Clinical Trial Designs for Rare Disorders: A Scoping Review of the Effectiveness of Pharmacologic Interventions in...

Rare disorders (RDs) collectively affect a substantial proportion of the population, yet most lack clinically approved, mechanistically targeted therapies. Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and a major genetic contributor to autism spectrum disorder, exemplifies this gap. Despite more than 3 decades of preclinical research and numerous pharmacologic clinical trials informed by disease mechanisms, no targeted therapy for FXS has received regulatory approval. This scoping review aims to evaluate the design characteristics, outcome measures, and reported effect sizes of pharmacologic clinical trials in FXS to highlight methodological limitations that may have hindered the accurate assessment of therapeutic efficacy in FXS and to inform future trials in RDs.

We conducted a scoping review of published interventional studies involving individuals with FXS, identified through searches of PubMed, Excerpta Medica Database (EMBASE), PsycINFO, and CENTRAL. Eligible studies were pharmacologic trials that reported sufficient statistical information to calculate effect sizes for recurrent behavioral outcome measures. 23 trials met inclusion criteria, comprising 14 placebo-controlled randomized controlled trials (RCTs) and 9 open-label studies, with a total of 1,469 participants. Recurrent outcome measures included the Aberrant Behavior Checklist (the FXS-specific ABC-Cfx), the Clinical Global Impressions-Improvement scale, the Vineland Adaptive Behavior Scales-Second Edition (VABS-II), and the Visual Analog Scale (VAS) for Anxiety (VAS Anxiety). The median absolute effect sizes were small among RCTs (|d| = 0.22) and moderate among open-label studies (|d| = 0.70). Across studies, substantial heterogeneity was observed in trial design, sample size, participant characteristics, and outcome measures, complicating cross-trial comparisons and interpretation of efficacy signals.

Collectively, existing pharmacologic trials in FXS have demonstrated limited and inconsistent treatment effects, with interpretation constrained by small sample sizes, heterogeneity in designs and outcome measures, and differences in participant characteristics. Greater standardization of trial design and outcome assessment, improved alignment between outcome measures and treatment mechanisms, and careful consideration of participant stratification are critical to improving signal detection in future trials. These insights have broader relevance for RD research, where methodological rigor is essential to translating promising mechanisms into effective therapies.