Looking at the Man in the Mirror: What to Do When You Find Non-Compliance?

1. Stanley Estime, MSCI QA/QI Specialist February 12, 2014 Looking at the Man in the Mirror: What to Do When You Find Non-Compliance?

2. Agenda Why is reporting required? Types of Reportable New Information Top Ten Investigator Common Deficiencies Creating an RNI Submission in ESTR Post Reporting: What’s Next? Reporting Scenarios

3. Why is reporting required? DHHS and FDA regulations require that IRBs have: Written procedures for ensuring prompt reporting of any unanticipated problems or serious continuing noncompliance. 21 CFR 56.108(b)(1) and 45 CFR 46.103(b)(5) New information becomes available during study which may require IRB/Investigator to reassess the risk/benefit to participants Last but not least to avoid continuous non-compliance

4. To Report or Not to Report?

5. Reportable “New” Information Change in Risks/Benefits Adverse Events (Internal and External) Findings/Allegations of Regulatory Non-Compliance Audits/Inspections by Federal Agency Protocol Deviations/Violations Breach of Confidentiality Incarceration of Enrolled Participants Participant Complaints Protocol Suspension/Termination

6. Reporting Adverse Events Useful to maintain an Adverse Event Tracking log: • Date of Event • Description • Severity • Expectedness* • Relatedness* • Date Reported to the IRB, Sponsor or FDA *A harm is unexpected when its specificity and severity are not reflected in the IRB-approved protocol/consent form. *A harm is possibly related when the research procedures more likely than not caused the harm

7. Report Findings of “Regulatory” Non-compliance • Examples include: • Conducting human research procedures without IRB approval • Failure to obtain/document informed consent from participants • Improper use of a witness during consent process • Investigator not maintaining regulatory or participant files

8. Report Audit Inspection • Report any audits by federal agencies: • FDA, OHRP, DOD, VA • Pre-Audit Notification  Recommend QIP - Also notify QIP/IRB of any sponsor inquiries which may potentially result in an audit • Post Audit Notification  IRB • i.e. suspension/termination of research by sponsor

9. Report Protocol Deviations/Violations WHO is at fault? • Failure to follow protocol due to actions or inactions of investigators, staff, or participants WHAT needs to be reported? • Any deviation from the IRB-approved protocol which places participants at increased risk of harm or requires change to the protocol in order to eliminate an apparent hazard to participants

10. Report Breach of Confidentiality • For example: A stolen laptop containing identifiable study information or an email containing the names of participants inadvertently sent to individuals outside the research team. • Breach information may be damaging to participants’ financial standing, employability, reputation or place participant at criminal or civil liability

11. Report Incarcerations • Any participant who is incarcerated during the course of the study for a protocol which has not been previously approved to enroll prisoners

12. Report Participant Complaints • “Significant” complaints by participants that the PI cannot resolve: • Rights; • Welfare; • Safety; OR • Willingness to participate

13. Protocol Suspension/Termination • Any premature suspension or termination of the research by the sponsor, investigator, or institution

14. OHRA Reporting Time Frame Within 5 business days from the time the study team became aware of the information Ensure knowledge of Sponsor’s and/or FDA reporting requirements when applicable

15. Top Ten Investigator Common Deficiencies Identified through QIP Onsite Reviews & For Cause Audits • Inadequate knowledge of regulatory requirements/institutional policies • Failure to follow IRB-approved protocol • Failure to report protocol violations • Failure to report adverse events & UAPs • Improper documentation of informed consent • Failure to document subject eligibility • Incomplete/inaccurate source documentation • Poor/insufficient record keeping • Lack of IRB approval • Lack of study monitoring

16. Creating an RNI Submission in ESTR • An RNI (Reportable New Information) submission can be created: • From the personal workspace for RNIs NOT associated with a particular study • From the approved study workspace for RNIs related to that specific study Study Workspace: Personal Workspace: 16

17. RNI Form in ESTR • The RNI Form captures the following information: • Date PI became aware of the information • Category of the new information (New or increased risk or unexpected and possibly related harm) • Description of the information • If the new information in the PI’s opinion: • Poses a change to the study risk(s) • Requires a modification to the approved research Note: If new information is associated with more than one study a separate report should be created for each 17

18. Tips for Completing RNI Form • Enter Protocol # as part of description of new information as well as indicate the corrective action plan by the study team (Question 3) • Users will only be able to link to studies for which they are already affiliated (Question 5). • Attachments on RNI workspace are only used as reference/supporting documents and will not be “approved” as part of RNI submission. Any documents requiring IRB approval should be attached to appropriate ESTR section via Initial, Continuing, or Modification submission (Question 6) 18

19. IRB Actions - Post Reporting

20. Post Reporting: RNI Notification Notification of Acknowledgement This report of new information has been acknowledged. No further action is required.

21. Reporting Tools Utilize tools to keep track of reporting/ensure proper reporting: Adverse Event Tracking log Protocol Violation/Deviation Tracking log http://www.hsph.harvard.edu/ohra/qip/study-management-tools/

22. Reporting Scenario? During a monitoring visit the following observations were discovered: • Unsigned copies of participant consent forms • Dates missing from executed consent documents • Protocol deviations • A note-to-file regarding a missing study laptop which was later recovered by HUPD • Case report forms on file for a participant enrolled into the incorrect arm of the study. He withdrew after his first study visit as a result of complaints of headaches possibly associated with study medication. Which of the following observations would you report to the IRB as an RNI?

23. When in Doubt? Quality Improvement Program Staff • Stanley Estime, sestime@hsph.harvard.edu, 617-432-2164 • Lisa Gabel, lgabel@hsph.harvard.edu, 617-432-5842 • Leslie Howes, lhowes@hsph.harvard.edu, 617-432-2153 IRB Operations Staff • Department Assigned IRB Review Specialist: http://www.hsph.harvard.edu/ohra/department-assignments/ • IRB Administrative Chair Julie Kaberry, jkaberry@hsph.harvard.edu, 617-432-2149