NN DM 1002 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR DATA MANAGEMENT PLAN DEVELOPMENT SOP: NN DM 1002 Version No: 2.0 Effective Date: 21Oct20

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8 NN DM 1002 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR DATA MANAGEMENT PLAN DEVELOPMENT SOP: NN DM 1002 Version No: 2.0 Effective Date: 21Oct2016 DATA MANAGEMENT PLAN DEVELOPMENT Supercedes Document: Version 1.0 Effective Date:13May POLICY A comprehensive Data Management Plan will be created for the NeuroNEXT Network that describes areas of Data Management (DM) oversight and activities that will be conducted for the Network. The NeuroNEXT Network comprehensive Data Management Plan may include, but is not limited to, the following components: Overview Website development Database model Database and website environments Electronic CRF (ecrf) development and testing Save-audit testing Subject identification system Clinical data entry procedures Reports Data backup and archiving Data sharing Electronic data transfer Adverse event tracking and management MedDRA coding system Data quality assurance Glossary Appendices, including all study-specific Data Management Plans The NeuroNEXT Data Coordinating Center (DCC) DM Team will collaborate with the NeuroNEXT Clinical Coordinating Center (CCC) to develop the comprehensive Data Management Plan. The Plan will be maintained by the DCC DM Team, and may be updated (as needed) in collaboration with the CCC. Study-specific Data Management Plans A study-specific Data Management Plan will be developed by the DCC DM team for each study protocol, in collaboration with the CCC, the Protocol Principal Investigator (PPI) and study team, and others as needed. The study-specific Plan will be included as an appendix to the NeuroNEXT comprehensive Data Management Plan. The study-specific Plan is established at the beginning of the study, and will be maintained as a living document. The primary purpose of the study-specific Data Management Plan is to convey website details, protocol information, and data entry application details to the IT application developers at the DCC. While the Plan may contain informational materials related to the project, certain information provided in the Plan may be considered to be written specifications. Components that may be included in the study-specific Data Management Plan are described in section 8.C. NN DM 1002 Page 2 of 6

9 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 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. 3. ROLES AND RESPONSIBILITIES The DCC DM Team is responsible for creating a comprehensive Data Management Plan for the NeuroNEXT Network with an appendix for each study protocol, in consultation with the CCC and NeuroNEXT Leadership (CCC PI and DCC PI). The DCC DM Team will maintain the comprehensive Data Management Plan, and will update the Plan as needed in collaboration with the NeuroNEXT CCC. Individual Study-Specific Data Management Plans will be created and maintained by the DCC Data Management Team as appendices to the main Data Management Plan in collaboration with, but not limited to, the NeuroNEXT CCC, the Protocol Principal Investigator (PPI) and study team,, and others as needed. The responsibility to conduct any or all of these activities may be delegated at the discretion of the Sponsor to the DCC. Those individuals and entities also take on responsibility for meeting regulatory requirements on behalf of the Sponsor, but the Sponsor has the ultimate responsibility, and must therefore supervise those delegated activities effectively. 4. APPLICABLE REGULATIONS AND GUIDELINES ICH E6, 2.10 The Principles of ICH GCP ICH E6, 6.0 Clinical Trial Protocol and Protocol Amendment(s) ICH E8 General Considerations for Clinical Trials (December 1997) 5. REFERENCES TO OTHER APPLICABLE SOPS NN GA 103 NN GA 107 NN CS 702 NN CS 703 NN CS 704 NN CS 705 NN QA 801 NN QA 802 NN BIO 904 NN BIO 905 NN BIO 906 NN DM 1001 NN DM 1003 NN DM 1004 NN DM 1005 Document Development and Change Control Data Sharing Application Development and Validation IT Environments System Security Measures and Website Access Data Backup, Recovery, and Contingency Plans Quality Assurance Audits Quality Management Generation and Validation of Analysis Data Sets Validating Statistical Programs and Deliverables Presenting Statistical Results for a Final Study Report Clinical Data Management Case Report Form Development Specifications Development, Testing Plans, and Validation Documentation Data Collection and Data Handling NN DM 1002 Page 3 of 6

10 NN DM 1006 Adverse Event Coding 6. ATTACHMENTS AND REFERENCES NN DM A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: AE CCC CFR DCC DM FDA GCP ICH PPI QA SAE 8. SPECIFIC PROCEDURES Adverse Events Clinical Coordinating Center at Massachusetts General Hospital Code of Federal Regulations Data Coordinating Center at The University of Iowa Data Management Food and Drug Administration Good Clinical Practices International Conference on Harmonisation Protocol Principal Investigator Quality Assurance Serious Adverse Events A. Maintaining the NeuroNEXT Network Comprehensive Data Management Plan The DCC DM Team will create the NeuroNEXT Network comprehensive Data Management Plan as described in the Policy section, and will maintain the Plan as described below: DCC DM Team Lead Determine who is responsible for reviewing and modifying the comprehensive Data Management Plan. DCC DM Team As needed, update the Data Management Plan to reflect changes in DM procedures. DCC DM Team After all revisions are complete, update the version date and increment the version number to the next whole number (1.x to 2.0). NN DM 1001 NN GA 103 B. Creating and Maintaining a Study-Specific Data Management Plan DCC DM Lead Assigned DCC Team Member DCC DM Lead Assign a Data Management Team member to create and maintain the study-specific Data Management Plan. Create the study-specific Data Management Plan, and include applicable components described in section 8.C. Review the study-specific Data Management Plan and offer feedback, if necessary. NN DM 1002 Page 4 of 6

