加速肿瘤药物开发:具有扩展队列的早期临床无缝试验设计简介

Expedite development of oncology drug: early phase seamless clinical trial design with expansion cohort

临床试验作为新药开发过程中时间、资源和成本投入最多的关键环节,面对肿瘤患者巨大而迫切的未满足的临床需求,如何高效开展临床试验,让饱受疾病折磨的患者尽快用上好药,是监管当局和制药企业当务之急。为了加快推进药物的研发,本文介绍具有扩展队列(expansion cohort)的早期临床无缝试验设计(seamless trials design),即通过一定的方法和标准(如动态处理数据、队列扩展等),将传统的分期试验压缩成一个单一的连续试验(大型FIH试验的试验设计),以实现传统多个分期试验所需实现的目标(例如安全性和有效性无缝推进、单次给药和多次给药无缝推进、有效人群无缝探索等),具有提高研发效率、降低试验成本、缩短临床开发总时间等优点(后文简称为无缝设计)。然而,无缝试验设计相对于传统分期设计,无论是对研发还是监管都提出了严峻的挑战,试验快速推进的同时,如何在不降低审评标准的前提下,保证受试者伦理风险控制?本文对无缝设计的定义、设计要点及风险控制等,结合FDA最新版本的指南进行全面介绍,以期为我国早期临床试验的设计和实践提供参考。

Clinical trials are the key aspect in the drug development,which spend on the most time,resources and cost.Faced with the huge and urgent unmet clinical needs of tumors,how to carry out clinical trials efficiently and enable patients suffering from diseases to use promising drugs as soon as possible is the urgent task for FDA and pharmaceutical companies.In order to accelerate the research and development of Oncology Drug,this review will introduce the early phase seamless trial design with expansion cohort,that is,the traditional phased trial is compressed into a single continuous trial(large-scale FIH trial Design),through certain methods and standards(such as dynamic data analysis,cohort expansion,etc.),to achieve the goals required for traditional multi-phased trials(such as seamlessly proceeding from safety and effectiveness,seamless advancement of single and multiple doses ascending,seamless exploration of effective populations,etc.).It has the advantages of improving research and development efficiency,reducing trial cost and shortening the total time of clinical development(hereinafter referred to as seamless design).However,compared with the traditional phased design,seamless trial design poses severe challenges to both research and development and supervision.While the trial is advancing rapidly,how to ensure the control of patients’ethical risk without lowering the review standards?In this paper,the definition,considerations of design points and risk control of seamless design are comprehensively introduced in combination with the latest version of FDA guidelines,so as to provide references for the design and practice of early clinical trials in China.