The following article investigates several systematic reviews into sex and gender representation in individual clinical trial patient populations. In these studies sex ratios are assessed and evaluated by various factors such as clinical trial phase, disease type under investigation and disease burden in the population. Sex differences in the reporting of safety and efficacy outcomes are also investigated. In many cases safety and efficacy outcomes are pooled, rather than reported individually for each sex, which can be problematic when findings are generalised to the wider population. In order to get the dosage right for different body compositions and avoid unforeseen outcomes in off label use or when a novel therapeutic first reaches the market, it is important to report sex differences in clinical trials. Due to the unique nuances of disease types and clinical trial phases it is important to realise that a 50-50 ratio of male to female is not always the ideal or even appropriate in every clinical study design. Having the right sex balance in your clinical trial population will improve the efficiency and cost-effectiveness of your study. Based upon the collective findings a set of principles are put forth to guide the researcher in determining the appropriate sex ratio for their clinical trial design.
Sex difference by clinical trial phase
- variation in sex enrolment ratios for clinical trial phases
- females less likely to participate in early phases, due to increased risk of adverse events
- under-representation of women in phase III when looking at disease prevalence
It has been argued that female representation in clinical trials is lacking, despite recent efforts to mitigate the gap. US data from 2000-2020 suggests that trial phase has the greatest variation in enrolment when compared to other factors, with median female enrolment being 42.9%, 44.8%, 51.7%, and 51.1% for phases I, I/II to II, II/III to III, and IV4. This shows that median female enrolment gradually increases as trials progress, with the difference in female enrolment between the final phases II/III to III and IV being <1%. Additional US data on FDA approved drugs including trials from as early as 1993 report that female participation in clinical trials is 22%, 48%, and 49% for trial phases I, II, and III respectively2. While the numbers for participating sexes are almost equal in phases II and III, women make up only approximately one fifth of phase I trial populations in this dataset2. The difference in reported participation for phase I trials between the datasets could be due to an increase in female participation in more recent years. The aim of a phase I trial is to evaluate safety and dosage, so it comes as no surprise that women, especially those of childbearing age, are often excluded due to potential risks posed to foetal development.
In theory, women can be included to a greater extent as trial phases progress and the potential risk of severe adverse events decreases. By the time a trial reaches phase III, it should ideally reflect the real-world disease population as much as possible. European data for phase III trials from 2011-2015 report 41% of participants being female1, which is slightly lower than female enrolment in US based trials. 26% of FDA approved drugs have a >20% difference between the proportion of women in phase II & III clinical trials and the prevalence of women in the US with the disease2, and only one of these drugs shows an over-representation of women.
Reporting of safety and efficacy by sex difference
- Both safety and efficacy results tend to differ by sex.
- Reporting these differences is inconsistent and often absent
- Higher rates of adverse events in women are possibly caused by less involvement or non stratification in dose finding and safety studies.
- There is a need to enforce analysis and reporting of sex differences in safety and efficacy data
Sex differences in response to treatment regarding both efficacy and safety have been widely reported. Gender subgroup analyses regarding efficacy can reveal whether a drug is more or less effective in one sex than the other. Gender subgroup analyses for efficacy are available for 71% of FDA approved drugs, and of these 11% were found to be more efficacious in men and 7% in women2. Alternatively, only 2 of 22 European Medicines Agency approved drugs examined were found to have efficacy differences between the sexes1. Nonetheless, it is important to study the efficacy of a new drug on all potential population subgroups that may end up taking that drug.
The safety of a treatment also differs between the sexes, with women having a slightly higher percentage (p<0.001) of reported adverse events (AE) than men for both treatment and placebo groups in clinical trials1. Gender subgroup analyses regarding safety can offer insights into the potential risks that women are subjected to during treatment. Despite this, gender specific safety analyses are available for only 45% of FDA approved drugs, with 53% of these reporting more side effects in women2. On average, women are at a 34% increased risk of severe toxicity for each cancer treatment domain, with the greatest increased risk being for immunotherapy (66%). Moreover, the risk of AE is greater in women across all AE types, including patient-reported symptomatic (female 33.3%, male 27.9%), haematologic (female 45.2%, male 39.1%) and objective non-haematologic (female 30.9%, male 29.0%)3. These findings highlight the importance of gender specific safety analyses and the fact that more gender subgroup safety reporting is needed. More reporting will increase our understanding of sex-related AE and could potentially allow for sex-specific interventions in the future.
Sex differences by disease type and burden
- Several disease categories have recently been associated with lower female enrolment
- Men are under-represented as often as women when comparing enrolment to disease burden proportions
- There is a need for trial participants to be recruited on a case-by-case basis, depending on the disease.
