Twenty-four years after the NIH established the Office of Research on Women's Health, and 21 years after the NIH Revitalization Act of 1993 first required that women be included in clinical trials, certainly the letter of the law has been achieved. Women are now the majority of participants in NIH-funded trials.

The whole picture, though, is much more complex, and more uneven. Increased participation has led to gains in some areas. But in other areas, far too little is known about whether and how drug responses and optimal treatments differ for men and women.

Not very long ago at all, the lack of women in clinical trials was due to outright discrimination. In 1977, the FDA barred women of childbearing age from participating in most early stage clinical research, a ban that was officially recognized as detrimental to women's health in the mid-1980s, when the NIH first adopted guidelines (that remained widely ignored until the NIH Revitalization Act of 1993) encouraging the inclusion of women in clinical research.

These days, the issue, as it often is with women's issues, is more complex.

It is clear that there has been progress. But it has been uneven, and perhaps surprisingly there is no obvious relationship between the success and whether a condition is specific to females or not.

Breast cancer, which is overwhelmingly a women's disease, was singled out in a 2010 Institute of Medicine report on women's health research as a condition where there has been much progress. Ovarian cancer, on the other hand – which can be due to the same underlying genetic factors in some cases – has seen little progress.

In diseases that can affect both men and women, progress has been equally mixed. The treatment of cardiovascular disease has made strides in women; treatment of lung cancer, not so much.

And even in trials in which women are equally represented, the data generated on their unique responses often go to waste.

Only a minority of trials analyze their subgroups separately – and so even if a treatment has different effects in men and women, those effects may not be recognized if such subgroup analysis is missing.

The Society for Women's Health Research (SWHR) is one organization that is pushing to make such subgroup reporting mandatory in practice. At an April FDA hearing on issues and challenges with the collection, analysis and availability of demographic subgroup data, SWHR president and CEO Phyllis Greenberger urged the FDA to "enforce existing regulations and guidance that require subgroup reporting and analysis be submitted by sponsors for the safety and effectiveness of all medical products. . . . The FDA should finalize draft guidance for sex-specific analysis they proposed in 2011 and issue similar guidance for race and ethnic minorities and the aged."

The SWHR has long lobbied for the inclusion of women – and minorities – in medical research as part of a broader focus on "transforming women's health through science, advocacy and education," according to the organization's mission statement.

Overall, the FDA and NIH "have improved a lot," Phyllis Greenberger told BioWorld Today. "If nothing else, they have improved in the recognition that it's important." And that improvement has been accelerating. "In 2014, we have probably made more progress than in the 24 years leading up to it."

But just how much progress has been made remains impossible to know.

For one thing, the NIH has "never broken down the trials by diseases," Greenberger pointed out. There is the real possibility that an overall participation rate of 50 percent may be the net result of a few large trials that are made up exclusively of women, plus many trials where women are still underrepresented.

Breast cancer, for example, is a very active trial area – much more active than its closest male-specific pendant, prostate cancer – and so breast cancer trials alone may contribute disproportionately to the overall number of women in trials.

With the passage of the 2012 FDA Safety and Innovation Act (FDASIA), Congress mandated that the FDA issue a public report on the extent to which demographic subgroups, including sex, age, race and ethnicity, are included in new drug applications.

In late November, as part of that effort toward greater transparency, the FDA released demographic "snapshots" of demographic information for the trials that led to the approval of six drugs in May and June of 2014. If they are snapshots, they are the equivalent of an embarrassing Instagram post.

While the majority of the trials did include separate analyses for men and women, patients older and younger than 65, respectively, were only analyzed separately in half of the trials.

And the analysis of racial subgroups was simply dismal. In only one of six trials – that for Jublia (efinaconazole, Dow Pharmaceuticals Inc.), approved in June 2014 for the treatment of onychomycosis, or toenail fungus – was minority participation sufficient to enable a separate analysis of different ethnic subgroups. That analysis found a trend toward greater efficacy in Asians, either because there was no difference or because the groups were too small – the data can't say. And according to the FDA snapshots website, "difference in side effects by race was not evaluated."

The data prompted the SWHR to issue a press release stating, "We commend the FDA for the effort in collecting and releasing these data to the public and we believe it is an initial first step towards reducing the disparities and lack of information on sex and ethnic differences. But as is evident, the percentage of minority participation is dismal and while there are women in all of the trials, the numbers are not statistically significant to reach any clinical relevance."

