Research Involving Human Subjects Elyse I. Summers, J.D. Director, Division of Education and Development Office for Human Research Protections (OHRP) Department of Health and Human Services (HHS) Ann Hardy, Dr.P.H. NIH Extramural Human Research Protection Officer Office of Extramural Research (OER) National Institutes of Health (NIH) 1 NIH Regional Seminar Program Funding and Grants Administration Ft. Lauderdale, FL June 24, 2011
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Research Involving Human Subjects Elyse I. Summers, J.D. Director, Division of Education and Development Office for Human Research Protections (OHRP) Department.
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Research Involving Human Subjects
Elyse I. Summers, J.D.Director, Division of Education and DevelopmentOffice for Human Research Protections (OHRP)
Department of Health and Human Services (HHS)
Ann Hardy, Dr.P.H.NIH Extramural Human Research Protection Officer
Office of Extramural Research (OER)National Institutes of Health (NIH)
NIH Regional Seminar Program Funding and Grants AdministrationFt. Lauderdale, FL June 24, 2011
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Outline
Part I Who is OHRP and Why Should I Care? Ethical Principles HHS Regulations & Applicability Exempt Research
NIH Policies and Procedures How to complete the Human Subjects Section of your
NIH grant application
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Outline Part II Protections Afforded by the Regulations: Assurances,
NIH Inclusion Policies Post-award responsibilities Certificates of Confidentiality
Case studies and Q & A
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What is the Office for Human Research Protections (OHRP)?
Provides leadership in protection of rights, welfare, and wellbeing of subjects involved in research conducted or supported by US Department of Health and Human Services
Provides clarification and guidance
Develops educational programs and materials
Maintains regulatory oversight
Provides advice on ethical and regulatory issues pertaining to biomedical and behavioral research
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OHRP’s Organizational Structure
OHRP, Office of the DirectorJerry Menikoff, Director
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
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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)
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NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS
Ann HardyNIH Extramural
Human Research Protection Officer
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Sponsoring Agency Responsibilities 45 CFR 46 requires that Agencies
evaluate all applications and proposals involving human subjects for
1. Risks to human subjects 2. Adequacy of protections 3. Benefits4. Importance of knowledge to be gained
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Sponsoring Agency Responsibilities
On the basis of this evaluation [NIH] may approve or disapprove the application … or enter into negotiations to develop an approvable one (45 CFR 46.120).
◦ Human Subjects evaluation can affect grant application score
Federal funds… may not be expended for research involving human subjects unless the requirements of this policy have been satisfied (45 CFR 46.122)
◦ Grant cannot be funded if there are human subjects problems
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Human Subjects Section of Grant Application
Risks to Human Subjects◦ Human subjects involvement and characteristics
Demographic and health characteristics Inclusion and exclusion criteria Rational for involvement of vulnerable populations
◦ Sources of materials What materials (specimens, records, data) How will materials be collected Who has access to information
◦ Potential Risks Physical, psychological, financial, legal or other risks Alternative treatments/procedures
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Human Subjects Section (con’t)
Adequacy of Protection Against Risks◦ Recruitment◦ Informed consent/assent ◦ Protections against risk
Procedures to minimize risk; protect privacy and confidentiality
Potential Benefits of Research to Human Subjects and Others◦May not be direct benefit to subjects◦Compensation is not a benefit◦Discuss risks in relation to anticipated
benefits
Importance of Knowledge to be Gained◦Discuss in relation to risks
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Additional NIH Requirements For Clinical Trials:
◦Data and Safety Monitoring Plan or Board ◦Registration in ClinicalTrials.gov as appropriate
For Clinical Research◦ Inclusion of Women, Minorities and Children
Targeted/planned Enrollment Tables
Justification if NO human subjects but are using human specimens and/or data
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Definition of Clinical Research
Patient-oriented research Epidemiologic and behavioral studies Outcomes research and health services research
Does not include in vitro studies that only use human specimens that are not linked to a living person
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Not Required for Application
After peer review, for grants likely to be funded, NIH requests (just-in-time):◦ OHRP Assurance Number◦ Certification of IRB review and approval◦ Certification that Key Personnel have completed
appropriate human subjects research education
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Preparing the Human Subjects Section
Use SF 424 or PHS 398 Instructions as appropriate
All proposed research will fall into one of six scenarios:A. No Human SubjectsB. Non-Exempt Human Subjects ResearchC. Exempt Human Subjects ResearchD. Delayed-Onset of Human Subjects ResearchE. Clinical Trial F. NIH-defined Phase III Clinical Trial
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Scenario A: No Human Subjects
Are Human Subjects Involved? ___ Yes __X_ No
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PHS 398
Heading “Protection of Human Subjects”
“No Human Subjects research is proposed in this application”
SF 424 Human Subjects
No Human Subjects section is required
Provide justification if using human specimens/data
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Research Involving Coded Data or Specimens
OHRP Policy Guidance 2004, 2008 If research involves only secondary
analysis of coded data/specimens collected for another reason, it is NOT human subjects research if:◦ None of investigators can
readily ascertain the identity of subjects (provider has no other role in research and does not release key)
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Scenario B: Non-Exempt ResearchAre Human Subjects Involved? X_ Yes ___ NoResearch Exempt? ___ Yes _X_ NoClinical Trial? ___ Yes _X_ NoNIH-Defined Phase III CT?___ Yes _X_ No
Human Subjects Section- no page limitations◦ Address 4 required points (risk, protections, benefits,
