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July 15, 2007--- www.sciam.com

	
Race in a Bottle
	
Drugmakers are eager to develop medicines targeted at ethnic groups,  
but so far they have made poor choices based on unsound science
	
By Jonathan Kahn
	
Two years ago, on June 23, 2005, the U.S. Food and Drug  
Administration approved the first “ethnic” drug. Called BiDil  
(pronounced “bye-dill”), it was intended to treat congestive heart  
failure—the progressive weakening of the heart muscle to the point  
where it can no longer pump blood efficiently—in African-Americans  
only. The approval was widely declared to be a significant step  
toward a new era of personalized medicine, an era in which  
pharmaceuticals would be specifically designed to work with an  
individual’s particular genetic makeup. Known as pharmacogenomics,  
this approach to drug development promises to reduce the cost and  
increase the safety and efficacy of new therapies. BiDil was also  
hailed as a means to improve the health of African-Americans, a  
community woefully underserved by the U.S. medical establishment.  
Organizations such as the Association of Black Cardiologists and the  
Congressional Black Caucus strongly supported the drug’s approval.

A close inspection of BiDil’s history, however, shows that the drug  
is ethnic in name only. First, BiDil is not a new medicine—it is  
merely a combination into a single pill of two generic drugs,  
hydralazine and isosorbide dinitrate, both of which have been used  
for more than a decade to treat heart failure in people of all races.  
Second, BiDil is not a pharmacogenomic drug. Although studies have  
shown that the hydralazine/isosorbide dinitrate (H/I) combination can  
delay hospitalization and death for patients suffering from heart  
failure, the underlying mechanism for the drug’s efficacy is not  
fully understood and has not been directly connected to any specific  
genes. Third, and most important, no firm evidence exists that BiDil  
actually works better or differently in African-Americans than in  
anyone else. The FDA’s approval of BiDil was based primarily on a  
clinical trial that enrolled only self-identified African-Americans  
and did not compare their health outcomes with those of other ethnic  
or racial groups.

So how did BiDil become tagged as an ethnic drug and the harbinger of  
a new age of medicine? The story of the drug’s development is a  
tangled tale of inconclusive studies, regulatory hurdles and  
commercial motives. BiDil has had a relatively small impact on the  
marketplace—over the past two years, only a few million dollars’  
worth of prescriptions have been sold—but the drug has demonstrated  
the perils of using racial categories to win approval for new  
pharmaceuticals. Although African-Americans are dying from heart  
disease and other illnesses at younger ages than whites, most  
researchers believe the premature deaths result from a complex array  
of social and economic forces [see “Sick of Poverty,” by Robert  
Sapolsky; Scientific American, December 2005]. Some medical  
professionals and policy experts, however, have pointed to BiDil as  
proof that genetic differences can explain the health disparity.  
Worse, some pharmaceutical companies are now using this unfounded  
argument to pursue other treatments targeted at various ethnic  
groups, a trend that may segregate medicine and fatten the profits of  
drugmakers without addressing the underlying causes that are killing  
so many African-Americans before their time.

Birth of BiDil

The BiDil saga began more than 20 years ago with a pair of studies  
designed to gauge the effects of vasodilating drugs—which widen  
blood vessels—on heart failure, a debilitating and ultimately fatal  
disease that afflicts millions of Americans. Until then, doctors  
treated heart failure with diuretics (to reduce the accumulation of  
fluid that results from inadequate pumping) and digoxin (to increase  
the contraction of the heart muscle) but had little else at their  
disposal. In the early 1980s Jay Cohn, a cardiologist at the  
University of Minnesota, hypothesized that administering two  
vasodilators, hydralazine and isosorbide dinitrate, might ease the  
strain on weakened hearts by relaxing both the arteries and veins.  
Together with the U.S. Veterans Administration, Cohn designed and  
conducted two trials to assess this theory.

