BIDIL: FALSE PROMISES
 

by Jonathan Kahn

On June 23, 2005 the Food and Drug Administration approved a drug to treat heart failure in African Americans, and only African Americans. This race-specific drug is called BiDil. BiDil is not a new drug. It is merely a combination into a single pill of two existing generic drugs that have been used to treat heart failure regardless of race for over a decade.

BiDil is noteworthy because it is the first race-specific drug ever approved by the FDA. It has been touted by the FDA and others as a significant step toward the promised era of personalized pharmacogenomic therapies. Upon closer examination, however, BiDil's story is not one of pursuing personalized medicines but rather of exploiting race to extend patent protection over a therapy that should be available to all, regardless of race.

BiDil is marketed by NitroMed, a hitherto small Massachusetts biotech company with no other products currently on the market. BiDil does indeed appear to help a significant number of people suffering from heart failure — a debilitating and ultimately fatal disease afflicting several million Americans. There is no scientific evidence, however, that race has anything to do with how BiDil works. This is for the simple reason that the data supporting NitroMed's submission to the FDA was based on a clinical trial (A-HeFT: African-American Heart Failure Trial) that enrolled only “self identified” African-Americans. [1,2] With no comparison population, no legitimate claims can be sustained that BiDil works differently or better in African-Americans than in anyone else.

The FDA, however, accepted NitroMed's argument that, because the trial population was African-American, the drug should be labeled as indicated only for African-Americans. This unsubstantiated claim sends the troubling message that the subject population's race was somehow a relevant biological variable in assessing the safety and efficacy of BiDil. Ominously, the FDA's approval also gives the federal government's imprimatur to the use of race as, in effect, a genetic category. 

Most drugs on the market today were tested almost exclusively in overwhelmingly white male populations. But we do not call these “white” drugs — nor should we. Rather, the operating assumption for approving these drugs was that the unmarked racial category of “white” was equivalent to the category “human being.” In approving BiDil as a drug only for African-Americans, the FDA has also implicitly adopted an assumption that the category “black” is something less fully representative of humanity than the category “white.” 

Why then did NitroMed seek race-specific approval for its drug? Perhaps the answer lies not in medicine but in commerce. NitroMed holds a patent for a non-race-specific use of BiDil that expires in 2007. The race-specific patent NitroMed has recently obtained will last until 2020. These extra thirteen years of patent protection may present a compelling commercial reason for seeking to cast BiDil as a racial drug — but this is a reason not supported by medical evidence. [3]

Additionally, why did the FDA grant NitroMed's request for race-specific approval when it could have simply approved the drug without reference to race? Part of the answer may be found in the strategic way in which the case for BiDil has been framed by misleading, and sometimes inaccurate, statistical information. First and foremost among these claims has been the assertion that African-Americans die from heart failure at a rate twice that of white Americans. Proponents of BiDil used this purported statistical disparity to buttress the argument that heart failure is somehow a “different disease” in African Americans, one that needed to be addressed at the genetic level. [4] This statistic, however, is egregiously wrong. A visit to the Centers for Disease Control statistical information web site, wonder.cdc.gov, reveals the actual ratio to be approximately 1.08 to 1.5 Through a curious series of events, involving incorrect citations, use of a decade-old study, and the eagerness of some to accept assertions of racial difference, the 2:1 mortality statistic was widely taken up by many media outlets (via NitroMed's press releases) and professional journals. 

Skewed Data

Of particular significance and influence was a 1999 article by Dries et al. in the New England Journal of Medicine which asserted that “The population-based mortality rate from congestive heart failure is 1.8 times as high in black men as for white men and 2.4 times as high for black women as white women.”[6] These figures, it turns out, were derived from a 1987 editorial by Richard Gillum of the National Center for Health Statistics. Gillum's article did use these figures but with an important qualification. He specified explicitly that they applied only to “persons aged 35 to 74 years.” Leaving out this age-specific qualification is a major problem on its own, but Gillum also noted in the same editorial that the ratio of black to white mortality in persons over age 75 approached 1, i.e. 1:1.[7] 

An article on these statistical missteps was published in late 2003. [8] Yet, a little over a year later, a new version of the statistic emerged to help frame BiDil's final drive toward FDA approval. In a press release issued on January 11, 2005, NitroMed asserted that “African Americans between the ages of 45 and 64 are 2.5 times more likely to die from heart failure than Caucasians in the same age range.” [9] NitroMed then repeated the statistic in a February press release announcing the FDA's acceptance of its amended new drug application. Unlike the previous 2:1 statistic, this new statistic is technically accurate. NitroMed failed to mention, however, that only about 6% of overall mortality from heart failure occurs in the 45-64 age range. About 93% of mortality occurs after age 65, and in that group there is almost no difference in age-adjusted mortality rates between blacks and whites. Indeed, the crude death rate for blacks is actually lower than that for whites. [10]

Why this investment in creating a major racial difference where none exists? One might well ask: if you have a medical interest in the underlying etiology of a disease do you look at a subgroup where 6% of mortality occurs or at one in which 93% of mortality occurs? If, however, you have a commercial interest in convincing the FDA and capital markets that there is a legitimate basis for approving a race-specific drug, then showing a huge difference becomes central to marketing your product — but, of course, you do not mention that your subgroup represents only 6% of overall mortality.

