Sex and Race in Clinical Trials

New standards and research methods aim to provide more useful information on population subgroups.

The research community and federal agencies have struggled for more than a decade to obtain information about variable drug effects on patients based on race, ethnicity, gender, and age. The campaign to move away from clinical trials populated by young, healthy white males is intensifying now as more evidence emerges on how sex and race affect individual responses to medical treatment. The desire to reduce disparities in health care for racial and ethnic minorities is further heightening the need to include these populations in clinical trials, as is information on how drugs affect women and men differently. Researchers also are looking to study how drugs affect pregnant and lactating women, recognizing the difficulties of including these groups in premarket clinical studies.

The Food and Drug Administration has issued numerous guidances to encourage sponsors and researchers to collect and analyze clinical trial data from population subgroups. These include International Conference on Harmonization (ICH) standards designed to allow trials in one geographic region to provide evidence acceptable to other regulatory bodies. The National Institute of Health's Office of Research on Women's Health, established in 1990 to address concerns about a general lack of women participating in studies, now is encouraging research to assess basic cellular pharmacologic factors that contribute to sex differences in drug effect.

This was the subject of an American Society for Clinical Pharmacology and Therapeutics (ASCPT) symposium in June. Participants examined how pharma-cokinetic (PK) and pharmacodynamic (PD) studies may provide evidence on sex-based differences in drug response and adverse events. Purdue University professor Kevin Sowinski called for more research on the underlying mechanistic issues of PK and PD differences, particularly related to pregnancy, the menstrual cycle, and menopause. IBS, cardiovascular disease, and psychiatric disorders were also discussed.

Similarly, the Society for Women's Health Research addressed challenges and opportunities in collecting subgroup data on women in clinical trials at a meeting last October on "Clinical Trial Design for Sex Analysis." Researchers emphasized the importance of including women in early studies in order to design appropriate late-stage trials. Stanford University School of Medicine professor Donald Stanski noted that Phase III studies of tirilazad failed because the development team did not recognize early on that women required higher doses than men. Stanski and Carl Peck of Georgetown University's Center for Drug Development Science propose using quantitative techniques to analyze Phase I PK/PD data from men first and then collect data from a minimal number of women to determine the significance of sex-specific differences.

Decade of effort
FDA began to urge sponsors to study more women and minorities in the early '90s. A 1993 guidance called for analysis of trials by gender, including evaluation of PK data in women. This document officially ended FDA's 1977 policy that excluded women of childbearing potential from participating in early-phase clinical trials. FDA also clarified that it may refuse to file an application if sponsors fail to evaluate the safety and effectiveness of a new therapy in "pertinent subsets," such as gender, age, and race.

The FDA Modernization Act of 1997 (FDAMA) required FDA to examine the inclusion of racial and ethnic groups in clinical trials. That led to FDA's 1998 "Demographic Rule" (Regulation of Investigational New Drug Applications and New Drug Applications). It requires sponsors filing new drug applications (NDAs) to submit safety and efficacy data by gender, age, and racial subgroups, but does not specifically require inclusion of these subgroups in studies.

Several ICH standards address issues related to subgroup analysis in clinical trials. The ICH 1998 guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data (E5) aims to reduce the need for additional clinical studies in nations where a company plans to market a drug by encouraging bridging studies that demonstrate data developed in one region is relevant to another. In June 2004, FDA further elaborated in a Q&A guidance on how sponsors should evaluate which ethnic factors affect foreign clinical data.

In addition to encouraging sponsors to collect race and ethnicity data along with sex and age data, a 1999 guidance recommends using population pharmacokinetics to find differences in drug safety and efficacy among ethnic and racial subgroups. To clarify how researchers should collect this data, FDA advised sponsors in January 2003 to use the five racial/ethnic categories of the Office of Management and Budget (OMB). FDA acknowledges that these categories reflect social norms more than scientific evidence, but recognizes the value of collecting standardized information that can be analyzed and compared by different parties. Some researchers believe, however, that data based on such categories may become less relevant in light of evidence that an individual's specific genetic variants, disease state, and multiple environmental factors may have a greater impact on drug response than race and ethnicity. FDA has received comments on this proposal and is weighing further revision.

