Despite representing 49.7% of the global population, on average females make up only 41.2%* of clinical trials.
The problem gets worse when we delve into specific disease areas. 51%* of cancer patients are female, but they make up only 41%* of clinical trial participants. When it comes to psychiatric conditions the underrepresentation is starker still; females represent 60%* of the patient population, and a mere 42%* of clinical trial participants.
While females are increasingly well represented in Phase 3 studies where the proposed new treatment is compared to the current standard treatment, they remain under-represented in the earlier stages of clinical trials. This is a problem. At Phase 1 of a trial we learn crucial information about the safety of the proposed treatment, what dosage level is optimal and using which delivery method. At Phase 2 we learn how effective the treatment will actually be and for which specific diseases.
Why it matters
The lack of representation of females in clinical trials proportionate to their share of the disease burden is not just unfair, it’s life threatening.
Worse health outcomes for women
As Charlotte Davis highlighted in the first in our series, the failure to include a sample of women that is representative of their share of the specific disease burden in Phase 1 & Phase 2 clinical trials results in us lacking the data that would otherwise enable us to understand and therefore address the physiological, hormonal and cellular differences that we know exist in women.
“This sex inequality hides in plain sight today: most drugs are prescribed to women and men at the same dose. Many currently prescribed drugs were approved by the US Food and Drug Administration (FDA) prior to 1993, with inadequate enrolment of female animals in preclinical research and of women in clinical trials“.
As Zucker and Predergest highlight, widely used sleep medication zolpidem (Ambien) used to be prescribed to females and males at the same dose. The standard dose produces much higher blood concentrations and longer drug elimination times in females than males. In practical terms, the consequence is serious side effects in females including increased traffic accidents the morning after taking the medication. It was only after discovering that sleeping medication may have contritbuted to 500,000 ‘excess deaths’ in the US in 2020, that the FDA stepped in forcing manufacturers of zolpidem to half the dose prescribed to women.
Women missing out on effective treatments
As Caroline Criado Perez explains in her seminal book, Invisible Women, a research round-up found that five times as many research studies exist on erectile dysfunction than PMS. As a result, there is a range of effective treatment for erectile dysfunction and very little available for PMS.
In 1989 sildenafil citrate, the medical name for Viagra, was created and initially tested as a treatment for heart disease. The participants in the study, all of whom were male, reported an increase in erections. By March 1998 Viagra had been approved by the FDA to treat erectile dysfunction. The rest, as they say, is history. But not so for women. In 2013, a double-blind, randomised, controlled trial of sildenafil citrate on females suggested that sildenafil (Viagra) provided effective pain relief for PMS. Unfortunately the funding ran out, meaning researchers did not meet their sample size, and could not confirm their hypothesis. And so, to this date, we still lack effective treatments for PMS.
Money left on the table
Within three months of its launch, Viagra had already earned Pfizer $400 million USD, and has consistently generated sales of around $1.8 billion. This is just the tip of the iceberg. By failing to represent females at a level commensurate to their share of the disease burden in Phase 1 and 2 clinical trials, imagine what other potentially life changing treatments females are missing out on, and how many billions of dollars pharmaceutical companies are missing out on making.
Why are women still under-represented in clinical trials?
The reasons women are under-represented in clinical trials are multiple and complex, here are just a few:
Exclusion criteria
Exclusion criteria exclude females in disproportionate numbers to males. Women of child-bearing age are often excluded from clinical trials because of concerns that drugs could harm foetuses. And, because women on average live longer than men, upper age limits disproportionately exclude women.**
Top-down approach to trial design
The location of clinical trials tends to be determined by where trial investigators and research hospitals are located, rather than by where the population who carries the disease burden is located. Participation in clinical trials can involve the participant travelling long distances and taking substantial time off from work and care-giving responsibilities. This has a disproportionate impact on women, who are paid less on average than men, so are less likely to be able to afford to take the time off work and take on a larger share of the care-giving responsibilities.
