临床试验设计

1、临床试验设计CLINICAL RESEARCH & CLINICAL TRIALSHow To Design a Clinical ProtocolOlivier JINXian-Janssen PharmaceuticalSRx Medical Affairs第1页相关定义USEFUL DEFINITIONS第2页临床研究分期 TRIAL PHASES第3页一期临床 (Phase I)Initial safety trials on a new compound, usually conducted in normal male volunteers. An attempt is made

2、to establish the dose range tolerated by volunteers for single and multiple doses.研发药品首次在健康男性志愿者身上进行剂量耐受试验。经过单次或者屡次给药了解试验药品可耐受剂量范围。第4页一期临床 (Phase I)Phase I trials are sometimes conducted in severely ill patients, e.g.（有时选择重症病人）In the field of cancer（癌症病人）Or in less ill patients when pharmacokinetic

3、issues are addressed, e.g.（药代动力学研究有时需要病人参加）Metabolism of a new antiepileptic medicine in stable epileptic patients whose microsomal liver enzymes have been induced by other antiepileptic medicine第5页一期临床 (Phase I)Pharmacokinetic trial are usually considered Phase I trials regardless of when they are

4、conducted during a medicines development 在药品研发过程中，药代动力学研究普通被视为一期临床，而与开展研究时间无关。第6页二期临床 (Phase IIa)Pilot clinical trials to evaluate efficacy (and safety) in selected populations of patients with the disease or condition to be treated, diagnosed, or prevented.在特定病人群体中对研究药品疗效（包含安全性）进行初步评定。Objectives ma

5、y focus on: （主要为回答以下问题）Dose-response（有效剂量）Frequency of dosing（给药频率）Type of patient（适用人群）Numerous other characteristics of safety and efficacy（以及其它疗效与安全性特点）Usually open label design（通常为开放性设计）第7页二期临床 (Phase IIb)Well-controlled trials to evaluate efficacy (and safety) in patients with the disease or co

6、ndition to be treated, diagnosed or prevented. These clinical trials usually represent the most rigorous demonstration of medicines efficacy. Sometimes referred to as pivotal trials选择某类病人进行严格比较/对照试验，这类临床试验普通作为研发药品疗效主要支持证据。被视为药品注册关键性试验。第8页三期临床 (Phase III)Phase III clinical trials generate additional

7、data on both safety and efficacy in relatively large numbers of patient in both controlled and uncontrolled trials. （III期临床有相对大样本量，提供试验药品疗效及安全性方面补充信息。设计上可采取对照或者非对照形式）。These trials often provide much of the information needed for the package insert and labeling of the medicine.（药品使用说明所需要大量信息常源于III期试验

8、结果 ）。第9页三期临床 (Phase IIIb)Clinical trials conducted between regulatory submission of an NDA (New Drug Application) and approval of a regulatory dossier for marketing authorization.III期b指：自向药审机构递交新药注册申请到申请药品被同意上市这一段时间内，进行任何相关药品临床试验。第10页四期临床 (Phase VI)Studies or trials conducted after a drug is markete

9、d to provide additional details about the drugs efficacy or safety profile. （上市后药品临床研究或者试验，以提供药品疗效或者安全性方面补充信息）。Dosages, durations of the treatment, medicine interactions, and other medicine comparisons may be evaluated.（包含剂量、疗程、药品间相互作用以及不一样药品间对照/比较研究）。New age groups, races, and other type of patient

10、s can be studied.（新年纪组、不一样人种以及其它类型患者能够是IV期临床研究范围）。Sometimes including Post Marketing Surveillance（包含PMS）。第11页四期临床 (Phase VI)Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies. 发觉及确认药品不良

11、反应及发生率，研究相关风险原因是IV期临床研究主要方面。If a marketed drug is to be evaluated for a new indication, then those clinical trials are considered Phase IIIb or event Phase II clinical trials.假如临床研究目标是为开发药品新适应征，这类研究被视为IIIb或者II期。第12页四期临床 (Phase VI)The term Post Marketing Surveillance is frequently used to describe th

12、ose clinical studies in Phase IV (i.e. the period following marketing) that are primarily observational or non-experimental in nature, to distinguish them from well controlled Phase IV clinical trials or marketing studies.PMS普通指IV期临床研究中，那类观察性、不带有试验性质研究。应将这类研究与其它比较/对照式IV期临床试验或研究加以区分。第13页临床试验分型 (Clini

