Transcript 臨床試驗於研究設計與計畫撰寫方面之法規科學考量

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
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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。
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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
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Definition of Clinical Trial by The US NIH
• A prospective biomedical or behavioral research
study of human subjects that is designed to answer
specific questions about biomedical or behavioral
interventions (such as drugs, treatments, devices, or
new ways of using known drugs, treatments, or
devices).
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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）。
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Definition of Clinical Trial in ICH E6 GCP
•
Any investigation in human subjects intended to
1. discover or verify the clinical, pharmacological, and/or
other pharmacodynamic effects of an investigational
product(s),
2. identify any adverse reactions to an investigational
product(s),
3. study absorption, distribution, metabolism, and
excretion of an investigational product(s)
with the object of ascertaining its safety and/or efficacy
•
The terms clinical trial and clinical study are synonymous.
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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
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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「小機率事件實際上的不可能性」原理 (p<α)，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。
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The four types of interpretations that can be
made from a clinical trial
Power = 1-β
β
α
p: 試驗組與對照組無差別的機率
α: 無效藥被當成有效的機率
β: 有效藥被當成無效的機率
1 - β: Statistical power (有效藥被當成有效的機率)
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Source: Johan Karlberg and Marjorie Speers. Reviewing Clinical Trials:
A Guide for the Ethics Committee, 2010
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Randomized Controlled Trial
Target Population
External Validity
(Generalizability)
Study Population
Participants
Non-participants
Internal Validity
(Comparability)
Randomization
Intervention A
Intervention B
Outcome
Outcome
Source: George Wells. Designing Clinical Trials: Protocol Writing, Design Features,
and Grantsmanship, 2009
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Validity in Clinical Trial Design
Source: Phillip Good. A Manager’s Guide to the Design and Conduct
of Clinical Trials, 2002
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臨床試驗之研究設計
The Regulatory Perspective:
• Clinical trials are conducted 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 blinding
– Randomized controlled clinical trials (RCT)
– Randomized, double-blind, placebo-controlled clinical trials
• Adequate and well-controlled studies (USA 21 CFR 314.126)
• Quantitative and qualitative standards for demonstrating
effectiveness of drugs and biologics
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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?
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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
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國科會計畫與臨床試驗計畫書
國科會計畫
臨床試驗計劃書
撰寫目的
向國科會申請經費
前瞻性研究計畫
Prospective plan
撰寫格式
依國科會計畫範本
依照 ICH E6 GCP Section 6 之綱要
撰寫重點
讓經費審查委員了解，是否 讓IRB/IEC與TFDA/CDE審查，對受
值得補助？以及預算編列是 試者保護是否足夠?試驗設計是
否合理？
否符合法規科學要求?
計畫實施步 為編列預算，採分年分項列 以受試者個體為主，描述每位受
驟之描述
舉
試者將進行哪些處置?
審查原則
綜合考量主持人先前之相關 設計是否合乎倫理與科學原則?
研究，該研究是否符合補助 計畫步驟是否清楚? 藥品與試驗
要點，預算編列是否合理等 之安全性是否在可接受範圍?
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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/efficacyguidelines.html)
• ICH E3 Structure and Content of Clinical Study Reports
(www.ich.org/products/guidelines/efficacy/article/efficacyguidelines.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_l
ist_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_no=2&now_fod_lis
t_no=155&level_no=2&doc_no=39878)
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試驗計畫書主要應載明事項(主要審查事項)
1.
2.
3.
4.
5.
6.
7.
8.
9.
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 safety）
統計（Statistics）
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Clinical Trial Protocol (ICH E6 Section 6)
1. General Information
2. Background Information
3. Trial Objectives and
Purpose
4. Trial Design
5. Selection and Withdrawal
of Subjects
6. Treatment of Subjects
7. Assessment of Efficacy
8. Assessment of Safety
9. Statistics
10. Direct Access to Source
Data/Documents
11. Quality Control and Quality
Assurance
12. Ethics
13. Data Handling and Record
Keeping
14. Financing and Insurance
15. Publication Policy
16. Supplements
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2. Background Information
1. Name and description of the investigational product(s)
2. A summary of findings from nonclinical studies that potentially
have clinical significance and from clinical trials that are relevant
to the trial
3. Summary of the known and potential risks and benefits, if any, to
human subjects
4. Description of and justification for the route of administration,
dosage, dosage regimen, and treatment period(s)
5. A statement that the trial will be conducted in compliance with
the protocol, GCP and the applicable regulatory requirement(s)
6. Description of the population to be studies
7. References to literature and data that are relevant to the trial, and
that provide background for the trial
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3. Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the
trial
•Example: Primary Objective
Principal 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 less 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.”
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4. Trial Design
1. A specific statement of the primary endpoints and the
secondary endpoints, if any, to be measured during the trial
2. 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
3. A description of the measures taken to minimize/avoid bias,
including:
(a) Randomization
(b) Blinding
4. 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 investigational product(s)
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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 entire 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 written or electronic record of data), and to
be considered to be source data
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Outcome Measures and Evaluation
Primary outcome (primary efficacy endpoint)
• Outcome associated with primary objective
• Most important outcome, so questions of relevance and
importance in assessing the primary question will be raised
Secondary outcomes (second efficacy endpoints)
• Outcomes associated with secondary objectives
• Less important than primary outcome
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Primary Efficacy Endpoint
• General Guideline:
- Objective endpoints are better than subjective ones.
