GRSJ224/Gender Bias In Clinical Trials

For decades, women of childbearing age have been excluded from clinical trials for fear that drugs could harm a fetus. As a result, trials were mostly conducted on men, and those results were then extrapolated to apply to women. This is problematic because diseases cause different symptoms in men and women, and treatment that work on men may not necessarily work on women. Other reasons that are often cited for the exclusion is that women have more variance in hormones, which makes it more complicated and expensive to study, and that if women and men require different dosage requirements, it will make the marketing of the product more difficult. These are not new arguments, and shows the lack of progress on this issue.

History

Fears about taking drugs during pregnancy are not unfounded. In the past 50 years, there were two major tragedies that led to this stigma: Thalidomide, and DES.

Thalidomide

In 1956, Thalidomide was released as a drug for morning sickness. It was advertised as extremely safe and became an over-the-counter drug in many countries. In 1962, it was discontinued after it was established that thalidomide causes birth defects. By then, worldwide usage of the drug caused ~8,000 - 12,000 babies were born with a birth defect. It was later revealed that the original clinical researchers for thalidomide suppressed reports of side-effects. This caused widespread panic and a sigma of taking pharmaceuticals in pregnant women was created.

DES

DES was a synthetic oestrogen drug released in the 1940s that became FDA approved to prevent miscarriages. It had over 200 papers published stating its effectiveness in acne, cancer treatment, and health during pregnancy. In 1953, the original research on DES was overturned when another study couldn’t replicate its results, however the study did not find any harm in the drug so it was still allowed to be prescribed. In 1970, after more research, the drug was discontinued after was confirmed that prenatal exposure to DES can cause cancer. While its discovery did not result in the same widespread panic as thalidomide, it confirmed the risk that women should not be taking drugs while pregnant.

After Thalidomide and DES

After the tragedies of thalidomide and DES, regulations and research guidelines changed worldwide. In the US, clinical research regulations labeled pregnant women as “vulnerable populations” alongside children and prisoners. In 1977, the FDA established guidelines that excluded any women of childbearing age (post puberty and premenopausal) from participating in clinical trials, except for the last stage. By the 1990s, the effects of excluding women from pharmaceutical tests were becoming apparent so since then, policies have been created to encourage more testing on women. A 2014 Canadian research guideline explicitly requires a justification for the exclusion of any pregnant woman from a trial, and a 2020 US guideline from the National Institute of Health (NIH) recommends the participation of pregnant women in research. Despite the mounting policies to include pregnant women in clinical trials, in reality, many ethics board will still nearly automatically reject a pregnant woman. There is an established norm that it’s better to be safe than sorry, and that taking drugs during a pregnancy is always a risky behaviour.

Systematic Review of Bias

A systematic review of clinical trials conducted for antipsychotic drugs found that out of 132 trials, only 36.11% of total participants were women, only 3 trials discussed the drug's effect on gender, and none of trials included any analysis of the drug's interaction with hormonal contraceptives. When analysis by gender was done, it was done post hoc, not planned into the design of the trial from the beginning. This means the results and dosage of the trials will be generalized to apply to women, but for antipsychotic drugs that remain in the body for a long time, this makes it harder to adjust adverse reactions.

Bias in Animal Studies

Animal studies form the foundation of many human trials, so a bias in animal studies will have an effect on women's healthcare. A study in 2009 on 2000 animal studies found that many are still avoiding using female animals. For example, anxiety and depression are twice as likely to occur in women, but less than 45% of the studies

on anxiety and depression used female animals. Women are more at risk for stroke, but only 38% of stroke studies used female animals. One reason for the prejudice against female animals is the belief that female animals will create more variance in the data due to their reproductive cycles. However, a meta analysis conducted in 2005 found no additional variance between female and male rats.

How to Correct Gender Bias

Stringent measures need to be put in place by regulators and journal editors to highlight and curb the gender imbalance. The National Institute of Health (NIH) requires sex equity in clinical trials and analysis need to be performed on a gender basis. Journal editors can request those who only used one gender exclusively to put put that in the title of their paper, and this will encourage researchers to use a more balanced sample. We also need ways to encourage women to be willing to participate more. Trial researchers need to persuade pregnant women that it is safer to take drugs in a trial with a controlled environment and follow-ups, than it is to take drugs at home that are "prescribed off label".