Supporting Evidence in Phase 2 Cancer Trial Protocols: A Content Analysis.

Background: Phase 2 trials are instrumental for designing definitive efficacy trials or attaining accelerated approval. However, high attrition of drug candidates in phase 2 raises questions about their supporting evidence.

Methods: We developed a typology of supporting evidence for phase 2 cancer trials. We also devised a scheme for capturing elements that enable an assessment of the strength of such evidence. Using this framework, we content analyzed supporting evidence provided in protocols of 50 randomly sampled phase 2 cancer monotherapy trials starting between January 2014 and January 2019, available on ClinicalTrials.gov.

Results: Of the 50 protocols in our sample, 52% were industry funded. Most invoked supporting evidence deriving from trials against different cancers (n = 28, 56%) or preclinical studies (n = 48, 96%), but not from clinical studies involving the target drug-indication pairing (n = 23, 46%). When presenting evidence from models, only one protocol (2%) explained their translational relevance. Instead, protocols implied translatability by describing molecular (86%) and pathophysiological (84%) processes shared by model and target systems. Protocols often provided information for assessing the magnitude, precision and risk of bias for supporting trials (n = 43, 93%, 91%, 47%, respectively). However, such information was often unavailable for preclinical studies (n = 49, 53%, 22%, 59%).

Conclusion: Supporting evidence is key to justifying the commitment of scientific resources and patients to a clinical hypothesis. Protocols often omit elements that would enable critical assessment of supporting evidence for phase 2 monotherapy cancer trials. These gaps suggest the promise of more structured approaches for presenting supporting evidence.