Equivalence assessment for interchangeability based on two-sided tests.

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Biostatistics
• Drug Development

Background:

• Drug interchangeability assessment evolved beyond average bioequivalence, with FDA guidance in 2003 focusing on population and individual bioequivalence.
• Existing FDA procedures faced criticism for lacking sampling distribution and consistency with average bioequivalence requirements.
• Previous alternative methods proposed calculating the probability of individual response differences within specified limits.

Purpose of the Study:

• To generalize the two-sided tolerance interval-based interchangeability assessment.
• To remove assumptions of equal sample size and variance in interchangeability testing.
• To derive a power function for the proposed method and compare it with existing approaches.

Main Methods:

• Generalized the two-sided tolerance interval approach for interchangeability.
• Derived a power function for the generalized method.
• Conducted simulation studies to compare type I error rate, power, and sample size with an existing approximation method.

Main Results:

• The generalized tolerance interval approach provides a more consistent and adaptable method for assessing drug interchangeability.
• Simulation studies demonstrated the performance characteristics of the new method in terms of error rates, power, and sample size requirements.
• The proposed method addresses limitations of previous simulation-based critical points and offers an alternative to the Tse approximation.

Conclusions:

• The generalized tolerance interval method offers a statistically sound and practical approach to drug interchangeability assessment.
• This method provides a more reliable framework for regulatory decisions regarding test and reference drug products.
• Further research can extend this approach to various clinical trial designs and statistical assumptions.