Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada

Abstract

The present study was aimed to study the requirements of bioequivalence for the registration of pharmaceutical products in the USA, Europe and Canada. Before going into bioequivalence studies it is essential for the pharmaceutical industry to study the guidelines of bioequivalence for the respective country where the industry wants to market its products and thus enter into generic market. This study reviews the requirements of bioequivalence with study parameters such as study design, fasting or fed state studies, volunteers recruitment, study dose, sampling points, analytical method validation parameters, moieties to be measured in plasma, pharmacokinetic parameters, criteria for bioequivalence, GCP requirements etc, which are needed for the pharmaceutical industry to carry out bioequivalence studies and to file ANDA. Test products and reference products are needed for this study. Test products are usually manufactured by a sponsor and reference products are provided by the government laboratories of the respective countries. Sampling points also vary with respect to the regulatory guidelines of these countries. All these countries follow ICH GCP guidelines. The criterion of bioequivalence for these countries is 90% CI 80-125% for C max, AUC t , AUC0-∞.

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

“…Although BE studies usually recruit a small number of healthy subjects, they are calculated to detect any difference in the BE metrics. The authors in their clinical study used only eight subjects without indicating its study power, while regulatory agencies require a minimum of 12 subjects [66]. PK-Sim ® was claimed to be useful in separating the confounding factors of intestinal and first-pass metabolism that would affect the deconvoluted in vivo dissolution data traditionally used in IVIVC; however, little information was obtained regarding its use [67].…”

Comparative bioavailability study of phenytoin in healthy Nepalese volunteers

“…According to international guidelines bioequivalence study should be performed on a minimum of 12 subjects to ensure a power of at least 80%. 10 Exclusion criteria were history of hypersensitivity to phenytoin, history or presence of gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of common medications; history or presence of cardiovascular or hematological disease, any clinically significant illness during the 4 weeks prior to day 1 of this study, maintenance therapy with any drug or history of drug dependence, alcohol abuse, or serious neurological or psychological disease; participation in a new drug study in the last 6 months; HIV and Australian Antigen positive subjects; clinically relevant abnormal physical and/or clinical findings at the screening; any drug intake in the last 30 days; donated blood in the previous month. Study procedure: The study participants were randomized using sealed envelope system to avoid bias of treatment allocation.…”

Nonbioequivalent prescription drug interchangeability, concerns on patient safety and drug market dynamics in Brazil

“…The kinetic parameters related to the extent (i.e., AUC 0-t up to the last measure, and AUC 0-∞ extrapolated to infinity) and the rate (C max and T max ) of bioavailability are determined for both drug products. 11,12 . The primary concern underpinning regulatory rigorous criteria for drug bioequivalence is to ensure that patients are protected against approval of generic products that are not bioequivalent and, consequently, not safely interchangeable with a reference drug.…”

“…It is of note that the width of the 90% CI reflects to some degree the within-subject variability in the test and the product variability. In principle, a test product that does not differ from the REF might eventually fail to pass bioequivalence study criteria if variability of one or both products is high and the study involves a small number of volunteers (i.e., the test has insufficient statistical power) 4,6,10,12 . It is also possible that a test drug with a low variability passes the bioequivalence test even if the test drug and REF product exhibit large differences in the average response of pharmacokinetic parameters.…”