Background and scope: Whether generic drug products are truly therapeutically identical and interchangeable with their innovator counterparts is still a matter of debate. This review discusses the controversies related to the criteria for bioequivalence and therapeutic equivalence. These concerns are illustrated by using the calcium antagonist amlodipine besylate (innovator drug) versus amlodipine maleate (generic), indicated for the treatment of hypertension and angina pectoris, as an example.
Methods: English-language publications were searched in Medline and EMBASE to retrieve all references on amlodipine maleate and literature related to the regulatory guidelines for bioequivalence and therapeutic equivalence to August 2008. Websites from the European and US regulatory authorities were also consulted.
Findings: According to regulatory definitions, generic drug products need to be identical to their reference with respect to the active substance, the route of administration as well as quality standards. In contrast to innovator drugs, which have to demonstrate their clinical efficacy and safety, generics are considered therapeutically equivalent based on simple bioequivalence testing. In addition, bioequivalence is established with a disputable study method (single dose in a small group of healthy subjects) and statistics (broad acceptance intervals). Consequently, a potential negative impact of alternative salt forms or excipients on the clinical profile of a drug may remain undetected. To exemplify this, although amlodipine maleate is known to contain (degradation) impurities with (potential) biological activity, it is found per definition bioequivalent to its innovator drug, amlodipine besylate. However, only two clinical studies compared the antihypertensive and safety profiles of both drugs up to 3 months, without CV event endpoints.
Conclusions: The validity of the current criteria for interchangeability of generic and innovator drugs remains controversial and may compromise the response and/or safety of patients. In the case of amlodipine, thorough long-term clinical investigations of commercial amlodipine maleate salt preparations including hard endpoints may be needed to justify their use.