ABSTRACT. In vitro-in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997. Despite the publication of this guidance, the deficiencies related to IVIVC are still identified by the Division of Bioequivalence in the process of Abbreviated New Drug Application (ANDA) review. Thus, the main objective of this article is to present the most commonly occurring deficiencies associated with IVIVCs via selected case studies from the ANDAs for oral ER drug products only. We searched internal FDA databases from January 1996 to December 2014 to identify the ANDAs for proposed generic oral ER drug products containing IVIVC. Only 14 ANDA submissions had IVIVC data, and most were not acceptable. Only one ANDA submission included adequate information related to IVIVC data enabling the completion of BE review within first review cycle. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs.

The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints.

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The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.