More Women Need To Be Involved In
Medical Device Trials
June 8, 2012
Written by Rochelle Green (FiDA blog bold added)
Hundreds of thousands of women at
risk for irregular heart rhythms have a battery-powered, iPod-sized gadget
embedded in their chests. The implantable cardioverter defibrillator (ICD) can
be a lifesaver, shocking a dangerously fast heartbeat back to normal.Yet the
actual benefit to women is uncertain, because ICDs were approved by the Food
and Drug Administration (FDA) based on clinical trials made up mostly of
men. That’s typical of testing of many high-risk devices, according to
medical reports. And even in the clinical device trials that do include women,
generally the outcomes aren’t reported by sex.
The result is a critical gap in the
data doctors rely on when making decisions about a treatment’s benefits and
risks for women. It can also pose troubling dilemmas later on, said
cardiologist Rita F. Redberg, a professor of medicine at the University of
California, San Francisco. That was the case in 2009, when data pooled from
clinical trials showed that ICDs were no better than drugs at reducing a
woman’s risk of death.
“The time to collect data in both
sexes is before FDA approval,” said Redberg. “Especially with implanted
devices, where there’s no going back.”
Only recently has the FDA proposed
guidelines to improve the representation of women in clinical device trials.
Intended for the medical device industry, which sponsors most of the research
submitted for review, the guidelines are expected to become final by year’s
end. Similar standards for drug testing were put in place some 20 years ago,
following a long period during which women of childbearing age were explicitly
excluded from most studies.
The proposed FDA guidelines are
nonbinding, however, and some experts who favor the new recommendations are
skeptical that the medical device industry will comply.
“Industry is always most attentive to
the bottom line,” said Christine Carter, vice president for scientific affairs
at the Society for Women’s Health Research (SWHR) in Washington, D.C. “So
companies will continue to lament that trials are expensive and that recruiting
more women is a problem.” Device makers will change their study protocols just
enough to meet FDA requirements, Carter predicted, but protocols will be “less
than ideal for those of us concerned with sex differences and women’s health.”
SWHR and other groups have urged the
FDA to strengthen the document by finalizing it as a rule. The debate
highlights the competing interests that the agency struggles to balance, with
industry and some lawmakers in one camp, demanding faster approvals and “less
burdensome” regulation, and health advocates in another, warning that patient
safety is at risk.
To U.S. Rep. Rosa DeLauro, the issue
is science, not politics. “We know there are real medical distinctions between
genders that must be recognized when the government is deciding whether to
approve a new device,” she said.
Opening A Window On Women’s Health
Until the mid-1980s, clinical trials
were practically a men’s only club. Studies funded by the National Institutes
of Health (NIH) and pharmaceutical firms—the largest contributors to biomedical
research in the United States—drew subjects primarily from a pool of white
males. The first randomized trial using estrogen to prevent heart disease
consisted entirely—and counter-intuitively—of men.
Women were considered too complicated
to study, given their cycling hormones and the chance that those of
childbearing age could expose a fetus to unintended risk, said SWHR’s Carter.
Gender wasn’t yet recognized as a factor in health and illness, and it was
assumed that study results in men would be just as useful for women.
As biomedical research advanced,
however, women began to suspect that their health needs were being left behind,
experts say. The results of clinical trials in men weren’t always extended to
women, depriving them of powerful new treatments like cholesterol-lowering
drugs, according to an Institute of Medicine report. And the male model didn’t
always correspond to women’s experience of health and disease.
In the early 90s, women’s health
advocates began to mobilize, according to Carolyn Mazure, director of Women’s
Health Research at Yale. “They took it to Congress,” she said, educating key
legislators about the exclusion of women from medical research and the lack of
information about gender differences related to health.
In 1993, Congress passed legislation
requiring that women and minorities be included in all NIH clinical research.
The FDA reversed its policy barring women of childbearing age from certain drug
studies, encouraging their inclusion in all clinical drug trials. The measures
also required study results to be analyzed by sex.
As an NIH researcher at the time,
Mazure witnessed history in the making. “The idea that we now needed to include
women and minorities in our research—we found it revolutionary,” she recalled.
Her program at Yale promotes research on gender differences in health by
providing seed money to get innovative projects off the ground.
In the past 20 years, scientists have
discovered that sex differences are significant at every stage of life and at
every biological level, from the single cell to the whole body. Gender
influences how people experience disease, metabolize drugs, respond to pain,
and much more. While the findings support the need for sex-based research, the
going is slow, said Carter.
“There’s still only 30 percent—maybe
up to 40 percent—of women involved in clinical trials, and too often their data
isn’t analyzed separately from men’s,” she said.
A major challenge is changing the
mindset of researchers, she said. She described how, at a recent SWHR
roundtable with more than a dozen Alzheimer’s disease experts, she had asked
about the sex differences they had found in their research. Almost all
responded that they hadn’t looked at the data that way.
“We’re finding this over and over,
with experts in different fields,” she noted. “If you’re not aware that there
are biological differences between the sexes, you don’t look for it in your
data.” With each roundtable, however, she convinces more scientists to look at
outcomes based on sex. “It’s time to make this more mainstream,” she said.
In the meantime, the effects of the
old mindset are still in evidence: in one example, women account for just 30
percent of subjects in the clinical trials supporting the American Heart
Association’s 2007 guidelines for cardiovascular disease prevention in women.
Twenty of the 156 studies were men-only, according to a published gender
analysis of the studies from which the guidelines were drawn.
The paucity of women “wasn’t a big
surprise,” said Dr. Chiara Melloni, assistant professor of medicine at the Duke
Clinical Research Institute in Durham and lead author of the analysis. But it’s
a reminder to design studies with gender differences in mind, she said.
Bringing Device Studies Up To Speed
If the FDA’s device center has been
slow to tackle the gender gap, its new guidelines are a prescription for
change, agency officials say.
In a key provision, researchers are
advised that men and women should be enrolled in proportions that reflect the
gender distribution of the underlying disease. Cardiovascular device studies,
for example, should enroll men and women in equal numbers, since each sex is equally
at risk for the disease. Until now, most such studies have included just half
as many women as men, according to an FDA review of cardiovascular devices
approved in a recent five-year period.
Since medical device studies have
traditionally been small, the new enrollment goals will likely require more
women, and possibly bump up the number of subjects overall. The guidelines
provide strategies for recruiting female subjects, and advice on examining data
for potential differences by sex. And they call for sex-specific outcomes to be
reported on device labels, a practice that consumer health groups have been
advocating for years.
In practice, the vast majority of
medical devices reviewed by the FDA are cleared for use without human testing,
if they are deemed “substantially equivalent” to devices already on the market.
Only 1 percent of devices undergo rigorous review and clinical trials before
they can be marketed.
Even so, the new guidelines for
device trials are an important advance, experts say. Dr. Patrice
Desvigne-Nickens, a program director at the National Heart, Lung, and Blood
Institute, praised the FDA for alerting device makers to the new imperative in
clinical research. “To not look for gender differences is unacceptable,” she
said.
Joleen Chambers on June 11,
2012 at 4:14 pm
Thank you for this excellent and informative article. Sadly, if
a woman researches any implanted medical device she will find that data is
hidden behind a barrier of “proprietary” claims by the industry. She is more
likely to find hard data about any kitchen appliance than an implanted medical
device. Gender clinical studies are another layer of insufficient scientific rigor.
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