NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR · ICH E6, 5.23 Multicenter Trials . ICH E6, 6.0...

NN BIO 902 Page 2 of 6

NN BIO 902

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR STATISTICAL ANALYSIS PLAN DEVELOPMENT

SOP: NN BIO 902 Version No: 2.0 Effective Date: 21Oct2016

STATISTICAL ANALYSIS PLAN DEVELOPMENT

Supercedes Document: Version 1.0 Effective Date: 13May2012

1. POLICY

This SOP describes procedures for the development of a Statistical Analysis Plan (SAP) for NeuroNEXT studies. A SAP is a controlled document that accompanies the study protocol and that may include, but is not limited to, discussion of the following components:

• Primary and Secondary Objectives

• Primary and Secondary Endpoints

• Sample Size Justification

• Interim Monitoring Plan

Biostatisticians at the Data Coordinating Center (DCC) will serve as the primary authors of the SAP. During the development of the SAP, the DCC Study Biostatistician will collaborate with the DCC PI, the Protocol Principal Investigator (PPI), and the External Biostatistician (if applicable) to:

• broadly define the context and scope of the study;

• define a suitable study population;

• develop specific statements that describe the study’s primary and secondary objectives;

• define the study treatment/intervention(s) and the dosage regimen of the investigational product (if applicable);

• determine measures taken to minimize bias, including randomization and blinding;

• establish procedures for withdrawal of subjects from the study.

The SAP will include the required components described in Section 8.B of this SOP, and may include a schematic diagram of the trial design, procedures, and stages.

The finalized SAP for a U01-funded study will be versioned and signature-approved by the DCC PI, the CCC PI, and the PPI. The finalized SAP for X01-funded or SBIR-funded studies will be versioned and signature-approved by the DCC PI, the CCC PI, the Academic PI, and the Company PI.

2. SCOPE

This SOP has been developed to be in alignment with federal regulations and Good Clinical Practices (GCP) as set forth in the 1996 ICH E6 Consolidated Guidance. The policies and procedures described in this SOP apply to the NeuroNEXT Clinical Coordinating Center (CCC) and DCC within the context of their oversight and advisory roles for the NeuroNEXT Network, and to all NeuroNEXT investigators, staff, subcontractors, or other entities associated with the NeuroNEXT Network who manage, oversee, and conduct research regulated by FDA and/or applicable review committees.

These policies and procedures also apply to the External Biostatistician (if applicable to the study), and any other NeuroNEXT personnel who may be involved in development of a SAP for a NeuroNEXT study.


3. ROLES AND RESPONSIBILITIES

DCC Biostatisticians are responsible for developing a SAP for each NeuroNEXT study, in collaboration with the DCC PI, the PPI, and the External Biostatistician (if applicable), and for ensuring that the procedures described in this SOP are followed by NeuroNEXT personnel who are involved with SAP development.

4. APPLICABLE REGULATIONS AND GUIDELINES

ICH E6, 4.5 Compliance with Protocol

ICH E6, 4.9 Records and Reports

ICH E6, 5.1 Quality Assurance and Quality Control

ICH E6, 5.4 Trial Design

ICH E6, 5.5 Trial Management, Data Handling and Record Keeping

ICH E6, 5.23 Multicenter Trials

ICH E6, 6.0 Clinical Trial Protocol and Protocol Amendment(s)

ICH E8 General Considerations for Clinical Trials (December 1997)

ICH E9 Statistical Principles for Clinical Trials (September 1998)

ICH E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001)

5. REFERENCES TO OTHER APPLICABLE SOPS

NN BIO 901 Working with an External Biostatistician

6. ATTACHMENTS AND REFERENCES

NN BIO 902 – A Document History

NN BIO 902 – B Statistical Analysis Plan Signature Page for U01-Funded Studies

NN BIO 902 – C Statistical Analysis Plan Signature Page for X01-Funded and SBIR-Funded Studies

7. TERMS AND ABBREVIATIONS

The following terms and abbreviations are used in this document:

Academic Principal Investigator (PI) The Principal Investigator for an X01-funded or SBIR-funded grant originating at an academic institution.

CCC Clinical Coordinating Center at Massachusetts General Hospital

Company Principal Investigator (PI) The Principal Investigator who represents the industry partner for an X01-funded or SBIR-funded grant.

DCC Data Coordinating Center at The University of Iowa

External Biostatistician A Biostatistician who is not a member of the DCC Biostatistics Team.

Lead Biostatistician The primary Biostatistician for a study

Protocol Principal Investigator (PPI) Principal Investigator of a NeuroNEXT protocol


SAP Statistical Analysis Plan

Study Biostatistician A member of the DCC Biostatistics team. At least one Study Biostatistician will be assigned to each NeuroNEXT study. The Lead Biostatistician may also act as a Study Biostatistician for a specific study.

8. SPECIFIC PROCEDURES

A. Creating a Statistical Analysis Plan

# Who Task Attachment/ Reference

Related SOP

1. DCC Lead Biostatistician

Assign Study Biostatistician(s) to develop the SAP.

