Pharmaceutical alternatives : considerations for generic substitution

Walker, Roderick B. Verbeeck, Roger-K. [UCL] Kanfer, Isadore

The issue of interchangeability/switchability relating to pharmaceutical alternatives is a controversial one and poses a challenge to regulatory authorities in particular where the consideration of generic substitution is important (1). The term pharmaceutical alternative as defined in the EU guideline (2) is used to define pharmaceutical products that have the same active moiety but that may differ in chemical form (i.e., salt, ester etc.) of that active compound or in dosage form or strength. A similar definition exists in the text “Approved Drug Products with Therapeutic Equivalence Evaluations” (Orange Book) published by the Food and Drug Administration (FDA) (3). While both the European Agency for the Evaluation of Medicinal Products (EMEA) and the FDA recognize the concept that pharmaceutical alternatives may be shown to be bioequivalent, the Orange Book (3) clearly states that only therapeutic equivalents that are pharmaceutical equivalents can be considered substitutable, whereas the EMEA states that either pharmaceutical equivalents or pharmaceutical alternatives may be considered as therapeutic equivalents provided that the excipients contained in the formulation do not impact on the safety and efficacy profile of the dosage form (2). Pharmaceutical equivalents are defined in the Orange Book (3) as drug products that contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration amongst others. The EMEA further stipulates that in order to conclude that a product is therapeutically equivalent with another product, clinical evidence of the safety and efficacy of the test product must be forthcoming and therefore bioequivalence testing of two products containing different salts of the same moiety may not suffice to establish substitutability.