Montclair State Montclair State University, University, Montclair, NJ Montclair, NJ The Human Subjects’ Protection Regulations and You: What Everyone Should Know January 19, 2011 Elyse I. Summers, J.D. Director Division of Education and Development
Jan 28, 2016
Montclair State University,Montclair State University,Montclair, NJ Montclair, NJ
The Human Subjects’ Protection Regulations and You: What
Everyone Should Know
January 19, 2011
Elyse I. Summers, J.D.Director
Division of Education and Development
OutlineOutline
History/Background Ethical Principles Overview of OHRP Shared Responsibilities Activities Update
Philosophical BasisPhilosophical Basis
Immanuel Kant (1724 - 1804): “For all rational beings come under the law
that each of them must treat itself and all others never merely as means, but in every case at the same time as ends in themselves.”
Pre WWIIPre WWII
Edward Jenner (1789) Smallpox Vaccine
Claude Bernard (1865) Ethical Maxims
Louis Pasteur (1885) Rabies Vaccine
Walter Reed (1900) Yellow Fever
NurembergNuremberg
During the Nuremberg War Crimes Trials, 23 German doctors were charged with crimes against humanity for “performing medical experiments upon concentration camp inmates and other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts.”
The Nuremberg Code (1947)The Nuremberg Code (1947)As part of the verdict, the Court
enumerated some rules for "Permissible Medical Experiments", now known as the “Nuremberg Code”. These rules include:
voluntary consent benefits outweigh risks ability of the subject to terminate
participation
Declaration of HelsinkiDeclaration of Helsinki
Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects
“Concern for the interests of the subject must always prevail over the interests of science and society.”
Post WWIIPost WWII
Willowbrook (1950s)mentally retarded children were deliberately infected with
hepatitis virus Jewish Chronic Disease Hospital
(1960s)Live cancer cells were injected into 22 senile patients
Milgram (1963)"Behavioral study of odedience"
Humphries (1970)Tearoom Trade: Impersonal Sex in Public Places
Beecher ArticleBeecher Article
“Ethics and clinical research”
Henry K. BeecherNew Engl J Med 274 (1966):1354-60
22 published medical studies presenting risk to subjects without their knowledge or approval
Published in some of the most prestigious journals and conducted at some of the most prestigious institutions
Public Health Service PolicyPublic Health Service Policy
NIH Director and Surgeon General requested that the National Advisory Health Council review human subject protections
Council recommended prior institutional review for PHS supported research to:– Protect the rights and welfare of the subjects– Assure appropriate methods of informed consent– Determine acceptable balance of risks and
benefits Adopted as Public Health Service policy in 1966 Beginnings of the Institutional Review Board (IRB)
Tuskegee Syphilis StudyTuskegee Syphilis StudyAmerican medical research project conducted by the U.S. Public Health Service from 1932 to 1972, examined the natural course of untreated syphilis in black American men. The subjects, all impoverished sharecroppers from Macon county, Alabama, were unknowing participants in the study; they were not told that they had syphilis, nor were they offered
effective treatment.
National Research ActNational Research Act
1973 Kennedy Hearings “Quality of Health Care - Human Experimentation”
1974 National Research Act– Established the “National Commission for
the Protection of Human Subjects of Biomedical and Behavioral Research”
– Required IRBs at institutions receiving HEW support for human subjects research
The Belmont ReportThe Belmont Report
Ethical Principles and Guidelines for the Protection of Human Subjects of
Research
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
April 18, 1979
The Belmont ReportThe Belmont ReportBasic Ethical Principles: Respect for Persons
– Individual autonomy– Protection of individuals with reduced
autonomy Beneficence
– Maximize benefits and minimize harms Justice
– Equitable distribution of research costs and benefits
Office for Human Research Office for Human Research Protections (OHRP)Protections (OHRP)
(Formerly Office for Protection from Research Risks)
OHRP OversightOHRP Oversight
All research involving human
subjects conducted or supported by the Department of Health and Human Services (HHS) -- 45 CFR Part 46
Protecting Human Subjects Protecting Human Subjects is a is a
Shared Shared ResponsibilityResponsibility
SubjectsSponsor
Advocates
IRB
Research Team
Institution
Government PublicFamily
Investigator
“Top 10”Shared Responsibilities
Responsibility #1Responsibility #1
Recognize when the
regulations apply
to planned activities45 CFR 46.101 and 102
Determining ApplicabilityDetermining Applicability
Does activity involve research?
Does research involve human subjects?
Is the human subject research exempt?