The first Vasodilator Heart Failure Trial (V-HeFT I) tested the H/I  
combination against a placebo and a drug called prazosin, which is  
used to treat high blood pressure. The results seemed to show great  
promise for the combination. The second trial, V-HeFT II, tested H/I  
against enalapril, a first-generation angiotensin-converting enzyme  
(ACE) inhibitor. (ACE inhibitors lower blood pressure by curbing the  
production of vessel-constricting peptides.) As it turned out,  
enalapril proved more effective than H/I for treating heart failure.  
 From that point forward, ACE inhibitors became the new first-line  
therapy for heart failure patients. Doctors began recommending  
hydralazine and isosorbide dinitrate—both available as inexpensive  
generic pills—for those who did not respond well to ACE inhibitors.

Cohn, however, remained committed to developing a treatment that  
combined hydralazine and isosorbide dinitrate because he believed in  
its effectiveness. In 1987 he applied for a patent on the method of  
using the drugs together to treat heart failure in all people,  
regardless of race. (He could not get a patent on the drug  
combination itself because both medicines were already available in  
generic form.) He then licensed the patent rights to Medco, a small  
pharmaceutical firm in North Carolina, which took steps in the early  
1990s to put the H/I combination into a single pill—and BiDil was  
born.

Medco and Cohn brought BiDil to the FDA for approval in 1996. In  
early 1997 the agency refused to approve the drug. Ironically, most  
of the doctors on the FDA’s review panel thought BiDil did in fact  
work and said they would consider prescribing it. The problem was not  
with the drug but with the statistical data from the V-HeFT trials,  
which were designed not to meet the regulatory standards for FDA  
approval but to test the hypothesis that vasodilators could treat  
heart failure. After the rejection, Medco’s stock plummeted by more  
than 20 percent, and the company let the patent rights revert to  
Cohn. By 1997 half of the 20-year life of the original BiDil patent  
had already passed, which may explain Medco’s reluctance to sink  
more money into the drug.

BiDil’s Racial Rebirth

It was only at this point that race entered the story. After the  
FDA’s rejection of BiDil, Cohn went back to the V-HeFT results from  
the 1980s and broke down the data by race, examining how well African- 
Americans had responded to the competing treatments. Such  
retrospective “data dredging” can yield useful insights for  
further investigations, but it is also fraught with statistical  
peril; if the number of research subjects in each category is too  
small, the results for the subgroups may be meaningless. Cohn argued  
that H/I worked particularly well in the African-Americans enrolled  
in the V-HeFT studies. The clearest support for this claim came from  
V-HeFT I, which placed only 49 African-Americans on H/I—a tiny  
number considering that new drug trials typically enroll thousands of  
subjects. In 1999 Cohn published a paper in the Journal of Cardiac  
Failure on this hypothesized racial difference and filed a new patent  
application. This second patent was almost identical to the first  
except for specifying the use of H/I to treat heart failure in black  
patients. Issued in 2000, the new patent lasts until 2020, 13 years  
after the original patent was set to expire. Thus was BiDil  
reinvented as an ethnic drug.

Race-specific patent in hand, Cohn relicensed the intellectual- 
property rights to NitroMed, a small Massachusetts firm. The FDA then  
gave NitroMed the go-ahead to conduct the African-American Heart  
Failure Trial (A-HeFT), a relatively small study involving 1,050 self- 
identified African-Americans. In A-HeFT, half the heart failure  
patients took BiDil while the other half received a placebo; at the  
same time, the patients in both groups continued taking their already  
prescribed treatments for heart failure (for example, about 70  
percent of the subjects in both groups were on ACE inhibitors). The  
results were strikingly positive: the mortality rate in the BiDil  
subjects was 43 percent lower than that in the placebo group. In  
fact, BiDil appeared so effective that A-HeFT’s Data Safety  
Monitoring Board suspended the trial early, in July 2004, so that the  
drug could be offered to the subjects in the placebo group as well.  
NitroMed’s stock surged on the news, more than tripling in value in  
the following days. The next June the FDA formally approved BiDil  
with a race-specific label, indicating that it was for use in black  
patients.

