The roughly five million Americans who suffer from heart failure, a chronic and deadly disease, could be part of a radical change in the practice of medicine later this year. Cardiologists across the country will likely begin to prescribe a new, and by most accounts highly promising, drug based on an unusual criterion: whether the patient is black or white – or, to be more precise, whether the person identifies him- or herself as an African American.
Sometime by midyear, the U.S. Food and Drug Administration will decide whether to approve BiDil, a heart failure medicine developed by NitroMed, a small pharmaceutical company in Lexington, MA. Experts say that the drug, if approved, will be the first pharmacuetical targeted exclusively at a specific racial group. While physicians often prescribe medicines differently for white and black patients, the new pill could mark a change in how drugs are clinically tested, reviewed by the FDA, and marketed. And its arrival has set off a heated debate among physicians, geneticists, and social scientists over the biological justification for and social ramifications of so-called race-based medicines – and over how drug developers should handle information about genetic variations in the world’s different populations.
At the core of the controversy is a disagreement over whether lumping people into a few broad racial categories has any medical value as a shortcut to more-detailed genetic analysis. The debate is particularly urgent because biomedical researchers have begun to identify subtle genetic differences among population groups and are finding preliminary but provocative clues as to why populations often react differently to drugs. Most notably, the International HapMap Project, a consortium of leading genomic researchers, is cataloguing genetic variations by examining the frequency with which certain blocks of DNA occur in different groups around the world (see “Genes, Medicine, and the New Race Debate,” June 2003, p. 40). One goal of the HapMap project and related research is to give physicians and drugmakers the tools needed to more accurately predict how different patients will respond to drugs. But fully fleshing out the genomic variations among population groups – and relating them to differences in drug responses – will take years.
Enter NitroMed and BiDil, a pill that, literally, reduces group differences in drug response to black and white. Some argue that it is a form of high-tech racial marketing done by a pharmaceutical industry eager to sell to well-defined groups of consumers. Others, including many physicians, counter that BiDil and other potential race-specific drugs represent a shortcut, albeit a crude one, to using genetic variation to more effectively and safely prescribe medicines. According to this argument, considering the race of a patient is simply a commonsense approach until using more-detailed genomic information becomes practical.
“There are extraordinary opportunities in the tailoring of medicines. It is plainly the future,” says M. Gregg Bloche, a physician and law professor at Georgetown University. But using race as a shortcut to that future, he says, “presents all sorts of risks.”
The problem, say critics of BiDil, is that while genetic patterns are related to a population’s shared ancestries and geographic histories, what are conventionally called races are socially constructed categories that have little basis in biology or genetics. Marketing BiDil only to black patients “is a bad idea,” says Charles Rotimi, an epidemiologist and acting director of the National Human Genome Center at Howard University in Washington, DC. The problem, he says, “is in using a social label that we know is not directly related to genetics” to categorize responses to a drug. That practice, says Rotimi, ignores the complexities and subtleties of population genomics, conflating genetics and race.
Making the debate over BiDil even more contentious is the convincing evidence that the drug is, for many heart failure patients, a lifesaver. Of the five million Americans suffering from heart failure, about 725,000 are African American. And there is evidence that, as a group, African Americans tend not to respond as well to some conventional heart failure drugs, such as angiotensin-converting enzyme (ACE) inhibitors. By nearly all accounts, BiDil could help a significant portion of these African-American patients.
Indeed, NitroMed’s clinical trial of BiDil in African Americans – a 1,050-patient study called A-HeFT – was halted last year because results indicated that the drug was helping patients dramatically, and experts considered it unethical to continue denying the benefits of the drug to those trial participants receiving placebos. While the patients in the study were already taking a number of conventional heart failure medicines – some as many as a dozen – adding BiDil to that mix decreased their mortality rate by 43 percent. “When a drug reduces the risk of death by that much,” says Clyde Yancy, a cardiologist at the University of Texas Southwestern Medical Center at Dallas and an A-HeFT investigator, “it gets the attention of the medical community. It’s a significant opportunity for treating an important disease.”
“A Different Disease”
The drug that became known as BiDil didn’t start out as a racially targeted medicine. The story of how it came to be the center of the debate on race-based medicines is long and convoluted. It is also a story that, in some ways, reflects the frustration of trying to find more-effective treatments for heart failure, a disease that has reached epidemic proportions: with around 500,000 new cases diagnosed every year, it is the only major form of cardiovascular disease on the rise, and annual death rates have more than doubled since 1979. While the pharmaceutical industry has developed a series of new drugs for the disease over the last decade or so, less than 50 percent of patients survive more than five years.