11 4. 5. DCC DM Team Lead DCC DM Team Leader Include the final study-specific Data Management Plan as an appendix in the NeuroNEXT Network comprehensive Data Management Plan. Periodically review the study-specific Data Management Plan, and track any major changes on a document change log. C. Components of a NeuroNEXT Study-Specific Data Management Plan Each Study-Specific Data Management Plan may include, but is not limited to, the components described in this section DCC DM Team Study Overview Study Team Describe the rationale, intervention, and study design. CRF Development Describe all CRFs that are developed for the study, and the process for developing, finalizing, and approving paper CRF templates for the study. DCC DM Team Electronic CRF Availability Describe the availability of ecrfs including, but not limited to, the order of events and CRF visits. DCC DM Team Subject Identification Describe the subject ID system, if different than the NeuroNEXT customary system. DCC DM Team Access to Subject Enrollment and Data Entry DCC DM Team Website DCC DM Team Reports DCC DM Team and DCC QM Team DCC DM Team Glossary Describe these processes in detail. Describe any additional necessary information about the website that is not included in the comprehensive Data Management Plan. Describe basic reports that the Data Management team may produce that are not already mentioned in the comprehensive Data Management Plan. Data Quality Assurance Describe any QA processes and QC metrics that are specific to the NeuroNEXT study. Define any study-specific terms NN DM 1003 NN CS 704 NN CS 704 NN CS 704 NN BIO 904 NN BIO 905 NN BIO 906 NN QA 801 NN QA DCC DM Team Incorporate additional sections, as appropriate. NN DM 1002 Page 5 of 6

12 Attachment NN DM A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Data Management Plan Development SOP NN DM 1002 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 13Apr May Removed references to the Protocol Steering Committee and the approval process for study-specific Data Management Plans. Simplified the development, review, and revision processes. Modified or removed several components of study-specific plans. Other minor edits. Updates for v2.0 21Sep Oct2016 NN DM 1002 Page 6 of 6

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14 NN DM 1003 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR CASE REPORT FORM DEVELOPMENT SOP: NN DM 1003 Version No. 2.0 Effective Date: 21Oct2016 CASE REPORT FORM DEVELOPMENT Supercedes Document: Version 1.0 Effective Date: 29Apr POLICY Case Report Forms (CRFs) are designed to capture all clinically-relevant data that are collected for an approved NeuroNEXT protocol (e.g. subject demographic data, results of physical, radiological and laboratory examinations, and analytical and clinical data). Depending on the requirements of the protocol, a CRF development team consisting of the Protocol Principal Investigator (PPI) and representatives from the NeuroNEXT Clinical Coordinating Center (CCC) and the Data Coordinating Center (DCC) may be formed to design and develop CRFs for the protocol using standardized CRFs and common data elements (CDEs) when possible. After all CRFs for a protocol are finalized, they will be signed by the final reviewers, which may include the PPI, the DCC Data Management Lead, and other applicable DCC and CCC personnel. A CRF may originate from the DCC, or the DCC may support CRF development and management by a third party. All CRFs are prepared using version control measures. After the CRFs have been finalized, the DCC will begin development of the electronic CRFs (ecrfs) and the Electronic Data Capture system (EDC). The DCC will work with the PPIs to ensure that they are aware that delays in CRF development may result in delays in development of the EDC system and possible escalation of the costs associated with development and implementation. To limit the costs associated with development of the EDC, it is the policy of the DCC to limit changes to CRFs once the development process has begun. 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 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. 3. ROLES AND RESPONSIBILITIES The DCC is responsible for supervising the implementation of this procedure. The DCC may delegate the responsibility for designing a CRF to a designated qualified individual. The DCC is responsible for preparing the initial drafts of case report forms, in conjunction with the PPI and the Study Team. The PPI, the DCC Data Management Lead, and other applicable CCC and DCC personnel are responsible for signature-approving all CRF templates. The responsibility to conduct any or all of these activities may be delegated at the discretion of the Sponsor to the CCC and/or the DCC. Those individuals and entities also take on responsibility for meeting regulatory requirements on behalf of the Sponsor, but the Sponsor has the ultimate responsibility, and must therefore supervise those delegated activities effectively. 4. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR Protocol Amendments NN DM 1003 Page 2 of 6

15 ICH E6 2.2, The Principles of ICH GCP ICH E6, 2.10, 2.11 The Principles of ICH GCP ICH E6, 5.5 Trial Management, Data Handling, and Recordkeeping 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) 5. REFERENCES TO OTHER APPLICABLE SOPS NN GA 103 Document Development and Change Control NN RA 204 Informed Consent Form Preparation NN CS 702 Application Development and Validation NN DM 1001 Clinical Data Management NN DM 1002 Data Management Plan Development NN DM 1004 Specifications Development, Testing Plans, and Validation Documentation NN DM 1005 Data Collection and Data Handling 6. ATTACHMENTS AND REFERENCES NN DM 1003 A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: CCC CDE Clinical Study Site (CSS) DCC DM IT Protocol Principal Investigator (PPI) Clinical Coordinating Center at Massachusetts General Hospital Common Data Elements Clinical site that conducts research for a NeuroNEXT protocol within or outside the Network Data Coordinating Center at The University of Iowa Data Management Team at the DCC Information Technology Team at the DCC Principal Investigator of a NeuroNEXT protocol 8. SPECIFIC PROCEDURES A. Case Report Form Development PPI, CCC, DCC When applicable, convene a CRF Development team, consisting of the PPI and appropriate representatives from the CCC and DCC. CRF Review the protocol and identify specific data points NN DM 1001 NN DM 1003 Page 3 of 6

