When a study was released in 1988 showing that aspirin helps prevent heart attacks, it was heralded as research with huge potential impact for extending life and reducing health-care costs.
But the research had a separate--unintended--effect. Given that the 22,071 research participants were all men, some medical experts were soon asking: What about women?
Do medications work the same for men and women, blacks and whites, young and old?
In many cases, researchers simply don't know because a significant number of drug studies have been performed only on white, middle-aged men, say several medical experts who advocate big changes in the makeup of clinical studies to test new drugs. Health officials are still trying to gauge just how common the practice of excluding women has become. But, in recent years, several expensive and highly anticipated medical studies on health matters relevant to both sexes, such as cholesterol and aging, have been restricted to male test subjects only.
And the problem isn't confined to a gender gap. Physicians who treat minority groups are calling for more research on differing drug reactions related to ethnicity and race.
The problem of bias in health research was brought to light in June in a General Accounting Office report finding that women are often excluded from studies on new drugs and other medical research funded by the National Institutes of Health despite an official policy begun in 1987 to include women. The agency funds all federal medical research in the United States.
The GAO report resurrects the question of whether research results on men can be applied to women, and indicates that not enough scientists are considering the question, said Joanne Howes of Bass & Howes, a Washington consulting firm on women's health issues.
"What the GAO study said was that barely anyone at NIH knew the policy (to include women) existed. It hasn't made any difference," she said.
According to the GAO report, the policy "has not been well communicated or understood within NIH or in the research community."
Traditionally, women have been excluded from research because of reproductive concerns: A woman might become pregnant during a study and experience fetal damage or that study results might be skewed by hormone fluctuations related to the menstrual cycle.
But sometimes researchers simply favor white men because they are easier to recruit than women and minorities, experts say.
NIH has vowed to correct the imbalance. And there are signs that the agency will be pressured to do so.
Howes has helped organize a new advocacy group, the Society for the Advancement of Women's Health Research, to address areas of concern. And a group of Democratic senators on Tuesday introduced a women's health package to the Senate that would authorize a center for women's health research at NIH and require the inclusion of more women in clinical trials.
Meanwhile, differences in drug reaction will be a major focus of a multiethnic research center for psychobiology that will open this fall at Harbor-UCLA Medical Center. The center, which has been funded by the National Institute of Mental Health, will be operated by a consortium of medical experts from several institutions.
But despite the heightened consciousness, federal officials say it is impossible to determine the extent of bias in health research and whether it leads to serious health consequences.
"I think the answer is you can't make an across-the-board generalization," said Iris Schneider, co-chairwoman of the Advisory Committee on Women's Health Issues at NIH. "We don't have good data at this point, and the GAO has been unable to get it, on how much research is excluding women. We don't know if it's 10% of the studies or 50% of the studies.
"Obviously, women aren't running around the country dropping like flies. But there are probably some instances in which women could be getting better treatment if more was known."
In many other diseases, she said, "there isn't much reason to believe that the treatment works differently in men than women."
According to Schneider, some scientists, such as those in cancer research, have a better record for including women, while other experiments, such as those on heart disease, are almost notorious for excluding women tests subjects. Although fewer women than men suffer from heart disease in middle-age, heart disease is still the top-ranking cause of death among women.
Howes' group believes that the practice of excluding women in medical research is widespread.
"We found that in a number of studies that came out last year, women were not included as part of the clinical trials," she said. "The aspirin study is the most famous. But there were others."
AIDS researchers have noted that many of the early drug trials were conducted on men, leaving the growing population of women and children with AIDS at a disadvantage, Howes said. And a famous, long-term study on lifestyle factors related to cholesterol levels and the development of heart disease, the Multiple Risk Factor Intervention Trials, was appropriately nicknamed MR. FIT: It included 15,000 men and no women.
In another often-cited example, a major, longitudinal study funded by the National Institute on Aging on the effects of normal human aging followed only men from its inception in 1958 until 1978, when women were recruited. Thus, long-term data on women is still unavailable.
The gender gap "cuts across a lot of research," Howes said. "We need to start with the mind-set that women's physiology and men's physiology differ in significant ways. We need to aggressively investigate whether there are likely to be gender differences. And where those differences exist, we need to make sure that women's health is getting a fair share of the budget."
