Bioequivalence Requirements in the European Union: Critical Discussion
Journal Title: The AAPS Journal - Year 2012, Vol 14, Issue 4
Abstract
The aim of the present paper is to summarize the revised European Union (EU) Guideline on the Investigation of Bioequivalence and to discuss critically with respect to previous European requirements and present US Food and Drug Administration guidelines its more relevant novelties such as the following: in order to facilitate the development of generic medicinal products, the EU guideline includes the eligibility for Biopharmaceutics Classification System (BCS)-based biowaivers not only for BCS class I drugs but also for class III drugs with tighter requirements for dissolution and excipient composition. The permeability criterion of BCS classification has been substituted with human absorbability, as per the Biopharmaceutical Drug Disposition Classification System. The widening of the acceptance range for Cmax is possible only for highly variable reference products with an additional clinical justification. This scaled widening is carried out with a proportionality constant of 0.760 which is more conservative than the FDA approach and maintains the consumer risk at a 5% level when the intra-subject CV is close to 30%, due to the smooth transition between the scaled and the constant criteria. The guideline allows for the possibility of two-stage designs to obtain the necessary information on formulation differences and variability from interim analyses as a part of the pivotal bioequivalence study, instead of undertaking pilot studies. The guideline also specifies that the statistical analyses should be performed considering all factors as fixed, which has implications in the case of replicate designs.
Authors and Affiliations
Alfredo García-Arieta, John Gordon
Keywords
Related Articles
- EP ID EP681272
- DOI 10.1208/s12248-012-9382-1
- Views 87
- Downloads 0
ADME of Antibody–Maytansinoid Conjugates
The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three A...
Characterization of Supersaturatable Formulations for Improved Absorption of Poorly Soluble Drugs
With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum...
Comparison of Methods for Handling Missing Covariate Data
Missing covariate data is a common problem in nonlinear mixed effects modelling of clinical data. The aim of this study was to implement and compare methods for handling missing covariate data in nonlinear mixed effects...
Microdialysis of large molecules
Microdialysis has been used in many tissues, including skin, brain, adipose tissue, muscle, kidney, and gastrointestinal tract, to recover low-molecular mass endogenous mediators, metabolites, and xenobiotics from the in...
Carrier-based strategies for targeting protein and peptide drugs to the lungs
With greater interest in delivery of protein and peptide-based drugs to the lungs for topical and systemic activity, a range of new devices and formulations are being investigated. While a great deal of recent research h...