Observations from the UM Office of Human Research Compliance Review

1. Observations from the UM Office of Human Research Compliance Review April 13, 2010 Ron Maio D.O., M.S. Terry VandenBosch R.N., Ph.D, CIP, CCRP Ted Hamilton, M.S.

2. How Much Clinical Research?

3. National Perspective

4. Schools at UM • Literature, Science, and the Arts • Medicine • Music, Theatre & Dance • Natural Resources & Environment • Nursing • Officer Education Programs • Pharmacy • Public Health • Public Policy • Social Work • Architecture & Urban Planning • Art & Design • Business • Dentistry • Education • Engineering • Graduate Studies, Rackham School of • Information, School of • Kinesiology • Law

5. OHRCR Organizational Chart

6. OHRCR Mission • “To facilitate safe, ethical, efficient and high quality human subjects research” http://www.research.umich.edu/ohrcr/index.html

7. OHRCR Mission Compliance Review Outreach Mission Leadership Knowledge Education

8. Our different “jobs” condensed • OHRCR is not the IRB • OHRCR provides a set of checks and balances for human subjects protections in the UM HRPP • IRB • What do they say they will do? • OHRCR • Are they doing what they said they would do? http://www.hrpp.umich.edu/om/

9. OHRCR Advisory Committee • Advice on creating and sustaining a model system for internal review of research • Sounding board and support for new initiatives • 15 members drawn from across the campus

10. What Have We Been Doing? • Compliance Reviews • Not for cause • Routine Research Education and Regulatory Reviews (RRERRs) • For Cause • HRPP survey • Review of Components HRPP (e.g. BEU) • Review of IRB Demonstration Projects • Providing feedback to HRPP • Outreach • Conferences/Training/Panels/Presentations

11. Compliance Review

12. Compliance Review

13. OHRCR: Partners not the Police

14. General Principles for Meeting Regulatory Responsibilities

15. Regulations & Ethics • Ethical principles the basis for conducting research • Regulations developed on ethical principles • Regulations developed in response to egregious, harmful research behaviors • Regulations not specific • Regulations don’t address everything that is important • No regulations to assess decision-making capacity of potential research subjects • Guidance interprets the regulations and gives examples • OHRCR reviews to regulations and guidance • Noncompliance with regulations in OHRCR reports

16. What Does OHRCR Look for? • What does OHRCR look for? • Does the activity match the IRB approved protocol? • Regulatory outcomes of each phase • Documentation • Documentation principles • Page 1 of 10 • Dates • Attribution (who? Printed and signed) • Attribution by staff to whom activity was delegated and who are qualified to undertake the activity

17. ALCOA (FDA) • FDA Documentation Guidance • A-attributable (who, when) • L-legible (readable with pen, no white out) • C-contemporaneous (up-to-date) • O-original (source document) • A-accurate (verifiable with source)

18. Resources • University of Michigan HRPP Operations Manual • http://www.hrpp.umich.edu/om/ • MICHR • email network • June 1 & 2 research staff conference • tools and resources at website • Clinical Trials Network “Best Practices” Forms • https://www.ctnbestpractices.org/ • University of Pittsburgh-Sample Forms • http://www.rcco.pitt.edu/educ/ECO_Examples.htm

20. What is a RRERR?*It is an acronym for… Routine Research Educational and Regulatory Review *We never say the “A” word… (Audit)

21. Types of Reviews • For-cause review: When allegations, indications or suspicions of possible human subjects-related noncompliance prompt an investigation. This as also sometimes referred to as a directed review. • Not-for-cause review: When the investigation is a routine review and the subjects, studies, or systems are chosen randomly or as described in OHRCR SOPs. • Routine Research Educational and Regulatory Review (RRERR): A type of not-for-cause review that is based on a sampling plan for the current fiscal year.

22. What to Expect During a RRERR Nothing to get worried about! Two sessions* • Interview with the Principal Investigator (≈ 1 hr) • Chart review with the study coordinator (≈ 1 ½ hr) The second session will involve… • Review of CRFs and Consent Forms • Inspection of work area with regard to security and accessibility • Will ask questions about computer security, data portability, file encryption, etc. *May be scheduled on separate days or on the same day back-to-back

23. What are we looking for? Protocol OHRCR

24. Noncompliance* • Noncompliance: The failure of a person or organization to act in accordance with the requirements of a law, regulation, policy, or the requirements and/or determinations of an IRB; • Serious Noncompliance: Noncompliance that materially increases risks or causes substantive harm to research participants or materially compromises the rights or welfare of participants; • Continuing Noncompliance: A pattern of actions or omissions that suggest a likelihood that instances of noncompliance will recur without intervention, or a failure to comply with a directive from an IRB to address as episode of noncompliance. IRB makes the official determination of whether or not noncompliance is serious and/or continuing. *U-M Human Research Protection Program-Operations Manual ; Part 12, July 2009

25. We may look at… Consent Forms ORIOs Inclusion/Exclusion Criteria Adverse Events Investigator-Sponsor Responsibilities for IND/IDE holders