16 Development Team CRF Development Team DCC DM DCC DM that will be required for the planned statistical analyses. When possible, NINDS Common Data Elements (CDEs) are to be utilized within and across studies. Refer to the Data Management Plan, as appropriate. Determine the appropriate CRF format (paper-based, computer entry, electronic diary, or Internet-based). Create draft CRFs, using standardized CRFs when possible. Circulate the draft CRFs among the CRF Development team and other appropriate reviewers for review of content and format. All relevant parties should conduct a careful review to ensure that the proposed CRFs capture all necessary subject and protocol data. NN GA 103 NN DM 1004 DCC DM Revise CRF drafts as needed. NN GA 103 CRF Development Team CRF Development Team DCC DM Review the CRF to ensure that the CRF language is clear, consistent, and captures all desired data points, especially primary endpoints. During the final review process, make and document minor revisions to the CRFs as directed by the final reviewers, including the Sponsor and/or CCC, as appropriate. When final revisions are completed, forward all CRFs to the NINDS CDE team to review for compliance with CDE requirements. NN GA DCC DM Retain copies (in PDF format) of all CRFs that have been implemented for the protocol s data collection system. 11. DCC DM Secure the signatures and approval dates of CRF Development team final reviewers in appropriate boxes on the Change Control Form or on a signature approval form. NN GA 103 NN GA DCC DM When protocol amendments are finalized, revise CRFs, if applicable, to reflect changes to the protocol. 13. CCC or DCC DM Implement, review, and approve any subsequent changes to the CRF as described in NN GA 103. Document all CRF revisions that occur after the initial finalization. NN GA DCC DM For all amendments, secure the signatures and approval dates of final reviewers in appropriate boxes on the Change Control Form or a signature approval form. NN GA 103 NN DM 1003 Page 4 of 6

17 B. Case Report Form Version Control DCC DM DCC DM DCC DM DCC DM Study Team DCC DM DCC DM DCC DM DCC DM Prior to finalization of the initial CRFs for a study, the CRF versions are documented by a version date (date change was made) and a version number. Preliminary version numbers should be restricted to values that are less than 1.0 (e.g..10,.20, etc.). Designate the final, approved versions of all initial CRFs for a study as version 1.0. The version date for all initial CRFs for a study is the date that the CRFs were finalized and approved. Minor changes do NOT require a signature approval. A minor change refers to any change to a CRF that does NOT require a modification to the database and that does not change validation programming (e.g. rewording a question, correcting spelling errors, changing formats or fonts). For a minor change, increment the CRF version number to a succeeding numerical value that does not change the current whole number (e.g. 1.0 to 1.1). Major changes to an approved CRF require a signature approval. A major change is any change to a CRF that results in changes to the database (e.g. adding a question that creates a field in the database, deleting a question that removes a field in the database) and/or changes to the validation programming. For a major change to a CRF, increment the new version number to the next whole number (e.g. 1.2 to 2.0). Create and maintain a change table to continually track changes to version numbers and version dates, and to specify reason(s) for any change(s) to CRFs. Review changes with the Study Team. Send a signature approval form to the appropriate signatories for approval of requested major changes. 10. DCC IT The version number for CRFs (paper templates) does NOT necessarily match the ecrf version number. The ecrf version number is determined independently by the DCC IT Developers. NN GA 103 NN DM 1001 NN GA 103 NN GA 103 NN GA 103 NN GA 103 NN GA 103 NN GA 103 NN GA 103 NN CS 702 NN DM 1003 Page 5 of 6

18 Attachment NN DM A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Case Report Form Development SOP NN DM 1003 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 30Mar Apr Added that the Study Team participates in preparing initial drafts of CRFs. Clarified that the PPI, DCC Data Management Lead, and other applicable CCC and DCC personnel are responsible for signature-approving all CRF templates for a NeuroNEXT study. Revised signature approval procedure for major changes to an approved CRF to state that the changes are approved by the appropriate signatories (removed reference to Sponsor approval of changes). Updates for version Sep Oct2016 NN DM 1003 Page 6 of 6

