires special attention, given the underlying medical conditions, concomitant medications, and the inevitable risk of drug-drug interactions. Against this background, the ICH has developed guidelines for the study of drugs for the elderly. For drugs that are widely used in the elderly, studies need to be conducted in all age groups, including the elderly, and clinical trials should be conducted in populations that are representative of those who will be treated with the drug.

The guideline specifies an age range for older adults (age 65 and older) and should try to include patients aged 75 years and older. Clinical protocols should generally not have an artificially defined upper age limit, and should not exclude patients with other concomitant medical conditions as necessary. The older the medication-using population, the more necessary it may be to include older adults in the study.

In addition, FDA has made recommendations on how to present clinical experience in the elderly population in clinical data and application materials, how to conduct pharmacokinetic studies, pharmacodynamic/dose-effect studies, and drug-drug interaction studies in special populations.

03. E5 Ethnic Factors in the Acceptability of Foreign Clinical Data, Jun 1998

The aim of this guideline is to require that the impact of racial factors be adequately assessed while providing patients with evidence of benefit from the drug.

E5 defines racial factors as those associated with the genetic and physiological (endogenous), as well as cultural and environmental (exogenous) characteristics of a population, and recommends a basic framework for assessing the impact of racial factors on drug efficacy.

04. The Food and Drug Administration Safety and Innovation Act, 2012

FDASIA, passed by Congress in 2012, requires FDA to review racial and ethnic subgroup data in marketing applications for drugs, biologics, and medical devices and to make the results of its review available to the public.

05. Collection of Race and Ethnicity Data in Clinical Trials, Oct 2016

Originally issued in 2014, this draft guidance is FDA's expectations and recommendations for the use of standardized methods for collecting and reporting race and ethnicity data in clinical trials of FDA-regulated drugs conducted in the United States and outside the United States.

The FDA expects sponsors to enroll subjects that reflect the demographic characteristics of clinically relevant populations in terms of age, sex, race, and ethnicity. Inadequate participation and/or incomplete data analysis from clinically relevant subpopulations may result in insufficient safety and efficacy information that is ultimately reflected in the specification for that product. Therefore, it is recommended that the use of standardized terminology for age, gender, race, and ethnicity help to ensure consistency in the quality of data collected from subgroups.

The guidance recommends that sponsors should discuss plans to address the inclusion of clinically relevant subgroups with FDA as early as possible, generally no later than the EOP2 Meeting.

Consideration needs to be given to potential racial and ethnic disparities related to the evaluation of drug therapy:

• Prevalence
• Diagnostic and treatment patterns
• Subgroups included in previous studies
• Any clinically significant subgroup differences in safety or efficacy

06. Enhancing the Diversity of Clinical Trial Populations-Eligibility Criteria, Enrollment Practices, and Trial Designs, Nov 2020

FDA recommends that sponsors take a variety of approaches to broaden the eligibility criteria for enrollment in clinical trials to ensure that the study population better reflects the population of patients who are likely to use the drug in clinical practice.

In terms of enrichment trial strategies, certain populations can be targeted for inclusion, making it easier to demonstrate the likely effects of the drug. By ensuring that subjects have a specific level of disease, subset of diseases, or genetic markers, an enrichment strategy can increase the likelihood that a trial will show a potential effect.

Prognostic enrichment enrolls subjects who are more likely to reach the study endpoint or who have more severe disease, thereby reducing the size of the trial needed to show an effect.

Predictive enrichment refers to the selection of subjects who are most likely to respond to the test drug based on their genetic, pathologic, or physiologic characteristics in order to increase the efficiency of the trial.

Subjects may also face the following difficulties in participating in clinical trials.

• Trials that require subjects to visit a specific site frequently may impose additional burdens on patients, particularly the elderly, children, persons with disabilities and cognitive disabilities who require assistance with transportation travel or nursing care, or patients from rural or remote areas.
• Financial costs (e.g., travel, delays in work, etc.) may discourage trial participation, and trial follow-up may interfere with the work and lives of patients and their caregivers.
• For individuals who receive current medical care regularly, additional study follow-up may be psychologically, physically, and financially burdensome and detrimental to recruitment.
• Mistrust of clinical research in certain populations may also affect patient recruitment.

07.(Draft Guidance) Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Apr 2022

This draft guideline aims to ensure that diverse clinical trial participation improves the reliability of overall population safety and efficacy evidence generation. The guidance is a further expansion of the guidance on collecting and reporting data on racial and ethnic populations issued in 2016.

FDA recommends that sponsors should submit Racial and Ethnic Diversity Plans as soon as possible during the development of a drug. FDA considers this plan to be an important part of the product development program and recommends that sponsors communicate with FDA about the plan at key milestone meeting nodes, typically the EOP2 meeting.

The guidance is intended to advise sponsors on how to develop a diversity plan and to identify some of FDA's basic requirements for the content and format of the plan. The guidance recommends that IND holders include the program in their annual reports and list the proposed number of individuals and the number of individuals who have entered clinical studies to date, by age group, race, and gender.

In addition, the FDA requires applicants to provide efficacy and safety data by sex, age, and race in their NDA filings, and should specify the dose or dosing regimen required for specific subgroups.

Proregulations is committed to helping new drug discovery companies around the world achieve subject diversity in their clinical trials and ensure that the final results are broadly applicable, ethical, scientific and compliant. If you are interested in our services or need more details, please contact us.