NN SS 401 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR SITE SELECTION AND QUALIFICATION

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2 NN SS 401 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR SITE SELECTION AND QUALIFICATION SOP: NN SS 401 Version No.: 2.0 Effective Date: 21Oct2016 SITE SELECTION AND QUALIFICATION Supercedes Document: Version 1.0 Effective Date : 06May POLICY The NeuroNEXT Executive Committee (NEC) will select Clinical Study Sites (CSS) for participation in each Network study, based on the following criteria: Scientific expertise in the disease indication Projections of patient availability Geographic distribution History of productivity (when available) Site capacity For the purposes of site selection, the 25 funded NeuroNEXT Clinical Study Sites (CSS) are each considered as a single unit. NeuroNEXT CSS that do not have a fully-executed Master Clinical Trial Agreement (MCTA) and Central Institutional Review Board (CIRB) Reliance Agreement (RA) on file at the Clinical Coordinating Center (CCC) will not be considered for participation in a NeuroNEXT study until such agreements are executed. If a NeuroNEXT CSS previously indicated interest for two studies and was not selected for either, that CSS will automatically be placed on the list of initial sites for the third study for which they indicate interest. The Protocol Principal Investigator (PPI) may request the addition of non-neuronext CSS for participation to ensure adequate recruitment. If the NEC determines that there is a need for additional non-network CSS, the NEC may make this recommendation to the NINDS. The addition of non-neuronext CSS is dependent upon NINDS approval. Any Non-NeuroNEXT CSS under consideration will be required to: confirm their interest in participating in the study; confirm the willingness of their Institution to sign a MCTA and CIRB RA with the CCC; and cede review for the study to the NeuroNEXT CIRB. Each CSS selected to participate in a study will be qualified by the NeuroNEXT Data Coordinating Center (DCC) study monitor and/or Clinical Coordinating Center staff (CCC), unless prior qualification of the CSS is deemed to be sufficient. A qualification telephone screening process and/or pre-study site visit will be used to review the appropriateness of the investigator, his/her staff, facility and resources, and to gauge the understanding of NeuroNEXT policies and applicable regulatory requirements by the investigator and his/her key research staff. 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 Upon receipt of funding, the NEC is responsible for selecting CSS and communicating its final decision to all interested CSS. NN SS 401 Page 2 of 5

3 The NEC is responsible for determining if there is a need for participation of additional non-neuronext CSS in a Network study, and if so, recommending those CSS to NINDS for approval according to the criteria described the Policy section of this SOP. NINDS is responsible for reviewing and approving/disapproving the addition of any non-neuronext CSS. Prior to their consideration as a CSS, each CSS is responsible for: completing a study-specific questionnaire, confirming their interest in participating in the study, and confirming the willingness of their Institution to cede review for the study to the NeuroNEXT CIRB. After site selection by the NEC, the DCC/CCC is responsible for conducting assessments of each CSS to determine if the investigator is appropriate and if the site is adequately prepared to conduct the study. 4. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR General Responsibilities of Sponsors 21 CFR Selecting Investigators and Monitors 21 CFR Disqualification of a Clinical Investigator ICH E6, 2.7 ICH E6, 5.1 ICH E6, 5.6 ICH E6, 5.7 FDA FDA The Principles of ICH GCP Quality Assurance and Quality Control Investigator Selection Allocation of Responsibilities Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: FDA Inspections of Clinical Investigators (June 2010) Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Clinical Investigator Administrative Actions Disqualification (May 2010) 5. REFERENCES TO OTHER APPLICABLE SOPS NN GA 104 NN GA 106 NN GA 107 NN GA 109 NN SM 601 NN SM 602 Conflict of Interest and Financial Disclosure Requirements for Clinical Study Sites Publication Policy Development Data Sharing 6. ATTACHMENTS AND REFERENCES NN SS 401 A Sharing Data with Industry Collaborators Central Institutional Review Board (CIRB) Reliance Process Central Institutional Review Board Reporting Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: CCC CIRB CSS DCC FDA ICH Clinical Coordinating Center at Massachusetts General Hospital Central Institutional Review Board Clinical Study Site(s) Data Coordinating Center at The University of Iowa U.S. Food and Drug Administration International Council for Harmonisation NN SS 401 Page 3 of 5

4 MCTA NEC PPI RA Master Clinical Trial Agreement NeuroNEXT Executive Committee Protocol Principal Investigator Reliance Agreement 8. SPECIFIC PROCEDURES A. Site Selection # Who Task Attachment / References 1. CSS Prior to site selection, the CSS must confirm its interest in participation and willingness to cede review of the study to the CIRB. 2. CSS Must have executed MCTA and RA on file at CCC prior to consideration for site selection. Related SOP NN SM 601 NN SM 602 NN GA 104 NN GA 106 NN GA 107 NN GA 109 NN SM 601 NN SM NEC Select sites for each Network study based on criteria stated in the Policy section of this SOP, and communicate final site selection to all interested CSS. B. Site Qualification # Who Task Attachment / References 1 DCC/CCC Perform site qualification visit (remotely or in person) prior to site participation in each study. Related SOP 2 DCC/CCC Ensure that the investigator and his/her staff understand and accept: the roles and obligations as defined in the study contract and protocol; applicable regulatory requirements; and their responsibilities to the NeuroNEXT CIRB. 3 DCC/CCC Assess and verify that the investigator: meets experience and eligibility requirements; has sufficient time to complete the study; has support staff with the necessary training, experience, and credentials; and has facilities that are suitable to conduct the study. NN SS 401 Page 4 of 5

