International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences

Abstract

The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.

Regulation of Generic Drugs in Japan: the Current Situation and Future Prospects

“…This method is used to avoid BE studies during generic drug development and is referred to as the BCS-based biowaiver. This concept has already been accepted in the USA and Europe (11). The PMDA and MHLW are considering whether BCSbased biowaivers should be accepted in Japan.…”

A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme

“…As oral drug absorption is controlled by the permeability of the drug substance through the gastrointestinal tract membrane and the solubility/dissolution of the drug dose in the gastrointestinal milieu (3), the rate and extent of absorption would be the same if the gastrointestinal concentration-time profile of the same drug substance under all luminal conditions were the same and if the excipients did not affect the absorption/permeability process. Despite being based on this single principle, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies (4).…”

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences

“…At present, the use of pharmacokinetic studies to determine BE for systemically acting drug products is common across regions (2). These drugs reach their sites of action through systemic circulation.…”