1. 授課老師 : 劉仁沛教授 國立台灣大學 與 國家衛生研究院 臨床試驗 Design and Analysis of Clinical Trials Conduct I: Preparation of a Protocol 1 【本著作除另有註明外，採取創用 CC 「姓名標示 －非商業性－相同方式分享」台灣 3.0 版授權釋出】創用 CC 「姓名標示 －非商業性－相同方式分享」台灣 3.0 版

2. I.Introduction II.Components of a protocol Title Page (Synopsis) Notification of the Sponsor Table of Contents Introduction (Background and Rationale) Objectives Study Target Populations Study Design Treatment Plan Evaluations and Measurements Efficacy, Safety and Others 2

3. Methods to Minimize Bias Statistical Methods and Data Management Handling and Accountability of Investigational Drugs Discontinuation / Protocol Changes Institution Review and Consent Obligations of Investigators and Administrative Aspects Study Flow Chart References Appendices III.Review Process, Issues and Quality IV.Discussion and Summary 3

4. 4 Introduction A protocol is the document that specifies the research plan for a clinical trial. Document The most important single document for quality control of a clinical trial Document for communication with other centers, investigators and personnel Peer review document Internal External Legal document Ethical obligation

5. 5 Introduction Purposes Prospectively design a trial to unbiasedly answer the scientific questions and make a valid inference to the targeted patient population Plan Completion specifications for Research question Targeted population Design characteristics Treatment characteristics Data collection Data analysis Conclusions and interpretation Research Management

6. 6 Introduction Requirement Scientifically valid Ethical Flexible Structured Logical Complete Most difficult part in development of a protocol Formulation and development of an important, feasible scientific questions Resources (patients, funds, time, personnel) to answer the questions

7. 7 Components of a protocol Title Page Protocol title Protocol no. Study phase Name of drug Dosage form, route of administration Objective Patient population Design Multicenter Blinding

8. 8 Components of a protocol Title Page Method of assignment Concurrent control Estimated total sample size Primary efficacy variables Adverse events Plan for data analysis Last revision Principle investigator and phone number Sponsor’s medical monitor and phone number

9. 9 Components of a protocol Example U.S. FDA proposed protocol cover sheet Taiwan DOH summary of a clinical trial Synopsis A one-page description of the complicated and lengthy protocol. Table of Contents Structure Page number or location of each section A list and the location of appendices Example

10. 10 Notification of Sponsor In the event of any death, serious or alarming adverse events, or unusual frequency of adverse events. The principal medical monitor or sponsor should be notified promptly by telephone, event though the events may not appear to be drug related. The adverse events must be recorded on the appropriate adverse event page of the case report form page.

11. 11 Medical Monitor XXX YYY ZZZ, MD Address Business Phone: Business Hour: Home Phone: Fax Number Nights, weekends, and holidays Physician on Call:

12. 12 Introduction (Background) Background of the disease under study Introduction to the investigational drugs and its development status Rationale and justification for the study Mechanism Hypothesis to be tested Difference Equivalence Two-sided One-sided non-inferior Superiority

13. 13 Introduction (Background) Previous animal experience and data Safety Effectiveness Previous human experience and data Pharmacological properties Pharmacodynamic characteristics Effectiveness Safety Citation of any relevant references

14. 14 Objectives A statement of the scientific questions addressed in the protocol Clear Concise Precise Quantitative (difficult) Questions Hypotheses

15. 15 Objectives General This proposed study is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the safety and efficacy of the investigational drug at dosage (frequency and, sometimes duration), compare to placebo, in the treatment of postmenopausal women with osteoporosis.

16. 16 Primary Objectives This proposed study is a randomized, double- blind, placebo-controlled trial conducted in x centers to evaluate the safety and efficacy on bone mineral density and the incidence of fractures of the investigational drug at dosage (frequency), compared to placebo, in treatment of postmenopausal osteoporosis.

