1. Monthly IRB-Investigator Meeting Compliance at CUMC Common Noncompliance Findings and How to Avoid Them January 26, 2012 George Gasparis Jessica Randall Executive Director, HRPP/IRB Compliance Oversight Manager

2. January 26, 2012 Objectives Today’s session will provide insights on: Overview of Columbia’s Compliance Oversight Program Process for Handling Allegations of Non-Compliance Definition of Serious Non-Compliance Reporting to the IRB, Federal Agencies Common Findings Corrective Action Plans Page 2

3. Event Reminders Save the Date: Thursday, February 22, 2012 (3:30-4:30): MIM (Todd Amphitheatre – P&S 16-405) –ClinicalTrials.gov with the Clinical Trials Office (CTO) Tuesday, April 10, 2012: IRB 101 (10:00-2:00) (Alumni Auditorium - Black Building) Annual IRB Education Conference: Monday-Tuesday, May 7-8, 2012 (Lerner Hall – Morningside Campus) Regular Events Office Consultation Hours: Tuesdays 10:00-11:00 in the IRB Office (722 W. 168 th St., MSPH, 4 th floor) RASCAL Workshops: every other Tuesday 3:30-4:30 (Hammer 202A Computer Lab) –1/31: Renewals/Modification –2/14: Consent –2/28: New Protocols January 26, 2012Page 3

4. General Announcements IRB Administrative Quiet Hours: Monday-Friday, 11:00-1:00: –call 212-305-5883 with urgent issues during this time. Education Requirements: –CITI 3 year re-certification will be starting in March for those completed 3+ years ago Like us on Facebook! Follow us on Twitter! –http://www.facebook.com/ColumbiaIRB or @ColumbiaIRBhttp://www.facebook.com/ColumbiaIRB January 26, 2012Page 4

5. January 26, 2012 Compliance Oversight Program The Columbia Oversight Team handles the following oversight activities: -all reporting requirements under 45 CFR 46 and FDA regulations; -investigation of allegations of noncompliance; -conducts not-for-cause audits; -also investigates IRB review of the study. Page 5

6. January 26, 2012 Compliance Oversight Program (cont’d) The Columbia Oversight Team handles the following oversight activities: -review of all subject complaints reported to the IRB; -review results of external monitoring activities and maintain repository of reports (e.g., FDA, NCI oncology-group studies, etc.); -provides guidance/consultation for FDA audits; -provides consultation for corrective action plans. Page 6

7. January 26, 2012 Compliance Oversight Team (COT) Jessica Randall – COT Manager Vanessa Laroche – IRB Auditor Diana Wong – IRB Auditor Dan Matulich – IRB Auditor George Gasparis – Director Page 7

8. January 26, 2012 Comply with what? Standards for Human Subjects Protections Ethical Principles Belmont Report, Declaration of Helsinki Federal Regulations -HHS Regulations - 45 CFR 46 -FDA Regulations – 21 CFR 50, 56, 312, 600, 812 -Privacy Rule -NY State Law – Article 24A (2440-6); Article 7 (79-1) Federal Guidance – (e.g., Good Clinical Practice) Institutional Policies Page 8

9. January 26, 2012 Basic Regulatory Requirements for Investigators – 45 CFR 46 (HHS Regulations) ABCs of regulations All federally supported human subjects research must ensure: A – Assurances of Compliance for all performance sites B – Board approval (IRB, ethics cmte., research ethics board) C – Consent from every subject (unless waived by the IRB) D – Disclosure - reporting of serious noncompliance, unanticipated problems involving risks to subjects or others, suspensions or terminations Page 9

10. January 26, 2012 Serious noncompliance may include, but is not limited to: 1) failure to obtain or maintain IRB approval before conducting any research involving human subjects/conducting research during a lapse in approval; 2) enrollment of subjects without obtaining legally-effective informed consent 3) failure to report serious and unanticipated problems involving risks to subjects or others in accordance with institutional policy; Page 10

11. January 26, 2012 Serious noncompliance may include, but is not limited to (cont’d): 4) implementing a substantive modification prior to obtaining IRB approval; 5) significant violations of the protocol; 6) ongoing noncompliance. Page 11

12. January 26, 2012 45 CFR Part 46.103(b)(5) & 21 CFR 56.108(b) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Department or Agency head (and FDA when applicable) of: (i) any unanticipated problems involving risks to subjects or others; (ii) or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and; (ii) any suspension or termination of IRB approval. Page 12

