Schellekens Huub, Stegemann Sven, Weinstein Vera, de Vlieger Jon S B, Flühmann Beat, Mühlebach Stefan, Gaspar Rogério, Shah Vinod P, Crommelin Daan J A
Department of Pharmaceutical Sciences, Utrecht University, P.O. Box 80.082, 3508 TB, Utrecht, The Netherlands,
AAPS J. 2014 Jan;16(1):15-21. doi: 10.1208/s12248-013-9533-z. Epub 2013 Sep 25.
The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.
本批判性综述的目的是就引入非生物复杂药物（NBCD）的后续版本达成全球共识。非生物复杂药物是一种药品，不属于生物药品，其活性物质不是同分子结构，而是由不同的（密切相关且通常为纳米颗粒状）结构组成，这些结构无法通过现有理化分析手段分离、完全定量、表征和/或描述，且差异的临床意义未知。NBCD的组成、质量和体内性能高度依赖于活性成分的制造工艺，在大多数情况下还依赖于制剂的制造工艺。本文通过讨论脂质体、铁碳水化合物（“铁糖”）药物和格拉替雷类药物的“家族”，阐述了NBCD后续版本开发所面临的挑战。建议采用与生物类似药相同的NBCD仿制品上市许可原则：需要动物和/或临床数据，以及需要证明质量、安全性和有效性方面的相似性。NBCD的监管方法必须考虑到药物的具体特性、其制剂和制造工艺以及由此产生的关键属性，以实现其预期的质量、安全性和有效性。与生物类似药一样，对于NBCD产品，应评估并在科学证明可行的情况下应用特定家族方法，包括先进的质量方法、药效学标志物和动物模型。关于NBCD的替换和互换性，以生物类似药为例也是可取的，即：（1）应不鼓励在无医疗保健专业人员参与的情况下进行替换，以确保对个体患者治疗的可追溯性；（2）如果患者情况良好，应让个体患者继续接受特定治疗，仅在不可避免时才进行更换；（3）如果发生更换，应监测新产品的安全性和有效性。