Skewed Reporting

The dynamic relation between markets and the skewed interpretation of clinical trial data has recently moved beyond BiDil to support larger claims about the legitimacy of developing race-specific drugs. Last November, in a special supplement on race and genetics, Nature Genetics published an article by Sarah Tate and David Goldstein titled “Will Tomorrow's Medicines Work for Everyone?” Among other things, the article stated “29 medicines (or combinations of medicines) have been claimed, in peer-reviewed scientific or medical journals, to have differences in either safety or, more commonly, efficacy among racial or ethnic groups.” [11] 

This number was immediately taken up throughout the media and certain professional contexts as providing “further” evidence of supposedly “real” biological differences among races. Moreover, reports of these striking results were almost invariably paired with a discussion of the near contemporaneous formal announcement of the A-HeFT results for BiDil. Thus, for example, after discussing BiDil, an article in the Los Angeles Times referred to “a report in the journal Nature Genetics last month [that] listed 29 drugs that areknown to have different efficacies in the two races [emphasis added].” [12]

Similarly, a Times of London article asserted that “only last week, Nature Genetics revealed research from University College London showing that 29 medicines have safety or efficacy profiles that vary between ethnic or racial groups [emphasis added].”[13] And a New York Times editorial titled “Toward the First Racial Medicine” began with a discussion of BiDil and went on to note that “By one count, some 29 medicines show evidence of being safer or more effective in one racial group or another, suggesting that more targeted medicines may be coming.”[14] The linking of BiDil to the “29 medicines” is not accidental. They are paired to give the impression that there is some “real” difference underlying racial response to these drugs. 

Skewed Thinking 

There is a major problem with these stories. They totally misrepresent the findings and assertions of the Tate and Goldstein piece. Remember first, that Tate and Goldstein asserted that these 29 medicines have only been “claimed” to have racial differences in safety or efficacy. They go on, in the next sentence to assert, “But these claims are universally controversial, and there is no consensus on how important race or ethnicity is in determining drug response [emphasis added].”[15] In fact, of the 29 medicines identified, Tate and Goldstein considered only 4 to provide evidence that a genetic causation is related to the differential drug response; and only an additional 9 to provide evidence that “the association has a reasonable underlying physiological basis.” [16] For the remaining 16 medicines, Tate and Goldstein found either no demonstration of a physiological basis to any observed difference, or possibly false positive claims. Moreover, of the 13 medicines with some supporting evidence of racial difference, three were ACE inhibitors — whose claims of racial difference have been hotly contested in the professional literature — and one was BiDil. [17] All of the 13 dealt with hypertension, and the International Society on Hypertension in Blacks has issued guidelines arguing against race-specific treatment of hypertension. [18] 

One might dismiss the distortion of the Tate/Goldstein article as mere sloppy journalism. But the use, or rather misuse, of the “29 medicines” statistic has been embraced in more expert and often more conservative circles. Prominent here are John Entine and Sally Satel, both fellows at the American Enterprise Institute (AEI). Both have gained a good deal of notoriety for their popular works on race and genetics: Entine, for his book, Taboo: Why Black Athletes Dominate Sports and Why We are Afraid to Talk About it, and Satel for, among other writings, a prominent New York Times Magazine article titled “I am A Racially Profiling Doctor.” [19,20] Entine framed a recent AEI symposium on BiDil by noting that, “Only last month, the prestigious journal Nature Genetics reported that at least 29 medicines have so far been identified that are either safer or more effective in certain populations because of genetic differences between those population groups.”[21] Satel echoed Entine's move in a more qualified manner later in the AEI symposium when she asserted that “generally, when we're talking about BiDil and things like that, its skin color as a marker for genetic heritage.”[22] Then, a month later she repeated Entine's claim about the “29 medicines” and genetics almost word for word in an article for the conservative Manhattan Institute titled, “Race and medicine can mix without prejudice: How the story of BiDil illuminates the future of medicine.”[23] Not only do Entine and Satel elide any reference to Tate and Goldstein's qualifying analysis, they also extend the purported connection between race and drug response into the realm of genetics. BiDil provides the starting point for this move toward identifying race with genetic difference — a difference that the A-HeFT investigators themselves do not make. 

This marks a critical moment of reification of race as genetic.[24] By connecting BiDil to the manipulated “29 medicines” statistic, Satel and Entine cast BiDil as the poster drug for the future of addressing racial difference in medicine. Entine's and Satel's message is that race and genetics correlate closely enough to provide the basis not only for general medical practice but for addressing specific health disparities. We should remember that these discussions are also indirectly being framed by the misleading assumption that A-HeFT proved that BiDil worked differently in African-Americans. The related message is that the correlation also provides the basis for market driven pharmaceutical development of new drugs, such as BiDil, to address these differences.

