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

32.

• (parallel design)

• (crossover design) (period) (wash-out period) (carryover effect)

33. 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

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

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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