2. DCC Study Biostatistician

Collaborate with the DCC PI, the PPI, and the External Biostatistician (if applicable) during the development of the SAP.

NN BIO 901


Create the SAP, including the required components described in Section 8.B, and taking into account any protocol-specific requirements.

B. Required Components for a Statistical Analysis Plan


Related SOP


Overview Broadly define the scope of the study and define the study population. Summarize measures taken to minimize bias, including randomization and blinding.


Study Treatment/Intervention Define the study treatment/intervention and the dosage regimen of the investigational product (if applicable).


Primary and Secondary Objectives Create statements that define the primary and secondary objectives of the study.

• Develop specific statistical hypotheses that address the study’s primary and secondary objectives.

• Specify the statistical methods that are used to address secondary hypotheses and safety hypotheses.


Primary and Secondary Endpoints Define specific primary and secondary endpoints that relate directly to the statistical hypotheses developed in Step 3. Include language in the protocol that clearly defines the primary endpoint and provides rationale for its use.


Hypothesis Tests Specify statistical tests or statistical modeling used in conjunction with primary endpoint to test the primary objective.



Related SOP


Missing Data Specify methods for handling missing data, and clearly state whether or not the study follows the Intention to Treat (ITT) principle.


Sample Size Justification The sample size should be large enough to address the primary objective of the study. Clearly describe sample size calculations, and include the following information:

• the primary endpoint;

• the test statistic used to test the primary hypothesis;

• the null hypothesis;

• the alternative hypothesis at a chosen value of the test statistic;

• Type 1 and Type 2 error levels.


Safety Monitoring Plan Develop a safety monitoring plan that describes how safety will be assessed throughout the life of the project, and how any interim analyses will be conducted.


Study-Specific Components Develop a plan to address any study-specific requirements that are not included in the above components.


Schematic Diagram If useful for explaining the study design, create a schematic diagram of the trial design, procedures, and stages.

C. Approval and Sign-Off


Related SOP

1. DCC PI, CCC PI, and PPI

For a U01-funded study, approve the final Statistical Analysis Plan by signing and dating the Statistical Analysis Plan Signature Page.

NN BIO 902 – B NN BIO 901

2. DCC PI, CCC PI, Academic PI, and Company PI

For X01-funded or SBIR-funded studies, approve the final Statistical Analysis Plan by signing and dating the Statistical Analysis Plan Signature Page.

NN BIO 902 – C NN BIO 901


Attachment NN BIO 902 - A. Document History

NeuroNEXT Network Standard Operating Procedure (SOP) Statistical Analysis Plan Development

SOP NN BIO 902

Version Description of Modification Reason or Justification for Modification Issue Date Effective Date

1.0 New N/A 13Apr2012 13May2012

2.0

Updated Policy section and required components of a SAP (Section 8.B), and removed references to Protocol Steering Committee participation in the SAP development process. Modified signatories for the SAP, and differentiated between the signatories for a U01-funded grant and signatories for X01-funded and SBIR-funded grants.

Updates for version 2.0 to align with revised DCC SOP and to include references for X01-

funded and SBIR-funded grants. 21Sep2016 21Oct2016

Attachment NN BIO 902 – B U01-Funded Studies Template v1.0 – 23Jun2016

<Version #> <Date>

NeuroNEXT Network Statistical Analysis Plan for

<Study name> <Grant number>

Approved by: _____________________________________ _______________________

DCC Principal Investigator (signature) Date

_____________________________________ DCC Principal Investigator (printed name)

_____________________________________ _______________________ CCC Principal Investigator (signature) Date

_____________________________________ CCC Principal Investigator (printed name)

______________________________________ _______________________ Protocol Principal Investigator (signature) Date

_____________________________________ Protocol Principal Investigator (printed name)

Attachment NN BIO 902 – C X01-Funded and SBIR-Funded Studies Template v1.0 – 23Jun2016

<Version #> <Date>

NeuroNEXT Network Statistical Analysis Plan for


Approved by: _____________________________________ _______________________

DCC Principal Investigator (signature) Date


_____________________________________ _______________________ CCC Principal Investigator(signature) Date

_____________________________________ CCC Principal Investigator (printed name)

______________________________________ _______________________ Academic Principal Investigator (signature) Date

_____________________________________ Academic Principal Investigator (printed name)

______________________________________ _______________________ Company Principal Investigator (signature) Date

______________________________________ Company Principal Investigator (printed name)


NN BIO 903

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR CREATING, VERIFYING, IMPLEMENTING, AND ARCHIVING A RANDOMIZATION

SEQUENCE OR ALGORITHM


CREATING, VERIFYING, IMPLEMENTING, AND ARCHIVING A RANDOMIZATION

SEQUENCE OR ALGORITHM


1. POLICY

Randomization assignment systems for all NeuroNEXT clinical trials will be developed, verified, implemented, and archived at the NeuroNEXT Data Coordinating Center (DCC). Depending on the type of trial and the requirements of the protocol, a fixed randomization sequence or adaptive randomization algorithm will be created.

