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Women and men have different metabolic reactions to medications. While it may be obvious news to administrators and investigators, the government agency responsible for ensuring the differences are documented isn’t doing its job. That’s the mixed assessment from a new report released by the congressional watchdog agency, the General Accounting Office (GAO).
The good news is that the GAO found that clinical trials adequately include women in new drug testing. The bad news is that the U.S. Food and Drug Administration (FDA) doesn’t adequately oversee the testing through outcomes data related to the differences in sex.
The report, titled Women’s Health: Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement (GAO-01-754), found three areas of concern regarding regulations from the U.S. Food and Drug Administration (FDA). First, there is a small number of women enrolled in early, small-scale safety studies. Second, GAO investigators doubt that new drug application sponsors and FDA reviewers took advantage of available data to learn more about the effects of drugs in women and to explore potential sex differences in dosing. Third, the FDA does not have adequate management systems in place to monitor the number of women enrolled in clinical trials, or to ensure sponsors and reports comply with regulations for presenting outcome data by sex and that sex-related issues are adequately addressed in reviews.
Prior to publishing the report, GAO staff investigated the FDA’s progress in including women in clinical drug trials since 1992. Specifically, the GAO report addresses:
The FDA published three documents since 1992 in an attempt to address the inclusion of women in clinical drug trials. The first, a set of guidelines, was published in 1993. Subsequently, new regulations were announced in 1998 and 2000.
GAO investigators acknowledge that the 1993 guidelines lacked the force of law, but the legally binding regulations from 1998 and 2000 provide fewer specifics on complying with the regulation. Investigators also note that the regulations enacted in 2000 allow the FDA to suspend research programs where eligible men and women are excluded from participation based solely on their reproductive potential. The regulation does not, however, specify a particular number of men or women to be enrolled. (For GAO estimates on participation by sex, click here.)
GAO investigators conclude that the FDA is ineffective in overseeing the presentation and analysis of data related to sex differences in drug development based on the following:
— There is no management system in place to record and track the inclusion of women in clinical drug trials or to monitor compliance with relevant regulations.
— The FDA is unaware that many new drug application submissions failed to meet standards.
— The FDA does not routinely review required tabulations of demographic data by sex in annual reports for drug development.
— FDA management lacks procedures to determine whether written reviews of new drug applications prepared by its medical officers adequately discuss sex differences.
— FDA’s medical officers are not required to discuss sex differences in their reviews of new drug applications, and GAO found that many of them do not do so (click here to see chart).
— Roughly 30% of new drug applications specified that concentrations of the drug in the bloodstream were greater in people who weigh less (such as women), FDA reviewers did not comment in their summaries on the lack of dose adjustments based on sex.
The FDA’s written response to the GAO charges includes its improvements to existing management techniques, says Theresa M. Mullin, PhD, acting associate commissioner for planning at the FDA. Medical office reviewers soon will fill out templates and demographic worksheets to help monitor women in clinical studies, notes Mullin. "In addition, increased electronic submission of new drug applications by sponsors will allow reviewers easy access to demographic information for further analyses," wrote Mullin in the report.
In addition, the FDA’s Office of Women’s Health is establishing a clinical trials demographic database in conjunction with all FDA medical product centers. The database will help monitor the inclusion of women in clinical trials, and track other demographic variables could affect the evaluation of safety and efficacy, explains Mullin. Factors such as race, age, and geographic information will be collected. "The database will help determine level of analysis, differences identified, statistical or clinical relevance, and labeling," writes Mullin. The database is intended to start in fiscal year 2002, depending on resources, she adds.
The Office of Women’s Health plans to offer training and educational seminars based on the recent Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter? Topics covered in the seminar include the biological basis of gender differences and improving the overall consistency in reviews regarding gender differences.
Lastly, Mullin notes that the FDA had all of the stated improvements in planning well before the GAO began its investigation.
(Editor’s note: The first copy of each GAO report is available free of charge. Additional copies are $2 each. To order by mail, write: U.S. General Accounting Office, P.O. Box 37050, Washington, DC 20013. Make checks and money orders payable to the Superintendent of Documents. Or order by telephone: (202) 512-6000. Fax: (202) 512-6061.
• Drug Safety: Most Drugs Withdrawn in Recent Years had Greater Health Risks for Women (GAO-01-286R, Jan. 23, 2001).
• Women’s Health: NIH has Increased Its Efforts to Include Women in Research (GAO/HEHS-00-96, May 2, 2000).
• Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing (GAO/HRD-93-17, Oct. 29, 1993).
• National Institutes of Health: Problems in Implementing Policy on Women in Study Populations (GAO/T-HRD-90-50, July 24, 1990).