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20 NN DM 1004 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR SPECIFICATIONS DEVELOPMENT, TESTING PLANS, AND VALIDATION DOCUMENTATION SOP: NN DM 1004 Version No. 2.0 Effective Date: 21Oct POLICY SPECIFICATIONS DEVELOPMENT, TESTING PLANS, AND VALIDATION DOCUMENTATION Supercedes Document: Version 1.0 Effective Date: 29Apr2012 The Data Management (DM) Team at the NeuroNEXT Data Coordinating Center (DCC) participates in all aspects of clinical data management, including the development of User Specifications and Testing Plans for electronic CRFs and protocol websites, the testing of these applications, and the creation of validation documentation. Validation documentation consists of two primary components: 1. The FogBugz tracking system, which provides a tracking mechanism and case history for specifications and testing plan development, testing results, and the location of the validation documentation (screenshots); and 2. The Validation Document which contains screenshots representing testing results for each requirement listed in the testing plan. 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. 3. ROLES AND RESPONSIBILITIES For most projects, the DCC is generally responsible for the following aspects of data management: development of User Specifications and Testing Plans for electronic CRFs and protocol websites, the testing of these applications, and the creation of validation documentation. The responsibility to conduct any or all of these activities may be delegated at the discretion of the Sponsor to the DCC or to subcontractors of the DCC, where applicable. Those individuals and entities also take on responsibility for meeting regulatory requirements on behalf of the Sponsor, but the Sponsor has the ultimate responsibility, and must therefore supervise those delegated activities effectively. 4. APPLICABLE REGULATIONS AND GUIDELINES ICH E6 Good Clinical Practice: Consolidated Guidance, April 1996 ICH E6, 2.10 ICH E6, 5.1 The Principles of ICH GCP Quality Assurance and Quality Control FDA Guidance Computerized Systems Used in Clinical Investigations, FDA, May 2007 FDA Guidance Computerized Systems Used in Clinical Trials, FDA, April 1999 FDA Guidance FDA Guidance 21 CFR Part 11, Electronic Records; Electronic Signatures Scope and Application, FDA, August 2003 General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002 NN DM 1004 Page 2 of 7

21 5. REFERENCES TO OTHER APPLICABLE SOPs NN CS 702 Application Development and Validation NN DM 1001 Clinical Data Management NN DM 1002 Data Management Plan Development NN DM 1003 Case Report Form Development NN DM 1005 Data Collection and Data Handling 6. ATTACHMENTS AND REFERENCES NN DM 1004 A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: CCC Clinical Study Site (CSS) DCC DM IT Protocol Principal Investigator (PPI) Clinical Coordinating Center at Massachusetts General Hospital Clinical site that conducts research for a NeuroNEXT protocol within or outside the Network Data Coordinating Center at The University of Iowa Data Management Team at the DCC Information Technology Team at the DCC Principal Investigator of a NeuroNEXT protocol 8. SPECIFIC PROCEDURES A. Specifications Development for ecrfs After the paper CRF templates for a project are approved by the CRF Development Committee and the Sponsor (if applicable), a user specifications document is created for each CRF template. User specifications (specs) are created by the DCC DM Team in consultation with the Study Team, and describe the user requirements for an electronic Case Report Form (ecrf) or website module. To maintain continuity and to track the evolution of an ecrf application or website module throughout its life cycle, only one specifications document is used for each ecrf or module that is developed. A change table is added to each newly created user specifications document so that later modifications may be tracked. Modifications are inserted into the original specification document. 1. DCC DM Create only one specifications document for use throughout the life of an ecrf or website module. Collaborate with the IT Team during the spec development process to ensure that specifications clearly define and describe the user requirements. Related SOP NN DM 1001 NN DM 1002 NN DM 1003 NN DM 1004 Page 3 of 7

22 Related SOP 2. DCC DM Develop the specification document. 3. DCC DM Track future modifications to an ecrf in the change table in the spec document, and insert any modifications to the requirements into the spec document. B. Creation of Testing Plans Comprehensive testing is critical for ensuring that an ecrf or other application is functioning according to specifications. For each specification document, a corresponding testing plan is created that describes the testing conditions for thoroughly testing all of the requirements that are detailed in the specifications document. The testing plan contains the following components that must be completed for each of the testing conditions: Sequence Number a unique identifier for each test condition. Requirement Number the same requirement number used in the Specifications Document. Testing Conditions the instructions to be followed in order to test the requirement. Expected Result the expected result after the test condition is completed. Test Result (Pass/Fail) a Pass/Fail result is recorded in this column at the time of the test. Pass indicates that the testing condition performed as expected. Comments any comments associated with the test; generally used to describe what happened when a test failed. An electronic testing plan workbook is created to document the testing of an ecrf or website module throughout its life cycle. Each sheet in the workbook represents the testing that has been completed for a particular work effort within a specific testing environment. For new ecrf development, the testing plan worksheet contains test conditions for all user requirements. For modifications to an ecrf, the subsequent worksheets that are added to the testing plan refer only to test conditions for the modified or added requirements. 1. DCC DM Create a testing plan that describes the testing conditions that are used to test all of the requirements detailed in the specifications document. An Excel spreadsheet workbook is the preferred tool that is used by the DCC to create testing plans. Related SOP NN DM DCC DM For form modifications, refer only to the modified requirements in subsequent testing plan worksheets. C. Application Development and Testing After specifications have been finalized and a testing plan has been created, a case is created in the FogBugz application to initiate the process of IT development, testing, and the eventual NN DM 1004 Page 4 of 7