The Lead Biostatistician will collaborate with the DCC PI and the Protocol Principal Investigator (PPI) to define parameters to be considered during development of the randomization sequence or algorithm. DCC Biostatisticians will then generate a brief randomization plan for the trial based on the parameters that were agreed upon during the protocol design phase. If appropriate for the project, a Biostatistician who is external to the DCC may participate in developing the assignment system and generating the randomization plan. The plan will be approved by the DCC PI, the PPI, and the External Biostatistician (if applicable) before the assignment system is created.

Clinical Study Sites (CSS) will randomize subjects through the electronic data capture (EDC) system. If the system is temporarily unavailable at the time of randomization, the CSS will follow a backup procedure that has been established and approved by the PPI and the DCC PI.

This SOP describes general procedures for:

• defining a fixed randomization strategy or adaptive randomization algorithm; • creating, verifying, and implementing the randomization sequence; • CSS subject randomization and access to the randomization sequence if the electronic data

capture system is temporarily unavailable at the time of randomization; and • documenting and archiving the randomization sequence.

The final randomization sequence or algorithm will be signature-approved by the DCC PI, the DCC Lead Biostatistician, and the External Biostatistician (if applicable).

2. SCOPE

This SOP has been developed to be in alignment with federal regulations and Good Clinical Practices (GCP) as set forth in the 1996 ICH E6 Consolidated Guidance. The policies and procedures described in this SOP apply to the NeuroNEXT Clinical Coordinating Center (CCC) and DCC within the context of their oversight and advisory roles for the NeuroNEXT Network, and to all NeuroNEXT investigators, staff, subcontractors, External Biostatisticians (if applicable), or other entities associated with the NeuroNEXT Network who manage, oversee, and conduct research regulated by FDA and/or applicable review committees.


The DCC is responsible for adhering to the procedures outlined in this SOP. The DCC PI, the Lead Biostatistician, and the Information Technology Lead have general responsibility for creating, implementing, and maintaining fixed randomization sequences and adaptive randomization algorithms. The DCC Lead Biostatistician is responsible for consulting with the DCC PI, the PPI, and the External Biostatistician (if applicable) during the development of the randomization sequence or algorithm for each study.






ICH E6, 5.4 Trial Design


ICH E6, 5.23 Multicenter Trials

ICH E6, 6.0 Clinical Trial Protocol and Protocol Amendment(s)



ICH E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001)


NN BIO 901 Working with an External Biostatistician

NN BIO 902 Statistical Analysis Plan Development


NN BIO 903 – A Document History

NN BIO 903 – B Randomization Sequence Signature Page

NN BIO 903 – C Randomization Algorithm Signature Page

Design and Analysis of Clinical Trials (Wiley Series in Probability and Statistics): Concepts and Methodologies. Chow, Shein-Chung Liu, Jen-Pei, John Wiley and Sons, Inc. 2003

Clinical Trials: A Methodologic Perspective (Wiley Series in Probability and Statistics). Piantadosi, Steven, John Wiley and Sons, Inc. 1997



Adaptive Randomization Sequence A randomization sequence in which the probability of assignment of a subject to each treatment group depends either on observations made to subjects previously enrolled, or on the distribution of baseline covariates. As a result, the assignment of subjects to treatment groups cannot be defined in advance


CSS Clinical Study Site(s)


DM Data Management

DM Lead Leader of the Data Management team at the DCC

External Biostatistician A Biostatistician who is not a member of the DCC Biostatistics Team


Fixed Randomization Sequence A randomization sequence in which the assignment of subjects to treatment groups can be defined in advance. This will generally be defined in the study protocol, including any blocking or stratification strategies. As subjects enroll in the study, they will be assigned to treatment group according to the randomization sequence (i.e., the first enrolled subject will be assigned to the first treatment listed on the randomization sequence, the second subject enrolled will be assigned to the second treatment listed in the randomization sequence, and so on).

IT Information Technology

IT Lead Leader of the Information Technology team at the DCC

Lead Biostatistician Primary Biostatistician for a study

NINDS National Institute of Neurological Disorders and Stroke

PPI Protocol Principal Investigator

QA Quality Assurance

QA Officer Quality Assurance officer for a study

Randomization Plan This document describes the overall plan for implementing a randomization for a protocol, and includes the plan for generating the randomization sequence for a fixed randomization, or creating and implementing rules for an adaptive randomization.

Study Biostatistician A member of the DCC Biostatistics team. At least one Study Biostatistician will be assigned to each study, but only one Biostatistician will be assigned to prepare the randomization. The Lead Biostatistician may also act as a Study Biostatistician for a specific study.


A. Defining the Randomization and Creating a Randomization Plan


Related SOP


Collaborate with the PPI, DCC PI, and the External Biostatistician (if applicable) to define parameters to be incorporated into a randomization plan for the protocol.

NN BIO 901


Assign Study Biostatistician to prepare the randomization plan.


Prepare a randomization plan that includes a written description of the randomization strategy or algorithm based on the randomization procedures stated in the study protocol. For a fixed randomization sequence, the randomization plan describes:

• the method that will be used to generate the random treatment assignment



Related SOP

• a back-up randomization procedure. For an adaptive randomization algorithm, the randomization plan describes:

• the algorithm to be implemented • how the algorithm will be tested to ensure that

it is working correctly before implementation • a back-up randomization strategy.

