A nested group sequential framework for regional evaluation in global drug development program.

Area of Science:

• Biostatistics
• Clinical Trial Design
• Pharmacometrics

Background:

• Multiregional clinical trials (MRCTs) assess regional efficacy and generalizability.
• Evaluating target region consistency with overall results is standard practice.
• Existing frameworks like Huang et al.'s (2012) for simultaneous global drug development programs (SGDDP) require further operational consideration.

Purpose of the Study:

• To propose a novel nested group sequential program for regional efficacy evaluation within MRCTs.
• To extend the SGDDP framework by incorporating interim analyses during both MRCT and local clinical trial (LCT) phases.
• To enhance the control of family-wise type I error and increase program flexibility.

Main Methods:

• The proposed program allows interim analyses after the MRCT and during the LCT phase.
• A virtual trial approach using a discounting factor is introduced for LCT sample size estimation.
• An iteration method calculates sample size and interim analysis stopping boundaries.

Main Results:

• The nested group sequential program effectively controls the family-wise type I error rate.
• The proposed sample size estimation method was validated through simulations.
• The impact of varying weights, target ethnic (TE) population effect sizes, and design settings was explored.

Conclusions:

• The nested group sequential program offers a flexible and statistically robust approach for regional efficacy evaluation in MRCTs.
• The method provides a valuable extension to existing SGDDP frameworks.
• The approach is applicable across various endpoint types, including normal, binary, and survival data.