BiDil: Assessing a Race-Based Pharmaceutical ABSTRACT
Isosorbide and hydralazine in a fi xed-dose combination (BiDil) has provoked controversy as the fi rst drug approved by the Food and Drug Administration marketed for a single racial-ethnic group, African Americans, in the treatment Life Sciences, Michigan State University, of congestive heart failure. Family physicians will be better prepared to counsel their patients about this new drug if they understand a number of background issues. The scientifi c research leading to BiDil’s approval tested the drug only in African American populations, apparently for commercial reasons, so the drug’s effi cacy in other populations is unknown. Race as a biological-medical construct 3Center for Ethics and Humanities in the is increasingly controversial; BiDil offers a good example of how sociocultural Life Sciences, Michigan State University, factors in disease causation may be overlooked as a result of an overly simplistic assumption of a racial and hence presumed genetic difference. Past discrimina-tion and present disparities in health care involving African American patients are serious concerns, and we must welcome a treatment that promises to benefi t a previously underserved group; yet the negative aspects of BiDil and the process that led to its discovery and marketing set an unfortunate precedent. Primary care physicians should be aware of possible generic equivalents that will affect the availability of this drug for low-income or uninsured patients. Ann Fam Med 2006;4:556-560. DOI: 10.1370/afm.582.
Family physicians have no doubt been approached by their African
American patients with congestive heart failure (and perhaps with other heart diseases), asking about the new “for blacks only” medi- cine, isosorbide dinitrate and hydralazine hydrochloride (BiDil). Perhaps patients of other ethnic backgrounds have also asked their physicians about this drug. The media has covered the drug approval process exten-sively before and after a Food and Drug Administration (FDA) advisory committee recommended approval of BiDil for the specifi c indication of congestive heart failure in African Americans—the fi rst drug to be approved for a single racial group.1,2 Advising our patients requires that we understand the science behind this new pharmaceutical development. It also requires that we be fully aware of the economic, social, cultural, and ethical issues lurking in the background of this purported discovery. In this article, we provide an overview of these issues and try to place the decision as to whether to rec-ommend or prescribe BiDil in context for family physicians. Confl icts of interest: none reported SCIENTIFIC BACKGROUND
Understanding the science undergirding BiDil requires a brief histori- cal review, as well as a discussion of the scientifi c data. African American patients are more likely to die of heart failure compared with whites. Explanations are wide-ranging and include delay in diagnosis and treat- ment; limited access to coronary care; high prevalence of high-risk indi- Galveston, TX 77555-1311 [email protected] viduals with hypertension, diabetes, and dyslipidemia; and such related ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 4, NO. 6 ✦ NOVEMBER/DECEMBER 2006 B I D I L : A R AC E - B A S ED P H A R M AC EU T I C A L behavioral risk factors as physical inactivity and smok- may seem strange to many physicians, but it is cur- ing.3 One explanation focuses on impaired bioavail- rently a hotly debated issue amongst social and genetic ability of nitric oxide, which is thought to contribute scientists. For example, 2 prominent research journals to the structural remodeling of the left ventricle that recently devoted special issues to the controversy.8,9 increases the rate of death and complications. It has We will touch upon only a few highlights.