4. DCC PI, PPI, External Biostatistician (if applicable)

Review and approve the randomization plan. NN BIO 901


After review and approval of the randomization plan, and prior to implementation, attach a version number and version date in the footer of the document.

B. Creating, Verifying, and Implementing a Fixed Randomization Sequence


Related SOP


Assign Study Biostatistician to generate the randomization sequence.


Prior to enrollment of the first subject, prepare a randomized sequence of treatment assignments according to the procedure outlined in the randomization plan, the description in the study protocol, and the approved specifications. Include the following components in the randomized sequence: • an electronic file with the required randomization

sequences, in a format agreed upon by the Lead Biostatistician and the leader of the information technology team;

• a detailed description of the contents of the file, including column contents and all codes that were used;

• a tabulation of the treatment assignment verifying that the appropriate blocking strategy has been used and an appropriate number of treatment assignments have been made in each block and for each stratum;

• a listing of any computer program(s) used to generate the sequence.


Review the electronic file visually, and by preparing appropriate tabulations, to verify that the randomization plan has been followed.

4. DCC Lead Biostatistician and DCC Study Biostatistician

Review together any discrepancies that are found. The Study Biostatistician resolves any deviations from the randomization plan and repeats the verification.



Related SOP


Once both statisticians agree that the randomization plan has been accurately executed, forward the electronic file to the Information Technology (IT) Lead.

6. DCC IT Lead Enter randomization sequences into appropriate randomization table. Print the contents of the randomization table.


Compare original randomization table to print-out from database to validate that randomization sequences have been properly inserted into database table.

8. DCC PI, DCC Lead Biostatistician; External Biostatistician (if applicable)

Review and signature-approve the final randomization sequence.

NN BIO 903 - B

C. Creating, Verifying, and Implementing an Adaptive Randomization Algorithm


Related SOP


Assign a Study Biostatistician to create specifications for development of an algorithm for the adaptive randomization.

2. DCC Study Biostatistician, DCC DM Team

Refer to the randomization plan to create specifications that include requirements for all rules that must be implemented for the adaptive randomization.

3. DCC Study Biostatistician, DCC DM Team

Create a testing plan to validate the algorithm that contains testing conditions for all requirements in the specifications.


Send the specifications and testing plan to the IT Lead for implementation.

5. DCC IT Lead Develop and implement the randomization algorithm.


Validate the requirements according to the testing plan.

7. DCC PI, DCC Lead Biostatistician; External Biostatistician (if applicable)

Review and signature-approve the final randomization algorithm.

NN BIO 903 - C


Store the electronic files containing the algorithm in a secure and restricted area on the DCC shared drive.


D. Clinical Study Site Randomization Procedures


Related SOP

1. CSS At the time of randomization of a study subject, complete the randomization process through the electronic data capture system.

2. Authorized CSS Personnel

If the electronic data capture system is temporarily unavailable at the time of the randomization, follow the backup procedures that have been developed and approved for the study.

3. Authorized CSS Personnel

Follow the procedure that has been developed regarding the final disposition of any backup randomization materials at the end of study.

E. Documenting and Archiving the Randomization


Related SOP

1. DCC Un-blinded Study Biostatistician and DCC IT Lead

Access to the electronic randomization sequences will be limited to the DCC un-blinded Study Biostatistician and authorized DCC IT personnel.

2. DCC Lead Biostatistician, DCC IT Lead

Store the randomization plan and copies of the programs that were used to generate the randomization sequences or algorithm on a restricted area of the DCC shared drive. Access to these documents will be limited only to authorized personnel.



NeuroNEXT Network Standard Operating Procedure (SOP) Creating, Verifying, Implementing, and Archiving a Randomization Sequence or Algorithm

SOP NN BIO 903


1.0 New N/A 13Apr2012 13May2012

2.0

Clarified approval process and signatories, added signature page templates as attachments, and other minor edits throughout.

Updates for version 2.0. 21Sep2016 21Oct2016

Attachment NN BIO 903 – B Template v1.0 23Jun2016

Version <X.0> <Date>

NeuroNEXT Network Randomization Sequence for


Approved by: _____________________________________ _______________________ DCC Principal Investigator (signature) Date


_____________________________________ _______________________ DCC Lead Biostatistician (signature) Date

_____________________________________ DCC Lead Biostatistician (printed name)

_____________________________________ _______________________ DCC External Biostatistician (signature) Date

_____________________________________ DCC External Biostatistician (printed name)

Attachment NN BIO 903 – C Template v1.0 23Jun2016

Version <X.0> <Date>

NeuroNEXT Network Randomization Algorithm for


Approved by: ________________________________________ ____________________ DCC Principal Investigator (signature) Date

________________________________________ DCC Principal Investigator (printed name)

________________________________________ ____________________ DCC Lead Biostatistician(signature) Date

________________________________________ DCC Lead Biostatistician(printed name)

________________________________________ ____________________ DCC External Biostatistician (signature) Date

________________________________________ DCC External Biostatistician (printed name)


NN BIO 904

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR GENERATION AND VALIDATION OF ANALYSIS DATA SETS


GENERATION AND VALIDATION OF ANALYSIS DATA SETS


1. POLICY

This SOP describes NeuroNEXT Data Coordinating Center (DCC) procedures for creating and validating analysis data sets for:

• critical study analyses (analyses of the primary and secondary endpoints as described in the Statistical Analysis Plan [SAP]; interim analyses; and analyses for the final study report and primary manuscript; and

• analyses that are requested by study investigators or other authorized researchers and approved by the Sponsor and/or CTSDMC Leadership (e.g. for abstracts, presentations, or secondary analyses after the conclusion of the study).

