Statistical Analysis Plan and Clinical Study Report Zibao Zhang (张子豹), PhD Associate Director, Biostatistics PPD China Presented at the 2nd Clinical Data Management Training September 2010, SMMU, Shanghai

Before Presentation… This slide deck is based on Jain Chung’s presentation for the 1st CDM training course in 2008.

Study Start Up Conduct Close out DM Flow Data Key In External Data Loading In Protocol Development Develop Database Database Lock CRF Development Data Quality Review Coding Data Management Plan Medical Review SAE Reconciliation Data Extraction Yes No Any Query? DM send Query Report QA staff Quality Control Data analysis Database Quality Control Report Site Respond Queries Update Database Clinical Study Report Study Start Up Conduct Close out

Outline Introduction of Statistical Analysis Plan Introduction of CSR contents Final TLFs and Review CSR

ICH E9 Statistical Principles

ICH E3 Clinical Study Reports

Introduction of Statistical Analysis Plan (SAP) What is SAP? Why need a SAP? When write a SAP? What are included in the content? Who write the SAP?

Statistical Analysis Plan is ... (ICH E9) a document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data.

What is SAP? Also called Data Analysis Plan (DAP) An essential document for biometrics activities A guidance for a final clinical study report A guidance for analysis program development

Why Need a SAP? Provide details of data handling rules and statistical analysis methods used for efficacy and safety reporting Identify all tables, listings, and figures to be used for the reports Document detail deviations from the protocol Facilitate SAS program development Fulfill Health Authority requirements

When write a SAP? Study Timeline FPI IA LPI LPLO DB Lock CSR Study Setup Study Conduct Data clean Final Analysis Interim Analysis Finalized Protocol SAP Pre-lock Analysis Final SAP Annotated CRF

What Are Included in the Content? General information Evaluations Perform. Before DB closure Analysis Populations Patient Disposition Baseline Characteristics Efficacy Analysis PK/PD Analysis (if applicable) Safety Analysis … References Appendices The structure of study SAP may vary across companies but the main contents listed will be the same.

1. General Information Protocol number Title Study Objectives Study design Sample size and randomization algorithm Design details: single or multi-centre, randomization, level of blinding, controls and design, duration of study phases (run-in, treatment and wash-out) and treatment dose studied Randomization methods: stratification, adaptive randomization, any limits applied to the randomization No change to previous DAP Guideline Using cut and paste is a good method to avoid inconsistencies between protocol and DAP

2. Evaluations Performed Analysis before Database Closure Evaluation of possibility of introduction of biases DSMB activities Interim analysis Procedures used for program development and validation Exact procedure for handling blinding Early/late pre-analysis reviews of blinded data These should be documented according to Ad hoc request SOP or Requirements Management SOP

2.2 DSMB Composition, purpose and responsibility Membership (internal, external or mixed) Project team members involved Performed by third party outside Biometrics: Reporting objects should not be described in SAP but in DSMB Charter

2.3 Interim Analysis Interim analysis performed by Biometrics have to be included the followings in the SAP The purpose Timing of analysis Un-blinding procedure/integrity Individual patient results or patient summaries, display of treatment arms (yes/no) Distribution of results Display of treatment groups (actual or dummy) For interim analysis report, the following details should also be described: parameter/population analyzed, statistical method used for adjusting p-values, possible actions following results and responsibilities for taking decisions on follow-up actions

3. Analysis Populations Definition of patient populations including details of the criteria used for classification ITT (FAS) PP Safety Others Others could be pharmacokinetic or genetic

4. Patient Disposition Counting the number of patients Included in the study Randomized Treated In ITT and PP In Safety Analysis Prematurely withdrawn

5. Baseline Characteristics Assess the comparability among treatment groups Demographics Baseline characteristics Previous disease/medications Concomitant medication/procedures Dealing with imbalanced trt arms should be included in the section on “Additional Exploratory analysis ” of the DRAM

