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T 10: Teething Problems of Global Harmonization with Regard to Bioequivalence Assessment: Proton Pump Inhibitors

Poster Presenter

      E. Dennis Bashaw

      • Senior Science Advisor, Office of Clinical Pharmacology
      • FDA
        United States


To provide an overview of the regulatory framework for the US and EU with focus on PK parameters in BE studies; to demonstrate the differences in conducting regulatory/scientific review between the FDA and EMA using PPIs; to discuss the prospect of global harmonization in BE assessment.


The study was conducted at the FDA. Relevant materials were gathered by: (1) analyzing the current regulatory BE requirements for drug approval; (2) evaluating publically available BE assessment reviews for approved PPI formulations from the website: “Drugs@fda”.


The US and EU regulatory agencies have established stringent requirements for the design, performance and evaluation of BE studies to ensure that only quality drug products reach the marketplace. The current statistical approach to BE assessment by both regulatory authorities is based on the “two one-sided test” procedure in which the 90% CI around the Geometric Mean of the test and reference values of AUC and Cmax is required to fall within 80.00-125.00% BE limits. The objective of these studies being to demonstrate equivalence in the “rate” and “extent of absorption” between formulations. The EMA guideline also allows in the case of highly variable drug products (HVDP) a widening of this 90%CI to a maximum of 69.84 – 143.19% for Cmax, but not for AUC, provided that the difference can be clinically justified in that there are no safety and/or efficacy concerns present. Additionally, in such a situation the EMA requires tor the acceptance interval to be widened that the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30. There is no corresponding mechanism for the widening in the US. All PPIs approved in the US met the 80-125% limits. The EMA, on the contrary, approved PPI formulations where the 90%CI limits for Cmax ranged from 69.87 to 186.96%. The estimated 90%CI for the AUC was within the 80—125% limits. Since approval a number of safety concerns with long-term PPI use have surfaced, ie fracture risk. It could be hypothesized that the high Cmax values demonstrated by BE studies could represent a risk that was not assessed during the development program where only short term usage was studied. Current usage patterns of PPIs demonstrate common treatment durations in terms of years rather than weeks. Future studies evaluating the possible long term safety concerns should be considered along with the impact of higher Cmax values on safety.


The FDA used more stringent BE PK criteria for approval of PPI formulations than the EMA. Consensus on Cmax issues has not been reached between regulatory agencies. Global harmonization could be the next step in the continuing process to improve BE guidelines to guarantee efficacious and safe drug products for consumers in all parts of the world. Disclosures: This project was supported in part by an appointment to the research participation program at the Center of Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

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