But researchers have good reason to believe that BiDil would also be  
effective in nonblack patients. Indeed, Cohn himself has said he  
believes the drug should work in people of all races. So why did the  
developers of the drug test it in only one ethnic group? The answer  
seems to be driven more by commerce than by science. If the FDA had  
approved BiDil for the general population, the patent protection for  
the drug’s manufacturer would have expired in 2007. Restricting the  
clinical trial to African-Americans maximized the chances that the  
FDA would approve the race-specific use of BiDil, giving NitroMed an  
additional 13 years to sell the H/I combination without competition.

Segregated Medicine

Science and commerce have always proceeded together in advancing  
medicine, but in the case of BiDil the balance seems to have gotten  
out of whack. There can be no doubt that Cohn and the other medical  
professionals behind the drug’s development sincerely want to  
improve the lives of the many people suffering from heart failure. In  
this respect, the approval of BiDil is certainly a good thing. But  
Cohn and NitroMed have also used race to obtain commercial advantage.  
The patented drug costs about six times as much as the readily  
available generic equivalents. The high cost has already made many  
insurers reluctant to cover BiDil and may place it beyond the reach  
of the millions of Americans without health insurance. Moreover, the  
unprecedented media attention to the race-specific character of the  
drug may lead many doctors and patients alike to think that non- 
African-Americans should not get the drug, when, in fact, it might  
help prolong their lives.

Perhaps most problematically, the patent award and FDA approval of  
BiDil have given the imprimatur of the federal government to using  
race as a genetic category. Since the inception of the Human Genome  
Project, scientists have worked hard to ensure that the biological  
knowledge emerging from advances in genetic research is not used  
inappropriately to make socially constructed racial categories appear  
biologically given or natural. As a 2001 editorial in the journal  
Nature Genetics put it, “scientists have long been saying that at  
the genetic level there is more variation between two individuals in  
the same population than between populations and that there is no  
biological basis for ‘race.’” More recently, an editorial in  
Nature Biotechnology asserted that “race is simply a poor proxy for  
the environmental and genetic causes of disease or drug response....  
Pooling people in race silos is akin to zoologists grouping raccoons,  
tigers and okapis on the basis that they are all stripey.”

The FDA’s approval of BiDil was based on accepting NitroMed’s  
argument that the drug should be indicated only for African-Americans  
because the trial population was African-American. This labeling  
sends the scientifically unproved message that the subject  
population’s race was somehow a relevant biological variable in  
assessing the safety and efficacy of BiDil. Most drugs on the market  
today were tested in overwhelmingly white populations, but we do not  
call these medicines “white,” nor should we. The FDA’s unstated  
assumption is that a drug that proves effective for white people is  
good enough for everyone; the same assumption should apply when the  
trial population happens to be black. Otherwise, the FDA is implying  
that African-Americans are somehow less fully representative of  
humanity than whites are.

In November 2004 Nature Genetics published an article by Sarah K.  
Tate and David B. Goldstein of University College London entitled  
“Will Tomorrow’s Medicines Work for Everyone?” The paper noted  
that “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.” Journalists immediately quoted the study as providing  
further evidence of biological differences among races; for example,  
an article in the Los Angeles Times, after discussing BiDil, referred  
to “a report in the journal Nature Genetics last month [that] listed  
29 drugs that are known to have different efficacies in the two  
races.” (The italics are mine.) Similarly, a story in the Times of  
London 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.” (Again, the italics are mine.) And a New York Times  
editorial entitled “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.”

One small problem: these newspaper stories totally misrepresented the  
Nature Genetics piece. Tate and Goldstein asserted that the racial  
differences in drug safety or efficacy have only been claimed, not  
proved, and in the next sentence they go on to say, “But these  
claims are universally controversial, and there is no consensus on  
how important race or ethnicity is in determining drug  
response.” (My italics again.)