been proposed that African American patients may It has for some time been taken for granted that have a disproportionately lower nitric oxide bioavail- racial categories are of use to the physician in assess- ability. Isosorbide acts as a nitric oxide donor and ing the risks of various diseases. The latest genomic hydralazine as an antioxidant, and so together they science has, however, failed to provide much support might ameliorate the long-term effects of heart failure.4 for our intuitions about racial categories in medicine. A combination of isosorbide and hydralazine It has been shown generally that there is more genetic (160 mg and 300 mg total daily dose, respectively) diversity within a so-called “racial” cohort than there was compared with enalapril (20 mg) in the second is difference between 2 such cohorts. Nor does the Vasodilator-Heart Failure Trial.5 Mortality at 2 years human genome, in general, show the sorts of radical was signifi cantly lower in the enalapril arm. A later discontinuities among different racial groups that our retrospective review of those data, however, found commonplace intuitions would call for; instead, we see that white patients had disproportionate benefi t from much more evidence of gradual blending. Craig Ven- enalapril, whereas the subset of African American ter, who helped produce the fi rst map of the human patients appeared to receive substantially more ben- genome, commented regarding BiDil, “It is disturbing efi t from the isosorbide-hydralazine therapy.6 As of to see reputable scientists and physicians even catego- this point, no one had yet tested the hypothesis that rizing things in terms of race.… There is no basis in isosorbide and hydralazine, added to a regimen that the genetic code for race.”10 Given the new genomic already included an angiotensin-converting enzyme science, we must at least entertain the hypothesis that (ACE) inhibitor, might provide benefi t to patients with our intuitions were shaped, not by true empirical data, but in large part by vestiges of now-discredited bio- The African American Heart Failure Trial (A-HeFT) logical theories of race, while acknowledging that most was set up by the commercial sponsor, NitroMed, to physicians today are not consciously racist nor intend test this hypothesis. Only African American patients were enrolled in the trial. About 1,000 patients were A recent review of genomic science by a group of randomized to a fi xed-dose combination of isosorbide social scientists offered the conclusions that we must and hydralazine (target daily dose, 120 mg and 225 continue to do research on race in medicine, because mg, respectively) or placebo added to their existing whatever its biological basis (or lack of same), race medications (69% were on ACE inhibitors at baseline). remains a very important social construct, and as such, Follow-up was planned for 18 months, but the study it has tremendous power to infl uence health and ill- was stopped early (mean duration of follow-up, 10 ness.11 For example, some heart diseases may affl ict months) because of excess mortality in the placebo African Americans more than whites because of the group (54 vs 32 patients; 43% relative risk reduction; chronic stresses associated with being a member of number needed to treat = 25). The composite outcome a minority group rather than because of genetic fac- score (based on death, hospitalization, and quality of tors. Simply eliminating race as a variable in medical life) was signifi cantly better in the drug group.4 research would undermine our ability to detect these Based on these impressive fi ndings, an FDA advisory factors and can therefore hardly be helpful in reducing panel recommended on June 16, 2005, that BiDil be the serious disparities that remain a problem in Ameri- approved specifi cally for the treatment of heart failure can medicine. At the same time we must actively avoid in African American patients. Because A-HeFT enrolled the intellectual trap of assuming that disease incidence only African American subjects, the question of whether disparities among racial or ethnic groups are rooted other patients might also benefi t from adding isosorbide in genetic differences. We also must not assume that and hydralazine to their existing drug regimens for con- small effects may be attributable to sociocultural vari- gestive failure remains unanswered at this time.7 ables and that large effects always signal a biologic or genetic basis. Race as a Scientifi c Construct
In the face of recent genomic data, some have As we begin to address the broader issues that frame felt the need to try to preserve our old intuitions and the scientifi c discussion of BiDil’s uses and limits, we to rescue a concept of race that is, on the one hand, inevitably encounter the current debate over the use of clearly biologically grounded, but on the other hand, race in medicine and medical science. This controversy avoids invidious discrimination. According to the view ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 4, NO. 6 ✦ NOVEMBER/DECEMBER 2006 B I D I L : A R AC E - B A S ED P H A R M AC EU T I C A L called “geographic race,” self-ascribed racial groups been notably balanced and candid in assessing both tend to correspond reasonably well with the continent the pros and cons of the research and its broader from which one’s ancestors came. Continent of origin (and hence race) might then be a useful proxy indica- Nevertheless, BiDil appears to be in large part a tor of important clusters of genetic traits. Data have creature of marketing. The decision to seek a patent been derived from haplotype mapping that appear at for a race-specifi c application extended the patent pro- fi rst glance to support such a view.12 These fi ndings, tection BiDil will enjoy by 13 years.11 BiDil reportedly however, remain highly controversial and have been will be marketed at $1.80 per pill (with means-based soundly challenged in terms of their practical general- discounts offered by the company), roughly 4 to 7 izability and biomedical importance.13,14 times the cost of generic isosorbide plus hydralazine.2 The African American Heart Failure Trial (A-HeFT) BiDil and Past Invidious Discrimination
