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Purpose <p>Establishing bioequivalence (BE) for narrow therapeutic index (NTI) drugs presents unique challenges due to the delicate balance between therapeutic efficacy and toxicity. Recognizing the critical nature of NTI drugs, regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted stricter, though differing, BE criteria for NTI drugs. This manuscript aims to align with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M13’s goal of harmonizing BE standards globally.</p> Methods <p>We propose alternative FDA NTI BE criteria by capping the minimum BE limits, applying alpha adjustment, and applying a point estimate constraint. We compare the operating characteristics—Type I error rate, statistical power, and sample size requirements—of the current and proposed FDA criteria with those of the current EMA criteria and the alternative approach proposed by Paixão <i>et al</i>. Strengths and limitations of each criterion are analyzed, and areas for potential alignment across regulatory frameworks are discussed.</p> Results <p>The proposed FDA alternative criteria offer improved performance over the current FDA criteria, particularly its low power for drugs with low within-reference standard deviation (e.g., σ &lt; 0.1), maintenance of Type I error control, and close alignment with Paixao’s proposed EMA alternative.</p> Conclusions <p>Our proposed alternative FDA criteria provide both theoretical and empirical support, which will help ICH M13 Expert Working Group in developing the ICH M13C guideline with the goal of harmonizing NTI BE study design and criteria across different regulatory agencies.</p>

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A Proposal for Alternative FDA Bioequivalence Criteria for Narrow Therapeutic Index Drug Products to Support Future Harmonization

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Wanjie Sun,
  • Donald Schuirmann,
  • Fairouz Makhlouf,
  • Mark Donnelly,
  • Wenlei Jiang,
  • Hongling Zhang,
  • Mehul U. Mehta,
  • Lei Zhang,
  • Nilufer Tampal,
  • Stella Grosser

摘要

Purpose

Establishing bioequivalence (BE) for narrow therapeutic index (NTI) drugs presents unique challenges due to the delicate balance between therapeutic efficacy and toxicity. Recognizing the critical nature of NTI drugs, regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted stricter, though differing, BE criteria for NTI drugs. This manuscript aims to align with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M13’s goal of harmonizing BE standards globally.

Methods

We propose alternative FDA NTI BE criteria by capping the minimum BE limits, applying alpha adjustment, and applying a point estimate constraint. We compare the operating characteristics—Type I error rate, statistical power, and sample size requirements—of the current and proposed FDA criteria with those of the current EMA criteria and the alternative approach proposed by Paixão et al. Strengths and limitations of each criterion are analyzed, and areas for potential alignment across regulatory frameworks are discussed.

Results

The proposed FDA alternative criteria offer improved performance over the current FDA criteria, particularly its low power for drugs with low within-reference standard deviation (e.g., σ < 0.1), maintenance of Type I error control, and close alignment with Paixao’s proposed EMA alternative.

Conclusions

Our proposed alternative FDA criteria provide both theoretical and empirical support, which will help ICH M13 Expert Working Group in developing the ICH M13C guideline with the goal of harmonizing NTI BE study design and criteria across different regulatory agencies.