Beyond Bleeding: Unpacking Gender Disparities in Von Willebrand Disease Clinical Trials of the Past Half-Century

Introduction: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, characterized by deficiencies or defects in von Willebrand factor (VWF), leading to impaired platelet adhesion and coagulation cascade dysfunction (1). Randomized clinical trials (RCTs) play an important role in evaluating therapeutic interventions and improving clinical management strategies for VWD patients worldwide (2). Over the past decades, a distinct gender participation gap has become apparent, favoring females in the enrollment of clinical trials for VWD, but fluctuating overall. Our study aims to investigate the contributing factors to this imbalance, such as physio-pathological reasons, socio-demographic characteristics, accessibility barriers, and awareness limitations. Methods: In this descriptive, retrospective study, we conducted a comprehensive search across multiple databases including PUBMED, ClinicalTrials.gov, Cochrane Central, and EMBASE from January 1970 to July 2024. We identified publications reporting RCTs focused on VWD, and data were extracted on the number of participants, their gender distribution, the countries where trials were conducted, and the year of publication. Descriptive statistical analyses were performed to summarize these variables and explore trends over time. Results: We identified 20 studies encompassing a total of 2445 individuals with VWD. Among these trials, 46.6% of participants were male and 53.3% were female. The majority of RCTs, approximately 84.62%, were conducted in the United States, underscoring its leading role in VWD research. Germany represented 23.08% of the trials, followed by Italy with 19.23%. Austria and the Netherlands each accounted for 11.54% of the trials. Canada and Ukraine were also significant locations, hosting 11.54% of the trials each, while Japan and the United Kingdom hosted 7.69% each. Additional countries involved in trials included Australia, Argentina, Belarus, Bulgaria, Colombia, Croatia, Czech Republic, France, Hungary, Lebanon, Poland, Russia, Spain, Switzerland, Taiwan, and Turkey, each contributing 3.85% of the trials. Analysis of publication trends revealed that 50% of the RCTs were conducted between 1970 and 2011. The male-to-female ratio varied across different time periods: it was 1.3 for RCTs performed between 1970 and 2000, indeterminate for RCTs between 2001 and 2011 (with studies exclusively in females during this period), and 0.78 for RCTs conducted between 2013 and 2024, reflecting evolving gender distributions in VWD research over time. Conclusions: In conclusion, this study provides an overview of the landscape of RCTs in Von Willebrand Disease research from 1970 to 2024. The predominance of trials conducted in the United States underscores its pivotal role in advancing knowledge and treatment strategies for VWD globally. The fluctuating male-to-female ratio across different study periods highlights shifting demographic trends and emphasizes the importance of gender-specific considerations in clinical trial design and interpretation. Moving forward, continued international collaboration and diversity in trial locations are essential to further enhance our understanding and management of this challenging bleeding disorder. An important observation from this analysis is the varying male-to-female ratio over different periods, particularly noting a bias towards female participants in recent years. The discovery of an indeterminate ratio during 2001 to 2011, where only studies exclusively involving females were identified, suggests potential biases in participant recruitment strategies or study design preferences during that period. Moving forward, efforts to promote inclusivity and diversity in participant recruitment could help mitigate biases and ensure equitable representation across all demographic groups affected by VWD.

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