5 Attachment NN SS A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Site Selection and Qualification SOP NN SS 401 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 06Apr May Clarified that the CCC participates in assessment and qualification of CSS. Minor edits and formatting corrections. Updates for version Sep Oct2016 NN SS 401 Page 5 of 5

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7 NN SS 402 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR SITE INITIATION VISITS AND SITE TRAINING SOP: NN SS 402 Version No: 2.0 Effective Date: 21Oct2016 SITE INITIATION VISITS AND SITE TRAINING Supercedes Document: Version 1.0 Effective Date: 06May POLICY The activities associated with the Initiation Visit for a NeuroNEXT Network study may be conducted at a kick-off meeting, during a visit by Clinical Coordinating Center (CCC) and/or Data Coordinating Center (DCC) personnel to the Clinical Study Site (CSS), and/or via teleconference or webconferencing. During the Initiation Visit, the objectives and the methodology of the clinical study are reviewed with the site investigator and staff, and appropriate training of the site s research team is conducted in compliance with International Conference on Harmonisation/Good Clinical Practice guidelines. The objectives of the Initiation Visit are to: verify that the site has completed study preparation procedures; verify that all regulatory documents are in place; verify that the site is eligible to receive the investigational product, if applicable; review the protocol, case report forms (CRFs) and other worksheets; review all regulatory requirements; provide the plan for study monitoring; provide the site with Study Team contact information; confirm the PPI/Sponsor s expectations for the conduct of the study. An initiation visit checklist that summarizes all the topics that must be reviewed with the investigator and his/her staff may be developed to assist during the Initiation Visit. Before subjects may be enrolled in a study, all Investigators, Coordinators, and other study staff members (where necessary) must participate in training regarding the conduct of the trial. The CSS will be made aware of any training and certifications that must be completed before personnel will be permitted to enroll subjects. If a CSS adds a new staff member at any time during the trial, the new staff member will be trained regarding the conduct of the trial, and will be required to complete all necessary training and certifications required for the trial, prior to that person s direct involvement in the trial. 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, or other entities associated with the NeuroNEXT Network who manage, oversee, and conduct research regulated by FDA and/or applicable review committees. NN SS 402 Page 2 of 7

8 3. ROLES AND RESPONSIBILITIES The NeuroNEXT CCC and DCC are responsible for the following activities: Ensuring that all participating investigators understand and accept the obligations incurred in undertaking a clinical study Training the investigator and all other key site personnel in the use of the investigational product, if applicable, and the conduct of the clinical protocol Conducting the Initiation Visit and site training at the large-group Investigators Meeting, at clinical site(s), or via teleconference/webinar. The CCC is responsible for providing the DCC with information about the site s study preparation, training activities and regulatory documents. The responsibility to conduct any or all of these activities may be delegated at the discretion of the PPI/Sponsor to the NeuroNEXT CCC or DCC or to subcontractors of either. Those individuals and entities also take on responsibility for meeting regulatory requirements on behalf of the PPI/Sponsor, but the PPI/Sponsor has the ultimate responsibility and must therefore supervise those delegated activities effectively. 4. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR Responsibilities of Sponsors ICH E6, 2.0 ICH E6, 4.5 ICH E6, 5.3 ICH E6, 5.5 ICH E6, 5.7 ICH E6, 5.8 ICH E6, 5.15 ICH E6, 5.23 The Principles of ICH GCP Compliance with Protocol Medical Expertise Trial Management, Data Handling and Record Keeping Allocation of Responsibilities Compensation to Subjects and Investigators Record Access Multicenter Trials FDA Guideline The Monitoring of Clinical Investigations (January 1988) 5. REFERENCES TO OTHER APPLICABLE SOPS NN RA 203 NN PM 504 NN PM 505 NN SM 602 NN DM 1005 Site Regulatory File Maintenance Investigational Site Staff Training Investigational Product Management Central Institutional Review Board Reporting Responsibilities Data Collection and Data Handling 6. ATTACHMENTS AND REFERENCES NN SS 402 A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: CCC CIRB CRF Clinical Coordinating Center at Massachusetts General Hospital Central Institutional Review Board Case Report Form NN SS 402 Page 3 of 7

9 CSS DCC FDA GCP ICH PPI Clinical Study Site Data Coordinating Center at The University of Iowa U.S. Food and Drug Administration Good Clinical Practices International Council for Harmonisation Protocol Principal Investigator 8. SPECIFIC PROCEDURES A. Initiation Visit Preparation # Who Task Attachment/ Reference Related SOP 1. DCC Lead Coordinator In collaboration with the CCC, schedule an Initiation Visit, allowing sufficient time for all activities, depending on the protocol. Review purpose of visit if necessary. NN PM DCC Lead Coordinator In collaboration with the CCC, confirm the status of the study regarding CIRB review and approval, status of other regulatory reviews, and if applicable, FDA status. NN SM CCC Project Manager, DCC Lead Coordinator, Prior to the visit, prepare by reviewing the protocol, CRFs and any other relevant documents. If needed, prepare slide presentations. B. Investigative Site Training # Who Task Attachment/ Reference Related SOP 1. CSS Personnel Participate in training regarding the conduct of the trial, and complete any required certifications before enrolling any study subjects. 2. CCC Project Manager and DCC Lead Coordinator During the Site Initiation Visit meeting, ascertain the investigator s understanding of all elements of trial conduct through discussions and questions. 3. CCC Project Manager and DCC Lead Coordinator Review the required elements of the investigator s study file and the importance of maintaining accurate and up-to-date records NN RA CCC Project Manager and DCC Lead Coordinator CCC Project Manager and DCC Lead Coordinator CCC Project Manager Confirm existence of all applicable and required NN RA 203 documentation in the investigator s study file. 1 Review the clinical protocol, informed consent form and CRFs. Review procedures for obtaining and documenting informed consent, including required signatures and disposition of copies. NN SS 402 Page 4 of 7