17. 17 Secondary Objectives To evaluate the effects of the investigational drug on parameters of bone metabolism. Do not address hypothesis of Difference Equivalence Two-sided One-sided non-inferiority Superiority

18. 18 Study Targeted Populations Inclusion criteria Exclusion criteria Detailed Specific Quantitative Prior to Initiation of treatment Randomization Qualification for study Quantitative description Total sample size Factors affecting accrual Competing studies Alternative treatments

19. 19 Study Design Type Concurrent placebo control Concurrent active-control No. of treatment groups Single arm Two arms Multiple arms Statistical Design Parallel group Crossover Titration enrichment No. of centers No. of patients to be recruited at each center

20. 20 Study Design Levels of blinding Open-labeled Single-blind Double-blind Triple-blind Phases of the trial Screening Pre-randomization placebo run-in Pre-randomization titration Double-blind randomized Washout period Post-treatment follow-up

21. 21 Treatment Plan Controls Concurrent placebo control Concurrent active control No concurrent control Investigation Drugs – Dose and Route Description Formulation Dosage Supplier By each treatment group

22. 22 Treatment Plan Method of Dispensing When How Bottle Blister pack To whom By whom

23. 23 Treatment Plan Method of Randomization By center By stratified variables Permuted block randomization Some other adaptive methods Time of randomization Assignment of Patient Identification Patient Number (Chronicle Order) 7-digit number First two – protocol Middle two – center Last three – patient no. Randomization Number

24. 24 Treatment Plan Method of Labeling Double-blind 2-part tear-off label Conditions and consequences of breaking the random code Affixed to the CRF Label Protocol number Patient number Date of dispensing Instruction Warning and emergency no.

25. 25 Treatment Plan Method and Time of Administration Method Oral Quantity and frequency Ⅳ Preparation, rate Loading and maintenance doses Subcutaneous injection Time of Administration With respect to meals Instruction for missing medications

26. 26 Treatment Plan Dose modification Conditions and consequences Duration of Treatment Concomitant Medications and other Therapy

27. 27 Evaluations and Measurements When visit number, study day, and time Visit No.Study DayTreatment PeriodNo. of Tablets Dispensed 1-28Screening and start of placebo run-in28 placebos 20Randomization and start of DB Baseline28 3 DB28 456DB28 584DB28 6112DB28 7140DB28 8168DB Efficacy 28

28. Evaluations and Measurements Time should be selected to demonstrate efficacy, e.g. just prior to dosing Define baseline (zero time point) and the post- treatment time point to establish efficacy Detailed narrative description of procedures for evaluations and measurements

29. 29 Evaluations and Measurements Clinical evaluations Medical history Medication history Physical exam Vital signs Concomitant medications Adverse events Laboratory determinations General laboratory tests Hematology Blood chemistry urinalysis

30. 30 Evaluations and Measurements Hormone assays Parameters of bone metabolism Plasma assays for PD Special evaluations Bone densitometry X-ray of spine Mammography Fractures Pap smears

31. 31 Evaluations and Measurements Example: Primary efficacy endpoints Incidence of new fractures vertebral and nonvertebral at the end of 2 years ( ≒ 102 weeks) Bone mineral density (BMD) of lumbar spine (AP view, L2 – L4) at the end of 2 years ( ≒ 102 weeks)

32. 32 Evaluations and Measurements Secondary efficacy endpoints BMD of femoral neck BMD of nondominant radius (midshaft) Serum osteocalcin Serum alkaline phosphatase Urinary pyridinoline Urinary hydroxyproline

33. 33 Evaluations and Measurements Safety endpoints Physical and pelvic exam/PAP smear Exam of the breast by palpation and mammography Lab tests Adverse events Endocrinological evaluations E1, E2, and FSH

34. 34 Evaluations and Measurements Validity of Evaluations and Measurements Reduction of bias Reduction of variability Standardization among centers BMD by dual-energy x-ray absorptiometry with the use of Hologic QDR-1000 or 1000/W (Hologic Waltham, Mass) densitometers. All scans were reviewed without knowledge of the treatment assignment at a central facility, which provided factors to correct for calibration drift in the machines as necessary.

35. 35 Laboratory Evaluations GLP Lab Central Lab Standardization among different labs Normal range Different Central Labs General laboratory – Lab 1 (IN) Hormone assay – Lab 2 (CA) Lipid profiles – Lab3 (TX) Label for lab samples Date and time drawn Accession number Processed blindly

36. 36 Adverse Events Concept: safety before efficacy Definition Procedures for AE information Indirect questioning using a non-leading question Please do not prepare a set of possible AEs and ask patients whether they experienced them

37. 37 Adverse Events All AEs must be recorded on CRF, not just serious AEs. Description of events Onset date and time w.r.t. to treatment Nature Duration Intensity (severity) Seriousness Relationship Action taken Resolution

