Women have been underrepresented in clinical trials for a long time. There was this wrong notion that the only difference between men and women in terms of healthcare was just about their reproductive system. However many pathologies actually progress differently in men and women and even drugs might have distinct effects. Such differences should be explored to reach good quality and more equal healthcare provision. Let’s try to understand what changes should take place starting from the reflections of those who work in clinical research covering different roles.
Women are traditionally underrepresented in clinical research. Are the biological reasons that suggest not enrolling women still valid?
Caterina Caminiti Women’s participation in clinical trials is still inadequate and the restrictions limiting the enrolment of pregnant women or women of childbearing potential are partly responsible for this disparity. The biological reasons that are usually adopted, such as the risk of harming the foetus in case of pregnancy and the greater stability of male physiology are objective and consistent, but are not always justified, for example, by the actual teratogenic risk of the drugs under study. Today researchers are quite free to determine when to exclude women of childbearing potential or when to impose limitations on their participation by requiring them to use a specific contraception method. Quite often the reasons behind the exclusion or the limitation are not expressed nor are they supported by data from previous studies. The restrictions often seem disproportioned compared to the risk and are more motived by the concern for the legal responsibilities linked with the potential of harming the woman or the foetus than a real risk. Even though it is legitimate to be concerned about the accountability aspect, you should not ignore the principle of equality and the right to access clinical research. Furthermore, excluding women of childbearing potential from clinical trials lowers the ability to generalise the results of the study and exposes young women, who will eventually receive the treatments anyway, to completely unknown risks.
Quite often the reasons behind the exclusion are not expressed and they often seem disproportioned compared to the risk. They are more motived by the concern over legal responsibilities linked with the potential of harming the woman or the foetus than a real risk. — Caterina Caminiti
Therefore it is necessary to shift from an “implicit” type of decision-making process to the obligation to clearly state the biological reasons for the restrictions, in the study, the information sheet and the scientific publication, and support these with data from preclinical pharmacokinetic and pharmacodynamic studies. This would also be crucial to facilitate patients’ understanding and to support and improve their decision-making process, which might still result in them deciding to participate to clinical trials that have potential risks, for both personal and altruistic reasons.
Ursula Kirchmayer The reluctance towards enrolling women in clinical research is understandable when you think about the thalidomide scandal from the Sixties. Most have been very cautious since then, which meant excluding some population groups that were supposedly more at risk because of the clinical trials, thus creating data that could not be applied to the general population. At the same time, in clinical practice drugs that were not studied in some population groups are prescribed in case of serious conditions, leaving the responsibility of assessing the risk/benefit with doctors and their female or male patients. In the context of this limbo, post-authorisation studies, which utilise the information collected around the use of drugs in real clinical practice, have a very important role in completing the safety profile of a drug for the entire population, including the groups that were excluded from the trials.
Post-authorisation studies play a very important role in completing the safety profile of a drug for the entire population, including the groups that were excluded from the trials. — Ursula Kirchmayer
Therefore it is very important to incentivise the systematic and detailed collection of information on the use of drugs and any clinical outcomes in order to generate data on the risk/benefit of a new drug after it is put on the market and to activate real-time monitoring. An example of this would be the Sentinel initiative of the Food and drug administration.
Rita Banzi I don’t think there are biological reasons or lifestyle related factors that justify gender disparity in clinical trials. Studies should include groups that reflect a similar gender distribution of the target population that would utilise the treatment in clinical practice. It is important to read the gender disparity information present in the studies and compare this with the incidence of the studied condition and its gender-based mortality/morbidity. Greater inclusivity in the trials, especially those conducted on treatments meant for bigger population groups composed of men and women alike, would mean being able to generate data that can be better generalised to the context in which the treatment will be provided. Furthermore, the study of a more heterogeneous population enables researchers to identify and better investigate the effects of the treatment on subgroups where it is more or less active or more or less tolerated. Some conditions also present differently in men and women (for example some mental health conditions) so it is essential to collect data on both populations. Finally, women simply live longer than men so they tend to be more exposed- and for longer periods- to healthcare treatments.
Greater inclusivity in the trials would mean being able to generate data that can be better generalised to the context in which the treatment will be provided. — Rita Banzi
Carmen Mazzola From the research perspective, what companies could do to fill this gap is to focus on it in their approach to clinical trial designs but also at the preclinical stage, where they could study the biological mechanisms that lead to specific clinical presentations. Companies should have deep core knowledge of the biology and genetics associated to the treatment areas they are researchi
ng. Deep understanding of the subject would enable them to identify the target group that is more affected by that specific condition and whenever women make up a significant percentage of that group the study designs should reflect that. If a condition affects women three times as much as it does men this proportion should be reflected in the trials. That’s not all; any research conducted on women must take into account the hormonal context of the specific phase in the women’s life because this is another factor that definitively impacts their pathology and potential treatment outcomes. Therefore the process of designing research studies should begin with recreating conditions that are as close as possible to the real world ones.
