Bioequivalence Requirements in the European Union: Critical Discussion

Abstract

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 C max 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 intrasubject 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.

Statistical Comparison of Dissolution Profiles to Predict the Bioequivalence of Extended Release Formulations

“…Several questions remain open as to which is the most suitable procedure to declare BE (38,55,(59)(60)(61)(62) and which other mathematical expressions could model drug release more mechanistically (63,64). If these customized DPC tests are attempted to be used for generic drugs, serious harmonization efforts should be made to share these IVIVC models between agencies and manufacturers.…”

Utility of Pilot Studies for Predicting Ratios and Intrasubject Variability in High‐Variability Drugs

“…Pilot studies were considered to have demonstrated bioequivalence if the 90% confidence interval of the ratio of the means for the pharmacokinetic parameters (AUC 0-t and C max ) is within the acceptance interval of 80.00-125.00% [1,2,[10][11][12][13][14].…”

“…However, it is true that authors such as Fuglsang [7], Mathew et al have studied different methods and tools for the development of pilot studies. Standardization of these procedures could ensure appropriate design and development of pilot studies, which would in turn enable correct evaluation of the drug and successful design of the pivotal study.In pivotal studies, the test and reference formulations can be considered bioequivalent if the 90% confidence interval of the ratio of the means of the pharmacokinetic parameters (area under the plasma concentration curve from administration to the last observed concentration at time t [AUC 0-t ] and maximum plasma concentration [C max ]) is within the acceptance interval of 80.00-125.00% [1,2,[10][11][12][13][14]. Even though demonstrating bioequivalence of the formulations is not the purpose of a pilot study, the results may help to design a pivotal study appropriately [1,3,[5][6][7][8]15,16].…”

Asthma and COPD: Interchangeable use of inhalers. A document of Italian Society of Allergy, Asthma and Clinical Immmunology (SIAAIC) & Italian Society of Respiratory Medicine (SIMeR)

“…In case the therapeutically active moiety is known and M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 marketed drug product already exists, a generic applicant will provide evidence on the quality of the new generic product with reference to existing safety and efficacy data when submitting a generic of the product. Although bioequivalence principles have firmly been defined [5], at present there is no international consensus on many of the details regarding the requirements for the design, conduct and evaluation of bioequivalence studies. Consequently, each regulatory authority [see e. g. [8][9][10] has issued its own corresponding guidelines.…”