38. 38 Adverse Events Definition of serious AEs and procedures for reporting and actions taken (ICH) Results in death Life threatening Inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Provision of personnel and phone numbers Definition of attributions to investigational drugs Not-related Possibly related Probably related Definitely related

39. 39 Adverse Events Definition of intensity Mild Moderate severe Coding systems (MedDRA, COSTART) Serious AE reporting Regulatory requirements Laboratory test abnormality

40. 40 Conduct of the Study Narrative description of every evaluation performed at each visit for all visits Provision of a flow chart in appendices Patient compliance Definition of criteria for a satisfactory compliance Description of a method for measurement of compliance Consequences of poor compliance

41. 41 Methods Used to Minimize Bias Conduct of clinical trials Use of randomization Use of double-blind design Use of placebo control Use of central labs for blinded evaluation Use of indirect questioning techniques for collection of adverse event information

42. 42 Data processing Random codes are generated by computer Patients enrolling into the study will be assigned successive number in chronically order at each site All in a blinded fashion Data entry and data key verification No treatment assignment on CRF No knowledge of treatment randomization listing available to personnel of data entry activities Editing listing and data review by data coordination and clinical research are conducted in a blinded fashion Evaluability for efficacy analysis (patient or patient-visit) will be performed in a blinded fashion according to inclusion/exclusion criteria.

43. 43 Statistical Methods and Data Management Data management procedures Standard procedures Data management system Data entry Data review Personnel Data coordination and clinical research Procedures Formatted screen Range checking Relational consistency Editing listing Corrections Audit trail

44. 44 Sample size determination Clinical consideration or statistical justification Define the minimum clinically meaningful difference to detect Define the minimum clinically equivalence limit to be acceptable Formulation of the hypotheses in objectives into statistical null and alternative hypotheses State the false positive (type Ⅰ ) and true positive (power) rate State the statistical methods to (in accordance with design) calculate the sample size Adjustment for multiple groups or dropouts

45. 45 Presentation of efficacy and safety parameters Efficacy parameters Safety parameters Other special parameters Define the statistical parameters based on primary, secondary efficacy and safety endpoints Continuous data Raw response Change from baseline Percent change from baseline

46. 46 Presentation of efficacy and safety parameters Categorical data Proportion Odds ratio Relative risk Censored data 5-year survival rate Median survival

47. 47 General statistical considerations Randomization and blinding Dropouts, premature discontinuation and missing data Data sets for analysis Intention-to-treat analysis Once randomized then analyze Baseline Covariates Multicenter study Adjustment for multiple testing Interim analysis Patient listings

48. 48 Statistical procedures Parametric methods Descriptive statistics Mean, median, standard deviation, range, 95% C.I. For each treatment and for the difference between groups

49. 49 Statistical procedures Inferential statistics T-test, ANOVA, ANCOVA, and p-values (1- sided or 2-sided)

50. 50 Nonparametric methods Descriptive statistics Median, interquartile range, Lehmann-Hodge estimator, 95% C.I. Inferential statistics Wilcoxon rank sum test and p-values (1-sided or 2-sided)

51. 51 Categorical methods Descriptive statistics Proportions, odds ratios, relative risks, and 95% C.I. Inferential statistics Fisher’s exact test, chi-square test, Mantel- Haenszel test, log-linear model and p-values (1- sided or 2-sided)

52. 52 Survival methods Descriptive statistics Kaplan-Meier estimators, 95% C.I. Inferential statistics log-rank test and Cox’s proportional hazard model and p-values (1-sided or 2-sided)

53. 53 Statistical Methods and Data Management Statistical analysis of demographic data Comparability among treatment groups Statistical analysis of efficacy parameters Description of statistical analysis planned for each efficacy parameter

54. 54 Statistical Methods and Data Management Statistical analysis of safety parameters Description of analysis planned for each safety parameter. Usually, descriptive statistics suffice Adverse events Laboratory evaluations Physical exams Vital signs Concomitant medications Specification of coding system for AEs used in analysis COSTART (US FDA) or MEDDRA (ICH) Statistical analysis for special parameters

55. 55 Handling and Accountability of Investigational Drugs Shipment of investigational drugs Concept Investigational drugs are with unproved safety and efficacy and should not be released to the unauthorized persons or patients not enrolled in the study. The should be rigorously controlled by the sponsors and authority.

