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When two formulations of the same drug or two drug products are claimed bioequivalent, it is assumed that they will provide the same therapeutic effect or that they are therapeutically equivalent. In this case, most people interpret that they can be used interchangeably. Two drug products are considered pharmaceutical equivalents if they contain identical amounts of the same active ingredient. Two drugs are identified as pharmaceutical alternatives to each other if both contain an identical therapeutic moiety, but not necessarily in the same amount or dosage form or as the same salt or ester. Two drug products are said to be bioequivalent if they are pharmaceutical equivalents (i.e., similar dosage forms made, perhaps, by different manufacturers) or pharmaceutical alternatives (i.e., different dosage forms) and if their rates and extents of absorption do not show a significant difference to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of action when administered at the same molar dose under similar conditions in an appropriately designed study.

Bioequivalence is the property of two dosage forms or active ingredients with similar blood concentration levels that produce the same effect at the site of physiologic activity.

Bioequivalence studies are very important for the development of a pharmaceutical preparation in the pharmaceutical industry. The target of such study is to evaluate the therapeutic compatibility of tested drugs (pharmaceutical equivalents or pharmaceutical alternatives).

Bioequivalence assessment for generics approval can only be done under the so-called Fundamental Bioequivalence Assumption which states that “If two drug products are shown to be bioequivalent, it is assumed that they will generally reach the same therapeutic effect or they are therapeutically equivalent.” Under the Fundamental Bioequivalence Assumption, one of the controversial issues is that bioequivalence may not necessarily imply therapeutic equivalence and therapeutic equivalence does not guarantee bioequivalence either. The verification of the Fundamental Bioequivalence Assumption, however, is often difficult, if not impossible, without the conduct of clinical trials. In practice, there are four possible scenarios when assessing bioequivalence for generics approval:

1. Drug absorption profiles are similar and they are therapeutic equivalent; – In this case, PK responses such as AUC and C_max serve as surrogate endpoints for clinical endpoints for assessment of efficacy and safety of the test product under investigation.

2. Drug absorption profiles are not similar but they are therapeutic equivalent;- this is the case where generic companies try for generic approval of their drug products especially when their products fail to meet regulatory requirement for bio equivalence.

3. Drug absorption profiles are similar but they are not therapeutic equivalent;

4. Drug absorption profiles are not similar and they are not therapeutic equivalent.

The most common design of bio equivalence studies is a two-sequence two-period two-treatment crossover design, where inclusion of 90% confidence intervals of pharmacokinetic metrics in a pre-defined acceptance range has to be shown. However the limitation of this study design is that  it does not provide independent estimates of intra-subject variabilities since each subject receives the same treatment only once. In the interest of assessing intra-subject variabilities, the following alternative higher-order crossover designs for comparing two drug products are often considered:

• Design 1: Balaam’s design – i.e., (TT, RR, RT, TR);

• Design 2: Two-sequence, three-period dual design – i.e., (TRR, RTT);

• Design 3: Four-period design with two sequences – i.e., (TRRT, RTTR);

• Design 4: Four-period design with four sequences – i.e., (TTRR, RRTT, TRTR, RTTR).

For comparing more than two drug products, a Williams’ design is often considered. For example, for comparing three drug products, a six-sequence, three-period (6×3) Williams’ design is usually considered, while a 4×4 Williams’ design is employed for comparing 4 drug products. Williams’ design is a variance stabilizing design.

The general criteria of bioequivalence does not take into consideration the therapeutic window (TW) and intra subject variability (ISV) of drug and a flexible criteria interms of safety (upper bioequivalence limit) and efficacy (lower bioequivalence limit) was required for the drugs with a high ISV and narrow or wide TW. For these drugs, scaled average bioequivalence are considered.