PDF(Pubmed)
Abstract：
In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.
摘要：
在一个充满成本压力的时代，替代仿制药是医疗保健系统的主要成本控制策略之一。尽管有明显的经济利益，在少数情况下，替代可能需要谨慎甚至禁忌。在大多数司法管辖区，为了获得批准，具有品牌等同物的通用产品的生物等效性需要通过健康受试者的生物利用度研究来证明。罕见疾病,定义为低患病率的医疗条件，是一组通常很严重的异质性疾病，禁用,进步,退化,危及生命或长期衰弱，不成比例地影响年轻人和老年人。尽管罕见疾病有这些独特的特征，一般生物等效性研究通常以单剂量进行,排除儿童或老年人.此外，仿制药/生物仿制药产品的辅料和生产工艺可能与品牌产品不同，这可能会影响产品的保质期，它的外观,气味,味道,生物利用度，安全性和效力。这可能导致批准在其目标人群中不具有生物等效性/可比性或符合生物等效性但不符合治疗等效性标准的仿制药/生物仿制药。另一个问题涉及由于生物蠕变现象而无法保证的仿制药和生物仿制药的互换性。这篇综述总结了孤儿药的通用替代的潜在问题，并讨论了潜在的问题病例，包括狭窄的治疗指数药物或治疗失败可能导致严重并发症甚至死亡的关键条件。最后,我们提出需要完善监管框架，重点是沙特阿拉伯，通用替代和最近朝着这个方向的努力。
