Sex differences and women’s representation in clinical trials

women clinical trials
© iStock/alvarez

Professors Irving Zucker and Brian J Prendergast tell us about the impacts on women of sex biases in clinical drug trials.

In 1993, the US National Institutes of Health (NIH) introduced its Revitalization Act, which mandates that Phase 3 clinical trials funded by the NIH must actively include women and minority group subjects, where this is appropriate to the research. Nearly three decades on, female representation remains minimal in studies on both human and animal subjects; while many trials which do include female subjects do not then acknowledge sex differences in their data analysis or results: a 2015 review of 107 randomised controlled trials (RCTs) featuring male and female subjects found that only 26% of the trials reported outcome by sex or recognised sex as a variable. The remaining 74% omitted sex from their analyses entirely.

In their new study, ‘Sex differences in pharmacokinetics predict adverse drug reactions in women’, published in the Biology of sex differences journal in June, University of California, Berkeley Professor Irving Zucker and University of Chicago Professor Brian J Prendergast examined the frequency of adverse drug reactions (ADRs) experienced by women in comparison to men. The authors explain: “Women experience adverse drug reactions nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics (PKs) predict sex differences in ADRs.” HEQ speaks to Professors Zucker and Prendergast about female representation in drug trials and the disproportionate impact on women of failing to account for sex differences in clinical data.

Women were long excluded from clinical trials due to concerns over the effects of fluctuating hormones on data; and even now many studies on both human and animal subjects do not fully analyse sex differences in data. What do you think are the reasons behind this? What could be the wider benefits to clinical research of disaggregating data by sex?

The exclusion of women of childbearing potential from clinical drug trials was influenced by adverse effects of drugs on pregnant women (for example, thalidomide and diethylstilbestrol produced birth defects and increased cancer risks, respectively). The unsubstantiated belief that hormonal variations associated with menstrual and oestrous cycles render females more variable and difficult to study than males has been refuted in multiple studies. The assumption, also now discredited, that results from investigations of men apply without modification to women contributed to the marked underrepresentation of women in drug trials. Stipulation by the US National Institutes of Health that study protocols must include both sexes is a good prescription to increased participation of females in biomedical research; but a number of studies which enrol both males and females do not then disaggregate data by sex and thus fail to uncover novel sex-specific drug treatments that can benefit both women and men.

Could the difference between men and women in terms of the effects of drugs be a contributing factor to higher rates of opioid addiction among women than men?

Opiate addiction rates are higher among women than men and reflect sex differences in pharmacokinetics. Plasma oxycodone concentrations are 25% higher in women than men given the same standard dose, even when adjusted for body weight. Women are more sensitive to the positive subjective effects of oxycodone even though they experience significantly more side effects. Opiate consumption to cope with negative affect and pain is significantly greater in women than men for oxycodone and hydrocodone. Morphine attenuates cardiovascular reactivity in an ischemic pain task in men but not in women; women are significantly more likely to experience emesis and nausea and more likely to manifest respiratory depression after morphine treatment. The existence of sex differences in opioid pharmacology merits increased attention.

Your study found sex differences in adverse drug reactions even after correcting for sex-based differences in body weight – what other biological differences between men and women could account for the differing drug responses?

Women generally have a lower body weight and organ size and a higher percentage of body fat, affecting absorption and distribution of drugs. Drug clearance is strongly linked to sex-specific expression of metabolic enzyme systems and renal clearance of drugs is decreased in women because of a relatively lower glomerular filtration rate. Women have a slower gastric emptying time and lower gastric pH, lower plasma volume, body mass index, average organ blood flow and total body water differences, all of which affect drug distribution and pharmacokinetics. Responses to drugs are also affected by physiological changes during the menstrual cycle.

What actions can clinical researchers and drug manufacturers take, both at the research stage and once a drug goes to market, to ameliorate differing effects of drugs by sex?

Credible evidence of sex differences in pharmacokinetics and adverse drug reactions should be made available in drug labels. For drugs with higher female pharmacokinetics, the initial dose should be lower for women than men and increased only if the lower dose fails to achieve the desired therapeutic effect. Establishing sex parity in the drug approval process should be explicitly identified as a long-term goal. Pharmaceutical companies should pay more attention, beginning in the early drug development phases to sex-appropriate dosing.

Professor Irving Zucker
Departments of Psychology and Integrative Biology
University of California, Berkeley
Professor Brian J Prendergast
Department of Psychology and Committee on Neurobiology
University of Chicago

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