Presentation on theme: "Research Involving Human Subjects"— Presentation transcript:
1 Research Involving Human Subjects NIH Regional SeminarYvonne Lau, MBBS, MBHL, PhDDirector, Division of Education and Development (DED)Office for Human Research Protections (OHRP)Department of Health and Human Services (HHS)Ann Hardy, DrPHNIH Human Research Protections OfficerOffice of Extramural Research, NIHMeredith Temple O’Connor, PhDNIH Inclusion Policy Officer
2 Session OverviewHuman Subjects Regulations and application of the Common RuleNIH policies for grant applications proposing human subjects researchNIH policies on inclusion of women, minorities and children in NIH-funded research
3 Learning ObjectivesDescribe the ethical rationale for the federal regulations on human research protectionsApply the basics of the Common RuleRecognize the requirements for human subjects in NIH grant applicationsProvide post-award requirements for research involving human subjectsExplain the requirements for addressing inclusion of women, minorities, and children in NIH grant applicationsProvide an understanding of what studies inclusion policy applies toList post-award requirements for monitoring inclusion in clinical research
5 Office for Human Research Protections (OHRP) MissionProvides 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 materialsProvides ethical guidance & regulatory interpretation of the HHS-regulations for human research protectionsConducts 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 knowledge45 CFR (d)Research serves the Common GoodResearch subjects are the ‘means’ to achieve this goalPrimary 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 TrialHenry Beecher NEJM 1966Tuskegee Syphilis Experiment
10 Tuskegee Syphilis Study (1933-72) Subjects were not told that they were participating in a research studySubjects were not offered penicillin when this became established as the standard of treatmentSubjects were even prevented access to it1974: National Research Act1979: Belmont Report1981: Protection of Human Subjects Laws
11 The Belmont Report (1979) Three Basic Ethical Principles Respect for PersonsPromoting autonomyBeneficenceMaximize benefits; minimize harmsJusticeEquitable 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 NeonatesSubpart C - PrisonersSubpart D - ChildrenSubpart E - IRB RegistrationAlt Text: an image of a pregnant, possibly incarcerated, teen14
15 HHS vs. FDA Regulations Differences in Scope HHS regulations applied to HHS-funded researchFDA regulations applied to clinical investigations involving FDA regulated products: drugs, devices, or biologicsBasic requirements for IRBs and informed consent are congruentDetailed 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 minimizedRisk/benefit ratio reasonableSubject selection equitableInformed consent – obtained & documentedData monitored, as appropriatePrivacy and confidentiality, as appropriateAdditional protections for subjects vulnerable to coercion or undue influence§46.111(a) & (b)
18 Purpose: Subjects can make an informed decision about participation Informed ConsentPurpose: Subjects can make an informed decision about participationWhat are the key elements?InformationComprehensionVoluntariness
20 When do the Regulations Apply? Kevin L. Nellis, MS, MT(ASCP)February 8, 2008When 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 ComplianceAlt Text: the image represents money support as a way to trigger applicability of the regulationsAlt Text: the box with a check mark represents an institution voluntarily applying the regulation to all research regardless of the source of support2020
21 How to Apply the Regulations? Kevin L. Nellis, MS, MT(ASCP)February 8, 2008How 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 ChartsAlt Text: image of a book depicting government regulations2121
22 Is it ‘Research’?Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge45 CFR (dA 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 obtainsdata through intervention or interaction with the individual, oridentifiable private information** Identity of the subject is or may readily be ascertained by the investigator or associated with the information23
24 Is this Human Subjects Research? Quiz QuestionA study protocol describes the following proposed research activities:Investigator will receive biological specimens from an outside sourceInvestigator cannot identify the individuals to whom the specimens pertainSpecimens were not obtained for purposes of the current researchIs this Human Subjects Research?24
25 Is the Human Subject Research Exempt? Categories of Exempt Research* 1. Normal educational practices in established educational settings2. 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 children4. Research using existing data, if publicly available or recorded without identifiers5. Evaluation of public benefit service programs6. Taste and food quality evaluation and consumer acceptance studies46.101(b)(1-6)25
26 Is this Human Subjects Research Exempt? Quiz QuestionA study protocol describes the following proposed research activities:the study involves prisoners as subjectsThe subjects will be asked to complete surveys about food preferencesThe information is neither identifiable nor sensitiveIs this Human Subjects Research Exempt?26