10 # Who Task Attachment/ Reference Related SOP 7. CCC Project Manager and DCC Lead Coordinator Reinforce the need for strict adherence to the protocol. 8. DCC Lead Coordinator, Review instructions for completion of CRFs, including corrections and queries. Emphasize the need for timely and accurate completion of CRFs. NN DM DCC Lead Coordinator, Review the use of relevant logs and forms with all site personnel. 10. CCC Project Manager and DCC Lead Coordinator, If applicable, instruct relevant site personnel (including research pharmacist) on the pharmacologic aspects of the investigational product. NN PM CCC Project Manager, DCC Lead Coordinator, If applicable, review investigational product allocation and randomization, as defined in the protocol. NN PM CCC Project Manager, DCC Lead Coordinator, If applicable, review procedures for product accountability, storage, dispensing, reconciliation, as well as discrepancy investigation requirements and inventory recordkeeping. 13. CCC Project Manager, DCC Lead Coordinator, If applicable, verify receipt and records pertaining to investigational product already on site. NN PM DCC Lead Coordinator and DCC Monitor If applicable, confirm physical requirements (e.g., product inventory and storage, document and record storage). NN PM CCC Project Manager, DCC Lead Coordinator, Review protocol requirements regarding the recognition, handling, recording and reporting of adverse events, including regulations and reporting timeframes. NN SM CCC Project Manager, DCC Lead Coordinator, Review laboratory assessments and reporting procedures (with laboratory personnel if appropriate). Specifically address unusual or critical requirements. 17. CCC Project Manager and DCC Lead Coordinator Confirm that enrollment of the first subject may not occur until all Initiation Visit procedures and regulatory requirements have been completed. Note: 1 For example, protocol and Investigator Statement, CIRB-approved informed consent form, CIRB approval letter, CIRB member roster and other regulatory authority approvals. NN SS 402 Page 5 of 7

11 C. Documenting the Initiation Visit # Who Task Attachment/ Reference Related SOP 1. CCC Project Manager, DCC Lead Coordinator, Record date(s) of visit(s) by monitors and other s on a site visit log. 2. DCC Lead Coordinator, Complete an Initiation Visit Checklist during the visit, if applicable. 3. DCC Lead Coordinator, Review the completed checklist (if applicable) or other documentation of the Initiation Visit with the Sponsor, if applicable. 4. DCC Lead Coordinator, File the checklist or other documentation of the Initiation Visit in the appropriate section of the Regulatory Master File. NN RA DCC Lead Coordinator, Send a post-visit letter summarizing the visit and listing pending items. NN SS 402 Page 6 of 7

12 Attachment NN SS A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Site Initiation Visits and Site Training SOP NN SS 402 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 06Apr May Added language to indicate that the Initiation Visit and site training could be conducted at the large-group Investigators Meeting. Modified assignments in the Specific Procedures section. Other minor edits. Updates for version Sep Oct2016 NN SS 402 Page 7 of 7

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14 NN SS 403 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR ROUTINE MONITORING VISITS SOP: NN SS 403 Version No: 2.0 Effective Date: 21Oct2016 ROUTINE MONITORING VISITS Supercedes Document: Version 1.0 Effective Date: 06May POLICY This SOP describes procedures regarding scheduling, frequency, preparing for, and conducting a routine monitoring site visit for NeuroNEXT clinical trials. Routine monitoring visits to Clinical Study Sites (CSS) will be scheduled according to the requirements of the approved study monitoring plan. Guidelines for scheduling monitoring visits for each NeuroNEXT CSS will be determined by the NeuroNEXT Data Coordinating Center (DCC) in consultation with the Clinical Coordinating Center (CCC) and according to the stage of development and complexity of the studies at the CSS, the rates of subject accrual, and other factors. These visits are conducted for routine monitoring only and are intended to ensure that the protocols and applicable regulatory requirements are being followed, that subjects rights and safety are being protected, and to confirm data integrity and quality. The objectives of routine monitoring visits are to: document and report on clinical study progress; document that the protocols and associated forms are current; update the site team of any changes in study conduct/documentation; ensure that the PPI/Sponsor requirements and investigator obligations are met; ensure continued acceptability of the investigator, site team and facility; obtain and review current clinical data, reports, and source documents; ensure adequate investigational product inventory and accountability, if applicable. Activities conducted during the preparation for a monitoring visit include reviews of study documents, data queries, data reports, previous monitoring reports, and supplies of study materials (if applicable). During the monitoring visit, the monitor performs the following activities: assesses the overall status of the study, staff, and facilities to determine whether the study is being conducted per protocol and in compliance with regulatory requirements; conducts a CRF review that includes checks of all adverse event documentation; verifies the presence of all essential documents and records related to investigational products and clinical supplies (if applicable); and determines if protocol violations have occurred and, if so, are documented properly. After the monitoring visit, the monitor documents the results of the monitoring visits and completes a post-visit monitoring letter for each study that conveys any issues discovered during the visit and the need for data corrections, if appropriate. 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 NN SS 403 Page 2 of 8

