| Human
Subjects
Eric Klinger (with contributions by Jeffrey Kahn) May, 1999
Learning Objectives
University Policies and Procedures
Curriculum Overview
Case Studies
Information Resources
Learning
Objectives
- List three basic principles for the treatment of human subjects.
- Briefly describe the jurisdiction, mission, structure and functions
of an IRB, including mechanisms for accountability and enforcement.
- Given descriptions of situations involving the use of humans
in research, the learner will indicate a) whether and b) why consent
for participation is required.
Greater depth:
- If oversight is required in a situation involving the use of
humans in research, the learner will indicate a) when and b) how
institutional oversight is applied.
- Develop a research proposal and consent forms that meet the
basic criteria for IRB approval.
- Given a list of populations (including various categories of
vulnerable populations), the learner will identify those that
are covered by special rules.
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University
Policies and Procedures
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Curriculum
Overview
Brief History of the Problem
Abuses of human subjects, such as Nazi research on concentration
camp inmates, the Tuskegee study of syphilis sufferers, U. S. military
experiments with radiation effects, and arbitrary use of medical
patients in research hospitals, dramatized the need for a system
to protect human subjects from abuse and to accord them their rights
to self-determination, safety, and dignity. Building on the Nuremberg
Code, which had been established in response to atrocities committed
by Nazi researchers, institutions responsible for research or its
funding have developed an ethical framework for the protection of
human subjects.
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Principles of Human Subjects Protection
In 1978, the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research issued the Belmont Report,
which encoded three basic principles for the treatment of human
subjects: respect for persons, beneficence, and justice. These approximately
correspond to the operational need for informed consent of subjects,
reasonable ratios of benefits to risks, and equitable selection
procedures and treatment. Vulnerable populations must receive special
attention to assure the appropriate application of these principles.
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What and who is the Institutional Review Board
(IRB)?
Jurisdiction
Federal law requires that all institutions that accept federal
funds for the conduct of research with human subjects institutionalize
means for protecting them from harm. The administrative vehicle
for assuring protection in each such institution is the IRB. In
principle, then, the mission of an IRB extends to all research
employing live human subjects in its institution. Although some
activities, such as educational testing for research purposes,
may be legally exempted from its review, IRB’s generally
include all research with human subjects in their purview. IRB’s
are empowered to review and approve, reject, postpone, or modify
all proposals for research with human subjects. No such research
may proceed without IRB approval.
Mission
The mission of the IRB is to assure that the protection of the
rights and welfare of human research subjects within its institution.
Structure
An IRB must consist of at least five properly qualified but otherwise
diverse members, of whom at least one must be a scientist, at
least one must be a nonscientist, and at least one must be unaffiliated
with the institution, including not having an immediate family
member affiliated with it.
Who reports to whom?
The Office for Protection from Research Risks (OPRR) of the National
Institutes of Health approves the composition of IRB’s and
monitors their activities. Within their institutions, IRB’s
report to the Institutional Official, who reports to OPRR. (At
some institutions, including the University of Minnesota, the
Institutional Official is authorized to administer human-subjects
regulations independently except for "adverse reporting"
of serious mishaps.) All principal investigators who use human
subjects in their research report to the IRB.
Federal Oversight
All oversight agencies perform at least occasional on-site inspections
and/or audits. The FDA conducts these on a regular schedule, whereas
other agencies tend to conduct them sporadically. For federal
agencies governed by OPRR, institutions commit themselves to OPRR,
via either a single project assurance (SPA) or multiple project
assurance (MPA), to oversee and perform research on human subjects
according to federal requirements specified in the Common Rule
and all relevant subparts of Title 45, Part 46, of the Code of
Federal Regulations, Protection of Human Subjects (45 CFR 46 (for
the Department of Health and Human Services) and/or other applicable
regulations as listed in the Federal Register. These assurances
are the institution's responsibility, with OPRR acting periodically
to audit institutions (usually for cause) to assure compliance.
Sanctions
Agencies may respond to noncompliance by suspending or terminating
support of projects and refusing future funding to noncompliant
investigators or institutions.
Examples: Suspension of NIH-supported research at Duke University
and at the West Los Angeles Veterans Medical Center.
