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FDA analysis: Women underrepresented in HF, CAD, ACS trials
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Women are underrepresented in pivotal clinical trials of drugs for patients with HF, CAD and ACS, according to an FDA analysis published in the Journal of the American College of Cardiology.
Representation of women was appropriate in trials of drugs for hypertension and atrial fibrillation, and women may have been overrepresented in trials of drugs for pulmonary artery hypertension, Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the FDA, and colleagues wrote.
“As we move into the era of precision medicine, that is assessing the impact of a wide range of patient and disease characteristics on drug effects, it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Woodcock said in a press release. “This will move us closer to our goal of providing the best information possible about the use of drugs for every patient.”
Enrollment of women
Woodcock and colleagues assessed the enrollment of women in trials supporting the approvals of 36 CV drugs between 2005 and 2015. They calculated prevalence-corrected estimates of participation by women according to disease area. This figure was determined by the percentage of women in a trial divided by the percentage of women in the disease population. The resulting prevalence-to-participation ratio was considered appropriate if it fell between 0.8 and 1.2.
The researchers also analyzed whether there were any clinically meaningful differences by sex in trial results.
Among the trials analyzed, the enrollment percentage of women ranged from 22% to 81% (mean, 46%), Woodcock and colleagues wrote.
The prevalence-to-participation ratio was less than 0.8, signifying underrepresentation of women, in trials for drugs to treat HF (0.5 to 0.6), CAD (0.6) and ACS or MI (0.6), according to the researchers.
The ratio was in the acceptable range for trials for drugs to treat AF (0.8 to 1.1) and hypertension (0.9) and was high in trials for drugs to treat PAH (1.4), Woodcock and colleagues wrote.
“Based on this work, future research is needed to identify factors leading to under-participation of women in cardiovascular clinical trials, particularly those occurring before screening,” Pamela Scott, PhD, director of research in the Office of Women’s Health at the FDA, said in the release. “Research is needed to better define barriers that limit participation of diverse populations, not only of women but of minority and older populations.”
Results of most trials did not differ by sex. The trial for the angina drug ranolazine (Ranexa, Gilead Sciences) showed women had fewer reductions in angina frequency and nitroglycerin use compared with men, and trials for three hypertension drugs showed clinically significant sex differences in safety, the researchers wrote, noting that in all four cases, the differences are described in the product labeling.
Possible consequences
In a related editorial, Louise Pilote, MD, MPH, PhD, from the divisions of general internal medicine and clinical epidemiology at McGill University Health Centre in Montreal, and Valeria Raparelli, MD, PhD, from the department of experimental medicine at Sapienza University of Rome, wrote: “The inadequate participation of women in clinical trials could result in several significant issues, including male-patterned inclusion criteria, sex-biased outcomes measurements, inadequate data analysis, and the missed opportunity to transfer results in clinical practice.” – by Erik Swain
Disclosures: The authors, Pilote and Raparelli report no relevant financial disclosures.
Perspective
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Carl J. Pepine, MD, MACC
It’s also important to note that women were underrepresented in the SPRINT trial (Wenger NK, et al. Am J Med. 2016;doi:10.1016/j.amjmed.2016.06.022). Thus, we don’t have the highest level of evidence to support the new lower target BP in women where hypertension is so prevalent.
Perspective
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Sonal Chandra, MD
These findings are in keeping with the historical trends where there persists a sex-based discrepancy resulting in underrepresentation of women in CV clinical trials despite similar prevalence, differing disease manifestation, physiological differences and worse outcomes. It is countercurrent to initiatives in personalized or genomic-based medicine or to the NIH initiative emphasizing sex-specific design and analysis in clinical trials.
In part, the underrepresentation is due to age of enrollment. Women present later in life, which may result in their exclusion from a trial due to age cutoff limits. Alternatively, women of childbearing age are sometimes not included due to fear of a drug’s effects on pregnancy or that hormonal variation may confound experimental outcomes. Also, there is the concept of generalizability, where findings of an overrepresented group can be applied on another. I think, in large part, this is driven by the initial trial design, which is not seeking a sex-specific variation or outcome.
An emphasis on understanding the sexual dimorphism that dictates epidemiology, disease manifestation and outcomes is needed not only in cardiology trials, but in clinical practice and guidelines. Educating the female research participants and potential referring clinicians on goals of research trials, which includes delving into sex-specific pathologies along with age-related risk, may improve enrollment as well. Federal or grant funding requiring equal representation of genders may be necessary.
Research trials need to heed the demands of our patients and practitioners. Gender-based disparities have been well established in clinical management, affecting access to and timing of therapeutic interventions and, therefore, prognosis. As we are changing our clinic practice to overcome our implicit biases, so should the researchers designing these trials. Otherwise, continued underrepresentation will hamper our understanding of female biology.
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