A seamless Phase IIB/III adaptive outcome trial: design rationale and implementation challenges
*Ivan Chan, Merck Research Labs  Joshua Chen, Merck 

Keywords: Seamless, Phase IIB/III, adaptive design

The licensed 4-valent prophylactic Human Papillomavirus (4vHPV) vaccine is highly efficacious in preventing cervical, vulvar, vaginal and anal cancers and related precancers caused by 4 HPV types 6, 11, 16 and 18. These types account for approximately 70% of cervical cancers. A 9-valent HPV (9vHPV) vaccine including the 4 original types (6, 11, 16, 18) plus the next 5 most prevalent types in cervical cancer (31, 33, 45, 52, 58) could provide approximately 90% overall cervical cancer coverage. To expedite the 9vHPV vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ~15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed 4vHPV vaccine and the development objectives for the 9vHPV vaccine. Subjects enrolled in the Phase IIB portion of the study who received either the selected 9vHPV formulation or 4vHPV vaccine contributed ~10% of person-years of follow-up due to its earlier start - thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authority, and managing changes in the assay for immunological endpoints. Lessons learned from this seamless adaptive design will be shared in this talk.