clinical research

Women in Clinical Trials

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Do Hormones Matter with Clinical Trials Research?

I am repeatedly struck by the avoidable ignorance that surrounds this industry. Women’s hormones are considered a fringe science by many, despite the fact that hormones modulate all bodily functions and impact all aspects of pharmacokinetic and pharmacodymanic response, the key variables evaluated in clinical trials research. Repeatedly, we face the assumption that hormones make no difference to women’s health – quite ironic since simultaneously hormones are blamed for everything from migraines to mental health.

And then there is the long held notion that we don’t need any more data in women’s health – quite striking considering only 30% of Ob/Gyn clinical practice guidelines are based on data. Just the other day, a well-positioned female physician, one of the fewer than 4% female healthcare executives, argued that while what we doing was interesting,  it was unnecessary because the 1993 Gender Guidelines ‘mandated’ women be included in clinical trials.

Perhaps some history is in order. Until 1993, women of ‘childbearing potential’ were prohibited from participating in clinical trials research. This means that all of the drugs developed before 1993 (most are still being used today) were not tested on women; any potential dosing differences, sex- specific side-effects could not be found until after the drug reached the market and even then it was and is difficult to ascertain because sex-specific analytics were not, and are still not, routinely performed. This makes proving sex-based adverse events all but impossible.

In 1993, thanks in large part to efforts of the first large group of women to enter the US Congress (women in Congress matter); the FDA removed its prohibition against women with childbearing potential participating in clinical trials. The regulations, however, were not established until 1998 and what was implemented, though an improvement over the earlier prohibition of women in clinical trials was less specific than the original guidelines and resulted in less than satisfactory results. When those regulations are evaluated alongside industry trends over the last decade, it becomes abundantly clear why women suffer disproportionately from adverse events compared to men and why everyone in the healthcare industry should be concerned.

From Proposed Guidelines to Regulation

The 1993 guidelines recognized that women might process and react to drugs differently than men (indeed they do and this has been shown repeatedly) and therefore, it was recommended that pharmacokinetic studies be done to evaluate the difference in drug absorption, distribution, metabolism and excretion. It was further recommended that menstrual status, hormonal supplementation (oral contraceptives, HRT and the like) be evaluated.

The FDA was quite clear in its ability to mandate these changes – there was none.  Indeed, all that was possible was suggestion.

The agency recognizes that this change in FDA policy will not, by itself, cause drug companies or IRBs to alter restrictions they might impose on the participation of women of childbearing potential. We do not at this time perceive a regulatory basis for requiring routinely that women of childbearing potential be included in particular trials, such as phase 1 studies. However, careful delineation of drug effects by gender is expected by the agency and the FDA is determined to remove the unnecessary federal impediment to the inclusion of women at the earliest stages of drug development.  The agency is confident that the ethical, social, medical, legal and political forces will allow greater participation of women at the earliest phases of drug development.

So, the FDA was confident that ethical and social pressures would convince pharmaceutical companies to do the right thing. How well has that gone? The guidelines also indicated that it was not necessary to include women in phase 1 or 2 trials because there was no evidence to suggest sex differences in drug effectiveness:

Because documented demographic differences in pharmacodynamics appear to be relatively uncommon, it is not necessary to carry out separate pharmacodynamic – effectiveness studies in each gender routinely.

To summarize, data were never collected in the first place to suggest sex-differences might exist (remember before 1993, women were prohibited from participating in clinical research) and because there were no data to suggest a sex-differences, there was no need for additional data – makes perfect sense to me.