13. January 26, 2012 Columbia University Policy All potential noncompliance with regulations, or University policy, for the protection of human subjects in research must be promptly reported to the IRB. Page 13

14. January 26, 2012 Concerns about possible Research Noncompliance may be discussed with an IRB Chair, the Executive Director of the IRB, the Associate Director of the IRB, or the Manager of the Compliance Oversight Team. Any individual may make an allegation of Noncompliance. Any such allegation shall be documented in writing and given to the Executive Director or Associate Director of the IRB. Page 14

15. January 26, 2012 NOTIFICATION TO REGULATORY AGENCIES OR FUNDING SOURCES The IRB will report noncompliance to: -designated IRB; -institutional officials, deans, department chairs; -legal counsel; -the appropriate regulatory agencies (e.g., OHRP, FDA, etc.) and sponsors. Page 15

16. TOP TEN AUDIT ISSUES 10.Regulatory Binders (or folders for regulatory approvals) are not appropriately maintained. -See Clinical Research Handbook for guidance January 26, 2012Page 16

17. TOP TEN AUDIT ISSUES 9. “Documentation? What documentation?” Lack of documentation –Missing source documentation –Keep notes on everything –Have a standard notes page –Document the visit dates, when consent was obtained, any questions answered, anything of interest – chronological order –Over time, staff and co-investigators change - documentation is critical January 26, 2012Page 17

18. TOP TEN AUDIT ISSUES 8. Organization of records “It’s time for my continuing review and I can’t find my protocol and/or consent form- can you send it to me?” –Put every document file location in the footer of documents so you will know where to find it. –Give the documents reasonable titles with version #’s –(i.e. ‘Study 9892, Version Date 01/03/12’ is a good title. ‘Blood study protocol’ is bad. Need version #’s or dates) –Keep protocol documents together in one folder and clearly marked in one folder on the network. Let your supervisor and those involved in data collection/management know where it is/grant access –Back-up your files regularly (i.e. M-F 4:45pm, every Friday 4pm, etc.) January 26, 2012Page 18

19. TOP TEN AUDIT ISSUES 8. Organization of records “It’s time for my continuing review (cont’d) –Confirm the number of subjects enrolled, completed, withdrawn, dropped out, etc. –Account for all modifications that have been made or need approval –Account for safety monitoring over the past year and ensure that all UPs had been reported –Account for progress reports; if SI study, annual update to FDA. January 26, 2012Page 19

20. TOP TEN AUDIT ISSUES 7. “Did I say that?” Not sticking by the recruitment plan set forth in the IRB protocol –Make recruitment plans clear and provide details and then follow the plan. i.e., ‘We will post fliers in the Emergency Department (flier attached) and we will call subjects who previously participated in IRB protocol # 0099-101 that agreed to be contacted for future research studies (see phone script attached).’ January 26, 2012Page 20

21. TOP TEN AUDIT ISSUES 6. Design study protocols carefully The IRB protocol is the exact plan you will be abiding by for the duration of the study (unless you submit an amendment). Any variation from that plan needs to be reported as a ‘deviation’ or ‘violation.’ Study visits should be planned around safety monitoring and scientific needs for the study with consideration of appropriate study visit windows to minimize deviations. Do the same for everyone in the same situation across the board January 26, 2012Page 21

22. TOP TEN AUDIT ISSUES 6. Design study protocols carefully (cont’d) Create appropriate inclusion and exclusion criteria that meet the scientific needs of the study and that consider feasibility. Provide clear endpoints and rules for changing dosages for management of toxicity Carefully select the type and frequency of study procedures that with consideration of feasibility January 26, 2012Page 22

23. TOP TEN AUDIT ISSUES 5. “My Coordinator Left Me and Now My Study’s A Mess” (sounds like a bad country song) The Principal Investigator is ultimately responsibility for the study. You play your part, but they need to be in the know. Appropriate resources January 26, 2012Page 23

24. TOP TEN AUDIT ISSUES 4. Using non IRB-approved documents (fliers, brochures, phone calls, e-mails) - need a script- altering even a number on a flier needs to be re-approved by the IRB (expedited most times) –Changing a number on a flier? Send it back to IRB for re-approval/re-stamping. January 26, 2012Page 24

