Sickle cell disease trials redefined: Toward unified clinical endpoints through international consensus

Abstract

Abstract Introduction Despite significant progress in the treatment of sickle cell disease (SCD), many clinical trials (especially recent phase 3 trials) have failed to meet their primary endpoints. Some approved therapies have even been withdrawn from the market, emphasizing the need for more reliable methods to assess treatment outcomes. A major contributing factor is the lack of standardization in the definition and measurement of clinical endpoints, which complicates cross-study comparisons and interpretation of treatment efficacy. These inconsistencies further hinder the development of clear guidance for regulatory agencies and pharmaceutical companies. With the rapid growth of SCD trials, especially those exploring gene therapy and disease-modifying treatments, there is an urgent need for consensus on clinically meaningful and practical endpoints. To address this, we conducted an international consensus exercise using a structured methodology to identify and standardize key clinical endpoints for SCD trials. Methods We employed a modified Delphi method to achieve expert consensus on core clinical endpoints for SCD trials. A panel of 15 senior hematologists from five continents participated. A six-member steering committee drafted 20 consensus statements, organized under five categories: (1) terminology and definitions, (2) vaso-occlusive episodes (VOEps), (3) pain-related endpoints, (4) hemolysis as an endpoint, and (5) anemia-related outcomes. Each expert rated the statements using a 3-point Likert scale (agree, neutral, or disagree). Consensus was defined at ≥65% agreement. Statements not meeting this threshold were to be revised following expert feedback. A single round of voting was conducted as on August 4, 2025. Results The process yielded strong consensus across several key domains. Approximately 73.33% of experts agreed on a comprehensive definition for vaso-occlusive episode (VOEp) to include vaso-occlusive crisis (referring exclusively to pain crisis) and other SCD-related complications, such as acute chest syndrome, priapism, hepatic, and splenic sequestration. All experts (100%) endorsed applying this unified definition across all SCD trials, including those involving gene therapy. There was unanimous agreement (100%) that pain frequency and its reduction should be prioritized as primary endpoints in clinical trials focusing on pain reduction or resolution. Additionally, 86.67% of experts supported the inclusion of this endpoint in both pediatric and adult pain-specific studies. Functional ability was also unanimously endorsed (100%) as an important complementary measure alongside pain intensity. Regarding hemolysis, all experts (100%) agreed that it should be considered a secondary endpoint in patients with recurrent pain episodes. A hemoglobin increase of atleast 1 g/dL was supported by 86.67% of experts as a meaningful clinical endpoint for SCD. Further, 86.67% of experts endorsed distinguishing between acute and chronic hemolysis for subgroup analysis. As for anemia management, there was unanimous agreement (100%) on the importance of differentiating hemoglobin correction targets between acute and chronic anemia in patients with SCD. Conclusion This international consensus marks a pivotal step toward standardizing clinical endpoints in SCD trials. It emphasizes the importance of uniform definitions for VOEp, prioritization of pain-related outcomes, and the inclusion of hemolysis markers and functional ability in outcome assessments. Areas that require further deliberation include the role of pain endpoints in adult-specific trials and the refinement of anemia management strategies. A second round of voting is planned to resolve these issues and advance toward a comprehensive endpoint framework for future SCD trials.