Therefore the process of designing research studies should begin by recreating conditions that are as close as possible to the real world ones. — Carmen Mazzola
Do financial factors, such as the potential insurance costs, impact the decision to limit or prevent the enrolment of women or the ability to do gender-stratified analysis of the data collected?
Rita Banzi They certainly do. I think the main cause for the lower inclusion of women in clinical drug trials is the alleged and potential risk of problems linked to possible pregnancies, which would mean paying more for the insurance cover, and the need to plan for interventions that reduce the incidence of pregnancy during the trial. In my personal experience I had to negotiate aspects linked to insurance coverage for women of childbearing potential in really absurd and almost paradoxical contexts. One time it was with a trial on Alzheimer-associated dementia that had the following inclusion criteria: participants over 50 years, thus supposedly including a very small amount of patients of childbearing potential. The other time was with a non-pharmacological study of Covid-19 positive patients, where some insurance companies refused to even offer any coverage options because the research included both men and women.
How does gender-stratification benefit clinical research?
Caterina Caminiti Sex and/or gender-based analysis of the results is essential to improve accuracy and to avoid misinterpretation of data. Stratification increases the chances of identifying any significant effects, sheds light on at least part of the variability that cannot be explained, reduces confounding factors, increases repeatability and can reduce the overall number of experiments needed. It is important to integrate sex and/or gender-based analysis of the data since the planning stage of all research, not just in studies that focus specifically on assessing gender-based differences.
Overall the inclusion of sex and/or gender-based analysis in a research study is thought to require twice as many participants. However, that is not always the case. More efficient trial designs can incorporate both sex and gender while maintaining a control over variance. One of these strategies would be to adopt a factorial design, whereby the effect of two experimental factors with different levels is tested and data are collected on all the possible combinations of factors and levels. This enables you to assess the effect of each factor as well as the interaction between the various levels of the factors. In such cases you might need to increase the sample slightly, by 14-33 per cent, to account for the added parameter you want to assess, but it would not be necessary to double the number of participants.
How are clinical research methodologies changing in order to collect gender-based data?
Caterina Caminiti Despite the progress made around methods for gender-based analysis there are still various methodological challenges. For example, while sex is a biological variable that is well understood and analysed we cannot say the same about gender. The notion of gender (meant as psychosocial sex) is complex and multifaceted, and its application in the healthcare context often requires the collaboration of social sciences experts. In fact, we are still lacking a standard definition and a systematic method to assess the way gender interacts with health, also because it is not something you can easily translate into variables that you can analyse statistically. Some researchers tried to solve this issue. For example, a pan-Canadian study in Pelletier utilised a binary gender index (masculinity versus femininity) made of seven variables and it was discovered that the incidence of relapse and death 12 months after the diagnosis of acute coronary syndrome in young adults was associated to gender rather than biological sex.
Another methodology related challenge is about going beyond binary notions- female/male, women/men- to assess both sex and gender. In the United States 0.6 per cent of the population, almost 2 million people, identifies as transgender, and more than fifteen countries offer a third sex “box” on legal documents, birth certificates and passports. Research should keep up with the pace of social shifts and more efforts are definitively necessary to develop similar standardised measures.
This change is struggling to take shape because it would have to begin with questioning and upsetting social and financial norms, and power relations acting on areas that intersect and interact with one another, and it would require different types of practices that need to be given the adequate space. — Cinzia Colombo
Additional challenges include the assessment of other social variables (race, ethnicity, culture, socioeconomic status, etc.) and the way they intersect with sex and/or gender. Sex and gender are intertwined and cannot be isolated from other characteristics so we need models and methods that can help us understand these interactions. There is much work left to do in order to systematically integrate sex and/or gender analysis in research, ranging from strategic considerations to ascertain the research priorities to guidelines that establish the best practices to formulate research questions, design methodologies and interpret data. In order to make real progress, funding agencies, regulatory bodies and specialised journals should impose stringent limitations to avoid getting scientific discoveries that keep on ignoring the impact of sex/gender on health, generating distorted results that can harm part of the population- more often women.
Rita Banzi I think that there is more awareness of gender-based considerations when planning and designing the conditions of trials, at least in some clinical contexts. It is important that this awareness develops and grows to include biological aspects and also social and psychological ones, which are essential for the definition of gender identity. We need to be practical and collect scientific data on this as well.
Can artificial intelligence help to widen the admission criteria for trials without increasing the risk of toxicity to participants?
Ursula Kirchmayer I actually think that the use of artificial intelligence could generate data outside clinical trials. I am referring to the analysis of large data sets obtained from social media. In cases where the use of a drug was not studied in some subgroups due to its potential toxicity, tracing and analysing the information exchanged on social media might help to get data related to drug safety or to assess whether the results obtained from set population groups could be transferred to other ones.