Human Subject Regulations Decision Chart: http://www.hhs.gov/ohrp/humansubjects/guidance/
decisioncharts.htm
Examples of Investigator Activities: Is Examples of Investigator Activities: Is There Research Involving Human There Research Involving Human
Subjects?Subjects?45 CFR 46.102(d), (f)45 CFR 46.102(d), (f)
Obtaining information about living individuals by intervening or interacting with them
Obtaining identifiable private information about living individuals
Obtaining informed consent Interacting with subjects Studying, interpreting, or analyzing
identifiable private information or data
Examples of Investigator Examples of Investigator Activities: Might It Be Exempt Activities: Might It Be Exempt Research?Research? 45 CFR 46.101(b)(1)-(5)45 CFR 46.101(b)(1)-(5)
Some research is “exempt” from federal regulations
Institutions typically have SOPs to describe how and where and by whom exempt determinations are made
See, OHRP FAQs at: http://www.hhs.gov/ohrp/news/recentnews.html#20091015
Exempt ResearchExempt Research 45 CFR 46.101(b)(1)-(5)45 CFR 46.101(b)(1)-(5)
Normal educational practices in established educational settings
Educational tests, surveys, interviews, or observation of public behavior unless identified and sensitive
Research using existing data, if publicly available or recorded without identifiers
Research on elected or appointed public officials or candidates for public office
Evaluation of public benefit service programs
Taste and food quality evaluation and consumer acceptance studies
Research that is “exempt” includes:
Responsibility #2Responsibility #2
Comply with relevant
Federal regulations 45 CFR 46
Regulations for Protection Regulations for Protection of Human Subjects of Human Subjects
45 CFR 4645 CFR 46• Subpart A – basic HHS Policy - “The
Common Rule”or Federal Policy - Other federal departments & agencies
have adopted Subpart B - Pregnant Women, Human
Fetuses, and Neonates Subpart C - Prisoners Subpart D - Children
6
Responsibility #3Responsibility #3
Initial Review45 CFR part 46.109(a)-(d); 46.110;
46.111
Materials Submitted to the Materials Submitted to the IRBIRB
Protocol, grant proposal,
informed consent(s)
Recruitment materials and plan
Any IRB mandated or other
related documents
Considerations for IRB Considerations for IRB Review and ApprovalReview and Approval
Understand regulatory framework and IRB expectations and policies– For example, convened board (45 CFR 46.109) or
expedited review (45 CFR 46.110)?
– If the latter, must be on “the list” (no more than minimal risk and involve only procedures…) (45 CFR 46.110(a) and (b); 63 FR 60364-67)
Considerations for IRB Considerations for IRB Review and Approval, contReview and Approval, cont’’dd Expedited Review: “The List” – no greater than minimal risk
– 45 CFR 46.102 (i) – The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.
Expedited Review: “The List” – and involves, e.g.,– collection of limited blood samples;– collection of data through physical sensors placed on
body; – collection of data from voice and other recordings, etc.– non-IND, non-IDE studies originally reviewed by
convened board and there determined to be no greater than minimal risk and no additional risks identified.
Considerations for IRB Considerations for IRB Review and Approval, contReview and Approval, cont’’dd Provide sufficient information and materials
– Criteria for 46.111 determinations:e.g., risk/benefit ratio; appropriate recruitment; safeguards for vulnerable subjects (such as, avoiding coercion)
– Creates legally effective informed consent, assent, and permission materials
– Consider characteristics of local research Recognize and manage conflicts of interest
– (e.g., disclose, reduce, eliminate) Comply with IRB decisions and requirements Respond to IRB requests in a timely fashion
Responsibility #4Responsibility #4
Prospective IRB review of
proposed changes
to research45 CFR 46.103(b)(4)(iii)
No Changes to Research No Changes to Research Without IRB Review and Without IRB Review and
ApprovalApproval Prompt reporting to the IRB of proposed
changes in a research activity
Changes in approved research may not
be initiated without IRB review and
approval except when necessary to
eliminate apparent immediate hazards
to the subject §46.103(b)(4)(iii)
Responsibility #5Responsibility #5
Continuing Review45 CFR 46.109(e)
New OHRP Guidancehttp://www.hhs.gov/ohrp/policy/
continuingreview2010.pdf
Continuing Review Status Continuing Review Status ReportReport
Number of subjects accrued Unanticipated problems (or adverse
events) Withdrawal of subjects Complaints about the research Summary of any recent literature,
findings, or other relevant information, especially information about risks associated with the research
Copy of the current informed consent document
Amendments or modifications
Lapse in Continuing ReviewLapse in Continuing Review
ALL ACTIVITIES MUST STOP!
No enrollment of new subjects IRB will determine if currently
enrolled subjects can continue study related interventions/activities
Data analysis activities with private identifiable information
Responsibility #6Responsibility #6
Obtain and document legally
effective informed consent,
assent, and parental permission in
accord with §46.116, 46.117 and
applicable subpart(s) and as
approved by the IRB.
