Medical Examiner

Drug Problem

Women aren’t properly represented in scientific studies.

With all the hype about personalized medicine—one day, doctors will use patients’ genomes to tailor treatments—one would hope that the medical community already had a decent grip on differences between the sexes. After all, says Teresa Woodruff, a professor of obstetrics and gynecology at Northwestern University, “You really can’t get to personalized medicine until you at least split the population in half.” Unfortunately, that hasn’t happened yet. Last month, Woodruff co-authored one of three related editorials in Nature illuminating the now decades-long sex bias in biomedicine, which leads doctors to preferentially study diseases and test drugs in males. It’s a practice that not only puts women at risk, Woodruff argues, but also limits the scope of our scientific knowledge.

We learn pretty early in life that most basic difference between men and women: Men have penises, and women have vaginas. But more fundamentally, our cells contain different chromosomes—women are dealt two X chromosomes, men an X and a Y—and, therefore, many different genes. Most genes on one of the female X chromosomes are silenced so that there’s only one functional copy of each, but there are exceptions; and while many Y chromosome genes direct testis development, others influence hormones and the brain. Even the genes we share are made into proteins at different rates: A study published in July 2006 in Genome Research compared the levels of gene expression in male and female mice and found that 72 percent of active genes in the liver, 68 percent of those in fat, 55.4 percent of the ones in muscle, and 13.6 percent of genes in the brain were expressed in different amounts in the sexes.

These discrepancies influence what is likely to ail you. For instance, three times as many women suffer from autoimmune diseases as men, and the statistics are reversed for autism. Sex also impacts how a person responds to medication: Women taking antidepressants and antipsychotics tend to have higher drug concentrations in their blood than men do; they also require half as much influenza vaccine for the same level of protection, though they are always given the same amount. In an  analysis  of 163 new drug applications submitted to the Food and Drug Administration between 1995 and 2000 that included a sex analysis, drug concentrations in blood and tissues from men and women in 11 of the drugs varied by as much as 40 percent. * However, the applications included no sex-based dosing recommendations. Finally, women are more likely than men to experience adverse drug reactions: Eight out of 10 prescription drugs  pulled  from the U.S. market from 1997 to 2001 caused more side effects in women. *

Yet scientists and clinicians often ignore sex differences, if they are even aware of them. According to a study in-press in Neuroscience and Biobehavioral Reviews, out of nearly 2,000 animal studies published in 2009, there was a bias toward the use of male animals in eight of 10 disciplines. Neuroscientists used 5.5 males for every one female, pharmacologists used five, and physiologists used 3.7. And despite the fact that women are twice as likely to suffer from major depression, fewer than 45 percent of animal studies on these disorders used females. “The zeitgeist is that sex is a modulatory factor and doesn’t play a big role,” says Arthur Arnold, a professor of integrative biology and physiology at the University of California-Los Angeles. But, he says,“sex makes a big difference.”

Clinical trials are men-centric as well. According to a 2006 study in the Journal of Women’s Health, women made up less than one-quarter of all patients enrolled in 46 examined clinical trials completed in 2004. And although more women than men die from heart disease each year, a 2008 study published in the Journal of the American College of Cardiology reported that women comprised only 10 percent to 47 percent of each subject pool in 19 heart-related trials.

Of course, this bias isn’t malicious—just a little lazy. Because males don’t have a menstrual cycle, their hormones do not fluctuate much over time, making them a more homogenous study population and ensuring that results are easier to analyze and interpret. There are also historical reasons for excluding women, particularly those in their child-bearing years. In the 1950s, the sedative thalidomide caused pregnant women to give birth to babies with missing limbs, and DES, an estrogenlike drug prescribed to prevent miscarriages, increased the risk that female babies would develop rare vaginal cancers later in life. When these findings came to light, clinicians and drug companies became cautious. “There was this worry: What about women who might get pregnant?” says Ruth Faden, executive director of the Johns Hopkins Berman Institute of Bioethics.

In 1977, partly in response to these tragedies, the FDA banned women who could become pregnant from participating in early-stage clinical trials. In practice, the ban ended up applying not just to women who were likely to conceive, but also women who were not sexually active, who used contraception, or who were homosexual. The law was upheld until 1993, when concerns arose that it left the health of women in the dark and that it implied “a lack of respect for their autonomy and decision-making capacity,” as one New England Journal of Medicine report noted. Then Congress passed the 1993 National Institutes of Health Revitalization Act, which required that all NIH-funded Phase 3 clinical trials include women unless exclusion was deemed appropriate, such as with trials testing potential drugs for prostate cancer or erectile dysfunction. But the pro-male tendency lingered (and has never been addressed by the FDA, which handles industry-funded trials), and many women who have since been included in trials have been required to ensure they will not get pregnant: A 2000 study published in Obstetrics & Gynecology reported that contraception or sterility was required in 41.7 percent of 410 study protocols analyzed from 1994 to 1997.

So what about pregnant women, then? The fact is, “pregnant women get sick, and sick women get pregnant,” says Francoise Baylis, a professor of bioethics and philosophy at Dalhousie University in Canada and author of one of the other two Nature editorials. For instance, though one in every eight pregnant women takes antidepressants, pregnant women are routinely excluded from clinical trials under the guise of protecting fetuses from potential harm. There are other disincentives, too, especially for pharmaceutical companies: Pregnant women are “not a huge market, and it does carry this potential risk of liability,” Baylis says. Pregnant women are taking more medicines than ever these days, too. For one thing, they are having babies later in life—when they tend to be on more drugs—and medical breakthroughs have made some pregnancies possible for the very first time, like in women with cystic fibrosis. Baylis and Faden argue that there should be trials designed to test drugs in pregnant women who are going to be taking them no matter what. “Then you’ve got structures in place to collect data, you’ve got structures in place to look for unanticipated or unwanted adverse events,” Baylis says.

Ultimately, a careful consideration of sex differences would work to everyone’s benefit—including the drug companies. Viviana Simon, vice president for scientific affairs at the nonprofit Society for Women’s Health Research in Washington, D.C., points out that far fewer novel drugs are being approved now than in the past, with most drugs failing in clinical trials. Perhaps by considering sex differences earlier on, some of these disappointments could be avoided. But this kind of change requires scientists to do more than just meet sex quotas in studies and trials—researchers must begin to frame questions in ways that consider the possibility of sex differences, just as they are now starting to do for other individual differences. As Faden says, scientists need to realize that “women are not men without penises.”

Correction, July 29, 2010: This piece originally implied that the FDA analyzed only 11 new drug applications, when in fact the FDA analyzed 163 new drug applications that included a sex analysis. Of these, 11 exhibited the drug concentration differences described. ( Return to the corrected sentence.) The piece also originally implied that side effects to these drugs were experienced only by women. Men and women both experienced problems, but the severity and frequency was greater in women and warranted withdrawing the drugs from the market. (Return  to the corrected sentence.)

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