Men are from Mars, Women are from Venus –remember that book? It was published in 1992, and although it was really talking about relationship issues between the sexes, it seems to hint at other, more physiological differences that underpin the disparity -differences that have sometimes been overlooked, or perhaps ignored, in many pharmaceutical drug studies. http://www.cbc.ca/news/health/sport-exercise-menstrual-cycle-1.3618140
The justifications seem reasonable at first glance. There are cyclic changes in women –alterations in the hormonal milieu that make it difficult to standardize conditions for studying the drug in question. For example, progesterone is only found in women after ovulation, and this might alter the metabolism or effect of the drug being studied. Or estrogen –the quintessential female hormone- might alter the effects of the study drug differently than the testosterone milieu of men. Might alter the risks. Indeed, the CBC article quotes Georgie Bruinvels, the lead author of a paper in the British Journal of Sports Medicine: “Evidence actually suggests that women are almost twice as likely to have an adverse reaction to a drug than a male counterpart,” she said. In fact, a U.S. accountability study found “80 per cent of drugs there are withdrawn from the market due to unacceptable side-effects on women.”
And then, of course, there is the risk of inadvertent exposure of an unexpected fetus to the study drug. So why take the chance? Well, for a start, except for pregnancy of course, the sexes share most of the same problems: heart disease, hypertension, diabetes, strokes, arthritis, pain… to name just a few. But if the drugs created to combat these conditions are only tested on men, the information obtained may not apply to women. At the very least, doses may have to be altered. For example, ‘In 2013, the U.S. Food and Drug Administration released a safety announcement about the sleep aid, zolpidem, also known as Ambien. It recommended the bedtime dose be lowered for men and women. It also warned that women are more susceptible to risks associated with the medication because they metabolize the drug at a slower rate than men.’
In Canada, there is an attempt to rectify the gender bias in studies: ‘[…] a policy of the Canadian Institutes of Health Research requires researchers to say how they are dealing with sex and gender when applying for research grants.’
But the issue of sex biased research applies not only to human studies, believe it or not. It can even apply to animal surrogates studied to provide drug data –laboratory mice: http://www.cbc.ca/news/technology/mouse-sex-studies-1.3545486 The same reason -hormonal cycles- is the reason given for choosing male mice as subjects, although the validity of this justification has been questioned. And the results of using male mice has had similar, if not more severe, repercussions: ‘A stomach drug called cisapride that was sold in the 1990s under the name Prepulsid was withdrawn by Health Canada in 2000 because it sometimes caused irregular heartbeat and sudden death “in women only”.’
Or, take Jeffrey Mogil, a neuroscientist and pain specialist at McGill University who ‘estimates that in pain research, 80 per cent of published studies use male mice or rats, even though 70 per cent of people with chronic pain are women.’ And further, ‘Published studies on male mice showed that blocking immune cells called glial cells could block pain. When Mogil repeated the studies on mice of both sexes, he found they worked in male mice, but not females.’
There has been an attempt to rectify this bias: ‘The Canadian Institutes of Health Research, the main federal funding agency for health and medical research, has been trying to address the sex bias in rodent research. Since 2010, researchers have been required to answer questions about whether they will account for sex in their studies.’
Given the need for drug data on both sexes before the resulting medication or therapy is safely released to the general public, what can be done? Well, in most well-designed studies, there are two groups: the group given the medication, and a ‘control’ group who is, as much as possible, identical to the studied group. The general idea is to decrease the number of variables to a minimum, so that the only difference in the study group is the drug.
So, to start with, the study could be partitioned according to the menstrual cycle in women –with the use of a simple blood test to check for progesterone if there is any doubt, or if the menstrual cycle is sufficiently irregular or unpredictable. Thus, after controlling for such things as weight, other medications, health, and past history (as one would do anyway to establish control groups) three arms to the study could be included to address the disparities: 1. Men –knowing that they would have minimal estrogen on board; 2. Women –a). pre-ovulatory (i.e. no progesterone in blood) and b). post-ovulatory women (progesterone in blood). Of course, given that there would also have to be matching controls, this would add extra costs –and probably time- to complete the study. But I would imagine these would be counterbalanced by the costs of developing a drug that might have to be withdrawn from the market for unexpected side effects -on women, say– not to mention any resulting law-suits or ethical considerations held against the company.
And what about inadvertent pregnancy exposures to the drug? Oral contraceptives themselves may interfere with the study drug metabolism so either women on this type of contraception could be added to the study as yet another arm or, more feasibly, women using other reliable, non hormonal contraceptives could be enrolled, including women who have had a surgical sterilization procedure (e.g. tubal ligation).
All of these permutations and combinations may seem daunting, and yet surely the validity and applicability of the study results are what count in the end. As Mahatma Gandhi once said: ‘It is health that is real wealth, and not pieces of gold and silver.’ I just wish he’d said it louder.