By Ariana Eunjung Cha
Washington Post Staff Writer
Monday, July 28, 2003; Page A01

OAKLAND, Calif. -- Three times a day, nine patients at General Hilliard's popular private clinic here take a tiny orange pill for their heart troubles as part of a nationwide study that some describe as the future of drug treatment and others call medical heresy.

The diverging views stem not from what the experimental drug contains but who is allowed to take it -- only people who identify themselves as African American.

The hope is to create the first prescription medicine intended for a specific racial group. The pursuit of such a treatment, however, has become the subject of impassioned debate and research in the medical community.

As more new drugs are made to attack disease based on their genetic origins, doctors are divided over whether race or ethnicity should play a role in treatment decisions. And, if so, there is this practical question: In a world of mixed heritages, how does a doctor even determine a person's race?

"The more we learn about how drugs work the more we see a genetic component and the race question is among the biggest mysteries," said Hilliard, who has been practicing cardiology for nearly three decades.

The notion of race was advanced centuries ago as a method of social and political grouping when new transportation methods allowed people from far-flung parts of the world to regularly interact with each other. The divisions often were drawn by the superficial: skin and hair color, shape of the eye.

However, recent advances in genetic mapping have all but dismissed race as a biological construct. Race accounts for only a tiny amount of the 0.1 percent genetic variation between one human and other. That means that someone who is considered black, for instance, might have more genes in common with someone who is white rather than someone who is also black.

Yet, on the other hand, science also has shown that certain groups share inherited traits, and often similar ailments.

FDA Gives Approval for Testing

The federal Food and Drug Administration gave biotech start-up NitroMed Inc. the green light to study whether its drug should be approved for use in a single racial group. NitroMed is testing its therapy at 160 sites on what it hopes will eventually be 1,100 patients. Results could be announced in as soon as a year.

While some doctors have for a long time adjusted dosages or favored certain medications over others because of a patient's race, government approval of the NitroMed drug would be the first time a drug has been sanctioned specifically for use in one racial or ethnic group.

The tests come as interest grows in the medical community over the possibility of race-based treatments. The FDA issued guidelines this year on how racial information should be collected in clinical trials. And a few months ago, doctors and researchers in the New England Journal of Medicine debated the issue in a special section of the influential publication.

Recent drug test results have suggested some promising but inconclusive trends: Tests of an AIDS vaccine made by Brisbane, Calif.-based VaxGen Inc., for instance, seemed to show that it was a failure in whites but might have some promise in blacks and Asians. The breast cancer drug Tamoxifen, by British pharmaceutical giant AstraZeneca PLC, seemed to be a bit less effective in blacks than whites.

Some experts argue that the sample sizes were too small to draw any real conclusions and that if the analysis was done another way no racial differences would be found. Nevertheless, some doctors have seized on such data to tailor their treatments by race, switching drugs or changing dosages. They say that while race may be an imprecise measure of people's genetic reaction to drugs, it is the best proxy for such a correlation available now.

"Ignoring racial and ethnic differences in medical and biomedical research will not make them disappear," Esteban Gonzalez Burchard, an assistant professor at the University of California at San Francisco, concluded in a recent journal article he wrote with others.

Critics, though, say promoting certain drugs for race-specific markets could lead to stereotyping and discrimination. They say racial categories are more a societal construct than a scientific one. Indeed, the FDA has advised researchers to use the same race and ethnicity groupings as the U.S. Census, categories that resulted to a large extent from political lobbying.

"I think it's just bizarre, marketing a drug just to people who are black. The scientific evidence supporting the notion that there's a differential response in race is weak or nonexistent," said Richard A. Cooper, chairman of the preventive medicine and epidemiology department at Loyola University in Illinois, who has written extensively about race and medicine.

Many scientists expect the debate to eventually shift as more becomes known about the role genetics play in how patients respond to drug therapies.

Scientists suspect that the frequency of certain genes, including those for how drugs are metabolized, is higher in certain races because of the way populations of people settled and evolved. Tay-Sachs disease, for example, is most commonly found in people of Jewish descent and cystic fibrosis is common in certain European populations. Eventually, biotech researchers hope to design drugs that target specific genes, eliminating the need to weigh racial or ethnic characteristics when making therapy decisions.

Until such precision is possible, the medical community continues to search for suitable proxies. Much of the research on race-based medicine has focused on heart ailments, the No. 1 cause of death of Americans. According to numerous studies, black Americans suffer disproportionately from cardiovascular disease -- some say, for instance, that they may be twice as likely to suffer heart failure and twice as likely to die from the disease as whites.

There have been numerous theories about why.

Do blacks suffer more because of environmental factors -- diet or living conditions? Or is it genetic? Or are the differences a result of discriminatory practices in medical treatment? One theory suggests that blacks are not able to deal with salt in the same way as whites. Today some scientists think it is possible blacks do not suffer disproportionately from heart disease but simply age faster than whites as a result of the stress of dealing with racism in their everyday lives.