Implications

This is where reification in the context of medical practice intersects with broader strategies regarding commerce and the politics of difference. At work here is an appropriation of race, as used as a signifier in the BiDil story, to serve larger political agendas aimed at transmuting health disparities — rooted in social and economic inequality — into mere health “differences” — rooted in biology and genetics. Attempts to address social “disparity” generally implicate the power of the state or other non-market institutions consciously to intervene both in the allocation of resources and the sanctioning of racist practices. In reality, such attempts to address genetic “difference” are treated as though they are located at the level of the molecule and targeted by pharmaceuticals developed and dispensed through the purportedly impersonal forces of the market. Implicit in the logic of conservatives such as Satel and Entine, who use BiDil to characterize disparate health outcomes in terms of genetics, is an argument for privatizing efforts to address what are currently characterized as economically and socially based health disparities.

The story of BiDil clearly raises concerns over the dangers of reifying race in a manner that can lead to new forms of discrimination. BiDil, however, is part of a much larger dynamic of reification in which the purported “reality of race” as genetic is used to obscure the social and political reality of “racism.” For all the legitimate concerns that the genomics revolution might lead to new forms of discrimination, we must also be alert to the potential appropriation of genetics to obscure or justify existing inequalities.

Jonathan Kahn is a professor at the Hamline University School of Law. He writes on issues in history, politics, and law and specializes in biotechnology implications for our ideas of identity and citizenship.

 

References

1. Kahn, J. 2005. Ethnic Drugs. Hastings Center Report, January/February 2005.
2. Taylor A, et al. 2004. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. New England Journal of Medicine. 351: 2049-2057.
3 .See, e.g. Kahn J. 2004. How a Drug Becomes 'Ethnic': Law, Commerce, and the Production of Racial Categories in Medicine.” Yale J. of Health Policy, Law & Ethics 4: 1-46.
4. Yancy C. The Role of Race in Heart Failure Therapy. Current Cardiology Rep. 2002;. 4:218-25 
5. Kahn J. Getting the Numbers Right: statistical mischief and racial profiling in heart failure research. Perspectives in Biology and Medicine. 2003; 46:473-83, 474.
6. Dries, D.L. et al. Racial differences in the outcome of left ventricular dysfunction. N. Engl. J. Med. 1999; 340: 609-16, 609.
7. Gillum R.F. “Heart Failure in the United States, 1970-1985.” American Heart Journal 1987;113: 1043-45.
8. Supra 5
9. BiDil® Named to American Heart Association's 2004 'Top 10 Advances' List, http://www.nitromed.com/ 01_11_05.asp. Accessed 5/19/05.
10. To obtain this information, I visited the CDC's Wonder web site at http://wonder.cdc.gov. The percentages are derived from queries for information concerning compressed mortality by race, age adjusted for ages 45 to 64 and ages 65 and above. In the over 65 age group, the crude death rate for blacks is 142.9 per 100,000; for whites it is 153.3 per 100,000. Accessed 1/11/05.
11. Tate S. and Goldstein D. 2004. "Will Tomorrow's Medicines Work for Everyone? Nature Genetics 36, S34 - S42.
12. Maugh T. Drug For Blacks Only Stirs Hope, Concern. Los Angeles Times, November 9, 2004. http://www.latimes.com, Accessed 2/9/05. 
13. Ahuja A. We can treat your heart disease ... if you're black. Times of London, October 29, 2004. http://www.timesonline.co.uk. Accessed February 9, 2005. 
14. Editorial. 2004 “Toward the First Racial Medicine.” New York Times, November 13, 2004. http://www.nytimes.com, Accessed 2/9/05
15. Supra 11, S34.
16. See, e.g. Kahn J. 2004. How a Drug Becomes 'Ethnic': Law, Commerce, and the Production of Racial Categories in Medicine. Yale J. of Health Policy, Law & Ethics 4: 1-46, 22-23.
17. Supra 11, S36-37.
18. Moore Jeremy, Hypertension Treatment Among Blacks: Should it be different? Today in Cardiology, October 2003. http://www.todayincardiology.com/200310/ treatment.asp?old=never
19. Entine J. 2001. Taboo: Why Black Athletes Dominate Sports and Why We are Afraid to Talk About it
20. Satel, S. 2002. I Am a Racially Profiling Doctor. New York Times Magazine, May 5, 2002.
21. Entine J. 2004. Transcript. Race, Medicine and Public Policy. Nov. 12. 2004. www.aei.org/include/
event_print.asp?eventID=937 Accessed 2/9/05. 
22. Ibid.
23. Satel S. 2004. Race and medicine can mix without prejudice: How the story of BiDil illuminates the future of medicine. Medical Progress Today, December 10, 2004.. http://www.medicalprogresstoday.com/spotlight/spotlight_indarchive.php?id=449. Accessed 3/23/05. 
24. Duster T. 2005. “Enhanced: Race and Reification in Science.” Science 307: 1050-51.

 
 
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