臨床試驗的研究設計 2 hr

1. Protocol design James Cheng-Chung Wei, MD,PhD.

2. Protocol

3. 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)

4. 5. 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 6. The Evidence Pyramid 7. Starting from

Ask a good (exciting) question!

8. Ask a good (exciting) question

Clinical relevant

Unmet medical needs

Ask your question in one sentence

Dont be too ambitious

Innovative

Unanswered questions

Review & critical appraisal of literatures

Answerable

Practical methodology

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

Delicate care of individual patient

Detail records

Collect patients

Setup database

Thinking

10. Ask a good question

(PICOT)

P: Participant

I: Intervention (E:Exposure)

C: Comparison

O: Outcome

T: Time

11. Before study design

Literatures search

Background, Introduction

Whats your hypothesis?

Study Aim

12. Clinical Trials Design

Case report, 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)

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 95 kg.

Conclusion: Drug A can reduce body weight?

14. Uncontrolled studies

One arm study

( Natural course)

Hawthorne effect

placebo effect

regression to the mean

Known disease course

Objective and well accepted endpoints

Clear documentation

15. 16. Gold standard ~ randomized controlled trials 17. Structure of Randomized Control Trials Parallel, two arms design Randomized Endpoints Trial subjects TreatmentControl 18. Trial subjects selection

Inclusive criteria

Homogenecity

Exclusive criteria

Efficacy

Safety

19. How to find agood intervention for clinical trial?

Literatures review

Modern research

Experts opinions

Pilot clinical trials

20. Intervention (treatment)

Clear dosing SOP

Dosing ranging study

Washout period

Run-in period

Allowed medication

Prohibit medication

Rescue medication

21. Methods of control

Placebo control

(bias)

Standard control (active control)

22. Bad controls

Self control (before-and-after study)

Historical control

Blank control

23. 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?

24. Double blind +/- double dummy Randomization Endpoints Trial subjects A "Placebo or B 25. Blind Method

Single blind

Double blind

26. Randomization

( Baseline comparability)

27. Randomization

eg. 4, 6, 8

eg. BMI, gender

28. Block Randomization

computer-generated 60 5 2 1 6 arms

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. (primary endpoint)

(indication)

(surrogate endpoint)

31. Dose ranging study anti-dsDNA Ab 10 IU/ml Meet allcriteria Randomization (~ 588 patients) 20% 40% 40% ~ 196 patients ~ 392 patients

Both Pre-screening and Screening consent forms obtain prior to

study activities .

32. ATTAIN study abatacept in inadequate responders to TNF-targeted therapy Day 1 12 months 24 months Randomization Placebo + DMARD (n=133) Fixed-dose abatacept~10 mg/kg + DMARD (n=258) Randomization=2:1 Anti-TNF inadequate responders with active disease (n=393)* Co-primary endpoints: ACR 20 and Physical Function Fixed-dose abatacept~10 mg/kg + DMARD (n=317) Double-blindOpen-label phase 6 months Open label phase ongoing *DMARDs continued, antiTNF washout period (2860 days); Based on patient weight range; Patients randomized to the placebo group in the first 6 months switched to abatacept during OL period; LTE=long-term extension Genovese M, et al. N Engl J Med 2005;353:11141123 33.

Active AS

MNY criteria

BASDAI>6

ESR>28

NSAID failure

Randomisation

Questionnaire

X ray: KUB, C, L spine lat view

Bath indices

ESR, CRP

Stock serum

Mo 2, 5, 11

Bath indices

ESR, CRP

Stock serum

X ray: KUB, C, L spine lat view

Bath indices

ESR, CRP

Stock serum

Biologics + NSAID + Sulfasalazine Biologics - NSAID - Sulfasalazine Factorial design 2 5 11 Biologics + NSAID - Sulfasalazine Biologics - NSAID + Sulfasalazine

Endpoints

mSASSS

ASAS20

Biomarkers

BS-alkP

Osteocalcin

Wnt, dkk-1

BMP, MMP

23 34. 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 35.

(parallel design)

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

36. Phase II/III design 37. Double blind double dummy design Non-inferiority vs superiority design Abatacept SC (weekly) Placebo IV (monthly) +IV loading dose Abatacept IV (monthly) Placebo SC (weekly) Abatacept SC (weekly) 15 Day 169 Commercial Availability 720 subjects 720 subjects Long-Term Extension ongoing Short Term 6 months 113 1 43 29 57 85 Days 141 Monthly Phone Visits +Quarterly Office Visits All subjects 38. 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

39. Study flow chart 40. Statistics &Sample size estimation

(variance)

(dropout rate)

41. Sample size estimation web http://stat.ubc.ca/~rollin/stats/ssize/

Comparing a Mean to a Known Value

Comparing Means for Two Independent Samples

Comparing a Proportion to a Known Value

Comparing Proportions for Two Independent Samples

Unmatched Case Control Studies

http://www.csh.org.tw/into/herb 42. Comparing Proportions for Two Independent Samples 43. Comparing Means for Two Independent Samples http://stat.ubc.ca/~rollin/stats/ssize/ 44. TCM in Patients with Hyperuricemia. A DBPC clinical trial

0.05 0.2 0.8

(UA) (1) 9mg/dl 7mg/dl (2) 8.5mg/dl (SD) 2 (1-2)/SD= 56

20% 56 x 10/8=70

(interim analysis)

45. Ultracet in Ankylosing Spondylitis. A DBPC clinical trial.

It was assumed that the BASDAI scores of treatment group ( 1 ) were reduced to 2 from 6, and the BASDAI scores of control group ( 0 ) were reduced to 3.5 from 6.

A 2-side test was used, with type error ( ) = 0.05, statistical power (1- )= 0.8 and standard deviation ( SD ) = 1.5.

The expecteddropout ratewas 20%.

Finally, the study required only 19 subjects in each group to achieve 95% power.

The target sample size for the study was 38.

46. Data Management Process CRF CRF CRA CDM CRF Data lock Data entry Data entry: Data validation Data analysis 47. Case Report Form

Monitor

Inspection

49. Research team & Resources

Principal investigator (PI), Co-PI, Sub-PI

Study nurse / Clinical research coordinator (CRC)

Statistician / Epidemiologist

50. 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 51.

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

臨床試驗的研究設計 2 hr

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