Checkmate! You’ve succeeded. After years of laboratory and other pre-clinical work, your company has earned the green light to begin clinical trials to test its groundbreaking new drug. In preparing the protocol and designing each phase of the clinical trial, there are critical questions that every sponsor must answer. One of the most important of these is, “In whom should we study the drug?” Of course, this answer will depend largely upon the population for whom the drug is intended, the sponsor’s ability to recruit study participants, and other factors. Nevertheless, it is essential that clinical trials are sufficiently diverse to ensure safety and efficacy and, also, to withstand scrutiny.

The game of chess is a near perfect metaphor for diversity in clinical trials. The “chess protocol” accounts for every contingency, and nothing is left to chance. There are no missing pieces. In case you are not a chess Grandmaster, like Bobby Fischer, here are a few basics. A chessboard is made up of 64 squares evenly divided between 32 light/ white squares and 32 black/dark squares. A proper chessboard is perfectly symmetrical, with eight ranks and eight files. To play the game correctly, the chessboard must be oriented so that a light/white square is in the bottom right corner of the board. Without a properly oriented chessboard to serve as a foundation, the game cannot be played properly. In addition, players must have all the pieces placed in their designated squares. If even one piece is missing, the game cannot be played as intended. The same is true of clinical trials. There can be no missing pieces.

In this analogy, having clinical trials that are scientifically, ethically, and legally sound is “king.” And, even an amateur chess player knows that protecting the king is essential. If the king is in jeopardy, simply put, nothing else matters. The purpose of this article is to provide some basic strategies and reminders to assist you in protecting your king.

Why is Diversity in Clinical Trials Important?

Racial and ethnic minorities are the fastest growing segment of the U.S. population. It is well-known in the medical and scientific community that some medicines have the potential to work differently depending upon a patient’s race or ethnicity. In fact, “[e]thnicity is one factor that may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy.”¹ Further, “[g]iven that the applicability of clinical study results to the treatment of an individual patient is a critical consideration in a physician’s choice of drug therapy, drug development should seek to ensure that a clinical pharmacologic evaluation includes a population that is representative of the target therapeutic population.”² In short, because ethnic differences may be one factor in determining the risk-benefit ratio of a drug therapy in a specific patient, these differences should be considered during drug development.³

In addition to the scientific and medical cases for diversity in clinical trials, in some instances, study funding may be contingent upon a showing of diversity. For example, in 1993, Congress enacted the National Institutes of Health (NIH) Revitalization Act of 1993 (PL 103-43). In studies conducted or supported by NIH, the Revitalization Act requires that the Director of NIH ensure, among other things, that:

• Women and minorities are included in all NIH-funded clinical research, unless a clear and compelling rationale and justification establishes to the satisfaction of NIH that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research;
• Phase III clinical trials include women and minorities in numbers adequate to allow for valid analyses of differences in intervention effect;
•  Cost is not allowed as an acceptable reason for excluding these groups; and,
• NIH initiates programs and support for outreach efforts to recruit and retain women and minorities and their subpopulations as volunteers in clinical studies.

Finally, but not least significantly, in addition to scientific/medical considerations and potential funding requirements, FDA has expressly stated that “if there is an inadequate evaluation for safety and/or effectiveness of the population intended to use the drug, including pertinent subsets, such as gender, age, and racial subsets, the Agency may refuse to file the [NDA].”⁴

Defining, Collecting, and Reporting “Diversity”

The FDA has taken steps to provide standardized methods of defining, collecting, and reporting race and ethnicity information in clinical trials to ensure consistency in demographic subset analyses, to compare results across studies, and to assess potential subgroup differences in safety and effectiveness. In 1998, the FDA published the Demographic Rule, which requires IND and NDA⁵ sponsors to present a summary of safety and effectiveness data by demographic subgroups (e.g., age, gender, race).⁶ The 1998 Demographic Rule also requires sponsors to provide an analysis of whether modifications of dose or dosage intervals are needed for specific subgroups.⁷

