1. 1 Informed consent Bernard Lo, M.D. August 11 and 12, 2010

2. Neonatal blood samples  Screen for birth defects  Required by law  Parental consent not required  Later used for research on  Preterm birth  Environmental levels of pesticides  Gene-environment interactions (smoking, folic acid, cleft palate) 2

3. Questions for audience  Do regulations permit research be carried out on leftover neonatal spots without consent?  Yes /No / Unsure 3

4. Questions for audience  Should regulations permit research be carried out on leftover neonatal spots without consent?  Yes /No / Unsure 4

5. Neonatal blood samples  Parents in Texas sued over storage of samples for for research without consent  2002 Texas law allows opt-out  5.3 million samples from before 2002 destroyed 5

6. Use of neonatal blood spots for research  Permitted under federal regulations  Ethically contested 6

7. 7 Outline for today  What does informed and voluntary consent require?  How can consent be improved?  What are exceptions to consent?  Why are some exceptions in regulations ethically problematic?

8. Why is consent needed?  Research compared to clinical care  Risks and benefits uncertain  Risk/benefit balance less favorable  Purpose is not to benefit participants 8

9. Rationale for informed consent  Respect for values and choices of subjects  Deter research with unacceptable risks 9

10. Questions for audience  After signing consent forms, do most participants understand key features of study?  Do IRB modifications improve consent? 10

11. 11 1. HIV prevention trial  RCT of diaphragm + gel vs. diaphragm + placebo in women in Africa at risk for HIV infection  Both arms receive free condoms

13. 13 What must researchers disclose?  Nature and purpose of research  Research procedures, risks, benefits  Unforeseeable risks  Participation voluntary, may discontinue  IRB template

14. 14 Why is informed consent difficult?

15. 15 Why is informed consent difficult?  Participants commonly misunderstand  Not understand how RCT differs from clinical care  Believe that study interventions are Standard therapy Best treatment for condition No additional risks For their personal benefit

16. 16 Why is informed consent difficult?  Participants commonly misunderstand  Basic features of trial design May be in control group Randomization Therapeutic options restricted by study design rather than individualized for them

17. 17 Why is informed consent difficult?  Vulnerable participants  Low health literacy, low literacy  Poverty, few options  Cultural context  No informed consent in clinical care  No acknowledgement of medical uncertainty

18. 18 How can informed consent be enhanced?  Empirical studies  Spend more time talking to participants  Questions and feedback  Shorter, simpler consent forms  Multimedia -- mixed evidence

19. 19 How can informed consent be enhanced?  Practical suggestions  Take point of view of participant  Use simple language that 8th grader can understand  Explain how RCT differs from clinical care  Invite questions

21. 21 How can informed consent be enhanced?  Focus on comprehension by participant, not consent forms  Administer questionnaire to ensure appreciation of key aspects of study

22. 22 What is essential for participants to comprehend?

23. 23 What is essential for participants to comprehend?  Could still get HIV  Don’t know whether intervention works  May not get active intervention  Keep using condoms every time

24. 24 What is essential for participants to comprehend?  May refuse to participate  May withdraw from study

25. 25 Why is voluntary consent difficult?  Hard to say no to persons in power  Defer to husband or father  Relationship to investigator Student Employee  Undue monetary influence

26. Research participants who may lack decision-making capacity  Persons receiving CPR, ICU care  Severe dementia  Severe psychiatric illness  Young children 26

27. 27 Concerns about participants who lack decision-making capacity  Not appreciate risks  Not able to refuse  Might be subjected to risks that competent persons would refuse

28. Options if lack decision-making capacity  Exclude from trials  But lack evidence safety and effectiveness of treatments  Additional protections 28

29. 29 Additional protections if lack decision-making capacity  Formal assessment of decision-making capacity  Permission from surrogate  Assent of participant

30. 30 Additional protections for vulnerable partcipants  Closer monitoring for adverse effects  Subject advocate who can withdraw participant from study  IRB include persons familiar with the condition that impairs capacity  Research advance directives

31. Questions for audience Without consent, may researcher  Use EMR to study whether patients have worse outcomes if admitted over weekend?  Use leftover cancer tissue to identify prognostic markers? 31

32. Ethical rationale for no consent  Very low risk  No physical risks  Confidentiality the main risk  Cannot be breached if not identifiable  Benefits of research >> risks 32

33. Ethical rationale for no consent  No one would or should object if asked  Cancer tissue would be discarded  Leftover tubes of blood  Impracticable to get consent  Could not carry out important study 33

34. 34 Consent not required 1. Not human subjects research  No IRB review 2. Exempt from human subjects regulations 3. Qualifies for waiver

35. What is human subjects research?  Interact with person OR  Use identifiable private information  Not human subjects research if data and materials cannot be identified  Examples of tissue from cancer surgery 35

36. 1. Not human subjects research  De-identified data and materials  Coded data and materials, researcher cannot access keys to code  None of 18 HIPAA identifiers  Code may be retained by database or biobank 36

37. 2. 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 37

38. 2. Exempt from federal regulations  Existing data or materials  Publicly available  Existing data or specimens if researcher records information in manner than subjects cannot be identified Can look at medical records 38

39. 39 Studies that require identifiers  Link specimens with clinical records  Prognostic markers in cancer  HER2/neu overexpression = poor prognosis  Trastuzumab effective only in patients who overexpress HER2/neu

40. 40 3. Waiver of consent  Minimal risk  Not adversely affect rights and welfare  Could not be practicably carried out  IRB may allow identifiable data to be used without consent  Use identifiers to link different databases

41. Research with cancer specimens  Not human subjects research if  Completely de-identified  Coded and researcher has no access to key  Can determine prevalence of marker 41

42. Neonatal spots  Not human subjects research if  Completely de-identified  Coded and researcher has no access to key  Waiver of consent  Can link spots to medical records 42

43. Neonatal spots  Permissible in regulations  Approved by IRBs  But still problematic  New standard is to offer opt-out for research 43

44. Questions for audience  Do regulations permit whole genome sequencing on de-identified materials?  Yes /No / Unsure  Should regulations permit whole genome sequencing on de-identified materials?  Yes /No / Unsure 44

45. 45 Re-identification in whole genomic sequencing  Reference samples in forensic databases  DOJ has 8.3 million profiles  STRs at 13 locations  Full genome sequence yields DOJ identifiers

46. Whole genome sequence an overt identifier?  Need access to DOJ database  Is access to DOJ identifiers more secure than access to SSN?  May need to rethink concept of “de- identified” samples 46

47. Concerns about whole genome sequencing  Subject may consider information very private and sensitive  Privacy concerns access to information about self  May not want others to access  Even if identity not explicitly known 47

48. Concerns about whole genome sequencing  Some donors may object  When giving blanket consent for research, donors did not consider this  If donors had been told, would they object?  Respect donors who have strong objections 48

49. Questions for audience  Genetics of criminal behavior  Match DOJ database with neonatal blood spots without consent  Do regulations permit this?  Yes /No / Unsure  Should regulations permit this?  Yes /No / Unsure 49

50. Objections to certain research on existing samples  Genetics of criminal and antisocial behavior  Stigmatize vulnerable populations  Undermine individual responsibility  Human evolution  Derivation of embryonic stem cells from IVF embryos 50

51. Options  Sensitive research only with express consent  IRB determination of “sensitive”  More specific consent at donation  Re-consent participants?  Make research much more difficult 51

52. Take home message  Consent is important but challenging  Important exceptions to consent permitted in federal regulations  But some exceptions ethically contested  Ethical standards may be stricter than regulatory requirements  Ultimate researcher is repsonsible 52