Meredith Peter A
Division of Cardiovascular and Medical Sciences, Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK.
Curr Med Res Opin. 2009 Sep;25(9):2179-89. doi: 10.1185/03007990903116867.
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.
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.
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.
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.
仿制药产品在治疗效果上是否真的与原研药相同且可互换，仍是一个有争议的问题。本综述讨论了与生物等效性和治疗等效性标准相关的争议。以用于治疗高血压和心绞痛的钙拮抗剂苯磺酸氨氯地平（原研药）与马来酸氨氯地平（仿制药）为例来说明这些问题。
在Medline和EMBASE中检索英文出版物，以获取截至2008年8月所有关于马来酸氨氯地平的参考文献以及与生物等效性和治疗等效性监管指南相关的文献。还查阅了欧洲和美国监管机构的网站。
根据监管定义，仿制药产品在活性物质、给药途径以及质量标准方面需要与参比制剂相同。与必须证明其临床疗效和安全性的原研药不同，仿制药基于简单的生物等效性测试被认为具有治疗等效性。此外，生物等效性是通过一种有争议的研究方法（在一小群健康受试者中进行单剂量给药）和统计学方法（宽泛的接受区间）来确定的。因此，替代盐形式或辅料对药物临床特征的潜在负面影响可能未被发现。举例来说，尽管已知马来酸氨氯地平含有具有（潜在）生物活性的（降解）杂质，但根据定义它被认定与原研药苯磺酸氨氯地平生物等效。然而，仅有两项临床研究比较了两种药物长达3个月的降压和安全性特征，且没有心血管事件终点。
目前仿制药与原研药可互换性标准的有效性仍存在争议，可能会损害患者的反应和/或安全性。就氨氯地平而言，可能需要对市售马来酸氨氯地平盐制剂进行全面的长期临床研究，包括硬终点指标，以证明其使用的合理性。