Before data sets are created, all DCC databases are carefully developed, and the SOPs related to database development and validation (e.g., NN CS 702, NN CS 703, NN DM 1004),data collection and management (e.g., NN DM 1001, NN DM 1005), and routine monitoring visits (NN SS 403) are followed. The procedures described in these SOPs help to ensure that all data stored in DCC electronic databases are complete, and that all targeted data have been validated against source documents at the Clinical Study Sites (CSS).

Before the data sets are created, a written Statistical Analysis Plan (SAP) is developed that includes plans for final analyses as well as an a priori defined plan for interim analyses (see SOP NN BIO 902). Study endpoints that will be analyzed in the final and interim analyses are defined in the SAP. Analysis data sets are created so that the endpoints may be determined and analyzed according to the parameters defined in the SAP.

The SAS® statistical package is the primary tool used for analyses conducted at the DCC, and all analysis data sets are initially created in the SAS® format. If specific analysis methods require the use of another statistical format, the SAS® files are exported to that format.

2. SCOPE



DCC Biostatisticians are responsible for adhering to the procedures outlined in this SOP, and for ensuring that the procedures are followed by other DCC staff members who may participate in biostatistics projects.

The Study Biostatistician is responsible for generating specifications for analysis data sets (in consultation with the DCC Lead Biostatistician, the DCC PI, and the PPI as necessary), for creating and validating the SAS® data set, and for converting the SAS® data set to another format (if required for the analysis).


4. APPLICABLE REGULATIONSAND GUIDELINES

ICH E3 Structure and Content of Clinical Study Reports








NN CS 702 Application Development and Validation

NN CS 703 IT Environments

NN BIO 905 Validating Statistical Programs and Deliverables

NN DM 1001 Clinical Data Management

NN DM 1004 Specifications Development, Testing Plans, and Validation Documentation

NN DM 1005 Data Collection and Data Handling


NN BIO 904 - A Document History





DM Data Management

DM Lead Leader of the Data Management team at the DCC


IT Information Technology

IT Lead Leader of the Information Technology team at the DCC

Lead Biostatistician Primary Biostatistician for a study

PPI Protocol Principal Investigator

QA Quality Assurance

QA Officer Quality Assurance officer for a study

SAP Statistical Analysis Plan

Study Biostatistician A member of the DCC Biostatistics team. At least one Study Biostatistician will be assigned to each study. The Lead


Biostatistician may also act as a Study Biostatistician for a specific study.


A. Generating Specifications for Analysis Data Sets # Who Task Attachment/

Reference Related SOP

1. DCC PI, DCC Lead Biostatistician, and DCC Study Biostatistician

For critical study analyses, thoroughly review the SAP and other relevant documents, and discuss the analysis with the PPI.


For critical study analyses designated in the SAP, obtain an in-depth understanding of study design, endpoint definitions, and the relevant statistical methods.


Consult with the PPI to resolve questions or to clarify ambiguities before generating analysis data sets.


Understand the structure of study database so that any necessary data manipulations may be performed.

5. DCC Lead Biostatistician and DCC Study Biostatistician

Develop specifications for all derived variables that will be used in the analyses.


If an analysis will be based on locked data, coordinate with all NeuroNEXT DCC and CCC staff to ensure that the electronic study database is complete and ready to be locked before a data lock is performed.

B. Creating Analysis Data Sets


Related SOP

1. DCC IT Lead or designee

Perform data lock, if applicable, using agreed-upon specifications.


If a data lock is not conducted, create a frozen snapshot of the source data to be used in generating the analysis data set, and store the frozen source data in the appropriate location.


Perform necessary data manipulations, such as data table merges.



Related SOP


Create derived variables based on specifications.


Validate the derived variables: • Develop test code to create derived

variables. • For critical study analyses, assign a

second Biostatistician to independently code and create derived variables.

• Compare values for derived variables and identify all values where there is disagreement.

• Resolve cases where there is disagreement.

NN BIO 905

C. Validating Analysis Data Sets


Related SOP


Validate the analysis data set: • Ensure that the appropriate

observations are included in each table • Ensure that the appropriate variables

are included in each table. • Ensure that treatment assignments are

accurate. • Examine each variable in a data table

to ensure that there are no unexpected missing values

• Examine each variable to identify possible outliers.


Work with DCC IT and DCC Coordinators to determine if unusual values are real or should be corrected.

D. Converting SAS® Data Sets to other Formats


Related SOP


If required for the analysis, convert SAS® data sets to the desired format.