6. Efficacy Analysis Sufficient level of details to enable a third party to repeat the analysis Definition of time windows Definition of baseline values Descriptions of derivation algorithms Definitions of primary, secondary, tertiary endpoints Statistical methods and models used Detail information of handling multiplicity and missing data Sensitivity analysis (e.g. different data handling rules) Robustness analysis (e.g. different analysis populations) Subgroup analyses Additional Exploratory Analysis Derivation algorithms : Change from baseline, means Classifications: etc: Exploratory and ad-hoc parameters Sufficient detail= able to repeat analysis Consistency of treatment effects across centers/blocs =treatment by centre interactions Robustness of primary endpoint: with regards to effect of dropouts, data handling rules and model assumptions All outputs including population should be listed If study populations the same eg (safety=ITT) outputs don’t need to be repeated

7. PK/PD Analysis if applicable PK/PD analysis datasets The data presentations for the PK profiles and derived PK parameters that produced for the CSR {This should be done in collaboration with Clinical Pharmacologist} Modeling, derivation and simulation performed by Clinical Pharmacologist if applicable Activities around derivation of the PK parameters, population PK modeling and other modeling and simulation activity out of our scope

8. Safety Analysis Exposure to study medication Adverse Events (specifies special adverse events) AE by body system and preferred terms Serious AEs AE by intensity and by relationship Withdrawals Death Laboratory Parameters Special Areas of Interest (anything additional) Vital Signs ECGs

May also be Included in SAP… Immunogenicity analyses (if applicable) Follow up analysis Changes from protocol DAS and additions after Database closure Separate (sub-)sections for: statistical methods, multiplicity adjustments, ground rules and data Handling conventions Immunogenicity Analyses (if applicable) Used in vaccine immunogenicity trials Follow up analysis SAP covers all analyses to be done for a study including Interim, safety, study and follow-up reports. Describe the analyses for each report Include references to the analyses already described in the SAP List of outputs (tables, listings and plots) that will be done All follow-up analysis done for the same protocol need to be added to the SAP even if unplanned Changes and additions after Database closure May address in the SAP Changes to pre-database closure defined analyses Includes all changes made since last SAP version before DB closure Should be preceded by the completion of the requirement change document Post hoc analyses Additional endpoints/analysis added for the report after DB closure

References List all references used in the SAP

Appendices List of appendices attached to the SAP Appendices may include an example of a questionnaire, an example of statistical output, study flow chart, key derivation or definitions, list of TLFs, etc.

Who write the SAP? Study Statistician

Introduction of CSR Contents

Process for Development Clinical Study Report PGM ST Finalized Protocol SAP SAP TLFs Program Development SAP(A) Prelock Run(s) Program Validation SAP(B) CS: Database Lock DM Review SAP Stat Outputs Available ST may develop the SAP TLF shells with PGM, and author the CSR with CS. ST – statistician PGM – programmer CS – clinical scientist DM – data management team Outputs Review ST & PGM Finalize CSR Structure and identify tables required Starting CSR Section 1 & 2 CSR DRAFT Starting Section 3,4,5

Sample of CSR Report Body In the format of the Journal-Style scientific paper Background, Rationale and Objectives Materials And Methods Results 3.1 Study Population 3.2 Efficacy Results 3.3 Pharmacodynamic, Pharmacokinetic and PK/PD Modeling 3.4 Safety Analysis 4. Discussion 5. Conclusion 6. References Appendices The Structure, Format, Content, and Style of a Journal-Style Scientific Paper http://abacus.bates.edu/~ganderso/biology/resources/writing/HTWsections.html#sections

