Until relatively recently, women were rarely included in clinical trials, and because of this there is a lack of evidence-based information about how to treat women. It was believed that the only differences between women and men were in the reproductive system, and researchers also preferred to work with male mice because they had – allegedly – a less complicated hormone system than female mice.
The impact of this is profound. Because women as a group were left out of many medical studies, women experience adverse effects from medications at twice the rate of men. Despite living longer than men, women spend 25% more of their lives managing chronic illnesses because of these historical gender biases in medicine.
Today, we know that biological sex can have an impact on how likely we are to get certain diseases, on how our body responds to disease and presents symptoms, and how we react to different medications. And we know that these differences are not just confined to the ‘bikini zone’ – the reproductive system. But yet, there is an immense knowledge gap about women’s health, which if filled could boost the global economy by USD 1 trillion (EUR 0.88 trillion) according to a recent report by McKinsey.
Improving the proportion of women in clinical trials
In the EU, an evaluation of 22 marketing authorisation dossiers submitted to the EMA between 2011 and 2015 revealed that women were underrepresented in phase III trials for treatments for schizophrenia, hepatitis C, hypercholesterolemia, HIV and heart failure. To tackle this, the EU Clinical Trials Regulation was passed in 2014, stating – amongst other things – that subjects participating in clinical trials should represent the gender and age groups that are likely to use the medication.
The IHI READI project is working directly on improving diversity in clinical studies. This project aims to develop a holistic, integrated system to ensure that underrepresented groups, including women, are included in clinical trials. The move will help address health disparities and enhance research quality.
Safe medicine use for pregnant and breastfeeding women
If you’re pregnant or breastfeeding, little is known about which medicines you can take safely. For good reasons – safety concerns for young and unborn babies – pregnant and breastfeeding women have been routinely left out of clinical trials. This means that clinicians often have to make judgment calls on whether a woman should continue to take medications when pregnant or breastfeeding based on scarce and anecdotal information.
The ConcePTION project reasoned that a large amount of real-world data exists regarding medicine consumption during pregnancy or breastfeeding, and that this data should be harnessed to yield evidence-based insights that could help to guide clinicians’ decisions.
Amongst other things, the project:
- created the first Europe-wide breast milk biobank for research purposes;
- developed tools to predict which drugs are likely to be transferred to breast milk, investigating 10 compounds ranging from medications for migraine to neuropathic pain;
- established a web-based drug information knowledge bank;
- created an app, Meds4Mums2B, for safety information exchange
- created a data pipeline for pharmacoepidemiology studies based on real-world data sources. Moreover, the EHR data pipeline was already being used for more than 15 EMA-requested multisite studies (including COVID-19 vaccines) by multiple networks
Combating cancers that primarily affect women
Some diseases only affect women, and due to the knowledge gap in women’s health there is often an incomplete understanding of the underlying mechanisms of those diseases, how likely a woman is to get these diseases, and what the best treatments might be.
Breast cancer is the most common cancer experienced by women, and one in four women will be diagnosed with it before the age of 75.
New cell therapies (such as CAR-T therapies) are showing promising results, but they come with some unique challenges – these treatments often have side effects all over the body, some of which are tolerable and some of which are not. The complexity of cell therapies also means that the human body can sometimes respond in unexpected ways.
The imSAVAR project developed the first breast cancer-on-chip model tailored to cell therapy testing for safety and efficacy.
“CAR-T cell therapy has already shown exceptional success in the treatment of blood cancer and many clinical trials are underway for solid tumors. In this respect, the breast-cancer-on-chip model provides us with a scalable and explorative platform to evaluate CAR-T cell therapy in the field of gynecological oncology,” says Miriam Alb of the University Hospital of Wurzburg, who led imSAVAR’s work on immuno-oncology models.
The model will help researchers to determine whether CAR-T therapies will be safe and effective for women, or whether adjustments are needed. The model developed incorporates a suite of the body’s cells, giving a more realistic picture of how the body could respond to the cell therapies.
“There is a critical need for predictive human model systems, particularly in women’s health research,” says Peter Loskill, head of organ-on-chip research at the Eberhard Karls University Tübingen, who is working on the imSAVAR project. “Organ-on-chip technology presents a promising solution to bridge this gap, and our breast-cancer-on-chip model facilitates the development and testing of novel therapeutic strategies.”
imSAVAR is not the only project delivering results that will help fight breast cancer. The IMMUCAN and PERSIST-SEQ projects are also shedding light on the mechanisms behind resistance to immunotherapy in breast cancer, while OPTIMA is using real-world data and AI to help clinicians figure out the most appropriate treatment for individual breast cancer patients. Two new IHI projects, ACCELERATE.EU and ILLUMINATE, are investigating how theranostics – an innovative branch of treatment where a diagnostic test and a therapy that bind to the same target are paired up and administered to the patient – could be a novel way to treat breast and ovarian cancer.