15 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 designating a trained and qualified member of the research team to serve as study Monitor. The is responsible for preparing for, conducting, and documenting all monitoring visits. The responsibility to conduct any or all of these activities will be delegated at the discretion of the Sponsor/PPI 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 21 CFR Selecting Investigators and Monitors 21 CFR Review of Ongoing Investigations ICH E6, 4.1 ICH E6, 5.5 ICH E6, 5.18 FDA Investigator s Qualifications and Agreement Trial Management, Data Handling and Record Keeping Monitoring Guidance for Industry: Oversight of Clinical Investigations A Risk-Based Approach to Monitoring (August 2013) 5. REFERENCES TO OTHER APPLICABLE SOPS NN RA 202 NN RA 203 NN SS 402 NN SS 404 NN PM 501 NN PM 504 NN PM 505 NN SM 602 NN SM 603 NN DM 1001 Trial Master File Maintenance Site Regulatory File Maintenance Site Initiation Visits and Site Training Site Performance Monitoring Communication Investigational Site Staff Training Investigational Product Management Central Institutional Review Board Reporting Subject Eligibility and Enrollment Clinical Data Management 6. ATTACHMENTS AND REFERENCES NN SS A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: AE CCC CIRB CRF CSS DCC Adverse Events Clinical Coordinating Center at Massachusetts General Hospital Central Institutional Review Board Case Report Forms that are completed for each study subject at the sites Clinical Study Site(s) Data Coordinating Center at The University of Iowa NN SS 403 Page 3 of 8

16 FDA ICH PPI RMF U.S. Food and Drug Administration International Council for Harmonisation Protocol Principal Investigator Regulatory Master File 8. SPECIFIC PROCEDURES A. Scheduling/Frequency of Monitoring Visits # Who Task Attachment/ Reference Related SOP 1. DCC Lead Coordinator, Develop a monitoring plan that includes conducting a minimum of one monitoring visit at each CSS with an ongoing protocol per year. 2. Review study reports to determine when to schedule CSS visits according to the monitoring plan. 3. Conduct unscheduled or more frequent monitoring visits to CSS as needed. 4. Contact the investigator or and study coordinator regarding scheduling and conducting monitoring visits. NN PM Confirm date and logistics of the monitoring visit in writing and provide the investigator with a list of source documents and records (e.g., medical records, laboratory records, etc.) to be reviewed. NN PM Create a monitoring report to track CSS visits. B. Preparing for a Monitoring Visit # Who Task Attachment/ Reference Related SOP 1. or CCC Project Manager Review the relevant contents of the project and site files in the study RMFs, if applicable, prior to the monitoring visit. NN RA Review the current version of the clinical protocols and informed consent forms prior to the monitoring visit, if applicable. 3. Review the data reports and data queries for any data received to date for each study. 4. Review previous monitoring reports for any outstanding items that must be addressed prior to, or during, the next scheduled visit. 5. Determine the CSS inventory of study supplies, including forms or other relevant materials and investigational products (if applicable). Arrange to provide additional items as necessary. NN SS 403 Page 4 of 8

17 C. Conducting a Monitoring Visit 1. Overall Study Status # Who Task Attachment/ Reference 1. Verify that the CSS subject files for the study contain all required documents and records, and that they are accurate, complete, and current. Related SOP NN RA If requested by the CCC, confirm with the investigator that the CSS routinely files and forwards essential and required information to other required parties (e.g. CIRB) appropriately. RA 203-B NN SM DCC Lead Coordinator and DCC Monitor Assess subject enrollment rates and examine unexpectedly high or low recruitment. NN SM Review study screening and enrollment logs for information on subjects who failed to meet inclusion criteria, did not give informed consent, or withdrew from the study for any reason. NN SM Confirm eligibility of enrolled subjects. 6. Confirm that all subjects have signed the correct version(s) of the informed consent form. 7. Evaluate status of follow-up plans and visits for subjects and identify problems. 8. Confirm that safety and efficacy assessments are conducted per the study protocols. 9. Verify that all specimens for protocol-specific laboratory studies are being stored and forwarded properly and that specimen preparation documentation is maintained. NN PM Meet with investigator and key staff to discuss any scientific or administrative problems and possible solutions. 2. CRF Review # Who Task Attachment/ Reference 1. Verify that CRFs¹ are being completed in a timely manner and per protocol requirements. Related SOP NN DM Review the CRFs scheduled for review (as outlined in the monitoring plan) to ensure that they are complete, legible, consistent with protocol specifications, and signed by the appropriate site personnel. 3. For randomized studies, verify that the randomization procedures are being carried out per the study protocols. 4. Evaluate allocation of investigational products, if applicable. NN PM 505 NN SS 403 Page 5 of 8

