Despite significant advances in medical science, women's health has often been overlooked in drug development, leading to a persistent gap in understanding female-specific health needs. Traditional practices have relied heavily on male-centric models, from preclinical animal studies to clinical trials, often resulting in drugs that are less effective and potentially more harmful for women. At the forefront of change, Fab Biopharma is challenging these norms by focusing on female physiology, inclusion, and real-life needs and developing biologics that address the unique health issues faced by women. With a commitment to diversity and a female-oriented approach, Fab Biopharma is not only filling critical knowledge gaps but also pioneering new paths in the biopharmaceutical industry.
Challenging the Male-Centric Bias in Drug Development
Despite the clear biological differences between men and women, and the varying diseases that disproportionately affect each gender, women have historically been underrepresented in drug development — in terms of not only participation but consideration. This oversight has perpetuated a significant knowledge gap in understanding female physiology, pathology, and pharmacology, which persists today.
Recent research across various medical disciplines has uncovered significant differences in drug metabolism profiles between men and women across numerous drug classes. It has become evident that women differ from men in terms of absorption, distribution, metabolism, and elimination (ADME) of active drug substances, highlighting a critical need for sex-specific dosing that is currently absent for most medications on the market.1 Furthermore, the presence of a second X chromosome in women as opposed to a Y chromosome in men profoundly influences disease development, progression, and treatment responses. Notably, recent studies have explored the role of the Xist ribonucleoprotein complex, which is essential for X-chromosome inactivation. Abnormalities in Xist expression have been linked to the development of autoimmune diseases, which disproportionately affect women.2,3 For example, some of the Xist RNP nucleoproteins may act as autoantigens, inducing some of the autoantibodies found in the female-dominant autoimmune diseases systemic lupus erythematosus and Sjögren’s disease. These findings underscore the complexity of genetic influences on health conditions and the necessity of further research to unravel these mechanisms and integrate them into personalized medical approaches.
Gender-specific variations have been identified in several areas, including mental health, cardiovascular health, and immune responses. Women often experience different symptoms and outcomes related to bone health, endocrinology, vaccine responses, chronic pain, cancer, and autoimmune diseases compared to their male counterparts. Additionally, research on menopausal symptoms like vaginal dryness and the requisite hormonal therapies is scant, underscoring a broader trend of neglect in women's health issues.
In the realm of bone health (osteoporosis and osteopenia) — with an increased risk of bone fractures a critical quality-of-life issue for aging women —therapeutic options are limited. Treatments, such as bisphosphonates, parathyroid hormone therapies, and monoclonal antibodies like Denosumab, are available but come with significant drawbacks. Denosumab, for example, must be administered indefinitely to prevent osteoclast formation, as cessation leads to accelerated bone resorption. Another treatment, Romosozumab, which inhibits the protein sclerostin that blocks bone formation, is effective for only about a year and carries a severe black box warning due to potential cardiac risks.
Cardiology presents unique challenges for women, who are less likely to suffer from coronary artery disease, but their presentation of myocardial infarction is different from men, as symptoms are variable and often less intense, making it harder to diagnose. Women are more prone to conditions like embolisms or arterial dissections. Despite these differences, women are less frequently treated for conditions such as high cholesterol and atrial fibrillation and often receive fewer life-saving interventions like heart transplants or bypass surgeries compared with men. This disparity in treatment is reflective of a broader disinterest among physicians, which translates to a lack of innovation of the part of drug companies in developing treatments tailored to women's cardiovascular needs.
The gender bias extends into preclinical research, where male animals predominantly populate studies, skewing data that informs human trials. For example, neurology studies have reported that up to 50% utilize only male mice, despite evidence from meta-analyses showing that male mice exhibit greater variability in hormones, metabolism, and morphology than females.4
This gender imbalance in research has real-world consequences in clinical trials. In studies of a neurological bleeding disorder, for example, the underrepresentation of women in early phases meant that differences in how the drug was metabolized were not fully understood until later trials, where it was discovered that women metabolized the drug two to three times faster than men, necessitating higher dosages. Attempts to approve the drug for men only were not sanctioned by the U.S. Food and Drug Administration (FDA), highlighting the need for more inclusive research practices.
Although recruitment of women in clinical trials has improved, averaging 40–50% participation, significant challenges remain, especially in fields like cardiology and immunotherapies, where gender imbalances persist. Additionally, the criteria for including women of childbearing age are restrictive. They are required to use contraception to avoid pregnancy, which can deter participation. If they become pregnant, they must discontinue the medication. A lack of finalized FDA guidance on pregnancy in clinical trials further complicates this issue.
