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Wayne State University Wayne State University Detroit, MI Detroit, MI
The Human Subjects’ Protection Regulations and You: What
Everyone Should Know
October 25, 2010
Elyse I. Summers, J.D.Director
Division of Education and Development
OutlineOutline
History/Background Ethical Principles Overview of OHRP Investigator 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.”
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
“Top 10”Investigator Responsibilities
Protecting Human Subjects Protecting Human Subjects is a is a
Shared Shared ResponsibilityResponsibility
SubjectsSponsor
Advocates
IRB
Research Team
Institution
Government PublicFamily
Investigator
Investigator Responsibility Investigator Responsibility #1#1
Recognize when the
regulations apply
to planned activities
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 Examples of Investigator ActivitiesActivities
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
Investigator Responsibility Investigator Responsibility #2#2
Comply with relevant
Federal regulations
Regulations for Protection Regulations for Protection of Human Subjects of Human Subjects
45 CFR part 4645 CFR part 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
Investigator Responsibility Investigator Responsibility #3#3
Initial Review
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 IRB expectations and policies Provide sufficient information and materials
– Criteria for 46.111 determinations– Provides safeguards for vulnerable subjects– 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
Investigator Responsibility Investigator Responsibility #4#4
Prospective IRB review
of proposed changes
to research
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)
Investigator Responsibility Investigator Responsibility #5#5
Continuing Review
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
Investigator Responsibility Investigator Responsibility #6#6
Obtain and document legally
effective informed consent,
assent, and parental permission in
accord with §46.116 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 §46.116
[46.111(a)(4)]
– 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
Investigator Responsibility Investigator Responsibility #7#7
Realize your role
when reporting
certain incidents
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, cont’dReporting Process, cont’d
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
Investigator Responsibility Investigator Responsibility #8#8
Record Retention
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
Investigator Responsibility Investigator Responsibility #9#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
Investigator Responsibility # Investigator Responsibility # 1010
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?
Investigator Responsibility # Investigator Responsibility # 1111
Know your institution’s policies and procedures
Summary- Summary- Investigator ResponsibilitiesInvestigator 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
(5 staff)
Division of Compliance Oversight
(4 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 (see:
http://www.hhs.gov/ohrp/education/index.html#materials)
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 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
Draft Guidance Documents Draft Guidance Documents Posted for Public Comment - Posted for Public Comment -
Status Status Draft Guidance on IRB Continuing
Review of Research (posted November 6, 2009; 8 individuals and 10 organizations commented).
Draft Guidance on IRB Approval of Research with Conditions (posted November 6, 2009; 5 individuals and 7 organizations commented).
Request for Information and Request for Information and Comments (ANPRM) on IRB Comments (ANPRM) on IRB
AccountabilityAccountability March 5, 2009 notice in Federal Register
solicited comments on whether HHS should pursue a notice of proposed rulemaking.
The contemplated new rule would allow OHRP to hold IRBs, and the institutions or organizations operating them, directly accountable for meeting certain requirements of 45 CFR part 46.
Goal is to encourage institutions to be more willing to rely on external IRBs and reduce administrative burden without diminishing human subjects protections.
Recently Issued Final Recently Issued Final Guidance Documents -- FAQsGuidance Documents -- FAQs
Frequently asked questions (FAQs) regarding quality improvement activities (posted December 30, 2008; http://www.hhs.gov/ohrp/qualityfaq.html).
FAQs regarding exempt research determinations (posted October 15, 2009; http://www.hhs.gov/ohrp/policy/exempt_res_det.html).
Revised FAQs regarding the IRB registration process (posted March 29, 2010; http://www.hhs.gov/ohrp/IRBfaq.html).
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 listserv: for instructions on signing up, see http://www.hhs.gov/ohrp/news/distributionlist.html
OHRP website: www.hhs.gov/ohrpOHRP telephone (toll free): 1-866-447-4777OHRP e-mail: [email protected] staff telephone numbers/emails:
http://www.hhs.gov/ohrp/about/staff.html