Some design issues in phase 2B vs phase 3 prevention trials for testing efficacy of products or concepts

Area of Science:

• Vaccinology
• Clinical Trial Design
• Infectious Disease Prevention

Background:

• Preventive vaccine candidates require efficacy evaluation after demonstrating immunogenicity in Phase 2 trials.
• No licensed vaccine currently exists for many infectious diseases, necessitating robust efficacy trials.
• Selecting the optimal initial efficacy trial size (Phase 2b vs. Phase 3) is a critical decision.

Purpose of the Study:

• To compare the expected utility of Phase 2b and Phase 3 prevention efficacy trials.
• To inform the decision-making process for designing initial efficacy trials for candidate vaccines.
• To propose a comprehensive framework for optimizing initial efficacy trial size.

Main Methods:

• Utilized the HIV vaccine field as a case study.
• Described distinguishing characteristics of Phase 2b and Phase 3 prevention efficacy trials.
• Applied Pascal's decision-theoretic framework to compare trial types.

Main Results:

• The decision-theoretic framework integrates multiple utilities: accuracy of conclusions, timeliness, precision of effect estimation, and resource expenditure.
• This framework offers a more complete approach to selecting optimal efficacy trial size compared to traditional power calculations.
• Phase 2b and Phase 3 trials have distinct roles, either contributing to licensure or advancing scientific concepts.

Conclusions:

• The proposed decision-theoretic framework aids in selecting the optimal initial efficacy trial size.
• Consideration of diverse factors beyond statistical power is essential for efficient trial design.
• Informed trial design is critical for advancing vaccine development, particularly for diseases without existing licensed vaccines.