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中山醫學大學附設醫院
臨床試驗之研究設計簡介
Clinical Trial Protocol design
魏正宗
James Cheng-Chung Wei, MD,PhD.
過敏免疫風濕科主任、中藥臨床試驗中心主任

ScienceScience
? Science is built up with facts, as a houseScience is built up with facts, as a house
is with stones. But a collection of facts isis with stones. But a collection of facts is
no more a science than a heap of stonesno more a science than a heap of stones
is a house.is a house.
? Measurable, reproducible andMeasurable, reproducible and
comparablecomparable..
Jules Henri Poincare : La Science et LJules Henri Poincare : La Science et L’’Hypothese ( 1908)Hypothese ( 1908)

魏正宗中山醫學大學附設醫院中藥臨床試驗中心

新藥開發流程
Scale-up
臨床前研究臨床試驗新藥審核
12-24 months
1-4
month
9-12
months 12-24 months
6-18 months
Phase II
Phase IV
Pharmacology and Pharmacokinetics
Animal Safety Testing
Submit
IND
Submit NDA NDA Approval
FormulationChemistry and Physical Characterization
Phase III
新藥監視
Botanicals with historical
documentation of safe human use

The Evidence Pyramid

Starting from
? Ask a good (exciting) question!

Ask a good (exciting) question
? Clinical relevant
? Unmet medical needs
? Clear
? Ask your question in one sentence
? Don’t be too ambitious
? Innovative
? Unanswered questions
? Review & critical appraisal of literatures
? Answerable
? Practical methodology

Ask a good question
問題之結構 (PICOT)
? P: Participant
? I: Intervention (E:Exposure)
? C: Comparison
? O: Outcome
? T: Time

Before study design
? Literatures search
? Background, Introduction
? What’s your hypothesis?
? Study Aim

Clinical Trials Design
? Case series
? Early exploratory study (Pilot study)
? Phase II Randomized controlled trial
(Proof-of-concept study)
? Dose range study is necessary
? DBPC trial is preferred
? Phase III Randomized controlled trial
(Confirmatory study)

Case series:
Drug A in the treatment of URI
? Sample size: 30
? Trial subjects: common cold
? Intervention: Drug “A”
? Duration: 14 days
? Endpoint: symptoms
? Result: 90% cured.
? Conclusion: Drug A is effective in the
treatment of common cold?

Cases series
Drug A in the treatment of obesity
? Sample size: 30
? Trial subjects: obesity
? Intervention: Drug “A”
? Design: open study, one arm
? Duration: 30 days
? Endpoint: body weight
? Result: 100 kg to 90 kg.
? Conclusion: Drug A can reduce body
weight?

Uncontrolled studies
? 缺點 : 沒有對照就沒有鑑別
1. 自然病程 (Natural course)
2. 霍桑效應（ Hawthorne effect ）
3. 安慰劑效應（ placebo effect ）
4. 向均數回歸（ regression to the mean ）

Uncontrolled studies
? Needs
? Known disease course
? Objective and well accepted endpoints
? Clear documentation

中山醫學大學附設醫院中藥臨床試驗中心
臨床試驗設計的 Gold
standard
~ 隨機對照試驗
（ randomized controlled
trials ）

Structure of Randomized Control
Trials
Treatment
Control
Randomized EndpointsTrial
subjects

Trial subjects selection
? Inclusive criteria
? Homogenecity
? Exclusive criteria
? Efficacy
? Safety

TCM in the treatment of hyperuricemiaTCM in the treatment of hyperuricemia
Patients selectionPatients selection
? Inclusion criteria: serum uric acid level moreInclusion criteria: serum uric acid level more
than 8 mg/dl.than 8 mg/dl.
? Exclusion criteriaExclusion criteria
? recent gouty attack within 2 weeksrecent gouty attack within 2 weeks
? serum creatinine more than 3 mg/dlserum creatinine more than 3 mg/dl
? AST more than 100 IUAST more than 100 IU
? change of background uric acid-lowering therapieschange of background uric acid-lowering therapies
including allopurinol, benzbromarone, probeneci,including allopurinol, benzbromarone, probeneci,
sulfipyrazone, azathioprine, aspirin (>325 mg),sulfipyrazone, azathioprine, aspirin (>325 mg),
atorvastatin, fenofibrate, losartan, thiazide, steroid,atorvastatin, fenofibrate, losartan, thiazide, steroid,
estrogen, oral contraceptive pills within 2 weeks.estrogen, oral contraceptive pills within 2 weeks.

How to find a good intervention
for clinical trial?
? Literatures review
? Modern research
? Expert’s opinions
? Pilot clinical trials

Methods of control
? Placebo control
? 目的在於克服對照組病人由於心理因素所造成
的偏倚 (bias)
? 常用無藥理作用的乳糖、澱粉等，安慰劑要求
在外觀、顔色、形狀與試驗藥物完全一致
? 要特別注意醫療道德上的可行性。
? Standard control (active control)
? 研究藥物的療效時，可以公認的常規有效療法
作爲對照。

“Bad” controls
? Self control (before-and-after study)
? 如用藥前後的自身對比觀察；
? 對照與實驗在同一物件身上進行，例如身體對稱部位
的比較觀察
? Historical control
? 已先前研究之結果為對照
? 只適用於”不隨時空環境不同而改變結果”之疾病
? Blank control
? 在對照組不加任何處理的“空白”條件下進行觀察。

Controlled trial:
Drug A and B in the treatment of obesity
? Sample size: 30 in each arm
? Intervention: Drug “A” or “B”
? Duration: 14 days
? Result: in arm A: 100 kg to 50kg, in arm B: 80
kg to 40 kg.
? Conclusion: Drug A is better than B in
reducing body weight?

