1. 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 LHypothese ( 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? ~Fromgooddaily 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 TreatmentControl 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 agood intervention for clinical trial?

Literatures review

Modern research

Experts opinions

Pilot clinical trials

21. Structure of Randomized Control Trials Randomized Endpoints Trial subjects TreatmentControl 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 HO 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) CMCTCChinese Medicine Clinical Trial Center Administrative 2 assistants Clinical affairs 1 CRA/HN 4 CRC Data management 1 Statistic PhD 2 Statistic MS 2 MD1 Pharmacist 20 Consultants 37.

,

38. Contact us: CSMUH Chinese Medicine Clinical Trial Center http://www.csh.org.tw/into/herb James Cheng-Chung Wei, MD, PhD ( )[email_address]