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Procedures of the IRB
Responsibilities of Principal Investigators
Principal investigators must possess skills adequate to their
proposed research, design research that meets quality assurance
standards and whose benefit to subjects or society justifies the
risks to subjects, submit fully detailed research plans, ensure
that no human subject be enlisted without prior informed consent,
take all necessary safeguards to minimize risks and to protect
the interests of vulnerable populations, assure the adequate training
of their personnel, adhere to high ethical standards, and comply
with all institutional and governmental regulations.
Risk/benefit Analysis
The IRB is charged with estimating the risks of harm to subjects
from participation in research, in comparison with the risks of
everyday normal life or of standard alternative treatments of
disorders, and the likely benefits to subjects or to society,
excluding remuneration and subjective benefits. It will refuse
to approve research designs that fail to minimize risks or in
which the risks outweigh the likely benefits.
Continuing Review
Approved research projects remain under IRB oversight until their
completion. Principal investigators file annual reports to the
IRB, in addition to special reports of unforeseen mishaps involving
human subjects, on the basis of which the IRB decides whether
to renew approval of the project for another year.
Levels of Review
There are three levels of review of projects. All experimental
investigations or others deemed to pose nontrivial risk are subjected
to full review by the IRB. Some investigations that entail minimal
risks, such as anonymous surveys or surveys involving innocuous
material, may be considered exempt from formal review. Nevertheless,
these require an application form that is approved by administrative
staff of the IRB and filed. In between there is the possibility
of expedited review of investigations using certain closely defined
categories of research operations, in which approval is based
on an evaluation by a subset of IRB members.
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Informed Consent
Form and Process
All human participants in research are required to indicate their
consent by signing a consent form indicating their understanding
of the purpose of the research, of the proposed procedures, risks,
and benefits, and of their rights in the situation, and registering
their consent. Consent must be informed, in that subjects must
be given full disclosure of the nature of their participation
(except in rare instances in which deception is scientifically
necessary and justifiable) and must indicate comprehension of
the information. Consent given by subjects may be withdrawn by
them at any time without adverse effects on their relationship
to the research institution.
Subject Control Over Data
Subjects retain the right to withhold or withdraw the data they
contribute.
Recruitment Issues
- Participation must be purely voluntary. There must be no elements
of coercion in securing subjects participation.
- Incentives for participation must avoid undue inducement that
may serve as a subtle form of coercion, or at least undue influence.
- Subject selection criteria must avoid discriminating against
classes of humans on the basis of sex, age, ethnicity, or other
major characteristics, except as required for scientific reasons.
- If incentives are extended to some members of a group, these
must not disadvantage other, nonselected members. For example,
if subjects are students who receive for their participation extra
points in a course in which grades are assigned to fixed percentages
of students, students not selected may be disadvantaged. It is
important that subject selection strive for fairness to those
not selected.
- Deception must be justified by scientific necessity and benefit.
Deceived subjects must subsequently be debriefed. Deception is
assumed to be rarely necessary.
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Privacy and Confidentiality
All research investigations must protect the privacy of their subjects.
Data regarding individuals must be stored in a form that prevents
the individuals’ identification. Subjects’ contributions
to the research must be kept confidential except for aggregate reporting
or description that removes or alters identifying information to
make it unrecognizable by the subject and by individuals acquainted
with the subject.
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Risk Minimization
Research procedures must minimize risks to subjects consistent
with adequately justifiable scientific necessity. All risks must
be fully and comprehensibly disclosed to subjects and receive their
consent.
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Monitoring and Observation
From the beginning of research operations, principal investigators
are responsible for monitoring operations through periodic analysis
of data to assure that the investigation continues to promote the
goals of the research. Principal investigators must also monitor
through observations designed to assure the continuing integrity
of research operations, especially as these may impact research
subjects.
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Reporting Requirements
Deviations from approved protocols and unforeseen mishaps involving
human subjects must be reported by principal investigators to their
IRB’s and by IRB’s (or, in the case of the FDA, by principal
investigators) to their institutional officials and on to the respective
funding agencies.
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Record-keeping
The IRB is required to keep detailed records of its deliberations
and of all research proposals that come before it and of their disposition.
