1、臨床試驗於研究設計與計畫撰寫方面 之法規科學考量,財團法人醫藥品查驗中心臨床組審查員陳民輝醫師,1,Disclaimer,本次之演講內容，凡涉及政策方向及法規解釋之適用範圍，應以衛生主管機關之說明為準。,2,Outlines,一、臨床試驗之常用定義二、臨床試驗研究設計之基本概念三、臨床試驗計畫書之考量與撰寫原則四、結語,3,Definition of Clinical Trial by The US NIH,A prospective biomedical or behavioral research study of human subjects that is designed to an
2、swer specific questions about biomedical or behavioral interventions (such as drugs, treatments, devices, or new ways of using known drugs, treatments, or devices).,4,人體試驗國內法源依據,醫療法第78條：為提高國內醫療技術水準或預防疾病上之需要，教學醫院經擬定計畫，報請中央主管機關核准，或經中央主管機關委託者，得施行人體試驗。但學名藥生體可用率、生體相等性之人體試驗研究得免經中央主管機關之核准。非教學醫院不得施行人體試驗。但醫療
3、機構有特殊專長，經中央主管機關同意者，得準用前項規定。前二項人體試驗計畫，醫療機構應提經醫療科技人員、法律專家及社會公正人士或民間團體代表，且單一性別不得低於三分之一之人員會同審查通過；計畫變更時，亦同。審查人員並應遵守利益迴避原則。人體試驗管理辦法第2條：新藥品、新醫療器材於辦理查驗登記前，或醫療機構將新醫療技術列入常規醫療處置項目前，應施行人體試驗研究（以下稱人體試驗）。,5,Definition of Clinical Trial in ICH E6 GCP,Any investigation in human subjects intended todiscover or verify
4、 the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s),identify any adverse reactions to an investigational product(s), study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety
5、 and/or efficacy The terms clinical trial and clinical study are synonymous.,6,Outlines,一、臨床試驗之常用定義二、臨床試驗研究設計之基本概念三、臨床試驗計畫書之考量與撰寫原則四、結語,7,8,臨床試驗之基本統計概念,敘述統計描述資料的性質，如平均值與標準差。推論統計的觀念是用樣本的統計量來推測母群體的參數。統計推論的假設檢定：假設檢定一般都以無差別為出發點，作為原始假設 (虛無假設 = 試驗組與對照組無差別)，對立假設就是有差別(研究假設 = 試驗組與對照組有差別)。利用機率性質的反證法，以小機率事件實際上
6、的不可能性原理 (p)，來否定無差別，從而證明有差別(亦即說明研究試驗的介入處置是有效的)。臨床試驗研究設計之基本概念要符合統計假設檢定的基本原理，才能利用統計的假設檢定，進行合理的推論。,9,The four types of interpretations that can be made from a clinical trial,Power = 1-,p: 試驗組與對照組無差別的機率: 無效藥被當成有效的機率: 有效藥被當成無效的機率1 - : Statistical power (有效藥被當成有效的機率),10,Source: Johan Karlberg and Marjorie
7、Speers. Reviewing Clinical Trials: A Guide for the Ethics Committee, 2010,11,Randomized Controlled Trial,Target Population,Study Population,Non-participants,Participants,Randomization,Intervention A,Outcome,Intervention B,Outcome,External Validity(Generalizability),Internal Validity(Comparability),S
8、ource: George Wells. Designing Clinical Trials: Protocol Writing, Design Features, and Grantsmanship, 2009,12,Validity in Clinical Trial Design,Source: Phillip Good. A Managers Guide to the Design and Conduct of Clinical Trials, 2002,13,臨床試驗之研究設計,The Regulatory Perspective: Clinical trials are condu
9、cted to test new medicinal products and medical procedures in humans to provide clinical evidence of effectiveness and safety.Three cornerstones of clinical trial design: randomization, control, and blindingRandomized controlled clinical trials (RCT)Randomized, double-blind, placebo-controlled clini
10、cal trialsAdequate and well-controlled studies (USA 21 CFR 314.126)Quantitative and qualitative standards for demonstrating effectiveness of drugs and biologics,14,Questions Before Going to Clinical Trial,先確認是否值得進行本試驗?確認整個試驗團隊是否準備好了?是否已經擁有試驗藥物相關之劑量與毒性資料?以及試驗藥物與常併用藥物之交互作用資料?是否已經了解本試驗將排除某些族群受試者?而這些族群若
11、都排除在外，本試驗是否仍值得進行?(還有市場嗎?)試驗執行期預估多久?何種情況下，將會終止試驗?,15,Outlines,一、臨床試驗之常用定義二、臨床試驗研究設計之基本概念三、臨床試驗計畫書之考量與撰寫原則四、結語,16,國科會計畫與臨床試驗計畫書,17,臨床試驗計畫書格式及內容可參考國內外規範,ICH E6 (R1) Good Clinical Practice Section 6 (www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html)ICH E3 Structure and Content o
