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Delivering an Integrated Summary of Safety: Resolving Data Inconsistencies and Complex Derivations to Support Regulatory Submission 

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Published: October 22nd, 2025

Phastar supported a sponsor in preparing an Integrated Summary of Safety (ISS) for an investigational drug in sickle cell disease, pooling data from three studies: two Phase 3 randomized trials (single- and multiple-dose) and one open-label extension. 

Key Challenges: 

  • Inconsistent ADaM Structures: Critical domains (ADSL, ADLB, ADAE, ADVS) required reconciliation. 
  • Varying Safety Set Definitions: Differences across studies complicated treatment and baseline flag creation. 
  • Complex Derived Variables: ADAE derivations demanded strict adherence to coding standards. 
  • Compliance Calculation Discrepancies: Divergent approaches had to be standardized. 
  • MedDRA Up-Versioning: Two up-versioning steps were required for consistent adverse event coding. 

Our Approach: 

  • Standardized ADaM structures across all studies. 
  • Implemented flexible flagging logic to accommodate differing safety sets. 
  • Designed robust logic for complex ADAE derivations, ensuring consistent adverse event capture. 
  • Aligned compliance calculations with a body weight–adjusted formula. 
  • Managed MedDRA up-versioning to maintain data integrity. 
  • Maintained strong client engagement with weekly operational meetings to ensure rapid issue resolution and alignment. 

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