1. 1 Research Involving Human Subjects NIH Regional Seminar Yvonne Lau, MBBS, MBHL, PhD Director, Division of Education and Development (DED) Office for Human Research Protections (OHRP) Department of Health and Human Services (HHS) Ann Hardy, DrPH NIH Human Research Protections Officer Office of Extramural Research, NIH Meredith Temple O’Connor, PhD NIH Inclusion Policy Officer Office of Extramural Research, NIH

2. Session Overview Human Subjects Regulations and application of the Common Rule NIH policies for grant applications proposing human subjects research NIH policies on inclusion of women, minorities and children in NIH-funded research 2

3. Learning Objectives Understand the ethical rationale for the federal regulations on human research protections Apply the basics of the Common Rule Recognize the requirements for human subjects in NIH grant applications Understand the post award requirements for research involving human subjects Know the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Understand what studies inclusion policy applies to Understand post award requirements for monitoring inclusion in clinical research 3

4. OFFICE FOR HUMAN RESEARCH PROTECTIONS (OHRP) - WHO ARE WE?OHRP 4 Mission Provides leadership in the protection of the rights, welfare and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services (HHS)

5. OHRP Structure Office of the Director Division of Education & Development Division of Policy & Assurance Division of Compliance & Oversight 5

6. HHS REGULATIONS ON HUMAN RESEARCH PROTECTIONS 6

7. What is Research? Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge 45 CFR 46.102(d)  Research serves the Common Good  Research subjects are the ‘means’ to achieve this goal  Primary interest of research is not about benefiting subjects 7

8. The Ethical Conundrum Treating research subjects as PEOPLE, not merely just a tool 8 Serving the common good through human research

9. Tuskegee Syphilis Study (1933-72)  Subjects were not told that they were participating in a research study  Subjects were not offered penicillin when this became established as the standard of treatment  Subjects were even prevented access to it  1974: National Research Act  1979: Belmont Report  1981: Protection of Human Subjects laws 9

10. The Belmont Report Three Basic Principles 1. Respect for Person s  Promoting autonomy 2. Beneficence  Maximize benefits; minimize harms 3. Justice  Equitable distribution of burden & benefits 10

11. HHS Regulations on Human Research Protections 45 CFR Part 46  Subpart A – “The Common Rule”  Subpart B – Pregnant women and fetus  Subpart C - Prisoners  Subpart D – Children  Subpart E – IRB Registration 11

12. “The Common Rule” 45 CFR Part 46 Subpart A Adopted by 18 federal departments & agencies 12

13. “The Common Rule” Providing the ABCs in Human Protections  Institutional Assurance of Compliance (Federalwide assurance - FWA)  Institution Review Boards (IRB)  Informed Consent 13

14. Federalwide Assurance (FWA)  Required when institutions are engaged in non- exempt human subject research conducted or supported by a federal department/agency  Documentation of institution’s commitment to protecting the rights and welfare of human research subjects; comply with applicable regulations  Designate the IRB(s) to be used to review applicable human subjects research 14

15. IRB Review & Oversight  Institutional Review Board (IRB) A committee charged with the review of research involving human subjects to assure that their rights and welfare are adequately protected.  Approve research when specific requirements are met (§46.111) 15

16. Informed Consent  Respect for Persons  Subjects can make informed decisions about participation  Subjects Protection  Subjects have input into the risks that are acceptable to them  Heightens subjects awareness when risks become reality  Specific Requirements (§46.116) 16

17. 17 HHS vs. FDA Regulations  Differences in Scope HHS regulations apply to HHS-funded research FDA regulations apply to clinical investigations involving FDA regulated products: drugs, devices, or biologics  Consider Where your research $ come from? Does your research involve drugs, devices, biologics regulated by FDA? Will you be considering the US market for the drugs, devices, biologics that you study?

