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)

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

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

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

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

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

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

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

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

14. Why is informed consent difficult?

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. 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. 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. 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. 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. 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. What is essential for participants to comprehend?

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

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

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

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

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?

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

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

34. Consent not required • Not human subjects research • No IRB review • Exempt from human subjects regulations • 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

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

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

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

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. 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

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

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

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

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

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

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

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

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