Within the field of heart failure medicine, Jay Cohn, the developer of BiDil and inventor on a patent for its use in treating heart failure in African Americans, is a towering figure. A professor of cardiology at the University of Minnesota and director of its Rasmussen Center for Cardiovascular Disease Prevention, Cohn was a founder of the Heart Failure Society of America and has participated in a number of the field’s landmark clinical trials of new treatments.
In the 1970s, Cohn was a young, ambitious cardiologist looking for some way to offer hope to his heart failure patients. At the time, there were no drugs that could significantly change the course of heart failure, he recalls. Patients were given digitalis, a 200-year-old medicine used to strengthen the contractions of the heart, and diuretics to alleviate the buildup of fluids, but neither of these drugs averted the fate of the patients. “You got worse and you died,” says Cohn.
To change that grim prognosis, Cohn and his colleagues began testing intravenous medications to relax patients’ arteries, believing that opening up the arteries would reduce the work the heart had to do. By 1980, Cohn and his partners had come up with an oral treatment that combined a pair of compounds, one that dilated blood vessels and another that boosted levels of nitric oxide, which is thought to be a natural vasodilator in the body. The cardiologists then began a 640-patient study at more than a dozen U.S. Veterans Administration hospitals around the country to evaluate the effects of the vasodilator therapy on those suffering from heart failure.
The results of the V.A. studies showed that patients appeared to gain some slight benefit from the drugs in terms of reduced mortality, prompting various cardiologists’ groups, including the American Heart Association, to begin recommending that the combination be given to those who did not respond well to other heart failure treatments. A second trial at the V.A. hospitals was completed in 1991. This time the test compared the two-drug treatment developed by Cohn and his colleagues to the ACE inhibitor enalapril, a newly developed type of vasodilator.
In 1996, Medco Research, a small North Carolina drug firm that had licensed rights to the medicine from Cohn, tried to gain FDA approval for the drug combination, which by then had been packaged as a single pill called BiDil. The FDA advisory panel, however, rejected the application for the heart failure medicine, citing insignificant evidence of its efficacy.
It was soon after FDA rejection that BiDil was reborn as a race-specific drug. In 1999, Cohn and several colleagues went back to the V.A. studies and reanalyzed the data. “To our surprise, blacks dramatically benefited compared to whites,” says Cohn. While Cohn says he suspects BiDil “will work for everyone,” the numbers showed that in whites, on average, the benefit of the drug was marginal – so small that it was statistically insignificant in such a limited sample. But in blacks, the drug combination reduced mortality by 47 percent in the first V.A. study (a finding similar to A-HeFT’s later 43 percent improvement); in the second set of trials done at the V.A. Hospitals, whites responded better to enalapril than to BiDil, but many black patients responded poorly to the ACE inhibitor. For those patients, BiDil appeared to be an effective alternative.
In retrospect, says Cohn, the results shouldn’t have been surprising. At around that time, he points out, other studies suggested ACE inhibitors were less effective in African Americans than in whites, and there was evidence that black and white patients responded differently to drugs for hypertension, the leading cause of heart failure in African Americans. Still, acknowledges Cohn, why BiDil works better in blacks than in whites is something of a mystery. “I don’t pretend to understand all the factors,” he says. “And I don’t suggest it’s a uniform difference. But on average, responses appear to be different.”
One possibility is that the effectiveness of BiDil depends on the etiology of the disease – why patients suffer heart failure in the first place. The disease can be caused by various factors, including previous heart attacks or a history of hypertension. And, suspect some experts, BiDil works best for those patients, whether white or black, who have developed heart failure through hypertension.
If true, that conjecture would help explain the difference, on average, between white and black responses to BiDil. African Americans suffer from high rates of hypertension, and over 50 percent of blacks with heart failure are thought to have it due to histories of high blood pressure. In contrast, most whites, roughly 70 percent, get heart failure due to heart attacks or chronic heart disease. The reason for the high rate of hypertension in blacks remains uncertain. Some studies point to environmental factors, while others seem to implicate specific genetic variants. Muddling the situation even further, according to Yancy, there is some evidence that genetic factors make hypertension more damaging to tissues in black patients than in whites, so that it is, in effect, a more “malignant” condition in African Americans than in whites.
Whatever the underlying reasons, for cardiologists treating patients, says Yancy, “heart failure is a different disease in blacks. It’s different in how it presents itself.” Blacks, he points out, suffer from heart failure at a younger age, and they do not respond as well to hospitalization and treatments. BiDil works in part by addressing deficiencies of nitric oxide, which many African Americans show a reduced ability to utilize, says Yancy.
