新药临床试验前安全药理学研究的发展过程

对安全药理学研究历史沿革的了解,有助于新药研发者理解其在新药开发过程中的不可替代性和重要意义,从而使研发人员在试验设计和综合分析各项研究结果 时,能具有宏观把握思维.本文从监管角度讲述了国内外在新药开展临床试验的安全药理学研究的一些过程.     

试论安全药理学研究的基本要求及规范化

安全药理学（safety pharmacology）研究是新药非临床安全性评价的一项重要内容，主要研究药物在治疗范围内或治疗范围以上剂量时，出现潜在的不期望的不良影响，并研究观察到的／或推测的药物不良反应机制。从而最大限度地保障新药进入临床研究之前或上市之后，及早发现可能出现的治疗作用之外的不良反应。安全药理学研究概念最早出现于1997年人用药品注册技术国际协调会（ICH）的实施新药临床研究所需非临床安全性试验的时间安排（M3指导原则）和生物技术药物的临床前安全性评价（S6指导原则）中，要求在非临床安全性评价中必须进行安全药理学研究，用于支持药物的人体临床研究。ICH于2000年发布的《人用药品安全药理学研究指南》促进了该学科的快速发展，使安全药理学的设计原则、研究内容、动物模型选择、观察指标确定等有了规范的要求。     

试论安全药理学研究的基本要求及规范化

安全药理学（safety pharmacology）研究是新药非临床安全性评价的一项重要内容，主要研究药物在治疗范围内或治疗范围以上剂量时，出现潜在的不期望的不良影响，并研究观察到的／或推测的药物不良反应机制，从而最大限度地保障新药进入临床研究之前或上市之后，及早发现可能出现的治疗作用之外的不良反应。安全药理学研究法定概念最早出现于1997年人用药品注册技术国际协调会（ICH）的实施新药临床研究所需非临床安全性试验的时间安排（M3指导原则）和生物技术药物的临床前安全性评价（S6指导原则）中，要求在非临床安全性评价中必须进行安全药理学研究，用于支持药物的人体临床研究。ICH于2000年发布的《人用药品安全药理学研究指南》及近年大量文献对安全药理学设计原则、研究内容、动物模型选择、观察指标确定等提出了规范化的要求，从而促进了该学科的快速发展。     

中药新药研发的立题依据及评价思路

立题依据是中药新药研发的一项重要内容,本文分析了当前注册申请的中药新药不同的立题依据,介绍了源于古方、依据临床应用经验、依据中医药理论组方、依据现代药理研究结果等不同的立题依据在新药研发中的风险和优势,分析了申报资料应注意哪些问题,如何开展相关的研究工作,如何才能提高新药研发的成功率。并从审评角度分析了非临床药效学试验的必要性,药效学试验应重点关注的内容,以及其结果对支持中药新药进行临床试验在立题依据方面的作用。     

创新药物转化研究中ADME的评价

新药研发是一复杂的庞大系统工程, 所涉及的学科门类众多, 研究周期长。而转化研究有助于构建创新药物的基础研究、临床前研究和临床疗效评价直至新药制造和临床应用的系统研发链, 顺畅基础医学和生物学与创新药物研发、临床医学之间的信息和研究关联, 缩短创新药物从实验室到临床应用的研发周期。在新药研发和临床应用过程中, 化合物的体内过程 (吸收、分布、代谢、排泄, ADME) 是其成药性的重要指标。化合物ADME/T性质在创新药物转化研究中发挥重要作用并贯穿研发过程。因此, 在药物设计及新药开发早期就开展药物代谢研究, 有利于提高新药研发的成功率, 降低新药开发的成本, 获得安全、有效的治疗药物。     

定量药理研究方法学培训与研讨班

由于新药研发成本大、周期长,为此美国FDA提出了“基于模型的药物研发”理念,专门成立了“定量药理学审评组”,成效巨大。目前新型定量药理学方法不断涌现,学科广泛交叉。在此新形势下,上海中医药大学药物临床研究中心和国家新药临床评价研究技术平台（上海市精神卫生中心）,在孙瑞元教授等支持下,     

安全药理学的国内外发展概况

安全药理学(safety pharmacology)作为新药临床前安全性评价领域中一个重要的组成部分,主要是应用实验动物体内和体外的方法,评价和预测新药在人体临床试验中可能出现的不良反应,近年来愈来愈受到各国药品监督管理局和新药研究与开发人员的普遍关注.人用药品注册技术国际协调会(ICH)于2000年11月发布的"人用药品安全药理学研究指南(S7A)" 使该学科得到了快速的发展.2002年2月ICH又发布了"评价人用药品潜在致心室复极化延迟作用(QT间期延长)的安全药理学研究(S7B)"草案,从而使国际间对安全药理学研究的技术要求趋于统一.S7A和S7B的内容对安全药理学的定义、目的、推荐的研究方法和规定的研究内容,以及有关的研究原则提出了全面要求.为使从事新药临床前安全性评价和研究人员了解和熟悉有关规定和进展情况,现将有关发展动向作一概述.     

