A Balancing Act. Why We All “Prosper” from Gender Balance in Clinical Trials - Brendan Buckley

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tepco's chief medical officer, Brendan Buckley, joins the podcast to discuss women and cardiovascular disease. Earlier this year on world heart day, the tekrar editorial team posted a piece about how a bigger push needs to be made to address the clinical trial gender gap. This came after a study showed that women make up just 38% of participants in cardiovascular trials.

Now, Brendan is here to explain more about the importance of gender parity and how he was involved in a cardiovascular disease trial with perfect relative gender balance back in the 90s. If we go back to basics, the purpose of clinical trials is to determine whether a medicine works in practice for the population that are likely to require it. And in cardiovascular disease, women just as much as men get coronary artery disease and other cardiovascular conditions. So we need to study new medicines in women just as much as we do in men.

The problem has been over the years that clinical trials have been designed as much as possible to be completed quickly and to use as few participants as their statistical design will allow. And because men have cardiovascular event rates more frequently are more likely than women, investigators over the years have tended to pack their trial populations with men simply because men will get more heart attacks, more strokes and so forth. But it leaves a question then hanging as to whether their treatment can be regarded as being equally effective in women as in men. If there is no proof of that, so that's why this situation has evolved over time.

It's a matter of just the pragmatic logistics of getting the trial done quickly, but it does leave physicians wondering whether a treatment will be as effective in women. And we can't forget that there are significant differences hormonally, most obviously, which raise a question in relation to the transferability of data from men to women automatically. It's quite incredible

that you ran a trial with relative gender balance back in the 90s. Yet there are still so many hurdles to overcome when it comes to equality in trials today.

Could you explain more about the trial you were involved with? Back in the late nineties, a group of us designed a trial called prosper. This was a collaboration between the universities in Glasgow, Leiden and cork, and the question we wanted to ask was a very simple one. Statin drugs to lower cholesterol had been shown in a number of very large studies in middle aged men to prevent heart attack and stroke.

The questions that were left, however, from those very encouraging results were whether the drugs worked well in women and whether their effect continued beyond middle age. So prosper was designed to look at whether these drugs worked in the over 70s. We recruited the population between 70 and 82 years of age, and we balanced it, so the number of women in the trial exactly represented their proportion in the general population in that age group. So there was slightly more women than men in Prosper.

Overall, we had about 5,800 and of those, about 3,000 were women. The trial was designed basically to answer the question that any general practitioner might have if a 74-year-old woman worked and their surgery. Should I put this person on the statin? And what's the evidence that would persuade me to do so?

So that's how the trial was designed. It was a real world question to answer the conundrum that a GP would have with, say, a woman in her seventies, walking in with a history of family history of cardiovascular disease, something like that. So gender balance was really crucial to answer the question of our imaginary general practitioner in that situation. And the trial ran extremely well.

It was there was no difficulty in recruiting women and retaining them in the trial. And in fact, the retention rate of all participants in the trial was very high. And that's because we did it in a general practice setting rather than in hospital clinics. So

how did that work in practice?

If you were a participant in the trial, you toddled down to your local GPs office for your study visit and it was very conveniently done. So the whole study was set up in a very specific way to answer the real world question of a real world doctor. So this was somewhat unusual in the 90s. That's true up to that point.

And that was the great era also of the big blockbuster cardiovascular outcomes trials in which the end points were things like counting the number of heart attacks, strokes, deaths from heart attack that occurred in the trial population and pragmatically, just to get those trials to run efficiently with the smallest number of participants and the greatest number of outcome events. They tended to be done concentrated on men, but there were studies done on women. There was a very famous nurses study done, for instance, in Boston, but they tended to be the exception. And they were balanced by, studies say, on aspirin and cardiovascular prevention that were done in male American physicians.

There, generalizability to the overall population of men and women was questionable until we were able to do studies that involved women appropriately in appropriate numbers, most besides as well that ethnic groups were relatively poorly represented in that era in big studies of that nature. So

I've got to ask, what was the outcome of the proper trial? It showed very clearly that the treatment with the particular statin we used pravastatin decreased heart attack, stroke both in men and women in about two to about the same extent that was true about the relative risk reduction was about 25% So that was a fairly standard statin result lined up with all the previous statin studies.

But it was the first one really to, I think, have a study population, which was genuinely representative of people walking around outside there on the street. So

moving forward, what steps do you think can be taken to make sure women are not disadvantaged in clinical trials? I think it's very important that investigators think beyond the pure pragmatism of doing a study. I think the question that a trial fundamentally should seek to answer, especially at big phase III outcomes trial and specifically in cardiovascular disease, are and its related conditions like diabetes.

I think the questions to be answered should be generalizable to the overall population, so we really shouldn't ask questions of does this drug help men and then expect medical practitioners to say, well, it helps men, so it's probably going to help women as well. I think trials need to be designed specifically to include a representative proportion of the population. Increasingly, regulators are conscious of that as well, and their guidelines certainly draw attention to this necessity. But there is always a temptation to go for selected populations that have high event rates simply to allow the trial to be conducted more quickly and more smoothly.

But if they don't answer the fundamental questions of what does the average doctor do as a result of the trial, the trial to some extent must be regarded as being incomplete or even possibly failing to an extent. So we have to design stage, ask the immediate first question does the population that we're putting in here represent that which the average doctor is going to see? And does it include representation of women as they appear in the proportion in the population generally? So there's been a lot

of talk about hybrid or decentralized trials during the pandemic.

Do you believe that these types of trials can help with gender balance by providing more options for women? I think we've got to recognize when we design how we conduct any particular trial that the challenges that women have maybe somewhat different to those that men have, and particularly in relation to attending study visits. So child care is the one that really obviously stands out and the logistics of attending the study and conducting one's job and potentially childcare as well. These complicate life for study participants who are women.

No, they do so for some men as well, but I think the burden still realistically falls more on women than it doesn't, then. So I think trials that can be conducted closer to the participant where the. Participant lives, these are obviously an advantage compared with requiring a participant to get in the car, find parking in the large hospital, find their way through the hospital and all the time worrying about picking the kids up from school. So the decentralized model is fine in general, and hybrid trials work also very well and that they minimize those burdens on women in particular.

So in many ways, prosper was decentralized because it was moved to GPs offices with Prosper. We was probably one of the earliest trials that could be regarded as decentralized, but it was still conducted in study centers. Just happened to be that these were in the patients general practitioners office close by where they lived, and that made life a lot easier for them. So we moved the trial out to meet the patient rather than to meet the participant, rather than moving the participant at great inconvenience into a hospital car park and then onto the lift and then getting lost in the corridors.

And that contributed greatly to the success to the success of the study.

So we could expand this to all sorts of trials then, which is great news. We could do that, I think with a bit of part in some of those large outcome studies and diabetes and cardiovascular disease and what we're doing that we shouldn't forget that there are other minority populations that we should have in trials and that we thought we can increase their representation again so that doctors who are treating them can answer the question is this trial relevant to this patient?

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