Bias in diagnosis pathways
Healthcare professionals are statistically less likely to recognise female risk factors and symptoms than males.
The bleeding disorder Hemophilia is a condition that affects both males and females. However, women with moderate Hemophilia receive a diagnosis 6.5 months later than men. This is despite the fact that women are more likely to notice symptoms of a bleeding disorder than men.
A woman is 50% more likely than a man to receive the wrong initial diagnosis for a heart attack***.
On average it takes 7 to 8 years for women to be diagnosed with endometriosis. 40% of women have 10 or more GP appointments before they are referred to a specialist.
Since it takes longer for women to get an accurate diagnosis, their opportunity to discover and get onto clinical trials that could help them is diminished.
Data gaps
Since there is currently less research done on females than males, it is difficult for pharmaceutical companies to ascertain exactly how much money they could make from funding research into treatment for women’s health issues, PMS being one example. What is more, not all of the clinical trials that do include females disaggregate female and male data. So, even when we include females, we miss out on collecting vital data about sex differences that could result in breakthrough treatments or be the difference between picking up on a physiological difference in side effects between females & males or missing it.
Working towards an equitable future
It’s clear that the status quo is not good enough. So, what can be done to shift the dial towards an equitable future for women?
The potential solutions are many and several. There is no silver bullet, but there are a number of actions we can take, which cumulatively will lead to a more equitable future. We list some of them below:
Recruit more women into clinical trial leadership
Most trials are led by white men. However, trials led by women are proven to have better odds of reporting on and enrolling underserved populations****.
Take a citizen centric approach to trial design
Reduce the burden of participation on women. Where possible, de-centralise clinical trials, enabling participation from home, or locating them where the people who carry the disease burden live and work so they don’t have to go out of their way to participate. Where de-centralisation isn’t possible, install facilities that will enable people to take time out of care-giving responsibilities on site e.g. creches.
Pictured: The Astra Zeneca Heart Bus – taking HFpEF research to patients
Educate on and challenge gender bias
Educate health care professionals and trial investigators on gender bias and hold people accountable to biased and discriminatory behaviour. Until we reach a point where women are diagnosed as efficiently and accurately as men, there is not level playing field for accessing clinical trials.
Empower women
Empower women to collect data on their symptoms, advocate for their health, demand better treatment and find and participate in clinical trials.
Balance is a menopause app that enables women to track and evidence their symptoms, and use the data to demand treatment from their healthcare providers.
Touch is a black breast cancer charity co-founded by CEO Ricki Fairley, who works tirelessly to empower black women to recognise the symptoms of triple negative breast cancer, advocate for their own healthcare, demand better treatment, and match them to clinical trials.
Time for change
It’s clear that the status quo is not good enough, women remain without adequate medical treatment for a plethora of health conditions, and money that could be made developing drugs to give us better health outcomes is being left on the table. It’s time to act.
Want to know more about how to better represent women in clinical trials? You can catch Lucy at: Women’s Health Innovation Summit on 26th-27th April, in Basel, Switzerland. Want help addressing a lack of diversity and inclusion within your sphere of influence? Get in touch: hello@kinneirdufort.com
References:
*Analysis by Primavera Spagnolo, HMS assistant professor of psychiatry at Brigham and Women’s of data from ClinicalTrials.Gov of 1,433 trials with 302,664 participants over a four year period
**Exclusion of Older Adults and Women from Recent Trials of Acute Coronary Syndromes (nih.gov)
***Sex Differences in Cardiac Risk Factors, Leifheit-Limson et al (2015) | Bias and Biology, BHF
****Trial leadership by women is associated with racial diversity among heart failure clinical trial participants: a systematic bibliometric review 2000–2020 – European Heart Journal – Oxford Academic (oup.com)
Balance: balance-menopause.com
Touch: touchbbca.org
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