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Supervision and Training of Personnel
Principal investigators are responsible for assuring that their
research personnel are adequately trained for the research operations
they perform and for the ethical conduct of research. They are also
responsible for continuing supervision of the research operations
under their purview.
Information for investigators employing particular classes of subjects
and methods.
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Populations
[ -- Populations Chart or link to that chart needs to be here --
]
[ -- See: http://www.research.umn.edu/ethics/modHuman.html
-- ]
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Case
Studies
The Case of Duke University:
From the Chronicle of Higher Education, May 28, 1999:
Government Restores Duke U.'s Right to Conduct Research on
Humans
Normality returns after suspension at the medical center,
but officials at other institutions are reviewing their research
programs
By PAULETTE WALKER CAMPBELL
As the Duke University Medical Center recovered last week from
a brief but chaotic suspension of most of its medical studies,
scientists and administrators across the country began asking
hard questions about their own research protocols and about the
politics behind Duke's punishment.
This month, the federal Office for Protection from Research Risks
-- which monitors all human experiments conducted with federal
money -- revoked the medical center's license to conduct federally
sponsored research after finding 20 ethics and safety violations
that the center had failed to correct since mid-December (The
Chronicle, May 21).
The research-protection office restored Duke's license four days
later, after university officials submitted extensive new plans
to strengthen safeguards for humans participating in experiments.
Nonetheless, the suspension of research at a highly regarded
teaching hospital "scared people in the highest echelons
of university administrations," said Robert J. Levine, a
professor of medicine at Yale University School of Medicine and
author of Ethics and Regulation of Clinical Research (Yale University
Press, 1988). "The question, Could this happen here?, has
to be on their minds."
Gary P. Ellis, director of the federal research office, said
it had been deluged with phone calls from university officials
asking about the best ways to manage their institutional review
boards, or I.R.B.'s -- the panels responsible for screening human-subject
research proposals for safety violations.
"The calls indicate that much reflection is taking place
across the country," Mr. Ellis said.
University administrators may have cause for concern. Since October,
Mr. Ellis's office has suspended research licenses for Duke and
two other institutions; the last suspension before those was in
1990. The office, too, allowed the two other institutions -- Rush-Presbyterian/St.
Luke's Medical Center and the West Los Angeles Veterans Hospital
-- four and six years, respectively, to correct their deficiencies
before revoking their licenses. But only four months had passed
when the research-protection office concluded that officials at
Duke's medical center were dragging their feet on making the necessary
changes.
Many observers now wonder if the agency, despite its limited
resources, is cracking down on I.R.B.'s. The office has two full-time
and two part-time investigators, working on a $3-million budget,
to oversee human and animal research at nearly 3,000 U.S. institutions.
Mr. Ellis acknowledged that it may appear that tougher enforcement
is under way. "The time between our discovering the deficiencies
at Duke and revoking their license may appear to be short,"
he said. "But there is no pattern here. This is just how
this one case worked out."
University administrators are also worried about recent government
reviews indicating that I.R.B.'s at research universities across
the country were plagued by many of the deficiencies uncovered
in Duke's system.
"There is no question that the amount of documentation that
O.P.R.R. required is far in excess of what we had done in the
past and, in my opinion, of what many of the nation's I.R.B.'s
are doing," said Ralph Snyderman, the chancellor for health
affairs for Duke's medical center and dean of the medical school.
Nonetheless, he added, "that is what they believe they need,
to insure the public that sufficient oversight is being given
to research involving human subjects. They are the ones responsible,
and if they need more documentation, we will provide it."
The research-protection office found that Duke's sole I.R.B.
-- which oversees about 2,000 studies -- provided perfunctory
oversight of many of them. In a 1996 report to Congress, investigators
with the General Accounting Office found that continuing reviews
were either superficial or not done at all at many institutions.
"In some cases, I.R.B. administrative staff with no scientific
expertise -- not I.R.B. members themselves – review continuing-review
forms, ensuring only that the information has been provided,"
the report states.
Duke's review board also failed to comply with federal conflict-of-interest
rules. The membership of the medical center's I.R.B. included
the director and the assistant director of the medical center's
Office of Grants and Contracts, which is responsible for bringing
in grants. Federal investigators with the G.A.O. and the Department
of Health and Human Services have found that several review boards
have been housed in the offices in charge of winning research-project
dollars for the universities.