25. TOP TEN AUDIT ISSUES 3. Failure to obtain legally-effective consent and/or HIPAA Authorization Obtaining consent is a PROCESS (IRB consent and HIPAA authorization) not just a signature. –Have an effective consenting process. Spend more time on subject questions now, have less problems later. –i.e. subject was mailed a page of their consent form –Subject signs and dates and PI/co-I then signs and dates- dates need to match! January 26, 2012Page 25

26. TOP TEN AUDIT ISSUES 3. Failure to obtain legally-effective consent and/or HIPAA Authorization (cont’d) HIPAA Authorization form and IRB consent form are not signed at the same time and/or the Authorization form is signed after a portion of the study is completed. -Before you collect any data make sure every subject signs both forms at the screening before ANY procedures take place or any questionnaires are completed. Non IRB-approved forms are signed. Check boxes for additional tests/samples/procedures not checked or initialed. January 26, 2012Page 26

27. TOP TEN AUDIT ISSUES 2. Failure to obtain IRB approval -initiation of any research related activities prior to IRB approval. -conducting research related activities during a lapse in IRB approval; January 26, 2012Page 27

28. TOP TEN AUDIT ISSUES 1. Know your Limitations Keep an open dialogue with the PI (s/he is ultimately responsible for their study) keep a detailed calendar and notes - document everything! Set weekly meetings with your supervisor. Don’t know the answer? Ask or call the IRB or Compliance Manager. Rather ask now than have issues later. “Yeah…I’m going to need you to come in on Saturday… and Sunday too…” January 26, 2012Page 28

29. January 26, 2012 Common Findings Initiation of research prior to IRB approval or signing of contract Enrollment/research activities during lapsed periods; Over-enrollment beyond FDA or IRB-approved sample size Failure to use the IRB-approved consent form Use of an expired IRB-approved consent form Failure to obtain legally-effective consent Inappropriate signatures and/or dates on the consent document Failure to file signed consent document in medical record Lack of or incorrect HIPAA form Page 29

30. January 26, 2012 Common Findings (cont’d) Lack of documentation (i.e., source documents; research procedures; documentation of consent process) Subject did not indicate/initial choice (yes or no) for additional tests or samples to be held for future purposes. Failure to follow the protocol Failure to satisfy inclusion/exclusion criteria Failure to obtain Sponsor and IRB approval for eligibility waivers Failure to report unanticipated problems promptly to the IRB Failure to report SAEs to the sponsor (and FDA for investigator held IND/IDE studies) Page 30

31. January 26, 2012 Common Findings (cont’d) Failure to obtain IRB approval of modifications Failure to maintain drug accountability records Unauthorized personnel ordering study drug Unauthorized personnel administering study drug Unauthorized personnel performing clinical procedure Failure to protect confidentiality/privacy of study data in accordance with the protocol; Inappropriate access to medical records Conducting research without appropriate training Page 31

32. January 26, 2012Page 32 General Considerations for Corrective Action Plans Account for noncompliance findings Conduct root-cause analysis Develop processes that will prevent future noncompliance Consider ability to implement and maintain new process Consider burden of maintaining new process

33. January 26, 2012 Most Serious Finding of Noncompliance – Failure to Obtain IRB Approval -Key is understanding how to apply the definitions of “human subject” and “research” Page 33

34. January 26, 2012 When Does Human Subjects Research Need IRB Review? Not Human Subjects No IRB Review Research Needed QA Training Evaluation Basic Science Evaluation Basic Science Surveillance Polling Surveillance Polling (Exempt Research Needs Determination of Status by IRB) (Exempt Research Needs Determination of Status by IRB) HHS Regulations Human Subjects Research that is not exempt Needs IRB Review Page 34

35. January 26, 2012 Columbia IRB Mission - Facilitate the Ethical Conduct of Research Education Training Compliance Oversight Join the IRB Listserv Consultation Hours Service-oriented Page 35

36. Education Training January 26, 2012 Required Training: Completion of CITI Web-based training modules Research with Minors FDA –regulated research Continuing education requirement (March 2012) Columbia HIPAA training module Clinical Research Coordinator training (October 2010) Sponsor-Investigator training Page 36

37. January 26, 2012 Columbia IRB Websites: -CUMC http://www.cumc.columbia.edu/dept/irb/ Children as Study Subjects in Research: http://www.cumc.columbia.edu/dept/irb/policies/index.html#irb -CU IRB http://www.columbia.edu/cu/irb/ Children as Study Subjects in Research: http://www.columbia.edu/cu/irb/policies/index.html Page 37