Related SOP


Perform QC checks to verify the integrity of the converted file and to ensure that values have been imported accurately and completely:

• Spot-check the converted data set against the original data set.

• Tabulate simple descriptive statistics • Compare the results in the two

environments • Maintain documentation of the

comparison.



NeuroNEXT Network Standard Operating Procedure (SOP) Generation and Validation of Analysis Data Sets

SOP NN BIO 904


1.0 New N/A 13Apr2012 13May2012

2.0

Expanded Policy section and certain specific procedures (Section 8.B) to distinguish between critical study analyses and additional analyses that are requested by investigators. Added description of data freezes used to generate certain analysis data sets, and outlined QC checks that are performed after converting SAS data sets to other formats.

Updates for Version 2.0. 21Sep2016 21Oct2016


NN BIO 905

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR VALIDATING STATISTICAL PROGRAMS AND DELIVERABLES

SOP: NN BIO 905 Version No.: 2.0 Effective Date: 21Oct2016

VALIDATING STATISTICAL PROGRAMS AND DELIVERABLES


1. POLICY

The purpose of this SOP is to describe the levels of validation that are required for statistical analysis programs and deliverables that are generated for the NeuroNEXT Network. NeuroNEXT Data Coordinating Center (DCC) Biostatisticians follow procedures described in a DCC internal SOP (CTSDMC SOP BIO 904) to develop programs to perform statistical analyses that are described in study-specific Statistical Analysis Plans (SAP) or that are requested by the Protocol Principal Investigator (PPI) during the course of a NeuroNEXT clinical trial.

The programs that generate statistical deliverables and perform statistical analyses are validated at one of four levels, depending on the nature and complexity of the analysis or deliverable and its relative impact on the study:

• Level One – Validating statistical programs used to generate critical study analyses (analyses of the primary and secondary endpoints as described in the SAP, interim analyses, and analyses for the final study report and primary manuscript).

• Level Two – Validating statistical programs used to generate tables and figures that are to be included in DSMB reports, study annual reports, and quarterly safety reports.

• Level Three – Validating statistical programs used to generate tables and figures that are included in ongoing study reports (e.g. weekly or monthly reports).

• Level Four – Validating statistical programs for ad hoc requests for analyses or deliverables from study investigators.

For critical study analyses, two Biostatisticians who have been assigned to the project independently write programming code to produce data sets, and perform independent analyses of those data sets (Level One validation). The results of the independent analyses are compared and any discrepancies are resolved.

Deliverables (e.g. report tables or figures) that are sent to an external group are validated similarly. For Level Two validation of deliverables, the Lead Biostatistician and Senior Leadership perform a review of the deliverables to identify any errors, inconsistencies, or unusual values. The Lead Biostatistician performs this review for Level Three validation. The contents of deliverables are checked and verified prior to their distribution outside of the DCC.

Statistical programs that are developed in response to ad hoc requests for analyses or deliverables from study investigators, are reviewed internally before they are distributed (Level Four validation).

2. SCOPE




NeuroNEXT DCC Biostatisticians are responsible for adhering to the procedures outlined in this SOP.

The Lead Biostatistician is responsible for ensuring that these procedures are followed by DCC Biostatistics Team Members (Study Biostatisticians) who develop, document, or validate statistical analysis programs for a NeuroNEXT study.

The Lead Biostatistician, in consultation with DCC Senior Leadership, is responsible for advising Study Biostatisticians on validation strategies and the appropriate level of validation for analyses and deliverables.

Study Biostatisticians are responsible for validating the programs developed to perform the statistical analyses and deliverables that are generated at the DCC.




NN BIO 902 Statistical Analysis Plan Development

NN BIO 904 Generation and Validation of Analysis Data Sets

DCC BIO 904 Developing, Documenting, and Storing Statistical Programs and Deliverables

NN BIO 906 Presenting Statistical Results for a Final Study Report

6. ATTACHMENTS

None


The following terms and abbreviations are used in this document: CCC Clinical Coordinating Center at Massachusetts General Hospital

DCC Data Coordinating Center at The University of Iowa Lead Biostatistician The leader of the DCC Biostatistics team (a defined position in

the DCC). The Lead Biostatistician may also serve as a Study Biostatistician for a specific study.

Study Biostatistician(s) A member of the DCC Biostatistics team.



A. Validating Statistical Programs

# Who Task Attachment Related SOP

1. Lead Biostatistician

Assign Study Biostatisticians to execute and validate the programs used to perform analyses described in the SAP.

NN BIO 902 DCC SOP BIO 904

2. Study Biostatisticians

Determine the appropriate validation strategy and the level of validation (Level One, Level Two, Level Three, or Level Four) that is required for the deliverable or analysis, in consultation with the Lead Biostatistician.


Create formal documentation of the validation process for critical study analyses (Level One validation).


For all other types of analyses, document the completion of the validation through email communication, and store the email with the program, report, or deliverable.

B. Validating Level One Programs for Critical Study Analyses


1. Lead Biostatistician and Study Biostatisticians

Follow procedures in DCC SOP BIO 904 to prepare the analysis results.

