The proportion of women in randomized clinical trials (RCTs) for Alzheimer’s disease (AD) was lower than the proportion of women in the U.S. and European population with AD, a systematic review and meta-analysis found.
In addition, few Alzheimer’s RCTS reported sex-stratified results, according to Maria Teresa Ferretti, PhD, of the Women’s Brain Project in Guntershausen, Switzerland, and co-authors.
“In this systematic review and meta-analysis, of the 56 selected RCTs, 59.0% of the included participants were women, and 57.9% were women in the subgroup of trials of experimental drugs,” Ferretti and colleagues wrote in JAMA Network Open.
“Although this indicated greater trial enrollment of women compared with men, these numbers are significantly lower than the proportions of women reported in real-world populations with AD (68.2% in Europe and 62.1% in the U.S.),” they added. “These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.”
The Women’s Brain Project aims to identify sex and gender determinants to brain health, Ferretti said in an email to BreakingMED. The group is committed to identifying patient differences and characteristics in diseases like Alzheimer’s to achieve precision medicine, she noted.
In this study, the researchers identified pharmaceutical RCTs for AD with more than 100 participants, including 56 primary articles on AD from 2008 to 2019. They also considered 13 secondary articles on AD and eight articles on mild cognitive impairment. Variables of interest included number of participants, sex, and age; disease severity; experimental or approved status of the treatment, including herbal remedies; and whether the study included a sex-stratified analysis in its protocol, methods, or results.
Of 56 RCTs for AD involving 39,575 participants, 23,348 women were included. Overall:
- The mean proportion of women in RCTs of approved drugs was 67.3%, and trials of approved drugs had a higher probability of including women than trials of investigational drugs (OR 1.26, 95% CI 1.05-1.52; P=0.02).
- The mean proportion of women in RCTs of investigational drugs was 57.9%. The proportion of women in RCTs of investigational drugs was significantly lower than the proportion of women in the general population with AD in the U.S. (difference −4.56%, 95% CI −6.29% to −2.87%; P<0.001) and Europe (difference −10.67%, 95% CI −12.39% to −8.97%; P<0.001).
- Baseline AD severity and trial location were both associated with the probability of women being enrolled in a trial: baseline severity OR 0.98 (95% CI 0.97-1.00; P=0.02), location in Europe OR 1.26 (95% CI 1.05-1.52; P=0.01), and location in North America OR 0.81 (95% CI 0.71-0.93; P=0.002).
- Only seven articles (12.5%) reported sex-stratified results.
“Clinical trials are expensive, time-consuming, and difficult to complete, and the data from trials should be used and made accessible to the fullest extent,” observed Janice Schwartz, MD, of the University of California, San Francisco, and Sandra Weintraub, PhD, of Northwestern University in Chicago, in an accompanying editorial.
“Potential group differences in responses to medications need to be more widely investigated, and available data needs to be made more user friendly to facilitate incorporation into our knowledge base and clinical care,” the editorialists noted. “Finally, it is important to also close the gaps in our knowledge about subgroups of patients with AD beyond sex or gender.”
A 2019 report noted that the study of sex and gender differences in Alzheimer’s is in its infancy compared with other areas of medicine. “The field of cardiology has shown that there are sex and gender differences in risk factors, symptom presentation, mortality, and treatment response for cardiovascular diseases,” the author pointed out. “Better understanding of these sex and gender differences has led to improved care and treatment for both women and men. The same positive outcome can occur for the prevention and treatment of AD dementia.”
The findings of this systematic review and meta-analysis could stimulate discussion about three important aspects of diversity in RCTs, Ferretti and co-authors suggested. As with any multifactorial disease, a realistically diverse patient population might be needed to detect relevant outcomes in a trial, they noted. “For example, RCTs for migraine, a disease that largely affects women and for which several new drugs have been discovered, enroll more women than men, with proportions that reflect the expected real-world sex ratio,” the researchers wrote.
In addition, specific challenges may apply to certain populations of women. Exclusion criteria for RCTs — for instance, based on educational level — might systematically exclude more women than men, Ferretti and colleagues said.
Finally, publishing practices should be accountable, the researchers pointed out. Complete protocols were available in 30.4% of published results, “a percentage that should increase for the sake of transparency,” they noted. “Describing sex-stratified data (even if no differences are found) should become a routine in clinical data publication, and is also important for avoiding publication bias.”
Limitations included the exclusion of trials studying only pharmacokinetics or safety. Some potential sex differences in these dimensions were not included, despite known sex differences in safety and pharmacokinetic profiles for some drugs used in AD, such as antipsychotic medications.
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The proportion of women in randomized clinical trials (RCTs) for Alzheimer’s disease (AD) was lower than the proportion of women in the U.S. and European population with AD, a systematic review and meta-analysis found.
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Few Alzheimer’s RCTS reported sex-stratified results.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Researchers were supported by the Charles University Grant Agency, Second Faculty of Medicine, by the Avast Foundation together with the Czech Alzheimer’s Foundation, and by grants from the National Health and Medical Research Council, Australia, and the Alzheimer’s Association.
Ferretti reported receiving personal fees from Eli Lilly and Company outside the submitted work and serving as the chief scientific officer of Women’s Brain Project during the conduct of the study.
Schwartz and Weintraub had no disclosures.
Cat ID: 33
Topic ID: 82,33,282,485,730,33,255,925
