In the United States, drug products are deemed therapeutically equivalent if they meet the regulatory criteria of pharmaceutical
equivalence and bioequivalence (1). Designation of therapeutic equivalence dictates interchangeability between a generic drug
and its reference-listed drug (pioneer) product. As defined in Approved Drug Products with Therapeutic Equivalence Evaluation (i.e., the Orange Book):
Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage
form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity).
Hence, the regulatory concept of therapeutic equivalence only applies to drug products containing the same active ingredient(s)
and does not encompass a comparison of different therapeutic agents used for the same clinical indication(s).
According to US regulations, bioequivalence means
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 (2).
Based on this definition, theoretically several methods can be used to demonstrate bioequivalence. However, the US Food and
Drug Administration further recommends that drug sponsors use the following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, to demonstrate bioavailability and bioequivalence:
- Pharmacokinetic studies (e.g., blood, plasma, serum) in humans
- Pharmacokinetic studies (e.g., urine) in humans
- Pharmacological or pharmacodynamic studies in humans
- Well-controlled clinical trials
In vitro tests acceptable to FDA
- Any other approach deemed adequate by FDA (2).
Therefore, pharmacokinetic studies using blood-level measurement have generally been used to demonstrate bioequivalence. This
approach is especially applicable for systemically absorbed drugs found in many orally administered dosage forms and transdermal
delivery systems because for such products, drug concentrations in the blood or plasma reflect drug availability at the site
of action. The pharmacokinetic approach, however, cannot be applied to locally acting drug products because their blood/plasma
concentrations may not reflect drug availability at the site of action. Another limitation in using pharmacokinetic studies
lies in the fact that blood/plasma concentrations may be too low to be measured for these products. Consequently, bioequivalence
methods recommended by FDA for locally acting drugs are tailored to individual dosage forms and drug products using various
approaches (3). For example, to establish bioequivalence of orally inhaled products, FDA has required in vitro tests for comparison of device performance, pharmacodynamic studies for comparison of local delivery between products, and
pharmacokinetic studies to ensure that systemic exposure to the drug is minimal. Likewise, depending on individual drugs or
drug products, bioequivalence of gastrointestinal (GI) acting products is currently evaluated using one or more of the following
methods: in vitro binding assay, in vitro dissolution studies, pharmacokinetic studies, and clinical trials.