Food and Drug Administration Advances Drug Safety for Women: First Steps in a Long Journey

Abstract

We read with enthusiasm the article by Jenkins et al.¹ published in this issue of the Journal of Women's Health. The original 2001 U.S. Government Accountability Office (GAO) report revealed that 8 of 10 drugs that had been withdrawn from the U.S. market between 1997 and 2000 demonstrated greater risks for women than for men, including fatal arrhythmias, valvular heart disease, and liver failure.² We have drawn on the information presented in this report many times over the years in our lectures and presentations raising awareness about the risks to women from these understudied and subsequently dangerous pharmaceutical agents. Sadly, if women had been included in appropriate clinical trials of these drugs, trials that disaggregated and reported data by sex, these serious adverse drug reactions (ADRs) would have been discovered premarket, sparing women's health and avoiding significant suffering.

Jenkins et al.'s¹ review of the impact of Food and Drug Administration (FDA) guidelines put in place in the subsequent 17 years in response to the initial report makes it clear that the changes instituted to promote drug safety for women had measurable and sustainable effects. Although the records that the authors were able to examine were incomplete and precluded a thorough analysis of all of the drugs reported on in the 2001 GAO report, their findings of a 67% reduction in yearly postmarket drug withdrawals due to unanticipated ADRs in women supports the effectiveness of the FDA's changing policies. The number of drug trials enrolling women has grown exponentially in response to the Demographic Rule,³ which insists on representation of both sexes as participants in drug trials, and the FDASIA Section 907 Action Plan, which called for reporting disaggregated analysis of sex data. In addition, FDA provided official guidance monitoring drugs' effects on cardiac arrhythmias and liver failure particularly for women.⁴ These policies had an impact. Hopefully, they will stand as a harbinger for more action in the future.

Biological Sex Is Not a Subgroup

Although data about biological sex need to be disaggregated, it should not be viewed as merely another subgroup to analyze. Biological sex is foundational, and for the majority, represents a binary variable. Is there another scientific variable that is more foundational that the chromosomal complement? Biological sex influences a host of cellular, anatomical, and physiological processes within the human body. It must not be viewed in the same category as gender identity, race, socioeconomic status, or age. For example, let us consider a drug's life cycle in the human body as determined by pharmacokinetics. The components are absorption, distribution, metabolism, and excretion. There is demonstrable evidence that sex-based physiological differences are at play in all four components of this cycle effecting drug efficacy and safety. Men and women have different average body weights, body fat percentage, plasma volume, and organ blood flow all impacting drug absorption and distribution.⁵ Animal models have identified >1000 genes in the liver that show sexually dimorphic expression altering metabolism.⁶ Many drugs, including acetaminophen, benzodiazepines, ondansetron, and propranolol, have renal clearance rates that vary by sex.⁷

Historically, women were not enrolled in clinical trials because both the pharmacokinetics and pharmacodynamics of most drugs vary across the phases of menstrual cycle responding to changes in sex hormone plasma concentrations and in response to exogenous oral contraceptives and hormone therapy. Pregnancy introduces additional complex unpredictable risks to the fetus (e.g., thalidomide) and large changes in sex hormone concentrations. Evidence-based medicine grounded in clinical research is effective because it is fluid and always evolving as new evidence becomes available. Complex problems such as the effects of hormone fluctuations in women that change drug metabolism demand more in-depth research not avoidance due to complexity. For example, a recent study on antiplatelet therapy has demonstrated that women exhibit differential benefit as sex hormone concentration interplays with platelet biology.⁸ The plasma concentration of antiepileptic medications varies across the menstrual cycle and can become subtherapeutic during the follicular phase resulting in seizures that could have been avoided by appropriate temporal changes in dose.⁹