was designed to study a formulation of the 2 medica- Many African American patients perceive that their tions that did not match available generic doses community has historically been subjected to invidi- (37.5 mg of hydralazine, instead of the most common ous racial discrimination by a white-dominated medical available generic forms, 25 or 50 mg). If physicians, system. Whereas the infamous Tuskegee study has trying to save money for the patient or the insurer, been the lightning rod for much of this sentiment, it attempt to substitute a generic dose, they are open to is important to recall that many other events, both criticism if the patient does poorly, because they have before and after Tuskegee, all served to create a well- failed to match precisely the dosage regimen that has grounded impression that the medical care received by been validated in a major controlled trial. African Americans fell short of what was available to The present defenders of BiDil have admitted that white patients.15 Even today, many life-extending pro- race is a poor scientifi c prop upon which to base the cedures are used much less often among African Amer- effi cacy of a drug. They insist that eventually we will ican patients than among whites despite an absence of fi nd the true genetic basis of the differential response to this medication; at that later date, some form of In the face of this unfortunate history, it is hard to pharmacogenetic screening test will presumably iden- avoid the conclusion that the emergence of an effective tify all the patients, of whatever race, who will benefi t drug that is somehow “for blacks only” is a long over- from the drug. In the meantime, of course, they con- due bit of poetic justice. Whatever one might think of tend that we should not withhold an effi cacious drug the scientifi c pathway that led to BiDil being approved from a subgroup known to benefi t, regardless of how specifi cally for African Americans, or of the other issues we will review below, the mere fact that a new What would be the fi nancial incentive for the drug seems to offer hope to African Americans with a manufacturer to undertake the next round of pharma- serious chronic disease is a cause for celebration. It is cogenetic research? Companies seek to expand, not to very important that we not allow other legitimate con- contract, the markets for their drugs. Under the pres- cerns to make us appear insensitive to this unfortunate ent marketing structure, the company can sell BiDil to history of discrimination in health care. African American patients; depending on how well the drug performs in practice, the company can also count on a certain amount of off-label prescribing as physi- THE ECONOMICS OF BIDIL
cians elect to try it for patients of other races. To what The great majority of clinical trials of drugs in the extent would the identifi cation of a specifi c genetic United States are now funded by the pharmaceutical trait, correlated with positive therapeutic response, be industry.17 The average major drug fi rm spends 2 to 3 likely to expand that market? As long as there is some times as much on marketing as it does on research and probability that the results of that further research development.18 There is increasing evidence that all could cause the market to shrink, even if by a small too often the industry allows the marketing tail to wag amount, there is every incentive for the company to the research dog.19 Unfortunately, BiDil provides sev- In sum, BiDil is on the scene today mostly in The African American cardiologists who partici- answer to the question of how a company could gener- pated in the BiDil study had to walk a fi ne line—avoid- ate a profi t and much less in answer to the question of ing too close an alliance with for-profi t interests could which drug would best help which group of patients easily have led to turning down a rare opportunity and why. Family physicians might be leery of offering to do important research on heart disease in African too much support to this so-called way of “advancing” American patients. As a rule, these investigators have ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 4, NO. 6 ✦ NOVEMBER/DECEMBER 2006 B I D I L : A R AC E - B A S ED P H A R M AC EU T I C A L Reinvigorating Race as a Medical Category
