The Hypocrisy

Exclusion of Men from Breast Cancer Clinical Trials

“It defies logic for researchers to acknowledge gender difference by claiming women’s hormones can affect study results – for instance, by affecting drug metabolism – but then to ignore these differences, study only men and extrapolate the results to women.” -- Leslie Laurence and Beth Weinhouse, Outrageous Practices (1994)

It only took a few minutes of clicking to find what I was looking for – a clinical trial for breast cancer that excluded men. Next, I cross-checked this study on the ClinicalTrials.gov website with the NIH RePORTER website, which lists details of studies funded by the U.S. National Institutes of Health (NIH). Yes, this one was funded by the NIH, and it excluded men.

NIH is the biggest public funder of biomedical research in the world. In 2022, the NIH spent 43 billion dollars on research to improve human health. Of this total, approximately 550 million was spent on breast cancer research.

As a physician-scientist funded by the NIH for nearly 20 years, I knew the written and unwritten rules for obtaining grant funding very well. It was essential that you made a Herculean effort to include both sexes in your research, or your study would not be funded. Excluding men from their clinical trial was a big ‘no, no’. But this practice had become accepted in breast cancer research. How had they gotten away with it?

I thought I knew the answer but wanted to review in my head the history that had gotten us to this place. As an obstetrician and researcher, I had been spent two decades advocating for the inclusion of pregnant women in research studies and clinical trials. The exclusion of women in research had been the status quo until the mid-1980’s. The idea was that women might become pregnant and any research involving drugs might either harm a fetus or their future fertility. Out of an abundance of caution, it was thought best to exclude them. 

This policy resulted in all women being excluded from clinical trials regardless of their age, pregnancy status, use of contraception, and desire for future fertility. The drug trials for HIV in the 1980’s afforded a real opportunity for people to benefit from antiretroviral drugs before they were FDA approved. Women were excluded from these trials, which became a rallying point for activists and sparked protests.

It wasn’t until 1989 that NIH “encouraged” the inclusion of women and minorities in research. If women were excluded, scientists were expected to state their scientific rationale. The next year, the Congressional Caucus for Women's Issues asked the General Accounting Office to investigate whether this new policy resulted in the inclusion of more women in research. In short, it hadn’t. The investigation found that the NIH policy had been inconsistently applied and poorly communicated. So, Congress passed a law in 1993 to mandate NIH inclusion of women and minorities.

The push for research to equally study the interaction between disease and a person’s sex came in 2016 with a new policy called the NIH Policy on Sex as a Biological Variable. It wasn’t enough to simply include both men and women in research anymore. Scientists needed to plan their research and the way they would analyze the data to learn how the disease or their intervention impacted men and women differently.

“NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in vertebrate animal and human studies. Strong justification from the scientific literature, preliminary data, or other relevant considerations must be provided for applications proposing to study only one sex.” – NIH Policy on Sex as a Biological Variable

I remember sitting on an NIH “study section” that reviewed grants in 2016, shortly after the policy was put in place. Any grant that didn’t have a plan for studying sex as a biological variable was immediately docked one point, which was enough to move a grant destined for funding into the reject pile.  

These policies were designed to prevent exclusion of women from biomedical research funded by the NIH. But could NIH-funded clinical trials exclude men? By the rules, the researchers would need a very strong scientific rationale for doing so. For example, one might argue that the biology of male breast cancer was so vastly different from that in women that it represented a completely different disease. From what I had read, this would be difficult to argue.

NIH Clinical Research Center in Bethesda, Maryland

Yes, male breast cancer didn’t respond as well to certain drugs used in women. But wasn’t this a rationale to include them in clinical trials so that we could figure which drugs would and wouldn’t work in men? In fact, this was the point of the NIH policy on studying sex as a biological variable in research. So that we could discover why cancer-fighting drugs might work differently in men and women. I began to get worked up and a little angry.

Turning my attention back to the breast cancer study that excluded men, I began to dig a little deeper. I read through the study synopsis and reviewed the inclusion and exclusion criteria. Before I leapt to judgment, I wanted to see it from the point of view of the scientist running this study.

As a researcher, I knew it was scientifically cleaner to design a study with only one sex. Male breast cancer was a rare disease, making up only 1% of all the breast cancer diagnoses. Including them might result in very few male participants; whether they could be analyzed in the same group as women was unclear. However, this would not be a rationale accepted by the NIH to exclude men according to their policy.

Possible reason number two. It would make the study less expensive by not investing funds to recruit men with breast cancer into these studies, who would require more effort to track down and include. Ironically, the idea of reducing costs was part of the thinking in the 1970’s to exclude women from research. It was argued that it would cost too much to include women in drug research because one would need to determine whether they were pregnant and using appropriate contraception. Including only men in biomedical research would be more cost efficient. This was no longer an acceptable reason to exclude women in research per NIH policy. Nor men, for that matter.

I decided to ask the study’s lead researcher and the NIH program official administering the grant why men had been excluded from the study. It took only a few minutes to find their emails and compose a few lines of text.

My question was simple. Why were men excluded from this study on the impact of exercise on breast cancer? What was the scientific rationale for their exclusion? I ended the email with a note that I was an NIH-funded researcher looking for clinical trials in which my husband could participate. If nothing else came of this, I wanted them to know that men with breast cancer existed. And deserved equal access to the breast cancer clinical trials designed for women.

Now, I would sit back and wait for their response. Even if the lead researcher chose not to respond, the NIH program official would be compelled to review the exclusion of men by this study and whether it had broken the NIH policy. At least I hoped that it would have this effect.