现代定量药理学的研究进展及展望

定量药理学是运用数学和统计方法,定量研究药理作用规律的一门分支学科,该学科在新药研发及临床药物治疗中正在发挥愈来愈重要的作用。近年国外学界提出了基于模型的新药研发等新理念,将定量药理学的重要性提升到了新的高度,定量药理学正迈入一个新的时代。国内该学科已有二十多年的发展历史,打下了良好的基础,但较国际先进水平还有一定差距,目前正面临着新的发展契机,机遇与挑战并存。本文首先辨析了学科定义,并简要回顾了国内外的学科发展简史;重点介绍了该学科的重要研究领域及热点技术,包括群体药动学/药效学、暴露-反应（药动学-药效学）关系、临床试验模拟、新型临床试验设计、生物标记物、疾病模型和试验模型、建模与模拟的方法学等;简介了基于模型的新药研发的新理念;最后,对该学科的国内发展前景进行了展望。     

“全国儿童新药临床试验学术研讨会”第二轮通知

儿童是新药研发的特殊群体,很多药品都没有儿童用药的临床研究数据,导致儿童超说明书用药现象十分严重,存在临床安全隐患。随着对于儿童用药安全的日益关注,开展规范化的多中心儿童药物临床试验迫在眉睫。如何开展儿科新药临床研究,成为儿科医师、药师及药物临床试验机构人员急需掌握的知识和技能。由中华医学会儿科学分会儿科临床药理学专业组和《中华儿科杂志》编辑委员会主办,北京大学第一医院儿科和首都医科大学附属北京儿童医院及汉唐博瑞·医学学术机构共同承办的“全国儿童新药临床试验学术研讨会”将于2012年10月19至21日在北京举行。     

医疗机构基于“三结合”中药新药研发及管理体系的构建

目的：在中药审评审批制度改革的政策背景下,围绕医疗机构,探索中医药理论、人用经验和临床试验相结合（简称“三结合”）的审评证据体系落地举措,为医疗机构中药制剂及中药新药研发提供参考。方法：根据“三结合”审评证据体系下中药新药研发的相关要求,从机构层面加强人用经验研究相关配套建设,从管理层面搭建中药研发、成果转化服务平台,从临床层面规范开展人用经验研究,构建医疗机构中药新药研发及管理体系。结果：医疗机构中药新药研发及管理体系的构建,有助于将临床诊疗数据转变为支持中药新药注册的人用经验证据,通过提高中药研发水平促进中药新药转化。结论：在医疗机构构建基于“三结合”的中药新药研发及管理体系,是“三结合”审评证据体系落地、政策引导研发实践的路径之一。     

对临床药理学一些基本问题研究的思考

临床药理学是研究药物与人体相互作用及其规律的一门学科。临床药理学基本原理在药物的临床研究与评价、药物不良反应监测等方面做了大量工作,取得了明显进展。然而,对临床药理学的共性、关键性和前沿性的基本问题研究更应给予高度关注,在进一步做好常规性临床药理学服务工作的同时,积极加强临床药理学学术问题的探索,为临床安全有效合理用药提供理论支撑。药物相互作用、多药耐药(MDR)、遗传药理学、药物基因组学、药动学/药效学(PK/PD)模型、性别药理学、基于药物作用于人体病理组织细胞的药效学和分子机制的研究等临床药理学的共性、关键性和前沿性问题已引起人们的重视。本文就临床药理学研究的一些基本问题的思考作一简述。     

Current regulatory perspectives on genotoxicity testing for botanical drug product development in the U.S.A.

Genotoxicity testing is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. It is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in tumorigenic or heritable mutation potential of the drug. Botanical new drugs in the U.S. are entitled to a waiver for preclinical pharmacology/toxicology studies, including genotoxicity testing, in support of an initial clinical trial under IND, contingent on previous human experience. Recently, ethical concerns have been raised over conducting Phase I/II clinical trials of new drugs with positive genotoxicity findings in healthy volunteers. Although the relevance of this issue to patients, as opposed to healthy volunteers, depends on the drug’s indication, duration of treatment, and specific findings related to the assays, the regulatory view is to avoid exposing patients to genotoxic compounds unnecessarily in clinical trials. This philosophy may impact on herbal supplement marketing and botanical drug development, in that genotoxicity data are often lacking while consumers are exposed to the herbal supplement, or healthy volunteers are tested in an initial Phase I/II clinical trial on the botanical drug. This paper presents results of a survey conducted on genotoxicity data in botanical INDs submitted to the Agency and discusses the significance of this information. The information presented indicates that the sponsors of botanical INDs have increasingly recognized the importance of genotoxicity information and may have prioritized its acquisition in their strategic drug development programs.     