Informed ConsentInformed Consent
Informed consent will be sought from each
prospective subject or the subject’s legally
authorized representative, in accordance with, and
to the extent required by §46.111(a)(4); 46.116;
46.117– required unless IRB finds and documents that the criteria
for a waiver or alteration of informed consent are satisfied
– IRB may require written statement be provided to subjects
The Consent ProcessThe Consent Process
Use currently approved informed consent document
“Re-consent” as appropriate Provide copy to subject or LAR Subpart D –
– Child Assent– Parental or guardian permission
Responsibility #7Responsibility #7
Realize your role
when reporting
certain incidents45 CFR part 103(b)(5)
OHRP Reporting OHRP Reporting RequirementsRequirements
Institutions MUST report:
Unanticipated Problems Involving Risks to
Subjects or Others
Serious or Continuing Noncompliance with
the Regulations or IRB Requirements
Any suspension or termination of IRB
approval
What is an Unanticipated What is an Unanticipated Problem?Problem?
Incident, experience, or outcome that is:
Unexpected (nature, severity,
frequency)
Related or possibly related to research,
AND
Suggests greater risk of harm than
previously known or recognized
An adverse event occurs in one or more subjects.
1. Is the adverse event unexpected in nature, severity, or frequency?
2. Is the adverse event related or possibly related to participation in the research?
3. Does the adverse event suggest that the research places subjects or others at a greater risk of physical or
psychological harm than was previously known or recognized?
Report the adverse event as an unanticipated
problem under 45 CFR part 46
The adverse event is not an unanticipated problem and
need not be reported under 45 CFR part 46
YES
YES
YES NO
NO
NO
Algorithm for Determining Whether an Adverse Eventis an Unanticipated Problem
Only Report Unanticipated Only Report Unanticipated Problem to OHRPProblem to OHRP
Reporting ProcessReporting Process
INVESTIGATOR RESPONSIBILITIES:
Describe incident
Suggestive Corrective Actions &
Possible Modifications
Reporting Process, contReporting Process, cont’’dd
IRB RESPONSIBILITIES: Reviewing of incident and report by PI Confirm that corrective actions are sufficient Report to OHRP:
– Project title, PI name, HHS or other federal support
– Details of UP(s), serious or continuing noncompliance,
or reason for suspension or termination of IRB approval
– Description of any corrective action or modification to
the research required by IRB or institution
Responsibility #8Responsibility #8
Record Retention 45 CFR 46.115
Record RetentionRecord Retention
Maintaining records per IRB requirements
3 years after the study is completed– At least three years past completion of
the research activity– Accessible for inspection and copying– In accord with institutional policies &
other regulations
Responsibility #9Responsibility #9
Fulfill responsibilities when study is
completed
When is Study Completed?When is Study Completed?
When all following completed: Interactions & intervention
Data collection
Analysis of identifiable private information
Note that institutions/IRBs/funding entities may
have additional requirements
Study Completion Study Completion ResponsibilitiesResponsibilities
Notify IRB that study has closed Retain signed consent documents
and other IRB records Store study data consistent with IRB
plan Honor commitments
Responsibility # 10Responsibility # 10
Compliance with the
IRB determinations
ComplianceCompliance
Definition of non-compliance:anything that is done outside
of IRB approval except to avoid apparent or immediate hazard
What is serious and continuing? -- 45 CFR 46.103(b)(5)
Responsibility # 11Responsibility # 11
Know your institution’s policies and procedures
Key Points: Key Points: Shared ResponsibilitiesShared Responsibilities
Follow Belmont Report, Federal regulations, IRB & institutional procedures and policies
Promptly report changes to the IRB Obtain, document, and retain legally
effective informed consent Ensure ongoing protections Understand role when reporting
incidents to OHRP
What’s Going On?
OHRP Organizational ChartOHRP Organizational Chart
Office of The Director SACHRPInternational
Program
Division of Education and Development
(6 staff)
Division of Compliance Oversight
(5 staff)
Division of Policy and Assurances
(10 staff)
Update on Education ActivitiesUpdate on Education Activities
Office of The Director SACHRP
International Program
Division of Education and Development
Division of Compliance Oversight
Division of Policy and Assurances
Upcoming OHRP Research Upcoming OHRP Research Community Fora (RCFs)Community Fora (RCFs)
Houston, TX (MD Anderson Cancer Center) –
January 24, 2011
Boston, MA (Dana Farber Cancer Institute, Harvard) – June 21, 2011
St. Louis, MO (Washington University) – September 26, 2011
Educational VideosEducational Videos
Online Educational VideosOnline Educational VideosNow ShowingNow Showing
Research use of human biological specimens and other private information.