23 move of the application to the Production environment, where the application is made available to Clinical Study Sites (CSS). Prior to application development, the DM and IT Team Leads prioritize and batch together cases for development into a FogBugz Milestone. Cases are then assigned to the IT Developers for coding. Internal correspondence between Data Managers and Developers is tracked in the associated development case during the application development and testing process. When the case is available for testing, the tester completes each test condition listed on the testing plan worksheet, documents whether the test passed or failed, and adds comments to describe the nature of an error or bug. Once testing is completed, the testing plan worksheet is attached to the appropriate FogBugz case. 1. DCC DM After the specifications have been finalized and a testing plan has been created, create a case in the FogBugz application to initiate the IT development and testing process. 2. DCC DM Follow the procedures described in NeuroNEXT SOP NN CS 702 to test the application in the Test and Stage environments, and document all testing results in the testing plan workbook. Related SOP NN DM 1001 NN CS DCC DM For failed test conditions, provide clear descriptions of what was tested, the result, and how the result differed from the expected result (if applicable) in the testing plan workbook. 4. DCC DM If necessary, meet with the developer to clarify testing issues or to discuss possible modifications to the user specifications. D. Validation Document The Validation Document is generated during testing in the Stage environment. 1. DCC DM After testing is completed, create a validation document, if applicable. Related SOP NN DM DCC DM Create screen shots to document the testing of each requirement, when appropriate. 3. DCC DM Label each screen shot with the corresponding Requirement number, the Sequence number tested, and the date of the screenshot. NN DM 1004 Page 5 of 7

24 E. Save/Audit Testing This testing ensures that each data item on an ecrf maps to the correct data field and data table in the database. Save/Audit Testing is performed by using the electronic data capture (EDC) website and SAS software (SAS Institute Inc, Cary, NC). 1. DCC DM Perform save/audit testing for all new studies and/or new ecrf development. NN DM 1001 F. Milestone Review While the Milestone is in the Stage environment, the DCC DM team performs targeted testing to help ensure that the application has not been affected by programming changes. # Who Task Attachments /s Related SOP 1. DCC DM Create a FogBugz case to track the Milestone review DCC DM Tester DCC DM Tester DCC DM Lead DCC DM Tester Perform a Milestone review in the Stage environment (using a Milestone checklist, if applicable) to check the functionality of all modules and the general performance of the website to ensure that the application has not been affected by programming changes. Reviews may include, but are not limited to, checks of: Website access Website configurations ecrf submissions Adverse Event Reporting System Post-complete change functionality Meet with DCC DM Lead to discuss any issues that were discovered during the review. Determine if issues are significant enough to delay the move to Production, or can be addressed in a subsequent Milestone. In the FogBugz case, describe the issues to be addressed and assign the case to the DCC IT developer. 6. DCC IT Resolve the issues described in the FogBugz case, and assign the case to the DCC Tester. 7. DCC DM Tester Ensure that all issues have been resolved before assigning to the DCC IT Lead or designee for the move to Production. NN DM 1004 Page 6 of 7

25 Attachment NN DM A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Specifications Development, Testing Plans, and Validation Documentation SOP NN DM 1004 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 30Mar Apr Removed outdated procedures and revised several procedures related to specifications development, testing plans, application development and testing, validation documentation, and save/audit testing so that the SOP reflects current procedures. Clarified that relevant procedures in this SOP apply also to developing, testing, and validating website modules. Added a section on Milestone review. Updates for v2.0 21Sep Oct2016 NN DM 1004 Page 7 of 7

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27 NN DM 1005 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR DATA COLLECTION AND DATA HANDLING SOP: NN DM 1005 Version No.: 2.0 Effective Date: 21Oct2016 DATA COLLECTION AND DATA HANDLING Supercedes Document: Version 1.0 Effective Date: 29Apr POLICY This SOP provides guidance for NeuroNEXT Data Coordinating Center (DCC) staff regarding proper procedures for electronic data collection and electronic data handling to ensure confidence in the reliability, quality, and integrity of electronic data. 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. 3. ROLES AND RESPONSIBILITY The DCC is responsible for adhering to the procedures outlined in this SOP, and for ensuring that procedures are adhered to by individuals requesting data from the DCC. 4. APPLICABLE REGULATIONS AND GUIDELINES ICH E6 Good Clinical Practice: Consolidated Guidance, April CFR Part 11 Electronic Records; Electronic Signatures FDA Guidance Part 11, Electronic Records; Electronic Signatures Scope and Application, FDA, August 2003 FDA Guidance Computerized Systems Used in Clinical Investigations, FDA, May 2007 FDA Guidance Computerized Systems Used in Clinical Trials, FDA, April 1999 FDA Guidance NIH General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002 HIPAA Privacy Rule: Information for Researchers < 5. REFERENCES TO OTHER APPLICABLE SOPS NN SS 402 NN SS 403 NN SS 405 NN PM 503 NN PM 504 NN CS 702 Site Initiation Visits and Site Training Routine Monitoring Visits Study Close Out Visits Study Materials Development Investigational Site Staff Training Application Development and Validation NN DM 1005 Page 2 of 8

28 NN CS 704 NN CS 705 NN CS 706 NN BIO 904 NN DM 1001 NN DM 1002 NN DM 1003 NN DM 1004 NN DM 1006 System Security Measures and Website Access Data Backup, Recovery, and Contingency Plans Retention and Protection of Electronic Records Generation and Validation of Analysis Data Sets Clinical Data Management Data Management Plan Development Case Report Form Development Specifications Development, Testing Plans, and Validation Documentation Adverse Event Coding 6. ATTACHMENTS AND REFERENCES NN DM 1005 A Document History NN DM 1005 B Data Change Request Form Template 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: CCC Clinical Study Site (CSS) DCC DM IT Protocol Principal Investigator (PPI) Clinical Coordinating Center at Massachusetts General Hospital Clinical site that conducts research for a NeuroNEXT protocol within or outside the Network Data Coordinating Center at The University of Iowa Data Management Team at the DCC Information Technology Team at the DCC Principal Investigator of a NeuroNEXT protocol 8. SPECIFIC PROCEDURES A. Data System Validation and Security DCC DM and IT DCC IT Conduct verification testing and validation to help ensure and document that the electronic data capture system is validated for its intended use. Ensure that the electronic data system is secured with restricted access. NN CS 702 NN DM 1001 NN DM 1003 NN DM 1004 NN CS DCC IT Ensure that the electronic data system is appropriately backed-up and/or replicated. NN CS 705 NN DM 1005 Page 3 of 8