But if, in fact, BiDil works best for those who develop heart failure because of hypertension, it also could benefit thousands of non–African Americans. And clearly the potential deficiencies of nitric oxide found in some heart failure patients are not strictly limited to blacks. Yancy, for one, says he is “absolutely confident” that BiDil will work for patients other than African Americans. Indeed, says Cohn, ideally BiDil would be given to all those heart failure patients in whom physicians could “identify nitric oxide deficiencies. Unfortunately, there is no simple test.” So for now, race remains the admittedly imperfect screen for those patients.
There, for many critics, lies the rub. Is it medically justifiable for physicians to translate the average responses of broad racial groups into clinical decisions affecting the lives of individual patients? Even more fundamentally, ask critics, how can medical decisions be based on a set of racial classifications that most scientists say have little genetic basis?
Federal guidelines used by the FDA to evaluate clinical trials acknowledge at least five distinct racial categories: American Indian or Alaska Native, Asian, black or African American, Native Hawaiian or other Pacific Islander, and white.
While each of these groups might have its own social and cultural heritage, and even ancestral lineage, there is little evidence of any genetic patterns that would neatly define them as discrete entities, and hence as distinct races. The conventional categories might serve a purpose for social, economic, and political reasons, but most geneticists question whether they have any biological justification. Even the few rare diseases popularly thought to predominate among particular races seldom adhere to conventional categories. For example, sickle-cell anemia, considered by many to be a “black disease,” occurs throughout the Mediterranean, as well as in Africa; parts of Greece have extremely high rates, while black South Africans do not carry the genetic traits causing the illness.
But while largely scorning conventional racial categories, population geneticists and researchers equipped with new genotyping tools are increasingly identifying patterns of genetic variants, particularly single-nucleotide polymorphisms (SNPs), that are prevalent among specific populations. Researchers have found that SNPs, variations of a single nucleotide at a particular spot on a chromosome, tend to occur in blocks called haplotypes. The HapMap project is documenting the relative frequencies of particular blocks in several different populations, including Han Chinese, Yoruba in Nigeria, Japanese, and Americans with north- or west-European ancestry. The project is finding that while the groups tend to share the same set of variants for a particular SNP block – typically there are a handful of versions of each block, and those versions are found in all groups – the relative frequency of a given version varies among populations.
At the same time that genomic researchers are trying to understand these group differences, journals are filled with studies attempting to relate medical conditions to genetic variants common among particular groups. For example, in a study in the American Journal of Epidemiology, researchers reported that black women were more likely than white women to have several genes linked to heightened inflammatory response (see “Inflammatory Genes,” March 2005, p. 79).
Particularly relevant to the prediction of drug response is the finding that groups can have different frequencies of some genetic variants associated with the body’s key metabolizing enzymes, which affect how drugs are broken down in the body. In fact, says David Goldstein, a human geneticist and director of Duke University’s Center for Population Genomics and Pharmacogenetics, of the 42 genetic variants that have been consistently shown to be tied to drug responses, two-thirds have different frequencies in people with European and African ancestries. “The naïve interpretation,” says Goldstein, “is that these variations would lead to average differences in the relevant drug response in the two communites.” While he adds that such a conclusion is too simplistic, he says the variations “do suggest” that genetics could play a role in determining how well drugs work in various groups.
But basing drug prescriptions on population genetics is still in its early days – and the way to do it remains controversial. The wrong approach, says Howard’s Rotimi, is to shoehorn complex data on genomic patterns into conventional racial categories. Rotimi argues that race is a very imprecise proxy for drug responsiveness. In the case of BiDil, he says, what’s missing is the identification of any relevant genetics that would justify its exclusive use in blacks.
Indeed, even as BiDil heads toward commercialization as a pill likely to be marketed solely to African Americans, there is near consensus among experts that it would also save the lives of countless other heart patients. How to more accurately determine which patients the drug will help is the real issue, according to many experts. NitroMed says it is looking for markers, both genetic and otherwise, that could be used to identify non–African American patients whom BiDil would help. But finding such markers will likely take time and money.
“If the clinical results [of the A-HeFT study] are really convincing, it probably should be approved,” says Goldstein. “But the larger question is what should be required by the FDA.” Goldstein says the agency needs to mandate a comprehensive analysis that will identify the specific types of patients who will benefit from BiDil. “It’s not sensible for FDA to rely on the goodwill of companies. It needs to be proactive.” Goldstein says the fact that African Americans are “spectacularly heterogeneous” means BiDil will work only for a certain fraction of them, cutting NitroMed’s potential base of customers. And pinpointing patients in an ethnically diverse population who would also benefit from BiDil will be expensive. “It’s too much to think companies will willingly spend money that is not in their commercial interest,” says Goldstein.
The terms of an FDA approval of BiDil would also be critical, says Goldstein. “If FDA says it works in blacks and not in whites, it is entirely incorrect. It needs to make clear that blacks are not a distinct genetic entity.” Resorting to race, he says, “is never a precise guide” to determining who will benefit from a drug. “If you don’t have other information, you might be prepared to use race as an interim measure, but you shouldn’t treat it as the end of the story.”