Focusing on Heart Failure

NitroMed was founded in the mid-1990s when a group of scientists formed a company to try and find a drug based on a chemical called nitric oxide. It is found naturally in the body and dilates the blood vessels allowing blood to flow more easily, easing the burden on the heart.

They conducted a large study in the general population of people suffering from heart failure, a condition in which the heart muscle is unable to pump blood adequately. Initially, it seemed the trial was a failure until scientists examined the results by race and saw something that made them catch their breaths: A significant percentage of the 400 black patients in the trial seemed to be living longer and better than those not on the medication.

NitroMed postulated that perhaps heart failure in blacks is somehow associated with how blacks produce and metabolize nitric oxide, said NitroMed President Manuel Worcel. Could it be that "African Americans have less nitric oxide and destroy it faster?" he said.

That seemed to be consistent with long-standing research suggesting that blacks do not respond well to treatment by drugs such as beta-blockers or ACE inhibitors, the most popular types of heart treatments. The effectiveness of ACE inhibitors is related to the production of nitric oxide.

Others were skeptical. They accused the company of taking ambiguous results and seizing on them as a marketing tactic.

Still, the results were intriguing enough that the company decided it wanted to take a second look. It asked the FDA whether the agency would consider approving a drug for use in a specific racial group. In March 2001, the FDA awarded NitroMed an "approvable" letter, which means that the agency preliminarily regards the medication to be safe and effective but that certain issues need to be resolved before granting final approval.

Robert J. Temple, associate director for medical policy at the FDA's Center for Drug Evaluation and Research, said approving the drug for use by blacks is simply an extension of the agency's current practice of including information on drug labels that note whether any difference in the a drug's effectiveness or safety have been found among racial groups. He acknowledged, however, that wording the usage instructions would be tricky.

The label would have to make it clear that "you're not sure what's totally going on [with some racial groups] but you'd point out benefits found in blacks," Temple said.

Even if the drug is approved for use only in blacks, there is nothing to prevent doctors from prescribing it for other racial groups if they think it might help. Physicians often use approved drugs for "off-label" reasons.

For now, the NitroMed study has won the political backing from a slew of prestigious groups -- the Association of Black Cardiologists, the National Medical Association, members of the Congressional Black Caucus -- and the financial support of a number of venture capital firms including Morgan Stanley & Co., Goldman Sachs & Co. and HealthCare Ventures.

That is how the trial of the orange pills, known as BiDil, came to Hilliard's fourth-floor medical offices. The NitroMed study is but one of roughly a dozen race-specific clinical trials that Hilliard has assisted in over the past five to six years.

The study setup is simple: Participants take BiDil or a placebo in addition to their regular medications. They stay on the drug for a year and a half. They are surveyed by phone each month and are given full in-person checkups every three months. The goal is to compare the lifespan and quality of life of patients who took the drug with those in the control group.

Definition Difficulties

Perhaps the trickiest part has been determining the target patients: Who is African American? Does a recent Nigerian immigrant qualify? What about someone who is black but thinks of himself as Latino?

The NitroMed researchers in fact debated for months about whether to limit the study to "African Americans" or to "blacks" or some other designation. They ultimately decided to go with African-Americans because they felt it was more precise than black since the study was not going to include many black people from other parts of the world.

To determine who met that definition, NitroMed allowed patients to categorize themselves, a practice that has increasingly become the norm in medical research but one that is not universally endorsed.

In fact, one of Hilliard's co-investigators, Charles Curry, a Howard University professor of medicine, is ambivalent about the trials because of the possibility of what he calls "racial profiling."

"We all know we're all mixed up so much you can't really say what [we] are," he said. "People self-designate at how they think they are but that doesn't really have a biological basis."

Elyse Frazier, 56, a patient of Hillard's clinic, is a testament to the difficulty. When research coordinator Jackie Rayford asked her if she might be interested in the study for African Americans, she was puzzled. She considered herself black in matters of politics, but it was not a question she had ever been asked before in a health context. Frazier's mother is half black, half Cherokee Indian. Her father is half black, half Blackfoot Indian.

"Do you consider yourself African American?" Rayford asked.

Frazier answered that she did and Rayford informed her she was eligible for the study.

Frazier, a retired nurse's assistant who suffered a heart attack in 1980 and was recently diagnosed with heart failure, said she enrolled in the NitroMed study because she hopes to help future generations, including her children and grandchildren. But, she wonders, will all of them be eligible for the medication? Based her calculations, one of her grandsons, she points out, is 3/8 black, 1/16 Cherokee, 1/16 Blackfoot, 1/4 white and 1/4 Mexican.