29 B. Electronic Data Collection 1. Study Team Ensure that the clinical protocol, User Guides, and/or Manuals of Operation describe in detail all methods that are to be used for collecting, evaluating, changing, and submitting study data to the DCC. 2. DCC DM, IT, Study Team Ensure that the same fundamental elements of data quality (attributable, legible, contemporaneous, original, and accurate) that are expected of paper records are incorporated into the electronic data system. NN DM 1001 NN DM 1003 NN DM DCC DM, IT, Study Team Identify valid values or ranges, data types, skip-out relationships, and mandatory requirements that are to be checked by automated page validation systems. NN CS DCC DM, IT, Study Team Ensure that appropriate logic checks are programmed into the data entry system to help prevent entry of discrepant data. NN CS DCC DM and Study Monitors Ensure the accuracy and completeness of the electronic data collected. 6. DCC DM and Biostatisticians Generate reports to identify missing data and to help ensure timely data entry. 7. DCC DM and Protocol Coordinators Train individuals at the DCC and CSS (if applicable) in proper data collection and handling procedures via inperson or webinar training sessions, and document the training. 8. DCC DM and Protocol Coordinators Instruct trainees in proper procedures for entering and/or changing data (if authorized to do so), navigating the study website, and utilizing all applicable modules related to data entry (e.g. Query System). NN SS 402 NN PM 504 NN DM DCC DM and Protocol Coordinators Assign appropriate user roles after training has been completed and documented. 10. DCC IT, DM, and Protocol Coordination Maintain a listing of the individuals who are authorized to enter and/or change data. NN CS 704 C. Electronic Signatures and User Access 1. DCC Leadership Certify to the regulatory agency (FDA) that the electronic signatures in the DCC data systems are the legally binding equivalents of traditional handwritten signatures (as required by 21 CFR (c)). Submit certification (as set forth in 21 CFR ) in paper form signed with a traditional handwritten signature to the Office of Regional Operations 21 CFR Part 11 NN CS 704 NN DM 1005 Page 4 of 8

30 (HFC-100), 5600 Fishers Lane, Rockville, Maryland Submit certification prior to the use of electronic signatures, or at the time that the use of electronic signatures is initiated. A single certification may cover all electronic signatures used by persons in a given organization. 2. DCC IT and Protocol Coordination Instruct Users that they may only use their own passwords for gaining entry to the data system. Instruct Users that they may not share passwords with others. NN SS 402 NN PM 504 NN CS 704 NN DM 1001 Instruct Users that they may not log on to the data system in order to provide access to other persons. 3. Instruct Users to log off of the data system when they leave their workstation. Create an automatic log off or other protection for periods of system inactivity to prevent unauthorized data entry. NN SS 402 NN PM 504 NN CS 704 NN DM 1001 D. Query System DCC DM DCC IT, DM and/or Protocol Coordination DCC DM, IT, and Protocol Coordination DCC DM and/or Protocol Coordination Maintain Query System Specifications, and update as needed. Make the module available to authorized users for resolving post submission data inconsistencies. Provide training to the Users. Create a listing (specifications) of desired error checks (i.e. inter-form and intra-form logic checks). Modifications to Query System error checks (e.g. additions, deletions, changes) will be documented, and implementation will be managed through FogBugz cases and procedures. 5. Initiate error checks through the Query System on a regular basis according to the requirements for a study. Release error checks to clinical study sites as needed for resolution. NN DM 1004 NN SS 402 NN PM 504 NN CS 704 NN DM 1001 NN DM 1003 NN DM 1004 NN DM 1004 E. Manage ecrf Status 1. DCC DM Maintain Manage ecrf Status specifications. NN DM 1004 NN DM 1005 Page 5 of 8

31 2. 3. DCC IT and/or Protocol Coordination DCC DM Make this module available to authorized Users in order to manage the status of individual ecrfs and/or to mark entire visits as unobtainable. Provide training to the Users. Indicate in the specifications the possible statuses available for each form (i.e. Not started, Incomplete, Complete, Unobtainable, Deleted) based on the role of the User. NN SS 402 NN PM 504 NN CS 704 NN DM 1001 NN DM 1001 F. DCC Centralized Data Entry 1. DCC and CSS CSS responsibilities and procedures regarding forms sent to the DCC for data entry will be described in the Manuals of Operations (or similar) for the protocols. NN PM DCC DCC responsibilities and procedures regarding centralized data entry at the DCC will be described in the study Data Management Plan or similar protocol manual or document DCC Protocol Coordination DCC Protocol Coordination All paper forms received at the DCC for data entry will be date-stamped and logged. Perform a QC check of all data against the source documentation 5. Completion of data entry (first and/or second data entry) will be logged. 6. Second data entry of data for a form, if applicable, may not be completed by the person who entered the first set of data. 7. Data items that do not match after first and second entry will be compared, discrepancies will be resolved, and the corrected answer will be chosen. 8. The paper forms received by the DCC for data entry are subject to the same retention requirements as are all other data for the protocol. G. Electronic Data Transfer 1. DCC IT, DM When a study requires that the DCC receive or send electronic data from an outside source, collaborate with the appropriate entity to develop a Data Transfer Agreement. This document specifies how and when the data will be transferred, the expected data format, and the expected filename. NN DM 1005 Page 6 of 8