Reviewing and reporting unanticipated problems and adverse events
General informed consent requirementsIRB membership
Available on HHS YouTube channel and, for the first two, in RealPlayer format hosted on NIH website
Online Educational Videos:Online Educational Videos:Coming SoonComing Soon
IRB recordkeeping
Vulnerable populations
Update on Policy ActivitiesUpdate on Policy Activities
Office of The Director SACHRP
International Program
Division of Education and Development
Division of Compliance Oversight
Division of Policy and Assurances
Hot Off the Press: New Final Hot Off the Press: New Final Guidance Document Guidance Document
Guidance on IRB Continuing Review of
Research 11 Topics addressed, including:
-- process for conducting continuing review
-- flexibility regarding determining date for continuing review
Supersedes 2007 Guidance Issued: December 1, 2010
Hot Off the Press: New Final Hot Off the Press: New Final Guidance Document Guidance Document
Guidance on Institutional Review Board
Approval of Research With Conditions First ever formal OHRP guidance on this
topic, includes many explanatory examples. Addresses 9 topics, including: -- What actions an IRB can take
-- What circumstances preclude approval
-- IRB recordkeeping responsibilities Issued: December 1, 2010
Hot Off the Press: New Final Hot Off the Press: New Final Guidance Document Guidance Document
Guidance on Withdrawal of Subjects from Research: Data Retention and Other Related Issues
Clarifies that when a subject chooses to withdraw from an ongoing research study, or when an investigator terminates a subject ’s participation, investigator may retain and analyze already collected data relating to that subject, even if that data includes identifiable private information about the subject.
Issued: September 21, 2010
Other Policy ToolsOther Policy Tools
Frequently Asked Questions
-- E.g., IRB Registration; Quality Assurance; Exempt Research Determinations
Correspondence
-- E.g., Use of Student Pools; Interpretation of Expedited Review Category #3
Posting Documents for Public Posting Documents for Public Comment Comment
Establish dockets at
www.regulations.gov
Update on Assurance ActivitiesUpdate on Assurance Activities
Office of The Director SACHRP
International Program
Division of Education and Development
Division of Compliance Oversight
Division of Policy and Assurances
Federalwide Assurance (FWA) Federalwide Assurance (FWA) StatisticsStatistics
(as of 8/19/10)(as of 8/19/10)
Total number of FWAs approved since 2000: 16,079
Total number of currently active FWAs: 10,612
–Domestic: 8220 (77%)
– International: 2392 (23%)Number of domestic FWAs “checking the
box” to extend applicability:
–Extend subpart A (HHS promulgation of the Common Rule): 2596 (31%)
–Extend subparts A, B, C, and D: 2857 (35%)
–No extension: 2777 (34%)
IRB Registration Statistics (as IRB Registration Statistics (as of 8/19/10)of 8/19/10)
Total number of IRBs registered since 2000: 7618
Total number of currently active IRB registrations: 5516
–Domestic: 3553 (64%)
– International: 1963 (36%)Total number of institutions/organizations
with registered IRBs: 4698
–Domestic: 2912 (62%)
– International: 1786 (38%)
Update on Compliance Oversight Update on Compliance Oversight ActivitiesActivities
Office of The Director SACHRP
International Program
Division of Education and Development
Division of Compliance Oversight
Division of Policy and Assurances
Updated Compliance Oversight Updated Compliance Oversight ProceduresProcedures
Posted October 14, 2009; see http://www.hhs.gov/ohrp/compliance/ohrpcomp.pdf
“For-cause evaluations occur, at OHRP’s discretion, in response to OHRP’s receipt of substantive written allegations or indications of non-compliance with the HHS regulations.” [emphasis added]
OHRP Compliance Oversight OHRP Compliance Oversight ActivitiesActivities
New For-Cause Cases Initiated – New For-Cause Cases Initiated – 1990-2010 1990-2010
0
20
40
60
80
100
90 93 96 99 O2 O5 O8Year
# ofNew For-Cause Cases
OHRP Compliance Oversight OHRP Compliance Oversight ActivitiesActivities
New Not-For-Cause Evaluations – New Not-For-Cause Evaluations – 1990-2010 1990-2010
0
1
2
3
4
5
O2 O3 O4 O5 O6 O7 O8 O9 10Year
# ofNew Not-For-Cause Evaluations
OHRP Compliance Oversight OHRP Compliance Oversight ActivitiesActivities
Site Visits – 1990-2010 Site Visits – 1990-2010
0
1
2
3
4
5
6
90 93 96 99 O2 O5 O8Year
OHRP Compliance Oversight OHRP Compliance Oversight ActivitiesActivities
Suspend/Restrict Assurance – Suspend/Restrict Assurance – 1990-2010 1990-2010
0
2
4
6
8
90 93 96 99 O2 O5 O8
SuspendAssuranceRestrictAssurance
Year
#
Sources of Additional Information and Sources of Additional Information and GuidanceGuidance
OHRP website: www.hhs.gov/ohrp OHRP listserv: for instructions on
signing up, see website OHRP telephone (toll free): 1-
866-447-4777OHRP e-mail: [email protected]