Some believe it is necessary to get a “cultural shift”…
Rita Banzi It would benefit society as a whole, particularly the way the labour market is organised. I think the shift should be about creating a more open-minded view of inclusivity and collaboration, but usually it just ends up being about a war between the sexes that, frankly, seems to have little relevance.
Cinzia Colombo There should be a significant shift given the progress made in research- and other areas- through decades of fighting and advocating by women’s groups. Instead this change is struggling to take shape because it would have to begin with questioning and upsetting social and financial norms, and power relations acting on areas that intersect and interact with one another, and it would require different types of practices that need to be given the adequate space. Change needs collective action and crucial and necessary structural interventions as well as daily action involving areas such as education, employment, social networks, spaces and times dedicated to caring activities or to interactions with the medical and healthcare context. It might seem like a trivial thing to point out but it calls into question conditions that many women experience. During a webinar on discrimination against women I heard a colleague say, “We need to be alive in order to be healthy”. According to data from the ISTAT (the National Institute of Statistics) 111 women were killed in 2019 in Italy.
Carmen Mazzola In terms of cultural shift it would be ideal to get patients increasingly more engaged with choosing what research topics should be focused on and planning clinical trials. I’m thinking of women as expert patients involved in assessing outcomes that aren’t necessarily just clinical ones but also experiential ones, so that the value added by the adoption of a treatment can be assessed promptly, even before obtaining real world data.
The phenomenon of women underrepresentation that is typically observed in other fields of medicine does not take place in oncology. That’s a good thing. However, there are other underrepresentation phenomena that call into question the generalisation of data from registration trials in oncological contexts. — Francesco Perrone
What is the situation with regards to oncological studies?
Francesco Perrone The applicability of trial results onto clinical practice, once a new drug is approved by the regulatory agencies, is a very big concern in oncology. The features of the patients enrolled in clinical trials play a crucial rule because if they are representative of the population present in clinical practice there is a better rationale to use the new drug after it is introduced in the market. The phenomenon of women underrepresentation that is typically observed in other fields of medicine does not take place in oncology. That’s a good thing. However, there are other underrepresentation phenomena that call into question the generalisation of data from registration trials in oncological contexts. For example, it is demonstrated and recognised that in practice clinical trials include a much smaller group of old patients compared to what you then find in clinical practice. This happens either because of explicit age based exclusion criteria or, more often, because of researchers adopting a cautious approach and eventually excluding older patients who then risk experiencing side effects that are probably underestimated. It is one of the reasons why some oncologists committed to develop areas of research dedicated to older patients, with trials where they apply “opposite” age limitations as studies can only take place with patients who are older than a set age, usually 70 or 65 years. On one hand this strategy allows for the representation of older patients to be rebalanced and on the other hand it means that trials specifically focused on certain peculiarities of old age- such as concurrent disease, geriatric conditions and the resulting need to adapt drugs dosages and their means of administration- can take place.
Another lost battle?
In addition to the increased presence of women in clinical trials, there is also demand for plans that are more tailored to the needs of women and people from the LGBTQIA+ community. It is still an uphill battle.
I’ve been working in the healthcare sector for over forty years. I’ve always thought it was a priority to create changes that would lead to greater inclusion and respect for people, starting from acknowledging expertise and equal opportunities. Throughout my professional journey I’ve always been dealing with women’s needs in different areas. In the Lazio Region I’ve contributed to create the Guidelines for the Prevention and Fight Against Gender-Based Violence Affecting Women. Now I’m part of the Gender Medicine Group of the Italian National Institute of Health (ISS). Furthermore, I am the president of the Association for Women Who Underwent Breast Surgery (ANDOS) and a member of the Bollini Rosa committee of the Onda Foundation, for hospitals “designed for women”.
I acknowledge the fact that we’ve been fighting many battles for a socio-healthcare and healthcare system that pays more attention to women’s needs and that is more respectful of female workers. Some- though partial- progress was made. However, with the arrival of the pandemic unfortunately came a regression: many healthcare workers retreated behind their expertise; healthcare services and hospitals suddenly lacked the contribution of volunteering organisations. The healthcare emergency changed the order of priorities and that side notion, which enabled you to assess the needs of each individual person in their specific social context- no matter what this might be- faded.
Such lower level of attention to needs resulted in the overall regression of the system. The upsurge of violence impacting groups that are “weaker”- because they are disadvantaged in our society- demonstrates this. The weakest groups are made of women and all the people who identify as other genders, in a system that is no longer binary or should not be anymore. People from the LGBT+ community, those identifying as gender-fluid or other genders represent “minority groups” in the context of a healthcare system that does not look after them.
We all lose in a social system that does not guarantee equal rights and does not recognise diversity. This is the biggest social loss that we are responsible for, but it should also represent the starting point to change things.
Flori Degrassi
President of the Italian National non-profit Association for Women Who Underwent Breast Surgery (ANDOS)
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