Hidden Paradoxes in Generic Drug Substitution Affecting Pharmacotherapy

The issue of the generic versus brand-name drug inter-changeability is an intensely debated theme historically focused on whether bioequivalence testing can guarantee therapeutic efficacy. The controversy is supported by reports of the lack of therapeutic equivalence between some generic medicinal products and brand-name drugs, as well as by a great deal of editorials expressing a negative view on generic drug substitution. This could be of particular concern for critical therapeutic categories such as psy-chotropic, cardiovascular, and metabolic/endocrine drugs as well as for special subpopulations such as elderly, debili-tated/psychoneurotic patients, infants and children [1, 2]. To deal with this issue, large, prospective controlled evaluations have been proposed, providing information on how current bioequivalence and pharmacological equivalence translate into clinical equivalence [3]. In our opinion, however, although on one hand this strategy could be suitable in clinical trials to ascertain the " essential similarity " requirement in drug substitution—in terms of active ingredient (amount and type), route of administration, and therapeutic effectiveness—on the other hand, it might be insufficient in real practice to support the therapeutic equivalence for the general population. This could also be due to the possible influence of the marketing to patient's response. To better explain what we are saying, let us recall what follows. Our knowledge on the placebo effect, a phenomenon that has intrigued scientists since 1955 when Henry K. Beecher published the article " The powerful placebo " [4] and quantified the placebo effect [5], has evolved from being thought of as a nuisance in pharmacological intervention to the mechanistic aspects of its incontrovertible function. Two main models of how the placebo—or placebo related effects—works have been proposed. The " expectance theory, " which is essentially based on the patient's expectation of clinical benefits occurring in association with the verbal suggestion that clinical improvement will soon occur; the " classic conditioning " model foresees that after repeated associations between a conditioned stimulus (e.g., colour and shape of a pill) and an unconditioned stimulus (e.g., the active agent in the pill), the first stimulus alone may induce a conditioned response similar to the one induced by the active drug [6]. There is no doubt that, in randomized, double-blind controlled studies, the contribution of the placebo effect to therapeutic efficacy is " equally distributed " between patients receiving the generic product and the ones taking the brand name with an overall nondiscriminating therapeutic role between these two patient …