Sunday, November 17, 2019

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Stepping Stones and Poster Children

The productive power of the unknown to create a space for race is clearly evident in a 2008 article published by Robert Temple, Director of the Office of Medical Policy and the FDA's Center for Drug Evaluation and Research and his colleague, Shi-Mei Huang of the Office of Clinical Pharmacology. Discussing the role that genes and race play in predicting drug response, they cite a range of currently marketed drugs that include race-specific or genetic information on their labels and note,

Some of the observed racial differences may be explained by the genetic differences listed in the labeling (e.g. warfarin and carbarnazepine). Possible mechanisms for others either have not yet been included in labeling (e.g. rosuvastatin and tacrolimus) or are as yet unknown (e.g. isosorbide dinitrate-hydralizine, which is effective in heart failure in black patients.).”
Race, genes, and drugs are bound together through the concept of the unknown. In the example of warfarin, race is being used to identify differing allele frequencies across population groups. Yet in the case of isosorbide dinitrate-hydralizine, race is simply being used to account for an otherwise unexplained observation of purported differences in drug response across racial groups. All are deemed legitimate references by the FDA. As long as an unknown factor exists, there will be a space for race, or so it seems here.

The isosorbide dinitrate-hydralizine combination referred to by Temple and Huang is BiDil, the first drug ever approved by the FDA with a race-specific indication: to treat heart failure in a black patient. Dr. Steven Nissen, the chair of the FDA panel reviewing BiDil, directly cast race as an acceptable surrogate for genetics:

[W]hat we are doing is we are using self-identified race as a surrogate for genomic-based medicine and I don't think that is unreasonable. I wish we had the gene chip. I wish we could do it on a genetic basis. But, in the absence of that, we have some information that suggests that African Americans--we know that African Americans, self-identified, get a pretty robust response to the drug.”
Nissen related race to “some information,” but its true justification came from its purported ability to stand in for the unknown underlying genetics of drug response. Until adequate genetic technology came along, Nissen deemed race sufficient and therefore to be embraced.

Similarly, on the eve of BiDil's approval, Lawrence Lesko, director of the Office of Clinical Pharmacology at the FDA, and a point man in the FDA's efforts to integrate genomics into the drug approval process, asserted that race-based medicine could be a “stepping stone” to the higher goal of “target treatment.” As one news report put it:

Lesko and other advocates of this approach envision treatment tailored to people according to the results of genetic tests. They say that race-based medicine is just a first step toward discerning people's genetic makeup for the sake of better individual treatments.
The myriad controversies sparked by BiDil are here defused by casting race-based therapies as stepping stones. Any problems created by using race in biological context (e.g., the reification of race as genetic, the perpetuation of racial stereotypes that cast one race as more biologically “fit” than another, or concerns about the misallocation of scarce health care dollars) are minimized as temporary and hence a small price to pay for the ultimate goal of ““better individual treatments.” The advocates of race-based medicine might even concede the point that race is a crude surrogate for genetic or other biological variability and yet still use it. Thus, two senior FDA officials involved in the review and approval of BiDil declared,

Race or ethnicity is clearly a highly imperfect description of the genomic and other physiologic characteristics that cause people to differ, but it can be a useful proxy for those characteristics until the pathophysiologic bases for observed racial differences are better understood.
Similarly, the year after BiDil's approval, an article on “Race and Ethnicity in the Era of Emerging Pharmacogenomics” published in the Journal of Clinical Pharmacology asserted,

As the science of pharmacogenomics develops more accurate tools to identify the molecular underpinnings of drug response, the need for classification by race will be replaced by more accurate and specific identification of each individual person's likelihood of responding to a particular drug therapy.
Such instrumental characterizations construct race as a useful fiction--a means to an end that is to be discarded once its temporary utility has faded. Once again, in this grand march forward to pharmacogenomics, race, like Friedrich Engles' state, is supposed to “wither away.”

Some biomedical professionals take issue with this approach. One recent study by Yen-Revollo, Aumen, and McLeod specifically considered the legitimacy of using race as an interim surrogate for genetic variation:

Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in different racial groups, we investigated whether a patient's race could predict presence of drug-relevant genetic variants well enough to be used as a substitute for individual genotyping.


The study found that,

Our results clearly demonstrate that racial generalizations for treatment recommendations are not valid and are consistent with other recent publications regarding the suitability of using patient race to determine medical treatment.

And concluded,

The majority of genomic heterogeneity in pharmacologic genes was determined to be due to individual variation rather than racial grouping. Thus, race should not be used as a predictive substitute for individual patient genotyping.
Significantly, even as it debunked the legitimacy of using race as a surrogate, the study also considered its appeal:

Although progress has been made in identifying gene polymorphisms that influence response to several drugs, the promise of personalized medicine has not been realized as of yet because personal genotyping is cost prohibitive and most drug-genotype interactions remain unknown.Since individual causative alleles usually have distinct frequencies across the ‘Old World’ populations, there is potential utility in using race labels as a surrogate for genetic information, as a means to the ultimate goal of individualized therapy.
In this scheme, cost and the unknown are the operative factors leading toward the use of race “as a means to the ultimate goal of individualized therapy.”Theoretically, as costs come down and knowledge grows, the need for race will diminish. Yet means have a curious way of devolving into ends, and stepping stones may somehow remain underfoot long after a particular destination has been reached. So it appears to be with the unfolding case of warfarin in pharmacogenomics.

Vernellia R. Randall
Founder and Editor
Professor Emerita of Law
The University of Dayton School of Law

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