Human Research Protection Program

1. Human Research Protection Program Beth Shields, MA, CIP, CCRA Quality Assurance CoordinatorHuman Research Protection Program Quality Improvement Unit Beth.Shields@ucsf.edu 415-514-3823 CHR Post-Approval Event Reporting Wednesday, April 11, 2012

2. Outline for Today • Types of Post-Approval Events • What and How to submit to CHR • CHR/QIU role in review of Events • Tips for Reporting • Using iMedRIS to submit reports • Q & A

3. Post Approval Event Reporting to CHR – Why? Federal regulations and HRPP policies require reporting of any post-approval event that may meet the HRPP’s definitions of an Unanticipated Problem or Serious and/or Continuous Noncompliance. The CHR determines whether these definitions apply when evaluating post-approval reports.

4. Types of Post-Approval Event Reports • Serious and/or Unexpected Adverse Events • Protocol Violations/Incidents • Safety Information: • Investigator Brochure/Package Insert updates • DSMB/DMC Report • Audit Reports • Study Holds • Study Close-Out Reports

5. Adverse Events (AEs) &Serious Adverse Events (SAEs) Definitions andDetermining What To Report and What NOT To Report

6. Definition of “Adverse Event” An Adverse Event (AE) is defined as: any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. (emphasis mine) ICH E6 (1.2) However…

7. Not all AEs – or even SAEs – need to be reported to the CHR! • The CHR has specific criteria describing and defining specifically which AEs should be reported. • These criteria are available on the HRPP’s website at http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.asp

8. Determining What to Report Note: • Study sponsors and the FDA have expanded reporting requirements. • The VAMC has a shorter timeline (5 days) than UCSF for reporting certain categories of post-approval events (see http://www.research.ucsf.edu/chr/VA/chrVA.asp#considerations)

9. Adverse Events – Internal vs External “Internal” AEs occur in subjects enrolled by a UCSF investigator or at a UCSF-affiliated site. “External” AEs occur in study participants who are enrolled in the same study but at a site not under the control of a UCSF investigator.

10. Adverse Events – Internal If … The PI determines event to be: • Definitely; • Probably; or • Possibly Related and • Serious or Unexpected Then… Report the event to the CHR within 10 working days of learning of it

11. An AE is “Serious” if it results in one of the following: Death Life-threatening event Inpatient hospitalization or prolonged existing hospitalization (>24 hrs) Persistent or significant disability/incapacity Congenital anomaly/birth defect, or cancer Significant medical, surgical, or other intervention/precaution required to prevent one of the outcomes listed above Event occurred in a gene therapy study

12. An AE is Unexpected if it is: • More serious than expected • More frequent than expected • Due to overdose of study medication • Due to a protocol violation or • AE results in participant’s unexpected withdrawal from study

13. Adverse Events – External If… • The UCSF PI determines that the event: • Changes the study risks or benefits And/Or • Requires a modification to the CHR Application or the Consent form Then… • Report event to CHR within 10 working days of learning of it

14. AE’s that do not meet CHR 10-day reporting criteria • Do not submit using AE Reporting Form • For Internal Interventional Studies only, any unrelated death should be reported using the AE Summary Log • If Sponsor requires reporting an event that does not meet CHR criteria, use theAE Summary Log • Attach Log to Continuing Review Submission Formas an “Other Study Document”

15. Protocol Violations & Incidents Determining What To Report and What NOT To Report

16. Major Protocol Violations and Incidents – Examples • Incorrect research treatment or intervention given • Enrollment of participant ineligible per CHR-approved protocol • Procedure/lab required by protocol not done • Procedure/lab done outside the study window • Problem with the informed consent or recruitment process

17. Major Protocol Violations and Incidents - Examples Significant concern or complaint received Lapse in study approval Loss of adequate resources to conduct study Unauthorized disclosure of private information (e.g. stolen or lost research data, privacy incident) Report any Major Violation/Incident to the CHR within 10 working days of learning of it

18. Minor Protocol Violations and Incidents • Also known as Protocol Deviations • Unapproved changes, deviations, or departures from study design that: • Have not been reviewed and approved by the CHR but • Do not affect participants’ rights, safety, or well-being or impact study data • Document in study regulatory binder and develop a Corrective Action Plan (CAP) • Do not need to be reported to CHR

19. Other Safety Information Determining What To Report and What NOT To Report

20. Other Safety Information • Updated Investigator Brochure/Package Insert • DSMB/DMC Reports • Audit Reports with findings • Hold on Study Activities • Other Safety Information or Updates that may impact UCSF participants • Report to the CHR within 10 working days of learning of new information

21. Study Close-Out Report • Updates the CHR on conduct of the study since the last renewal • Required for all studies • Report within 10 working days of receiving Sponsor’s Close-Out letter or PI’s decision to close study

22. Study Close-Out Report Do not close out a study if: • Local enrollment to the study is ongoing • Local research-related interventions are ongoing • Local participant follow-up is ongoing • Data analysis or manuscript preparation requiring use of or access to individually identifiable information is ongoing • External sponsor has not given permission to close the study with the CHR.

