Chester Clinic

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What's Right (and Wrong) with Racially Stratified Research and Therapies Robert M. Sade, MD vinced the FDA to approve BiDil arose from several ear- Robert Sade is professor of sur- lier studies, especially the Vasodilator Heart Failure Tri- gery and director of the Institute als (V-HeFT).
of Human Values in Health Care The first V-HeFT (V-HeFT I) demonstrated the effec- at the Medical University of South tiveness of i-h in treating heart failure.2 A second study, Carolina. He has written several V-HeFT II, compared the effectiveness of this combina- hundred articles, book chapters tion with the angiotensin-converting-enzyme (ACE) in- and books on cardiothoracic hibitor, enalapril.3 It showed that enalapril was associat- surgery, medical education, bio- ed with a greater overall reduction in mortality than i-h. medical ethics and health poli- A subgroup of patients, however, did not do as well on cy, and serves as an editor of both the Annals of Thoracic enalapril as they did on i-h. A biotechnology company, Surgery and the Journal of Philosophy and Medicine.
NitroMed Inc., obtained intellectual property rights to a Sade chairs the Ethics Committee of the American Associa- fixed-dose combination of i-h (BiDil), but in 1996, the tion for Thoracic Surgery, and chairs the Standards and Eth- FDA did not approve marketing this combination as a ics Committee of the Society of Thoracic Surgeons. He has new drug because of lack of proof of its effectiveness.4 been a member of the American Medical Association's Reanalysis of the data from the earlier V-HeFT I & Council on Ethical and Judicial Affairs for nearly seven years II, this time stratifying by race, as the subjects identified and currently serves as chair of the council.
themselves, found that the combination treatment was key words: ACE inhibitors n race/ethnicity
just as effective in prolonging the lives of black patients with heart failure as ACE inhibitors were in whites.5 The 2007. From the Medical University of South Carolina (professor of surgery FDA indicated that if a clinical trial confirmed the effec- and director, Institute of Human Values in Health Care). Send correspon- tiveness of BiDil in blacks, approval of the drug specifi- dence and reprint requests for J Natl Med Assoc. 2007;99:xxx–xxx to: Dr. cally for black patients with severe heart failure would Robert Sade, Department of Surgery, 96 Jonathan Lucas St., Suite 409, PO probably follow.4 Box 250612, Charleston, SC 29425; phone: (843) 792-5278; fax: (843) 792-8286; A new RCT was designed and carried out in 2001– e-mail: [email protected]; website: http://values/musc.edu 2004, the African-American Heart Failure Trial (A-HeFT).6 This trial studied BiDil combined with con- ventional therapy for heart failure (which by that time In June 2005, BiDil®, a fixed-dose combination of included an ACE inhibitor) compared with conventional isosorbide dinitrate and hydralazine hydrochloride (i-h), therapy alone.4 The Association of Black Cardiologists became the first drug approved by the Food and Drug and NitroMed cosponsored the study, which was lim- Administration (FDA) for use only in a specific popu- ited to self-identified blacks who suffered from NYHA lation of individuals who self-identify as black (defined class-3 or -4 heart failure. In 2002, NitroMed was grant- as of African descent).1 This announcement was greeted ed a new patent, based on the use of BiDil specifically by rounds of applause and approval from medical pro- in black patients. This was the first patent ever granted fessional groups and the lay public—and negative reac- for a new drug limited to use only in one race. The orig- tions from others, ranging from cautionary statements inal patent was to expire in 2007, but the new patent to outright condemnation. Over the past year, the ques- pushed back the expiration date to 2020, preventing ge- tion of whether drug research that focuses on a specif- neric drug companies from manufacturing and selling i- ic self-identified race should be done at all has been a h for an additional 13 years. subject of spirited debate in the medical literature and A-HeFT studied 1,050 patients and showed that Bi- lay media. The randomized clinical trial (RCT) that con- Dil, when combined with standard therapy, increased JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 6, JUNE 2007 
RACIALLy STRATIFIED RESEARCH AND THERAPIES survival in the study group by 43% compared with stan- beta-blockers and tricyclic antidepressants, is function- dard treatment alone. The study group also had a 33% ally absent in 8% of whites but in <1% of Asians, lead- greater reduction in the rate of hospitalization for heart ing to different drug responses in these populations. CY- failure and significantly greater improvement in quality- P2D6 in Africans and African Americans frequently has of-life measures.6 impaired activity and is encoded by an allele that is vir- The FDA announcement of BiDil approval cited the tually absent in white and Asian populations.10 This par- facts that 750,000 black patients suffer from severe heart ticular genetic difference may have contributed to some failure, and those in the age range of 45–64 years carry of the differences in outcomes of the studies that lead to a 2.5 times' greater risk of death than similarly situated the approval of BiDil. Thus, there are at least some bio- white patients. There is no cure for severe advanced heart logical differences between races and ethnic groups that failure; 50% of the patients who have the disease die within may justify stratification of clinical trial groups by self- five years.1 The National Medical Association commend- identified race, even if a "scientifically valid definition" ed the FDA for approving the use of BiDil in blacks.
