Design clinical trials with women in mind4 Clinical trials should be designed to capture sex-based differences between men and women. For decades, clinical research has largely been overseen by men and designed with men as the default subjects; women’s health, if addressed at all, has been an afterthought. Even when women are included in clinical trials, sex-based differences are frequently overlooked in data analysis, obscuring critical insights into how hormonal fluctuations, metabolism and genetics influence disease progression and treatment efficacy. This male- centric approach to research has led to a significant gap in medical knowledge that is impeding advances in women’s health. Medical devices, for instance, have historically been designed with men’s physiology as the standard, despite clear anatomical and biomechanical differences between men and women. Some hip implants, for example, fail at nearly twice the rate in women due to differences in bone structure and load-bearing mechanics.47 Similarly, drug trials that fail to account for sex-specific variations in body mass, metabolism and hormone fluctuations may lead to incorrect dosing recommendations or increased risks of adverse effects for women. These examples underscore the critical need for clinical trials designed to capture meaningful sex-based differences, rather than relying on generalized findings that overlook half the population and – as seen with medical implants – often lead to higher failure rates in women.While little progress has been made in addressing these issues, the NIH policy on Sex as a Biological Variable provides an excellent framework for improving study design.48 This policy mandates that researchers consider sex as a critical factor in study design, ensuring that both male and female subjects are adequately represented and analysed in clinical research. Expanding on this, it asserts that clinical trials should be designed to account for known sex differences, with separate analyses for each sex when significant variations exist. Lastly, it encourages inclusion of both men and women when differences are uncertain, and broad participant representation when the data is inconclusive. Relying on men’s physiology and pathology as the foundation for treatment guidelines for both men and women does a profound disservice to women’s health. Designing clinical studies with women’s health not just in mind but at the forefront is a scientific necessity. Without research that accounts for sex-specific differences, medical advances will continue to be skewed towards the physiology of men, perpetuating inadequate care for women and inaccuracies in results. The following policy recommendations are intended to design clinical trials with women in mind (Figure 3): –Employ sex-specific biomarkers to understand differences in physiological mechanism and manifestation. Prior to designing clinical trials, requiring robust preclinical in-vitro and animal data on sex- specific biomarkers in lab testing and imaging will help to clarify the differences in the physiological mechanism and manifestation in men and women. These detection sources are the foundational indicators that prompt further enquiry and define how to design clinical trials, especially in the case of sex-specific differences. –Design clinical trials to account for sex-based differences in physiological mechanism and manifestation. When prior research confirms significant sex differences, clinical trials should be structured to answer separate primary questions for men and 4.1 Policy recommendations to design clinical trials with women in mind Prescription for Change: Policy Recommendations for Women’s Health Research 18

Prescription for Change 2025