1. Clinical Trial Protocol design James Cheng-Chung Wei,
MD,PhD.
2. Science
Science is built up with facts, as a house is with stones. But
a collection of facts is no more a science than a heap of stones is
a house.
Measurable, reproducible and comparable .
Jules Henri Poincare : La Science et L Hypothese ( 1908)
3.
4. Scale-up 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
Formulation Chemistry and Physical Characterization Phase III
Botanicals with historical documentation of safe human use
5. The Evidence Pyramid
6. Starting from
Ask a good (exciting) question!
7. Ask a good (exciting) question
Clinical relevant
Unmet medical needs
Clear
Ask your question in one sentence
Dont be too ambitious
Innovative
Unanswered questions
Review & critical appraisal of literatures
Answerable
Practical methodology
8. How to ask a goog question? ~From good daily patients care
Delicate care of individual patient
Detail records
Collect patients
Setup database
Thinking
9. Ask a good question
(PICOT)
P: Participant
I: Intervention (E:Exposure)
C: Comparison
O: Outcome
T: Time
10. Before study design
Literatures search
Background, Introduction
Whats your hypothesis?
Study Aim
11. 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)
12. 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?
13. 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?
14. Uncontrolled studies
:
( Natural course)
Hawthorne effect
placebo effect
regression to the mean
15. Uncontrolled studies
Needs
Known disease course
Objective and well accepted endpoints
Clear documentation
16. Gold standard ~ randomized controlled trials
17. Structure of Randomized Control Trials Randomized Endpoints
Trial subjects Treatment Control
18. Trial subjects selection
Inclusive criteria
Homogenecity
Exclusive criteria
Efficacy
Safety
19. TCM in the treatment of hyperuricemia Patients selection
Inclusion criteria: serum uric acid level more than 8
mg/dl.
Exclusion criteria
recent gouty attack within 2 weeks
serum creatinine more than 3 mg/dl
AST more than 100 IU
change of background uric acid-lowering therapies including
allopurinol, benzbromarone, probeneci, sulfipyrazone, azathioprine,
aspirin (>325 mg), atorvastatin, fenofibrate, losartan,
thiazide, steroid, estrogen, oral contraceptive pills within 2
weeks.
20. How to find a good intervention for clinical trial?
Literatures review
Modern research
Experts opinions
Pilot clinical trials
21. Structure of Randomized Control Trials Randomized Endpoints
Trial subjects Treatment Control
22. Methods of control
Placebo control
(bias)
Standard control (active control)
23. Bad controls
Self control (before-and-after study)
Historical control
Blank control
24. Controlled trial: Drug A and B in the treatment of obesity
Sample size: 30 in each arm
Trial subjects: obesity
Intervention: Drug A or B
Duration: 14 days
Endpoint: body weight
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?
25. Controlled trial: Drug A and B in the treatment of obesity
Sample size: 30 in each arm
Trial subjects: obesity
Intervention: Drug A or B
Duration: 90 days
Endpoint: body weight
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?
26. Double blind +/- double dummy Randomization Endpoints Trial
subjects A "Placebo or B
27. Randomization
( Baseline comparability)
28. Randomization
eg. 4, 6, 8
eg. BMI, gender
29. 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
30. Blind Method
Single blind
Double blind
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
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
34. Protocol
35. Research team & Resources
Principal investigator (PI), Co-PI, Sub-PI
Study nurse / Clinical research coordinator (CRC)
Statistician / Epidemiologist
36. Chung Shan Medical University Hospital Chinese Medicine
Clinical Trial Center GCRC (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 Administrative
2 assistants Clinical affairs 1 CRA/HN 4 CRC Data management 1
Statistic PhD 2 Statistic MS 2 MD 1 Pharmacist 20 Consultants
37.
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38. Contact us: CSMUH Chinese Medicine Clinical Trial Center
http://www.csh.org.tw/into/herb James Cheng-Chung Wei, MD, PhD ( )
[email_address] Chung Shan Medical University Hospital Chinese
Medicine Clinical Trial Center