Two trials prove that recruiting women isn’t as difficult as it sometimes seems

Simply asking goes a long way, advocates say

More than a decade after the National Institutes of Health (NIH) issued guidelines encouraging the inclusion of women as subjects in clinical research, they still are not fully represented in clinical trials that determine which drugs and treatments get marketed in this country.

Although progress is being made, advocates say, women still have a lot of catching up to do after decades of historical, cultural, and legal barriers that excluded them from both the benefits and risks of participation in medical research.

In fact, until 1993, regulations by the Food and Drug Administration prohibited the inclusion of women of childbearing age as subjects in early clinical trials. In the decade since those regulations were changed and the restriction removed, more women have been included, but we are just starting to see the results, says Sherry Marts, PhD, vice president for scientific affairs for the Society for Women’s Health Research, a Washington, DC-based nonprofit that encourages the inclusion of women as research participants and research into gender-linked differences in health and medicine.

"Even though the guidelines changed in 1993, it’s been like turning a battleship," she explains. "You have to consider trial design and finding ways to recruit and retain women into studies — that took a few years. It is really only in the last few years that some of the data are starting to emerge. That shows you how long it takes to change the system. Data that you collect today will be in front of the FDA in 10 years."

Though more women are being recruited and are participating in clinical trials, there is little evidence that researchers are examining the data to look for any differences in response that might be linked to gender, Marts says.

"That is sort of the follow-up issue to inclusion," she notes. "What’s the point if you are not going to at least look to see if there is a difference?"

Historically, women were excluded from participation as research subjects because of the risk untested agents posed to their future children, says Georgia Sadler, MBA, PhD, clinical professor of surgery in the Cancer Prevention and Control Program at the University of California-San Diego and director of the center’s community outreach program. Even today, investigators must take painstaking steps to ensure that participants are not pregnant when a trial starts and understand the importance of not becoming pregnant during the course of the trial.

"There is always the concern about doing harm; you want to weigh the risks and benefits," Sadler says. "You want more benefit than risk — that is the goal, especially when there could be another person involved, namely the child."

Prior to the change in regulation, women of "childbearing potential" — those who had not yet reached menopause or not undergone a sterilization procedure — were excluded from early trials of drugs that had not been tested for teratogenicity (the potential to cause birth defects).

Exceptions were made in instances in which a patient had a life-threatening condition and no other source of treatment was available, Marts adds.

"It meant that there were some women in cancer clinical trials, but it did keep them out of trials of most drugs and it certainly kept them out of the early phase trials," she says.

The male norm

And for a long time in medical circles, it was assumed that what worked in men would work — and work in the same way — for women and vice versa; drugs not proven effective in male subjects were assumed to have no value.

"For a long time in medicine, we had this thing called the male norm," Marts continues. "I say this in my talks, and it always gets a laugh, but it is true. It was just assumed that the male was normal and women were just small men with different plumbing and a hormone problem. Come to find out, we are not. Our biologies are very different and that has an impact on our health."

Recent experience has borne this out.

For example, the only two drugs currently marketed specifically to treat irritable bowel syndrome seem to be more effective in women. And there are drugs that are known to be metabolized differently in men and women.

"There are some drugs that women break down faster than men, so they may need a higher dose or more frequent dosing, and there are some where it is the other way around," Marts says. "It is very challenging to kind of break the data out and figure out exactly what is going on."

Pharmaceutical manufacturers have an understandable disincentive to discovering the need for different doses for different populations, she adds. It is great if one dose works for everyone, but that’s not always the case.

Although more women are being included in clinical trials, there is some residual perception that trials are easier with men as subjects.

"We understand perfectly that manufacturers have a profit disincentive to doing this because if they look for a difference and they find one, then they are going to have to label the drug as say, These people should take it,’ or These people should not,’" she says. "When you’re Drug Company X looking for the next blockbuster everybody’s-gonna-take-this drug, then you have some advocacy group come along and say, But does this work differently in women than in men?’ It is sort of like the reaction we get is, We don’t want to know.’"

Recruiting and retaining female subjects

There still is the issue of the risk to a female subject who is in the early stages of pregnancy but does not know it, or, equally dangerous, who becomes pregnant during the course of the trial.

Both Sadler and Marts say this potential complication is overblown in the minds of some researchers.

"You can ask a woman, Is there any chance you might become pregnant?’ By definition that means, Have you missed your period?" says Sadler. "Once you have determined that she is not pregnant right now, the next question would be, Are you trying to get pregnant or do you have any plans to get pregnant?’ If you have someone who says they are, then you could exclude them because of the potential to do more harm than good."

The riskier the product being tested, the more solid assurance the investigators will want that subjects are not going to become pregnant, she continues. "If you are doing things that are relatively safe, you might say, Well, being on birth control is probably adequate; but if you are testing a new drug for the first time in humans and it was highly toxic in animal models, you might say that unless the person has had her tubes tied or some other procedure, you might not want to take the chance."

It is also important, during the informed consent process, to emphasize this risk, emphasize the importance of not becoming pregnant and — should an unplanned pregnancy occur — that the investigators need to be notified immediately.

