Wayne State University
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
Outline
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History/Background
Ethical Principles
Overview of OHRP
Investigator Responsibilities
Activities Update
Philosophical 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 WWII
Edward Jenner (1789)
Smallpox Vaccine
Claude Bernard (1865)
Ethical Maxims
Louis Pasteur (1885)
Rabies Vaccine
Walter Reed (1900)
Yellow Fever
Nuremberg
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)
As part of the verdict, the Court enumerated
some rules for "Permissible Medical
Experiments", now known as the
“Nuremberg Code”. These rules include:
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voluntary consent
benefits outweigh risks
ability of the subject to terminate
participation
Declaration 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 Article
“Ethics and clinical research”
Henry K. Beecher
New Engl J Med 274 (1966):1354-60
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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 Policy
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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 Study
American 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 Act
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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 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 Report
Basic 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
Protections (OHRP)
(Formerly Office for Protection from Research
Risks)
OHRP 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 is
a
Shared Responsibility
Institution
Investigator
Sponsor
Subjects
Advocates
IRB
Research
Team
Family
Government Public
Investigator Responsibility #1
Recognize when the
regulations apply
to planned activities
Determining Applicability
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Does activity involve research?
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Does research involve human subjects?
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Is the human subject research exempt?
Human Subject Regulations Decision Chart:
http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.
htm
Examples of Investigator Activities
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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 #2
Comply with relevant
Federal regulations
Regulations for Protection
of Human Subjects
45 CFR part 46
• Subpart A – basic HHS Policy - “The Common
Rule”
or Federal Policy
- Other federal departments & agencies have
adopted
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Subpart B - Pregnant Women, Human Fetuses,
and Neonates
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Subpart C - Prisoners
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Subpart D - Children
6
Investigator Responsibility #3
Initial Review
Materials Submitted to the IRB
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Protocol, grant proposal, informed
consent(s)
Recruitment materials and plan
Any IRB mandated or other related
documents
Considerations for IRB
Review and Approval
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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
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Recognize and manage conflicts of interest
– (e.g., disclose, reduce, eliminate)
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Comply with IRB decisions and requirements
Respond to IRB requests in a timely fashion
Investigator Responsibility #4
Prospective IRB review of
proposed changes
to research
No Changes to Research
Without IRB Review and Approval
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Prompt reporting to the IRB of proposed
changes in a research activity
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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 #5
Continuing Review
Continuing Review Status Report
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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 Review
ALL ACTIVITIES MUST STOP!
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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 #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 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 Process
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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 #7
Realize your role when
reporting certain
incidents
OHRP Reporting Requirements
Institutions MUST report:
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Unanticipated Problems Involving Risks to
Subjects or Others
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Serious or Continuing Noncompliance with
the Regulations or IRB Requirements
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Any suspension or termination of IRB
approval
What is an Unanticipated
Problem?
Incident, experience, or outcome that is:
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Unexpected (nature, severity,
frequency)
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Related or possibly related to research,
AND
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Suggests greater risk of harm than
previously known or recognized
Algorithm for Determining Whether an Adverse Event
is an Unanticipated Problem
An adverse event occurs in one or more subjects.
1. Is the adverse event unexpected in nature,
severity, or frequency?
NO
YES
2. Is the adverse event related or possibly related to
participation in the research?
NO
YES
YES
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
NO
The adverse event is not an
unanticipated problem and
need not be reported under 45
CFR part 46
Only Report Unanticipated
Problem to OHRP
Reporting Process
INVESTIGATOR RESPONSIBILITIES:
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Describe incident
Suggestive Corrective Actions & Possible
Modifications
Reporting Process, cont’d
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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 #8
Record Retention
Record Retention
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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 #9
Fulfill responsibilities when
study is completed
When is Study Completed?
When all following completed:
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Interactions & intervention
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Data collection
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Analysis of identifiable private information
Note that institutions/IRBs/funding entities may
have additional requirements
Study Completion Responsibilities
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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 # 10
Compliance
with the
IRB determinations
Compliance
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Definition of non-compliance:
anything that is done outside of
IRB
approval except to avoid
apparent or immediate hazard
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What is serious and continuing?
Investigator Responsibility # 11
Know your institution’s
policies and procedures
SummaryInvestigator Responsibilities
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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 Chart
International
Program
Division of
Education and
Development
(5 staff)
Office of
The Director
Division of
Policy and
Assurances
(10 staff)
SACHRP
Division of
Compliance
Oversight
(4 staff)
Update on Education Activities
International
Program
Division of
Education and
Development
Office of
The Director
Division of
Policy and
Assurances
SACHRP
Division of
Compliance
Oversight
Upcoming OHRP Research
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 Videos
Online Educational Videos
Now Showing
Research use of human biological specimens and
other private information.
Reviewing and reporting unanticipated problems
and adverse events
General informed consent requirements
IRB 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:
Coming Soon
IRB recordkeeping
Vulnerable populations
Update on Policy Activities
International
Program
Division of
Education and
Development
Office of
The Director
Division of
Policy and
Assurances
SACHRP
Division of
Compliance
Oversight
Hot Off the Press: New Final
Guidance Document
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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
Posted for Public Comment - 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
Comments (ANPRM) on IRB
Accountability
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
Guidance 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
Comment
Establish dockets at
www.regulations.gov
Update on Assurance Activities
International
Program
Division of
Education and
Development
Office of
The Director
Division of
Policy and
Assurances
SACHRP
Division of
Compliance
Oversight
Federalwide Assurance (FWA) Statistics
(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 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
Activities
International
Program
Division of
Education and
Development
Office of
The Director
Division of
Policy and
Assurances
SACHRP
Division of
Compliance
Oversight
Updated Compliance Oversight
Procedures
Posted October 14, 2009; see
http://www.hhs.gov/ohrp/compliance/oh
rpcomp.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 Activities
New For-Cause Cases Initiated –
1990-2010
100
80
# of
New For- 60
Cause
40
Cases
20
0
90
93
96
99
Year
O2 O5 O8
OHRP Compliance Oversight Activities
New Not-For-Cause Evaluations –
1990-2010
5
4
# of
New Not- 3
For-Cause
Evaluations 2
1
0
O2 O3 O4 O5 O6 O7 O8 O9 10
Year
OHRP Compliance Oversight Activities
Site Visits – 1990-2010
6
5
4
3
2
1
0
90
93
96
99
O2
Year
O5
O8
OHRP Compliance Oversight Activities
Suspend/Restrict Assurance – 19902010
8
Suspend
Assurance
Restrict
Assurance
6
# 4
2
0
90 93 96 99 O2 O5 O8
Year
Sources of Additional Information and
Guidance
 OHRP listserv: for instructions on signing up, see
http://www.hhs.gov/ohrp/news/distributionlist.ht
ml
 OHRP website: www.hhs.gov/ohrp
 OHRP telephone (toll free): 1-866-447-4777
 OHRP e-mail: ohrp@hhs.gov
 OHRP staff telephone numbers/emails:
http://www.hhs.gov/ohrp/about/staff.html