Advancing research on autoimmune diseases that primarily affect women
One way that women’s bodies differ from men’s is that women develop a much stronger immune response to infections than men. However, this also means that that women are more prone to developing autoimmune or inflammatory diseases. We have 15 projects covering different autoimmune diseases. For instance, PRECISESADS discovered a new molecular classification of Systemic autoimmune diseases such as rheumatoid arthritis, Sjögren’s syndrome and lupus, which will facilitate the delivery of precision medicine.
Sjögren’s disease is a chronic autoimmune condition that predominantly affects women – studies indicate that over 90% of patients are female. There is a particular urgent need for research focused on improving outcomes for women with this disease, and the NECESSITY project is directly addressing this need.
By identifying novel biomarkers and developing patient centric clinical endpoints, the NECESSITY project is redefining how primary Sjögren’s disease (pSD) is diagnosed and managed. This is particularly impactful given how the disease can present itself in many different ways and how challenging it is to make a correct diagnosis on time.
“Sjögren’s disease overwhelmingly impacts women, and the NECESSITY project is paving the way toward more personalised and timely care. By developing tools that better capture the patient experience and disease progression with specific measures to incorporate how this disease affects women, we are directly improving outcomes for women across Europe,” said Professor Seror of the Hopitaux de Paris and Paris Saclay University, who led a NECESSITY study on how Sjögren’s patients could be categorised into different subgroups to help deliver more targeted and personalised treatments.
“With its multidisciplinary and patient-centered approach, NECESSITY is not only advancing scientific understanding but also ensuring that women living with autoimmune diseases receive the care they deserve,” she continued.
Learning more about how autism affects women
Not all diseases look the same in men and women. One example is autism – it presents differently in women compared to men, and because of that it has been historically underdiagnosed and much less is known about how autism affects women compared to men.
The AIMS2TRIALS project delved deeper into the biological basis of the sex differences and compared the brains of women with autism to men with autism and compared those to non-autistic brains as well. They found that the neuroanatomy of both autistic male and autistic female brains more closely resembled a non-autistic male over a non-autistic female. The project also examined symptoms of autism, like how much attention a person pays to faces and social interactions, and found that women looked at faces more than men regardless of whether they had autism or not. However, certain face-looking patterns did emerge when comparing autistic women to non-autistic women and autistic men to non-autistic men.
Future opportunities for research
Looking towards the future, we spoke to four representatives of the Netherlands Women’s Health Research and Innovation Center at Erasmus MC about what the research priorities for women’s health should be.
Investigating the benefits that a proper understanding of hormones could bring represents a unique opportunity, they said.
“We need to flip the conversation about hormones,” said Hanneke Takkenberg, professor of clinical decision-making in cardio-thoracic interventions at Erasmus MC and co-founder of the Netherlands Women’s Health Research and Innovation Center. “We need to find out more about hormones and use that information in a positive way, potentially as a source of treatment or as a way to protect against disease.”
Greet Vink, the director responsible for smart health tech at Erasmus MC who is also a co-founder of the Netherlands Women’s Health Research and Innovation Center, pointed out that studies have shown that female footballers get injured more often during the ovulation phase of their menstrual cycle. This might indicate that we need to re-think at which stage of the menstrual cycle should knee or hip surgeries be carried out on women.
Cardiovascular disease is another area where more research into sex-based differences is urgently needed. The most frequent causes of death amongst women in Europe are cardiovascular diseases, accounting for 43% of all deaths. Yet most of the existing cardiovascular treatments have been tested on men and are not ideal for women.
Stents, for instance, are generally designed for use in the arteries where men commonly experience blockages. But in women, blockages are more often seen in the microvascular arteries, which are smaller and more difficult to revascularise.
And even investigating whether heart disease is present poses risks.
“The diagnostic tools that are currently used to tell whether someone has a heart problem or not can actually provoke spasms and heart attacks in women,” says Jeanine Roeters van Lennep, internist in vascular medicine and co-founder of the Netherland Women’s Health Research and Innovation Center at Erasmus MC. Better tools that are designed with women patients in mind could address that.
Another challenge on the horizon is that AI tools, which are being used more and more for medical research, are being trained on the male-biased data that has been used up until now.
“We are making the same mistake again,” says Vink. “The data we are using for AI is full of biases. This presents a risk for women.”
AIMS2TRIALS, ConcePTION, imSAVAR, IMMUCAN, NECESSITY, OPTIMA and PERSIST-SEQ were supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.