Synopsis: Only about a third of research subjects in clinical studies are women. In basic research on animals and cells, female models are even more poorly represented. This results in poor understanding of how new drugs work on women and occasional drug recalls when major side effects are discovered after the fact. Experts discuss why such an imbalance occurs, its results, and how the problem is being addressed.

Host: Reed Pence. Guests: Dr. Teresa Woodruff, Director, Women’s Health Research Institute, Northwestern University; Dr. Melina Kibbe, Professor of Surgery, Northwestern University; Dr. Kathryn Sandberg, Director, Center for the Study of Sex Differences in Health, Aging & Disease, Georgetown Univeresity

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Gender Diversity in Basic Research

Reed Pence: Every now and then you hear about a drug being pulled off the market because of serious, unforeseen side effects. After millions of dollars invested in development and clinical trials, the drug’s promise is dashed. And often, it’s because a drug maker didn’t test the drug enough on women.

Teresa Woodruff: What they have seen over time is a profound impact on their bottom line. Eight of 10 drugs in a report for the general accounting office had been pulled from the market after FDA approval and post marking surveillance, because of the adverse events in women.

Pence: That’s Dr. Teresa Woodruff, Director of the Women’s Health Research Institute at Northwestern University.

Woodruff: Just last year there was the very notable case on Ambien, which is a well-known sleep aid. It’s been on the market for 20 years. It was pulled because of adverse events affecting women. For a man who took the drug at eleven o’clock at night it was cleared largely by six the next morning. For a woman who took the drug at eleven o’clock at night it didn’t clear her system until nine o’clock or ten o’clock the next morning. So, the adverse events were that women would still get up, but they would be sleepy and under the influence of the effects of Ambien. If we go back to that FDA filing where they showed that there was a difference in the clearance of the drugs for males and females, in that same FDA filing they said, ‘We don’t know the efficacy in females,’ and that’s because they didn’t’ test efficacy in females.

Pence: Ambien is back on the market now with labeling that instructs women to take half the dose for men. Dr. Melina Kibbe, Professor of Surgery at the Northwestern University Feinberg School of Medicine, says it’s the first time a drug has been labeled with different dosing for men and women.

Melina Kibbe: If this happens for Ambien, you have to ask yourself how many other drugs out there should have different dosing based on sex. I would say many, and this is where the FDA really needs to get involved. I would recommend that the FDA have much stricter requirements requiring equal enrollment of males and females in human clinical research, reporting the data by sex and analyzing the data by sex. We’re not there yet.

Pence: In fact, only about a third of clinical trial participants are women. Still, that’s better than it used to be. But Kibbe says equal enrollment isn’t enough. It makes no difference if the results are lumped together without an eye on differences in response.

Kibbe: It’s one thing to include men and women in a clinical trial, but then the problem is if you include both sexes, but you report the data in aggregate, then you won’t know if a drug had a better effect in men versus women. So, it’s really important to report the data as aggregate, but also to do sex based reporting of the data to show the effect in men versus women, and to analyze the data statistically by sex. That’s where we currently have a problem.

Pence: But that’s not the only one. If we’re considering a lack of representation of females as research subjects, Woodruff says we have to go back a lot earlier in the process than clinical trials.

Woodruff: There’s been a lack of inclusion of females in basic science. What that means is that the sex of animals in our basic science research funded by the federal government through the National Institutes of Health have not had that kind of attention.

Pence: So, even though clinical trials may include more females as study subjects, much of the work that goes on before that doesn’t. Dr. Kathryn Sandberg is professor, vice chair of research and director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University. She’s also chaired a panel advising the National Institutes of Health on the issue.

Kathryn Sandberg: If you’re thinking about the pipeline for new therapeutics, new drugs, new treatment paradigms, it all starts with pre-clinical research. That’s investigators like myself who work in a laboratory on animal models of disease or cellular models of disease. This is where we get our hints about what would be a good drug target. What most basic scientists have been doing in the past is using the male animal in models of disease; male animal models or cells from these animals. And that has biased the whole pipeline for drug discovery toward what’s optimal for the male.

Kibbe: Up until recently, there has been absolutely no guidelines at all or requirements requiring investigators to study novel therapies on male and female cells, and male and female animals. The majority of therapies that are developed from its infancy are pretty much tested on male cells or male animals, so by the time it makes it to the human studies we know that it works very well in the males, but we have no idea in female cells and female animals. This represents a problem for clinical trials, because at the most expensive end of the spectrum in human clinical trials is often times the first time it’s being evaluated in females.