Fortunately, the National Institute of Health (NIH), the federal funding agency for health-related research, took the reins with a clear mandate – no funding unless the study included women in clinical research.  The NIH Revitalization Act of 1993, followed by updates and regulations in 1994, 2000 and 2011, mandated that all NIH funded clinical trials have sample sizes adequate to support ‘valid analysis’ of gender and racial subgroup effects. Unfortunately, however, NIH-sponsored clinical trials represent only 20% of all clinical trials. The remaining 80% are sponsored by pharma and fall under the FDA’s guidelines. And even though, by all accounts the NIH has done substantially better than the FDA, a recent report by the National Heart, Lung and Blood Institute (NHLBI) – a sub agency of the NIH, found that in clinical trials between 1997 and 2006 where the outcome of the study was stroke, myocardial infarction or death found that women represented only 27% of trial participants and only 13-19 of the studies included sex-based analyses.

Back to the FDA Regulations

In 1998 and 2000, the FDA officially instituted the Guidance for Industry, requiring all new investigation drug (IND) and new drug application (NDA) submissions include data on trial participation, efficacy and safety, be presented by age, race and sex. A report in 2001 by the General Office of Accounting (GAO) (no further GAO reports could be found on this topic) evaluated the success and failures of the gender guidelines. It wasn’t pretty:

The 1998 regulation has the force of law, but it is less specific than the 1993 guidance. The regulation required that safety and efficacy data already collected be presented separately for men and women in new drug application summary documents. It does not include criteria for determining the number of women to be included in clinical studies, nor does it require any analysis of the data presented. The 1998 regulation also requires the tabulation of the number of study participants by sex in investigational new drug annual reports. The regulation enacted in 2000 allows FDA to halt research programs for drugs for life-threatening conditions if otherwise eligible men or women are excluded from participation in studies based solely on their reproductive potential, but it does not require inclusion of any particular number of men or women.

How well did the FDA do in meeting and enforcing the guidelines? According to the GAO:

  • NDA and IND summary documents and annual reports often failed to meet the data presentation requirements
  • 30% the new drug application summary documents submitted to FDA by drug sponsors did not fulfill the requirements for the presentation of available safety and efficacy outcome data by sex
  • 39% of IND annual reports did not include demographic information
  • The FDA has the authority to suspend proposed research for life-threatening conditions if men or women are excluded, but has not yet done so

As a result of the non-enforcement, the GAO found that although the number of women in clinical trials now averaged 52%, most were enrolled in later stages of the trial. Women represented only 22% of early phase clinical trials. This is where most of the safety and dosing considerations are determined.

Finally, and perhaps the most troubling aspect of this report was that, the FDA had no procedures in place to evaluate, manage or enforce the regulations. As a result, they had no way of knowing whether women were included in the trials in sufficient numbers or whether the medications or devices gaining approval had gender-specific safety issues.

What does this mean?

For all drugs and devices approved before the 1998-2000 regulations and likely many years after, the safety and efficacy data were lacking for women. Despite the 52% female participation number that is bandied about as proof positive that women are represented sufficiently in clinical trials, that number reflects later phase trials, after safety and efficacy parameters are established. In the early phase trials, the number of female participants remains at a paltry 22%. Today, when large women-only (Women’s Health Initiative and Women’s Health Study) research are removed from the tabulations, the mean proportion of women included in all clinical trials hovers around 27%.

Most recently, the Institute of Medicine (IOM) Committee of Women’s Health Research reports a continued lack of

taking into account of sex and gender differences in the design and analysis of studies, lack of reporting on sex and gender differences, has hindered identification of potentially important sex differences and slowed the practice in women’s health research and its translation into clinical practice.

And although the IOM reports that the most progress has been made in cardiovascular research, the NHLBI and Cochrane Reports suggest otherwise. The NHLBI found female participation hovering around 27% in certain cardiovascular trials and Cochrane Reports found that out of 258 clinical trials, only 196 included women and only 33% of those reported sex or gender analytics.

Cardiovascular disease is the most common cause of death in American women and in recently recalled medications for heart disease there were disproportionately higher fatalities and serious adverse events in women than in men.

With high risk cardiac devices, a recent review of FDA pre-market approved devices from 2000 – 2007 (78) found significant gender bias in sampling and data reporting and significant lack of sex-specific safety data.