Not all trials are NIH-sponsored, either. Data from industry trials are largely confidential, but what data there are suggest that women are still underrepresented.

Industry, too, at least has an awareness of the problem. "Diversity in trial enrollment is something that we constantly worry about," Jesse Berlin, vice president of epidemiology at Johnson & Johnson, told BioWorld Today.

CONFLICTING GOALS INTERFERE

But goals within trials can conflict. A biopharma company's first goal is to show that its experimental drug is safe and effective – without breaking the bank with its trials.

That goal begins with the need to get trials enrolled, so they do not drag on. If a trial is enrolling based on who shows up, and a condition is more prevalent in one sex, the other sex will end up underrepresented by default.

More generally, Berlin said, signal is easiest to distinguish from noise when trial populations are homogenous. Adding heterogeneity of trial participants means "you're adding heterogeneity of response."

For that reason, one line of reasoning holds that trials should pay particular attention to subgroup analyses only when there are a priori reasons to suspect that there will be biological differences. In a 2009 paper on the inclusion of women in clinical trials, Berlin and his colleague Susan Ellenberg wrote that "there is no question that some treatments do work differently in men and women, but the proportion of treatments for which men and women respond very differently is unknown."

The reason it is unknown leads smack into the next problem: Preclinical research, too, has long focused on male animals, and so in many cases there might be a priori reasons to suspect sex differences in reactions – if anyone were looking for them.

The NIH has been addressing the issue of sex bias in preclinical research. Earlier this year, the NIH announced it was developing policies that require applicants to balance sex of animals, and cell lines, in future grant applications, "unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions."

In September, the agency awarded more than $10 million in supplemental grants to enable grantees to study the effects of sex in preclinical and clinical research.

At a meeting of the NIH's Office of Research on Women's Health, NIH director Francis Collins said that "we don't want to rush into this in a way that seems heavy-handed or clumsy. But we are dead serious about actually implementing change in a way that is going to address an issue that has been neglected."

More generally, the notion that one sex is data and the other, somehow, noise, is itself a consequence of considering male physiology the norm.

As Greenberger said, if the point is to reduce noise, "why don't we do all research on women and see what happens to men in phase IV?"

Considering men the norm from which women deviate also means that clinical trials are designed in a way that can make participation hard for women. For example, more frequent office visits and overnight stays required by trial design can make women, who are more often caregivers, less likely to enroll in trials.

And efforts of the NIH and FDA have been concentrated in late-stage trials, while the sort of safety data that could result from differences in metabolism are the provenance of early stage trials.

PREGNANT WOMEN: AN ORPHAN POPULATION

Nowhere are those issues starker than in the subgroup of pregnant women, who remain, in the words of Maggie Little, "an orphan population" with respect to drug development.

This despite the fact that conditions such as diabetes and hypertension and neuropsychiatric illnesses – primarily depression – affect hundreds of thousands of pregnant women annually.

Little is a co-founder of the Second Wave Initiative, which advocates for a greater inclusion of pregnant women in clinical trials through a mix of incentives, changes in regulations and innovative trial designs.

Pregnant women, she told BioWorld Today, "are an ethically complex population. . . . Everyone agrees we have to limit the risk to the fetus, because it can't consent."

But rather than excluding pregnant women from research, the solution needs to be to design protocols "that pass ethical muster and still get us the data we need."

If women are sometimes implicitly considered extraneous, pregnant women can find themselves considered – implicitly or even explicitly – as little more than cargo vessels for the duration of their pregnancy.

In a case statement, on their website, the Second Wave Initiative points out that "seriously ill pregnant women who might medically benefit from participating in research can be denied access without any justification or review – a standard not applied to any other population."

Yet the consequences of not taking drugs during pregnancy can be worse than the consequences of taking them, for mother and fetus alike. This is well documented for maternal asthma, which is associated with worse outcomes for babies if it is poorly controlled during pregnancy, but not if it is well controlled – with drugs.

The bottom line, Little said, is that "pregnant women get ill, and ill women get pregnant. . . . It's research we need to figure out how to do."

Editor's note: BioWorld's Clinical Trial series continues in Wednesday's issue, with a focus on race and ethnicity.

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