Montclair State University, Montclair, NJ

1. Montclair State University,Montclair, NJ The Human Subjects’ Protection Regulations and You: What Everyone Should Know January 19, 2011 Elyse I. Summers, J.D. Director Division of Education and Development

2. Outline • History/Background • Ethical Principles • Overview of OHRP • Shared Responsibilities • Activities Update

3. Philosophical Basis Immanuel Kant (1724 - 1804): “For all rational beings come under the law that each of them must treat itself and all others never merely as means, but in every case at the same time as ends in themselves.”

4. Pre WWII Edward Jenner (1789) Smallpox Vaccine Claude Bernard (1865)Ethical Maxims Louis Pasteur (1885) Rabies Vaccine Walter Reed (1900)Yellow Fever

5. Nuremberg During the Nuremberg War Crimes Trials, 23 German doctors were charged with crimes against humanity for“performing medical experiments upon concentration camp inmates and other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts.”

6. The Nuremberg Code (1947) As part of the verdict, the Court enumerated some rules for "Permissible Medical Experiments", now known as the “Nuremberg Code”. These rules include: • voluntary consent • benefits outweigh risks • ability of the subject to terminate participation

7. Declaration of Helsinki Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects “Concern for the interests of the subject must always prevail over the interests of science and society.”

8. Post WWII • Willowbrook (1950s)mentally retarded children were deliberately infected with hepatitis virus • Jewish Chronic Disease Hospital (1960s)Live cancer cells were injected into 22 senile patients • Milgram (1963)"Behavioral study of odedience" • Humphries (1970)Tearoom Trade: Impersonal Sex in Public Places

9. Beecher Article “Ethics and clinical research”Henry K. Beecher New Engl J Med 274 (1966):1354-60 • 22 published medical studies presenting risk to subjects without their knowledge or approval • Published in some of the most prestigious journals and conducted at some of the most prestigious institutions

10. Public Health Service Policy • NIH Director and Surgeon General requested that the National Advisory Health Council review human subject protections • Council recommended prior institutional review for PHS supported research to: • Protect the rights and welfare of the subjects • Assure appropriate methods of informed consent • Determine acceptable balance of risks and benefits • Adopted as Public Health Service policy in 1966 • Beginnings of the Institutional Review Board (IRB)

11. Tuskegee Syphilis Study American medical research project conducted by the U.S. Public Health Service from 1932 to 1972, examined the natural course of untreated syphilis in black American men. The subjects, all impoverished sharecroppers from Macon county, Alabama, were unknowing participants in the study; they were not told that they had syphilis, nor were they offered effective treatment.

12. National Research Act • 1973 Kennedy Hearings “Quality of Health Care - Human Experimentation” • 1974 National Research Act • Established the “National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research” • Required IRBs at institutions receiving HEW support for human subjects research

13. The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979

14. The Belmont Report Basic Ethical Principles: • Respect for Persons • Individual autonomy • Protection of individuals with reduced autonomy • Beneficence • Maximize benefits and minimize harms • Justice • Equitable distribution of research costs and benefits

15. Office for Human Research Protections (OHRP) (Formerly Office for Protection from Research Risks)

16. OHRP Oversight All research involving human subjects conducted or supported by the Department of Health and Human Services (HHS) -- 45 CFR Part 46

17. Protecting Human Subjects is a Shared Responsibility Institution IRB Investigator Subjects Research Team Sponsor Advocates Family Government Public

18. “Top 10” Shared Responsibilities

19. Responsibility #1 Recognize when the regulations apply to planned activities 45 CFR 46.101 and 102

20. Determining Applicability • Does activity involve research? • Does research involve human subjects? • Is the human subject research exempt? Human Subject Regulations Decision Chart: http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm

21. Examples of Investigator Activities: Is There Research Involving Human Subjects?45 CFR 46.102(d), (f) • Obtaining information about living individuals by intervening or interacting with them • Obtaining identifiable private information about living individuals • Obtaining informed consent • Interacting with subjects • Studying, interpreting, or analyzing identifiable private information or data

22. Examples of Investigator Activities: Might It Be Exempt Research? 45 CFR 46.101(b)(1)-(5) • Some research is “exempt” from federal regulations • Institutions typically have SOPs to describe how and where and by whom exempt determinations are made • See, OHRP FAQs at: http://www.hhs.gov/ohrp/news/recentnews.html#20091015

23. Normal educational practices in established educational settings Educational tests, surveys, interviews, or observation of public behavior unless identified and sensitive Research using existing data, if publicly available or recorded without identifiers Research on elected or appointed public officials or candidates for public office Evaluation of public benefit service programs Taste and food quality evaluation and consumer acceptance studies Exempt Research45 CFR 46.101(b)(1)-(5) Research that is “exempt” includes:

24. Responsibility #2 Comply with relevant Federal regulations 45 CFR 46

25. Regulations for Protection of Human Subjects 45 CFR 46 • Subpart A – basic HHS Policy - “The Common Rule” or Federal Policy • Other federal departments & agencies have adopted • Subpart B - Pregnant Women, Human Fetuses, and Neonates • Subpart C - Prisoners • Subpart D - Children 6

