Generic medications: another variable in the treatment of illnesses

An additional problem with the bioequivalence principle may also stem from the manner it is established. Such studies are generally carried out in healthy young males. Obviously, gender, age and the physical condition of these subjects could be important variables contributing to significant differences in patient populations. The number of subjects to be tested in such studies varies from one country to another. In Canada and the European Union, a minimum of only 12 subjects need to be studied (Health Canada – Drug and Health Products, 1992; The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use 2001). Considering that levels of medications for an original formulation can vary several-fold, the reliability of the bioequivalence requirement could thus be erroneous in some studies. As an example, reports have documented important disparity in the bioequivalence of different formulations of the anti-rejection medication cyclosporine (Taber et al., 2005; Qazi et al., 2006). Preliminary evidence from a multicentre study indicated that generic cyclosporine lead to a significantly lower kidney graft survival than with the original product (–11% over one year in 397 patients) (Opelz, 2001). Enforcement of the postmarketing quality can be an additional issue contributing to the presence of poor quality generics on the market. Indeed, regulatory agencies may have insufficient resources for adequate monitoring, as recently recognized in the 2006 Report of the Auditor General of Canada (Government of Canada – Office of the Auditor General of Canada, 2006). For instance, there is a report of markedly different dissolution rates of two generic brands of slow-release preparations of carbamazepine (Gervasoni et al., 2004). One generic brand was identical to the original whereas two different lots of the other generic had essentially rapid dissolving properties. Upon analysis of the product producing discrepant results, it was determined that the ingredient methylcellulose that allows the extended release of the active ingredient was absent, thus actually making the preparation an immediate release formulation. Generic drugs are lower-cost versions of patent-expired, original brand name medications. The approval of a generic drug requires the manufacturer to show that their product contains the same quantity of the active ingredient and that it meets bioequivalence requirements. This signifies that when the generic medication is administered in the same manner as the brand formulation, similar concentrations are achieved, generally assessed in the plasma. Overall, the requirements of regulatory agencies theoretically should ensure that consumers are buying a product that is of equal quality, purity, effectiveness and safety as the original medication. This is probably the case for the majority of such less expensive versions of innovator medications. However, one can realize that clinically significant deviations of such basic principles can occur once the process for approval is understood. Regulatory agencies require that the bioequivalence of generics be within 80–125% of the brand medication (using the area under the curve method) in Canada, the US and the European Union (Commission of the European Communities – Committee for Proprietary Medicinal Products, 1991; Canadian Health Protection Branch, 1992; US Department of Health and Human Services – Food and Drug Administration, 1992). For most drugs, such variations are probably not crucial. However, in the case of an antiepileptic drug, a drop of 20% in plasma concentration could be sufficient to allow a recurrence of seizures. In the case of lithium administration to achieve a level in its upper therapeutic window, a 25% increase from 1.2 to 1.5 mEq/L could potentially lead to renal and/or thyroid toxicity. In contrast, manufacturers of innovator medications are held to a more stringent standard: their product must not show a greater than 5% variation (Borgheini, 2003). There are reports of lots of generics (i.e., carbamazepine and dilantin) being withdrawn due to concerns over clinical failures, which when tested produced bioinequivalence outside the above mentioned requirement (Meyer, 2001; Rosenbaum et al., 1994).

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