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Meta-Analysis
. 2021 Sep 1;4(9):e2124124.
doi: 10.1001/jamanetworkopen.2021.24124.

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis

Julie Martinkova  1   2 , Frances-Catherine Quevenco  2   3 , Helene Karcher  4 , Alberto Ferrari  2 , Else Charlotte Sandset  5 , Cassandra Szoeke  6 , Jakub Hort  1   7 , Reinhold Schmidt  8 , Antonella Santuccione Chadha  2   9 , Maria Teresa Ferretti  2
Affiliations
Meta-Analysis

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis

Julie Martinkova et al. JAMA Netw Open. .

Abstract

Importance: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.

Objective: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.

Data sources: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020.

Study selection: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment.

Data extraction and synthesis: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model.

Main outcomes and measures: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied.

Results: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P < .001) and Europe (68.2%; difference, -10.67% [95% CI, -12.39% to -8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03).

Conclusions and relevance: In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Quevenco reported being an employee of Roche Diagnostics International Ltd during the conduct of the study. Dr Karcher reported being an employee of Novartis during part of the conduct of the study. Dr Ferrari reported being an employee of Women’s Brain Project (WBP) and a consultant at Business & Decision Life Science, Italy, during the conduct of the study. Dr Sandset reported receiving honoraria for lectures from Bayer and Novartis unrelated to the submitted work. Dr Santuccione Chadha reported being an employee of Biogen after completion of this work and being the chief executive officer (unpaid position) of WBP during the conduct of the study. Dr Ferretti reported receiving personal fees from Eli Lilly and Company outside the submitted work and serving as the chief scientific officer of WBP during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Article Selection Flowchart
Primary articles were defined as the chronologically first article containing the main results of a trial; all other articles on the trial were considered secondary. AD indicates Alzheimer disease.
Figure 2.
Figure 2.. Proportion of Women in Primary Alzheimer Disease (AD) Articles
Percentages were obtained by pooling raw data of all patients in 56 primary articles, defined as the chronologically first publication of the main results of a trial. Squares represent percentages, with horizontal lines indicating binomial 95% CIs. Diamonds represent pooled estimates, with points of the lines indicating 95% CIs. The marker size is proportional to the precision of the estimate.
Figure 3.
Figure 3.. Temporal Trends in the Reporting of Sex-Stratification Analyses
The trend was significant only for the methods (R, 0.30; 95% CI, 0.05-0.59; P = .03). The y-axis represents the probability of inclusion of a sex-specific analysis in a study, with 1 indicating that the study included a sex-specific analysis and 0 indicating that the study did not include a sex-specific analysis. Data markers indicate observed data points, and shading, the 95% CI.
See this image and copyright information in PMC

Comment in

References

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