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.”