56. 56 Handling and Accountability of Investigational Drugs Sponsor vs. Investigator Clinical Supplies Shipment Form Medicine Disposition Form Address of the sponsor for return of all investigational drugs Within site Who dispenses the drugs (pharmacy) Pharmacy records (computerized)

57. 57 Discontinuation/Protocol Changes Patient withdrawal after randomization Dropouts initiated by patient Discontinuation initiated by investigator according to pre-specified criteria in the protocol Definition for criteria for patient discontinuation

58. 58 Discontinuation/Protocol Changes Categories for premature withdrawal Treatment failure Adverse experience Withdrawal of consent or other administrative reasons Failure to return to follow-up Death Information Date of withdrawal Treatment and date of treatment

59. 59 Discontinuation/Protocol Changes Protocol Changes Procedures for amendment Study Changes Procedures for documentation of protocol deviations and the reasons Study termination Conditions for termination of the study

60. 60 Informed consent Informed consent form must be reviewed and approved by IRB Signed and dated written informed consent forms must be obtained prior to participation into the trial by any patient Investigator must keep a copy of signed and dated written informed consent form of all patients for review by the sponsor’s monitor and authority

61. 61 Obligations of Investigators Investigational drug accountability Case report forms Laboratory and other reports Study monitoring Patient registry Information package about drugs Confidentiality

62. 62 Administrative Aspects Steering committee Data and safety monitoring committee Final study report Financing, insurance, and liability Publication policy Glossary

63. 63 Study Flow Chart Information of evaluations at each visit in a tabulated form

64. 64 Appendices Any relevant information AUA-7 symptom scores for BPH Bethesda PAP smear classification Package insert Histopathologic diagnostic categories for breast cancer with SNOMED (ICD-10) codes Procedures for certain evaluations Mammogram Sonogram absorptiometry Special statistical methods

65. 65 Review Process, Issues and Quality Review Process Internal Clinician, statistician Protocol review committee External Investigator IRB DOH

66. 66 Review Process, Issues and Quality Issues To formulate feasible scientific questions Reduction of incidence rate of 1 out of 100,000 for a certain AE by 50% To define the targeted patient population To select primary efficacy endpoints

67. 67 Review Process, Issues and Quality Issues To define clinically meaningful difference To determine the date and time for evaluations to demonstrate efficacy and safety To decide the right amount of data to be collected for demonstration of effectiveness and safety Balance between scientific validity and flexibility

68. 68 Review Process, Issues and Quality Quality Well edited, paged and bonded Clear, Concise Precise, Consistent Treatment is 4-hour Ⅳ infusion. Vital signs will be monitored every 15 minutes for the first 2-hour after initiation of infusion and every hour for the rest of 12- hour infusion.

69. 69 Discussion and Summary Plan for the trial Scientific valid Flexible Legal Simple Detailed Objectives Inclusion / exclusion criteria Study design Treatment plans Endpoint evaluations Statistical plans Informed consent

70. 70 Discussion and Summary Team work Clinicians Study monitors (CRA) Statisticians Data coordinators (DC) Investigators Study coordinators (SC)

71. 頁碼作品版權圖示來源 / 作者 1-75 本作品轉載自 Microsoft Office 2010 PowerPoint 設計主題範本 -Blends ，依據 Microsoft 服 務合約及著作權法第 46 、 52 、 65 條合理使用。 Microsoft 服 務合約 4 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.755 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 5 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.756 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 9 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.757 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 27 台灣大學劉仁沛教授。 以創用 CC 「姓名標示－非商業性－相同方式分享」臺灣 3.0 版授權釋出。 71 版權聲明 Visit No. Study Day Treatment PeriodNo. of Tablets Dispensed 1-28Screening and start of placebo run-in28 placebos 20Randomization and start of DB Baseline 28 3 DB28 456DB28 584DB28 6112DB28 7140DB28 8168DB Efficacy 28

72. 頁碼作品版權圖示來源 / 作者 37 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.780 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 40 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.780 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 43 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.783 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 58-59 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.792 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 65-68 《 Design and analysis of clinical trials: concepts and methodologies 》， 作者 :Chow, SC, Liu, JP ，出版社 : Wiley(third edition) ， p.795 。本作品依據著作權法第 46 、 52 、 65 條合 理使用。 http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html 72 版權聲明