Montclair State University, Montclair, NJ

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: ohrp@hhs.gov