Non-traditional study designs to demonstrate average bioequivalence for highly variable drug products

Area of Science:

• Pharmacokinetics and Drug Development
• Regulatory Science
• Clinical Trial Design

Background:

• Demonstrating average bioequivalence (ABE) for highly variable drug products typically requires large sample sizes in standard crossover studies.
• Regulatory standards for ABE require 90% confidence intervals for the ratio of geometric means of AUC and Cmax to be within 0.80-1.25.

Purpose of the Study:

• To present and illustrate non-traditional study designs, specifically replicate and group sequential-replicate designs, for demonstrating ABE.
• To show how these designs can overcome challenges in achieving ABE for highly variable drug products.

Main Methods:

• Application of replicate study designs to compensate for high intrasubject variation.
• Implementation of group sequential study designs to provide early conclusive evidence.
• Analysis and illustration using data from three separate ABE studies for a highly variable drug product across different dosage strengths.

Main Results:

• Replicate designs were successfully used in all three studies to manage high intrasubject variability.
• A group sequential design was employed in the final study, yielding early conclusive results.
• The presented designs effectively addressed the regulatory requirements for ABE.

Conclusions:

• Replicate and group-sequential designs are valuable tools for demonstrating ABE in highly variable drug products.
• These designs are recommended when intrasubject variability is high or uncertain, ensuring conclusive study outcomes.
• Utilizing these advanced designs can optimize bioequivalence studies for complex drug products.