Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics.
Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics.
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DOI：
10.3389/fmicb.2016.01209
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发表时间：
2016
影响因子：
5.2
通讯作者：
Nilsson AS
中科院分区：
文献类型：
--
作者：
Cooper CJ;Khan Mirzaei M;Nilsson AS
耐多药细菌在全球范围内的崛起，导致人们认为“抗生素末日”正在迅速来临。这导致了一些广为宣传的呼吁，呼吁全球资助倡议开发新的抗菌剂。东欧噬菌体治疗的悠久临床历史，加上最近在体外和体内的成功，证明了全噬菌体或基于噬菌体的抗菌剂的潜力。迄今为止，在欧盟或美国，没有完整的噬菌体或噬菌体衍生产品被批准用于人类治疗。至少有三个原因：(1)与传统抗生素相比，噬菌体具有不同的生物学、物理学和药理学特性。噬菌体需要复制才能达到可行的抗菌效果，导致复杂的药效学/药代动力学。（ii）单个噬菌体的特异性需要多个噬菌体治疗单一物种感染，通常作为复杂鸡尾酒的一部分。（iii）目前的抗菌剂审批流程是以化学药物为核心发展的，并不适合噬菌体。由于与传统抗生素的相似性，噬菌体衍生产品，如内溶素，适合在目前的工艺下作为生物治疗蛋白获得批准。这些标准使得噬菌体临床应用的批准在理论上是可能的，但在经济上是不可行的。在本综述中，将讨论整个噬菌体和噬菌体衍生产品目前审批过程的陷阱，以及包括适应性许可和“试用权”立法在内的替代审批途径的利用。
The global rise of multi-drug resistant bacteria has resulted in the notion that an “antibiotic apocalypse” is fast approaching. This has led to a number of well publicized calls for global funding initiatives to develop new antibacterial agents. The long clinical history of phage therapy in Eastern Europe, combined with more recent in vitro and in vivo success, demonstrates the potential for whole phage or phage based antibacterial agents. To date, no whole phage or phage derived products are approved for human therapeutic use in the EU or USA. There are at least three reasons for this: (i) phages possess different biological, physical, and pharmacological properties compared to conventional antibiotics. Phages need to replicate in order to achieve a viable antibacterial effect, resulting in complex pharmacodynamics/pharmacokinetics. (ii) The specificity of individual phages requires multiple phages to treat single species infections, often as part of complex cocktails. (iii) The current approval process for antibacterial agents has evolved with the development of chemically based drugs at its core, and is not suitable for phages. Due to similarities with conventional antibiotics, phage derived products such as endolysins are suitable for approval under current processes as biological therapeutic proteins. These criteria render the approval of phages for clinical use theoretically possible but not economically viable. In this review, pitfalls of the current approval process will be discussed for whole phage and phage derived products, in addition to the utilization of alternative approval pathways including adaptive licensing and “Right to try” legislation.