Strengthening analysis
FDA's 1993 guidance "lifted the bar" on including younger women in early trials, observed Susan Wood, director of FDA's Office of Women's Health, at the ASCPT symposium. Sponsors are enrolling sufficient numbers of women in early trials and are including gender information on product labels, according to FDA analysis of protocols and submissions. Data analysis is still weak, though, and it does not lead to changes in drug dosing on product labels.

To facilitate more timely assessment of how well sponsors use subgroup data from clinical trials, two years ago Congress called for FDA to develop an agency-wide database of demographic data on clinical trials. This Demographic Information and Data Repository is still in the planning stage as FDA strives to establish the technical parameters for this project and align it with the agency's evolving data management system.

Perils of pregnancy
Although clinical trials today routinely include multiple subgroups, pregnant and lactating women remain off most protocols. Sponsors and regulators agree that it is highly risky to include these groups in investigational programs, while also recognizing that these patients use drugs and often need more than the scant information now available on how a therapy may affect mother or child.

Most information on drug effects on pregnant women emerges after a drug is on the market. In June, FDA cautioned physicians about prescribing anti-depressants to women in the late stages of pregnancy, pointing to new product label information about possible harmful effects on newborns. FDA also warned women against using an unapproved foreign drug that was purported to increase breast milk production, but is linked to cardiac arrests and even death.

A May 2004 workshop on PK and PD in drugs in pregnant and lactating women sponsored by the American Association of Pharmaceutical Scientists (AAPS) addressed the challenge of designing studies to obtain useful information on this patient subgroup. Although NIH and FDA want to encourage more studies that examine drug use in pregnant women, Kathleen Uhl, Pregnancy Labeling Team leader in FDA's Center for Drug Evaluation and Research, acknowledges that researchers disagree on which drugs to study first-therapies with the most severe potential impact on pregnant or lactating women, or drugs used most frequently by these women.

Manufacturers have conducted trials on certain drugs designed for use by pregnant woman, such as Glaxo's tests of zidovudine in reducing maternal-infant transmission of HIV, but that is the exception to the rule. FDA is unlikely to require sponsors to include pregnant women in trials, but could pressure companies to justify exclusion criteria.

A more acceptable alternative for sponsors is to establish pregnancy registries for marketed drugs to collect adverse event data and safety signals on maternal effects. FDA requires manufacturers of high-risk products such as Roche's Accutane to establish registries and has suggested that several companies form collaborative registries for similar products. Regulators are also eyeing whether sponsor efforts to inform practitioners of pregnancy registries slip into the promotional area by implying product safety and efficacy.

FDA is updating a two-year-old guidance on pregnancy registries to clarify current policy and address new patient privacy issues. Although privacy rules allow adverse event reporting without specific patient consent, if registries are considered "research," they might require informed consent, which complicates the enrollment process.

Another FDA goal is the development of a guidance on pregnancy-related product labeling. One aim is to define those adverse drug events that warrant listing in a separate pregnancy section of product labeling, without further overloading already dense drug labels.

SIDEBAR 1: Closing Disparities of Care
The campaign to include racial and ethnic group members in clinical trials reflects broader efforts to reduce apparent gaps in minority health care services. A 2002 Institute of Medicine report on "Unequal Treatment" documented how patients from specific racial and ethnic backgrounds often receive disparate levels of care, even when they have insurance coverage and income comparable to white patients. Senate majority leader Bill Frist (R-TN) has proposed legislation to "close health care gaps" by requiring federal programs to measure health quality by set standards that would reveal unequal care. Health care providers and insurers are also collecting data on race and ethnicity to target certain groups for special preventive health and disease management programs.-JW

SIDEBAR 2: Women, Minorities Under-represented
Despite pressure from Congress and other groups, Yale researchers found that most multicenter cancer trials fail to enroll representative numbers of women and minorities. An analysis of participants in studies sponsored by the National Cancer Institute Clinical Trial Cooperative Group in two periods (1996-1998 and 2000-2002) shows little gain in subgroup enrollment-and an actual drop proportionally for Hispanic and black patients. The elderly also were poorly represented, considering the large percentage of older cancer patients. The study in the Journal of the American Medical Association (June 9, 2004) raises questions about what is an optimal degree of representation by minorities and other populations groups, and how to achieve that goal.-JW