Mind the gap: The need for gender-specific outcome measurement

It is well documented that women face delayed diagnoses, mischaracterised symptoms, and experience more years of ill-health compared to men. Research shows that women spend approximately 25% more of their lives in poor health than men, despite living longer on average.¹ This disparity reflects long-standing gaps in how medical research has been designed, funded, and executed, with many therapeutic areas that predominantly or only affect women remaining under-researched and underrepresented in clinical development.² One major and often overlooked factor contributing to this imbalance is the way health outcomes are measured in clinical trials, particularly through the use of Clinical Outcome Assessments (COAs).

COAs are fundamental tools for assessing treatment impact on patients’ quality of life and include patient-reported outcomes (PROs), clinician-reported outcomes (ClinROs), observer-reported outcomes (ObsROs), and performance-based assessments (PerfOs). These tools play a central role in evaluating whether medical treatment provides meaningful benefit. However, many tools used today were developed and validated in predominantly male populations and may not accurately reflect how diseases manifest in women. This mismatch can lead to missed nuances, underpowered endpoints, missed opportunities to demonstrate value and, perhaps most importantly, not providing benefit to both genders equally.

A recent analysis of COAs on ICON-sponsored Mapi Research Trust’s ePROVIDE platform revealed stark gaps in the availability and use of female-specific COAs across regulatory guidance and product labelling, for example. The findings suggest a need to move beyond simply enrolling more women in trials, to rethinking how COAs are developed, selected, and applied to show success in the female population.

When data paints a pained picture

Of the 527 COAs across 254 distinct indications relevant to therapeutic areas prioritised in the 2024 version of the FDA’s Women’s Health Research roadmap, only 47, or less than 10%, were developed with a female-specific population, with no COAs developed in women for 234 of the indications.³ The gaps were even more pronounced when looking across regulatory guidance and product labelling. Among 11 regulatory guidelines related to one of the roadmap’s priority therapeutic areas issued by the FDA and EMA that referenced COAs, none recommended COAs developed with an all-female population. Similarly, only eight of the 106 drug labels reviewed used COAs that had been developed with an all-female population. This data points to a deeper equity issue: even when women are included in clinical trials, not all instruments used to measure outcomes may be fit for their biology, symptoms, or lived experience, impacting outcomes and calling into question the real benefit and the regulatory confidence in trial results.

The need to move past a one-size-fits-all approach

Many diseases affect both genders, but present differently in women. In these instances, the current one-size-fits-all approach to outcome measurement risks overlooking key signals of treatment effectiveness.

Cardiovascular disease, for example, is the leading cause of death among women globally. Yet, its symptoms in women, such as nausea, fatigue, or shortness of breath, often differ from the "classic" chest pain presentation more typical in men.⁴ Despite this, only 12 COAs were identified for cardiovascular indications, and all were developed with a mixed population. Without tools tailored to capture how cardiovascular disease uniquely presents and progresses in women, trials may fail to demonstrate full therapeutic benefit.

Similarly, in musculoskeletal conditions, women are more likely to experience certain types of pain and joint degeneration, often different from the pain experienced by men. Yet, only 1.7% of COAs for this therapeutic area were developed with an all-female population.

Even in areas where gender-specific research is more common, such as oncology for breast cancer, disparities remain. The majority of female-specific COAs are concentrated in breast cancer and postmenopausal osteoporosis. While undoubtedly important, focusing only on breast cancer and osteoporosis fails to address many other high-burden conditions experienced by women.

Given these findings, it is clear that existing COA instruments have a fundamental gap and more PROs and other COAs must be developed with targeted input from women. These COAs must demonstrate validity evidence in relevant populations and be carefully selected for the specific disease context. Without this foundational work, the risk remains that what matters most to women will continue to be under-measured or misinterpreted.

Truly equitable research is possible

Equity in clinical research has focused significantly on representation and inclusion. While this is undoubtedly important, true equity requires going a step further and ensuring not only that women are included in clinical trials, but that the tools used to measure outcomes and endpoints are also designed to reflect the unique ways diseases manifest and impact them.

In practice, this could include, for example:

• Developing more COAs for women, with women’s input. This is especially important in therapeutic areas like psychiatry, cardiology, and auto-immune disorders,⁵ where gender differences are known to influence symptomology, disease course, and response to treatment.
• Re-evaluating existing COAs that may have been validated predominantly in men, and assessing their applicability in female populations.
• Including gender-based subgroup analyses in COA validation studies.
• Encouraging regulatory guidance by the FDA, EMA, and other agencies that explicitly calls for gender-relevant outcome measurement tools to be prioritised.

Truly equitable clinical research also calls for a shift in mindset. COA selection should not be a “box-checking” exercise. Which COAs to use and why is a strategic decision that influences how treatment value is assessed, both clinically and commercially. For conditions that affect all genders, relevant and specific COAs are not a luxury; they are a scientific necessity.

As clinical trials move towards increasing personalisation, the tools used to evaluate success must keep pace. As such, it will be critical to move beyond just investing in trial diversity, to also prioritise measurement diversity. Only then can our industry truly close the gender gap in clinical outcomes and develop therapies that improve the health of all patients.

References

¹ Ploszajski, A. (2024) “Women’s Health: Women's health is in crisis; Imperial experts are calling for a fairer system that works for everyone”. Imperial College London. 

² Whiting, K. (2024) “Women's health gap: 6 conditions that highlight gender inequality in healthcare”. World Economic Forum. 

³ US Food and Drug Administration. “Women’s Health Research Roadmap”. 

⁴ US Food and Drug Administration. “Women’s Health Research Roadmap”.

⁵ Colino, Stacey. “Women Are Still Under-Represented in Medical Research. Here’s Where the Gender Gap Is Most Pronounced”. TIME Magazine, November 1, 2024. 

About the authors

Salina Lien is a research associate at Mapi Research Trust, part of ICON, where she specialises in Clinical Outcome Assessments (COAs). She conducts literature reviews and manages data to help identify the most appropriate COAs for measuring treatment effectiveness in clinical trials.

Tilly Stott is a research associate at Mapi Research Trust, part of ICON, where she curates and produces scientific content related to clinical outcome assessments. She has recently completed a Master of Public Health at the University of Edinburgh, with her dissertation focused on patient-reported outcome measure development and intersectionality.