18. 18 HHS vs. FDA Regulations cont’d  Basic requirements for IRBs and informed consent are congruent  Harmonization efforts – joint guidance  Detailed differences at FDA WebsiteFDA Website

19. APPLYING THE HHS REGULATIONS 19

20. When do the Regulations Apply?  Research involving human subjects conducted or supported by HHS that is not otherwise exempt  Non-exempt human subject research covered by the Assurance of Compliance ‘Checking the box’ 20

21. 21 How to Apply the Regulations? 1. Does activity involve Research? 2. Does research involve Human Subjects? 3. Is human subjects research Exempt? ASK QUESTIONS IN THIS ORDER! See Human Subject Regulations Decision ChartsDecision Charts

22. Is it ‘Research’? Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge 45 CFR 46.102(d)  A team of physicians see a patient with an unusual constellation of symptoms.  They run a variety of diagnostic tests and procedures.  Results of the test do not yield a known diagnosis.  They write up a case summary of their observations and submits it to a medical journal for publication. Is this Research? 22

23. 23 Does it involve ‘Human Subjects’? Human subject – a living individual about whom an investigator conducting research obtains  data through intervention or interaction with the individual, or  identifiable private information* * Identity of the subject is or may readily be ascertained by the investigator or associated with the information

24. Quiz Question A study protocol describes the following proposed research activities:  Investigator will receive biological specimens from an outside source  Investigator cannot identify the individuals to whom the specimens pertain  Specimens were not obtained for purposes of the current research Is this Human Subjects Research? 24

25. 25 Is the Human Subject Research Exempt*? 1. Normal educational practices in established educational settings 2. Educational tests, surveys, interviews, or observation of public behavior -unless identified & sensitive** 3. Research on elected or appointed public officials or candidates for public office * Do not apply to prisoners ** Do not apply to children 4. Research using existing data, if publicly available or recorded without identifiers 5. Evaluation of public benefit service programs 6. Taste and food quality evaluation and consumer acceptance studies 46.101(b)(1-6)

26. Quiz Question A study protocol describes the following proposed research activities:  The subjects will be asked to complete surveys  The information is not sensitive & will not put subjects at risk of harm  The study involves prisoners as subjects Can this HS Research be ‘Exempt’? 26

27. Contact OHRP  Visit OHRP websitewebsite  OHRP email box ohrp@hhs.gov  Phone inquiries 240-453-6900  Join OHRP ListServ at http://www.hhs.gov/ohrp/newsroom/index.html 27

28. Ann Hardy, Dr.P.H. (hardyan@od.nih.gov)hardyan@od.nih.gov NIH Extramural Human Research Protection Officer NIH Office of Extramural Research (OER)

29. Understand the ethical rationale for the federal regulations on human research protections Apply the basics of the Common Rule Recognize the requirements for human subjects in NIH grant applications Understand the post award requirements for research involving human subjects Know the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Understand what studies inclusion policy applies to Understand post award requirements for monitoring inclusion in clinical research 29 Learning Objectives

30. 30 Regulatory Requirements for Sponsoring Agency (NIH) Agencies evaluate applications/proposals involving human subjects for risks, adequacy of protections, benefits and importance of knowledge to be gained ▫ NIH delegates to Peer Review Do not make an award unless regulatory requirements are met ▫ Administrative procedures to ensure compliance 30

31. Human Subjects Section In NIH Application (Non-exempt HSR) Risks ▫ Human subjects involvement and characteristics; vulnerable populations ▫ Sources of materials – what, how, access to identifiers ▫ Potential Risks – physical, psychological, social Adequacy of Protection Against Risks ▫ Recruitment; consent ▫ Procedures to minimize risks ▫ Additional protections for vulnerable subjects 31

32. Human Subjects Section In NIH Application (Non-exempt HSR) -2 Potential Benefits of Research to Human Subjects and Others ▫ May not be direct benefit to subjects ▫ Discuss risks in relation to anticipated benefits ▫ Should not include monetary compensation Importance of Knowledge to be Gained ▫ Discuss in relation to risks 32

33. 33 Additional NIH Requirements For Clinical Trials: ▫ Data and Safety Monitoring Plan or Board ▫ Registration in ClinicalTrials.gov For NIH-Defined Clinical Research ▫ Inclusion of Women, Minorities, and Children 33

34. 34 Preparing the Human Subjects Section Use Instructions for Preparing HS section Instructions for Preparing HS section Select one of 6 scenarios: A. No Human Subjects B. Non-Exempt Human Subjects Research C. Exempt Human Subjects Research D. Delayed-Onset of Human Subjects Research E. Clinical Trial F. NIH-defined Phase III Clinical Trial 34