Even less is known about differing drug reactions among minority groups. But physicians who treat members of minority groups have long recognized that they must adjust the dosages of certain drugs prescribed for blacks, Latinos or Asians because of inherent differences in drug reactions between groups, said Tony Strickland, assistant professor of psychiatry at Drew University of Medicine and Science and the UCLA School of Medicine.
Very few clinical trials on drugs used in psychobiology include minority groups or look for differences in drug reaction, said Strickland, an expert in bio-behavior research.
"This is a major problem because if you don't know the norms for a given group, you effectively do not allow them the benefits of good therapeutic intervention," he said. "You may contribute to their health adversely, particularly for people who do not tolerate certain drugs very well."
For example, Strickland said, the center will study differences in how blacks, Latinos and Asians react to lithium, a drug to control mania. Preliminary results suggest that blacks need comparatively less lithium as opposed to whites. The issue is important because lithium can contribute to hypertension, a disorder that already occurs at a much higher rate among blacks.
"It has vast implications for treatment," Strickland said. "Lithium per se is an extremely toxic drug. It's used to control mania. The fact that blacks would tolerate the drug less well than whites or would need lower amounts of the drug to achieve the same benefits is extremely important because it would reduce the risks of toxic side effects."
Dr. Keh-Ming Lin, an associate professor of psychiatry at Harbor-UCLA Medical Center, has found similar ethnic variations with Haldol, a drug that is used to control schizophrenia. Preliminary studies have shown that Asians require significantly less of the drug for it to be effective.
"Physicians who treat black patients regularly or Asian patients regularly--they know" about the differences, Strickland said. "They effectively modify drug doses to accommodate the needs of those patients. But if you have a center or group who doesn't have a lot of experience with these patients, you can run into some problems."
Lopsided research can present practical dilemmas to physicians. Despite expressing confusion about the use of aspirin in women to prevent heart attacks, for example, many doctors have decided not to wait for the results of a proposed similar study on women, said Dr. Anthony Furlan of the Cleveland Clinic.
"All the physicians I know are routinely putting women on aspirin who have had a heart attack or stroke," said Furlan, who has studied the effects of aspirin on stroke.
In general, scientists attempt to use test subjects who are as similar as possible in order to limit variables that might distort the results. White men might be recruited simply because they are the easiest to locate, some experts say.
But more likely, women are intentionally excluded from trials due to fears that drugs might cause infertility or endanger a fetus if a woman were to become pregnant. Researchers have also suggested that fluctuating hormone levels during the monthly menstrual cycle might distort drug results.
"I don't find that very acceptable because if women are going to take the drug, you have to know how they react to it," NIH's Schneider said.
"If the drugs do have a different effect at different points over our menstrual cycle, than we need to know about it. We shouldn't need to guess," Howes said. "It's mind-boggling that scientists (who have excluded women) didn't see that very clearly."
However researchers greatly fear liability if a pregnant woman or her fetus is harmed during research, said Dr. John Beary, senior vice president of science and technology at the Pharmaceutical Manufacturers Assn., a Washington-based trade organization.
"People are very anxious about getting involved in that area of research (involving reproduction) at all," Beary said. "The answer is not to suddenly study great numbers of women without thoughtfully looking at what the risks are."
The Pharmaceutical Manufacturers Assn. advocates discussions with medical specialists who serve women, the elderly or minority groups to define safe ways to expand research, he said.
But during an era of dwindling research funds, many scientists charge that expanding drug trials to include various subgroups, such as women and minorities, would make the studies unmanageable and far too costly.
"Let's be realistic, there is a financial consideration in the conduct of research," Strickland said. "If you double the number of people, it doubles the cost of the study."
But in areas that serve large numbers of minorities, research should focus on those populations, said Strickland, who added Latino test subjects to three of his studies recently to better match Los Angeles County's demographics.
"As many groups that can be reasonably managed and included should be represented," Strickland said. "The demographics beg that one makes these accommodations."
And old barriers must be overcome to widely recruit minorities into research, Strickland said. Some blacks are reluctant to participate in trials, he said, based in part on past horrors, such as experiments in the 1930s at the Tuskegee Institute in Alabama in which black men with syphilis were deliberately left untreated.
"There is tremendous skepticism on the part of these groups in participating if there has not been a history of doing work with the group," he said.