Controlled trial:
Drug A and B in the treatment of obesity
? Sample size: 30 in each arm
? Intervention: Drug “A” or “B”
? Duration: 90 days
? Result: in arm A: 100 kg to 80kg, in arm B: 80
kg to 70 kg.
? Conclusion: Drug A is better than B in
reducing body weight?

Double blind +/- double dummy
“A”
"Placebo”
or “B”
Randomization EndpointsTrial
subjects

隨機化 Randomization
? 每一個研究物件或觀察單位都有完全
均等的機會被抽取或分配到某一組
? 不受研究者或研究物件主觀意願所左
右。
? 隨機才能有”可比較性” (Baseline
comparability)

Randomization
? 簡單隨機化：可通過抛擲硬幣、抽籤、摸
球、亂數表來完成。
? 區組隨機化：根據受試者進入研究的時間
先後順序，將其分成內含相等例數（ eg.
4, 6, 8 ）的若干區組，而後，區組內的受
試者被隨機分配至不同組別。
? 分層隨機化：依研究需要的某些變項
（ eg. BMI, gender ）劃分為互斥的若干
層，然後確認各層在母群體中的比例，接
著按此比例分別自每一層利用隨機抽取樣
本。

Endpoints
? Scientific: well accepted, clear and
operable outcome measurements
? Survival> QOL>Symptomatic>Laboratory
? Surrogate endpoints
? TCM endpoints if operable
? Primary and secondary endpoints
? Safety and efficacy

盲法（ Blind Method ）
? 受試者或研究人員，可能導致對效果判
斷的偏倚，可通過盲法來控制．
? 可行性及倫理考量
? Single blind
? 只有研究者知道，而受試者不知道。
? Double blind
? 研究者（包括資料分析者）和受試者雙方都
不知道。

31
Crossover Clinical Trial
Drug B
Drug A
W
A
S
H
O
U
T
Phase 1
Period
Eligible
Patients /
subjects
Drug A
Drug B
Informed
consent
Drug B
Drug A
Phase 2

平行設計與交叉設計
? 平行設計 (parallel design) ：每位受試者僅能接
受一種治療，也就是說各治療組間彼此互為獨立。
由於統計模式的應用上無需做許多的假設即可成
立，許多傳統方法皆能適用，因而被較廣泛地使
用。
? 交叉設計 (crossover design) ：交叉設計則每位
受試者可以在不同的時段 (period) 接受不同的治
療，惟兩個治療時段間必須有沖洗期 (wash-out
period) ，以避免繼續效應 (carryover effect) 。

Adaptive designs
? Stopping trial early due to safety, futility,
or efficacy
? Two stage design
? Dose finding at stage 1
? Interim analysis
? Sample size re-estimation
? Adaptive randomization
? …

臨床試驗計畫書 Protocol
1. 研究背景
2. 具體研究目的
3. 具體試驗設計
4. 隨機化方案
5. 病人入選和排除標準
6. 試驗實施的具體流程
7. 主要分析指標和次要分析指標
8. 樣本大小的要求
9. 資料收集方法
10. 統計分析

Research team & Resources
1. Principal investigator (PI), Co-PI, Sub-PI
2. Study nurse / Clinical research
coordinator (CRC)
3. Statistician / Epidemiologist

Chung Shan Medical University Hospital
Chinese Medicine Clinical Trial CenterChinese Medicine Clinical Trial Center
GCRCGCRC (General Clinical Research Center)(General Clinical Research Center)
? SMO (site-management organization)
model granted by the DOH, Taiwan
SMO (site-management organization)
GCRC (General Clinical Research Center)
CMCTC Chinese Medicine Clinical Trial Center
SMO (site-management organization)
GCRC (General Clinical Research Center)
CMCTC Chinese Medicine Clinical Trial Center
Administrative
2 assistants
Administrative
2 assistants
Clinical affairs
1 CRA/HN
4 CRC
Clinical affairs
1 CRA/HN
4 CRC
Data management
1 Statistic PhD
2 Statistic MS
Data management
1 Statistic PhD
2 Statistic MS
2 MD
1 Pharmacist
20 Consultants
2 MD
1 Pharmacist
20 Consultants

中藥臨床試驗中心
中山醫學大學附設醫院中藥臨床試驗中
心
研究重點
? 整合醫學與另類醫學
? 中草藥臨床研究
? 保健食品及營養補充品
? 過敏 , 免疫及風濕病之治療
? 關節炎、痛風、僵直性脊椎炎
? 過敏、乾癬
? 免疫調節
? 臨床試驗服務平台
? 中草藥暨機能性食品臨床研究中心
? 生物科技之產學合作窗口

Chung Shan Medical University Hospital Chinese Medicine Clinical Trial Center
Contact us:Contact us:
CSMUH Chinese Medicine Clinical Trial Center
http://www.csh.org.tw/into/herb
James Cheng-Chung Wei, MD, PhD ( 魏正宗 )
wei3228@gmail.com

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