32 2. DCC IT, DM As part of the Data Transfer Agreement, or in a separate study document, obtain a Data Dictionary that provides a description of the specific data fields that are to be included in the data transfer. 3. DCC IT, DM It is preferable to retrieve data through a secure file transfer protocol (FTP) site or another secure site. Depending on the requirements described in the Data Transfer Agreement, other methods may be used. 4. DCC Archive the data file to the DCC file server. 5. Import the data into the appropriate database DCC Protocol Coordination and/or DM DCC DM, Protocol Coordination, or Biostatistics DCC DM, Protocol Coordination, or Biostatistics If applicable to a study, maintain a log (e.g. Excel spreadsheet) to track whether expected data have been received, and were received within the required timeframe. As appropriate to a study, generate and review reports to ensure that all expected data have been received and/or accounted for in the database. As appropriate to a study, generate and review reports to check the transferred data for discrepancies and for extreme values (if applicable). H. Data Change Requests 1. DCC If, at any time, a request to change subject data is made by a clinical site, and it is NOT possible to make this change via post-complete change, Query System, or another electronic/automatic system, a Data Change Request form is required. NN DM 1004-B 2. A Data Change Request form for the applicable study is completed, verified by the site, and sent to the DCC. 3. DCC DM The form is reviewed for completeness, logic, and for potential protocol deviations. The database is reviewed to confirm that the change has not already been made, and that it cannot be made through any other mechanism. 4. If a study uses paper CRFs as source documents, a copy of the corrected, applicable paper form must accompany the data change request (when possible). 5. All Data Change Request forms (and corrected paper forms, if applicable) are stored at the DCC by protocol, center, and subject. NN DM 1005 Page 7 of 8

33 Attachment NN DM A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Data Collection and Data Handling SOP NN DM 1005 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 30Mar Apr Updated procedures for electronic data system validation and security, electronic data collection, Query System, manage ecrf status, and DCC centralized data entry, and data change requests. Completely revised section 8.G for electronic data transfers to align with current procedures. Updates for v2.0 21Sep Oct2016 NN DM 1005 Page 8 of 8

34 Attachment NN DM 1005 B. Data Change Request Form Template Page 1 of 1 Instructions:Complete this form to request a data correction only if the ecrf in question does not allow a Post- Complete Change. (1) Enterthe date of the data change request in the Date of Request field. (2) Enter the individual Subject ID number into the Subject ID field. Remember, only one study subject per form! (3) Enter one data correction for each row in the table below. In the first column, enter the StudyVisit Name or Number. In the second column, enter the Study Visit Datethat was submitted for the ecrf. In the remaining columns, enter the ecrfname or #, item#, the data valuebefore correction, and the corrected value. (4) When finished, please print, sign, and date this form. (5) Fax this Data Change Request form and the pages of the corrected paper CRF (if applicable) to: NeuroNEXT Study, , or you may scan and the form to neuronext@uiowa.edu. (6) Retain a copy of this Data Change Request form in the subject s study file. The DCC will also store a copy of this form. Date of Request: / / (mm/dd/yyyy) SubjectID: - - Visit Name or Number Visit Date* ecrf Name or # Item# (e.g. 3.a.i) Data value before correction Corrected value / / (mm/dd/yyyy) / / (mm/dd/yyyy) / / (mm/dd/yyyy) / / (mm/dd/yyyy) / / (mm/dd/yyyy) *Study Visit Date submitted for the ecrf Completed by: / / Coordinator: print name Signature Date (mm/dd/yyyy) DCC use only Corrected by: / / DCC personnel: print name Signature Date (mm/dd/yyyy) Version 1.0 2/23/2012

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36 NN DM 1006 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR ADVERSE EVENT CODING SOP: NN DM 1006 Version No. 2.0 Effective Date: 21Oct POLICY ADVERSE EVENT CODING Supercedes Document: Version 1.0 Effective Date: 06May2012 The purpose of this SOP is to provide guidance regarding proper procedures for coding adverse events (AEs) and serious adverse events (SAEs) for clinical trials supported by the NeuroNEXT Network. The Medical Dictionary for Regulatory Activities (MedDRA) is used by the Data Coordinating Center (DCC) for coding AEs and SAEs. 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. 3. ROLES AND RESPONSIBILITIES The PPI and CSS are responsible for submitting AE reports in a timely manner using appropriate event terms. Depending on the nature and requirements of the study protocol, NeuroNEXT DCC personnel with clinical expertise and who have completed at least one MedDRA training course may be responsible for coding AEs and SAEs for NeuroNEXT clinical trials. If appropriate for the study, the DCC may request funding for a DCC Medical Reviewer (MR) to participate in AE/SAE coding. The DCC staff will assist the DCC MR by providing initial MedDRA code(s) for each AE/SAE report prior to review of the report and coding by the DCC MR. As required by the study protocol, the DCC MRs may be responsible for assigning the final MedDRA code(s) to each AE/SAE. 4. APPLICABLE REGULATIONS AND GUIDELINES ICH E6 Good Clinical Practice: Consolidated Guidance, April REFERENCES TO OTHER APPLICABLE SOPS NN RA 205 NN RA 206 Adverse Event Reporting Medical Monitoring and Safety Monitoring 6. ATTACHMENTS AND REFERENCES NN DM A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: AE Refers to an Adverse Event. As defined by the NINDS Glossary of Clinical Research Terms, an AE is any unfavorable and unintended diagnosis, symptom, sign (including an abnormal NN DM 1006 Page 2 of 6