  • FDA summaries did not report gender data in 28% of studies examined
  • For studies reporting gender distribution, 67% of the participants were men

So, the suggestion that additional data in women’s healthcare are not needed is unquestionably false and dangerously ill-informed. The notion that hormones, which regulate every aspect of pharmacokinetics and pharmacodynamics are an irrelevant and a fringe science, is ignorant bordering in negligent. It is time for women to stand up and demand inclusion and analytics by sex for all drugs and devices.

Postscript: NIH Update 2014

Since this article was first published in February 2013, the NIH has made inroads towards more thorough assessment of the role of sex in basic, pre-clinical research. Recognizing the almost total reliance on male animals and cells in preclinical research obscures key sex differences that should guide clinical studies, the NIH instituted new guidelines in October 2014

…that require applicants [for NIH grant funding] to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions. 

It remains to be seen how rigorously these new guidelines will be enforced and whether they will impact health research in any discernible way.

Postscript: Update 2019

From a recent 10 year follow-up study assessing sex-inclusive research practices of journal articles published within nine of the biological disciplines, including pharmacology, researchers found some improvement in most of the disciplines, except pharmacology. Compared to 2009, where only 29% of the studies reviewed included male and female subjects, in 2019, 49% included both. In contrast however, pharmacology trended downward with only 29% of articles reporting the use of both sexes in 2019 compared to 33% in 2009.  Nevertheless, even though more women were included in more research studies across the disciplines reviewed, few researchers thought it was important to analyze sex based differences. Indeed, of the 49% of journal articles that included both sexes in 2019, only 42% analyzed data by sex, compared to 50% in 2009. Ironically, in pharmacology although the total number of women decreased in studies during this time period, analyses of sex based differences was more frequent increasing from 19% in 2009 to 48% in 2019.

Overall, it appears that we have yet to make much progress.

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This article was first published in 2013. 

DES – The Drug to Prevent Miscarriage Ruins Lives of Millions

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Let’s rewind time. We’re in 1970. My mum, like millions of other women, puts all her trust and last hopes of carrying a successful pregnancy in the hands of health professionals. She accepts to take a drug recommended and prescribed in good faith by her doctor without knowing that years later it would have devastating consequences not only on her health but the health of her daughter and possibly her grand-children. She takes Diethylstilbestrol (or DES in short), the first synthetic man made female sex hormone (oestrogen) widely prescribed for public use in the mistaken belief that it would prevent miscarriage and loss.

Now let’s fast forward. We’re in 2001 three decades after my mum took DES. I’m in a hospital ward anxiously waiting for the results of a scan. I’m pregnant. “We’re so sorry, but you know 1 out of 5 pregnancies end in miscarriage. You should try again” I’m told. My head is spinning. What did my Mum said again? DES, yes DES, I remember now. She mentioned when I was just a teenage girl that research had confirmed that the drug taken throughout her pregnancy to prevent miscarriage was responsible for all sorts of dreadful health issues including a rare form of vaginal cancer, infertility and high risks pregnancies. What if this was responsible for the loss of my baby, I ask. “DES? What is DES? Never heard of it!” replies the consultant on duty that day. ”If you keep miscarrying, we’ll investigate further” he adds.

I don’t listen and seek help and advice from an organization founded by a mother who had been prescribed this drug and advocates for the many families affected by DES. A Professor, expert in fertility treatment, confirms a congenital uterine malformation typical of DES exposure and confirms that I’m a DES daughter, one amongst millions of other women whose mothers took Diethylstilbestrol during pregnancy.

If you were born or pregnant in the US between 1938 and 1971, and until the mid-’80s in some European countries, you may have been exposed to DES too and you may suffer from the consequences of this drug without even knowing it. Diethylstilbestrol has put the mothers prescribed the drug, their daughters and sons exposed in utero, and potentially their grandchildren due to the trans-generational effects of this synthetic hormone, at risk for serious health problems including but not limited to: structural damages in reproductive organs, high risk pregnancies and miscarriage, cancer, infertility and possible immune system impairment. Many other suspected effects are still awaiting further research but funding is critically missing.

