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Brody.indd
REFLECTION
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. INTRODUCTION 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 reportedSCIENTIFIC BACKGROUND CORRESPONDING AUTHOR
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
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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
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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 expandthat 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
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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
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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
production of racial categories in medicine. Yale J Health Policy Law online at http://www.annfammed.org/cgi/current/full/4/6/556.
11. Sankar P, Cho MK, Condit CM, et al. Genetic research and health
Key words: Minority groups; heart failure, congestive; genetic pre-
disparities. JAMA. 2004;291:2985-2989.
disposition to disease; delivery of health care; health services research;
12. Tang H, Quertermous T, Rodriguez B, et al. Genetic structure, self-
identifi ed race/ethnicity, and confounding in case-control associa-tion studies. Am J Hum Genet. 2005;76:268-275.
Submitted November 19, 2005; submitted, revised, January 31, 2006;
13. Cooper RS, Kaufman JS, Ward R. Race and genomics. N Engl J Med.
14. Jorde LB, Wooding SP. Genetic variation, classifi cation and ‘race’.
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