Pharmacogenetic Approaches to Optimize Bioequivalence Studies in Generic Drug Development.

Area of Science:

• Pharmacogenomics
• Drug Development
• Regulatory Science

Background:

• Interindividual genetic variability significantly impacts drug safety and pharmacokinetics.
• Pharmacogenetic (PGx) information is commonly used in new drug development but less explored in generic drug development.
• Integrating PGx into pharmacokinetic (PK) bioequivalence (BE) studies can improve subject safety and data robustness.

Purpose of the Study:

• To assess the current utilization of PGx information in generic drug development.
• To review US FDA product-specific guidances (PSGs) and submitted study protocols for PGx considerations.
• To understand the impact of PGx on subject selection and study design in PK BE studies for generic drugs.

Main Methods:

• Reviewed 15 US FDA PSGs containing PGx information for reference listed drugs (RLDs).
• Analyzed study protocols submitted under abbreviated new drug applications (ANDAs) or controlled correspondences for these RLDs.
• Examined the alignment of submitted protocols with PSG recommendations regarding PGx-based subject selection.

Main Results:

• Fifteen PSGs recommended PGx information for subject population selection, especially for drugs with enzyme deficiencies or CYP450 polymorphism.
• PGx considerations in PSGs primarily aimed to prevent adverse events (60%) or optimize PK BE study design (7%), or both (33%).
• Five of the 15 RLDs had submitted protocols incorporating PGx-related exclusion criteria, aligning with PSG recommendations.

Conclusions:

• Generic drug developers are beginning to integrate PGx considerations into PK BE studies, indicating growing recognition of its benefits.
• The number of submissions is currently low, but shows an increasing trend.
• Continued collaboration between regulators and industry is essential to broaden the application of PGx in generic drug development.