18 # Who Task Attachment/ Reference Related SOP 5. Check data in the CRFs scheduled for review against source documents to assess accuracy and completeness of the information. 6. Review and address omissions and queries, and ensure that corrections to the CRFs are properly completed prior to departure. 7. Tabulate changes and corrections for updating the study databases. 8. Assess whether all adverse events (AEs) have been documented and reported as specified by the protocols, and that other relevant regulatory procedures have been followed. NN SM 602 Note: ¹ CRF(s) can be paper or electronic. 3. Investigational Products and Other Clinical Supplies (if applicable) # Who Task Attachment Related SOP Staff and Facilities Verify storage of investigational products and other clinical supplies. Assess investigational product dispensing and accountability records. Examine storage freezers and other storage equipment to confirm they are appropriate for the clinical protocol s requirements, and that calibration and temperature logs are maintained in the CSS study files. NN PM 505 NN PM 505 NN PM 505 # Who Task Attachment Related SOP Communications Records Confirm each study investigator s control of the study and assess his/her ongoing participation and any responsibility delegations not previously reported. Assess the ongoing suitability of facilities and staff for conducting the study. Note and record any changes in staff or facility not previously reported. If applicable, discuss scheduling additional study training for new staff. NN SS 402 NN PM 504 # Who Task Attachment Related SOP 1. Confirm that copies of all critical correspondence (electronic, paper), including facsimile correspondence and notes of telephone conversations, are maintained on file at the CSS. NN RA 203 NN SS 403 Page 6 of 8

19 6. Protocol Violations # Who Task Attachment Related SOP Note whether the records show any evidence that protocol violations have occurred, and record the nature of these violations. For each study, review any issues related to study conduct or other incidents of noncompliance with the investigator and other key study personnel, and document the issues on the monitoring report. If needed, an ongoing process of counseling, reeducation and re-training shall be undertaken by the appropriate Study staff to ensure trial CSS compliance. 7. Documenting Results of Monitoring Visits NN SS 404 # Who Task Attachment Related SOP DCC Document all visits by monitors and other authorized parties on a Site Visit Log. Document the outcome of all scheduled and unscheduled monitoring visits. Complete a post visit monitoring letter for each study. The letter may include and address the following, if applicable: Protocol Compliance Subject enrollment and study timelines Review of regulatory documents and findings Review of subject files and source documents Investigational product accountability Data corrections Pending issues and action items Provide the CCC with copies of the completed Monitoring Visit Checklists, Reports, and the CSS post-visit monitoring letters for review. Provide the CSS Study PI and Study Coordinator with the post-visit monitoring letter(s). Instruct site to place the post-visit monitoring letter(s) in the study Regulatory binder. File the completed reports and letters in the appropriate site files in the RMF. NN SS 402 NN RA 203 NN SS 403 Page 7 of 8

20 Attachment NN SS A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Routine Monitoring Visits SOP NN SS 403 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 06Apr May Clarified that scheduling for monitoring visits is according to the study monitoring plan. Added CCC Project Manager responsibilities for reviewing study RMF files, and removed responsibility for DCC Monitor to reconcile the CSS study files with the RMF. Deleted obsolete FDA Guidance for monitoring, and added 2013 FDA Guidance on risk-based monitoring. Several other minor administrative edits. Updates for version Sep Oct2016 NN SS 403 Page 8 of 8

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27 NN SS 405 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR STUDY CLOSEOUT VISITS SOP: NN SS 405 Version No: 2.0 Effective Date: 21Oct2016 STUDY CLOSEOUT VISITS Supercedes Document: Version 1.0 Effective Date: 06May POLICY The study closeout visit is intended to bring the study to a close at a NeuroNEXT clinical study site (CSS). The closeout visit is conducted according to the study monitoring plan and is scheduled after all obtainable visits for study subjects at the CSS have been completed and all data have been entered. The term study closeout visit applies to all types of study closeout visits (on-site, regulatory only, remote) and all activities (pre-visit, during the visit, and post-visit) that are conducted by the NeuroNEXT Data Coordinating Center (DCC) and/or the Clinical Coordinating Center (CCC) until the study has been closed out at a CSS and with the Central Institutional Review Board (CIRB) and local site IRBs, as applicable. Closeout visit activities that are conducted by the CCC and/or the DCC include, but are not limited to: reviewing the contents of the Trial Master File, the Site Regulatory Binder, and CSS study files; verifying that required regulatory documents and study records are on file, organized, and stored in a secure location; verifying that all protocol deviations have been resolved and corrective actions have been implemented; reviewing regulatory requirements regarding records retention and CIRB reporting requirements with the investigator; reviewing remaining un-monitored clinical data and resolving remaining data issues (e.g. data queries); confirming the disposition of the investigational product/device, if applicable, and any other ancillary items used for the study; confirming that all subject laboratory specimens have been forwarded to the appropriate location; generating final closeout visit reports, following up on all observations until they are resolved, and transmitting copies of the completed reports to the CSS, the CCC or DCC (as applicable), and the PPI/Sponsor; verifying that all monitoring requirements set forth in the study monitoring plan have been completed; determining, at the request of the PPI/Sponsor, that the investigator s obligations have been met and that all applicable study and regulatory requirements have been fulfilled. If a CSS did not enroll any subjects, the CCC may conduct a remote closeout of regulatory documents via , teleconference or video conference. Depending on the study, a remote closeout of sites with limited enrollment or no unmonitored data since the last monitoring visit may be conducted by the DCC. NN SS 405 Page 2 of 10

