Two years ago, the Food and Drug Administration (FDA) issued a safety announcement informing insomnia sufferers that the widely prescribed pill Ambien (zolpidem) could impair the ability to drive and perform other morning-time activities. In the same announcement, the agency drew attention to the fact that women tend to clear Ambien from their bodies more slowly than men and specifically advised doctors to lower female patients’ bedtime doses of the drug. This marked the first time that the FDA had made a sex-specific labeling change to lower dosages of a drug.
Over the years, the FDA had received “spontaneous” reports of car accidents associated with Ambien. But the agency couldn’t make its dosing recommendations until researchers conducted a sex-specific analysis showing that eight hours after receiving a 10 mg dose, 15 percent of women had blood concentration levels of Ambien exceeding 50 ng/mL, compared to 3 percent of men. Those higher levels can cause driving impairment.
The FDA used to have a sex-specific recommendation that restricted “women of childbearing potential” from participating in early-phase studies for investigational drugs. The agency issued the 1977 guidance after the dangers of several drugs given to pregnant women came to light. The most infamous were reports from Europe in the early 1960s that thalidomide — a commonly prescribed antidote for morning sickness — caused 10,000 children to be born with phocomelia, a disorder characterized by shortened, or in extreme cases, absent or flipper-like limbs. It’s estimated as many as 4,000 of these babies died before their first birthday.
At the time, women were excluded from clinical investigations because health regulators wanted to protect fetuses, so the drug was never properly studied in pregnant animals or in clinical trials involving women before release. “Perhaps, had [women] been in clinical trials, we would have known much earlier about the devastating effects,” says Phyllis Greenberger, the president and CEO of the Society for Women’s Health Research, an organization founded in 1990 to raise awareness about sex disparities in medical studies.
Today, sex-specific research disparities still exist, but the situation is improving. In response to concerns and lobbying by women’s health advocacy groups, the FDA revised its original position by issuing new guidelines in 1993 that allow drugmakers and researchers to include women in earlier phases of clinical studies and call for them to perform analyses to determine sex-based differences in treatment response.
Since 1998, FDA regulations have required companies to analyze sex differences in drug trials. The sex of the subjects in a study was the most consistently reported demographic data in medical product applications submitted to the agency, the FDA reported in August 2013, but research within the past few years shows most studies still do not report outcomes by sex. “It’s not enough to have women and minorities in clinical trials,” Greenberger says. “There needs to be an analysis to see if there is a difference [in outcomes]. Just having them report the inclusion doesn’t do it.”
It’s not enough to have women and minorities in clinical trials. There needs to be an analysis to see if there is a difference [in outcomes]. Just having them report the inclusion doesn’t do it.
In releasing an action plan last year to improve the collection of sex, race, and age data in clinical trials, then FDA Commissioner Margaret Hamburg wrote that pharmacogenomics — the study of how genes impact people’s responses to drugs — and other scientific advances are improving our understanding of how subgroups of patients respond differently to healthcare interventions and are “helping to overcome the challenges of the ‘one-size-fits all’ model of patient treatment.”
Wolfgang Sadee, the director of the pharmacogenomics program at Ohio State University, has long been tracking how the interplay of sex hormones and genetic factors impact people’s response to drugs. For example, studies show that the enzyme CYP3A4, which is involved in metabolizing 50 percent of marketed prescription drugs, is more highly expressed in female livers than in male livers and can impact how quickly a drug is removed from the body. “That’s certainly due to hormonal effects and the systematic differences in males and females,” Sadee says. “With lots of Genome Wide Association Study (GWAS) results available, we now routinely adjust for both sex and age (puberty, menopause, etc.) as critical factors without which we can get wrong answers.”
Even if more sex-specific research is occurring, it takes a long time for this knowledge to trickle down to clinical practice. For example, although there is a large body of literature on how men and women have different symptoms of coronary artery disease (CAD), research shows doctors are more likely to diagnose and treat heart disease in a man than a woman, even if they have the same symptoms.
In 2010, Diane McGunigle, 58, a fitness trainer who ate right, ran marathons, was never overweight, and had never had high cholesterol, suffered a massive heart attack due to a blockage in the main artery running down the front of the heart. This type of blockage is ominously known as a “widow maker” for its low rate of survival.
One day, a few months before the attack, McGunigle felt like her heart was “literally about to beat out of her chest.” She drove herself to her primary care doctor, who chalked up her symptoms to anxiety. “She just didn’t see any signals,” says McGunigle, who suffered a heart attack at 52, the same age as her mother. “I’m not saying all doctors are like this,” she says, “but I just felt like she blew me off.”
But advances in genomics are starting to bring about new tools that may help doctors diagnose CAD with more confidence. CardioDx is a firm that markets what may be the only commercially available sex-specific blood test incorporating age, sex, and gene expression that doctors can use to assess whether a patient’s chest discomfort and other symptoms are due to obstructive CAD. “Previously women were thought of as small men,” says Mark Monane, the chief medical officer at CardioDx. “Diagnostic tests that are available today in general do not take into account key cardiovascular differences between men and women.”
CardioDx’s Corus CAD is different, according to Monane, because the components of the algorithm underlying the test are weighed differently. Along with sex, the test factors in age and the expression levels of genes to yield a likelihood score that can help clinicians determine if a person’s cardiac symptoms are due to obstructive CAD. The lower the score, the lower the risk that the patient’s symptoms are caused by obstructive CAD. Studies presented by CardioDx at a medical conference earlier this year showed that after doctors tested women with stable cardiac symptoms using the Corus CAD test, few women with low scores received additional testing and these women had good outcomes upon follow-up.
Improving Preclinical Studies
While drug and test developers are increasingly considering the impact of sex and biomarkers in the development of medical products, there are still critical gaps, particularly in preclinical research. As Virginia Miller, the director of Mayo Clinic’s Specialized Center of Research on Sex Differences Research and the Women’s Health Research Center, points out, researchers are still reluctant to factor in sex in preclinical studies involving cell lines and as a variable in studies investigating molecular pathways. “Sex differences must first be acknowledged as a possibility for contributing to precision medicine, investigated and tested as such, and then incorporated into the design of clinical studies,” says Miller.
Fortunately, the NIH has recognized this and is developing policies to address inclusion of both male and female animals, tissues, and cells in preclinical experiments. Additionally, as part of its plan announced last year to improve the collection of sex, race, and age data, the FDA is planning to publish “snapshots” of demographic information from newly approved drugs and improve its own data collections efforts to track treatment-related adverse events specific to subgroups.
With more women being enrolled in studies and included in longitudinal databases, there are novel ways of solving the gender gap in medical research, Sadee believes. “I think we have to be more imaginative about it.”