Gender Bias?

It is one of the sad facts of medical research that, until recently, women have been either neglected or specifically excluded from research studies. This has meant that information about appropriate treatment of diseases and reactions to drug therapy was based on studies conducted only on men.

The exclusion of women from drug trials was, in part, the result of the thalidomide tragedy of the 1950s. Thalidomide was approved in Europe for control of nausea during pregnancy. What was not known at the time was that the drug could cause severe skeletal deformities in the developing fetus. Twelve thousand infants were born with phocomelia, a birth defect in which the upper portion of the arms or legs are missing, leaving the hands or feet attached to the body by a short stump. Even in Canada, there were an estimated 100 cases of thalidomide-associated birth defects. In the United States, Dr. Frances Kelsey of the US Food & Drug Administration (FDA) blocked the distribution of the drug – not because of advance awareness of the birth defects, but because the drug had demonstrated effects on the nervous system.

Concern over the risk of a repeat of the thalidomide episode led the FDA, in 1977, to recommend that women of childbearing potential be excluded from drug research. The intent, although benevolent, was clearly based on the false assumption that there is such a thing as a generic human being, and that studies conducted in adult males could be freely extrapolated to other patient populations, including women, children, and the elderly. For example, a 1989 study of the use of aspirin as the first-line treatment of cardiovascular disease specifically excluded women. It was not until 1992 that two studies showed that the benefits of aspirin were greater in men than in women.

Most of the differences in drug response between women and men can be accounted for by some obvious factors: body size, amount of body fat (women have more), and age. But there are also less easily explained differences in gender-specific drug responses. According to the Society for Women's Health Research, there appear to be differences in the activity of liver enzymes between men and women. Since the effects of enzymes vary with different types of drugs, this can result in major differences in drug response. Some drugs are called pro-drugs, with no activity until they're changed to an active form by the liver. More often, drugs are metabolized and inactivated by the liver. Regardless of the result, sex-specific differences in enzyme activity can lead to sex-specific differences in drug response. This difference in liver activity may explain why women routinely wake from general anesthesia several minutes before a man, given an equivalent dose, would waken.

Implications for Pain Management

Some of the most interesting observations of the sexes' different reactions to therapy appear in the area of pain management. Women feel pain, particularly the pain of migraine headaches and arthritis, more intensely than do men. And while men have a better response to non-steroidal anti-inflammatory analgesics (NSAIDS, such as Motrin and Naprosyn) than women, women get greater pain relief from narcotics than do men. Therefore, male physicians may perceive a woman to be complaining excessively about pain, which he believes could be reduced with over-the-counter analgesics. Or he may believe her to be misrepresenting her pain in order to seek out narcotics. In contrast, a study by the Department of Psychology of Union College, Schenectady, New York, showed that female physicians routinely gave inappropriately low doses of narcotics to their male patients.

This may be only the start of understanding sex-specific drug responses. The March 27, 2003 online issue of the Proceedings of the National Academy of Sciences carried a study by researchers from McGill University in Montreal. The study indicated that women with red hair and fair skin were particularly responsive to the effects of the analgesic pentazocine (Talwin). The drug was tested in both men and women with different skin shades and hair color, but among men, red hair and pale skin didn't affect the drug response. (The lead author of that study, Jeffrey Mogil, the E.P. Taylor Professor of Pain Studies at McGill, has been credited with doing the pioneering work in demonstrating the sex specific nature of pain and analgesic response.)

In 1993, the FDA rescinded the rule against including women of childbearing potential in clinical trials and went the extra step of asking the National Institutes of Health to ensure that women were included in all future drug research. The newer studies reveal that drug researchers are showing increased awareness of gender specific response to drugs and are including more women in clinical trials.

Other Considerations

An FDA study of 185 drugs approved between 1995 and 1999 found that (despite the fact that 37 of those drugs have known gender-specific differences in interactions) there were no dosage differences based on sex. But while drug studies may include more women, study protocols, of necessity, try to isolate the effects of the study drugs from the effects of any other drugs the patient may be using. This is a legitimate goal, since the objective of most studies is to research the safety and effectiveness of a single drug, and the presence of other drugs in the body may confound variables. As basic as this concept is, however, it represents a subtle, but consistent, bias against women.

Older women, especially (because they live longer than men) are more likely to be taking drugs for several conditions at the same time. They are likely to be on drugs for a variety of other age-related conditions including depression, osteoarthritis, and glucose intolerance or type II diabetes, which puts them at a greater risk of drug interactions. The drug interaction studies are problematic because they may be limited to those drugs most likely to be used with the subject drug and will not consider possible interactions with the other drugs the patient may be using.

Although drug research has increasingly included women, Sherry Marts, PhD, scientific director of the Society for Women's Health Research writes that, "Despite mounting evidence showing that men and women respond differently to the same drug, most physicians and their patients are still not aware that sex matters when prescribing medications." Part of the reason, according to Marts is that while the gender differences are included in the research data, the information isn't always required in product labeling and so isn't accessible to clinicians.

According to legend, a Greek philosopher once wrote, "Man is a featherless biped." Hearing this, Diogenes threw the philosopher a plucked chicken and said, "there's your man." For decades, drug researchers have thought of humans as a bunch of plucked chickens, so that a study conducted among a group of 30-year-old white males was extrapolated to women, children, the elderly, and non-Caucasians without thought to differences in drug response. Perhaps at one time, when drugs didn't have very much effect anyway, this attitude could be justified. But, as drug design becomes more sophisticated and new treatments reach down to the genetic level for their actions, it's increasingly essential that studies consider human diversity as well as similarities. Efforts to include more women in drug studies aren't the end of the problem of bias in drug research, just a weak and tentative beginning.

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