13、cal Trial Phases)Each of these definitions is a functional one and the terms are not defined on a strict chronological basis.临床试验分期是功效性，不一定有严格时间次序。An investigational drug is often evaluated in two or more phases simultaneously in different clinical trials. Also, some clinical trials may overlap two

14、different phases.研发中药品常在同一时间进行不一样分期临床试验，一些试验本身就涵盖不一样分期研究内容。第14页临床研究 (Clinical Studies)The class of scientific approaches to evaluate the pathophysiology, diagnostic, techniques, measurements, treatments and prevention of medical diseases凡经过科学方法、伎俩分析、评价疾病病理生理学，诊疗方法，医疗技术，各类理化指标，治疗学及预防学等都属于临床研究范围。第15页临

15、床试验 (Clinical trials)A subset of those clinical studies that evaluates investigational medicines in Phase I, II, and III.以药品研发、注册为目标注册试验（I, II, III期）Phase IV evaluations in clinical trials using same or similar type of protocols to those used in Phase I and II are also referred to as clinical trials

16、.或一些IV期临床研究，采取了与I、II期相同或者相同试验设计，也属于临床试验。第16页不良反应 (Adverse Reaction)Unwanted effects (i.e. physical and psychological symptoms and signs) resulting from treatment. 指因研究药品引发、与治疗目标不相符、任何非预期身体或精神症状或体征。Synonyms include (同意词包含）：adverse medical effectsuntoward effectsside effectsadverse drug experienceadve

17、rse drug reactions第17页不良事件 (Adverse Event)The term is now used to include adverse reactions (to the medicine under study) as well as other non-treatment related adverse experiences.不良事件则包含研究药品引发不良反应及其它与治疗不相关任何不良体验。Adverse Event:该术语有意防止了可能暗示服药和不良反应之间关系第18页DISIGN A CLINICAL STUDY / TRIAL PROTOCOL 第19页

18、试验设计 (Design for Clinical Trials)Choosing the most appropriate design for clinical trial is similar to choosing ready-made clothes. (Spilker 1991)The selection of the most appropriate design or the optimal design depends on the questions asked including:The study objectivesThe nature of the study dr

19、ugThe disease status / condition under investigationOther considerations第20页研究 / 试验目 (Study / Trial Objectives)To clarify the study objective(s), the following questions are helpful:What aspects are being studied?Is it important to investigate other issues that may have an impact on the study drug?W

20、hich control(s) might be used?第21页研究 / 试验目 (Study / Trial Objectives)Study objectives a concise statements of the major and minor questions the study is intended to answer.是对研究试图回答问题简练描述。第22页研究 / 试验目 (Study / Trial Objectives)How Many Study Objectives May Be Posted?NOT TOO MANY!（一个研究目标不能太多）Posting t

21、oo many questions complicates the study and decreases the probability the study will be completed successfully（尝试回答过多问题是研究复杂化，降低研究成功机会）。Excessive number of subgroups of data may be created and become unmanageable（过多数据分组会使研究变得无法管理和控制）。第23页研究 / 试验目 (Study / Trial Objectives)Make sure you are asking th

22、e right question(s) （确定研究项目标价值）Review the relevant literature（阅读相关资料）Consult with senior colleagues or mentors（向有经验同事或师长请教）Present your tentative plan to an informal discussion group（方案讨论）第24页平行设计(Parallel Designs)A parallel design is a complete randomized design in which each patient receives one a

23、nd only one treatment in a random fashion and during the entire trial. Basically there are two types of parallel design for comparative clinical trials, namely,Group comparison (or parallel-group) designsMatched pairs parallel designsA parallel design is probably the most commonly used design in pha

24、ses II and III of clinical trials第25页平行设计(Parallel Designs)The treatments assigned to the two groups differ (e.g., a treatment group vs. a control group). Each treatment group usually, but not necessarily, contains the same number of patients.Between-patient differences are used to assess the effect

25、 being studied.第26页平行设计(Parallel Designs)Simple.Universally accepted.Applicable to acute conditions.Usually requires more patients than other comparative designs.第27页PatientsRUN INRANDOMIZATIONTestControl AControl BParallel-group Design第28页交叉设计(Crossover Designs)Within-patient differences (patients