23. CHR Review Process • Chair Review & acknowledgement • Chair may request additional information, require a modification, or forward to convened Meeting • Convened Committee Review • Determine if the report is an Unanticipated Problem, Serious Non-Compliance and/or Continuing Non-Compliance

24. Unanticipated Problem - definition • Involves risk to participants or others; • Is unexpected and research-related; and • The risk exceeds the nature, severity, or frequency described in the • Protocol, • Study consent form, • Investigator’s Brochure, or • Other study information previously reviewed and approved by the CHR.

25. Serious Noncompliance Failure to follow state or federal regulations for protection of the rights and welfare of study participants, University policies, or the requirements or determinations of the CHR and that, results in, or indicates a potential for: • a significant risk to enrolled or potential participants or others or • compromises the effectiveness of the UCSF HRPP or the University

26. Continuing Noncompliance A pattern of noncompliance that continues to occur after a report of noncompliance and a corrective action plan have been reviewed and approved by the CHR. • The pattern suggests the likelihood that instances of noncompliance will continue without intervention.

27. CHR Regulatory Reporting Requirements • Federal Agencies • Office for Human Research Protection (OHRP) • FDA • SF Veterans Affairs (if VA study) • Associate Vice-Chancellor for Ethics and Compliance • UCSF Legal Affairs • UCSF Privacy Office • Other offices or groups as required by the nature of the study

28. Top Tips for Submitting Post Approval Event Reports

29. Tips for Post-Approval Event Reporting Before reporting, make sure the event meets CHR 10-day reporting requirements Ask your PI or mentor for guidance Submit using appropriate iMedRIS form Answer all questions on the form completely Include supporting documents, if relevant

30. Tips for Post-Approval Event Reporting • Explain the context • Provide details - dates, lab values, what caused the event, etc • Explain the potential consequence, even if nothing happened • Provide a comprehensiveCAP • Do not include PHI in reports • Call QIU Analyst of Day and document your QIU consultation • If a Privacy Breach, contact the Privacy Office and provide documentation of that communication

31. Using iMedRIS to Submit Post Approval Events

32. Using iMedRIS to Submit Post- Approval Events • Submissions Dashboard & creating Submission Forms • Using Submissions History • Review by affiliated offices: • Privacy Office • Research Risk Mgmt • SFVAMC

33. Using iMedRIS to Submit Post- Approval Events • Provides immediate confirmation of submission • Documents CHR review and acknowledgment • Links follow-up AE reports to initial event reports

34. Quality Improvement Unit • Lisa Denney, MPH, CIPAssistant DirectorQuality Improvement Unit Lisa.Denney@ucsf.edu (415) 514-2152 • Beth Shields, MA, CIP, CCRAQuality Assurance Coordinator Beth.Shields@ucsf.edu (415) 514-3823 • Laurie Herraiz, RD, CCRPQuality Assurance CoordinatorLaurie.Herraiz@ucsf.edu (415) 514-9246

35. Resource Information • Guidance for Reporting Post-Approval Events to CHR: • http://www.research.ucsf.edu/chr/Guide/hsppGP.asp#Reporting • QIU section of HRPP Website: • http://www.research.ucsf.edu/chr/Qip/hsppQip.asp • SFVAMC Guidance: • http://www.research.ucsf.edu/chr/VA/chrVA.asp#considerations • Clinical Research Office (415) 221-4810 x6425 • Clinical Research Coordinators Website: • http://www.research.ucsf.edu/chr/Train/CRC_Group.asp • Affiliate Privacy Office Contact Information: • SFVAMC Elaine Tran, (415) 221-4810; Ext: 2135 • SFGH Philip Katzenberger (415) 206-6210 or main # 206-8000 • SFDPH Privacy Office (415) 206-2354

36. Upcoming HRPP Classes “Recruitment: What Methods Are Appropriate?” • Friday, May 4, 1:00 – 3:00 pm iMedRIS Training Classes Managing Approved Studies in iMedRIS (advanced) • Thursday, April 12, 10:00 – 11:30 am Introduction to iMedRIS • Thursday, April 26, 10:00 am – 12:00 pm See HRPP Website for more education opportunities: http://www.research.ucsf.edu/chr/Train/chrTrain.asp

37. Questions?