28 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 NeuroNEXT DCC and the CCC are responsible for conducting closeout visit activities with participating CSS according to the study monitoring plan. Closeout activities may take place after the last subject at a CSS has completed the study and all data entry has been completed. The responsibility to conduct any or all of these activities may be delegated at the discretion of the Sponsor to the DCC, the CCC, or to subcontractors (if 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 21 CFR Review of Ongoing Investigations 21 CFR Disposition of Unused Supply of Investigational Drug 21 CFR General Responsibilities of Investigators 21 CFR Investigator Recordkeeping and Record Retention 21 CFR Investigator Reports 21 CFR Inspection of Investigator's Records and Reports ICH E6, 4.12 ICH E6, 4.13 ICH E6, 5.18 ICH E6, 5.20 ICH E6, 5.21 ICH E6, 5.22 Premature Termination of a Trial Final Reports by Investigator Monitoring Noncompliance Premature Termination of a Trial Clinical Trial/Study Reports 5. REFERENCES TO OTHER APPLICABLE SOPS NN GA 104 NN GA 107 NN GA 109 NN RA 201 NN RA 202 NN RA 203 NN RA 205 NN RA 206 NN SS 401 NN SS 402 NN SS 403 Conflict of Interest and Financial Disclosure Requirements for Clinical Study Sites Data Sharing Sharing Data with Industry Collaborators Regulatory Authority Submissions and FDA Contact Trial Master File Maintenance Site Regulatory File Maintenance Adverse Events: Sponsor Responsibilities Medical Monitoring and Safety Monitoring Site Selection and Qualification Site Initiation Visits and Site Training Routine Monitoring Visits NN SS 405 Page 3 of 10

29 NN SS 404 NN SS 406 NN PM 501 NN PM 505 NN PM 507 NN SM 602 NN SM 603 NN CS 706 NN DM 1001 NN DM 1005 Site Performance Monitoring Suspension or Early Termination of a Study or a Clinical Site Communication Investigational Product Management Study Closeout Central Institutional Review Board Reporting Subject Eligibility and Enrollment Retention and Protection of Electronic Records Clinical Data Management Data Collection and Data Handling 6. ATTACHMENTS AND REFERENCES NN SS A Document History 7. TERMS AND ABBREVIATIONS The following terms and abbreviations are used in this document: AE CCC CIRB CRF CSS CSS PI DCC FDA ICH IRB PPI PSC RMF 8. SPECIFIC PROCEDURES Adverse Events Clinical Coordinating Center at Massachusetts General Hospital Central Institutional Review Board Case Report Forms that are completed for each study subject at the sites Clinical Study Site Clinical Study Site Principal Investigator Data Coordinating Center at The University of Iowa U.S. Food and Drug Administration International Council for Harmonisation Institutional Review Board Protocol Principal Investigator Protocol Steering Committee Regulatory Master File Additional acronyms used in this section: BIO DCC Biostatistics team; DM DCC Data Management team; IT DCC Information Technology team; PC DCC Protocol Coordination team; PM CCC Project Management team. A. Preparing for Study Closeout Visits # Who Task Attachment Related SOP 1. Study Team Develop a closeout visit plan that includes steps necessary to complete study closure at all participating CSS, including a timeline. NN SS 405 Page 4 of 10

30 # Who Task Attachment Related SOP 2. DCC PC 3. CCC PM, DCC PC, and PPI/Sponsor 4. CCC PM and/or DCC PC, or 5. DCC PC, DM, or BIO 6. DCC PC, CCC PM and PPI/Sponsor 7. DCC PC or 8. DCC PC, DM, BIO; CCC PM 9. DCC PC or 10. DCC PC or Verify that all subject visits and follow-up visits at the CSS are complete. Determine whether an onsite or remote closeout of regulatory documents will be conducted at a CSS. Review the relevant contents of the project and site files in the RMF, if applicable, prior to the closeout visit or teleconference/video conference. Note that for sites that did not enroll any subjects, closeout activities may be conducted via without teleconference/video conference. Generate a final report of all regulatory documents that have been uploaded to the study website and provide the report to the CCC PM for reconciliation. Determine whether an onsite or remote closeout of site files and study data will be conducted at a CSS. Review closeout visit monitoring requirements in the study monitoring plan. Determine reports/data listings that are needed for the closeout visit. Review previous monitoring reports to assess the scope of study documentation that must be available for review. If applicable, review data report and data queries for unmonitored data that are expected per the study monitoring plan since the time of the last monitoring visit. NN SS 403 NN SS 403 NN SS 403 NN SS 403 NN SS 403 NN DM Study Team Review data completeness reports to track missing data and incomplete forms until all are accounted for. 12. DCC PC 13. DCC IT and PC or 14. DCC PC 15. CCC PM and/or DCC PC, or Verify that data entry for the site is complete. Track and verify that all Data Change Requests are complete. Verify that all outstanding AEs and SAEs have been resolved according to the requirements described in the safety monitoring plan for the study. Verify that all protocol deviations have been resolved and corrective action plans have been accepted by the PPI/Sponsor or (if applicable to a study). NN DM 1005 NN RA 206 NN SM 602 NN SS 405 Page 5 of 10

