1. Practical issues in IRB review Bernard Lo, M.D. August 16 and 19, 2010 1

2. 2 Topics to cover  When is IRB review not necessary?  How to avoid delays in IRB review?  IRB review of multisite trials  Tips for IRB approval

3. 3 Infections related to central venous catheters  80,000 bacteremia episodes annually  Cost $45,000 per infection  28,000 deaths

4. 4 Reducing ICU catheter-related infections  Handwashing  Clorhexidine  Full-barrier precautions when inserting central lines  Avoid femoral sites  Remove unnecessary catheters

5. 5 Reducing ICU catheter-related infections  Standard recommendations not followed  Quality improvement project in 108 ICUS in 67 Michigan hospitals  Checklist  Monthly feedback

6. 6 Reducing ICU catheter-related infections Catheter-related bloodstream infections / 1000 catheter-days (mean) Baseline7.7 After 16-18 months1.4

7. 7 Reducing ICU catheter-related infections  After publication, OHRP investigation  Project was research: grant, publication  IRB review required  Consent from subjects

8. 8 Is IRB review necessary?  No risk to patients  Checklist procedures standard practice  Efforts to improve adherence not harm patients  Researchers receive hospital infection rates, no identifiable patient information

9. 9 Is IRB review necessary?  Primary goal of QI is to improve patient care, not generate knowledge  Intervention could be implemented as part of clinical care  Obligation to do QI  Instituting interventions without analyzing whether they work makes little sense

10. 10 Is IRB review necessary?  IRB review not feasible  45% of hospitals in project had no IRB  HIPAA does not require consent for QI  Review by clinical service directors

11. 11 When is IRB review not necessary? 1. Not research 2. Not human subjects research 3. Exempt from federal regulations  Certain survey, interview research  Certain research with existing data and biological specimens

12. Definition of research  “Systemic investigation … designed to develop or contribute to genralizable knowledge” 12

13. 1. Not research (hence no IRB review)  Innovative clinical practice  Public health practice  Surveillance, epidemiology, investigate outbreaks  May publish findings  Quality improvement? 13

14. Infertility in cancer survivors 14

15. Induced pluripotent stem cells (iPS cells)

16. Reproductive research with iPSC derivatives  Differentiate iPSCs into oocytes and sperm  Carry out IVF, observe embryo to see if normal development  Use iPSCs that are easy to work with 16

17. Questions for audience  Do regulations permit using de- identified somatic cells to derive iPSCs and gametes and fertilize gametes in vitro, without consent of somatic cell donors?  Yes /No / Unsure 17

18. Questions for audience  Should regulations permit using de- identified somatic cells to derive iPSCs and gametes and fertilize gametes in vitro, without consent of somatic cell donors?  Yes /No / Unsure 18

19. Definition of human subjects  Living individuals about whom an investigator obtains  Data through intervention or interaction OR  Identifiable private information 19

20. What is human subjects research?  Interact with person OR  Use identifiable private information  Not human subjects research if exisiting data and materials cannot be identified  Examples of tissue from cancer surgery 20

21. What is identifiable?  None of 18 HIPAA identifiers  Data and materials are coded but researcher cannot access keys to code  Code may be retained by database or biobank 21

22. Ethical rationale for no IRB review  If no human subject, no one can be harmed  Hence IRB review would not protect participants  But would pose administrative burdens 22

23. 2. Not human subjects research: Examples  Collect hospital-specific data on infection rates  Reproductive research with de- identified iPSCs  Coded neonatal spots 23

24. Reproductive research with iPSC derivatives  Not human subjects research if de- identified 24

25. Reproductive research with iPSC derivatives: concerns  Reproduction very private  Some object if such reproductive research done without their consent 25

26. Reproductive research with iPSC derivatives: concerns  Deeply held beliefs about reproduction:  Some believe that IVF is immoral  Some believe that embryos have moral status of persons, should not created or destroyed for research 26

27. Reproductive research with iPSC derivatives: concerns  Such individuals object to use of their biological materials in such research  Even if de-identified  Respect their values and preferences by asking their consent 27

28. Warning  Research permitted under federal regulations may not meet ethical standards  Ultimately researcher is responsible 28

29. 3. Exempt from federal regulations  Most survey and interview research  Unless subjects can be identified and responses could put respondents at risk Not if ask about illegal activities, sensitive or private topics 29

30. 3. Exempt from federal regulations  Certain existing data or materials  Publicly available  Researcher records information in manner than subjects cannot be identified Can look at medical records 30

31. 3. Exempt from federal regulations  Much research in educational settings 31

32. 32 How can we avoid delays in IRB review?

33. 33 Expedited IRB review  Reviewed by chair or designate, not full committee  Shorter time to approval

34. 34 When may IRB review be expedited? 1. Must be minimal risk 2. On list approved by DHHS

35. Definition of minimal risk  Probability and magnitude of harm or discomfort  Not greater than encountered in daily life or routine physical exam 35

36. Examples of minimal risk  Answering (non-sensitive) questions over telephone  Routine blood tests, EKG 36

37. Significance of minimal risk  May be eligible for  Expedited IRB review  Waiver of informed consent  In pediatrics, different categories of review and approval 37

38. 38 When may IRB review be expedited? 2. On list approved by DHHS  Noninvasive collection of specimens Urine, buccal swabs  Noninvasive clinical procedures EKG, ultrasound Not x-rays

39. 39 When may IRB review be expedited? 2. On list approved by DHHS  Venipuncture  Interview, focus group research  Research with existing data, specimens collected for nonresearch purposes  Minor changes to approved protocol Changes in questionnaire, tests run

40. 40 Questions?

41. IRB review of multisite studies  Review at each site causes long delays, requires great effort  Inconsistent requirements  May push clinical trials to clinical research organizations, independent IRB 41

42. Review of multisite studies  Cooperative arrangements  Defer review to other UC IRBs  Facilitated review by central IRB  NCI sends detailed review to sites May be useful in other types of studies  Facilitated review by single IRB member 42

43. Top 5 problems with IRB submissions 1. Study procedures not clear  Reader should be able to replicate study 2. Recruitment and consent process unclear  Who, where, when, how?  Vulnerable populations 43

44. Top 5 problems with IRB submissions 3. Inconsistency within protocol  Methods and consent sections not agree 4. Missing information 5. Undefined acronyms 44

45. Tips for IRB submissions  Know what CHR requires  Use correct templates and form  Special regulations for children, prisoners  Anticipate IRB concerns  Write for nonspecialists  Reviewers do not want to re-read to figure out what you are doing 45

46. Tips for IRB submissions  Ask the IRB questions  Find out what they are likely to have concerns about  Get it right the first submission  If difficult or sensitive issues, show that you considered alternatives and give reasons for your approach 46

47. Take home points  IRB review process will be easier for you if  You understand when expedited and waiver are permitted  Avoid common problems with IRB submissions 47

48. 48