Almost three decades ago, the FDA allowed women back into clinical research to participate as subjects, but the representation of females remains an issue, especially in Phase I trials. A recent study found that low recruitment of women is still a problem in industry-sponsored early-phase trials, with females accounting for 29–34% of participants due to the pharmaceutical industry’s overfocus on childbearing potential and fertility concerns.

Inclusion of only one sex in drug development can pose risks to another. If safety profiles are built on males, excluded women are more likely to react negatively to the treatment. In several indications, including cardiovascular disease, research is focused on men and neglects to enroll enough women, explains Dr Maria Brooks, professor of epidemiology and biostatistics at the University of Pittsburgh School of Public Health.

“Historically, it has been the case that we have generalised results for men to women. It is not to say that male generated data can’t be used to hypothesise, but it is crucial to understand that both sexes differ biologically,” says Brooks.

The lack of sex equity in clinical research boils down to the financial and legal risks associated with a participant becoming pregnant. Also, recruiting female subjects might seem to create additional layers of cost and burden to sponsors as they are more likely to have adverse reactions to the investigational drug and age-related biological differences create additional subpopulations.

But are sponsors being penny-wise and pound-foolish by prioritising the recruitment of males in early-stage clinical trials? Clinical Trials Arena spoke to experts on the importance of including females in the early stages of drug development and what can be done to ensure equal representation of both sexes.

Researchers are not held accountable

Although clinical research has made immense strides in sex equity, there is still some way to go. In 2015, the National Institutes of Health (NIH) released a policy to consider sex as a biological variable (SAVB) in research. It entailed the need for providing a strong justification to only include one sex in an NIH-funded study. Even though the policy was issued seven years ago, there is a lag period, says Dr Marcia Stefanick, professor of obstetrics and gynecology at Stanford University School of Medicine .

Yet, such policy does not guarantee an equal sex representation in clinical trials, says Dr Martha Gulati, cardiologist at Cedars-Sinai Heart Institute specializing in women’s heart disease. She explains while a strong justification for only one sex is needed and the NIH checks on the study at different stages, nothing happens if the trial is finished and not enough women were recruited. “NIH shouldn’t give the last check to the investigators if they completed the study, and they didn’t do what they said they will,” she adds.

Dr Martha Gulati, cardiologist at Cedars-Sinai Heart Institute specializing in women’s heart disease.

Jill Fisher, PhD, professor of social medicine at the University of North Carolina at Chapel Hill, is less optimistic about things changing anytime soon. She says that the pharma industry is behind when it comes to thinking about sex-based differences that might manifest in treatments. “If we really do want to make sure that women are better represented in early-phase trials, it has to come from an agency like the FDA saying that it’s required,” she notes.

Regulatory agencies need to hold researchers, whether they are pharma companies or universities, accountable, Gulati says. Even though the NIH Revitalization Act of 1993 revoked the FDA’s guideline in 1977 banning most women with childbearing potential from clinical trials, there was no federal oversight or mechanism to ensure accountability. “They need to be stricter on what populations are being recruited in the trials, so if they see that there are enough men, they need to ensure sponsors start enrolling women,” she notes, highlighting that the FDA should reflect if the trial was adequately done in the population the drug will be eventually used in.  

Sex differences influence drug research

Studying only one sex when developing new treatments misses a whole spectrum of information on how a drug works. This is because males and females have many differences in drug metabolism, pharmacodynamics (PDs), and pharmacokinetics (PKs), says Stefanick.

Indeed, females are more likely to experience adverse drug reactions (ADRs) than males. If the safety and tolerability data starts to be established in only one sex in Phase I trials, the bias will be moving forward in the drug development pipeline, Fisher says. “There is this sense that Phase I clinical trials are really just ticking a regulatory box that safety and tolerability have been assessed,” she adds.

Fisher shares her experience of interviewing a clinical investigator who ran a Phase I trial facility. In one trial, which allowed female participants, there were a lot more adverse events (AEs) than expected. “The pharma company wanted them to rerun the trial but this time they excluded women. The adverse event profile was much better, and it was much more what the pharmaceutical company was looking for,” she explains. “By excluding women, not only are they potentially saving themselves from liability if a woman should get pregnant, but they are also making their drugs appear safer or more tolerable than they really are.”

