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

Philippe Lechat1,2

  • 1Emeritus Professor, Paris-City University, Paris, France. philippe.lechat@aphp.fr.

European Journal of Drug Metabolism and Pharmacokinetics
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Average bioequivalence (ABE) ensures generic drugs are similar to reference drugs. However, for narrow therapeutic index drugs, individual patient interchangeability requires stricter bioequivalence criteria beyond current ABE methods.

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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.