RESCUE: ACRIN 4701 Protocol Development & Regulatory Compliance (PDRC)

1. RESCUE: ACRIN 4701Protocol Development & Regulatory Compliance (PDRC) Josephine Schloesser, ACRIN Monitor Chris Steward, ACRIN QC Auditor

2. PDRC Overview: • Regulatory Requirements • Adverse Events • Monitoring Program • Auditing Program • Image Review • Follow-up • Resources

3. Monitoring Process Monitoring process ensures the following: • The rights, safety and well-being of the human subjects are protected. • The reported trial data are accurate, complete and verifiable from source documents. • The conduct of the trial is in compliance with the currently approved protocol/amendments, with GCP and with applicable regulatory requirements.

4. Regulatory Requirements • Sites must have initial IRB approval for the protocol and site-specific informed consent form on file at ACRIN Headquarters prior to site activation. • International sites may use an Ethics Committee instead of an IRB • Other regulatory documents are may be required as the trial progresses, i.e. IRB annual IRB approval, amendment approvals • All documents faxed to ACRIN PDRC at 215 717-0936

5. IRB Approvals For Protocol, ICF & Amendments Annual reviews Revised ICFs Recruitment & retention materials Participant questionnaires Others as necessary Site Signature and Responsibilities Log Approved Medical Authorization Release Form ACRIN Statement of Investigator Regulatory Documents

6. Monitoring Program • Remote/off-site review by ACRIN Monitor(s) • Monitoring begins at the time of site qualification with review of site-specific regulatory documents and continues throughout the conduct of the trial • Frequency and timing depends on the rate of enrollment, site performance and protocol status • Review • Regulatory Documents / IRB Binder • Study-specific Processes • Participant Cases • Imaging Processes (with Image Management Center) • Adverse Events

7. Adverse Events • Monitoring for AEs is imperative • Proper documentation of protocol-specific AEs is mandatory • Assignment of grade and attribution is made by the Site Principal Investigator • Prompt reporting of AEs is the responsibility of the investigator and/or investigator-designee

8. Adverse Events • For trial purposes, only AEs considered possibly, probably or definitely related to study-related cardiac CTA will be collected; they must be managed, documented, and reported per protocol section 10.0 • AEs pertaining to standard-of-care practice should be reported and managed per your institution’s policies and procedures

9. Definition of AE Definition of Serious AE Grading Attribution Expected vs. Unexpected List of Expected AEs Recording of AEs When to Report How to Report Adverse Events Protocol Section 10.0

10. Adverse Events For additional information on AEs - • ACRIN website - Under the Regulatory Resources Tab the ACRIN AE Manual and other useful links can be found • ACRIN AE Coordinator – Cornelia (Lia) Worley cworley@acr.org 215 574-3236

11. Audit Program • On-site visits by ACRIN Auditor(s) • Review • Regulatory Documents / IRB Binder • Study-specific Processes • Participant Cases • Imaging Processes (with Image Management Center) • Facility and Imaging Area Tours • Interviews with Key Personnel • Adverse Events • Follow-up on Monitoring Report(s) • Follow-up on prior audit findings

12. Auditing Program • IRB Approvals • Initial protocol • Amendments • Annual reviews • Informed consents – initial & revised versions • Recruitment & retention materials • Participant questionnaires • Others as necessary • ACRIN Statement of Investigator • Site Signature and Responsibilities Log

13. Audit Program Process Review • Recruitment & Informed Consent • Eligibility Evaluation • Study Procedures • Adverse Event Process • CRF Completion

14. Audit Program Case Review Protocol Compliance Study Procedures Adverse Event Recording & Reporting GCP Compliance Supporting source documents CRFs completed accurately, completely, and per CRF instructions Data corrections Timely data submission Data entry accuracy

15. Image Review • ACRIN Image Management Center • Reviews images and imaging data • Provides quality and status reports to PDRC prior to monitoring and auditing • Monitors and Auditors • Review imaging data (collected on study CRFs) • Use reports provided by IMC • Assess compliance with the protocol • Assess for proper completion of imaging data collection forms

16. Follow Up • Formal report: observations and/or finding • Monitoring is on-going throughout the conduct of the trial • Additional auditing dependent upon outcomes • Findings and observations detailed in report • Possible Outcomes  Acceptable, Acceptable with Follow Up, and Unacceptable

17. Resources • ACRIN Links to many useful resources can be found on our website - http://www.acrin.org. To access these resources, click on the ‘ADMINISTRATION’ tab on the home page, then click on ‘REGULATORY RESOURCES’. • FDA Information Sheet Guidances http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm113709.htm • ICH E6 http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/good_clinical_practices.pdf • OHRP http://www.hhs.gov/ohrp/ • ORI http://ori.dhhs.gov/