Safety pharmacology in focus: new methods developed in the light of the ICH S7B guidance document

'Safety' continues to be a growth area in 'Pharmacology'. This issue of Journal of Pharmacological and Toxicological Methods is the third to be focused on methods development in the safety pharmacology area. The unusual nature of safety pharmacology mandates that methods development be done with, not only scientific validation, but also, adherence to the mandates of legislation to the forefront. This focused issue draws on a broad range of global safety pharmacology experts, many of whom operate in the industrial milieu. They have reviewed and updated current models, validated modifications, and have also introduced novel methodology important to the conduct of non-clinical safety pharmacology studies. The contributors were all active participants at the 5th Annual Safety Pharmacology Society (SPS) meeting held in Mannheim, Germany September 25-28, 2005. The publications presented here describe in vitro and in vivo pharmacological methods development that has been informed by the S7A regulatory guidance document for pre-clinical safety testing of drugs. While S7A describes the 'core battery' of methods used to characterize the safety pharmacology profile of a compound, the most recent news in Safety Pharmacology involves ratification of the related S7B safety guidance document. Unlike the past, S7B heralds a new era for the pharmaceutical industry since it now sets out how to address safety concerns of a new chemical entity (NCE) in relation to adverse actions on ventricular repolarization, a topic that has vexed industry and regulatory authorities for many years. Unsurprisingly there are many papers in the present issue that address this specific aspect of safety pharmacology. These include results from the Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) initiative, in which non-clinical in vitro (hERG and Purkinje fiber) and in vivo (QT dog study) assays were found to be useful in the determination of drug-induced QT prolongation risk, and thus provide better characterization of a biomarker for the potential risk in humans for development of the torsades de pointes syndrome. However, safety methods development does not begin and end with ventricular repolarization. This focused issue also describes the re-evaluation and validation of a primate CNS model for evaluating orthostatic hypotension, and outlines a simple and rapid rodent object recognition task model that can be used to assess the amnesic potential of an NCE. Reviews of respiratory safety studies as well as both in vitro and in vivo aspects of cardiovascular function are also described. There are also papers that describe the pharmacology of vehicles and solvents used to solubilize study drugs and the applicability of voltage-sensitive dyes to optically record cardiac action potentials from single myocytes. Thus, this issue of the Journal of Pharmacological and Toxicological Methods remains a primary resource for industrial and academic pharmacologists interested in better understanding non-clinical safety pharmacology methods.     

中国临床药理学发展概况与展望

临床药理学是研究药物与人体之间相互作用及其规律的一门科学,是涉及药理学、医学、药物学、生物学、护理学、毒理学、流行病学、遗传学、数学、统计学、经济学、社会和个体行为学等多学科的交叉学科或综合学科.主要研究内容包括人体(正常,病人)的药动学、药效学和遗传药理学、临床药物评价和Ⅰ、Ⅱ、Ⅲ、Ⅳ期临床试验、治疗药物检测、药物警戒、药物利用、药物流行病学、药物经济学、新药发现与开发等.以往认为临床药理学是药理学的分支学科,还有将药物临床试验等同于临床药理学,均难以涵盖临床药理学的研究内容.临床药理学是指导药物临床合理使用、新药临床安全性有效性评价以及新药发现与开发的科学基础.改革开放以来,中国临床药理学研究经历了知识普及与队伍培育、规范研究与不断提高、蓬勃发展与着力创新三个阶段,在指导临床合理用药、药物临床研究、新药创制、人才培养、国内外学术交流、著作教材和期刊建设以及学术组织建设等方面发挥了重要作用.该文就改革开放以来我国临床药理学发展概况与进展作一简要综述.     

Origins, practices and future of safety pharmacology

The origins of safety pharmacology are grounded upon observations that organ functions (like organ structures) can be toxicological targets in humans exposed to novel therapeutic agents, and that drug effects on organ functions (unlike organ structures) are not readily detected by standard toxicological testing. Safety pharmacology is " em leader those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relationship to exposure in the therapeutic range and above em leader " [International Conference on Harmonization (ICH) S7A guidelines; Safety Pharmacology Studies for Human Pharmaceuticals]. This publication provides a comprehensive review of the history of safety pharmacology, international regulatory guidelines that govern the practices of this important field, and the scientific challenges that are being faced by its rapid emergence in pharmaceutical development. The criticality of identifying undesired adverse effects of new drugs in nonclinical models, which reflect the overall human condition, is reflected in the importance of generating an integrated and accurate assessment of possible human risk. The conundrum posed by the challenge of formulating a reliable risk assessment is the importance of improving and enhancing the safe progression of new drugs to the marketplace, while preventing unnecessary delays (or discontinuances), based on nonclinical findings that are not relevant or interpretable in terms of clinical response or human risk.     