Second, regardless of the true ratio, the role of We have already reviewed the reasons as to why race, genetics in explaining the difference remains an seen as a biological variable rather than as a social untested hypothesis. For example, hypertension, one construct, is or should be falling out of favor in medi- of the major risk factors for congestive heart failure, is cal science. Given the history of how race has been more common within the African American commu- used to justify differential treatment, almost always nity; and chronic social stress has been implicated as a to the detriment of society’s less powerful groups, we possible contributor to the development of hyperten- have good reason to welcome this development, even sion. Diet, exercise, and other environmental variables though it originates in a scientifi c understanding of genomics rather than in an urge for social reform. There is a danger that the apparent success of BiDil By contrast, anything that seems likely to cement will lead to a further de-emphasis of research into further the notion of race as a real biological variable these social and environmental contributors to disease, in medicine, in addition to a marker of importance in while all the research funding is devoted to possible diagnosis and therapeutics, might appear to be a ret- genetic bases. We already have seen a major shift in rogression. Despite the comforting claims that BiDil is research funding in the United States as a result of about race only as a matter of temporary convenience, the heavy infl uence of the pharmaceutical industry. the popularity of this drug is almost certain to prompt A possibly highly effective nondrug treatment for a the general impression that race works as a medical life-threatening disease is today less likely to receive category. As Kahn has stated, “The role of the federal research support than a slightly effective drug therapy legal and regulatory system in producing BiDil as an for a minor lifestyle condition where a lucrative market ethnic drug is especially important because it lends the exists. The BiDil experience is likely to cause this dis- imprimatur of the state to the use of race as a biologi- Perhaps any negative fallout from rediscovering race Prescribing Issues
as a biological category will be readily contained in a For suitable patients with heart failure and on optimal society that is now better attuned to the dangers of rac- doses of other drugs, some might urge that we pre- ism. Or perhaps these ideas may have serious negative scribe BiDil specifi cally for those who can afford it as consequences that extend beyond the good that BiDil a way to reward the company for launching research might do for sufferers from congestive heart failure. specifi cally aimed at reducing health disparities on Past history leads one to tread warily along such a path. behalf of African Americans. We anticipate that the company will launch a publicity campaign among the Ignoring Nongenetic Contributors to Disease
African American community to make this case. Family physicians, well schooled in the biopsychoso- For patients unable to afford an expensive brand- cial model of health, ought especially to be concerned name drug, or for family physicians less impressed about an approach to research that de-emphasizes the with the scientifi c approach that the BiDil research search for social and cultural factors in disease.11,20 represents, it is important to consider possible lower- Advocates of BiDil have promoted the notion that cost generic options. One could, or instance, prescribe because African Americans die of heart failure at twice isosorbide 20 mg and hydralazine 25 mg 3 times daily, the rate as whites, such a great difference cannot be and titrate as tolerated to a ceiling dose of 40 mg of explained by sociocultural variables alone and must isosorbide and 75 mg of hydralazine 3 times daily—the refl ect underlying genetic differences. same target dose used in the A-HeFT trial, which was Kahn has effectively questioned this entire line of achieved by about two thirds of the subjects.4 Eventu- reasoning.10 First, the 2:1 ratio of deaths among Afri- ally using a 40-mg isosorbide tablet and 25-mg plus can Americans, a statistic used widely to raise investor a 50-mg dose form of hydralazine could require that capital for NitroMed and to secure political support the patient take 3 pills 3 times a day, as compared to 2 for BiDil, is derived from older data and looks only at BiDil 3 times a day. In either case compliance will be a people who are younger than 75 years. If one considers diffi cult issue with 3-times-a-day dosing. But patients newer data among all age-groups, the ratio appears to need to be aware that the benefi ts seen in A-HeFT be closer to 1.1:1. It is still true that African Ameri- should be readily achieved with a cheaper dosage form.
cans tend to die of heart failure at younger ages than In counseling patients and community groups, whites, and these data should not excuse us from con- clinicians need to place BiDil in its proper context. tinuing to battle the serious health disparities we know The medication appears to offer real benefi ts for some to exist. But the much-cited 2:1 ratio turns out to be patients. Until more research is done, we will not know what population groups in addition to African ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 4, NO. 6 ✦ NOVEMBER/DECEMBER 2006 B I D I L : A R AC E - B A S ED P H A R M AC EU T I C A L Americans might enjoy those benefi ts. The family 6. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in medicine community ought to encourage contin- response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. ued action to reduce health disparities, to promote research that addresses the psychological and social 7. Bloche MG. Race-based therapeutics. N Engl J Med. 2004;351: contributors to ill health alongside the biological fac- tors, to propose reforms so that future pharmaceuti- 8. Anderson NB, Nickerson KJ. Genes, race, and psychology in the cal studies will be driven more by science and less genome era: an introduction. Am Psychol. 2005;60:5-8.
by marketing, and generally to be skeptical of future 9. Special Issue: Genetics for the human race. Nat Genet 2004;36: 10. Kahn J. How a drug becomes “ethnic”: law, commerce, and the To read or post commentaries in response to this article, see it
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