of the study groups is not available.
The FDA approval of BiDil for use in blacks elicited Race is a very crude marker, and using self-identi- a range of approving statements.7 "I take anything that fication as a member of a particular race is particular- shows a benefit for heart failure as an advance" (Keith ly problematic, leading to a highly heterogeneous group Ferdinand, a member of the Association of Black Car- for study. More specific markers, based on genes asso- diologists); "Today's approval of a drug to treat severe ciated with diseases should be used in such studies.4 heart failure in self-identified black population is a strik- Self-identification as a member of a particular race con- ing example of how treatment can benefit some patients founds clinical studies for many reasons. For example, a even if it does not help all patients" (Robert Temple of substantial proportion of the American population is of the FDA); "In BiDil, we now have a treatment that has mixed racial origin, so the same person may self-iden- been shown to save the lives of black heart failure pa- tify in two, three or more racial groups. This is bound tients, helping a population that is disproportionally bur- to lead to highly heterogeneous racial groups for study. dened by cardiovascular disease" (Anne Taylor, lead A- More specific markers, such as the presence or absence HeFT investigator).8 of the specific enzymes or genes associated with diseas- At first blush, it seems odd to find fault with research es, should be used whenever possible in stratifying study that can lead to such positive results. But critics of the groups. Yet, until we know what the specific markers are study and of the FDA approval of the drug for use only and can identify them fairly easily, we must use more in blacks found plenty to criticize. The criticisms are, to approximate markers. In the HeFT series of studies, some extent, valid, but some are aimed at the wrong tar- self-identification by race was undoubtedly not the most get, and some are true but not relevant to this issue. Con- precise marker to use, but the investigators did not have sidering all of the criticisms together, they are not, in my a better one. Despite the imperfections of racial stratifi- opinion, sufficient to condemn the BiDil study nor to in- cation in the V-HeFT studies, significant and important hibit similar race-based research in the future. differences between whites and blacks were found, dif- The objections can be roughly divided into three gen- ferences that led to A-HeFT, and, ultimately, to an im- eral categories, with much overlap between them: bio- portant new treatment that works well in treating heart logical-scientific, marketing-financial and social, as dis- failure in self-identified blacks.
cussed below.
There is no reason to assume that a drug will work for all people in a particular group when it should be Biological and Scientific Issues
perfectly obvious that people in other groups also might A fundamental scientific problem with the idea of do- benefit.4,11,12 That is a true statement; not every black with ing research stratified by race is the claim that the very advanced heart failure will benefit from BiDil, and some concept of race is biologically meaningless: "Race is a whites and Asians will also benefit. The fact that peo- social construct, not a scientific classification." There- ple other than blacks might benefit was clearly recog- fore, there should be a "requirement to furnish a scien- nized by the investigators of A-HeFT: "A future strategy tifically valid definition of the population under study."9 would be to identify genotypic and phenotypic char- It is certainly true that race is not a scientific classifi- acteristics that would transcend racial or ethic catego- cation, and it may be largely socially constructed. This ries to identify a population with heart failure in which does not mean, however, that race is biologically mean- there is an increased likelihood of a favorable response ingless. Biological differences among races and ethnic to such therapy."6 This study clearly is only the first step groups have been well documented. For example, al- in a needed series of studies to delineate the biologi- though no polymorphic trait is unique to a particular ra- cal markers that will identify those most likely to ben- cial group, certain variants occur at different frequen- efit from BiDil. The fact that more work is needed does cies in different populations. CYP2D6, the cytochrome not suggest either that this study should not have been P-450 enzyme that is responsible for the metabolism of done or that future studies of specific races or ethnic  JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
VOL. 99, NO. 6, JUNE 2007 RACIALLy STRATIFIED RESEARCH AND THERAPIES groups would not be warranted. The path taken by re- better to BiDil make them superior or inferior. Concerns search that produces medical and biological advances is about misinterpretation and misuse of biological facts never straight, but neither is it a random walk. Most re- are well grounded, but, in view of the powerful benefits search advances our knowledge base in the correct gen- of BiDil to blacks, such concerns should be used neither eral direction, and an occasional study leads backwards. to condemn research stratified by race nor to denounce The BiDil study clearly demonstrated a new way to save the action of the FDA in approving BiDil.