DCC SOP BIO 904


For critical study analyses, assign two study biostatisticians to independently code and generate primary and applicable secondary endpoints.

3. Two Study Biostatisticians

Generate independent data sets from the raw data files.

NN BIO 904


Independently execute the data analyses described in the SAP.


Generate the results of the independent analyses.


Compare values for all primary and applicable secondary endpoints and identify all values where there is disagreement.


Address any differences found in the results, and resolve any questions.


Generate the analysis results for the report or manuscript.


Document the code validation process, and present the analysis results and the validation documentation to the Lead Biostatistician. • For the final study analysis, or if otherwise

requested, generate a summary report that describes the validation process, and include validation documentation (e.g. PROC COMPARE results).



10. Lead Biostatistician and DCC Director

Review the report and validation of the primary and applicable secondary endpoints.

11. Lead Biostatistician and Study Biostatistician

Collaborate to address any inconsistencies discovered during the review.

12. Study Biostatistician

Generate the final version of the analysis results.


Submit the final analysis results to the appropriate personnel for incorporation into the report or manuscript.

DCC SOP BIO 904 NN BIO 906

C. Validating Level Two Programs and Deliverables



Generate the deliverables (e.g. report tables and/or figures) according to procedures described in DCC SOP BIO 904.

DCC SOP BIO 904


Submit deliverables to Senior Leadership and the Lead Biostatistician for review.

3. DCC Senior Leadership and Lead Biostatistician

Review the deliverables to identify errors, inconsistencies, or unusual values.


Conduct a code review to determine the source of any errors, inconsistencies, or unusual values.

5. Lead Biostatistician and/or Study Biostatistician

Make any necessary corrections to the code.


Generate the final version of the deliverables, and perform a check to ensure that all code corrections have been properly implemented.


Submit the validated deliverables for incorporation into the report.

DCC SOP BIO 904

D. Validating Level Three Programs and Deliverables



Generate ongoing study deliverables (e.g. tables, figures, listings) according to procedures described in DCC SOP BIO 904.

DCC SOP BIO 904




Submit the deliverables to the Lead Biostatistician for review.


Review the deliverables to identify errors, inconsistencies, or unusual values. Consult with Senior Leadership, as needed.


Conduct a code review to determine the source of any errors, inconsistencies, or unusual values.

5. Lead Biostatistician and/or Study Biostatistician

Make any necessary corrections to the code.


Generate the final version of the deliverables, and perform a check to ensure that all code corrections have been properly implemented.


Submit the deliverables to the Study Team. DCC SOP BIO 904

E. Validating Level Four Programs and Deliverables



Generate the deliverable or analysis results according to procedures described in DCC SOP BIO 904.

DCC SOP BIO 904


Depending on the nature of the request and the level of validation required, perform a quality review of the program code used to generate the deliverable or analysis results.


If necessary, make any needed modifications to the code and re-generate the deliverable.


Submit the final version of the deliverable or analysis results to the requester.

DCC SOP BIO 904



NeuroNEXT Network Standard Operating Procedure (SOP) Validating Statistical Programs and Deliverables

SOP NN BIO 905


1.0 New N/A 13Apr2012 13May2012

2.0 This SOP was extensively revised and re-titled to align with recent updates to the analogous DCC SOP.

Major revisions to the analogous DCC SOP. 21Sep2016 21Oct2016


NN BIO 906

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR PRESENTING STATISTICAL RESULTS FOR A FINAL STUDY REPORT


PRESENTING STATISTICAL RESULTS FOR A FINAL STUDY

REPORT


1. POLICY

This SOP describes guidelines and procedures for writing quality statistical reports that adhere to professional standards and that clearly present the data analysis and results. Statistical reports should describe the nature of the NeuroNEXT Network study, the type of data that were collected and analyzed, the statistical methods used to analyze the data, and the results of the analysis.

All contents of figures, tables, and listings are cross-checked with the study database to ensure accuracy, and all statistics and results that are reported in the text of a report are verified to ensure that they are correct and validly interpreted.

2. SCOPE

This SOP has been developed to be in alignment with federal regulations and Good Clinical Practices (GCP) as set forth in the 1996 ICH E6 Consolidated Guidance. The policies and procedures described in this SOP apply to the NeuroNEXT Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC) within the context of their oversight and advisory roles for the NeuroNEXT Network, and to all NeuroNEXT investigators, staff, subcontractors, External Biostatisticians (if applicable), or other entities associated with the NeuroNEXT Network who manage, oversee, and conduct research regulated by FDA and/or applicable review committees.


NeuroNEXT DCC Biostatisticians are responsible for adhering to the procedures outlined in this SOP, and for ensuring that the procedures are followed by other DCC staff members who may participate in writing final study reports.