26、serve as their own control) 本身对照形式Increased sensitivity and smaller variability 敏感性增加，差异减小Fewer Patients required than with parallel designs to detect same effect.（与平行设计相比，需要更小样本量）Disadvantage of this design is Subject dropouts and missing data (analysis not as robust)（失访、数据缺失情况相对严重）Carry over (resi

27、dual) effects must be controlled（药品残余效应）A placebo “washout” phase may be required（清洗期）Baseline at start of each treatment must be comparable if not identical（必须注意基线可比性）第29页预试验(Common Reasons to Conduct Pilot Study)Feasibility（可行性）Stuff training（研究人员训练）Exploration of ethical questions especially with

28、 regard to placebo use （论证方案伦理问题，尤其是需要有抚慰剂对照）Subject recruitment （入组病人）Dose ranging of new compound（新药剂量范围）Initial efficacy evaluation in new therapeutic area（新治疗领域药品疗效）Initial efficacy evaluation in a new indication（药品新适应征疗效）Clarification of methodological parameters （相关参数评定）第30页预试验(Pilot Study or

29、Trial)Is not “quick-and-dirty”（不是快速而粗糙）Must be carefully designed and executed（必须设计严谨，认真实施）Can be open or blinded（能够是开放或者盲法）May include placebo or reference（能够是抚慰剂对照或药品间比较）Can become a “pivotal study or trial”（有可能成为正式研究）第31页盲法(The “Blind”)The term “Blind” refers to a lack of knowledge of the identit

30、y of the trial treatment.盲法指不知晓接收或实施了哪种治疗办法Is meant to decrease the biases that occur in clinical study / trial when patients are evaluated during treatment and a placebo-effect must be avoided.目标是为防止抚慰剂或者不一样治疗办法在感觉上造成偏差第32页设盲种类(Type of “Blinds”)Open label（开放）Single Blind（单盲）Double Blind（双盲）Combinat

31、ion of “Blinds”（不一样盲法组合）Full Double Blind（全双盲）Everyone who interacts with the subject directly is kept blind (Patients, Nurses, Investigator(s), Study Coordinator)Full Triple Blind（全三盲）Everyone who is involved in a full double blind plus: other health care personal, monitor(s), statistician(s), othe

32、r clinical staff at sponsors institution, data review committee, other groups.第33页样本量 (Sample Size)Sample size required for a clinical study / trial is defined as the number of patients who complete the study / trial rather than number who enter.（指完成研究数量而非受试者入组数量）If too few patients complete a trial

33、, risk of false positive result.（过少病人完成试验，假阳性结果风险增高）Number of patients in each group may be fixed at:Defined number（固定数量）within a broad or narrow range（设定样本量范围）by a minimum number or by a maximum number（设定最小数量或最大数量）Sequential: final number of patients enrolled will depend on analyses performed throu

34、ghout the trial（依据走势判断）第34页样本量 (Equal vs. Unequal Sample Size)Establish suitable ratio of patients between two or more treatment or study groups（确定各组样本量百分比）Two basic choices:Equal-size samples in all groups（等量）Unequal-but proportional size groups (e.g., 2:1 ratio that assigns twice as many patients

35、to receive drug X vs. placebo)（等比）第35页样本量 (Equal vs. Unequal Sample Size)For ethical consideration with the control (e.g. the placebo), we can allocate patients unequally to treatment groups (in a random fashion) to allow more patients to receive the treatment (e.g. in a 2 to 1 or 3 to 1 ratio).Equa

36、l size designs preferable as power is gained （尽可能等量分配样本量，统计学效率最高）If ratio no more than 2 or 3 to 1, loss of power may be acceptable.第36页Study / Trial Protocol Design文件查询，是立题前最主要准备工作了解课题研究背景，进展情况了解课题研究价值了解其它研究者试验思绪了解这些设计优点和不足了解公认研究方法，评定伎俩，观察时间计算样本量评定试验可操作程度了解试验中轻易出现问题，可能产生偏差文件查询路径：网路检索相关文章文件目录第37页Stu

37、dy / Trial Protocol Design研究目标：高质量回答一个主要问题。前瞻/回顾设计（Prospective / Retrospective Study）盲法 / 开放（Open / Blinding）随机（Randomization Process）对照（controlled or uncontrolled study）入组 / 排除标准（Inclusion / Exclusion Criteria）样本量（Sample Size）基于统计分析评定指标（assessment）有放矢，目标明确第38页Study / Trial Protocol Design药品清洗期 （Was

