One of the aspects to consider when designing clinical trials, and often a quite controversial one, is the ratio of male and female study participants. There are a number of criteria that can have an effect on the ideal or actual gender distribution for a study.
In this article we review the legal situation, typical gender distribution in published studies, Profil’s considerations for our own studies as well as other aspects important when planning an early phase trial.
The conduct of clinical trials with investigational medicinal products is subject to strict legal requirements.
Since 1993 the US Food and Drug Administration (FDA) has demanded that both genders are included in clinical trials [1] – the determination of potential gender differences within clinical studies was prescribed by law in the EU in 2001 and in Germany in 2004 [2, 3]. Good Clinical Practice (GCP) requires a justification for the chosen gender distribution [4].
A restriction in early phase clinical studies is that only the inclusion of post-menopausal or surgically sterilized women is allowed [5, 6]. Pregnant and lactating women as well as children and adolescents rank among vulnerable groups – special safety precautions are in place for them, limiting possible study participation (5).
In preclinical research however, the use of animals of both sexes is required in order to generate data with the highest possible predictive value for human use [7].
A review by Khan S. U. and colleagues [8] looked at the participation of women in clinical trials on lipid-lowering therapies. Sixty trials with a total of 485,409 participants were included. Overall, women’s participation rate was 28.5%. An increase in the inclusion of women could be observed from 1990-1994 (19.5%) to 2015-2018 (33.6%). The review also confirmed common eligibility criteria, e.g. to only include surgically sterilized or postmenopausal women (28.3%) or to exclude pregnant (23.3%) and lactating women (16.6%).
Compared with their disease burden, women were underrepresented in clinical trials on lipid-lowering drugs in the field of diabetes, heart failure, stable coronary artery disease and acute coronary syndrome.
Another publication [9] investigated the proportion of females in 740 completed cardiovascular trials registered in clinicaltrials.gov comprising 862,652 participants, of which 38.2% were women – from 2010 until 2017. Male participants prevailed overall. However, the proportion of women – varying depending on the disease and the kind of trial – had particularly increased in stroke trials and heart failure studies.
In contrast, two phase 3 clinical trials with COVID-19 vaccines showed a more or less balanced gender relation (49.4% and 47.3% women) [10, 11].
Profil is a full-service CRO conducting early phase clinical trials in diabetes, obesity and related diseases. The EMA guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus [12] states that “ideally, treatment groups should be sufficiently balanced with respect to age, gender, body mass index, severity and duration of disease“.
At Profil we perform first-in human (FIH) / first-in patient (FIP) studies in full compliance with regulatory requirements, and trial participants are carefully selected to avoid any unnecessary risk. The well-being of study participants is the top priority in all studies at Profil. Such FIH/FIP trials frequently exclude women of child-bearing potential due to non-availability of longer-term preclinical data on fertility and on human embryos and foetuses at that time [6, 13].
We always strive for a well-balanced gender relation when recruiting adult healthy volunteers or study participants with type 1 or type 2 diabetes for clinical trials. Nevertheless, a number of reasons may lead to the inclusion of a higher rate of male trial participants.
One of these could be related to glucose clamp trials, investigating the time-action profile of novel antidiabetic drugs, mostly novel insulins. In fact, men rather than women usually volunteer for this kind of trials. Moreover, the clamp procedure requires several in-dwelling venous cannulas to be placed at the participant’s forearms/ arms – thus, sufficient venous access is prerequisite for clamp participation and is often better in men.
Bioequivalence studies evaluating novel biosimilar insulin preparations might be a further reason. More male participants have been included in these trials as well.
The EMA guideline on biosimilar insulins [14] states “the study population should be homogenous and insulin-sensitive to best detect potential product-related differences and may consist of normal-weight healthy volunteers or patients with type 1 diabetes“. In addition, the guideline says “insulin sensitivity in women may vary during the menstrual cycle and it is unclear whether this may affect study results. Thus, inclusion of only men in the studies might be preferable“ [14].
These aspects highlight the importance to weigh against each other the different requirements from the various guidelines as well as the other impacting factors in order to satisfy all requirements and at the same time ensure high quality data.
As mentioned before, the men/women ratio in clinical studies is also of importance for other reasons. Thus, today within the clinical development of novel medicines gender differences are taken into account in a comprehensive way [1-4]. Drugs or investigational medicinal products dedicated solely for men or for women have become available, as the underlying diseases primarily affect men or women. In the case of women these are, e.g. breast cancer and ovarian cancer, in the case of men prostate cancer or haemophilia have to be mentioned – and of course the respective medications to treat these diseases [15].
Besides, clinical trial data should also provide information on whether there is a different response to a drug by women compared to men. One would like to learn from clinical studies about any gender-specific effects or potential adverse reactions of a given drug.
To sum up, the topic gender relation in clinical trials comprises several aspects – these should be paid particular attention to when planning and performing clinical trials. Keeping safety aspects in mind, a further increase in the trial participation rate of females is desirable, also with respect to a sufficient recruitment of trial participants.
References
[1] Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Federal Register 1993; 58 (139): 39406-16.
[3] Zwölftes Gesetz zur Änderung des Arzneimittelgesetzes vom 30. Juli 2004. Bundesgesetzblatt Jahrgang 2004 Teil I Nr. 41, ausgegeben zu Bonn am 5. August 2004: 2039
[4] GCP-Verordnung vom 9. August 2004 (BGBl. I S. 2081), die zuletzt durch Artikel 8 des Gesetzes vom 19. Oktober 2012 (BGBl. I S. 2192) geändert worden ist: 5.
[8] Khan SU et al. Participation of women and older participants in randomized clinical trials of lipid-lowering therapies – A systematic review. JAMA Network Open 2020; 3(5):e205202. doi:10.1001/jamanetworkopen.2020.5202
[9] Jin X et al. Women’s participation in cardiovascular clinical trials from 2010 to 2017. Circulation 2020 Feb 18: 141: 540-548
[10] Polack FP et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020; 383 (27): 2603-2615
[11] Baden LR et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021: 384 (5): 403-416