Bioequivalence Dr Mohammad Issa Saleh

Bioequivalence Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same.

Pharmaceutical equivalents and alternatives Medicinal products are pharmaceutically equivalent if they contain the same amount of the same active substance(s) in the same dosage forms that meet the same or comparable standards Medicinal products are pharmaceutical alternatives if they contain the same active moiety but differ in chemical form (salt, ester, etc.) of that moiety, or in the dosage form or strength It is well known that pharmaceutical equivalence does not necessarily imply bioequivalence as differences in the excipients and/or the manufacturing process can lead to faster or slower dissolution and/or absorption.

Bioequivalence Bioequivalence is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

Therapeutic equivalence A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and, clinically, shows the same efficacy and safety as that product, whose efficacy and safety has been established. In practice, demonstration of bioequivalence is generally the most appropriate method of substantiating therapeutic equivalence between medicinal products, which are pharmaceutically equivalent or pharmaceutical alternatives, provided they contain excipients generally recognized as not having an influence on safety and efficacy and comply with labeling requirements with respect to excipients.

Therapeutic equivalence However, in some cases where similar extent of absorption but different rates of absorption are observed the products can still be judged therapeutically equivalent if those differences are not of therapeutic relevance. A clinical study to prove that differences in absorption rate are not therapeutically relevant will probably be necessary

Design and conduct of bioequivalence studies Crossover design and alternatives Single- vs. multiple-dose studies Pharmacokinetic characteristics Subjects Statistical models

Standard 2×2 Crossover design Period I II Sequence 1 Reference Test Subjects Randomization Washout Sequence 2 Test Reference

Standard 2×2 Crossover design A bioequivalence study should be designed in such a way that the formulation effect can be distinguished from other effects. In the standard situation of comparing a test formulation (T) with a reference formulation (R), the two-period, two-sequence crossover design is the RT/TR design. Subjects are randomly allocated to two treatment sequences; in sequence 1, subjects receive the reference formulation and test formulation in periods 1 and 2, respectively, while in sequence 2, subjects receive the formulations in reverse order. Between period 1 and period 2 is a washout period, which has to be sufficiently long to ensure that the effect of the preceding formulation has been eliminated.

Alternative designs Under certain circumstances and provided that the study design and the statistical analyses are scientifically sound, alternative designs could be considered such as a parallel group design for substances with a very long half-life and replicate designs for substances with highly variable disposition.

Two-group parallel design Reference Subjects Randomization Group 2 Test

Two-group parallel design Each subject receives one and only one formulation of a drug in a random fashion. Usually each group contains the same number of subjects. Higher subject numbers compared to a cross-over design, since the between-subject variability determines sample size (rather than within-subject variability).

Two-group parallel design Advantages Clinical part (sometimes) faster than crossover. Straigthforward statistical analysis. Drugs with long half life. Studies in patients. Disadvantages Lower statistical power than crossover (rule of thumb: subject number should at least be doubled). Phenotyping mandatory for drugs showing polymorphism.

Single- vs. multiple-dose studies In general, single-dose studies will suffice Steady-state studies may be required in: The case of dose- or time-dependent pharmacokinetics. The case of some modified release products (prolonged release formulations and transdermal drug delivery systems), steady-state studies are required in addition to the single-dose investigations. Steady-state studies can be considered: If problems of sensitivity preclude sufficiently precise plasma concentration measurements after single dose administration

Subjects The subject population for bioequivalence studies should be selected with the aim of minimizing variability and permitting detection of differences between pharmaceutical products. Therefore, the studies should normally be performed with healthy volunteers. Subjects could belong to either sex; however, the risk to women of childbearing potential should be considered on an individual basis. In general, subjects should be between 18–55 years old, of weight within the normal range, preferably nonsmokers, and without a history of alcohol or drug abuse. They should undergo a routine screening of clinical laboratory tests and a comprehensive medical examination.

Subjects If the investigated active substance is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy volunteers, it may be necessary to use patients instead, under suitable precautions and supervision. Phenotyping and/or genotyping of subjects should be considered for exploratory bioavailability studies and all studies using parallel group design. If the metabolism of a drug is known to be affected by a major genetic polymorphism, studies could be performed in panels of subjects of known phenotype or genotype for the polymorphism in question.

Statistical models Average bioequivalence Population bioequivalence Individual bioequivalence

Average bioequivalence Based upon the two-period, two-sequence crossover design, average bioequivalence is concluded if the two-sided 90 % confidence interval for the test/reference ratio of population means is within the appropriate bioequivalence acceptance range, for example (0.80, 1.25).

Population bioequivalence Population bioequivalence encompasses equivalence of the entire distributions of the respective metric between test and reference Since the lognormal distribution is fully described by the median and the variance, population bioequivalence is commonly restricted to the equivalence of population medians and variances for test and reference Hence, the conventional RT/TR crossover design may be used to assess bioequivalence in a stepwise approach. Starting with average bioequivalence, population equivalence will be considered only if average equivalence is approved

Individual bioequivalence The primary objective for introducing individual bioequivalence is to account for subject by- formulation interaction, and to use the comparison of the reference formulation to itself as the basis for the comparison of test and reference. In contrast to average and population bioequivalence, individual bioequivalence compares within-subject distributions of the respective bioavailability metrics, and thus, needs at least replication of the reference formulation