In only four of the 29 medicines identified, Tate and Goldstein found  
evidence that genetic variations between races could possibly be  
related to the different responses to the drugs. (All four are beta  
blockers used for treating high blood pressure and other  
cardiovascular ills; some research indicates that these drugs work  
better in individuals carrying a gene variant that is more common in  
people of European ancestry than in African-Americans.) For nine of  
the medicines, the authors found “a reasonable underlying  
physiological basis” to explain why blacks and whites may respond  
differently to the drugs; for example, some scientists have  
speculated that ACE inhibitors may be more effective in people of  
European descent than in African-Americans because of variations in  
enzyme activity. (Other researchers have contested this hypothesis.)  
For five of the drugs, Tate and Goldstein found no physiological  
reasons to explain the varying responses; for the remaining 11 they  
concluded that the reports of differing responses may not be valid.

Racial Injustice

Nevertheless, the appeal of race-specific drugs is growing. In 2003  
VaxGen, a California biopharmaceutical company, made an abortive  
attempt to use a retrospective analysis of racial subgroups to  
salvage a proposed AIDS vaccine called AIDSVAX. Although the clinical  
trial for AIDSVAX showed no decrease in HIV infection rates in the  
study population as a whole, VaxGen claimed a significant reduction  
in infection among the black and Asian participants. But only a few  
hundred blacks and Asians were involved in the study, meaning that a  
handful of infections could have skewed the results. The claim of  
race-specific response was undercut later that year when another  
trial in Thailand showed that AIDSVAX was ineffective there as well.  
In a similar case, AstraZeneca, the British pharmaceutical firm,  
argued that its lung cancer drug, Iressa, worked better in the Asians  
enrolled in a 2004 clinical trial, which showed that the medicine did  
not improve survival rates overall. (Unconvinced, the FDA changed the  
labeling for Iressa, disallowing its use in any new patients.) More  
recently, AstraZeneca has conducted trials of Crestor, the company’s  
multibillion-dollar cholesterol-lowering drug, in African-Americans,  
South Asians and Hispanics. Consumer groups have claimed that Crestor  
is less safe than other cholesterol-lowering drugs, but AstraZeneca  
says the race-specific studies demonstrate the safety and efficacy of  
the medicine.

Researchers using race to develop drugs may be motivated by good  
intentions, but such efforts are also driven by the dictates of an  
increasingly competitive medical marketplace. The example of BiDil  
indicates that researchers and regulators alike have not fully  
appreciated that race is a powerful and volatile category. When used  
to bolster the commercial value of a drug, it can lead to haphazard  
regulation, substandard medical treatment and other unfortunate  
unintended consequences. The FDA should not grant race-specific  
approvals without clear and convincing evidence of a genetic or  
biological basis for any observed racial differences in safety or  
efficacy. Approving more drugs such as BiDil will not alleviate the  
very serious health disparities between races in the U.S. We need  
social and political will, not mislabeled medicines, to redress that  
injustice.
---------------------------------------

More to Explore
The Meanings of “‘Race” in the New Genomics: Implications for  
Health Disparities Research.  Sandra Soo-Jin Lee et al. in Yale  
Journal of Health Policy, Law, and Ethics, Vol. 1, pages 33–75; 2001.

Combination of Isosorbide Dinitrate and Hydralazine in Blacks with  
Heart Failure.  Ann L. Taylor et al. in New England Journal of  
Medicine, Vol. 351, pages 2049–2057; November 11, 2004.

How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of  
Racial Categories in Medicine.  Jonathan Kahn in Yale Journal of  
Health Policy, Law, and Ethics, Vol. 4, pages 1–46; 2004.

 From Disparity to Difference: How Race-Specific Medicines May  
Undermine Policies to Address

Inequalities in Health Care.  Jonathan Kahn in Southern California  
Interdisciplinary Law Journal, Vol. 15, pages 105–129; 2005.

Enhanced: Race and Reification in Science.  Troy Duster in Science,  
Vol. 307, pages 1050–1051; February 18, 2005.

For other related articles by Jonathan Kahn, go to http://ssrn.com/ 
author=180388
	
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