35. 35 Scenario A: No Human Subjects Are Human Subjects Involved? Yes X No Human subjects section NOT required BUT must provide justification if using human specimens/ data - samples provided from research repository without identifiers - samples are purchased from commercial vendor 35

36. Research Involving Coded Data or Specimens If research involves only secondary analysis of coded data/specimens it is NOT human subjects research if: ▫ Collected for other reason ▫ None of investigators can readily ascertain the identity of subjects (Provider has no other role in research) http://www.hhs.gov/ohrp/policy/cdebiol.html 36

37. 37 Scenario B: Non-Exempt Research Are Human Subjects Involved? X_ Yes ___ No Research Exempt? ___ Yes_X_ No Clinical Trial? ___ Yes_X_ No NIH-Defined Phase III CT? ___ Yes_X_ No Human Subjects Section- no page limitations ▫ Address 4 required points (risk, protections, benefits, knowledge) Inclusion of Women, Minorities, and Children 37

38. Human Subjects Section In NIH Application (Non-exempt HSR) Risks ▫ Human subjects involvement and characteristics; vulnerable populations ▫ Sources of materials – what, how, access to identifiers ▫ Potential Risks – physical, psychological, social Adequacy of Protection Against Risks ▫ Recruitment; consent ▫ Procedures to minimize risks ▫ Additional protections for vulnerable subjects 38

39. Human Subjects Section In NIH Application (Non-exempt HSR) -2 Potential Benefits of Research to Human Subjects and Others ▫ May not be direct benefit to subjects ▫ Discuss risks in relation to anticipated benefits ▫ Should not include monetary compensation Importance of Knowledge to be Gained ▫ Discuss in relation to risks 39

40. 40 Scenario C: Exempt Research Are Human Subjects Involved? X Yes No Research Exempt X Yes No Exemption Number _X_1 __2 __3 __4 __5 __6 Clinical Trial? ___Yes_X_ No NIH-Defined Phase III CT?___Yes_X_ No Human Subjects Section ▫ Justify selection of exemption(s) ▫ Sources of research materials Inclusion of Women, Minorities, and Children * *Not required for Exemption 4 40

41. 41 Scenario D: Delayed Onset HS Research Are Human Subjects Involved?_X_ Yes___No Research Exempt?___ Yes___ No Clinical Trial?___ Yes___ No NIH-Defined Phase III CT ?___ Yes___No Delayed Onset: Human subjects research anticipated but specific plans can’t be described in the application Human Subjects Section – explain why delayed onset If funded, awardee must provide FWA, IRB approval, human subjects and inclusion sections to NIH before involving human subjects 41

42. 42 Scenarios E & F: Clinical Trial Recently revised Definition of Clinical Trial: a research study in which 1 or more subjects are prospectively assigned to 1 or more interventions (including placebo) to evaluate effects on health-related biomedical or behavioral outcomes. NIH Defined Phase III Trial - broad-based, prospective trial, often to provide scientific basis for change in health policy or standard of care (Scenario F) All other Phases (Scenario E) 42

43. 43 Scenario E: Clinical Trial (not Phase III) Are Human Subjects Involved? _X_ Yes ___ No Research Exempt? ___ Yes _X_ No Clinical Trial? _X_ Yes ___ No NIH-Defined Phase III CT? ___ Yes _X_ No Provide information required for Scenario B (Non- Exempt Human Subjects Research) Must have a Data and Safety Monitoring Plan ClinicalTrials.gov 43

44. 44 Data and Safety Monitoring Plan Data and Safety Monitoring Plan includes: ▫ Overall framework for data and safety monitoring ▫ Responsible party for monitoring ▫ Procedures for reporting Adverse Events/Unanticipated Problems Data and Safety Monitoring Board (DSMB) required for: ▫ Multi-site trials > minimum risk and generally for Phase III trials Funding IC approval before enrollment begins 44

45. 45 Scenario F: NIH-Defined Phase III Clinical Trial Are Human Subjects Involved? _X_ Yes ___ No Research Exempt? ___ Yes _X_ No Clinical Trial? _X_ Yes ___ No NIH-Defined Phase III CT? _X_ Yes ___ No Provide information required for Scenario E Generally requires DSMB Additional inclusion policy requirements to be addressed related to study design 45

