Transcript Research Involving Human Subjects NIH Regional Seminar Yvonne Lau, MBBS, MBHL, PhD Director, Division of Education and Development (DED) Office for Human Research Protections.

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
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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
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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
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OHRP - WHO ARE WE?
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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).
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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
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ETHICS & REGULATIONS ON
HUMAN RESEARCH PROTECTIONS
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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
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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
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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
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The Belmont Report (1979)
Three Basic Ethical Principles
1. Respect for Persons
 Promoting autonomy
2. Beneficence
 Maximize benefits; minimize
harms
3. Justice
 Equitable distribution of burden &
benefits
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“The Common Rule”
45 CFR Part 46 Subpart A
Adopted by 18 federal departments & agencies
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“The Common Rule”
Basic Protections
1. Institutional Assurances
(Federalwide assurance - FWA)
2. Institution Review Boards (IRB)
3. Informed Consent
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Additional HHS Protections
• Subpart B - Pregnant Women, Human Fetuses,
and Neonates
• Subpart C - Prisoners
• Subpart D - Children
• Subpart E - IRB Registration
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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
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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?
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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)
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Informed Consent
Purpose: Subjects can make an
informed decision about participation
What are the key elements?
• Information
• Comprehension
• Voluntariness
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APPLYING THE HHS REGULATIONS
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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
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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 Charts
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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?
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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
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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?
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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
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)
** Exception for children
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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?
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Contact OHRP
• Visit OHRP website
• OHRP email box
[email protected]
• Phone inquiries
240-453-6900
• Join OHRP ListServ at
http://www.hhs.gov/ohrp/newsroom/index.html
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Ann Hardy, Dr.P.H. ([email protected])
NIH Extramural Human Research Protection Officer
NIH Office of Extramural Research (OER)
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
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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
▫
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Administrative procedures to ensure compliance
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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
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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
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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
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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
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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
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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
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Scenario B: Non-Exempt Research
Are Human Subjects Involved? X_ Yes
Research Exempt?
___ Yes
Clinical Trial?
___ Yes
NIH-Defined Phase III CT?
___ Yes
___ No
_X_ No
_X_ No
_X_ No
• Human Subjects Section- no page limitations
▫ Address 4 required points (risk, protections, benefits, knowledge)
• Inclusion of Women, Minorities, and
Children
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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
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Scenario D: Delayed Onset HS Research
Are Human Subjects Involved?
Research Exempt?
Clinical Trial?
NIH-Defined Phase III CT ?
_X_ Yes
___ Yes
___ Yes
___ Yes
___No
___ No
___ No
___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
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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)
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Scenario E: Clinical Trial (not Phase III)
Are Human Subjects Involved? _X_ Yes
Research Exempt?
___ Yes
Clinical Trial?
_X_ Yes
NIH-Defined Phase III CT?
___ Yes
___ No
_X_ No
___ No
_X_ No
• Provide information required for Scenario B (NonExempt 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
• Funding IC approval before enrollment begins
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Scenario F: NIH-Defined Phase III
Clinical Trial
Are Human Subjects Involved?
Research Exempt?
Clinical Trial?
NIH-Defined Phase III CT?
_X_ Yes
___ Yes
_X_ Yes
_X_ Yes
___ No
_X_ No
___ No
___ No
• Provide information required for Scenario E
• Generally requires DSMB
• Additional inclusion policy requirements to be
addressed related to study design
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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
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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
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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
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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!!
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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
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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
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Meredith D. Temple-O’Connor, Ph.D.
NIH Inclusion Policy Officer
Office of Extramural Research (OER)
National Institutes of Health
[email protected]
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
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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
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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
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Defining the Universe
•
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

▫
•
Additional requirements for NIH-defined Phase III clinical trials related to unbiased design and assessment of
potential differences
Bottom line:
▫
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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
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.
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)
•
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Bottom line: Does the study have the right
people for the science?
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
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Inclusion Enrollment Report Forms
• 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)
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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
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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
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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
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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)
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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
▫ http://grants.nih.gov/grants/funding/women_min/women_min
.htm
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