Sample of CSR Report Body In the format of ICH E3 “Structure and Content of Clinical Study Reports” 1. Title page 2. Synopsis 3. Table of contents 4. List of abbreviations 5. Ethics 6. Investigators and study administrative structure 7. Introduction 8. Study objectives 9. Investigational plan 10. Study patients 11. Efficacy evaluation 12. Safety evaluation 13. Discussion and overall conclusions 14. Tables, figures and graphs referred to but not included in the text 15. Reference list 16. Appendices

CSR Section 3 - Results 3.1 Study Population 3.1.1 Disposition of Patients 3.1.2 Patients Withdrawn Prematurely from treatment 3.1.3 Overall of Analysis Populations 3.1.4 Protocol Violations 3.15 Demographic Data and Baseline Characteristics 3.1.6 Previous Concomitant Medications and Diseases

CSR Section 3 - Results 3.2 Efficacy Results 3.2.1 Primary Efficacy Parameter 3.2.2 Secondary Efficacy Parameter (s) 3.1.3 Subgroup and Exploratory Analyses 3.3 Pharmacodynamic, Pharmacokinetic and PK/PD Modeling

3.4.3.3 Serious Adverse Events CSR Section 3- Results 3.4 Safety Analysis 3.4.1 Extent of Exposure to Trial Medication 3.4.2 Overview of Safety 3.4.3 Adverse Events 3.4.3.1 Overview Adverse Events 3.4.3.2 Deaths 3.4.3.3 Serious Adverse Events 3.4.3.4 Adverse Events and Laboratory abnormalities Leading to Withdrawal from treatment 3.4.3.5 Dose Modifications for Safety Reasons

CSR Section 3 - Results 3.4.4 Laboratory Parameters 3.4.4.1 Mean (or Median) Change from Baseline 3.4.4.2 Shift from Baseline 3.4.5 Vital Signs 3.4.6 ECGs

Other CSR Sections: 4, 5, and 6 4. Discussion 5. Conclusion 6. References Appendices

Review CSR, final TLFs Validation Consistency Interpretations Discussions

BACK-UP SLIDES

CSR Section 1: Background, Rationale and Objectives

CSR Section 2 - Materials and Methods 2.3 Compliance with Good Clinical Practice 2.3.1 Ethics 2.3.2 Audits 2.3.3 Data Quality Assurance 2.4 Trial Medication 2.4.1 Rationale for Dosage Selection 2.4.2 Formulation and Packaging 2.4.3 Assignment to Treatment Group/Sequence 2.4.4 Blinding 2.4.5 Drug Administration 2.4.6 Dose Modification 2.4.7 Dose Accountability and Compliance 2.1 Overall Study Design 2.1.1 Protocol Amendments 2.2 Study Population 2.2.1 Overview 2.2.2 Inclusion Criteria 2.2.3 Exclusion Criteria 2.2.4 Criteria for Withdrawal from Treatment or Study and Replacement Policy 2.2.5 Concomitant Medication, Treatments and Procedures

ICH E3 Structure and Content of Clinical Study Reports 1. Title page 2. Synopsis 3. Table of contents 4. List of abbreviations 5. Ethics 6. Investigators and study administrative structure 7. Introduction 8. Study objectives 9. Investigational plan 10. Study patients 11. Efficacy evaluation 12. Safety evaluation 13. Discussion and overall conclusions 14. Tables, figures and graphs referred to but not included in the text 15. Reference list 16. Appendices * Details for Sections 9 – 12 on next slides

ICH E3 Structure and Content of Clinical Study Reports (cont.) 9. Investigational plan 9.1 Overall study design and plan description 9.2 Discussion of study design, including the choice of control groups 9.3 Selection of study population 9.3.1 Inclusion Criteria 9.3.2 Exclusion Criteria 9.3.3 Removal of Patients from Therapy or Assessment 9.4 Treatments 9.4.1 Treatments Administered 9.4.2 Identity of Investigational Product(s) 9.4.3 Method of Assigning Patients to Treatment Groups 9.4.4 Selection of Doses in the Study 9.4 Treatments (cont.) 9.4.5 Selection and Timing of Dose for each Patient 9.4.6 Blinding 9.4.7 Prior and Concomitant Therapy 9.4.8 Treatment Compliance 9.5 Efficacy and safety variables 9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart 9.5.2 Appropriateness of Measurements 9.5.3 Primary Efficacy Variable(s) 9.5.4 Drug Concentration Measurements 9.6 Data quality assurance 9.7 Statistical methods planned in the protocol & determination of sample size 9.8 Changes in the conduct of the study or planned analyses