Moreover, women using oral contraceptives or undergoing hormone therapy are often excluded from trials. Most trial designs also fail to consider the unique needs of female participants, such as managing fatigue, which can affect trial outcomes and the relevance of the research to women's real-world healthcare needs. Also, additional resources and money are needed to allow women to participate in clinical trials that can last one year or longer — for childcare, traveling to the investigator site, and missing work for a clinic visit.
The cumulative effect of these biases is profound: women experience lower drug efficacy, inappropriate dosages, and a higher incidence of unexplored side effects, underscoring an urgent need for reform in how medical research is conducted and drugs are developed.
Pioneering Female-Centered Research Approaches
To ensure optimal drug development that addresses women’s health issues effectively, it is crucial to eliminate the historical male bias prevalent in the industry. The traditional approach, which treats the male body as the norm and the female body as atypical, must be reformed.
Focused research and development efforts are essential for diseases that are either exclusive to or predominantly occur in women. Preclinical studies should be redesigned to include both male and female animals, employed both separately and collectively, to comprehensively explore sex-specific responses at the cellular and organ levels. Moreover, women must be adequately represented in clinical trials for diseases that affect both genders to ensure that drug efficacy and safety profiles are accurately established for everyone. Physicians also need enhanced training and awareness about women’s health issues to promote equity in diagnosis and treatment processes. Leveraging the increasing volumes of real-world data could support these endeavors by providing more robust, gender-specific health insights.
The diversity of participants in clinical trials, including the involvement of pregnant women, presents complex challenges that require thoughtful solutions. For instance, during trials for medications treating lupus and HIV-1 , the improved health and quality of life that participants experienced increased the likelihood that they became pregnant, resulting in their classification as 'treatment failures' — rather than extraordinary successes — when they had to withdraw from the study. Trials addressing the COVID-19 pandemic highlighted similar issues, sparking significant debate about whether to vaccinate pregnant women.5 Clinical trials investigating new therapies in pregnant women are rare in initial clinical development studies. When pregnancy trials do occur, it is usually after a new drug is approved and a safety profile has been established, allowing a limited understanding of a new therapy’s risks in pregnancy outcome, fetal development, and to the newborn child.
As the scope of data collection widens and the capacity to analyze large data sets improves, the role of real-world data in fostering women-centric drug development is poised to expand significantly. Nevertheless, the accurate interpretation of these data is imperative. A pertinent example is the analysis of health study data on hormone therapy, which initially led to the broad, incorrect conclusion that hormone therapy universally increases the risk of breast cancer risk.6 This outcome stemmed from a failure to consider variations in hormone therapy types, dosages, and age. When properly managed, hormone therapy can be highly beneficial, but misconceptions based on flawed data analysis have led to its underutilization.
Transformative Impacts of Female-Centric Drug Development
Adopting a female-centric approach to drug development offers substantial benefits for both pharmaceutical companies and patients. By gaining a deeper understanding of the complexities, progression, and responses of diseases, researchers can develop more effective medications that lead to improved health outcomes. This approach not only fosters innovation in drug discovery but also facilitates the development of new classes of therapies and personalized medicines that meet previously unaddressed medical needs, enhancing both patient care and corporate profitability.
Enhanced inclusion and exclusion criteria in clinical trials, informed by a comprehensive understanding of gender differences, result in more effective trials with fewer costly failures. By understanding disease mechanisms and identifying new targets specific to female biology, the pharmaceutical industry can create drugs that are more effective for women, improve fertility and pregnancy outcomes, and support the overall health of future generations. Additionally, there is potential for increased disease remission rates, especially for conditions where women historically have lower remission rates than men.7,8
Addressing the root causes of diseases prevalent during women’s reproductive years not only improves outcomes for individual patients but also tackles complications that arise during pregnancy. Developing targeted treatments for lesser-known or under-researched autoimmune diseases that disproportionately affect women, such as Sjögren’s disease, can maintain or even improve their quality of life, keeping them active and productive in the workforce and their communities.
The cumulative impact of these efforts extends far beyond individual health. By focusing on female-specific health issues throughout the stages of drug discovery and development — from preclinical studies to late-stage clinical trials and even post-marketing studies — pharmaceutical research can contribute to societal health. Healthy women are foundational to the well-being of their families and communities, ultimately fostering healthier future generations.
Strategies for Implementing Gender-Inclusive Research
Transforming the male-centric focus in drug development demands a unified commitment from both industry and academia. To eradicate the prevailing gender biases and imbalances in research, comprehensive changes in policy and regulation are imperative. These reforms must pave the way for gender-equitable research practices across both preclinical studies and clinical trials.