Often referred to as the “Silent Thalidomide” by the media, diethylstilbestrol is considered as the world’s first drug scandal. Despite evidence of its ineffectiveness and danger, it continued to be prescribed to pregnant women beyond 1971 when the first link between DES and a rare form of vaginal cancer (clear cell adenocarcinoma) was formally established in Boston, Massachusetts.

Even though this drug was given to pregnant women decades ago, it affects and continues to affect millions of families today and possibly for many years to come. Yet, diethylstilbestrol has been and still is a well-kept secret, a taboo subject not only in families but within the medical community too.

No drug manufacturers, health authorities, nor governments have ever taken responsibility for the long term health side effects of this drug.

Don’t Pharmaceutical companies have a responsibility to their consumers to provide a product that is safe?

Four sisters recently filed a lawsuit against drug manufacturer Eli Lilly. They feel that their breast cancer was a direct result of Eli Lilly’s negligence. Eli Lilly has never accepted responsibility nor apologized for the DES tragedy, even though the company has paid millions in out-of-court settlements and verdicts to DES Daughters and Sons who suffered injuries from their exposure. The Melnick sisters reached a settlement with the drug company a few weeks ago, but Eli Lilly has not accepted any responsibility. Outraged by Eli Lilly’s failure to fess up on DES, Patricia Royall, a plaintiff in one of the 72 pending DES breast cancer lawsuits in Boston federal court and the District of Columbia, is now calling on the general public to sign a petition urging the drug manufacturer to apologize for the DES tragedy. From all corners of the globe, Australia to France, the UK to the Netherlands, Ireland to the USA, DES victims are crying out for justice.

Diethylstilbestrol is a world drug disaster yet very few people know about its tragic health consequences or have even heard about it. Public health awareness campaigns are vital to reaching out to the millions of people who have been exposed to this harmful drug. People who are not aware of their exposure to DES are not receiving proper medical treatment, or making truly informed decisions about their healthcare, as a result. It is equally important to educate the next generations of health professionals who have never heard of DES so they can provide adequate care to DES victims for years to come.

DES DaughterDES is not something of the past. People who have been exposed to this drug years ago are battling with health issues and fighting for their lives as I’m writing this blog post. Who knows what health problems the grandchildren of the mothers who were prescribed this drug will have to deal with as they grow up. I want my daughters to receive adequate medical care and monitoring if they ever have to suffer the consequences of this drug. This is why together with my husband we support the great work done by the very few International DES Action Groups who are providing valuable information and are advocating for the DES victims.

If you’re concerned that you may have been exposed to DES, please don’t let doctors dismiss your concerns. Contact your local DES Action Group for professional advice and guidance.  Connect with me and other DES daughters via my blog: DES Daughter Network and my website: Journal of a DES Daughter. You have the right to know.

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This article was published previously on Hormones Matter in February 2013. 

What do male rodents and human females have in common?

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Drug Development Conducted mostly in Male Rodents

According to most researchers, male rodents share enough in common with human females to extrapolate findings about the mechanisms and treatment of pain. A review of research in the journal Pain (2007) found that over a ten year period, fully 79% of all animal studies published, performed drug testing on male animals only. Only 8% of the published research included female animals and a mere 4% investigated the possible differences between males and females.

The preponderance of male rodents in animal research is in stark contrast to the higher prevalence of women suffering from pain related disorders. I find it difficult to justify using male rodents for drug research that will be translated to the female population, especially when the estrus and menstrual cycles influence so many pharmacokinetic variables.

What do you think? How do the numbers stack up in other areas of research?

Greenspan et al. Pain. 2007 Nov;132 Suppl 1:S26-45. Epub 2007 Oct 25.
To read the full article click here.