knowledge) Inclusion of Women and Minorities Targeted/Planned Enrollment Tables Inclusion of Children
Clinical Trial? ___Yes _X_ NoNIH-Defined Phase III CT? ___Yes _X_ No
Human Subjects Section◦ Justify selection of exemption(s)◦ Sources of research materials
Inclusion of Women and Minorities* Targeted/Planned Enrollment Tables* Inclusion of Children*
* Not required for Exemption 4
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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
Definition of Delayed Onset: Human subjects research is anticipated but plans for involvement of human subjects cannot be described in the application (45 CFR 46.118)
Human Subjects Section – explain why delayed onset If funded, you will have to describe human subjects
protections and provide assurance and IRB approval before involving human subjects
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Scenarios E & F: Clinical Trial
Definition of Clinical Trial: Prospective research study designed to answer questions about efficacy of biomedical or behavioral interventions
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)
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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_ No
Provide information required for Scenario B (Non-Exempt Human Subjects Research)
Must have a Data and Safety Monitoring Plan ClinicalTrials.gov
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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
IRB and funding IC approval before enrollment begins
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Scenario F: NIH-def. 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 ___ No
Provide information required for Scenario E Generally requires DSMB
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Analytic Requirement for Phase III CT
Research Plan must consider whether significant gender and/or race/ethnic differences in the intervention effect is expected based on prior studies◦ Yes: plan to conduct analysis to detect significant
differences in intervention effect for relevant subgroups
◦ No: gender and/or racial/ethnic selection criteria not required but inclusion and analysis of subgroups is encouraged
◦ Unknown: include sufficient subjects to conduct valid subgroup analysis
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End of Part I
Questions?
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Regulatory Protections for Research Subjects
Elyse I. Summers, J.D.Director, Division of Education and DevelopmentOffice for Human Research Protections (OHRP)
Department of Health and Human Services (HHS)
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Basic Protections
The regulations contain three basic protections for human subjects:
Institutional Assurance (FWA)
IRB Membership & Review
Informed Consent
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Institutional Assurance
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Institutional Assurance Required when engaged in non-exempt
human subject research
Documentation of institution’s
commitment to comply with applicable
regulations - §46.103(b) & (f)
Principal method of compliance
oversight
Federalwide Assurance (FWA) - only
option
Designate only registered IRB(s)
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IRB Membership
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Membership Requirements
Number of Members◦ minimum of 5 members - §46.107(a)
Experience and Expertise - §46.107(a) Diversity of Members - §46.107(a) & (b) At least one:
An application describes the following proposed research activities:◦ The investigator receives autopsy specimens from
a pathologist. ◦ The investigator also collects identifiable private
information about the individuals from medical records.
You Decide…Is this Human Subjects
Research?
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Case Study 1 (con’t)
No, this is not Human Subjects Research
Research involving only specimens and data from deceased individuals is not human subjects research
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Case Study 2
An application describes the following proposed research activities:◦ Investigator receives coded data from another
researcher’s ongoing clinical trial;◦ Provider has access to patient identifiers◦ Investigator will perform analyses on the coded
data◦ The Provider will provide clinical expertise to guide
analyses, help interpret the results and will be co-author on research publications
You Decide…Is this Human Subjects Research?
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Case Study 2 (con’t)
Yes, this is Human Subjects Research
Provider has access to identifiers and is considered an investigator on this project because he/she is doing more than providing data/specimens.
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Research Involving Coded Data or Specimens
OHRP Policy Guidance 2004, 2008 If research involves only secondary
analysis of data/specimens collected for another reason, it is NOT human subjects research if:◦ None of investigators can
readily ascertain the identity of subjects (provider has no other role in research and does not release key)
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Case Study 3 Study of children ages 2-15 years with
condition A. Involves blood collection, medical testing, and psychological testing
◦ Is this Human Subject Research?◦ What is level of risk?◦ Who provides consent?
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Case Study3 (con’t) Subset of most severely affected children
will be offered chance to participate in a randomized Phase 3 clinical trial of a promising drug vs placebo
◦ What is risk level and how does this impact the conduct of this study
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Subpart D – Additional Protections 45 CFR 46.404-407 An IRB can only approve research that
◦Not greater than minimal risk◦Greater than minimal risk
Prospect of direct benefit Minor increase over minimal risk; will yield
important generalizable knowledge about disease/condition
Other research that present opportunity to gain knowledge –Secretaries panel
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Case Study 4 Longitudinal study of adults with Down’s
syndrome; study involves drawing blood, fMRI scans, cognitive tasks. ◦ Is this a vulnerable population?
45 CFR 46.111(b) - additional safeguards to protect rights and welfare for study of vulnerable persons (including “mentally disabled persons”)
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Case Study 4 (con’t)
◦ Consent will be sought from the subjects’ care provider or person who bring them to research clinic
NIH guidance document on research involving individual with questionable capacity to consent (Nov 2009): http://grants.nih.gov/grants/policy/questionablecapacity.htm