ICH E3 Structure and Content of Clinical Study Reports (cont.) 10 Study patients 10.1 Disposition of patients 10.2 Protocol deviations 11. Efficacy evaluation 11.1 Data sets analyzed 11.2 Demographic and other baseline characteristics 11.3 Measurements of treatment compliance 11.4 Efficacy results and tabulations of individual patient data 12. Safety evaluation 12.1 Extent of exposure 12.2 Adverse events (AEs) 12.3 Deaths, other SAEs, and other significant adverse events 12.4 Clinical laboratory evaluation 12.5 Vital signs, physical findings and other observations related to safety 12.6 Safety conclusions 11. EFFICACY EVALUATION 13 11.1 DATA SETS ANALYSED 13 11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 13 11.3 MEASUREMENTS OF TREATMENT COMPLIANCE 15 11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL PATIENT DATA 15 11.4.1 Analysis of Efficacy 15 11.4.2 Statistical/Analytical Issues 15 11.4.2.1 Adjustments for Covariates 16 11.4.2.2 Handling of Dropouts or Missing Data 16 11.4.2.3 Interim Analyses and Data Monitoring 16 11.4.2.4 Multicentre Studies 17 11.4.2.5 Multiple Comparison/Multiplicity 17 11.4.2.6 Use of an "Efficacy Subset" of Patients 17 11.4.2.7 Active-Control Studies Intended to Show Equivalence 17 11.4.2.8 Examination of Subgroups 18 11.4.3 Tabulation of Individual Response Data 18 11.4.4 Drug Dose, Drug Concentration, and Relationships to Response 19 11.4.5 Drug-Drug and Drug-Disease Interactions 19 11.4.6 By-Patient Displays 19 11.4.7 Efficacy Conclusions 19   12. SAFETY EVALUATION 19 12.1 EXTENT OF EXPOSURE 20 12.2 ADVERSE EVENTS (AES) 21 12.2.1 Brief Summary of Adverse Events 21 12.2.2 Display of Adverse Events 21 12.2.3 Analysis of Adverse Events 22 12.2.4 Listing of Adverse Events by Patient 23 12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 23 12.3.1 Listing of Deaths, other Serious Adverse Events and Other Significant Adverse Events 23 12.3.1.1 Deaths 24 12.3.1.2 Other Serious Adverse Events 24 12.3.1.3 Other Significant Adverse Events 24 12.3.2 Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events 24 12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events 24 12.4 CLINICAL LABORATORY EVALUATION 25 12.4.1 Listing of Individual Laboratory Measurements by Patient (16.2.8) and Each Abnormal Laboratory Value (14.3.4) 25 12.4.2 Evaluation of Each Laboratory Parameter 25 12.4.2.1 Laboratory Values Over Time 26 12.4.2.2 Individual Patient Changes 26 12.4.2.3 Individual Clinically Significant Abnormalities 26 12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY 27 12.6 SAFETY CONCLUSIONS 27

References ICH Guidelines www.ich.org E9 Statistical Principles for Clinical Trials E3 Structure and Content of Clinical Study Reports

Contact Zibao Zhang, PhD AD BIOSTATISTICS PPD China T: +86 (21) 5383 4000 ext. 606 C: +86 139 1854 6055 E: zibao.zhang@excel-cro.com Addr: Suite 1709, Liu Lin Tower No.1 Huai Hai Zhong Lu, Shanghai