The Two Main Goals of Bioequivalence Studies.
The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product's in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered.
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada. l.endrenyi@utoronto.ca.
Laszlo
L
Endrenyi
SocraTec C&S, Oberursel, Germany.
Henning H
HH
Blume
Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
Laszlo
L
Tothfalusi
D019540:Area Under Curve; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
bioequivalence; clinical surrogate; product performance; regulatory expectations; sensitive discrimination