lives and to improve quality of life for many blacks; it took us a step forward toward treating heart failure. Fu- Financial and Marketing Issues
ture research will give us better and more sharply fo- No RCT with stratification by race has ever been cused tools to identify patients who are likely to benefit done that specifically compares i-h with ACE inhibitors, from specific therapies.
so we do not know if there is truly a difference among races. Rather than a study of blacks only, all patients should have been studied. The black population was spe- Differences in pathophysiology and responses to cifically studied because the company, NitroMed, knew drugs among groups of people may be based on factors and cynically used the differences between races found other than genetic, such as a mixture of socioeconom- retrospectively in V-HeFT II merely to gain an addition- ic, cultural, psychosocial and environmental factors. al 13 years of patent protection that would otherwise not Focusing on race may discourage investigation of these have been allowed. A-HeFT was motivated not so much nongenetic factors.4 It is certainly true that pathophysi- by the best science as by regulatory and market incen- ology and responses to drugs may be based on many tives.4,13 The facts underlying this criticism are true, but factors other than genetic, including those cited above. the inferences drawn from them miss the mark. While Research into disparities in healthcare has investigated many speak of regulatory and market incentives pejo- the role of just such factors in healthcare outcomes, and ratively, government has intentionally—for what it has we have learned much from those studies, yet a great viewed as the public good—made these factors substan- deal remains unknown. In view of the widespread, ac- tial motivators of research and development in the drug tive interest in elucidating the causes and prevention of industry (as well as most other industries). While some disparities in healthcare outcomes, it seems implausible may wish it to be otherwise, the main purpose for the that investigations that stratify populations by race will existence for any business is to make money for its own- discourage investigation of nongenetic factors in health- ers.14-16 The purpose of profits and the policies supporting care outcomes.
that purpose have driven the growth of the U.S. economy Official governmental approval of a drug that is spe- to its status of pre-eminence in the world. While some cifically designated only for blacks will bolster the repug- commentators may wish that pharmaceutical companies nant and discredited notion that blacks and whites have were motivated by the commentator's own particular vi- fundamental biological differences.7 The scars in our so- sion of the public good and by "pure" science, motiva- cial fabric from the wounds inflicted by the Tuskegee tions of these sorts cannot produce the wealth of new experiment persist and still cause considerable concern drugs that are constantly coming onto the market, cur- and discomfort when race is mentioned in the context of ing illnesses, preventing deaths and relieving suffering. healthcare, especially within the black community. Yet, Governmental regulations provide the framework of mo- not even the most radical critics of the BiDil drug tri- tivations and constraints within which companies must als have suggested any similarity to the Tuskegee study; conduct their business and manage their affairs. One can still, discomfort over race-based investigations is under- scarcely blame a company for doing what it is supposed standable. Tuskegee is not the only reason for concern to be doing—namely, making products that are useful in this regard, as studies of healthcare outcomes have and that people (or their agents) are willing to pay for— provided a continuing stream of evidence of differential within the constraints of law and regulation.