For clinical trials, innovative strategies are essential to improve the recruitment and retention of female participants. This includes optimizing site selection to be more accessible to women and redesigning trial protocols to address specific female health concerns. Additionally, providing supportive services, such as transportation, options for participation during travel, and compensation for missed work or childcare expenses, are critical to facilitate continued and active participation in both short and long-term (≥1 year) clinical trials. Collaborative efforts with patient advocacy groups and prominent female experts in the field are vital to ensure that the trials are responsive to the unique health needs of women and maintain their engagement during both clinical studies and long-term follow-up periods.
Enhanced training programs are necessary for current healthcare professionals and researchers to help them identify and counteract gender biases in their daily practices. Academic curricula must also be revised to integrate gender sensitivity, equipping future medical professionals with the knowledge and tools needed to prevent biases in their work.
Addressing the participation of pregnant women in clinical trials presents a unique challenge. The risks associated with taking novel medications during pregnancy vary widely, and a more nuanced approach is often required. Allowing women to make informed decisions about their participation can be more respectful and potentially beneficial than blanket prohibitions.
Additionally, the inclusion of diverse and female executives in pharmaceutical companies is crucial. Leaders who can offer insights from a female perspective are key to fostering an environment that naturally eschews the traditional male-dominated biases. Companies that prioritize female health concerns and integrate female leadership are better positioned to challenge the status quo and drive meaningful change in the industry.
Fab Biopharma: Innovating for Women's Health
Fab Biopharma is at the forefront of transforming the biopharmaceutical landscape with its dedicated focus on developing biologics specifically for women.9 Led by a seasoned team with decades of experience in drug development — from target discovery through to market — Fab Biopharma is committed to redefining how diseases are understood, how drugs are developed, and how clinical trials are conducted.
Currently, the company is making significant strides in targeting Sjögren's disease and lupus, employing cutting-edge bispecific soluble receptor fusion protein technology. Additionally, Fab Biopharma is advancing treatment candidates for osteoporosis, as well as scleroderma, further underscoring its commitment to addressing conditions that disproportionately affect women.
A key component of Fab Biopharma’s approach involves posing critical, strategic questions that have yet to be answered within the industry. This pioneering effort explores new territories with a focus that is both ethnically diverse and female-oriented, ensuring that a broad spectrum of women's health issues is addressed. The company places a high priority on maintaining transparent communication with all stakeholders — including regulators — to share insights and underscore the importance of accurate data interpretation.
Beyond developing new therapies, Fab Biopharma is also at the vanguard of utilizing male and female organoids in preclinical studies to explore sex-specific dosing in both animal models and humans. This approach is integral to designing clinical trials that more accurately reflect the diverse patient population they aim to serve. Moreover, the company is delving into why autoimmune diseases are more prevalent and harder to manage in women, aiming to enhance long-term remission rates for these conditions.
Fab Biopharma’s ultimate goal is to expedite the development of innovative solutions that will significantly advance the field of women's health, ensuring that future generations of women receive more effective, personalized medical care.
References
1. Anderson, Gail D. “Gender differences in pharmacological response.” Int. Rev. Neurobiol. 83: 1–10 (2008).
2. Dou DR, et al. “Xist ribonucleoproteins promote female sex-biased autoimmunity.” Cell. 187: 733–49.e16 (2024).
3. Andrade, Felipe. “Opinion: How does XIST promote sex bias in autoimmune diseases?” Front. Immunol. 10 Apr. 2024.
4. Beery, Annalise K. “Inclusion of females does not increase variability in rodent research studies.” Curr. Opin. Behav. Sci. 23:134-149. (2018).
5. Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials. U.S. Food and Drug Administration. Apr. 2018.
6. Vogel, Lauren. “Trial overstated HRT risk for younger women.” CMAJ. 189: E648–E649 (2017).
7. Maynard, Carson et al. “Sex Differences in the Achievement of Remission and Low Disease Activity in Rheumatoid Arthritis.” Arthritis Care Res. 72: 326–333 (2020).
8. Medina-Quiñones, Carmen V. et al. “Analysis of Complete Remission in Systemic Lupus Erythematosus Patients Over a 32-Year Period.” Arthritis Care Res. 68: 981–987 (2016).
9. Sun, Chia Chia and Gardiner Smith. “Revolutionizing Biologics (and Biology) through a Focus on Women.” Pharma’s Almanac. 9 Jul. 2024.