Underrepresented, Overmedicated, and Misdiagnosed

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Experts contend that FDA clinical trials fail to ensure adequate consideration of women’s health needs.

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Women constitute roughly half of the United States’ population. Why, then, are women continuously excluded from clinical drug trials?

For decades, the U.S. Food and Drug Administration (FDA) has faced criticism for failing to account for sex differences in its clinical trials. Initially, concerns about pregnancy limited women’s ability to participate in FDA testing procedures, as well as conceptions concerning increased costs for including women in medical research. Not until 1993 did regulators alter clinical trial guidance to include women in certain phases of testing.

At present, however, women remain underrepresented in clinical drug trials, and consequently face greater potential harms resulting from medications. FDA’s extensive history of excluding women from clinical trials continues to impact medical practices in the United States.

Because of the lack of sex parity in FDA drug trials, health care providers often prescribe men and women identical dosages of medications. Consequently, women experience more dire reactions to such medications, and tend to be overmedicated generally due to overestimated dosages.

Simultaneously, diseases disproportionately impacting women, such as Alzheimer’s disease or chronic pain conditions, are underdiagnosed, resulting in adverse outcomes for women suffering from such diseases.

Although FDA is currently undertaking strides to amend its prior lack of inclusivity, experts maintain that there is an existing gap in the regulatory framework to enforce adequate sex representation in clinical trials.

In this week’s Saturday Seminar, scholars examine the ways in which regulation can help achieve greater equity within the realm of women’s health.

  • In an article published in the AMA Journal of Ethics, Madris Kinard of Device Events and Rita F. Redberg of the University of California, San Francisco School of Medicine suggest how FDA could more effectively regulate devices intended for use in women. Kinard and Redberg report that, when researchers discovered that women’s intrauterine contraceptive devices were linked to infertility in 1976, FDA implemented a more rigorous regulatory process. An amendment to the federal Food, Drug, and Cosmetic Act, however, grandfathered in devices marketed prior to 1976. Although adverse event reporting aims to track issues with devices, Kinard and Redberg criticize FDA’s failure to mandate restrictions, recall devices, or enforce manufacturers’ compliance. Kinard and Redberg call for greater transparency in the reporting of adverse events and increased enforcement measures to protect women.
  • In an article published in JAMA Network, Jecca R. Steinberg of Northwestern Feinberg School of Medicine and several coauthors find that sex bias persists in clinical trials. Historically, clinical research has focused on male health, according to Steinberg and her coauthors. Although this bias has spurred legislative efforts to increase female inclusion, the Steinberg team’s study of clinical trials registered between 2000 and 2020 suggests that sex representation varies by medical specialty. Steinberg and her coauthors contend that increased parity and sex-specific analysis are necessary to promote reliable data.
  • In an article published by the Minnesota Journal of Law, Science & Technology, Cara Tenenbaum of Strathmore Health Strategy argues that artificial intelligence systems that use data pulled from various sources to provide medical resources and recommendations require “smart regulation.” Tenenbaum argues that such regulatory efforts can help to mitigate the gender biases historically associated with the development of medical evidence. For example, Tenenbaum explains how, after FDA published guidance outlining the agency’s expectations concerning the inclusion of women in drug development processes, the representation of women in clinical trials increased. Similar regulatory requirements could apply to artificial intelligence health systems to protect against the digital encoding of human biases, Tenenbaum argues.
  • Despite evidence of substantial gender differences in the efficacy of drug treatments, gender is “one of the most underappreciated variables in the clinical development of drugs,” contend Younes Benjeaa and Yves Geysels of Belgium’s University of Namur in a report issued by Applied Clinical Trials. For example, the U.S. General Accounting Office found that 70 percent of the drugs removed from the market between 1997 and 2000 posed greater health risks to women than to men, explain Benjeaa and Geysels. Rather than protecting fetuses and potential fetuses by conducting well-controlled clinical studies, Benjeaa and Geysels describe how FDA broadly excluded “women of child-bearing potential from certain phases of clinical research.” Although later guidance reversed this ban, important regulatory questions remain unanswered, including the question of how to know when women are being sufficiently represented in clinical trials, explain Benjeaa and Geysels.
  • To meet women’s health needs, FDA should leverage its Office of Women’s Health (OWH), argue Genevieve Grabman of the United Nations High Commissioner for Refugees and Cara Tenenbaum, former senior policy advisor for FDA, in an article published in the Food and Drug Law Journal. According to Grabman and Tenenbaum, FDA has failed to engage OWH in efforts to create equitable health outcomes since its conception. Grabman and Tenenbaum note that OWH staff serve in an advisory role to FDA’s commissioner when reviewing efficacy of medications and products. In addition, Grabman and Tenenbaum contend that OWH should play a greater role in regulating inclusivity in the study, labeling, and marketing of pharmaceuticals.
  • In an article published by the American Cancer Society, Zachary Klaassen of Augusta University and several coauthors examined FDA trials for oncology medications and found that women were often underrepresented in these trials when compared to women’s national cancer rates. Klaassen and his coauthors argue that FDA’s efforts to rectify gender parity in clinical trials remain ineffective. The Klaassen team offers potential solutions to remedy this discrepancy, such as increasing research and guidance on sex-specific responses to medication.

The Saturday Seminar is a weekly feature that aims to put into written form the kind of content that would be conveyed in a live seminar involving regulatory experts. Each week, The Regulatory Review publishes a brief overview of a selected regulatory topic and then distills recent research and scholarly writing on that topic.