outcomes that disfavor blacks. Much needs to be done to Companies that gain financially from race-based correct these well-documented disparities in healthcare. studies should devote a large share of their profits to re- FDA approval of BiDil suggests biological differences search aimed at uncovering underlying biological fac- between races, and the existence of such differences is tors.4 Investigation of underlying biological factors is well known. The known variations, however, are con- critically important to identifying more accurately those fined to a few genes and proteins that do not constitute who will or will not benefit from the use of a partic- "fundamental biological differences." What we must do ular drug; ultimately, most would agree that such re- is to treat genetically determined differences among rac- search should be done. Who should do it, however, is a es, ethnic groups and other demographic subdivisions question that is best left to the mechanisms that are al- as socially neutral: the fact that whites respond better to ready in place to make such decisions: private compa- enalapril than do blacks does not make them either in- nies guided by market factors and regulatory limits, and ferior or superior, nor does the fact that blacks respond the public institutions that investigate fundamental bio- JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 6, JUNE 2007 
RACIALLy STRATIFIED RESEARCH AND THERAPIES logical questions, such as universities and the National 3. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive Institutes of Health and other federal agencies. Institu- heart failure. N Engl J Med. 1991;325(5):303-310.
tions have been created to carry out basic research pre- 4. Bloche MG. Race-based therapeutics. N Engl J Med. 2004;351(20):2035- cisely because commercial companies do not and should not be expected to expend their limited resources on re- 5. Carson P, Ziesche S, Johnson G, et al. Racial differences in response to search and development that will not, in their view, lead therapy for heart failure: analysis of the vasodilator-heart failure trials. Vaso- dilator-Heart Failure Trial Study Group. J Card Fail. 1999;5(3):178-187.
to commercially viable products.
6. Taylor AL, Ziesche S, yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. NitroMed and the FDA have been unjustly criticized 7. Stein R. FDA approves controversial heart medication for blacks. Wash- for the way in which they have carried out their legal and ington Post. 2005;June 24:A15.
moral obligations. Even when the facts underlying the 8. NitroMed Inc. FDA approves BiDil for treatment of heart failure drug for black patients. June 23, 2005. www.nitromed.com/pdf/Approval%20Pres criticisms are correct, they have often been evaluated in the context of a particular social vision or a personal sense of morality rather than in the context of the policies, Accessed 09/18/06.
laws and regulations that actually govern the way all com- 9. Schwartz RS. Racial profiling in medical research. N Engl J Med. 2001; panies, including drug companies, must function.
10. Wood AJ. Racial differences in the response to drugs—pointers to Most critics have responsibly recognized the over- genetic differences. N Engl J Med. 2001;344(18):1394-1396.
arching value of BiDil in saving and improving the lives 11. Chepesiuk R, Jones J. Are race-specific drugs unethical? With BiDil of black patients with severe heart failure while noting on the market, experts weigh the moral implications. Black Enterprise. important social factors—such as the historical mis- n15890897. Accessed 09/18/06.
treatment of blacks and contemporary healthcare dis- 12. Moran AE, Cooper RS. Isosorbide dinitrate and hydralazine in blacks parities—that warrant caution and vigilance in design- with heart failure. N Engl J Med. 2005;352:(10):1041-1043.
ing and carrying out racially stratified RCTs. With that 13. A bitter pil for black hearts. The Black Commentator, 2005. www.alter- view, we could not agree more.
net.org/story/23185/. Accessed 03/23/06.
14. Friedman M. The social responsibility of business is to increase its profits. The New York Times Magazine. September 13, 1970.
1. Meadows M. FDA Approves Heart Drug for Black Patients. FDA Consumer 15. Sternberg E. The universal principles of business ethics. In: Business Ethics in the Global Market. Stanford: Hoover Institution Press; 1999:1-36.
2. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on 16. Sade RM. Medicine and managed care, morals and markets. In: Bond- mortality in chronic congestive heart failure. Results of a Veterans Adminis- eson J, Jones J, eds. The Ethics of Managed Care: Professional Integrity and tration Cooperative Study. N Engl J Med. 1986;314(24):1547-1552.
Patient Rights. Boston, MA: Kluwer Academic Publishers; 2003:55-74. n  JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
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Source: http://www.values.musc.edu/humanvalues/pdf/Racial%20StratificationJNMA0706.pdf