Attention to Sex as a Biological Variable in Phase III Neurological Trials Before and After the 2017 NIH Amendment: a Systematic Review in MS
Ayushi Balan1, Riley Bove2, Maria Pia Sormani3, Maria Houtchens4
1UCSF, 2University of California, San Francisco, 3University of Genoa, 4Brigham and Women's Hospital
Objective:
To evaluate whether analyses of SABV or gender in Phase III randomized controlled clinical trials (RCTs) for MS disease modifying treatments (DMTs) improved after 2017.
Background:
Despite established sex differences in risk and course for neurological diseases such as multiple sclerosis (MS), many clinical studies fail to adequately account for sex as a biological variable (SABV) or gender. In 2017, the NIH amended its SABV guidance to include all federally funded Phase III clinical trials.
Design/Methods:
A systematic review of all published Phase III RCTs registered on CT.gov for FDA-approved MS DMTs and published before 9/1/2022 was performed. Pharmaceutical companies provided additional information. Each study was graded according to specific criteria published by an expert review, and trials published before and after 2017 were compared.
Results:
40 pivotal trials evaluating 18 pharmacological products were identified. Before and after 2017, there was no difference (p>0.10) in the: proportion of trials comparing baseline demographic or disease characteristics by sex, characteristics which might influence trial outcomes (0/31 vs 0/9); prespecified stratification of clinical outcomes by sex (10/31 vs 4/9); post-hoc stratification of clinical outcomes by sex (9/31 vs 2/9); adequate power to evaluate for significant sex-specific efficacy or safety outcomes (3/31 vs 0/9); inclusion of older populations more likely to be postmenopausal (>55 years; 5/31 vs. 3/9). Labels for products with trials published after 2017 were more likely to report on sex-specific efficacy, safety or toxicity (6/13 vs 5/5).
Conclusions:
The 2017 NIH amendment to consider SABV in federally funded trials resulted in a modest improvement in SABV analyses in pharmaceutically-sponsored pivotal MS clinical trials. This represents a missed opportunity, as the availability of rigorously collected data as well as guidelines for analysis would allow for the analyses necessary to maximize safety and efficacy in specific patient populations.