37 laboratory finding), syndrome or disease which either occurs during the study, having been absent at baseline, or if present at baseline, appears to worsen. CCC CSS DCC DSMB DSMC LLT MedDRA MR NINDS PPI PT SAE SOC Clinical Coordinating Center at Massachusetts General Hospital Clinical Study Site(s) Data Coordinating Center at The University of Iowa Data and Safety Monitoring Board Data and Safety Monitoring Committee Lowest Level Term, as described in the MedDRA handbook Medical Dictionary for Regulatory Activities Medical Reviewer for Adverse and Serious Adverse Events at the DCC National Institute of Neurological Disorders and Stroke Protocol Principal Investigator Preferred Term, as described in the MedDRA handbook Refers to a Serious Adverse Event. As defined by the NINDS Glossary of Clinical Research Terms, an SAE is any untoward medical occurrence that: Results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, or Is a congenital anomaly/birth defect. System/Organ Class, as described in the MedDRA handbook 8. SPECIFIC PROCEDURES A. MedDRA Coding of Adverse and Serious Adverse Events # Who Task Attachment/ 1. DCC Lead Coordinator 2. DCC MedDRA Coding Personnel Assign NeuroNEXT DCC staff members who have completed at least one MedDRA training course to perform MedDRA coding. Review the submitted AE/SAE and contact the site investigator if the adverse event term does not appear to accurately reflect the event. NN DM 1006 Page 3 of 6

38 # Who Task Attachment/ 3. Each DCC MedDRA Coding Staff Member 4. DCC MedDRA Coding Personnel 5. DCC MedDRA Coding Personnel 6. DCC MedDRA Coding Personnel On a regular basis (as determined by the DCC Lead Coordinator), independently perform MedDRA coding to the Lowest Level Term (LLT) for all adverse and serious adverse events that have been submitted to the DCC through the electronic data capture system. Coding may be performed by one or two coders. If two coders, assign codes without consulting the other coder. If two coders are assigned, meet regularly (as determined by the DCC Lead Coordinator) to review and compare independent coding results to identify consistencies and discrepancies in coding. If a discrepancy is found, discuss the event and arrive at agreement about the coding. If applicable to the protocol, present both code opinions to the DCC Medical Reviewer (MR) for final coding. B. Consulting with a Medical Reviewer # Who Task Attachment/ 1. DCC MedDRA Coding Personnel If a DCC Medical Reviewer (MR) will be involved in the coding, meet with the DCC MR on a regular basis (as determined by the DCC Lead Coordinator) to review all AE and SAE reports and coding. 2. DCC MR Review the submitted AE/SAE and contact the site investigator if the adverse event term does not appear to accurately reflect the event. 3. DCC MR At the start of a new study, review all AE codes that have been provided by the DCC MedDRA Coding Personnel, and accept or reject the codes. Discuss coding discrepancies with the DCC MedDRA Coding Personnel. 4. DCC MR and DCC MedDRA Coding Personnel 5. DCC MedDRA Coding Personnel Collaborate to develop and agree upon conventions for reviewing and coding AEs. After conventions for coding AEs have been agreed upon with the DCC MR, it is only necessary to consult with the DCC MR for AEs that have discrepancies in coding opinions, if questions arise, or if new terms are proposed. 6. DCC MR Throughout the course of the entire study, review all codes for SAEs provided by the DCC MedDRA Coding personnel, and accept or reject the codes. NN DM 1006 Page 4 of 6

39 # Who Task Attachment/ 7. DCC MR or DCC MedDRA Coding Personnel Enter final MedDRA codes for all SAEs and for any AEs with discrepancies in coding or that contain new terms into the electronic data entry system for MedDRA coding. C. Adverse and Serious Adverse Event Tracking Reports # Who Task Attachment/ 1. DCC MedDRA Coding Personnel 2. DCC Biostatistician 3. DCC Lead Coordinator Work with DCC Biostatisticians to develop reports to track adverse and serious adverse events. Prior to meetings of study safety oversight committees (e.g. Independent Medical Monitor, DSMC, DSMB,), create reports of all AEs and SAEs that have been submitted by Clinical Study Sites (CSSs) through the electronic data capture system. Reports should include the MedDRA System Organ Class (SOC) and Preferred Term (PT) assigned by the DCC MedDRA Coding personnel and/or the DCC MR. Submit AE and SAE reports (blinded and unblinded) to the study safety oversight committees. NN DM 1006 Page 5 of 6

40 Attachment NN DM A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Adverse Event Coding SOP NN DM 1006 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 06Apr May Modified the Policy section to remove the phrase current version of the in reference to the use of the Medical Dictionary for Regulatory Activities (MedDRA) for AE/SAE coding. Update for version Sep Oct2016 NN DM 1006 Page 6 of 6

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