12、f Clinical Study Reports (www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html)藥品臨床試驗計畫書主要審查事項 93年02月18日公告 (www.doh.gov.tw/CHT2006/DM/DM2_p01.aspx?class_no=24&now_fod_list_no=9382&level_no=2&doc_no=30251) 臨床試驗報告之格式及內容基準 92年04月14日公告 (www.doh.gov.tw/CHT2006/DM/DM2_p01.aspx?class_n
13、o=2&now_fod_list_no=155&level_no=2&doc_no=39878),18,試驗計畫書主要應載明事項(主要審查事項),一般資訊（General information）背景（Background information）試驗目的（Trial objectives and purpose）試驗設計（Trial design）受試者的選擇及退出（Selection and withdrawal of subjects）給藥及處置方式（Treatment of subjects）療效評估（Assessment of efficacy）安全性評估（Assessment of
14、 safety）統計（Statistics）,19,Clinical Trial Protocol (ICH E6 Section 6),1. General Information2. Background Information3. Trial Objectives and Purpose4. Trial Design5. Selection and Withdrawal of Subjects6. Treatment of Subjects7. Assessment of Efficacy8. Assessment of Safety9. Statistics,10. Direct Ac
15、cess to Source Data/Documents11. Quality Control and Quality Assurance12. Ethics13. Data Handling and Record Keeping14. Financing and Insurance15. Publication Policy 16. Supplements,20,2. Background Information,Name and description of the investigational product(s) A summary of findings from nonclin
16、ical studies that potentially have clinical significance and from clinical trials that are relevant to the trial Summary of the known and potential risks and benefits, if any, to human subjects Description of and justification for the route of administration, dosage, dosage regimen, and treatment pe
17、riod(s) A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s) Description of the population to be studies References to literature and data that are relevant to the trial, and that provide background for the trial,21,3. Trial O
18、bjectives and Purpose,A detailed description of the objectives and the purpose of the trial Example: Primary ObjectivePrincipal hypothesis such as: An increase in efficacy with no increase in side effects A decrease in side effects with no decline in efficacy No worse than but less costly and/or les
19、s invasive“The purpose of this trial is to demonstrate that: in treating conditions A, B, C with subjects having characteristics D, E, F an intervention of the form G is equivalent to / as effective as / as or more effective than an intervention of the form H and has fewer side effects.”,22,4. Trial
20、 Design,A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages
21、 A description of the measures taken to minimize/avoid bias, including: (a) Randomization (b) Blinding A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labeling of the investigat
22、ional product(s),23,4. Trial Design,5. The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any 6. A description of the stopping rules or discontinuation criteria for individual subjects, parts of trial and entir
23、e trial. 7. Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any 8. Maintenance of trial treatment randomization codes and procedures for breaking codes 9. The identification of any data to be recorded directly on the CRFs (i.e. no prior wr
24、itten or electronic record of data), and to be considered to be source data,24,Outcome Measures and Evaluation,Primary outcome (primary efficacy endpoint)Outcome associated with primary objectiveMost important outcome, so questions of relevance and importance in assessing the primary question will b