Pence: Now, you might expect that there would be differences in animals between males and females. But a lot of basic scientific research is done on cells. Skin cells, heart muscle cells, kidney cells, and so on. You might not think there’s much difference between the male and female versions of those. But woodruff says think again.

Woodruff: What we’re talking about are the sex chromosomes — the XX and XY. That imprint of the chromosomal sex can have profound effects at the cellular level. We have hormonal effects, but we also have sex chromosome effects. It’s really important that, as a biomedical community, we appreciate that that’s strong biology. We’re talking about precision medicine or personalized medicine and the rise of genomic medicine. The biggest difference between the genomes is the X and Y chromosome content. Once the biomedical community understands this, it’s going to jump on it as a new opportunity for innovative new science, for paradigm shifting, for new mechanisms and concepts; it’s going to lead to a stronger, better pipeline of new research concepts that ultimately will be become tomorrow’s therapeutics or ways to counteract disease.

Pence: However, Kibbe says researchers have a long way to go before they include female models in equal numbers, or often even consider whether they do or not. Studies normally go to great lengths to describe the details of experiments — how long they took, the temperature cells were maintained at, and so on. But Kibbe’s review of animal and cell studies in five surgical journals shows that some information is routinely missing.

Kibbe: The first thing that shocked me in analyzing all these manuscripts was that a third of the manuscripts didn’t even state the sex studied. That surprised me. Then, when you actually look at the papers that reported the sex when using animals, 80% studied only males. When looking at cells, same thing — it’s about 70% studied only males. It’s really a significant problem. We also asked whether or not this practice of studying mostly males was getting better or worse over time. Again, an unexpected finding: we’ve actually gotten worse over time. In 1991, about 65% studied only males, in 2001, 72%, and in 2011, up to 85%, so it’s consistently gotten worse every decade.

Pence: But why? Why do researchers routinely ignore female animals and cells? Sandberg says researchers fall victim to myths just like the rest of us.

Sandberg: They are making the assumption that there’s no difference, that if we figure out the mechanism in the male, then we figure out a good drug target that it will also be good for the woman. The second reason is that scientists made an assumption, which is a myth, that if you study females you are going to have a lot more variability in your studies because females have hormonal cycles. This will mean you have to add a lot more animal groups. Scientists made the decision, ‘I don’t want to have so many animal groups; it’s going be much more expensive and much more time consuming to study. I’ll just study males, learn important things, and then apply it to females.’

Pence: Sandberg says many scientists accept that without question. But research has proven it’s not true. 

Sandberg: If you’re measuring that variability in the male and you compare it to the amount of variability in a female, you’ll find that, for most parameters, there’s more variability in the male than the female. This whole idea that you have to control for the hormonal cycle in your science is not true, but it’s been a myth that scientists have believed for a long time.

Pence: Finally, scientists are doing something about the situation. Some major scientific journals have begun requiring that researchers spell out the sex of a study’s subjects. And starting next year, a new policy at the National Institutes of Health will affect applications for funding of research on animals and cells.  

Sandberg: Come January, you’re going to have to explain in your grant application why you’ve chosen the sex of the animals or the cells that you are going to study, and what’s the reason behind it. If you are only going to study males you have to have a pretty good explanation. Otherwise, the peer review process will harm you and you will not be as competitive, and so you will not get funded.

Pence: However, those rules don’t affect all research. Privately funded studies, such as those done by drug makers, aren’t covered.

Woodruff: Pharmaceutical companies are not required to use females and males in equal numbers, or to study the differences, or to assess sex as one of the variables. My hope is that, with this attention on NIH federal funding, our pharma colleagues are also going to begin to look at sex as a real opportunity for increasing their bottom line. If they have drugs that have failed because they didn’t work in half the population, and now can tailor those drugs for males or females, in the end, that’s going to be good for their bottom line.

Pence:  So, yes, while Woodruff certainly sees the current situation as a problem, it could end up being even more of an opportunity.

Woodruff: We’re standing on the precipice of a revolution in biomedical science. Since there has been such paucity, such an absence of females as test subjects, or the sex chromosomes themselves being studied, once the doors are open to this whole new area, increasing the kind of science that can be learned, we’re going to learn so much more. I believe it’s going to revolutionize basic science. In the end, that is going to move forward into better clinical trials. We’re going to have better drugs that are going to be tailored to individuals. I see a real change in the next 10 years in the way we are experiencing health; science is going to lead the way towards a better appreciation of our own biology.

Pence:  You can find out more about all of our guests on our website, where you can also find archives of our programs. You can also find them on iTunes and Stitcher. I’m Reed Pence.

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