28 NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR HUMAN SUBJECTS RESEARCH Ann Hardy, Dr.P.H.NIH Extramural Human Research Protection OfficerNIH Office of Extramural Research (OER)
29 Learning ObjectivesDescribe the ethical rationale for the federal regulations on human research protectionsApply the basics of the Common RuleRecognize the requirements for human subjects in NIH grant applicationsProvide post-award requirements for research involving human subjectsExplain the requirements for addressing inclusion of women, minorities, and children in NIH grant applicationsProvide an understanding of what studies inclusion policy applies toList 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 gainedNIH delegates to Peer ReviewDo not make an award unless regulatory requirements are metAdministrative procedures to ensure complianceThe 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.30303030
31 Human Subjects Section In NIH Application (Non-exempt HSR) RisksHuman subjects involvement and characteristics; vulnerable populationsSources of materials – what, how, access to identifiersPotential Risks – physical, psychological, socialAdequacy of Protection Against RisksRecruitment; consentProcedures to minimize risksAdditional protections for vulnerable subjects
32 Human Subjects Section In NIH Application (Non-exempt HSR) -2 Potential Benefits of Research to Human Subjects and OthersMay not be direct benefit to subjectsDiscuss risks in relation to anticipated benefitsShould not include monetary compensationImportance of Knowledge to be GainedDiscuss in relation to risks
33 Additional NIH Requirements For Clinical Trials:Data and Safety Monitoring Plan or BoardRegistration in ClinicalTrials.govFor NIH-Defined Clinical ResearchInclusion of Women, Minorities, and Children3333
34 Preparing the Human Subjects Section Use Instructions for Preparing HS sectionSelect one of 6 scenarios:A. No Human SubjectsB. Non-Exempt Human Subjects ResearchC. Exempt Human Subjects ResearchD. Delayed-Onset of Human Subjects ResearchE. Clinical TrialF. NIH-defined Phase III Clinical Trial3434
35 Scenario A: No Human Subjects Are Human Subjects Involved? Yes X NoHuman 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 vendorAlternate text: The figure is a mouse sitting on the part of the slide that indicates “no human subjects.”353535
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 reasonNone 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 ___ NoResearch Exempt? ___ Yes _X_ NoClinical Trial? ___ Yes _X_ NoNIH-Defined Phase III CT? ___ Yes _X_ NoHuman Subjects Section- no page limitationsAddress 4 required points (risk, protections, benefits, knowledge)Inclusion of Women, Minorities, andChildren3737
38 Scenario C: Exempt Research Are Human Subjects Involved? X Yes NoResearch Exempt X Yes NoExemption Number _X_1 __2 __3 __4 __5 __6Clinical Trial? ___Yes _X_ NoNIH-Defined Phase III CT? ___Yes _X_ NoHuman Subjects SectionJustify selection of exemption(s)Sources of research materialsInclusion of Women, Minorities, and Children **Not required for Exemption 43838
39 Scenario D: Delayed Onset HS Research Are Human Subjects Involved? _X_ Yes ___NoResearch Exempt? ___ Yes ___ NoClinical Trial? ___ Yes ___ NoNIH-Defined Phase III CT ? ___ Yes ___NoDelayed Onset: Human subjects research anticipated but specific plans can’t be described in the applicationHuman Subjects Section – explain why delayed onsetIf funded, awardee must provide FWA, IRB approval, human subjects and inclusion sections to NIH before involving human subjects3939
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)4040
41 Scenario E: Clinical Trial (not Phase III) Are Human Subjects Involved? _X_ Yes ___ NoResearch Exempt? ___ Yes _X_ NoClinical Trial? _X_ Yes ___ NoNIH-Defined Phase III CT? ___ Yes _X_ NoProvide information required for Scenario B (Non- Exempt Human Subjects Research)Must have a Data and Safety Monitoring PlanClinicalTrials.gov4141
42 Data and Safety Monitoring Plan Data and Safety Monitoring Plan includes:Overall framework for data and safety monitoringResponsible party for monitoringProcedures for reporting Adverse Events/Unanticipated ProblemsData and Safety Monitoring Board (DSMB) required for:Multi-site trials > minimum risk and generally for Phase III trialsFunding IC approval before enrollment begins4242
43 Scenario F: NIH-Defined Phase III Clinical Trial Are Human Subjects Involved? _X_ Yes ___ NoResearch Exempt? ___ Yes _X_ NoClinical Trial? _X_ Yes ___ NoNIH-Defined Phase III CT? _X_ Yes ___ NoProvide information required for Scenario EGenerally requires DSMBAdditional inclusion policy requirements to beaddressed related to study designClinical 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 behavior434343
44 Peer Review of Human Subjects Section Each reviewer will assess human subjects protectionsActual or potential unacceptable risks, or inadequate protections, or insufficient informationPeer 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 awardAlternate text: The picture depicts a stack of dollars and a stack of gold coins with a red “X” through them.4444
45 Common HS Concerns Identified in Peer Review Human Subjects Section inadequateMissing/inadequate DSMP/BSource of specimens/data inadequately describedPhysical/psychological risks not adequately addressedInformed consent issuesConfidentiality of dataIncidental findings not addressedIn 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 approvalCertification that Key Personnel have completed appropriate human subjects research educationResolution of unacceptable Human Subjects SectionWritten response to ICNIH OER concurrenceAlternate 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 approvalUP/AE Reports – within 3 days or as requiredPrior NIH Approval for changes in human subjects research that increase riskAdd HS activities to non-HS award or add Clinical trialNew enrollment of preg. women, children or prisonersAddition that is greater than minimal risk or new info that study procedure/intervention is higher riskDiscuss 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 participationFor IRB approved studies that collect personal identifiers and sensitive infoDHHS Agencies that issue: CDC, IHS, SAMHSA, HRSA, FDA, and NIHFederal 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 PageNIH OER Human Subjects Website:NIH Revised Definition of Clinical Trial:NIH Data and Safety Monitoring4949
50 NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR INCLUSION OF WOMEN, MINORITIES, AND CHILDREN IN CLINICAL RESEARCHMeredith D. Temple-O’Connor, Ph.D.NIH Inclusion Policy OfficerOffice of Extramural Research (OER)National Institutes of Health
51 Learning ObjectivesDescribe the ethical rationale for the federal regulations on human research protectionsApply the basics of the Common RuleRecognize the requirements for human subjects in NIH grant applicationsProvide post-award requirements for research involving human subjectsExplain the requirements for addressing inclusion of women, minorities, and children in NIH grant applicationsProvide an understanding of what studies inclusion policy applies toList post-award requirements for monitoring inclusion in clinical research
52 NIH Inclusion Policies Inclusion of Women and MinoritiesMust be included in NIH-defined clinical research unless exclusion is justified for scientific reasonsJustify the proposed sample in the context of who is at risk for the disease/condition and the scientific goals of the specific studyPlans for outreach and recruitmentProvide Inclusion Enrollment Report form(s) with proposed sex/gender, race, and ethnicity of the sample5252
53 NIH Inclusion Policies (con’t) Inclusion of ChildrenChildren 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 yearsApplicants should justify the proposed age range of the participants, with specific attention to justifying the inclusion/exclusion of individuals under 2153
54 Defining the Universe Bottom line: Inclusion of women and minorities in all NIH funded or supported clinical research is mandated by lawWhat is subject to the statute/policies?All studies (intramural, extramural, contracts) that meet the NIH definition of clinical researchNIH 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 ResearchAdditional requirements for NIH-defined Phase III clinical trials related to unbiased design and assessment of potential differencesBottom 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 applicationPlans for inclusion of women and minoritiesIncludes addressing plans for valid analysis if conducting an NIH-defined Phase III clinical trialPlans for the inclusion of childrenInclusion enrollment reportPlanned or Cumulative (actual) depending on the study designNOTE: 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 CNeed to consider race and ethnicity separatelyWhich 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 plansPlans for inclusionJustification in the context of the sciencePeer 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 awardAlternate text: The picture depicts a stack of dollars and a stack of gold coins with a red “X” through them.5858
59 Common Inclusion Concerns Identified in Peer Review Inadequate information describing the sex/gender, race, ethnicity, and/or age(s) of the sampleInadequate justification for proposed sampleSex/gender, race, ethnicity, and/or age(s) breakdown not appropriate for the scientific goals of the study or not adequately justifiedUnrealistic samplingAppropriate from scientific perspective but not realisticCollaborations and outreach plans may helpIn 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 concernsWritten response to ICProvide inclusion enrollment report(s) if missing or need update as a result of peer review and/or programmatic adjustmentsThis now happens directly in the Inclusion Management System through CommonsAlternate 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/CenterProvided in Inclusion Management System through RPPR or through Commons StatusFor NIH-defined Phase III Clinical Trial– report any analysis or findings related to outcomes by sex/gender, race, and ethnicity if availableNote progress (or challenges) in recruitment as needed in RPPR2012 Policy – Prior NIH Approval for changes in human subjects research that increase riskChanges the project from no to yes for human subjects involvement or from no to yes for clinical trialDiscuss plans with NIH PO before startingEnsure 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 GuidanceFAQsHow To Videos and User Guides for working in the Inclusion Management SystemPodcastsNarrated slide decksGuide notices and other policy related documentsPublic website.htmAlternate 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.