PhRMA perspective on population and individual bioequivalence

Area of Science:

• Pharmaceutical Sciences
• Biostatistics
• Regulatory Science

Background:

• The U.S. Food and Drug Administration (FDA) proposed new bioequivalence guidance in 1999, introducing concepts of individual bioequivalence (IBE) and population bioequivalence (PBE).
• This draft guidance aimed to replace the 1992 guidance, which mandated average bioequivalence (ABE) for demonstrating in vivo bioequivalence.
• The proposed criteria utilized aggregate statistics, combining formulation mean differences and bioavailability variations within and between subjects.

Purpose of the Study:

• To critically review the FDA's second-draft guidance on in vivo bioequivalence, focusing on IBE and PBE concepts.
• To assess the clinical evidence supporting the proposed shift from ABE to IBE and PBE criteria.
• To evaluate the operational and public health implications of the proposed bioequivalence assessment methods.

Main Methods:

• Literature review to identify clinical evidence supporting IBE and PBE.
• Analysis of the statistical approach in the FDA's draft guidance, considering aggregate criteria.
• Examination of operational issues and potential trade-offs for innovator and generic companies, and consumers.

Main Results:

• No substantial clinical evidence was found to justify the increased burden of IBE and PBE over ABE.
• The technical statistical aspects of the draft guidance were deemed sound, but operational concerns remained.
• Uncertainty exists regarding the extent to which proposed guidance achieves prescribability and switchability goals.

Conclusions:

• The current lack of clinical evidence does not support a pressing need to change bioequivalence assessment practices.
• Concerns were raised that the proposed aggregate criteria might negatively impact public interest.
• Recommendations included further evaluation of simpler crossover designs and alternative methods for addressing limitations of ABE for specific drug types.