Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Sciences
• Regulatory Science

Background:

• Marketing authorization for generic drugs relies on average bioequivalence (ABE) using a 90% confidence interval (CI) of 0.8-1.25 for exposure ratios.
• ABE methodology may not ensure therapeutic impact for drugs with narrow therapeutic indices, questioning patient-level interchangeability.
• Regulatory agencies have proposed adaptations to ABE for highly variable drugs and those with narrow therapeutic indices.

Purpose of the Study:

• To review the limitations of average bioequivalence (ABE) methodology for ensuring drug interchangeability at the individual patient level.
• To discuss regulatory adaptations of ABE criteria for generic drug approval, particularly for narrow therapeutic index drugs.
• To propose alternative bioequivalence criteria for assessing drug interchangeability in individual patients.

Main Methods:

• Review of existing literature on average bioequivalence (ABE) and its limitations.
• Analysis of regulatory adaptations proposed by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).
• Discussion of statistical challenges and practical considerations for individual bioequivalence studies.

Main Results:

• Current ABE criteria do not guarantee therapeutic interchangeability for narrow therapeutic index drugs.
• Regulatory agencies like EMA and FDA have proposed stricter ABE limits or modified study designs (e.g., replicate cross-over studies).
• Despite amendments, individual exposure ratios can still vary significantly, posing challenges for interchangeability.

Conclusions:

• Average bioequivalence (ABE) alone is insufficient for ensuring interchangeability of generic drugs, especially for narrow therapeutic index medications.
• Proposed alternative criteria, such as using the 95% CI of individual exposure ratios scaled to the therapeutic margin, could enhance patient safety.
• Further research and analysis of real-world bioequivalence data are needed to validate these proposed criteria for regulatory acceptance.