In September 2005, FDA published its Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials. While the Guidance does not address the level of participation of racial and ethnic groups in clinical trials, it is a useful guide for ensuring demographic information is properly collected and reported. As noted in the Guidance, the United States Department of Health and Human Services (HHS) does not follow anthropologic or scientifically based designations, but instead, has adopted the standardized approach of the Office of Management and Budget (OMB). HHS, like OMB, chose to adopt standardized categories “because the categories are relevant to assessing various health-related data, including public health surveillance and research.”⁸ Accordingly, HHS recommends the following:

• Request race and ethnicity information in a two-question format, with the question about ethnicity preceding the question about race;
• Provide for self-reporting of race and ethnicity information whenever feasible and allow for the designation of multiracial identity;
• For ethnicity, provide “Hispanic or Latino” and “Not Hispanic or Latino” as minimum choices.

When race and ethnicity information are collected separately, provide the following minimum choices: “American Indian or Alaska Native,” “Asian,” “Black or African,” “Native Hawaiian or Other Pacific Islander,” and “White.”⁹ More detailed information may also be gathered and reported, but these designations are acceptable.

Barriers to Achieving Diversity

Despite a near consensus that diversity in clinical trials is important, it has been noted that barriers to achieving adequate representation persist, despite the best efforts of sponsors.¹⁰ Some examples of these barriers include:

• Economic factors, such as transportation or child care costs;
• Language factors, especially illiteracy and lack of English proficiency;
• Negative cultural attitudes about clinical studies;
• Distrust and fear of being test subjects for new treatments; and
• Limited access to routine and preventative healthcare.

Opportunities to Improve Representation¹¹

Although barriers persist, there are opportunities to improve, including:

• Design clinical trials that include health-care needs specific to ethnically diverse populations;
• Work with ethnically diverse physicians to recruit patients;
• Ensure clinical trials involve ethnically diverse investigators;
• Develop and support community out-reach programs;
• Utilize community-based focus groups
• Utilize appropriate educational information translated into native language(s)
• Distribute materials about the prevalence of certain diseases, available prevention programs, and access to clinical trials
• Work with existing programs, such as the National Medical Association’s Project I.M.P.A.C.T., the W. Montague Cobb/NMA Health Institute, and the National Hispanic Medical Association.

Conclusion

Lack of diversity in a clinical trial may negatively impact a healthcare professional’s ability to ensure the applicability of certain reported outcomes to an individual patient, especially with respect to the risk-benefit calculus. Additionally, in some instances, funding and even drug approval may be withheld if clinical trials are not sufficiently diverse or if data regarding diversity is not properly collected and reported. Ensuring diversity in clinical trials cannot be left to chance. Just as chess is a game of strategy, so are developing and conducting sufficiently diverse clinical trials. To avoid the pitfalls, you must employ long-range planning to place trials at a tactical advantage when it comes to ensuring diversity. In sum, you must ensure there are no missing pieces.

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[1] Su Yasuda, L. Zhang, and S-M Huang, “The Role of Ethnicity in Variability in Response to Drugs: Focus on Clinical Pharmacology Studies,” Clinical Pharmacology & Therapeutics, Vol: 84, Number: 3 (September 2008) at 417.

[2] Id.

[3] Id. at 422.

[4] Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials, Food and Drug Administration, September 2005, 2 n.6. (Referenced in subsequent notes herein as “Guidance.”)

[5] With respect to medical devices, as opposed to drugs, the 2005 Guidance notes that “[a]lthough the regulations governing medical devices do not include requirements for the collection of demographic data comparable to those for INDs and NDAs, for those cases in which race and ethnicity data are relevant to determining the safety and effectiveness of a device, FDA encourages sponsors to collect the data […].” Guidance at 2.

[6] 21 CFR 314.50 (d)(5)(v) and (vi)(a).

[7] cccccccc

[8] Guidance at 3.

[9] Guidance at 5.

[10] See, e.g., Virk, Karen P., “The Missing Minorities,” Good Clinical Practice Journal at 16 (November 2008).

[11] See, e.g., id.; see also, www.impact.nmanet.org.

Finis