By Evie M Delicha Ph.D
Defining the Problem
The role of race and ethnicity in biomedical research is constantly under debate. After sequencing the human genome and mapping human genetic variations, there are contradictory beliefs and practices about the use of race and ethnicity in clinical research. These beliefs and practices endorse the concept of a socially constructed race and ethnicity, yet at the same time they are often treated as genetic variables. Is it scientifically correct to treat race and ethnicity as genetic variables and draw conclusions about treatment response, pharmacokinetic profiling, or disease prevalence?
Race and Ethnicity as a Social Construct
Race is defined as a category or group of people having common hereditary traits, whereas ethnicity is based on a shared cultural heritage. The notion of race was first adopted by the Europeans in the 16th century, when they used the phenotypic characteristics to define physical divisions among humans according to hereditary characteristics as reflected in morphology, and roughly captured as Black, White, and Asian (or Negroid, Caucasoid, and Mongoloid). They used this separation to classify the different groups of people they encountered through continental exploration.
Nowadays, the definition of race endeavors economic, political-social and cultural practices. Countries (especially these with population diversity) are gathering data based on race and ethnicity in order to monitor civil rights, unemployment, health care services, and educational opportunities. In the USA, the Office of Management & Budget (OMB) issued the Race and Ethnic Standards for Federal Statistics and Administrative Reporting that are set forth in Statistical Policy Directive No. 15. The OMB proposed a minimum of five race categories: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, and White. As clearly stated in the Federal Register Letter (Oct 1997), these categories are viewed under the social perception of race in order to enforce civil rights laws:
“….The racial and ethnic categories set forth in the standards should not be interpreted as being primarily biological or genetic in reference. Race and ethnicity may be thought of in terms of social and cultural characteristics as well as ancestry…..”
The proposed OMB race categories were also adopted by the FDA for reporting in clinical trials. In Europe, the EMA is not suggesting any specific race categorization, but it views race as an intrinsic ethnic factor (ethnicity has a broader meaning than race). The EMA adopts their definition from the ICH E5:
“Intrinsic ethnic factors are factors that help to define and identify a subpopulation and may influence the ability to extrapolate clinical data between regions.”
The Geographic Barrier Reflects Fundamental Differences between Races and Ethnicities
Despite the fact that regulatory agencies are supporting the social definition of race and ethnicity, these variables were employed not only in epidemiology, but also in the reporting of clinical trial outcomes. Therefore, the obscure properties of race and ethnicity as genetic variables should be investigated. Is a person’s cultural or ancestral background a key determinant in clinical response?
In the educational material distributed by the Human Genome Project in 2001, it was stated that “two random individuals from any one group are almost as different (genetically) as any two random individuals from the entire world.” This statement essentially refutes the supposition that racial divisions reflect fundamental genetic differences. The quantification of similarities within or between population clusters mainly depends on the level of genetic information analyzed, as well as the statistical norms employed to quantify them. Further research of more detailed genetic profiling indicated that the Ancestry-Informative Markers (AIMs) exhibit substantial diversity in frequencies between different race and ethnicity groups, and this diversity reflects geographic adaptation. Geographic barriers to gene flow have generated noticeable genetic differentiation between groups of different ancestry. In that way, there is an apparent correlation between gene frequencies and geography.
The example of the Ashkenazi Jewish women provides further data to support the argument that geographic adaption is responsible for differences between populations (rather than race and ethnicity). The Ashkenazi Jewish women currently live all around the world, but they originally came from the same geographic regions (Germany, Russia, and Poland). They share the same AIMs, and as a group, are at a greater risk of breast cancer than the general population.
Such observations became the fundamental assumption stimulating the emergence of personalized medicine. Let’s not forget the the efficacy of isosorbide dinitrate plus hydralazine (BiDil) in African-Americans (which led to a unique and controversial approval from FDA). A few years later, the GRAHF trial showed that it was the -344 T/C promoter polymorphism of CYP11B2 that influences the clinical outcome, and this polymorphism is more common in African American patients. As another example one could think of sickle cell anaemia, which is observed with high frequency among those of African and Mediterranean ancestry. Following this first observation, it was found that a mutation in the HBB gene that arose in Africa is responsible for the presence of the disease, and therefore any person with this mutation can develop sickle cell anaemia.
Reporting of Race and Ethnicity in Clinical Trials
As previously discussed, race and ethnicity are defined in social terms. There is no biological or genetic rationale behind the definition of race and ethnicity. Nevertheless, let’s suppose that race and ethnicity information is essential in clinical trials, and let’s suppose that these terms are used as a proxy for the geographic ancestral origin which may alter the clinical benefit. If that’s the case, then why there is no homogeneity in reporting such data in published literature? Although reporting of race and ethnicity has increased during recent years in study publications, there is no uniform terminology employed, leading to a possible misinterpretation of factors affecting health outcome. It is unclear how to interpret differences in study outcomes across different countries, cultures, and health systems; and the complexity resulting from this admixture is a reason for additional ambiguity. Currently, there is an enforcement of existing journal policies on how populations are defined and characterized in terms of race and ethnicity, and the relevance of these variables to the study outcome. However, still these guidelines are vague, not specifying smaller geographical divisions. Geographic adaptation is often ignored in large clinical trials (Japanese and Indians might both be considered Asians). The same level of enforcement should be utilized by health authorities and regulatory agencies in order to update the current reporting standards, and restricting the terms of race and ethnicity in clinical trials only to demographic information and not applying them to clinical outcome. Any variation of clinical outcome should be viewed under the spectrum of ancestry which is not related to the social definition of race. Additionally, the regulatory agencies should move towards defining how genetic information should be analyzed in clinical trials, since genetic differences may alter the therapeutic result. The need is straight forward due to the increasing globalization of clinical trials, resulting in greater population diversity.
- Sankar P, Cho MK, Monahan K, Nowak K. (2014) Reporting Race and Ethnicity in Genetics Research: Do Journal Recommendations or Resources Matter?. Sci Eng Ethics. 2014 Nov 19 (ahead of print).
- Ortega VE, Meyers DA. (2014) Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol. Jan;133(1):16-26
- Ali-Khan SE, Krakowski T, Tahir R, Daar AS. (2011) The use of race, ethnicity and ancestry in human genetic research. HUGO J. Dec;5(1-4):47-63.
- Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials." U.S. Food and Drug Administration. September 2005. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126396.pdf
- Race, Ethnicity, and Genetics Working Group (2005) The use of racial, ethnic, and ancestral categories in human genetics research. Am J Hum Genet 77(4):519–532.
- Note for Guidance on Ethnic Factors in the acceptability of Foreign Clinical Data, (CPMP/ICH/289/95), September 1998. ICH Topic E 5 (R1), Step 5.
- Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity. Federal Register Notice October 30, 1997.
- I.F. Haney Lopez. The Social Construction of Race (chapter 17) in Critical Race Theory. The cutting edge.
- Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure (2004) N Engl J Med 351(20):2049-57