1. ~ James Cheng-Chung WEI, MD, PhD

2. 3. The Evidence Pyramid 4. How to Start?

Good daily patients care

Ask a good question

Search literatures

Design a protocol

Research team & resources

Institutional Review Board, IRB

Good clinical (trial) practice

Practical statistics

Write a paper

Submissions & publish

5. Ask a good (exciting) questionbefore designing a clinical trial

Unmet medical needs

• In view of holistic medicine

• Complimentary to mainstream medicine

Unanswered questions

• Critical appraisal of current evidence

Answerable

• Practical methodology

6. How to ask a goog question? ~Fromgooddaily patients care

Delicate care of individual patient

Detail records

Collect patients

Setup database

Thinking

7. Clinical Trials Design

Case series, Open exploratory study

Phase II Randomized controlled trial

• Dose range study is necessary

• Two stage design is a trend

• DBPC trial is preferred

Phase III Randomized controlled trial

8. Uncontrolled studies

Case series, Open study

Needs

• Scientific records

• Simple and well accepted endpoints

• Clear documentation

9. 10. 11. Defects of Uncontrolled studies

Disease natural course

Placebo effect

Horthorn effect

Regression to the mean

12. Gold standard ~ randomized controlled trials 13. Structure of Randomized Control Trials Randomized Endpoints Trial subjects TreatmentControl 14. Indications selection

Unmet needs

• Important diseases

• unsatisfactory efficacy or safety

• TCM better than western medicine

For examples:

• Cancer

• Cardiovascular disease

• Degenerative diseases: OA, dementia

• Immunological diseases: allergy, autoimmune disease

• Functional diseases: neurosis, aging

15. Trial subjects selection

Inclusive criteria

• Homogenecity

Exclusive criteria

• Efficacy

• Safety

16. How to find agood intervention for clinical trial?

Literatures review

Modern research

Experts opinions

Pilot clinical trials

17. Structure of Randomized Control Trials Randomized Endpoints Trial subjects TreatmentControl 18. Methods of control

Placebo control

• (bias)

Standard control (active control)

19. Bad controls

Self control (before-and-after study)

Historical control

Blank control

20. Add-on therapy design

Standard therapy as background for all arms

Add-on TCM or placebo to see the addictive effect

Ethic consideration

Better compliance

As complimentary therapies

21. 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?

22. Double blind +/- double dummy Randomization Endpoints Trial subjects A "Placebo or B 23. Randomization

( Baseline comparability)

24. Randomization

eg. 4, 6, 8

eg. BMI, gender

25. 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

26. Blind Method

Single blind

Double blind

27. (double-blind, double-dummy)

(double-blind, double-dummy)

28. 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 29.

(parallel design)

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

30. Adaptive designs

Stopping trial early due to safety, futility, or efficacy

Dose finding at stage 1

Interim analysis

Sample size re-estimation

Adaptive randomization

31. Sample size estimation

()

()

(variance)

(dropout rate)

32.

0.05 0.2 0.8

(UA) (1) 9mg/dl 7mg/dl (2) 9mg/dl (SD) 2mg/dl (1-2)/SD+ 25% 46

(interim analysis)

33. ITT vs PP

ITT (compliance)

Per-Protocol (PP) ( 75 )

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.

protocol

Good clinical practice

Case Report Form

Adverse events

38.

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