1. 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

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

3. 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

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

5. ICH E9 Statistical Principles

6. ICH E3 Clinical Study Reports

7. 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?

8. 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.

9. 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

10. 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

11. 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

12. 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.

13. 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

14. 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

15. 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

16. 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

17. 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

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Prematurely withdrawn

19. 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

20. 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

21. 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

22. 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

23. 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

24. References
List all references used in the SAP

25. 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.

26. Who write the SAP?
Study Statistician

27. Introduction of CSR Contents

28. 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

29. 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

30. 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

31. 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

32. 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

33. 3.4.3.3 Serious Adverse Events
CSR Section 3- Results
3.4 Safety Analysis
Extent of Exposure to Trial Medication
Overview of Safety
Adverse Events
Overview Adverse Events
Deaths
Serious Adverse Events
Adverse Events and Laboratory abnormalities Leading to Withdrawal from treatment
Dose Modifications for Safety Reasons

34. CSR Section 3 - Results 3.4.4 Laboratory Parameters
Mean (or Median) Change from Baseline
Shift from Baseline
Vital Signs
ECGs

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

36. Review CSR, final TLFs Validation Consistency Interpretations
Discussions

37. BACK-UP SLIDES

38. CSR Section 1: Background, Rationale and Objectives

39. 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 Protocol Amendments 2.2 Study Population Overview Inclusion Criteria Exclusion Criteria Criteria for Withdrawal from Treatment or Study and Replacement Policy Concomitant Medication, Treatments and Procedures

40. 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

41. 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

42. 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
Analysis of Efficacy 15
Statistical/Analytical Issues 15
Adjustments for Covariates 16
Handling of Dropouts or Missing Data 16
Interim Analyses and Data Monitoring 16
Multicentre Studies 17
Multiple Comparison/Multiplicity 17
Use of an "Efficacy Subset" of Patients 17
Active-Control Studies Intended to Show Equivalence 17
Examination of Subgroups 18
Tabulation of Individual Response Data 18
Drug Dose, Drug Concentration, and Relationships to Response 19
Drug-Drug and Drug-Disease Interactions 19
By-Patient Displays 19
Efficacy Conclusions 19
12. SAFETY EVALUATION 19
12.1 EXTENT OF EXPOSURE 20
12.2 ADVERSE EVENTS (AES) 21
Brief Summary of Adverse Events 21
Display of Adverse Events 21
Analysis of Adverse Events 22
Listing of Adverse Events by Patient 23
12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 23
Listing of Deaths, other Serious Adverse Events and Other Significant Adverse Events 23
Deaths 24
Other Serious Adverse Events 24
Other Significant Adverse Events 24
Narratives of Deaths, Other Serious Adverse Events and
Certain Other Significant Adverse Events 24
Analysis and Discussion of Deaths, Other Serious Adverse Events
and Other Significant Adverse Events 24
12.4 CLINICAL LABORATORY EVALUATION 25
Listing of Individual Laboratory Measurements by Patient (16.2.8)
and Each Abnormal Laboratory Value (14.3.4) 25
Evaluation of Each Laboratory Parameter 25
Laboratory Values Over Time 26
Individual Patient Changes 26
Individual Clinically Significant Abnormalities 26
12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY 27
12.6 SAFETY CONCLUSIONS 27

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

44. Contact
Zibao Zhang, PhD AD BIOSTATISTICS PPD China T: +86 (21) ext. 606 C: E: Addr: Suite 1709, Liu Lin Tower No.1 Huai Hai Zhong Lu, Shanghai