38、h out period）保持各试验组基线水平一致性，可比性 （Baseline Comparable)试验同时性试验室检验；仪器设备校对（Laboratory texts）诊疗标准一致性（Multi-center Trial）伦理道德问题（Ethical）试验可操作性（Feasibility）第39页Study / Trial Protocol Design课题选择（或为领先尝试，或较具研究价值）是自己专长领域，对题目有足够知识，临床经验及相关研究经验受试病人起源参试人员试验可操作性（试验条件，检测设备，伎俩）经费起源第40页Study / Trial Protocol Design严谨临床

39、试验方案：选择有价值研究课题。试验方法与研究本身严谨性没有必定联络，设计形式没有优劣之分。能够充分回答试验目标就是好方法。都能满足试验目标，则简单易行，便于操作方法是最正确方法。苛刻方案设计 严谨严谨 合理； 规范； 可操作；采取公认评定 / 观察标准；能最大程度地防止数据偏差。适当入组人数恰当统计学方法高质量试验方案。第41页Basic Statistical ConceptsRange（极差，全距）Mean（均数 ）Median（中位数）Variance / Mean square deviation (方差 2）Standard deviation / SD（标准差 ） = 68.27%

40、; 1.96 = 95%; 2.58 = 99%P value (P值意义及能够引申结论）第42页Case Record Form (CRF)CRF设计必须考虑数据录入、分析可操作性仅量搜集最原始数据，而不是需要计算数据如：减分率、疗效CRF表格中两类信息：录入分析用数据、提醒性数据提问应尽可能详细、细化、明了，防止过多思索仅可能以选择性问答方式提问，防止或降低需要文字描述问答。使用编码归类CRF随时搜集，随时录入是必要第43页临床科研设计基本标准第44页临床科研设计基本标准对照标准随机标准重复标准均衡标准第45页临床科研设计基本标准对照标准：对照设置是否合理是研究设计是否科学、严谨标志。设置

41、对照应注意问题：例数一致 组间一致(基线可比性)非处理原因一致第46页临床科研设计基本标准对照类型： 抚慰剂 / 空白对照 标准对照 相互对照 本身对照（治疗前后 / 交叉 / 同时本身 ） 历史对照第47页临床科研设计基本标准随机标准：医学试验不可能在总体中进行。为确保样本代表性，必须遵照随机标准，使各组间除处理原因外其它混杂原因尽可能保持一致。试验者不应该参加随机分配过程。第48页临床科研设计基本标准重复标准：足够样本量个案价值第49页临床科研设计基本标准均衡标准（非处理原因均衡一致）交叉均衡同时性第50页样本量预计观察指标总体标准差 （个体变异度）文件资料 过去经验预试验结果组间差值单侧

42、 / 双侧检验假设不一样 样本含量要求不一样结果不一样第51页Company Sponsored trials第52页Company Sponsored trials起动程序药厂调查问卷完成试验能力入组 / 排除标准合理性病人起源入组能力及时间保密协议第53页Company Sponsored trials阅读方案是否对试验有兴趣，是否有能力完成评定试验风险，方案是否损害病人利益试验经费是否合理评定试验可操作性入组 / 排除标准可行性？是否要求过多入组数量？病人是否愿意参试？受试者能否坚持到底（越烦琐，时间越长，退出率越高）试验对正常医疗工作影响每次诊视时间安排第54页Company Spon

43、sored trials明智研究者或基地如遇下述情况，应该拒绝接收试验：不切实可行入组 / 排除标准。无须要要求，过多限制，繁杂检验项目。与试验者或基地本身承受力不相当任务。第55页Company Sponsored trialsInformed ConsentIRB Approved病人有机会与试验者讨论知情同意书内容勉励病人讨论对试验任何担心，疑问告诉病人参加试验好处与风险必须明确告诉病人：受试者有权随时退出试验参试者，证实人必须共同签署知情同意书，病人或家眷留复件，原件存档第56页Company Sponsored trialsSource Documents（原始资料）In a cli

44、nical trial, all information entered on a case report form needs to be supported by source document. The background source documents for every patient should includeMedical history（原始病例）Physical examination results（体格/试验室检验汇报）Current medications（当前用药情况）Medication discontinued in the past 30 days（既往30天内用药情况）A note that the informed consent form has been signed（知情同意）Phone logs（联络电话）Appointment books（预约统计）Screening logs（筛选统计）第57页Company Sponsored trialsCase Report Form (CRF