These kinds of concerns point up the ambiguous role that race plays in modern medicine. Even backers of BiDil agree that they are using race only as a crude way to identify whom will benefit from the drug. “Race is an extremely poor proxy for genetics,” says Yancy. It is critical, he says, “to continue to try and identify the phenotypes that respond best to BiDil and not stop at the level of race. Race-based medicine is a step backwards.” At the same time, says Yancy, “It’s a long-standing observation that due to complex reasons, both biological and social, health outcomes are divided along the line of race. We have an obligation to patients to analyze why this difference exists.” Apparent racial differences in drug responses among groups, he suggests, can present valuable opportunities for biomedical researchers to better understand factors and mechanisms underlying diseases and drug response. “Using race is simply a convenient placeholder,” says Yancy. “You need to see what it represents.”
For many, the main motivation to better understand the factors behind ethnic differences is the troubling health disparities among groups in this country. Many of those disparities are likely due to varying access to health care and to other economic factors. But most existing medicines were tested in clinical trials in which most of the participants were white; if there are genetic differences in how various ethnic populations respond to drugs, they could be widening the gap in health outcomes.
Esteban Gonzalez Burchard has a quick and affable way of speaking that seems to suddenly slow and turn serious when he explains the subject of his research: why Hispanic populations suffer such dramatically different rates of asthma and respond so differently to asthma drugs. In the United States, Puerto Ricans have a higher rate of asthma than any other ethnic group and tend to respond poorly to albuterol, the leading asthma drug, while Mexican Americans have a low rate of the disease and are effectively treated with medications. It’s a perplexing epidemiology riddle as well as a public-health puzzle that affects thousands of lives. Says Burchard, “When a Puerto Rican kid takes albuterol, he is just not getting the same bang for his buck as any other kid.”
Like many other areas of genomic research, Burchard’s work is at an early stage, and the challenges he faces point up the difficulty of determining the role that ethnic differences play in diseases. Hispanics are extremely diverse culturally and socially; genetically, they have varying mixtures of African, European, and Native American ancestry. But by teasing out the relative contribution of each ancestral group in a particular population (Mexicans, for example, tend to have far smaller genetic inheritance from African ancestors than Puerto Ricans do), Burchard attempts to zero in on specific genetic factors.
Most recently, Burchard, a physician and assistant professor of medicine and biopharmaceutical sciences at the University of California, San Francisco, identified specific genetic variants that seem to be associated with a lesser response to albuterol in Puerto Ricans; in Mexicans, the same variant seemed to have no connection to albuterol. While such a finding might seem ambiguous and inconclusive, it’s suggestive to Burchard that some still unidentified factor is behind the ethnic difference. And Burchard says that that is just the point: he might not have yet found the smoking gun, but “I can smell the smoke.”
The opportunities created by looking at ethnic differences in medicine are “far bigger than BiDil,” says Burchard. Health disparities among racial groups are invaluable clues to untangling underlying genetic and environmental factors that could make it possible to design safer and far more effective drugs. And it is essential that those clues be followed, says Burchard. “We do see racial differences between populations and shouldn’t just close our eyes,” he says. “Unfortunately, race is a politically charged topic, and there will be evildoers. But the fear should not outweigh the benefit of looking.”
Whether BiDil, with its complicated history and decades-long evolution into a race-specific drug, is the right way to begin making sense of race, medicine, and genetics is debated. Jonathan Kahn, a law professor at Hamline University in Saint Paul, MN, who has written extensively about the history of BiDil and the legal issues surrounding it, maintains that the reasons that the drug is being marketed to African Americans have far more to do with business and patent issues than medical ones. And yet, says Kahn, if the FDA approves the drug exclusively for blacks, it “lends credence to the misguided idea that race is somehow genetic.”
Indeed, much of the controversy over BiDil is really about the message that the drug’s approval will send to the general public. No one claims that the drug will work only for African Americans; nor does anyone pretend to have identified specific genetic factors exclusive to black patients that account for the drug’s effectiveness. Like racial categories themselves, the group of patients whom BiDil will benefit remains ambiguous. But here the disagreement starts: is it worthwhile to use race as a crude, stopgap approximation, or is giving the pill only to black patients a dangerous shortcut to genetic profiling that many in the public will, intentionally or otherwise, misconstrue?
There is no easy answer to the question of how to best balance medical expediency with social consequences. But the real danger of BiDil as a race-based medicine could be in its potential to turn the public’s understanding of complex genomic research on differing drug response and disease susceptibility among populations into a simple black-and-white issue.