Sex bias in drug research: a call for change

The impact of an individual’s sex and their sex chromosomes on their health, experience of disease and response to treatment is just beginning of what needs to be studied and understood. It is only in the past decade that all medical research has been carried out on men, with no regard for any potential differences that might exist between the sexes. Evidence strongly suggests the assumption that both sexes will react in the same way has shaped a dangerous framework for medical research.

Scientific investigators traditionally focused on the male model for many reasons. The US National Research Act of 1974 instituted the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research as a consequence of the Tuskegee Syphilis Experiment, in which researchers knowingly withheld treatment to further the knowledge of disease progression. Subsequent to this, federal laws and regulations were enacted to protect human subjects in clinical investigations and, as a consequence, women of childbearing age became categorised as “protected subjects” to prevent unforeseen teratogenic harm to foetuses.

Furthermore, uncertainty surrounding whether women’s menstrual cycles and fluctuating hormones affect comparisons made between subjects led to the reliance on male animals and male subjects as the standards of research. Heightened risk, complexity and cost gave rise to the assumption that outcomes in men would be adequate proxies for outcomes in women.

By the late 1980s, understanding of sex and gender as they relate to human biology was being revolutionised. The National Institutes of Health (NIH) established a Public Health Service Task Force on Women’s Health, which began to shed light on the lack of knowledge of women’s health issues beyond reproduction, and that this was because of the lack of inclusion of women as subjects in research studies. As a result, a Clinical Equity Provision was included in the 1993 NIH Revitalization Act to ensure the efficacy of treatments for women would no longer be extrapolated from data derived from male participants but instead are scientifically determined. This legislation was the cornerstone of the science of sex and gender specific research.

Not the same

It may seem obvious that men and women are not the same. The human genome contains 23 chromosome pairs and one pair determines the sex of an individual — females are XX and males are XY. But sex chromosomes have other roles too. Let us think of it in a different way: how similar can women and men be if they have a completely different chromosome? The human genome of any two men is 99.9% identical. Similarly, the human genome of any two women is 99.9% identical. This means all of the phenotypic, environmental and hereditary differences between any two women or two men are accounted for by just 0.1% of their total genome.

According to David Page, director of the Whitehead Institute for Biomedical Research — a non-profit, independent research and educational institution — 98.5% of female and male genome is identical, suggesting that there is a tremendous amount of genetic information in the sex chromosomes controlling the development and function of not only sex organs and sex hormones, but also a myriad of biological attributes at every level of the organism: macro, micro, cellular and molecular.

Ignorant bias

Decades of ignorant bias cannot be solved by sprinkling a few women into clinical trials. True scientific research focusing on differences between women and men will require far more than enrolling women. From the initiation of research design, hypotheses must avoid assumptions of inclusivity hidden in language terms such as “subjects” or “patients”. Appropriate research methods and data analysis techniques will require disaggregation by sex and will report findings and establish appropriate conclusions that do not overgeneralise to populations that have not been studied^[1]
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Investigations that simply include both women and men in research studies without specifically formulating the design to detect differences by sex may, in fact, bias the results for both sexes. For example, Cao et al. found that foetal nicotine exposure during pregnancy was associated with the development of various psychiatric disorders and a potential for drug abuse during the child’s adolescence and that this propensity might be associated with effects on myelin gene expression. The relationship of nicotine to myelin gene expression turned out to be dependent upon the sex of the foetus: related genes were upregulated in male offspring and downregulated in female offspring^[2]
. If these outcomes had been pooled with consideration of the effect of sex, there would have been a null effect. Uncovering differences like these that are related to the sex of the research participant — whether human, animal or cell line — reinforces the need to expect and search for underlying processes, mechanisms and responses that may differ between sexes and to use this information to develop targeted, accurate and effective therapies for both women and men.

We must insist and ensure that women will be enrolled and properly studied in all future clinical trials of critical disease states for which sex differences are now known to be critical in defining pathophysiology, diagnosis, treatment and outcome, particularly for research into cardiovascular disease, stroke, sepsis, trauma, infectious diseases and mental health. In October 2015, the Government Accountability Office (a government agency that provides auditing, evaluation, and investigative services for the US Congress) reported that 57% of enrollees in all research the NIH was funding were women^[3]
. Before we rejoice in this statistic, it is important to understand that the NIH does not maintain, analyse, or report summary data to verify whether analysis of outcomes by sex are planned or even conducted. At this point, we cannot say that research trials are designed to identify potential differences in clinical outcomes by sex. Greater oversight is needed to ensure that research supported by the NIH will improve medical care and outcomes for both women and men.

Flawed practices

On 20 January 2015, US President Barack Obama announced the precision medicine initiative (PMI) in his State of the Union Address and called for US$215m in fiscal year 2016 to support the initiative. The PMI programme is designed to gain insight into biological, environmental and behavioural influences on diseases by supporting advances in research, technology and policies that help match individuals with tailored treatments^[4]
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The use of genetic information will certainly play a major role in certain aspects of precision medicine (e.g. pharmacogenomics) and investments into PMI programmes will accelerate biomedical discoveries. However, the ultimate goal of providing individualised and personalised, genomic patient care is far from the reality of healthcare delivery today. Instead, current practice is based on a ‘one-size-fits-all’ approach, which is grounded in research conducted on men. The size is male size; the chromosomes are XY; and the results may be irrelevant or harmful to women. Our current practice pattern is to order tests and prescribe medicines as we “wait and see”. Will the patient respond, recover or have side effects? Our flawed practices cannot and should not continue as we patiently await future evidence gleaned from hypothetical PMI programmes.

What can be done now

Researchers have the ability to design their studies using the knowledge we currently possess: sex and gender differences matter. Researchers must analyse and report these outcomes so that physicians are able to translate this information to the bedside immediately. The drug Ambien (zolpidem) is a perfect example. In 2013, the US Food and Drug Administration (FDA) recommended cutting the dose in half for women, but not men, after the results of driving simulation studies indicated women metabolise the drug at a slower rate. The FDA report came after 20 years of incorrect and dangerous prescribing of Ambien to women. Action was taken only after more than 700 reports of motor vehicle crashes associated with Ambien use that put the lives of many women, their children and other drivers on the road at risk^[5]
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The fact that one drug could have been so widely prescribed at a dangerous dose for half the population raises serious questions about the safety of our other current treatments and prescriptions. Certainly, research scientists will find it a daunting task to discover how many drugs that are currently in widespread use are underdosed or overdosed. We cannot allow the enormity of this task to keep us from carrying out the research while we continue to prescribe medicines that have unknown consequences for women.

We already possess the scientific ability to determine the differences in drug metabolism and dose response in women and men. This work must be done for each and every medicine currently in widespread use. First do no harm, as we are taught in medical, pharmacy and nursing schools. In this case we have practised ignorance but ignorance is no longer bliss, it is illogical and potentially harmful. There are no excuses left — half of our patients are women. They deserve the best that science and medicine has to offer.