26. Responsibility #3 Initial Review 45 CFR part 46.109(a)-(d); 46.110; 46.111

27. Materials Submitted to the IRB • Protocol, grant proposal, informed consent(s) • Recruitment materials and plan • Any IRB mandated or other related documents

28. Understand regulatory framework and IRB expectations and policies For example, convened board (45 CFR 46.109) or expedited review (45 CFR 46.110)? If the latter, must be on “the list” (no more than minimal risk and involve only procedures…) (45 CFR 46.110(a) and (b); 63 FR 60364-67) Considerations for IRB Review and Approval

29. Expedited Review: “The List” – no greater than minimal risk 45 CFR 46.102 (i) – The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Expedited Review: “The List” – and involves, e.g., collection of limited blood samples; collection of data through physical sensors placed on body; collection of data from voice and other recordings, etc. non-IND, non-IDE studies originally reviewed by convened board and there determined to be no greater than minimal risk and no additional risks identified. Considerations for IRB Review and Approval, cont’d

30. Provide sufficient information and materials Criteria for 46.111 determinations: e.g., risk/benefit ratio; appropriate recruitment; safeguards for vulnerable subjects (such as, avoiding coercion) Creates legally effective informed consent, assent, and permission materials Consider characteristics of local research Recognize and manage conflicts of interest (e.g., disclose, reduce, eliminate) Comply with IRB decisions and requirements Respond to IRB requests in a timely fashion Considerations for IRB Review and Approval, cont’d

31. Responsibility #4 Prospective IRB review of proposed changes to research 45 CFR 46.103(b)(4)(iii)

32. Prompt reporting to the IRB of proposed changes in a research activity Changes in approved research may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject§46.103(b)(4)(iii) No Changes to Research Without IRB Review and Approval

33. Responsibility #5 Continuing Review 45 CFR 46.109(e) New OHRP Guidance http://www.hhs.gov/ohrp/policy/continuingreview2010.pdf

34. Continuing Review Status Report • Number of subjects accrued • Unanticipated problems (or adverse events) • Withdrawal of subjects • Complaints about the research • Summary of any recent literature, findings, or other relevant information, especially information about risks associated with the research • Copy of the current informed consent document • Amendments or modifications

35. Lapse in Continuing Review ALL ACTIVITIES MUST STOP! • No enrollment of new subjects • IRB will determine if currently enrolled subjects can continue study related interventions/activities • Data analysis activities with private identifiable information

36. Responsibility #6 Obtain and document legally effective informed consent, assent, and parental permission in accord with §46.116, 46.117 and applicable subpart(s) and as approved by the IRB.

37. Informed Consent Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by §46.111(a)(4); 46.116; 46.117 • required unless IRB finds and documents that the criteria for a waiver or alteration of informed consent are satisfied • IRB may require written statement be provided to subjects

38. The Consent Process • Use currently approved informed consent document • “Re-consent” as appropriate • Provide copy to subject or LAR • Subpart D – • Child Assent • Parental or guardian permission

39. Responsibility #7 Realize your role when reporting certain incidents 45 CFR part 103(b)(5)

40. OHRP Reporting Requirements Institutions MUST report: • Unanticipated Problems Involving Risks to Subjects or Others • Serious or Continuing Noncompliance with the Regulations or IRB Requirements • Any suspension or termination of IRB approval

41. What is an Unanticipated Problem? Incident, experience, or outcome that is: • Unexpected (nature, severity, frequency) • Related or possibly related to research, AND • Suggests greater risk of harm than previously known or recognized

42. Algorithm for Determining Whether an Adverse Event is an Unanticipated Problem An adverse event occurs in one or more subjects. NO 1. Is the adverse event unexpected in nature, severity, or frequency? YES 2. Is the adverse event related or possibly related to participation in the research? NO YES 3. Does the adverse event suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized? YES NO Report the adverse event as an unanticipated problem under 45 CFR part 46 The adverse event is not an unanticipated problem and need not be reported under 45 CFR part 46

43. Only Report Unanticipated Problem to OHRP

44. Reporting Process INVESTIGATOR RESPONSIBILITIES: • Describe incident • Suggestive Corrective Actions & Possible Modifications

45. Reporting Process, cont’d IRB RESPONSIBILITIES: • Reviewing of incident and report by PI • Confirm that corrective actions are sufficient • Report to OHRP: • Project title, PI name, HHS or other federal support • Details of UP(s), serious or continuing noncompliance, or reason for suspension or termination of IRB approval • Description of any corrective action or modification to the research required by IRB or institution

46. Responsibility #8 Record Retention 45 CFR 46.115

47. Record Retention • Maintaining records per IRB requirements • 3 years after the study is completed • At least three years past completion of the research activity • Accessible for inspection and copying • In accord with institutional policies & other regulations

48. Responsibility #9 Fulfill responsibilities when study is completed

49. When is Study Completed? When all following completed: • Interactions & intervention • Data collection • Analysis of identifiable private information Note that institutions/IRBs/funding entities may have additional requirements

50. Study Completion Responsibilities • Notify IRB that study has closed • Retain signed consent documents and other IRB records • Store study data consistent with IRB plan • Honor commitments