46. Peer Review of Human Subjects Section Each reviewer will assess human subjects protections ▫ Actual or potential unacceptable risks, or inadequate protections, or insufficient information Peer review group will determine overall rating of “acceptable” or “unacceptable” Summary Statement:  PROTECTION OF HUMAN SUBJECTS: UNACCEPTABLE (Code 44)  Code 44 is a bar to award 46

47. Common HS Concerns Identified in Peer Review Human Subjects Section inadequate Missing/inadequate DSMP/B Source of specimens/data inadequately described Physical/psychological risks not adequately addressed Informed consent issues Confidentiality of data Incidental findings not addressed 47

48. Just-in-Time Requirements After peer review, grants likely to be funded: ▫ OHRP Assurance Number (FWA) ▫ Certify IRB approval  Can rely on other IRB ▫ Certify Key Personnel have taken human subjects research education  https://phrp.nihtraining.com/users/login.php https://phrp.nihtraining.com/users/login.php ▫ Resolve unacceptable Human Subjects Section  Written response to IC  NIH OER concurrence 48

49. After the Award… Now What? Human Research Protections : ▫ Annual IRB approval ▫ UP/AE Reports – within 3 days or as required ▫ Prior NIH Approval for changes in human subjects research that increase risk  Add HS activities to non-HS award or add Clinical trial  New enrollment of preg. women, children or prisoners  Addition that is greater than minimal risk or new info that study procedure/intervention is higher risk  Discuss plans with PO before starting!! 49

50. Certificates of Confidentiality (CoC) Purpose: ▫ Protects investigators/institutions from forced disclosure of identifiable research info (subpoena) ▫ Encourage participation For IRB approved studies that collect personal identifiers and sensitive info DHHS Agencies that issue: CDC, IHS, SAMHSA, HRSA, FDA, and NIH Federal funding not required but research must be health related (NIH and FDA issue bulk of CoCs for non-funded research) http://grants.nih.gov/grants/policy/coc/index.htm 50

51. Resources for NIH HS Policies SF 424 & Electronic Submission Page http://grants.nih.gov/grants/funding/424/index.htm NIH OER Human Subjects Website: http://grants.nih.gov/grants/policy/hs/ NIH Revised Definition of Clinical Trial: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html NIH Data and Safety Monitoring http://grants.nih.gov/grants/policy/hs/data_safety.htm 51

52. Meredith D. Temple-O’Connor, Ph.D. NIH Inclusion Policy Officer Office of Extramural Research (OER) National Institutes of Health inclusion@od.nih.gov

53. Understand the ethical rationale for the federal regulations on human research protections Apply the basics of the Common Rule Recognize the requirements for human subjects in NIH grant applications Understand the post award requirements for research involving human subjects Know the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Understand what studies inclusion policy applies to Understand post award requirements for monitoring inclusion in clinical research 53 Learning Objectives

54. NIH Inclusion Policies Inclusion of Women and Minorities ▫ Must be included in NIH-defined clinical research unless exclusion is justified for scientific reasons ▫ Justify the proposed sample in the context of who is at risk for the disease/condition and the scientific goals of the specific study ▫ Plans for outreach and recruitment ▫ Provide Inclusion Enrollment Report form(s) with proposed sex/gender, race, and ethnicity of the sample 54

55. NIH Inclusion Policies (con’t) Inclusion of Children ▫ Children must be included in clinical research unless there are scientific or ethical reasons not to do so ▫ “Children” are currently defined by the NIH as individuals <21 years  Note: Age of a child for inclusion purposes will change to <18 years starting with January 25, 2016 application receipt dates ▫ Applicants should justify the proposed age range of the participants, with specific attention to justifying the inclusion/exclusion of individuals under 21 55

56. Defining the Universe Inclusion of women and minorities in all NIH funded or supported clinical research is mandated by law and policy; inclusion of children mandated by policy What is subject to the statute/policies? ▫ All studies (intramural, extramural, contracts) that meet the NIH definition of clinical research  NIH definition of clinical research: (1) Patient-Oriented Research: Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual (e.g., IRB Exemption 4). Patient-oriented research includes (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical studies, or (d) development of new technologies; (2) Epidemiologic and Behavioral Studies; and (3) Outcomes Research and Health Services Research ▫ Additional requirements for NIH-defined Phase III clinical trials related to unbiased design and assessment of potential group differences Bottom line: ▫ If you answer yes to human subjects and not E4, you should address inclusion because there are very few studies that will not be considered NIH-defined clinical research. 56

