Pharma & drug development

Is a lack of female participants skewing heart disease trial results?

Heart disease is one of the leading causes of death in men and women, but women are commonly under-represented in clinical trials. Could this negatively impact the treatment of female patients, and if so, what is the industry doing to encourage more female participants to enrol? Abi Millar finds out.

Heart disease is a major health concern for both men and women. According to the British Heart Foundation, there are currently around seven million people living with heart and circulatory conditions in the UK – breaking down into an even gender split of 3.5 million men and 3.5 million women. Twice as many women die from coronary heart disease (the leading cause of heart attacks) as from breast cancer.

Despite these statistics, heart disease is often overlooked as a prominent female health issue. Especially because the disease tends to present differently in women, this is grounds for concern. There is a danger they will end up not only with male-skewed information, but male-skewed treatment, potentially leading to poorer clinical outcomes.

According to a recent study in the Journal of the American College of Cardiology, the skew extends to cardiovascular research too. The study found that women are under-represented in clinical trials for heart failure, coronary artery disease and acute coronary syndrome. (They are proportionately represented in trials for hypertension and atrial fibrillation and are actually over-represented in trials for pulmonary arterial hypertension.)

As Dr Janet Woodcock, study author and director of the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) explains, unrepresentative clinical trials can have implications for patient care.

“In my opinion, it’s about the basis of the variability of human response to drugs,” she says. “In some cases, sex is very important and in other cases it isn’t. In cardiology, though, there are issues relating to the different presentation of men and women with certain syndromes. The concern there is that women might be excluded because they present differently.”

Participation of women in clinical trials

In this study, researchers looked at 57 successful clinical trials that took place between January 2005 and September 2015. These trials – all for cardiovascular conditions – led to 36 FDA approvals for 35 drugs.

For each disease area, the researchers looked at the numbers of women and men participating, and calculated the participation to prevalence ratio (PPR). They arrived at this figure by dividing the percentage of women among the trial cohort (participation) by the percentage of women in the disease population (prevalence). The closer the figure was to one, the closer each trial was to proportional representation.

“What we have said is that anything from 0.8-1.2 is in that acceptable goal range,” says Dr Marjorie Jenkins, another of the study authors, who serves as director of medical initiatives and scientific engagement at the FDA Office of Women’s Health.

She adds that the study had three main objectives. Firstly, the researchers wanted to get the measure of women’s participation in clinical trials. (The proportion of women enrolled ranged from 22% to 81%, averaging out at 46%, while the PPRs per disease area ranged from 0.5-1.4.)

They also wanted to confirm the drugs were safe and efficacious for their target users, both men and women. Finally, they wanted to look into the trials’ inclusion and exclusion criteria (where available) to find out how that affected participation.

Despite women’s slight under-representation, the other aspects of the study yielded more positive conclusions.

“We found that the drugs are indeed safe and efficacious for the populations in which they’re going to be utilised,” says Jenkins. “Then we went back to that granular inclusion-exclusion data, and found that women are not disproportionately excluded because of these criteria as compared to men. So those were the focuses of the work.”

Reasons for the gender gap

The real reason for the gender skew, concluded the researchers, was less to do with clinical trial inclusion criteria, and more to do with the lower number of women referred for pre-trial screening. This means factors prior to screening are likely to blame.

“We believe the cardiology community itself needs to do more to evaluate what would identify women as subjects for clinical trials,” says Woodcock. “We’re hypothesising that somewhere in that pre-screening pipeline, there are influences there that are disproportionately excluding women.”

While the researchers themselves did not explore those influences, they think there might be a few possibilities.

“There are several reasons that are common in the literature,” says Jenkins. “These include caregiver responsibilities, transportation, geography, socioeconomic status, and comorbid medical issues. There is also some work that suggests women may be making decisions in conjunction with their partner or family, while males may tend to say yes at the ask.”

She adds that oftentimes, women are not asked to participate in clinical trials.

“The data show that the majority of the time women aren’t asked, but that when they are asked and when they do enroll they complete the trials at an equal or greater rate than men,” she says. “So that’s something of a culture change that we need to help spread the word about, to discuss with patients opportunities for clinical trials.”

Movement toward diversity

Moving forward, the study authors expect we will see further movement towards proportionality in cardiovascular clinical trials. While progress has been made in narrowing the gap, there is clearly still some way to go. Woodcock believes the shift will be tied to broader social changes.

“I think there are cultural changes in our society with a new generation of clinicians coming forward who have been trained differently,” she says. “What we found in the paper is that it’s within clinicians’ purview who they ask to enroll in a clinical trial, so as society changes I do think these disparities are going to narrow.”

Jenkins adds that both gender (the social construction) and sex (the biological variable) are relevant in this instance.

“There is a breadth of evidence out there regarding sex differences in cardiovascular disease,” she says. “A lot of research is being done in this arena, so the more science we have, the better able we’ll be to make those decisions across the board for patients and consumers.”

Of course, as we move into an era of personalised medicine, and drugs are laser-targeted at certain populations, sex differences won’t be the only issue at stake.

“In some areas the under-representation of racial and ethnic groups is much more severe than the unbalanced treatment of women,” says Woodcock. “There may be genetic differences in response to therapies that are more striking among those groups, so you have to think what are the underlying causes of variability in treatment response.”

Jenkins agrees that clinical trial cohorts need to be diverse, reflecting the populations that will actually use the products.

“Our work represents the most recent and robust study regarding participation of women in clinical trials, and it supports that FDA approved drugs for the conditions we studied are both safe and efficacious for men and women,” she says. “But while this is the case, we do recognise that we have more work to do in the area of engaging and recruiting women in clinical trials. The more data we have the better informed we will be.”

This article appears in the November 2018 edition of Pharma Technology Focus

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