"Such organizational placements, while not necessarily representing
a conflict, certainly can accentuate pressures on I.R.B.'s to
accommodate institutional financial interests," the report
by department investigators states.
The I.R.B. at Yale's medical school, for example, had for years
included its chief of grants and contracts as a voting member,
said Dr. Levine, the chairman of the review board there. But he
removed her voting status in the wake of Duke's crisis, after
the research-protection office sent an e-mail message advising
him to make the change.
"I don't agree that that was the right thing to do,"
Dr. Levine said. "She was not on the board to negotiate numbers
and dollars – she was there because she is familiar with
the administrative requirements governing research."
Bruce Gordon, the chairman of the I.R.B. at the University of
Nebraska Medical Center, said it seemed as if Duke had "pretty
substantive problems," such as failing to have a quorum at
I.R.B. meetings where votes were taken. But Dr. Gordon, like other
I.R.B. members across the country, said he was concerned that
"we are getting more and more instructions on what to do,
and no additional resources to do it."
The corrective plan that Duke negotiated with O.P.R.R. imposes
record-keeping improvements and requires that nearly 300 studies
remain suspended until an I.R.B. has reviewed them again. In addition,
Duke agreed to:
Exclude individuals from the medical center's Office of Grants
and Contracts from serving as voting members on the I.R.B.
Establish an educational program for I.R.B. members on the ethics
of human research and the regulation of human subjects.
Provide adequate justification for approving experiments involving
children. Perhaps most significantly, the medical center will
also establish a second I.R.B. The existing 25-member board assesses
about 70 research proposals a month, along with its responsibility
for the more than 2,000 clinical trials typically under way at
any one time at the medical center. The research-protection office
had said that the deficiencies in the medical center's I.R.B.
"were indicative of an I.R.B. overburdened by a large volume
of research."
Some scientists and government officials believe that human subject
research programs would be strengthened by establishing a national
accrediting system. The Department of Veterans Affairs this month
announced that it would convene a panel of experts to inspect
and accredit V.A. research facilities every three years. Also
this month, two organizations -- Public Responsibility in Medicine
and Research (PRIM&R) and Applied Research Ethics National
Association (ARENA) -- said that they intended to jointly develop
a voluntary accreditation program.
Accreditation "would assure an institution and the public
that there are adequate safeguards in place to protect the rights
and welfare of humans involved in research," said Joan Rachlin,
the executive director of PRIM&R.
Some university administrators said privately that politics may
have had as much to do with Duke's predicament as did failings
in its safety and oversight of human-subject research.
In recent years, the research-protection office has come under
fire from Congress and patient groups for its perceived failure
to protect research subjects.
"I think it is more than just a coincidence that the Inspector
General releases this damning report about I.R.B.'s last summer,
Congress holds a hearing about it, then all of a sudden O.P.R.R.
comes out with this flurry of suspensions," said an I.R.B.
member at a Western university who did not want to be identified.
"But I also know that O.P.R.R. realizes that the problems
in this system go way beyond I.R.B.'s. We need more institutional
support, more staff, more money. So does O.P.R.R."
Mr. Ellis denied that politics had played a part in any of the
office's recent suspensions.
"It would be inaccurate to conclude that O.P.R.R.'s recent
actions are based on anything other than the facts of each case,"
he said. "But with intense interest being expressed by Congress,
the President's National Bioethics Advisory Commission, and advocacy
groups, this is no time for dawdling in tuning up protections,
where needed, for human research subjects."
As things returned to normal at Duke, new questions arose about
the safety of human subjects at other institutions.
In a May 4 letter to President Clinton -- made public on the
day that Duke's suspension was lifted -- Harold T. Shapiro, the
president of Princeton University and chairman of the President's
bioethics commission, said the government's system for protecting
humans in research needed "significant revision."
Among the concerns listed in the letter were the fact that the
I.R.B. system is strained by, among other things, inadequate staffing
and education; by an explosion in research activity; and by the
trend toward collaborative research projects that are conducted
at more that one institution. The commission's full report and
recommendations are due to be released at the end of the summer.
The bioethics commission and a panel of outside scientists convened
by the National Institutes of Health have also been considering
the effectiveness of the research-protection office.