ICH E3 Structure and Content of Clinical Study Reports








NN BIO 904 Generation and Validation of Analysis Data Sets

NN BIO 905 Validating Statistical Programs and Deliverables


NN BIO 906 - A Document History







FDA Food and Drug Administration

GCP Good Clinical Practices


A. General Considerations


Related SOP

1. DCC Biostatisticians

When writing a final study report, DCC Biostatisticians should conform to standards of professional ethics for presenting and interpreting data analysis results. These standards include:

• ensuring that authorship conforms to the study’s standards;

• reporting statistical and substantive assumptions made in the study;

• identifying who is responsible for the statistical work;

• accounting for all data considered in the study and explaining the sample(s) actually used;

• reporting the sources and assessed adequacy of the data;

• reporting the data cleaning and screening procedures used, including any imputation performed for missing data;

• reporting clearly and fully the steps taken to guard validity (this includes addressing the suitability of the analytic methods and their inherent assumptions relative to the circumstances of the specific study, and identifying the computer routines used to implement the analytic methods);

• where appropriate, addressing potential confounding variables not included in the study;

• identifying the ultimate financial sponsor of the study, the stated purpose, and the intended use of the study results;

• when reporting analyses of volunteer data or other data not representative of a defined populations, including appropriate disclaimers;

• reporting the limits of statistical inference of the study and possible sources of error.


Include summary data in all reports; this will enable the reader to understand and interpret the data. When appropriate, use tables and figures. Report estimates along with their standard errors or

NN BIO 904



Related SOP

appropriate confidence intervals.


Clearly identify in report the authors and the data source.


Include a descriptive title in the report.

B. Statistical Methods


Related SOP


Clearly describe the statistical methods used for the analysis.


State whether the study was randomized (or other form of a designed experimental study), a panel study, case-control study, cohort study or other type of design.


State statistical methods clearly in the text. Where applicable, state the statistical models that were used, along with the assumptions upon which these models were based.


Specify whether the data are cross-sectional, longitudinal, or from a designed experiment. Indicate whether data were collected cross-sectionally, retrospectively, or prospectively.


State whether the data represent the full universe of cases in the place and time as specified by the study design, or that they represent a sample thereof.


Report the number of cases in the final analytic data set.


If applicable, state the number of cases lost to follow-up.

C. Presenting Statistical Analysis Results


Related SOP


Communicate the results of statistical analyses in a manner that is understandable and that follows professional standards.


Tabulate and present basic univariate descriptive statistics for each variable used in the analysis. For categorical variables, present a frequency distribution and note the modal category. For continuous variables, present at a minimum the sample mean, standard deviation, minimum and maximum values.



Estimate bivariate associations between independent and dependent variables, when applicable, using appropriate statistical methods, e.g., estimation of Pearson’s correlation, Analysis of Variance or cross-tabulations.


Label tabular and graphical summaries of descriptive statistics in a manner so that their contents are clearly understood:

• for both tables and graphs, include a title that describes the overall contents;

• for tables, row and/or column labels should clearly identify the contents of the table cells;

• for tables, put information that does not easily fit into labels in a note at the end of the table;

• for graphs, label axes and include a legend if needed.


For statistical tests of hypotheses: • state the test; • state null and alternative hypotheses clearly; • clearly interpret the results of hypothesis

tests. Where appropriate, observed values of test statistics and p-values should be reported.


For statistical models: • when statistical models are used, clearly state

the model along with its assumptions; • for categorical independent variables, present

estimated model coefficients and the size of each effect relative to the reference category;

• for continuous independent variables, report coefficients and express effect in 1-unit increase (if 1-unit increase is not of interest, use more meaningful increase to describe effect size);

• present main effects in the presence of interaction —supplement the estimated model coefficients with a table or graph to display the interaction effect;

• for generalized linear models and generalized linear mixed models, estimated model coefficients may be presented in terms of the link function, but key results should be reported using the inverse of the link function for ease of understanding;

• present estimated model coefficients with estimates of their variability (estimates may be in the form of standard errors or confidence intervals).


E. Conclusions


Related SOP


Summarize and interpret the results of the analysis.


State any conclusions that may be drawn from the analysis.

F. Validating and Documenting Report Contents


Related SOP


Validate the code used to generate the analysis results and any deliverables (e.g. tables, figures), and document the code validation process.


Verify that the contents of figures, tables, and listings are accurate. Verify that all numbers and results reported in the text are correct and validly interpreted.


Ensure that all information pertaining to the report and how it was generated are documented, reproducible, and easily accessible by NeuroNEXT DCC Biostatistics personnel.

NN BIO 904 NN BIO 905

G. Archiving the Final Report


Related SOP


Archive the report, the results of program validation, and a copy of the computer program(s) that produced the results, in a clearly defined folder on the DCC shared drive.


Communicate results of statistical analyses in the report in a manner that is clearly understood:

• use vocabulary that is understood by intended audience;

• identify and define any mathematical terms used;

• interpret results of analyses and relate them back to the main topic;

• specify the direction and the size of the association between important variables.



NeuroNEXT Network Standard Operating Procedure (SOP) Presenting Statistical Results for a Final Study Report

SOP NN BIO 906


1.0 New N/A 13Apr2012 13May2012

2.0

Changed title to reflect the focus of the SOP on preparing results for a final study report. Other minor modifications to align with analogous CTSDMC SOP.

Updates for Version 2.0. 21Sep2016 21Oct2016

NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR · ICH E6, 5.23 Multicenter Trials . ICH E6, 6.0...

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