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

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.

KEY WORDS: bioequivalence, biopharmaceutics classification system, biowaivers, generic drugs, regulatory authority

INTRODUCTION

Generic drugs are important options that allow greater access to health care. Generic drugs are copies of innovator (reference) drugs and are the same as those innovator drugs with respect to safety, strength, route of administration, quality, performance characteristics, and intended use (1). Throughout the world, an application for marketing approval of a new generic product must reference a corresponding product, which was approved on the basis of clinical trials to support claims of safety and efficacy. Various countries throughout the world, as well as organizations such as the Association of Southeast Asian Nations (ASEAN), European Union, and World Health Organization (WHO), have their own individual regulatory authorities and regulatory guidance for marketing approval of generic drug products (2).Within a jurisdiction, generic drugs are generally multisource drug products, defined as products marketed by more than one manufacturer and containing the same active pharmaceutical ingredient in the same dosage form intended to be administered by the same route of administration (3). Drug products that contain the same active ingredient(s) have the same dosage form and route of administration and are identical in strength or concentration are designated pharmaceutical equivalents (4). Drug products that contain the same therapeutic moiety, but which are different salts, esters, or complexes of that moiety, are designated as pharmaceutical alternatives.

The establishment of bioequivalence (BE) is fundamental in successful applications for generic drug products (5). BE is established in order to demonstrate therapeutic equivalence between the generic (test) drug product and corresponding reference drug product. Therapeutically equivalent drug products can be substituted with the full expectation that the substituted (generic or test) product will produce the same safety effect and safety profile as the originally prescribed (reference) product. Establishment of BE allows bridging of preclinical and clinical data associated with the reference product to the generic product.

Bioavailability (BA) is defined as the rate and extent to which an active ingredient or active moiety is absorbed and becomes available at the site of action. BE drug products are pharmaceutical equivalents or pharmaceutical alternatives that display comparable bioavailability when studied under similar experimental conditions. Two products are considered bioequivalent when the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions (6).

Drug rate and extent of absorption are typically assessed by conducting in vivo studies in human subjects in which generic and reference drug plasma pharmacokinetic (PK) profiles are characterized and compared. As per the different regulatory authorities, BE can be established by PK, pharmacodynamic, clinical, or in vitro endpoint studies, in general descending order of preference (7). Pharmacodynamic, clinical, and/or in vitro endpoint studies are generally used for locally active drugs for which PK studies may not be adequate to establish BE (8). Although “in vitro” is ranked below “clinical” in FDA’s regulations, there are situations in which an in vitro approach is equally (or more) sensitive, accurate, and reproducible than conducting an in vivo study with clinical endpoints for establishing BE between two products (9). Finally, for generic products for which BE to the corresponding reference products is self-evident, a regulatory agency may waive the requirement for conducting a BE study (10). This is commonly referred to as granting a “biowaiver.”

Since most generic drug marketing applications are for drugs intended to be systemically available, this review will emphasize comparisons of regulatory considerations governing BE studies with PK endpoints. In a BE study with PK endpoints, the PK data are used to obtain peak drug plasma concentration (C_max) as the BE measure of rate of absorption and area under the drug plasma concentration versus time profile [area under curve (AUC)] as the BE measure of extent of absorption. The time to peak drug plasma concentration, T_max, is also an indicator of drug rate of absorption. It is a common practice to log-transform generic and reference AUC and C_max values and compare the geometric mean ratios (GMRs). Two products are deemed bioequivalent if these generic/reference GMRs fall within specified BE limits.

The BA/BE concept is pivotal to generic drug development throughout the world. Currently available approaches to determine BE of generic products are largely standardized, although there are still differences that can potentially lead to barriers in international data exchange. The objective of the following article is to survey international approaches for demonstrating BE of generic drug products, with an emphasis on ways in which the approaches are similar versus ways in which the approaches differ. Identification of such similarities and differences is a preliminary step for exploring ways to promote collaboration and convergence among regulatory health authorities who are faced with making decisions about the BE of generic drugs relative to corresponding reference products.

It is important to note that BE documentation has a pivotal role in new drug development as well. BE studies are used to establish links among (1) early and late clinical efficacy trial formulations, (2) formulations used in clinical trial and stability studies, if different, and (3) clinical trial formulations and to-be-marketed formulations (11). BE studies may be necessary to support some types of post-approval manufacturing, site, or formulation changes. Although the focus of this article is on generic drug development, all of the approaches discussed herein also apply to BE studies in the context of new drug development.

METHODS

The objective of this review is to compare across various international jurisdictions and organizations the regulatory approaches for establishing BE of generic drugs to their corresponding reference drugs. The jurisdictions and organizations to be discussed will be those currently participating in the International Generic Drug Regulators Pilot (12,13). Table I lists the international jurisdictions and organizations to be discussed in this review, along with their corresponding regulatory agencies.

Table I

Regulatory Authorities and Bioequivalence (BE) Guidelines of Various Jurisdictions and Organizations Participating in the International Generic Drugs Regulators Pilot (IGDRP)

We compared similarities and differences in BE approaches for the following: