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Research Involving Human Subjects

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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

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

3 Learning Objectives Describe 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 Provide post-award requirements for research involving human subjects Explain the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Provide an understanding of what studies inclusion policy applies to List post-award requirements for monitoring inclusion in clinical research

4 OHRP - Who are we?

5 Office for Human Research Protections (OHRP)
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).

6 Division of Education & Development (DED)
Conducts educational programs, quality improvement activities & develop training tools & informational materials Provides ethical guidance & regulatory interpretation of the HHS-regulations for human research protections Conducts public outreach to enhance awareness of human research protections

7 Ethics & regulations on human research protections

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

9 Research Ethics – “In the name of the Common Good”: A discipline built out of tragedies
Nazi docs at Nuremberg Trial Henry Beecher NEJM 1966 Tuskegee Syphilis Experiment

10 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

11 The Belmont Report (1979) Three Basic Ethical Principles
Respect for Persons Promoting autonomy Beneficence Maximize benefits; minimize harms Justice Equitable distribution of burden & benefits

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

13 “The Common Rule” Basic Protections
Institutional Assurances (Federalwide assurance - FWA) Institution Review Boards (IRB) Informed Consent

14 Additional HHS Protections
Subpart B - Pregnant Women, Human Fetuses, and Neonates Subpart C - Prisoners Subpart D - Children Subpart E - IRB Registration Alt Text: an image of a pregnant, possibly incarcerated, teen 14

15 HHS vs. FDA Regulations Differences in Scope
HHS regulations applied to HHS-funded research FDA regulations applied to clinical investigations involving FDA regulated products: drugs, devices, or biologics Basic requirements for IRBs and informed consent are congruent Detailed differences at FDA Website

16 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. Why do we need IRB review?

17 To Approve Research – IRB Must Find
Risks minimized Risk/benefit ratio reasonable Subject selection equitable Informed consent – obtained & documented Data monitored, as appropriate Privacy and confidentiality, as appropriate Additional protections for subjects vulnerable to coercion or undue influence §46.111(a) & (b)

18 Purpose: Subjects can make an informed decision about participation
Informed Consent Purpose: Subjects can make an informed decision about participation What are the key elements? Information Comprehension Voluntariness

19 Applying the hhs regulations

20 When do the Regulations Apply?
Kevin L. Nellis, MS, MT(ASCP) February 8, 2008 When do the Regulations Apply? Research involving human subjects conducted or supported by HHS that is not otherwise exempt -OR- Non-exempt human subject research covered by Assurance of Compliance Alt Text: the image represents money support as a way to trigger applicability of the regulations Alt Text: the box with a check mark represents an institution voluntarily applying the regulation to all research regardless of the source of support 20 20

21 How to Apply the Regulations?
Kevin L. Nellis, MS, MT(ASCP) February 8, 2008 How to Apply the Regulations? Does activity involve Research? Does research involve Human Subjects? Is human subjects research Exempt? ASK QUESTIONS IN THIS ORDER! See Human Subject Regulations Decision Charts Alt Text: image of a book depicting government regulations 21 21

22 Is it ‘Research’? Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge 45 CFR (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?

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 23

24 Is this Human Subjects Research?
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 Is the Human Subject Research Exempt? Categories of Exempt Research*
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 * Exception for prisoners ** Exception for 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) 25

26 Is this Human Subjects Research Exempt?
Quiz Question A study protocol describes the following proposed research activities: the study involves prisoners as subjects The subjects will be asked to complete surveys about food preferences The information is neither identifiable nor sensitive Is this Human Subjects Research Exempt? 26

27 Contact OHRP Visit OHRP website OHRP email box ohrp@hhs.gov
Phone inquiries Join OHRP ListServ at

28 NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR HUMAN SUBJECTS RESEARCH
Ann Hardy, Dr.P.H. NIH Extramural Human Research Protection Officer NIH Office of Extramural Research (OER)

29 Learning Objectives Describe 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 Provide post-award requirements for research involving human subjects Explain the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Provide an understanding of what studies inclusion policy applies to List post-award requirements for monitoring inclusion in clinical research

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 The Department or Agency head will evaluate all applications and proposals involving human subjects submitted to the Department or Agency through such officers and employees of the Department or Agency and such experts and consultants as the Department or Agency head determines to be appropriate. This evaluation will take into consideration the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. (b) On the basis of this evaluation, the Department or Agency head may approve or disapprove the application or proposal, or enter into negotiations to develop an approvable one. Federal funds administered by a Department or Agency may not be expended for research involving human subjects unless the requirements of this policy have been satisfied. 30 30 30 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

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

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 33

34 Preparing the Human Subjects Section
Use 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 34

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 Alternate text: The figure is a mouse sitting on the part of the slide that indicates “no human subjects.” 35 35 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) Alternate text: A picture of a set of test tubes in a rack with the shadow of a scientist behind it.

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 37

38 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 38 38

39 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 39 39

40 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) 40 40

41 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 41 41

42 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 42 42

43 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 Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. Behavioral human subjects research involving an intervention to modify behavior 43 43 43

44 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 Alternate text: The picture depicts a stack of dollars and a stack of gold coins with a red “X” through them. 44 44

45 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 In order from most to least common in FY2002

46 Just-in-Time Requirements
After peer review, for grants likely to be funded, provide: OHRP Assurance Number (FWA) Certification of IRB approval Certification that Key Personnel have completed appropriate human subjects research education https://phrp.nihtraining.com/users/login.php Resolution of unacceptable Human Subjects Section Written response to IC NIH OER concurrence Alternate text: The graphic on this page is a clock with a smiley face and feet. 46

47 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!! Alternate text: The graphics at the top of this slide are dollar bills with a $ and smiley face and feet.

48 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) Alternate text: This graphic illustrates a shadow of a man’s head with a lock over it.

49 Resources for NIH HS Policies
SF 424 & Electronic Submission Page NIH OER Human Subjects Website: NIH Revised Definition of Clinical Trial: NIH Data and Safety Monitoring 49 49

50 NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR INCLUSION OF WOMEN, MINORITIES, AND CHILDREN IN CLINICAL RESEARCH Meredith D. Temple-O’Connor, Ph.D. NIH Inclusion Policy Officer Office of Extramural Research (OER) National Institutes of Health

51 Learning Objectives Describe 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 Provide post-award requirements for research involving human subjects Explain the requirements for addressing inclusion of women, minorities, and children in NIH grant applications Provide an understanding of what studies inclusion policy applies to List post-award requirements for monitoring inclusion in clinical research

52 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 52 52

53 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 defined by the NIH as individuals <21 years Applicants should justify the proposed age range of the participants, with specific attention to justifying the inclusion/exclusion of individuals under 21 53

54 Defining the Universe Bottom line:
Inclusion of women and minorities in all NIH funded or supported clinical research is mandated by law 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 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.

55 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 people for the science?

56 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

57 Inclusion Enrollment Report Forms
Now a structured data form in Forms C 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) 57

58 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 Alternate text: The picture depicts a stack of dollars and a stack of gold coins with a red “X” through them. 58 58

59 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 In order from most to least common in FY2002

60 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 Alternate text: The graphic on this page is a clock with a smiley face and feet. 60

61 After the Award… Now What?
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 2012 Policy – Prior NIH Approval for changes in human subjects research that increase risk Changes the project from no to yes for human subjects involvement or from no to yes for clinical trial 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) Alternate text: The graphics at the top of this slide are dollar bills with a $ and smiley face and feet. 61

62 Inclusion Resources for Investigators
Training and Guidance FAQs How To Videos and User Guides for working in the Inclusion Management System Podcasts Narrated slide decks Guide notices and other policy related documents Public website .htm Alternate text: This figure depicts a graphic of a “screen bean” person with a light bulb over their head and their hand raised by the light bulb.


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