Bioequivalence Behind the Scenes

Abstract

This paper focuses on some unresolved issues in bioequivalence. In these cases, intrinsic difficulties not clearly considered in EU and US FDA operating guidelines are involved. Careful attention to these issues and wide experience is required for tailoring specific bioequivalence study protocols. The aim is to reach a bioequivalence or bioinequivalence conclusion on the basis of test versus reference performance, avoiding less definite, borderline conclusions attributable to intrinsic difficulties in the specific study. In discussing these unresolved issues, the author suggests potential solutions, where possible, on the basis of personal experience and specific bibliographic references.

The difference in titer between test and reference would normally be in the range of 95–105%, but in some cases it would fall within the expanded range of 90–120%. This would call for a titer normalization in establishing bioequivalence. A long elimination half-life (t1/2) [e.g. 50 days with amiodarone] calls for decision making about study design, namely crossover or parallel group design, the latter design being more adequate for drugs cleared with a t1/2 >10 days. Ethical problems concerning drug administration in healthy individuals (e.g. cytostatic agents in single dose, and other drugs in a repeated-dose regimen) is another issue. Drugs that produce unacceptable side effects in a repeated-dose regimen should be studied in healthy volunteers only in single dose. Drugs characterized by high variability require a high number of participants in the trial. Endogenous substances, most of which are eliminated faster than they are absorbed, have plasma concentration-time behavior not predictive of bioavailability. When the endogenous substance is cleared via urine, cumulative urinary excretion is a better evaluation parameter than area under the plasma concentration curve. In other cases a repeated dose regimen to steady state can allow post-dose concentration without baseline subtraction to be considered in assessing bioequivalence. Drugs producing one or more active metabolite(s) raise different opinions on whether bioequivalence should be assessed for the drug, metabolite(s) or both. All active moiety, namely parent drug and metabolite(s) should be assayed. Bioequivalence, however, should be assessed on only one substance, preferably the parent drug. In the presence of a prevalent active metabolite, this metabolite should be preferred in assessing bioequivalence.

Insufficient sensitivity of the bioassay often compels an alternative solution, such as working in steady state or assaying the compound in urine. Polymorphic metabolism calls for a preliminary classification of volunteers in order to exclude poor metabolizers from bioequivalence studies of repeated-dose regimens. Topical application of drugs for topical effect calls for a therapeutic bioequivalence; this is because circulating concentrations are not an expression of activity, but only of safety. When there are several strengths of a given drug on the market, the replicator can profit from a waiver allowing only one strength to be checked when some conditions hold. Reversible metabolites should be considered active metabolites. This is because they can revert into the parent compound. Reversibility of metabolites is very common with endogenous substances, but it is also present with several exogenous substances.

The approaches selected to solve bioequivalence problems must not conflict with US FDA and EU operating guidelines, which, however, in some instances do not overlap. This would mean that it is mandatory to operate on a case-by-case basis.