31 # Who Task Attachment Related SOP 16. DCC PC 17. DCC PC 18. DCC PC 19. DCC PC or 20. DCC PC 21. DCC PC Contact the CSS PI and the CSS Coordinator to arrange onsite or remote closeout visit(s) within a specified time period after the last subject s participation has concluded (if applicable). For remote closeout visits, provide instructions to the CSS for teleconferencing or video conferencing (if necessary). Confirm date and logistics of the closeout visit(s) with the CSS PI and the CSS Coordinator in writing. Inform the Study Team of the closeout visit date(s). Remote closeout will be considered for CSS with limited enrollment or with limited data to be reviewed. If closeout at a CSS is to be conducted remotely by central review, contact the site and request that copies of completed paper CRFs for all subjects be sent to the DCC for review according to the provisions in the study monitoring plan. Review the paper CRFs against data listings to ensure that data have been entered correctly, and that there are no missing data. NN PM 501 NN PM 501 NN PM 507 NN PM 507 B. Conducting a Study Closeout Visit (For specific procedures related to closeout of regulatory documents, see Section 8.C) # Who Task Attachment Related SOP 1. DCC PC 2. DCC PC 3. DCC PC 4. DCC PC 5. DCC PC If a CSS has unmonitored data, conduct applicable tasks listed in NN SS 403 Routine Monitoring Visits. Resolve any outstanding data corrections or issues with missing or incomplete CRFs. Review the site s source documentation to ensure that it is current and complete. If applicable, reconcile and collect all original investigational product accountability records. If applicable, make copies of all investigational product accountability records for the study files at the CSS. NN SS 403 NN PM 507 NN DM 1005 NN RA 203 NN PM 505 NN PM DCC PC Verify the disposition of the investigational NN PM 505 NN SS 405 Page 6 of 10

32 # Who Task Attachment Related SOP 7. CCC PM and/or DCC PC, or 8. DCC PC product/device. Verify the disposition of study equipment, laboratory kits, and other study supplies (as applicable). Verify that any laboratory specimens that remain at the CSS are handled or forwarded to the appropriate location according to the requirements of the study protocol and the informed consent document(s) signed by the study subjects. NN PM DCC PC Conduct a closeout visit meeting with the CSS PI, CSS Study Coordinator, and any other applicable personnel. 10. DCC PC 11. DCC PC 12. DCC PC 13. DCC PC 14. DCC PC Discuss with the investigator the requirements for maintaining clinical study documentation in a secure location after study completion for the period of time specified by FDA and/or the PPI/Sponsor. Verify that the Delegation of Responsibility log has been updated with an end date for all personnel who were involved with study activities that will no longer occur. Obtain contact information for an individual at the site who may be contacted with questions if necessary after study closeout. Verify that all monitoring requirements described in the study monitoring plan have been completed. Document the study closeout visit, and collect the final monitoring log. NN RA 202 NN RA 203 NN CS 706 NN DM 1005 NN RA 202 NN RA 203 NN PM 501 NN SS 403 NN SS 402 NN SS 403 C. Conducting a Regulatory Document Closeout Visit # Who Task Attachment Related SOP 1. CCC PM and/or DCC PC, or Review the contents of the Site Regulatory Binder with the CSS Coordinator and other CSS personnel, if applicable. 2. CCC PM and/or DCC PC, or Confirm the long-term storage location(s) for the regulatory documents with the CSS. NN RA CCC PM and/or DCC PC, or Verify that the Delegation of Responsibility log has been updated with an end date for all applicable personnel. NN RA 202 NN RA 203 NN SS 405 Page 7 of 10

33 # Who Task Attachment Related SOP 4. CCC PM and/or DCC PC, or 5. CCC PM and/or DCC PC, or Verify that the site has completed all required regulatory activities. Send a post-review report to the CSS PI, the CSS Coordinator, the PPI/Sponsor, and the DCC. The report details all required corrections to study regulatory documents and identifies any missing documents that must be obtained prior to study closeout. D. Post-visit Activities and Study Closeout Visit Report(s) # Who Task Attachment Related SOP DCC PC DCC PC DCC PC DCC PC DCC PC CCC PM and/or DCC PC, or CCC PM or CCC PM or CCC PM and CIRB Liaison 10. DCC PC Instruct the CSS to transmit any required regulatory documents that were identified at the closeout visit to the CCC (as needed). Complete study closeout report(s) for regulatory documents and site file/study data (as applicable), and transmit the report(s) to the CSS PI, the PPI/Sponsor, and the CCC or DCC (as applicable). These reports summarize findings from the monitoring visit(s) and include instructions for study records retention. If applicable, include a list of clinical site responsibilities and deliverables prior to study closeout. Follow up on any issues discovered during the study closeout visit(s) and detailed in the study closeout visit report(s) until all are resolved. Verify that all outstanding corrections to the site data have been implemented through a post-complete change or a Data Change Request to the DCC. Confirm that the CSS PI and/or the responsible leader of the Study Team at each CSS has reviewed and signed off on all study data that have been submitted for all subjects at the close of the study. Make the final determination that the investigator s obligations have been met and that all study and regulatory requirements have been fulfilled. Verify that all required regulatory documents have been submitted to the Health Authority. Verify that the clinical site has updated the Delegation of Responsibility log to reflect the official date of CIRB closure as the end date for all active study personnel, request a copy for the CCC, and file the copy with the site regulatory documents. Complete closeout procedures with the CIRB. Provide the study PPI/Sponsor with the final NN RA 202 NN RA 203 NN PM 501 NN SS 403 NN SS 403 NN PM 507 NN PM 507 NN DM 1005 NN GA 107 NN GA 109 NN DM 1005 NN SS 405 Page 8 of 10