- True (Solid) endpoints are better than surrogate ones.
- The 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) the proportion (EMA preferred)
of individuals in the study population whose severity lies
below some predetermined fixed value.
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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; 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：
Don’t collect data you don’t need; store and analyze the data
you do collect.
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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
(comparability)
• 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
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Ethical Issues for Placebo Control
The Declaration of Helsinki states:
“The benefits, risks, burdens and effectiveness of a new
intervention must be tested against those 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 determine 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.”
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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 supportive 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。
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Active Control
•
•
•
•
要選擇 current standard therapy。
Trial 可採 superiority, non-inferiority 或 equivalence design。
亦可以由 non-inferiority 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.pdf
www.ema.europa.eu/pdfs/human/ewp/048299en.pdf
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulato
ryInformation/Guidances/UCM202140.pdf
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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 on knowledge of the study treatment
code
•Accidental administration of the investigational product to a
patient not participating in the research
•Any other instance as specified in the study protocol
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5. Selection and Withdrawal of Subjects
1. Subject inclusion criteria
2. Subject exclusion criteria
3. Subject 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 how subjects are to be replaced.
(d) The follow-up for subjects withdrawn from investigational
product treatment/trial treatment
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Patient Selection
Inclusion/Exclusion (Eligibility) Criteria:
• Clear and unambiguous statement of subject selection
criteria
• Include subjects depending on their
– risk of event of interest
– likely responsiveness to trial intervention
• Exclude subjects who
– may be placed at some increased risk
– already manifest outcome
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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、Drugs@FDA，或
drug labels。
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6. Treatment of Subjects
1. The treatment(s) to be administered, including the name(s)
of all the product(s), the dose(s), the dosing schedule(s), the
route/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
2. Medication(s)/treatment(s) permitted (including rescue
medication) and not permitted before and/or during the trial
3. Procedures for monitoring subject compliance
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Study Procedures
• Brief descriptions of any invasive procedures and specimen
collection and handling
• Dosage form (capsule, tablet, ointment, liquid)
• Route of administration (oral, intramuscular, intravenous)
• Frequency of administration
• Methods for handling any possible adverse reactions to
procedures
• Dose modification, delay, and interruption
• Concomitant and prohibited medications and therapies
• Rescue medications
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7. Assessment of Efficacy
1. Specification of the efficacy parameters
2. Methods and timing for assessing, recording, and analyzing
of efficacy parameters
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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)
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8. Assessment of Safety
1. Specification of safety parameters
2. The methods and timing for assessing, recording, and
analyzing safety parameter
3. Procedures for eliciting reports of and for recording and
reporting adverse event and intercurrent illnesses
4. The type and duration of the follow-up of subjects after
adverse events
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Adverse Events
•
•
•
•
Definition of AE (mild, moderate, severe, MedDRA, CTCAE)
Definition of serious AE (SAE)
AE of special interest
SAE reporting
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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?
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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?
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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
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Visit Schedule and Assessments
• 操作型定義，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ㄧ致
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Clinical Follow-Up Flow Chart
Schedule of Events
46
9. Statistics
1. A description of the statistical methods to be employed,
including timing of any planned interim analysis(ses)
2. The number of subjects planned to be enrolled. In
multicenter 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
3. The level of significance to be used
4. Criteria for the termination of the trial
47
9. Statistics
5. Procedure for accounting for missing, unused, and spurious
data
6. Procedures for reporting any deviation(s) from the original
statistical plan (any deviation(s) from the original statistical
plan should be described and justified in protocol and/or in
the final report, as appropriate)
7. The selection of subjects to be included in the analyses (e.g.
all randomized subjects, all dosed subjects, all eligible
subjects, evaluable subjects)
48
Statistical Tests and Models
Two parallel groups design:
Outcome
Measure
Basic Test
Model controlling for covariates
Binary
chi-square test
Fisher’s exact test
Logistic regression model
Continuous
Student t-test
Multiple regression model
Wilcoxon sign rank test
Time to event
logrank test
Cox proportional hazards models
Source: George Wells. Designing Clinical Trials: Protocol Writing, Design Features,
and Gantsmanship, 2009
49
Calculation of Sample Size
• The method for calculating sample size should be stated in
the protocol.
• Consider:
study design, hypothesis, nature of outcome, statistical
methods, measure of variation, number of tail, important
difference, and significance/power
• Tips:
α, β, δ
Allocation ratio
Variance (SD)
Drop out rate
50
How Sample Size Influences The Conclusion
Effect Size
Source: Johan Karlberg and Marjorie Speers. Reviewing Clinical Trials:
A Guide for the Ethics Committee, 2010
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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
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結語
• 臨床試驗計畫書格式及內容可參考國內外之規範，以「
ICH E6 (R1) Good Clinical Practice」、「藥品臨床試驗計畫
書主要審查事項」為主，佐以「ICH E3 Structure and
Content of Clinical Study Reports」、「臨床試驗報告之格
式及內容基準」。
• 本次演講希望能協助國內之臨床試驗從業人員，依循科
學與倫理的原則來體現臨床試驗之研究設計與計畫撰寫
，達到法規科學考量之要求。
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Thank You for Your Attention!
Comments are welcome!
[email protected]
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