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).

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).