设计和开展罕见亚型试验的统计方法.pdf

1、Statistical Approaches for Designing and Conducting Rare Subtype TrialsWanling XieDana Farber Cancer InstituteJuly 17,2025DisclosureConsulting to PCCTC Convergent TherapeuticsMarchetti et al,Int J Mol Sci.2021 Rarity:nccRCC accounts for 20-25%of kidney cancer.Diversity:It includes multiple subtypes,

2、each with distinct molecular and clinical characteristics.Prospective trials face challenges in all phases of drug development.Characteristics of nccRCCBarriers to nccRCC TrialsPhase I-Struggled without robust biomarkers for subtype-specific drug developmentPhase II-Needed to address heterogeneity d

3、espite the small sample sizesPhase III-Often not feasible due to slow patient accrual across rare subtypes-Difficult to define a control arm in the absence of SOC for many subtypesPhase IIIb/IV-Often used a descriptive design-Enrolled community-based patients-Sample size was based on feasibilityPati

4、ent Selection for nccRCC TrialsAll-Inclusive(all nccRCC subtypes)Faster recruitment Broad application of results Heterogeneous population Dilution of overall treatment benefit-Immunotherapy trials-Early-phase trials(safety or preliminary activity).Subtype-Specific(individual variants)Homogeneous pop

5、ulation Cleaner efficacy signals Slow enrollment Not translate to other nccRCC variants-Target-therapy trials Biomarker-Enriched(biology-driven responders)Increases the likelihood of observing clinical benefit Personalized medicine Comprehensive pre-screening Complex logistics and infrastructure-MET

6、-mutant target-therapy trialsSingle-Arm One-Stage Design Small sample size&faster completion No early stopping if the drug shows limited activitySingle-Arm Two-Stage Design Early futility analysis to minimize no.of patients exposed to inactive drugs Risk of premature termination if non-responding su