NIH Applicants Adapt To Study-Population Inclusion Guidelines

A federal law requiring National Institutes of Health-funded disease studies to show an adequate representation of women, minorities, and racial and ethnic subgroups is forcing researchers to adopt novel methods of inclusion. These methods often go far beyond incorporating minority groups into their research design plans. Means that investigators have adopted to attract and retain populations that conform to the new law include buying lunch, paying bus fare, opening satellite clinics, even going cross-country to find some groups. But while innovative researchers and clinicians work to accommodate these NIH inclusion guidelines, as they are called, debate continues about whether institution of these rules represents good science, appropriate social policy, or simply justice. The law, included in the NIH Revitalization Act of 1993, is an outgrowth of similar NIH regulations adopted in 1986 and 1987 and revised in 1990. All new grant proposals involving human subjects are required to include women, minorities and appropriate minority subpopulations--such as Aleuts, Amish, Caribbean blacks, or Cubans--in their clinical studies, explain convincingly why these groups are not included, or risk not being approved. In addition, under the law, women and minorities must be included in Phase III clinical trials in numbers that will allow valid analysis of differences between groups; recruitment programs should be promoted; and cost cannot be a reason to exclude any group. The rules took effect beginning with grants funded for the 1995 fiscal year. Initially, the law appeared to make a chilling impression on some researchers, who saw it as politically correct, but scientifically invalid (E. Marshall, Science, 263:602, 1994). While the majority of investigators interviewed for this article express support for the research importance of the guidelines, some rejected the value of the new rules entirely. Others--including the authors of an Institute of Medicine (IoM) report on the subject, commissioned by NIH--support the principle of inclusion, but question the scientific significance of the law and are critical of NIH for specific aspects of the guidelines. One scientist who claims the guidelines have strong scientific underpinnings is New York University Medical Center research administrator Kay Ryan, who is in charge of all clinical trials at NYU. "In the '80s, and certainly by the early '90s, physicians were beginning to see that some women didn't react to drugs the same way that men did." See a related story. The scientific justification for including minorities and subgroups, she explains, stems from the lack of these subgroups in previous clinical trials. "Once a drug became approved, they began to see that in certain subgroups, drugs didn't work the same way as in the general population, and they weren't sure why," Ryan says. She cites the case of a type of antihypertensive drug, adrenocortical extract inhibitors, that--after Food and Drug Administration approval-- was found to be ineffective in many African Americans. Another whole-hearted supporter is Delores L. Parron, a behavioral scientist who is associate director for special populations at the National Institute of Mental Health (NIMH) and one of the authors of the earliest guidelines (see accompanying story). "It is not a matter of politics," she asserts. "It's a matter of the quality of science." She adds: "Science is about studying the real world and the real world has not been all white and all male for a very long time." John Phair, an internist at Northwestern University Medical School, is former chairman of the executive committee of the Adult AIDS Clinical Trial Group (AACTG), an NIH-funded initiative that began in 1987 and includes 35 universities. To date, Phair says, the program has run more than 250 clinical trials of therapies for HIV infections and related diseases. As an old grant, the study was required only to meet the less-stringent guidelines in force in 1987. But Phair believes that there are questions that need to be answered in Phase I clinical trials over whether the pharmacokinetics (drug plasma concentration in relation to time) and pharmacodynamics (the body's response to specific drug concentrations) of drugs are the same in men and women. Since the study's inception, according to Phair, there have been increases in numbers of women, as well as African Americans and Hispanics. In 1994, Phair reports, the percentage of women in the study was slightly greater than the proportion of women nationally reported with AIDS to the Centers for Disease Control and Prevention; the study was "within several percentage points of meeting the demographics of African Americans nationally"; and they "have not done quite as well with the Hispanic community." Other researchers are skeptical about the guidelines' producing valid research. Alfred I. Neugut, an oncologist and epidemiologist at New York's Columbia-Presbyterian Medical Center who is studying the epidemiology of colon cancer, maintains that women and minorities should have "fair access to the most up-to-date therapies," often available only in clinical trials. But he calls this inclusion "scientifically irrelevant." Neugut explains: "If you really want to study an ethnic subgroup, you have to include enough subjects so you can analyze them separately. If you aim to reflect the population percentage in your trial, such as including 12 percent African Americans, then the number of subjects will usually be too small to be able to say anything meaningful about them. You're not really going to answer any scientific question." Even proponents of inclusion have some reservations about the new guidelines. The committee that produced the IoM report-- Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vols. 1 and 2 (A.C. Mastroianni, R. Faden, D. Federman, eds., Washington, D.C., National Academy Press, 1994)--was charged by NIH with examining the ethical and legal issues relating to women as clinical research subjects. According to Anna C. Mastroianni, an attorney who directed the IoM study, although the panel briefly reviewed the scientific legitimacy of the guidelines, its support for them came because, "from the committee's standpoint, [they decided to] take a look at science in the context of justice." Ruth Macklin, a professor of bioethics at Yeshiva University's Albert Einstein College of Medicine and a member of the IoM panel, concurs: "If women are different, then you've got to study women. If women are the same as men, then why not include them? That is a question of justice." But the IoM report authors also expressed significant concerns: "The committee acknowledges ... that most treatments and most diseases do not differ significantly by gender." The report went on to criticize NIH for going "too far by insisting that each and every clinical trial be designed to ensure sufficient numbers of subjects of both genders to permit subgroup analyses." It argued that the increased costs for "a trial-by-trial application of this requirement is neither good policy nor good science." NIMH's Parron, however, points to flexibility in the policy: "In some instances, [conforming to the guidelines is] a matter of writing an appropriate justification," she says. A researcher can "just tell us clearly why" he or she cannot comply with the rules in a particular study. "If the review committees agree, the study can proceed." Whether these guidelines promote good science, good citizenship, or both, researchers must now write their grant proposals to conform to them. Carlos E. Caban, director of NIH's Extramural Programs Management Office in the Office of Extramural Research, points out, however, that the law doesn't apply to most of the established studies. In fact, the studies on a list of the highest 1994 NIH grants that conform to the old guidelines -- covering investigator- initiated (R01) grants and ranked by monetary award--are technically exempt from much of the new law PrincipalStudy Name Amount Guy L. Clifton,Univ.TexasHealth Sciences Center National Acute Brain InjuryStudy--Hypothermia$2,271,836 Maria J. Wawer,Columbia Univ.STD Control for AIDS Prevention1,647,905 John C.S.Breitner,Duke Univ.Epidemiology of Alzheimer'sDementia1,558,317 Paolo G. Toniolo,NYU Med. Ctr.Women's Health Study 1,053,779 Larry C. Clark,Univ. of ArizonaNutritional Prevention of Cancer1,048,485 Curt R. Freed,Colorado Health Sciences Ctr.Embryonic Dopamine CellImplants for Parkinsonism1,019,956 * Individual-Investigator Awards, Source: National Institutes of Health NYU Medical Center epidemiologist Paolo Toniolo is on the list of the the highest R01 awards. His was a 1994 renewal of a grant initially awarded in 1984, prior to the inception of guidelines. Toniolo is examining the epidemiology of breast cancer. His study population is drawn from patients of Guttman Institute, a Manhattan mammography screening center. Every woman who walked through Guttman's door from early 1985 until 1991 was offered a chance to participate in the project, and Toniolo's study group is composed of 14,291 women of all races and socioeconomic strata. He maintains he has no problem retaining his study populations: "The minority women have been wonderfully collaborating. These are women that were willing to be part of the study." Another researcher on the list is clinical pharmacologist Curt Freed of the University of Colorado's Health Science Center in Denver, although his project also isn't required to be. The first year of Freed's grant for studying implantation of fetal tissue into the brains of Parkinson's disease patients was 1994. His study will enroll a total of 40 patients who are drawn from the clinics of Columbia-Presbyterian Medical Center in New York, located in a primarily working-class Hispanic community. "Parkinson's disease," Freed points out, "is mainly a disease of the elderly." It also affects more men than women. Of the 21 patients enrolled to date, two-thirds are men and one-third women. He is trying to recruit younger patients, under the age of 60. "Do transplants work well in elderly as well as younger patients? This is a scientific issue." But for many of the projects, recruitment and retention of minorities and women may require a lot of additional thought and planning beyond mere numbers (see story on page 14). John Diggs, vice president for biomedical research at the Washington, D.C.-based Association of American Medical Colleges, and formerly deputy director for extramural research at NIH, explains that recruitment and retention of minority populations cannot be handled with the same techniques and personnel used for majority populations. "I think that there's very little understanding or very little thought given to these things," Diggs states. He laments that there are not enough trained minority investigators and that white researchers have to understand that they need linkage to the minority community (see Opinion, page 12). And linkage itself will not deliver the patients, unless the members of the minority communities have some say in the conduct of the study. "They have to work collaboratively," he says. Diggs cautions that community leaders may be distrustful, perhaps remembering the infamous Tuskegee Syphilis Study, in which 400 African American men were not given access to antibiotics to treat their disease and did not give informed consent to the study. "We have to do a bit of forecasting on how many patients we expect to accrue," concedes health educator Caron Bowen of NYU Medical Center's Kaplan Comprehensive Cancer Center, an NIH-funded center, who is unsure of where her population sample will come from. NYU's Ryan says, "The money is going to have to be shifted into more outreach and possibly to reimbursing patients who may need assistance in coming into a center, or working with groups in satellite centers." A researcher in one part of the country, explains Bowen, may have to find a partner in another region to include more minorities or subgroups, an additional expense that is not typical for clinical studies. These additional costs, along with anticipated congressional budget-cutting, could affect research. "If there is a reduction in funds, and if there are significant costs to meeting the mandate, then you reduce the total scope of clinical research," Phair warns. Perhaps, after a period of applying the guidelines, NIH may find them unnecessary, some researchers speculate. Pamela Palanque-North, an industrial/organizational psychologist who is a trustee of the Ambulatory Care Network, a board overseeing all of the hospital clinics and emergency rooms at Columbia-Presbyterian, explains: "The reality is, there's not as much difference between us biologically as we may think." Myrna E. Watanabe is a science writer based in Yonkers, N.Y.

NIH Applicants Adapt To Study-Population Inclusion Guidelines

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