As defined by the Directive 2001/83/EC of the European Community [34], a generic drug contains an active component qualitatively and quantitatively identical to the reference drug, but excipients may differ. The reference is the original and innovative agent that has been made available to the market
and registered on the basis of a complete registration procedure, with full quality, safety and efficacy data. In contrast, marketing the selleck screening library generic form necessitates only an abridged procedure since it does not concern a new chemical entity. The manufacturer of a generic drug can submit an application for marketing authorisation built on the basis of the information provided by the full marketing procedure of the reference drug and on proving the bioequivalence of the two drugs, generic and reference, as recommended by the European Medicine Agency guideline [34]. The avoidance of studies of efficacy and safety reduces
markedly the development costs permitting selleck kinase inhibitor price reduction because major development costs are avoided. Market authorisation of a generic substitute relies heavily on the demonstration of bioequivalence. A bioequivalence study is a randomized clinical study, usually in healthy volunteers, that compares the bioavailability between the test product and a reference product. For oral agents, such as the bisphosphonates, this will include a comparison of absorption (area under the curve, AUC), the rate of absorption (Tmax) and peak concentration (Cmax) based on serum concentration or more usually with the bisphosphonates on cumulative urinary H 89 solubility dmso excretion (Ae) (Fig. 2). Equivalence is inferred when, for both AUC and Cmax, the 90% confidence interval for the ratio of geometric means for test and reference formulations lies within the range of 0.8–1.25 [34]. Fig. 2 Mean cumulative urinary excretion of alendronate 70 mg by mouth after the administration of test and reference formulations (n = 70) [redrawn from 61] Branded vs. generic bisphosphonates Gastrointestinal intolerance of amino-bisphosphonates is a well recognised side effect due in part to local effects on Rebamipide the oesophageal or gastric mucosa.
Gastrointestinal adverse effects that have been associated with oral bisphosphonates include dysphagia, oesophagitis, stomach ulceration and, more arguably, oesophageal cancer [35–39]. With alendronate, chemical oesophagitis may occur, promoted by an inadequate amount of water when swallowing the pill and failure to remain upright for some time after taking the drug [36, 40]. These adverse effects are mitigated somewhat by weekly or monthly rather than daily formulations but contribute to the poor adherence associated with the long-term management of patients with osteoporosis [41–46]. Since the introduction of generic bisphosphonates, reports have consistently concluded that adherence is poorer in patients who take generic alendronate than with the original product.