Sex differences by disease type
When broken down by disease type, the sex ratio of clinical trial participation shows a more nuanced picture. Several disease categories have recently been associated with lower female enrolment, compared to other factors including trial phase, funding, blinding, etc4. Women comprised the smallest proportions of participants in US-based trials between 2000-2020 for cardiology (41.4%), sex-non-specific nephrology and genitourinary (41.7%), and haematology (41.7%) clinical trials4. Despite women being
proportionately represented in European phase III clinical studies between 2011-2015 for depression, epilepsy, thrombosis, and diabetes, they were significantly under-represented for hepatitis C, HIV, schizophrenia, hypercholesterolaemia, and heart failure and were not found to be overrepresented in trials for any of the disease categories examined1. This shows that the gap in gender representation exists even in later clinical trial phases when surveying disease prevalence, albeit to a lesser extent. Examining disease burden shows that the gap is even bigger than anticipated and includes the under-representation of both sexes.
Sex Differences by Disease Burden
It is not until the burden of disease is considered that men are shown to be under-represented as often as women. Including burden of disease can depict proportionality relative to the variety of disease manifestations between men and women. It can be measured as disability-adjusted life years (DALYs), which represent the number of healthy years of life lost due to the disease. Despite the sexes each making up approximately half of clinical trial participants overall in US-based trials between 2000-2020, all disease categories showed an under-representation of either women or men relative to disease burden, except for infectious disease and dermatologic clinical trials4. Women were under-represented in 7 of 17 disease categories, with the greatest under-representation being in oncology trials, where the difference between the number of female trial participants and corresponding DALYs is 3.6%. Men were under-represented compared with their disease burden in 8 of 17 disease categories, with the greatest difference being 11.3% for musculoskeletal disease and trauma trials.4 Men were found to be under-represented to a similar extent to women, suggesting that the under-representation of either sex could be by coincidence. Alternatively, male under-representation could potentially be due to the assumption of female under-representation leading to overcorrection in the opposite direction. It should be noted that these findings would benefit from statistical validation, although they illustrate the need for clinical trial participants to be recruited on a case-by-case basis, depending on the disease.
Takeaways to improve your patient sample in clinical trial recruiting:
- Know the disease burden/DALYs of your demographics for that disease.
- Try to balance the ratio of disease burden to the appropriate demographics for your disease
- Aim to recruit patients based on these proportions
- Stratify clinical trial data by the relevant demographics in your analysis. For example: toxicity, efficacy, adverse events etc should always be analyses separately for male and female to come up wit the respective estimates.
- Efficacy /toxicity etc should always be reported separately for male and female. reporting difference by ethnicity is also important as many diseases differentially affect certain ethnicity and the corresponding therapeutics can show differing degrees of efficacy and adverse events.
The end goal of these is that medication can be more personalised and any treatment given is more likely to help and less likely to harm the individual patient.
There is room for improvement in the proportional representation of both sexes in clinical trials and knowing a disease demographic is vital to planning a representative trial. Assuming the under-representation is on the side of female rather than male may lead to incorrect conclusions and actions to redress the balance. Taking demographic differences in disease burden into account when recruiting trial participants is needed. Trial populations that more accurately depict the real-world populations will allow a therapeutic to be tailored to the patient.
Efficacy and safety findings highlight the need for clinical study data to be stratified by sex, so that respective estimates can be determined. This enables more accurate, sex/age appropriate dosing that will maximise treatment efficacy and patient safety, as well as minimise the chance of adverse events. This also reduces the risks associated with later off label use of drugs and may avoid modern day tragedies resembling the thalidomide tragedy. Moreover, efficacy and adverse events should always be reported separately for men and women, as the evidence shows their distinct differences in response to therapeutics.
1. Dekker M, de Vries S, Versantvoort C, Drost-van Velze E, Bhatt M, van Meer P et al. Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency. Frontiers in Medicine. 2021;8.
2. Labots G, Jones A, de Visser S, Rissmann R, Burggraaf J. Gender differences in clinical registration trials: is there a real problem?. British Journal of Clinical Pharmacology. 2018;84(4):700-707.
3. Unger J, Vaidya R, Albain K, LeBlanc M, Minasian L, Gotay C et al. Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials. Journal of Clinical Oncology. 2022;40(13):1474-1486.
4. Steinberg J, Turner B, Weeks B, Magnani C, Wong B, Rodriguez F et al. Analysis of Female Enrollment and Participant Sex by Burden of Disease in US Clinical Trials Between 2000 and 2020. JAMA Network Open. 2021;4(6):e2113749.