For many FDA-approved therapeutics, women remain underrepresented as was shown in a publication from the agency itself regarding a decadal review of safety and efficacy of FDA-approved cardiovascular drugs spanning 2005–2015.¹⁰ Drug developers must comply with the Demographic Rule data reporting requirements when submitting New Drug Applications to FDA. Yet are able to skirt the issue of reporting scientifically rigorous data analysis of sex differences in safety and efficacy since FDA does not define the expected percentage of women, which must be included in clinical drug trials utilized for drug approval. In other words, enrolling any percentage of women could be deemed sufficient by FDA when determining whether a particular drug obtains approval. For example, as recently as 2019 FDA approved an HIV prevention drug combination for treatment in men and transgender women, allowing the pharmaceutical developer to justify having no cisgender women in the clinical trials!¹¹ It took FDA 21 years after the initial approval of zolpidem to acknowledge the original dosing was a danger to women. FDA published new dosing requirements in 2013 reducing the original maximum dose for women by 50%.¹² Stronger regulations, without loopholes such as those outlined in this study, and FDA upholding both the content and the intent of regulations such as the Demographic Rule, could have prevented countless deadly adverse events in women.

COVID-19—No Time to Waste

Novel treatments and therapies are rapidly being developed and rushed to market to address the COVID-19 pandemic. Without mandated regulations, investigators have the option of reporting trials that are ambiguous, misleading, or dangerous for women. A recent report assessing 2484 COVID-19 trials in ClinicalTrials.gov database noted that sex and gender-based analysis was noted as a disaggregated variable in the data in only 16.7% of these trials; only 4.1% plan to provide a sex-based analysis.¹³ How are clinicians to decide whether these new therapies are effective or even safe for women? How are they to choose dosing or inform side effect concerns? Why does this travesty continue?

All Hands on Deck

The FDA is the agency within the Department of Health and Human Services whose mission is to enhance the health and well-being of all Americans by providing for sustained advances in the sciences underlying medicine and public health. This mission includes ensuring that drug therapies are both safe and efficacious for the population most likely to need them. If you agree with this statement, then men and women must be included in the pivotal trials in numbers large enough to ensure rigorous scientific analysis to account for clinically significant sex differences in drug efficacy and safety.

Although significant progress has been made as reported in this review article, there seem to be significant barriers remaining as we pursue our goal of achieving safety and efficacy for all drugs approved by the FDA, which could be utilized by men and women. Federal regulations, mandated policies, and effective incentives must be put in place to assure that medical care, including pharmacotherapy, is equally available, equally safe, and equally effective for all patients.

Call to Action

FDA must be held accountable for the scientific rigor of its data review and analysis in drug approval processes.

We must do more than rely upon FDA Adverse Event Reporting System data—as the authors mention, these reports are vital but require initiation and effort from physicians, pharmacists, and patients. These reports do not quantify the ADRs that are not rare or serious enough to motivate the reporting.

We must lobby congress to ensure FDA has the authority to mandate sex inclusive and disaggregated data to advance our understanding of sex-based drug efficacy and safety.

We must encourage local, regional, and national policies to ensure adequate reporting of public health data based on sex to national agencies, including the Centers for Disease Control and Prevention (CDC).

We must work to ensure gender reporting of participants and disaggregated results by sex within our circle of influence such as journal editorial staff, peer review policies, academic research meetings, and our individual hospital journal clubs.

Policy does change practice. We all must work to update policies ensuring that research is fair, equitable, safe, and rigorous.

References

Jenkins

, et al. Food and Drug Administration beyond the 2001 Government Accountability Office Report. Promoting drug safety for women. J Womens Health, 2021; 30:927–934.

Heinrich

. Most drugs withdrawn in recent years had greater health risks for women. Washington, DC: U.S. Government Accountability Office-01-286R, 2001.

Drug products withdrawn or removed from the market for reasons of safety or effectiveness, 21CFR216.24.2018. Available at: https://www.federalregister.gov/documents/2018/12/11/2018-26712/list-of-drug-products-that-have-been-withdrawn-or-removed-from-the-market-for-reasons-of-safety-or Accessed February 6, 2021 .

FDA. FDA action plan to enhance the collection and availability of demographic subgroup data. Washington, DC: FDA, 2014.

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