26. Number of RRERRs in 2009 • Total of 61 Initiated; 59 Completed; 1 in final stages of review; 1 with complex noncompliance extended to FY10 • Lower Risk Studies • 39 selected, 10 not eligible, 29 reviewed • Of the 29 reviewed, 23 were IRBMED studies, 3 IRB Health, 3 IRB Behav Sci • 3 were U-M sponsor/investigators holding INDs • Higher Risk Studies • 48 selected, 16 not eligible, 32 reviewed • Of the 32 reviewed, all were IRBMED • 7 were U-M sponsor/investigators – 6 with INDs and 1 with IDE

27. Areas of Noncompliance in 2009 • 23 of 61 (38%) RRERRs completed in 2009 identified one or more episodes of noncompliance • The main area of noncompliance was deviation of the informed consent process (11; 18.0%) • Other areas with findings: • Regulatory documents (IRB, FDA, etc.) (9; 14.8%) • Subject selection/Eligibility criteria (5; 8.2%) • Record keeping/Data confidentiality & security (3; 4.9%) • Untimely and/or incomplete adverse event reporting (1; 1.6%) • Study implementation (1; 1.6%) • Subject recruitment (1; 1.6%) • Of these 23, 1 study (1.6% of completed reviews) was found to have serious and continuing noncompliance by IRBMED

28. Noncompliance Has Consequences OHRCR PI

29. For Nonserious Noncompliance we may… • Make specific recommendations to PI to bring the study into compliance • Provide education or guidance where needed • Request an ORIO or amendment to be submitted to IRB as necessary • Assist investigators in meeting sponsor-investigator responsibilities or refer them to MICHR/MIAP

30. Serious and/or Continuing Noncompliance May result in… • Mandatory re-education or re-certification of PI • Removal as PI from study • Tarnished reputation • Loss of funding or sponsorship • Fines • Debarment from research Oops…

31. Serious or Continuing Noncompliance • OHRCR and IRB may make recommendations for sanctions or remediation for serious or continuing noncompliance (and they may not always agree) • The final determination is made by the Office of the Vice President for Research (OVPR)

32. Good Clinical Practice • GCP is an international ethical and scientific standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki. • Some RRERR findings may not be “regulatory noncompliance” but rather failure to follow GCP. • In such cases, we usually provide education and guidance to correct the problem but do not cite the finding as noncompliance in our report. Examples might include sloppiness, disorganized CRFs, or consent forms without header information (assuming it’s the correct version).

33. RRERR Report RRERR • Findings are written in a report • Corrective Action Plan is included, if necessary • Draft sent to PI to check for accuracy • Final Report sent to PI, IRB Director, IRB Co-Chairs, IRB SARA, and Associate Dean for Regulatory Affairs • Close-out letter is sent when all items in the Corrective Action Plan have been completed

34. Exemplary Practices Citations • Four studies (6.5%) were given “Exemplary Practice Citation” for FY09 for studies that exemplified excellence in research practices in two areas: 1) Principal Investigator participation and knowledge of the consent process in the initial informed consent process 2) Qualifications, training, and oversight of research coordinators

35. Helpful Hints…

36. Consent Forms • Use only the most recently approved consent document with watermarked dates • The safest way to ensure having the most recently approved ICD is by getting it directly from eResearch when you need it. Storing ICDs on your hard drive may increase the likelihood that you would use an outdated version • Study coordinators should be on the e-Research study team to be able to access the most recent version at any time • Avoid pre-assembling case report forms far in advance – same reason • Header info should be changed by IRB, not by you • Be sure to “stack” them properly in eResearch

37. ORIOs are as good as… • Stands for Other Reportable Information and Occurrences • Not a bad thing (sometimes stigmatized) • Auditors will tend to look more favorably upon deviations that are properly reported in a timely fashion • Also…if you were “RRERR’ed” at any time, you should submit this to IRBMED as an ORIO at the next SCR

38. Adverse Events • Underreporting may be a “red flag” for auditors • Study-specific AE reporting plan may save time and work, especially if expected AEs are known in advance

39. Sponsor-Investigator Studies • PI holds IND (drug) or IDE (device) • Investigator wears two hats: • Sponsor • Investigator • Investigator responsibilities include oversight of study–related activities and IRB reporting • Sponsor responsibilities include study monitoring, FDA reporting, and maintaining regulatory binder • MICHR/MIAP is a good resource for IND/IDE issues • S-I studies are high priority for OHRCR reviews

40. Which Studies are on our Radar? Top priority are usually… • Studies in which the PI holds the IND or IDE • Higher risk studies (e.g. oncology studies) • Investigator initiated; without external monitoring But ALL studies are fair game, so be prepared!

41. OHRCR Does More than Review Studies… We also conduct reviews of… • Other departments • Ancillary Units (BEU, IDS, MCRU) • Clinical Trials Office • IRB Findings are reported to OVPR OHRCR

42. Maybe We’ll Visit YOU Soon! OHRCR