25、e raisedSecondary outcomes (second efficacy endpoints)Outcomes associated with secondary objectivesLess important than primary outcome,25,Primary Efficacy Endpoint,General Guideline: - Objective endpoints are better than subjective ones. - True (Solid) endpoints are better than surrogate ones. - The
26、 fewer the end points, the better.Determine the efficacy endpoint: 1. Cure or control 2. Duration of the symptom or disease 3. Severity of the symptom or disease at some fixed point after the start of treatment This latter can be expressed either in terms of (a) a mean value (FDA preferred) or (b) t
27、he proportion (EMA preferred) of individuals in the study population whose severity lies below some predetermined fixed value.,26,Secondary Efficacy Endpoints,大多數情況之 secondary endpoints 為 safety endpoints。(Key) secondary efficacy endpoint 會有時針對 events of special interest (如：NSAIDs 之 GI side effects;
28、 OHA 之 hypoglycemic events)特定之 events of special interest 會成為 primary safety endpoint: 如輪狀病毒疫苗之腸套疊發生率。次要指標之設定原則： Dont collect data you dont need; store and analyze the data you do collect.,27,Randomized Controlled Clinical Trials,Randomization：使試驗介入處置 (intervention) 以外其他會影響試驗結果的因子，在試驗各組的分佈平均(compara
29、bility)Blinding：排除外在、人為的可能偏差 (bias)Control：排除試驗結果是由試驗介入處置造成以外的其他可能解釋 (alternative explanations)Stratification：使會影響試驗結果之因子在試驗各組的差異減低,28,Ethical Issues for Placebo Control,The Declaration of Helsinki states: “The benefits, risks, burdens and effectiveness of a new intervention must be tested against t
30、hose of the best current proven intervention, except in the following circumstances: The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to d
31、etermine the efficacy or safety of an intervention and the participants who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.”,29,Placebo Control,接受安慰劑並不等於臨床上完全未接受治療，仍會接受和試驗組一樣之安全監測與 best support
32、ive care。在 add-on design 時，安慰劑組與試驗組接受相同的 current standard therapy。Placebo control 可有助於鑑別 AE 是導因於藥品或是underlying disease。理論上，placebo control 可以減少所需之受試者人數；而使用 active control 所需之受試者人數較多。,30,Active Control,要選擇 current standard therapy。Trial 可採 superiority, non-inferiority 或 equivalence design。亦可以由 non-in
33、feriority 成功後，再測試 superiority。有時 active control 僅作為 assay sensitivity 之用 (主要療效假說仍是 test product 優於 placebo，例如 3-arm design)。參考資料:www.ema.europa.eu/pdfs/human/ewp/215899en.pdfwww.ema.europa.eu/pdfs/human/ewp/048299en.pdfwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM
34、202140.pdf,31,When to Break The Code?,Randomization procedures must be followed to ensure that the treatment code is only able to be broken in the event of any of the following occurrences (unless otherwise specified):Adverse event or medical emergency where the treatment of the patient is dependent
35、 on knowledge of the study treatment codeAccidental administration of the investigational product to a patient not participating in the researchAny other instance as specified in the study protocol,32,5. Selection and Withdrawal of Subjects,Subject inclusion criteria Subject exclusion criteria Subje
36、ct withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying: (a) When and how to withdraw subjects from the trial/ investigational product treatment (b) The type and timing of the data to be collected for withdrawn subjects (c) Whether and ho
