Lodola Alberto
ToxAdvantage, 248, rue de la Crapaudière, 37210, Noizay, France.
Methods Mol Biol. 2017;1641:3-24. doi: 10.1007/978-1-4939-7172-5_1.
We define "combination drugs" as "fixed-dose combinations" (FDCs), that is, two or more drugs (marketed or not) combined in a single pill or two or more separate drugs packaged together. FDCs have been available commercially for many years but only relatively recently have nonclinical development guidelines been released by a number of regulatory authorities and the World Health Organization; as yet there are no ICH guidelines specific to combination drugs. In general however, the ICH guidelines for monotherapy development provide a framework for FDC development. Depending on the type of drug combination (marketed drug/marketed drug; marketed drug/NME and NME/NME) the scope and complexity of toxicity studies will vary greatly. In all cases however, a key issue is the potential for pharmacokinetic and/or toxicologic interaction between the components. For a marketed drug/marketed drug combination a detailed review of the nonclinical data available may suffice, particularly when the components have a history of coadministration at about the same dose and ratio as that of the proposed combination. For a marketed drug/NME combination, in addition to a review of the data for the marketed drug, a full ICH program of studies will be required for the NME, and a study of up to 90-day duration (in one species) for the combination. With an NME/NME combination each component will require a full ICH battery of studies and a combination study in one species. In all cases additional studies may be needed to address data gaps. Given the many novel and complex issues which arise when developing FDCs we recommend that, whenever possible, the nonclinical study strategy is discussed with the regulatory authorities.
我们将“复方药物”定义为“固定剂量复方制剂”（FDC），即两种或更多种药物（已上市或未上市）组合在一片药中，或两种或更多种单独的药物包装在一起。FDC已在市场上销售多年，但直到最近一些监管机构和世界卫生组织才发布了非临床开发指南；目前尚无针对复方药物的ICH指南。然而，一般来说，ICH单一疗法开发指南为FDC开发提供了一个框架。根据药物组合的类型（已上市药物/已上市药物；已上市药物/新分子实体和新分子实体/新分子实体），毒性研究的范围和复杂性会有很大差异。然而，在所有情况下，一个关键问题是各成分之间药代动力学和/或毒理学相互作用的可能性。对于已上市药物/已上市药物组合，对现有非临床数据进行详细审查可能就足够了，特别是当各成分有以与拟议组合大致相同的剂量和比例共同给药的历史时。对于已上市药物/新分子实体组合，除了审查已上市药物的数据外，新分子实体还需要完整的ICH研究计划，并且该组合需要在一个物种中进行长达90天的研究。对于新分子实体/新分子实体组合，每个成分都需要完整的ICH系列研究，并在一个物种中进行组合研究。在所有情况下，可能都需要进行额外的研究来填补数据空白。鉴于开发FDC时会出现许多新颖和复杂的问题，我们建议尽可能与监管机构讨论非临床研究策略。
