Gender differences and clinical trial design

When thinking about gender differences and clinical trials, the first idea that generally comes to mind is the inclusion of limited numbers of women in all phases of clinical investigation. While this still holds true for several disciplines, we should realize that the problem is much more complex and will not be solved by the simple achievement of a 50:50 distribution of participants’ gender. Historically, women of childbearing age had been excluded from clinical trials after the thalidomide tragedy. More then 10,000 babies born to mothers who had taken the sedative and antiemetic during pregnancy developed severe malformations, including limb abnormalities and internal organ defects [1]. In the aftermath of this event and in an attempt to protect all unborn life from unknown drug side effects, all fertile women were banned from participation in clinical trials – pregnant or not. While surely protective against potential teratogenicity, the ban appeared less protective of womens’ health. When analyzing the drugs withdrawn by the US FDA due to severe and potentially life-threatening side effects in the years 1997–2000, of the ten drugs withdrawn, four cases were due to the increased incidence of torsade de pointes [2]. This represents a typically female side-effect, which roots in the biology of the female heart conduction. Females tend to have physiologically longer QT intervals, which might be further elongated by the influence of sex hormones. Drugs acting on the myocardial conduction will further this physiological mechanism, putting women at increased risk for conduction arrhythmias. Most importantly, the medications leading to this specific adverse event can hardly be predicted by their class; for instance cardiac medications as well as those prescribed for unrelated systems can lead to increased arrhythmia frequency [2]. Women appear to report increased frequencies of adverse events in most studies conducted to date. Reasons for this might be of multiple origins, including missed dosage adjustment, the potential influence of hormonal factors, increased frequency of comedication and possibly a tendency to report more side effects, maybe due to differences in perception of these side effects. The largest meta-ana lysis looking at this phenomenon was conducted by Martin and colleagues in 1998. The authors analyzed 48 cohort studies, including a total of 513,608 patients (55% women) and identified an age-standardized relative risk of an adverse reaction of 1.6 (1.5–1.7) in females compared with males [3]. These imbalances in side-effect distribution have been brought to the attention of major international regulatory agencies; most importantly the FDA in the USA and EMA in Europe. These agencies have reacted at different moments in time, the FDA guideline being published in 1993 [101] and the EMA guideline in 2005 [102]. While distinct in their formulations, both recommend the inclusion of sufficient numbers of subjects of both sexes in clinical trials, possibly at percentages adequate in representing the prevalence rates within the general population. The agencies have then conducted separate surveys to address the inclusion of both genders in clinical “...if we extend our gender-sensitive research beyond the well-regulated trial setting we might identify variables we would have never considered otherwise, and these might benefit all participants, not just women.”