Assessment of documentation & reporting methods for annual bleeding rate in hemophilia clinical trials: Communication from the ISTH SSC Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders.

Bleed outcome measures, such as the annual or annualized bleed rate (ABR), are key efficacy outcomes for assessing hemophilia therapies in both clinical trials and daily practice. Significant variability in bleed definitions, efficacy observation duration, statistical methodology have previously been reported across observational studies, registries, and investigational trials. Over a decade ago the ISTH SSC published consensus definitions for joint and muscle bleeding, target joints, and response to therapy. The present SSC project aimed to determine whether the availability of bleed definitions and awareness of the hazards of inconsistent bleed outcome measure implementation yielded increased uniformity in design and execution of contemporary hemophilia intervention pivotal trials. A review was conducted of the primary phase III publications for extended half-life (EHL) and high-sustained activity (HSA) clotting factor concentrates (CFCs), non-factor therapies (factor VIIIa mimetics and rebalancing agents), and gene therapies. Among the 27 trials assessed, the majority (67%) did not include a bleed event definition. Only 17 trials (63%) incorporated ABR into their primary efficacy outcome. All bleed events were reported by 74% of trials, 26% only reported all treated bleed events, and 33% reported both. In most trials the planned efficacy observation duration was less than 52 weeks. Implementation and transparency of uniform bleed definitions, observation duration, and analysis methodology, particularly for pivotal trials, would facilitate both comparability among therapeutics and shared decision making for personalized care. Further, consistent harmonized adoption for all investigational hemophilia trials, observational studies, and registries would enable improved outcomes comparisons and meta-analyses.