Specifically, both panels are looking at whether the research-protection
office should be moved. Currently, it is housed at the N.I.H.
Many critics say this poses a serious conflict as the N.I.H.'s
research is subject to O.P.R.R. regulation.
The N.I.H. panel was due to present its findings to agency officials
last week and is scheduled to make the report public next week
at a public meeting of the N.I.H. Director's Advisory Council.
http://chronicle.com
Section: Government & Politics
Page: A30
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The Case of West Los Angeles Veterans Medical
Center:
From the Chronicle of Higher Education, April 30, 1999:
U.S. Examines Human-Subject Research at 3 Veterans Hospitals
By PAULETTE WALKER CAMPBELL
Federal investigators announced last week that they were looking
into charges that scientists at three veterans hospitals violated
the rights of human subjects in biomedical-research studies.
Two of the hospitals are affiliated with universities, and a
negative finding could affect scientists at the institutions who
are involved in studies at the veterans' hospitals.
At a Congressional hearing last week to explore similar charges
against a veterans' hospital in West Los Angeles, J. Thomas Puglisi,
the director of the division of human-subject protections in the
federal Office for the Protection from Research Risks, said his
office was conducting inquiries at the James A. Haley Veterans
Administration Hospital, affiliated with the University of South
Florida in Tampa; the Cincinnati V.A. Medical Center, affiliated
with the University of Cincinnati; and the V.A. Medical Center,
in Philadelphia.
The Tampa research is in kidney diseases; Cincinnati's is in
psychiatry; and Philadelphia's involves cardiovascular ailments.
The announcement came less than a month after the research-protection
office suspended research at the West Los Angeles Veterans Hospital
for failure to protect human research subjects. That punishment
affected more than 100 scientists based at the School of Medicine
at the University of California at Los Angeles.
Of the 600 faculty members at the Health Sciences Center at the
University of South Florida, about 50 are conducting research
at the James A. Haley hospital, said Michael Hoad, a spokesman
for the Health Sciences Center at the University of South Florida.
"Of course, we don't assume that the Haley V.A. will suffer
the same fate as the West Los Angeles V.A.," Mr. Hoad said.
"If that happens, it would not threaten our research program,
but it would have a substantial effect."
Officials at the University of Cincinnati were not available
to comment.
At the Congressional hearing last week, several lawmakers questioned
whether the research-protection office could trust institutional
review boards -- local panels known as I.R.B.'s, which screen
research proposals to insure that human subjects are being protected.
Government officials, lawmakers, and patient advocates have raised
similar concerns for some time.
Mr. Puglisi could not say when the office would complete its
investigations.
http://chronicle.com
Section: Government & Politics
Page: A32
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Information
Resources
Web Sites
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References
Arboleda-Florez, J. & Weisstub, D. N. (1997). Ethical research
with the mentally ordered. Canadian Journal of Psychiatry, 42,
485-491.
Batchelor, J. A., & Briggs, C. M. (1994). Subject, Project
or Self? Thoughts on Ethical Dilemmas for Social and Medical Researchers.
Social Science and Medicine, 39, 949-954.
Board of Regents of the University of Minnesota (1994). "Research
Involving Human Subjects."
Committee on Science, Engineering, and Public Policy (1995).
On being a scientist: Responsible conduct in research. Washington,
D.C.: National Academy Press.
Mirvis, P. H., & Seashore, S. E. (1979). Being ethical in
organizational research. American Psychologist, 34, 766-780.
Office for Protection from Research Risks, National Institutes
of Health (1993). Protecting human research subjects: Institutional
Review Board Guidebook. Washington, DC: United States Government
Printing Office.
Ortmann, A., & Hertwig, R. (1997). Is deception acceptable?
American Psychologist, 52, 746-747.
Sieber, J. E. (1992). Planning ethically responsible research:
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CA: Sage.
Sigmon, S. T. (1995). Ethical practices and beliefs of psychopathology
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Swazey, J. P., Anderson, M. S., & Lewis, K. S. (1993). Ethical
problems in academic research. American Scientist, 81, 542-553.
*Taube, D. O., & Burkhardt, S. (1997). Ethical and legal
risks associated with archival research. Ethics & Behavior,
7, 59-67.
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