Even if females are included in the trial, avoiding the data analysis by sex does not paint the whole picture. Stefanick says that simply showing a percentage of female participants does not prove that the drug actually works in that population. However, this means that sponsors need to recruit enough of both sexes in the trials. “If you have 90% of men and only 10% of women, you won’t have enough data to show reliable results amongst females,” Brooks says.

Female-related costs in recruitment

While data from preclinical and non-human animal studies has challenged the notion that female readouts are more variable due to their oestrous and menstrual cycles than males, recruiting women is still often seen as an additional burden to clinical trial sponsors.

The first issue is female fertility and reproductive health. While females are now legally allowed to participate in clinical trials, sponsors have not relaxed a lot of their restrictions on the participation. This is likely due to clinical trials starting before reproductive toxicity testing is completed in non-human animals, Fisher says.

The female inclusion criteria often request two methods of birth control, but the industry still lacks trust in women not to get pregnant. Even though males are also instructed not to impregnate someone, there is no real accountability or surveillance, Fisher says. The inclusion of women is a financial and legal liability for pharmaceutical companies, as possible negative effects on the foetus and eventual child can pose additional costs, she adds.

Jill Fisher, PhD, professor of social medicine at the University of North Carolina at Chapel Hill.

Commitment to an early-stage clinical trial can present logistical challenges for women. Childcare responsibilities and juggling jobs are not a trivial set of barriers for women to overcome, Brooks says. Lack of day-to-day burdens makes male participants easiest to recruit. However, even if women do figure out childcare arrangements, many clinical trials still avoid enrolling them, Fisher notes.

A woman’s age is also an important factor in research. There are biological differences in pre- and postmenopausal women so ideally the drug should be tested in both populations. Stefanick says that if pharma companies are making an argument that they cannot afford to study two different groups of female population, it is “just sexism and market capitalism.”

While these are extra costs, precautions, and burdens on sponsors, they are valuable in terms of gaining a better understanding of how the drugs work, Brooks says. At the end of the day, it can be even more costly to withdraw the drug from the market if it has increased AEs or lack of effectiveness in women, she adds.

Improving sex equity in clinical research

If sponsors want to get better at sex representation, they need to give a seat for women at the table when trials are planned, discussed, and executed, Gulati says. “If you have a more diverse panel, board, or research team, you will get more diversity in clinical trials. This has always been the boys club,” she notes.

Enrollment is always a challenge in every clinical trial, but as female participants face additional barriers to participate, different approaches need to be taken. Brooks shares that reaching out to female- focused organizations or posting on Facebook groups can help with recruitment. Clinical Trials Arena previously reported on how to navigate the social media traps when recruiting for clinical trials.

It is crucial to include the female perspective to overcome female-related barriers. For example, Gulati was a part of a community-based study, the Women Take Heart Project, which recruited nearly 6,000 women. The recruitment was very quick because women were advising investigators on what is the best way to get females from the community into the trial. They offered valet parking services and provided babysitting while women filled out questionnaires and got bloodwork done.

Adding an enrollment cap on one population can help. For example, if a certain number of white men are enrolled, the focus should shift to other racial and ethnic groups, including men, as well as women to ensure diversity and balance, Brooks says.

Clinical research is shifting towards patient-centricity. Gulati says that including patients’ voices and asking them about how to overcome their population barriers will help to design a clinical trial. “Design your trials around the patients instead of the medical community,” she adds.

Takeaways:

  • No oversight and accountability are held on sponsors who are not including this population. Regulatory agencies and government funding institutions are encouraged to take action on researchers.
  • Tolerability and safety data based on males only creates bias that moves forward down the development pipeline. This poses an increased risk of ADRs for females.
  • Childbearing potential and possible harm to the foetus or eventual child are perceived as operational, financial, and legal challenges, but mask larger issues if a balanced sex representation is not ensured in clinical studies. Additionally, data analysis by sex should become a norm to properly characterise drugs’ safety and efficacy profiles in women.
  • Reaching out to female-focused organisations and social media groups can facilitate awareness of clinical trials and improve recruitment. Sponsors should incorporate females’ voices in designing clinical trials to facilitate their participation.