Utilisation of human pharmacology studies with biomarkers for new drug applications in Japan

OBJECTIVE: This study evaluated the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation conducted for new drug applications (NDAs) submitted to the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW). METHODS: A total of 50 new chemical entities (NCEs) posted on the Websites, which were approved from June 2000 to November 2001, were evaluated by investigating their approval information. The utilisation of human pharmacology studies with biomarkers was evaluated by focusing on the classification referred to biomarkers for either efficacy or safety estimation and timing of studies. RESULTS: The human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted in 20 compounds classified by utilising measures of either efficacy (17 compounds) or safety (seven compounds). In 4 of 17 NCEs, some of the biomarkers in human pharmacology studies were similar to the clinical endpoints for efficacy assessment in therapeutic exploratory and/or therapeutic confirmatory studies. For safety assessment in therapeutic exploratory and/or therapeutic confirmatory studies, clinical endpoints rather than biomarkers in human pharmacology studies were used in all seven NCEs. The timing of each type of clinical study could only be obtained for 15 NCEs. Of these 15 NCEs, human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted on six compounds. There were only two compounds for which human pharmacology studies with biomarkers for efficacy estimation were conducted before pivotal studies such as a therapeutic exploratory study or a bridging study. CONCLUSION: Our survey suggests that with Japanese NDAs, human pharmacology studies with biomarkers for either efficacy or safety estimation do not play a key role in accelerating drug development and maximising the knowledge gained from confirmatory trials. The relationship between a biomarker and a clinical endpoint should be investigated appropriately for accelerating drug development. We think that the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation in the regulatory review process for NDAs should be encouraged with the advancements of drug evaluation research using an appropriate biomarker based on clinical pharmacology.     

FDA的《长效局部麻醉药开发供企业用指导原则草案》介绍

美国食品药品监督管理局（FDA）于2023年3月发布了《长效局部麻醉药开发的供企业用的指导原则草案》。该指导原则针对长效局部麻醉药新药申请的不同适应证和说明书的声明,尤其是术后镇痛,提出了对这类药物开发和试验设计的详细而具体的许多建议,包括一般临床药理学、人因工程学评价、试验设计、临床有效性评价、临床安全性评价和说明书的声明等诸方面。而我国目前尚没有类似的指导原则,详细介绍FDA该指导原则的主要内容,期望对我国这类药物的开发研究及其监管有所帮助。     

创新药物临床试验中暴露量-效应关系研究的探讨

创新药物临床试验旨在为药物上市提供安全有效的依据,涵盖了临床药理学研究、剂量探索性临床治疗试验和确证性临床治疗试验,其中暴露量-效应关系研究已经成为临床研究的核心。本文在梳理了创新药物临床试验的前后过程以及逻辑关系的基础上,对暴露量-效应关系研究的相关内容、暴露量-效应关系研究在审评、提高临床研究质量、降低临床失败风险以及加速新药上市方面的重要性方面进行了探讨。     

Clinical pharmacology: special safety considerations in drug development and pharmacovigilance.

The dose of a drug is a major determinant of its safety, and establishing a safe dose of a novel drug is a prime objective during clinical development. The design of pre-marketing clinical trials precludes the representation of important subpopulations such as children, the elderly and people with co-morbidities. Therefore, postmarketing surveillance (PMS) activities are required to monitor the safety profile of drugs in real clinical practice. Furthermore, individual variations in pharmacogenetic profiles, the immune system, drug metabolic pathways and drug-drug interactions are also important factors in the occurrence of adverse drug reactions. Thus, the safety of a drug is a major clinical consideration before and after it is marketed. A multidisciplinary approach is required to enhance the safety profile of drugs at all stages of development, including PMS activities. Clinical pharmacology encompasses a range of disciplines and forms the backbone of drug safety consideration during clinical drug development. In this review we give an overview of the clinical drug development process and consider its limitations. We present a discussion of several aspects of clinical pharmacology and their application to enhancing drug safety. Pharmacokinetic-pharmacodynamic modelling provides a method of predicting a clinically safe dose; consideration of drug pharmacokinetics in special populations may enhance safe therapeutics in a wider spectrum of patients, while pharmacogenetics provides the possibility of genotype-specific therapeutics. Pharmacovigilance activities are also discussed. Given the complex nature and unpredictability of type B reactions, PMS activities are crucial in managing the risks drugs pose to the general population. The various aspects of clinical pharmacology discussed make a strong case for this field as the backbone of optimising and promoting safe development and use of drugs.