57. But what does it mean to include? Purpose Statement: NIH supported clinical research should address/include the population(s) at risk for the disease or condition under study. The purpose of NIH Inclusion Policies is to ensure that the distribution of study participants by sex/gender, race, ethnicity, and age reflects the population needed to accomplish the scientific goals of the study, rather than enumeration of research participants. All NIH-funded studies that meet the NIH definition for clinical research are subject to NIH Inclusion Policies, regardless of funding mechanism*. (*Funding mechanism includes any activity code associated with extramural grants, R&D contracts, and cooperative agreements as well as intramural projects and R&D contracts) Bottom line: Does the study have the right participants for the proposed science? 57

58. What’s required for inclusion in a competing application? Remember the “universe” to determine whether inclusion applies to your application Plans for inclusion of women and minorities ▫ Includes addressing plans for valid analysis if conducting an NIH-defined Phase III clinical trial Plans for the inclusion of children Inclusion enrollment report ▫ Planned or Cumulative (actual) depending on the study design NOTE: Follow the scenarios described in Human Subjects’ protection section to further understand what’s expected for different scenarios 58

59. Inclusion Enrollment Report Forms ▫ Now a structured data form ▫ Need to consider race and ethnicity separately ▫ Which form to use?  Planned or Cumulative? Separate report forms for US and International participants (even if part of the same study) 59

60. Peer Review of Inclusion Each reviewer will assess the inclusion plans ▫ Plans for inclusion ▫ Justification in the context of the science Peer review group will determine overall rating of “acceptable” or “unacceptable” Summary Statement:  INCLUSION OF WOMEN, MINORITIES, AND/OR CHILDREN: UNACCEPTABLE (U CODE)  Unacceptable (U) code is a bar to award 60

61. Common Inclusion Concerns Identified in Peer Review Inadequate information describing the sex/gender, race, ethnicity, and/or age(s) of the sample Inadequate justification for proposed sample ▫ Sex/gender, race, ethnicity, and/or age(s) breakdown not appropriate for the scientific goals of the study or not adequately justified Unrealistic sampling ▫ Appropriate from scientific perspective but not realistic  Collaborations and outreach plans may help 61

62. Just-in-Time Requirements After peer review, for grants likely to be funded: ▫ Work with Institute/Center staff to resolve unacceptable inclusion concerns  Written response to IC ▫ Provide inclusion enrollment report(s) if missing or need update as a result of peer review and/or programmatic adjustments  This now happens directly in the Inclusion Management System through Commons  Remember: If you make changes to inclusion data records through Commons, you need to route to your SO to send to NIH 62

63. Provide cumulative inclusion enrollment (e.g., actual enrollment) information at least annually or as frequently as specified by the funding Institute/Center ▫ Provided in Inclusion Management System through RPPR or through Commons Status For NIH-defined Phase III Clinical Trial– report any analysis or findings related to outcomes by sex/gender, race, and ethnicity if available Note progress (or challenges) in recruitment as needed in RPPR 2015 Updated Policy – Prior NIH Approval for changes in human subjects research that increase risk or delayed onset studies (Scenario D) ▫ Changes the project from no to yes for human subjects involvement or from no to yes for clinical trial ▫ Study not previously designed is ready to start ▫ Discuss plans with NIH PO before starting ▫ Ensure that inclusion plans and/or inclusion enrollment are provided (prior to start or at RPPR—check with funding Institute/Center for specific procedures) 63 After the Award… Now What? 63

64. Inclusion Resources for Investigators Training and Guidance ▫ FAQs ▫ How To Videos and User Guides for working in the Inclusion Management System  https://nih-extramural- intranet.od.nih.gov/d/IMS_Principal_Investigat ors https://nih-extramural- intranet.od.nih.gov/d/IMS_Principal_Investigat ors ▫ Podcasts ▫ Narrated slide decks Guide notices and other policy related documents Public website ▫ http://grants.nih.gov/grants/funding/women_min/women_min.htm http://grants.nih.gov/grants/funding/women_min/women_min.htm 64