37、w subjects are to be replaced. (d) The follow-up for subjects withdrawn from investigational product treatment/trial treatment,33,Patient Selection,Inclusion/Exclusion (Eligibility) Criteria:Clear and unambiguous statement of subject selection criteriaInclude subjects depending on theirrisk of event
38、 of interestlikely responsiveness to trial interventionExclude subjects who may be placed at some increased riskalready manifest outcome,34,Eligibility Requirements,診斷要明確，診斷方式要為目前之 gold standard。疾病嚴重程度與目前有無現行標準治療，皆會影響試驗設計與療效分析。收納族群太窄，代表性太差，很容易日後再重複做試驗。收納族群太寬，容易因為納入不適合之次族群而被法規單位要求停止試驗。排除條件依照藥品特性機轉列出可
39、能之禁忌症清單。可能產生藥物交互作用之清單(考慮禁止或有適當規範)。考量上述限制後，要是否可能收納足夠之樣本數。可參考類似試驗之設定，再依照本藥品特性修改：clinicaltrials.gov、clinicalstudyresults.org、DrugsFDA，或 drug labels。,35,6. Treatment of Subjects,The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the rou
40、te/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the tr
41、ial Procedures for monitoring subject compliance,36,Study Procedures,Brief descriptions of any invasive procedures and specimen collection and handlingDosage form (capsule, tablet, ointment, liquid)Route of administration (oral, intramuscular, intravenous)Frequency of administrationMethods for handl
42、ing any possible adverse reactions to proceduresDose modification, delay, and interruptionConcomitant and prohibited medications and therapies Rescue medications,37,7. Assessment of Efficacy,Specification of the efficacy parameters Methods and timing for assessing, recording, and analyzing of effica
43、cy parameters,38,Efficacy Endpoints,是否能驗證本試驗之目的?是否為能夠顯示藥品在該適應症療效之最有意義之臨床指標(clinical endpoint)?是否符合該適應症在該 phase 試驗設計原則? (e.g., PD parameters in phase 2 study)是否為國際法規單位所普遍接受之 endpoint (e.g., overall survival、PFS)Validated surrogate endpoint? (e.g., blood pressure、HbA1c ，or other PD parameters),39,8. A
44、ssessment of Safety,Specification of safety parameters The methods and timing for assessing, recording, and analyzing safety parameter Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses The type and duration of the follow-up of subjects after
45、 adverse events,40,Adverse Events,Definition of AE (mild, moderate, severe, MedDRA, CTCAE) Definition of serious AE (SAE)AE of special interestSAE reporting,41,Safety Considerations,試驗藥品可能的重大不良反應為何？不良反應有無適當控制？(dose reduction, delay, or interruption?)對於危險族群的保護措施為何？危險族群列入排除對象或增加監控？此藥品之風險相對應於適應症，對受試者是否
46、合理可承受?本試驗是否有 IDMC 密切監控?試驗藥品之常見不良反應為何?是否有告知受試者?,42,Checklist of Efficacy and Safety Measures,試驗治療方式本質為何? 如何給予? 給予期間多長?所要觀測之主要療效指標為何? 何時觀測? 如何觀測? 誰負責觀測? 測量單位為何? 誰負責判讀結果? 事前預估之定量結果為何?試驗當中必須觀察安全性資料：本藥品預期之短期副作用為何? 打算如何觀測它們? 事前預估之定量結果為何? 預期服藥多久後可觀測到? 本藥品預期之長期副作用為何? 打算如何觀測它們? 事前預估之定量結果 (如：每100位受試者發生率) 為何?,
47、43,Baseline Efficacy and Safety Measures,依照所設定之觀察指標(含主要與次要)收集基準期數據收集可能影響療效與安全性之基準期數據收集判定納入排除條件所需之數據收集作分層隨機分派所需之數據每樣數據依照收集方式分門別類撰寫，例如: interview, questionnaire, physical examination, specialized examinations (angiogram, ultrasound, MRI), and/or laboratory tests,44,Visit Schedule and Assessments,操作型定義
48、，在不同的期間擬進行什麼檢查或者治療，都應該書寫清楚如何進行療效的評估與分析安全性相關評估Flow chart 與計畫書內容應致,45,Clinical Follow-Up Flow Chart,Schedule of Events,46,9. Statistics,A description of the statistical methods to be employed, including timing of any planned interim analysis(ses) The number of subjects planned to be enrolled. In multi
49、center trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification The level of significance to be used Criteria for the termination of the trial,
