Comment from Yojana Patil

1. Diversity Action Plans (FDORA Mandate) •Context: The guidance cites the Food and Drug Omnibus Reform Act (FDORA) of 2022, but omits its requirement for Diversity Action Plans. •Clarification: Request the FDA specify whether a single overarching Diversity Action Plan is acceptable for a master protocol, or if individual plans are required for each substudy. •Infrastructure: Suggest adding guidelines on leveraging the master protocol's shared infrastructure and central recruitment efforts to meet diversity goals more efficiently. •Adaptive Strategies: Propose adding adaptive design elements that cap enrollment for overrepresented demographic groups to ensure adequate minority representation. 2. Endpoint Harmonization in Basket/Platform Trials •Context: The guidance emphasizes prespecifying statistical methods for leveraging data across substudies, but lacks criteria for selecting the endpoints themselves. •Standardization: Recommend the FDA clarify expectations for aligning clinical endpoints across different disease subtypes in basket trials to ensure pooled statistical analyses are clinically valid. •Heterogeneous Outcomes: Ask for acceptable statistical methodologies to bridge or translate heterogeneous endpoints when standardizing an outcome across all subtypes is not clinically viable. 3. Operational Integrity: Database Locks and SAP Timing •Context: The document highlights the risks of unblinding and information dissemination during interim analyses, but lacks operational mechanics for data locking. •Substudy Database Locks: Recommend specific protocols for locking a completed drug-specific substudy database while the broader platform trial continues enrolling. •Shared Control Protection: Ask the FDA to explicitly outline how to handle unblinding a shared control arm for one substudy's final analysis without compromising the blinding of ongoing substudies using that same control. •SAP Finalization: Suggest a strict requirement that a substudy's Statistical Analysis Plan (SAP) must be locked prior to its unblinding, with clarification on whether the master SAP must be amended simultaneously. 4. Biomarker and Diagnostic Assay Validation •Context: Master protocols often use specific biomarkers for drug-specific eligibility criteria, yet the guidance omits coordination with diagnostic validation. •Lab Testing: Request recommendations on utilizing centralized laboratory testing versus local site testing for biomarker-driven eligibility within a shared infrastructure. •Companion Diagnostics: Suggest adding a dedicated section on the regulatory expectations for co-developing in vitro companion diagnostics (CDx) alongside a master protocol. •Assay Bridging: Recommend guidance on handling scenarios where a diagnostic assay is updated or replaced during a long-running platform trial, including expectations for analytical bridging studies.