34 # Who Task Attachment Related SOP monitoring visit report(s). 11. CCC PM or File the study closeout visit report(s) with the regulatory documents. 12. Study Team Review and follow procedures described in SOP NN PM 507 Study Closeout. NN PM 507 NN SS 405 Page 9 of 10

35 Attachment NN SS A. Document History NeuroNEXT Network Standard Operating Procedure (SOP) Study Closeout Visits SOP NN SS 405 Version Description of Modification Reason or Justification for Modification Issue Date Effective Date 1.0 New N/A 06Apr May This SOP was extensively revised, and material pertaining to suspension or early termination of a study or a clinical site was relocated to a new NeuroNEXT SOP. Study closeout visits include all types of visits and activities that are conducted by the CCC and DCC to close out the study. The specific procedures section was modified and expanded to reflect procedures that are conducted before, during, and following study closeout visits, and includes procedures for conducting closeout of regulatory documents. Updates for v2.0 21Sep Oct2016 NN SS 405 Page 10 of 10

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37 NN SS 406 NEURONEXT NETWORK STANDARD OPERATING PROCEDURE FOR SUSPENSION OR EARLY TERMINATION OF A STUDY OR A CLINICAL SITE SOP: NN SS 406 Version No: 1.0 Effective Date: 21Oct2016 SUSPENSION OR EARLY TERMINATION OF A STUDY OR A CLINICAL SITE Supercedes Document: N/A Effective Date: N/A 1. POLICY This SOP describes policies and procedures for the suspension or early termination of a study or a clinical study site (CSS) that may be necessary under scenarios that include, but are not limited to, the following: enrollment at a CSS has not met expectations, and the Data Coordinating Center (DCC) (in consultation with the Protocol Principal Investigator [PPI], the Clinical Coordinating Center [CCC], and/or the NeuroNEXT Protocol Steering Committee [PSC], as applicable) has determined that participation of the CSS in the study should be terminated; protocol violations have occurred that may result in study subjects being put at risk of serious injury or that render the study data untrustworthy or invalid; monitoring at the CSS has shown continuing or other unacceptable noncompliance (violations) with the protocol, and the DCC (in consultation with the PPI, the CCC, and the NeuroNEXT PSC) has determined that the CSS must be terminated from participation; unreasonable risks posed by the investigation (e.g., serious adverse events) that warrant study termination have become evident; by order of the Sponsor, FDA, the central Institutional Review Board (CIRB), the local IRB (if applicable), or upon recommendations from the NeuroNEXT Data and Safety Monitoring Board (DSMB); or by request of the CSS. For any early termination of study participation at a CSS, subject enrollment is discontinued at the terminated CSS, but enrolled study subjects will typically complete their specified follow-up visits, depending upon the reason(s) for termination. For cases in which termination is due to protocol violations that may result in study subjects being put at risk or that may render the study data untrustworthy or invalid, the CSS investigator must cease enrolling subjects immediately and report the termination of the study (and reasons) to the CIRB, the local IRB, and other appropriate regulatory authorities. A study closeout visit will be conducted at a terminated CSS according to procedures described in SOP NN SS 405 Study Closeout Visits. The closeout visit will not occur until all obtainable enrollment and follow-up visits for study subjects at the terminated CSS have been completed. Closeout of study data for that CSS will be implemented according to procedures described in SOP NN PM 507 Study Closeout. In the event that the entire study is terminated early based on recommendations from the NeuroNEXT DSMB or directives from the FDA, the CIRB, or the Sponsor, the procedures described in this SOP and study closeout procedures described in SOPs NN SS 405 and NN PM 507 will be implemented at all CSS. NN SS 406 Page 2 of 8

38 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 Study Team is responsible for following procedures described in this SOP, including: monitoring study enrollment at CSS, and identifying sites that are lagging in enrollment; ascertaining and implementing measures to improve enrollment at lagging CSS; determining if significant protocol violations are occurring that justify terminating participation of a CSS for serious or ongoing noncompliance; escalating any significant findings to the Site Performance Team in compliance with the NeuroNEXT Site Intervention and Escalation Plan; conducting study closeout visits per SOP NN SS 405 at a CSS that has been terminated from further participation in the study, or at all CSS if the study has been terminated early. 4. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR Review of Ongoing Investigations 21 CFR Disposition of Unused Supply of Investigational Drug 21 CFR General Responsibilities of Investigators 21 CFR Investigator Recordkeeping and Record Retention 21 CFR Investigator Reports 21 CFR Inspection of Investigator's Records and Reports ICH E6, 4.12 ICH E6, 4.13 ICH E6, 5.18 ICH E6, 5.20 ICH E6, 5.21 ICH E6, 5.22 Premature Termination of a Trial Final Reports by Investigator Monitoring Noncompliance Premature Termination of a Trial Clinical Trial/Study Reports 5. REFERENCES TO OTHER APPLICABLE SOPS NN GA 105 NN RA 201 NN RA 202 NN RA 203 NN RA 205 NN RA 206 NN SS 401 NN SS 402 NN SS 403 Vendor Selection and Agreements Regulatory Authority Submissions and FDA Contact Trial Master File Maintenance Site Regulatory File Maintenance Adverse Events: Sponsor Responsibilities Medical Monitoring and Safety Monitoring Site Selection and Qualification Site Initiation Visits and Site Training Routine Monitoring Visits NN SS 406 Page 3 of 8