"It can happen, and that is when you need really good vigilance on the part of your research team," Sadler says. "What happens next is unique to every single trial. Every single investigator would be in close contact with the manufacturer of the drug and use his or her judgment about whether there are benefits to keeping her on the drug and whether the benefits outweighed the risks to the fetus."

Even with the change in the guidelines and attempts by many investigators to recruit female participants, women are not exactly knocking down clinic doors to get into trials.

Almost any conference involving research professionals will feature a session on recruiting women and minorities — and usually, it’s a single session titled, "Recruiting Women and Minorities," as if they were one population, Marts notes.

"You still tend to hear investigators say, Oh, but it is so hard to recruit and retain women," she says. "I always ask them, first of all, Are you listening to your site staff?’ Maybe they have some ideas about how to do this better."

Recent examples offer insight

There are some recent examples of large-scale clinical trials involving women and other populations thought difficult to recruit that can provide helpful lessons about how to recruit and retain study subjects.

The first, says Marts, is the Women’s Health Initiative, which recruited many older women and followed them for several years.

"People said it could never be done; you could never recruit that many older women and keep them in the trial," she says. "But, as we know, they did."

Other examples can be found in the HIV prevention trials that involve women who are either drug users, partners of drug users, or professional sex workers.

There are some study sites that have had 98% retention rates over two-year periods with these populations, Marts says. The sites developed unique ways of maintaining contact with these women, even though the subjects may have moved frequently, sometimes in and out of homeless shelters, or work in dangerous and illegal conditions — not exactly conducive to regular follow-up visits.

"What they are finding is that it takes more than just herding people into the clinic, performing the visit, writing the next appointment on a notecard, patting them on the head, and sending them out," Marts says.

Became women typically shoulder the lion’s share of responsibility for child care and household maintenance, clinics that offer weekend and evening hours and those that combine multiple services (blood draws, X-rays, other monitoring) at a single visit are often more amenable to female participants, she says.

They also may be concerned about the safety of the clinic’s location and whether security is provided.

Obviously, this is not a sole concern for female participants, Marts adds, and researchers may find that concessions they make to attract female participants may recruit more participants overall, too.

Did you ask?

Working on a contract with one of the HIV vaccine trials, Marts helped produce a video featuring the subjects talking about the benefits of participating in the study.

"There was one interview with a drug addict — who, in this instance, happened to be a man — and the interviewer asked, Why are you doing this? Why agree to be in the trial?’ The guy looks at her and says, "Lady, I am a junkie. No one has ever asked me for nothing. These people came, and they asked me to do something for other people, and how could I say no?’"

Because clinical trials have, in the past, focused exclusively on men, it’s possible that many women simply don’t recognize this as something that is possible for them — they don’t realize they would be able to contribute, Marts says.

"It is sort of a truism in the not-for-profit world that people don’t volunteer unless they are asked. One of the things that occurred to us early on after they changed the guidelines was that half the population had been reading about medical research and seeing reports in the news and it was always about men," she relates. "Heart disease in men, men should take aspirin, etc. We imagined that women simply don’t feel asked. They don’t feel welcome to participate in these studies."

To help remedy that problem, the society initiated its "Some Things Only a Woman Can Do" campaign, which included a web site, brochures, and other educational materials that encourage women to consider participating in clinical trials.

"It emphasizes that you don’t necessarily have to have a disease or condition to participate and women are really intrigued to find this out," she says.

Conducting clinical research on essentially one population — white men — has handicapped medical research in a number of ways. Clinical trials that include diverse groups of people can yield better information faster, says Sadler, whose research focuses on improving recruitment of both women and minorities.

"It is important, for example, to have women of childbearing age represented in clinical trials. Let’s say you are looking at blood pressure medication for hypertension; you would not want to exclude women between the ages of 18 and 50 — that is a large segment of the population that will eventually take this medication," she says. "Would you want them to take it without it ever having been tested in that population? That is essentially what happens now. If you have a study and you don’t have a large enough representation of African-Americans, Hispanics, or Asians, it is the same thing."

The issues go beyond just genetics and gender, she continues. For example, say a particular drug does really well in subjects who are Asian women, but none of the other participants. Researchers would then look to see why. Perhaps it is something in the diet that these women all had that enhances the drug’s efficacy? Once that is determined, that information could be included in the drug’s labeling.

Conversely, say a certain group does poorly in a trial. For example, all of the Hispanic men don’t respond. Perhaps there is a reason there. Once the likely cause is found, then researchers can recommend a possible solution.

However, if these people are never represented in clinical trials, this information is likely to never be found. Say the drug that worked so well for Asian women is only tested in groups of Caucasian men. It is found to not work well and is dropped, without researchers ever knowing its true potential.

Or a drug that has significant complications for people with certain dietary habits or genetic differences makes it to market. Patients who do not respond to the drug, or worse, experience a poor reaction, are rarely noted.

Outside a clinical trial, Sadler says, individual complications or adverse events are too far apart for their significance to be noted.

"One of the reasons we spend so much time educating health professionals and the public is to try to help communities to understand that no participation is really no voice," Sadler says. "So, someone has to step up to the plate. Obviously, we are not saying everyone should do everything, but keep your eyes and ears open and don’t have a knee-jerk negative response."