Transcript The Belmont Report - University of California, Irvine

USE OF HUMAN SUBJECTS
IN RESEARCH
Ruth A. Mulnard, RN, DNSc, FAAN
Associate Professor, Nursing Science
Vice Chair, Institutional Review Boards
Definition of Research

Research means a systematic investigation,
including research development, testing and
evaluation, designed to develop or contribute to
generalizable knowledge (45CFR 46.102).
Definition of Human Subject

Human subject means a living individual about whom
an investigator (whether professional or student)
conducting research obtains:
 (1)
Data through intervention or interaction with the
individual, or
(2) Identifiable private information.
Definition of INTERVENTION /
INTERACTION


Intervention includes both physical procedures by
which data are gathered (for example, venipuncture)
and manipulations of the subject or the subject's
environment that are performed for research
purposes.
Interaction includes communication or interpersonal
contact between investigator and subject.

What about web-based research?
Definition of PRIVATE INFORMATION

Private information includes information about behavior that
occurs in a context in which an individual can reasonably
expect that no observation or recording is taking place, and
information which has been provided for specific purposes by
an individual and which the individual can reasonably expect
will not be made public (for example, a medical record).
Private information must be individually identifiable (i.e., the
identity of the subject is or may readily be ascertained by the
investigator or associated with the information) in order for
obtaining the information to constitute research involving human
subjects.
How Are We Regulated?
International
– ICH Guidelines
Federal
– OHRP (Office for Human Research Protections) has
jurisdiction over Department of Health and Human Services
(DHHS) via 45CFR46
– FDA (Food and Drug Administration) has jurisdiction over all
research involving food, biologics, drugs and devices via 21
CFR
State of California
– Department of Health Services (DHS)
Local guidance and policy
– UC Office of the President (UCOP)
– Institutional Review Board (IRB)
Department of Health and
Human Services (DHHS)
45CFR Part 46 “Common Rule” (enforced by
OHRP):
“The Common Rule”: Federal Policy for the
Protection of Human Subjects
– Subpart A: Basic HHS Policy (basic human subjects,
IRB regulations)
– Subpart B: Pregnant women, Fetuses and Neonates
– Subpart C: Prisoners
– Subpart D: Minors
Food and Drug Administration
(FDA)
21CFR Parts 50 and 56 (enforced by FDA)
– IDE (Part 312) - Investigational New Device
Exemption
– IND (Part 812) - Investigational New Drugs/
Biologics
State of California - CA Health and
Safety Code: Section 24170-24179.5
Protection of Human Subjects in Medical
Experimentation Act
Requires "experimental subject's bill of rights"
Last page of the ICF
Defines Legally Authorized Representative (use
of surrogate)
Specifies that children 7 years of age or older
must also consent to research, not just their
parent (LAR)
Key Events that Influenced Policy
Development
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Nazi doctors trial 1946
The Tuskegee syphilis study 1932-1972
Radiation exposure studies 1944-1974
Thalidomide tragedy (Kefauver Amendment 1962)
The Milgram obedience experiments 1972
U. Pennsylvania gene therapy 1999
The Tuskegee Study
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U.S. Public Health Service project
600 low-income African-American males, 400 of
whom had syphilis infections, monitored for 40 years.
Free medical examinations were given but
participants were not told about their disease.
When penicillin became available in the 1950s, the
study continued and participants were denied
treatment. In some cases, researchers intervened to
prevent treatment by other physicians.
Many participants died of syphilis. The study was
stopped in 1973 by the U.S. DHEW only after its
existence was publicized.
The Development of Human Subjects
Protection Policy
The Hippocratic Oath
 The Nuremburg Code of 1947
 Declaration of Helsinki 1964
 National Research Act of 1974
 The Belmont Report of 1979
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The Nuremburg Code
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Informed consent without coercion
Human experiments should be based on animal
experimentation
Anticipated results should justify the experiment
Only qualified scientists should conduct medical research
Physical and mental suffering should be avoided
No expectation of death or disabling injury
Basic Ethical Principles

Respect for Persons
Individuals should be treated as autonomous agents
 Individuals with diminished autonomy are entitled to
protections


Beneficence
Do not harm
 Maximum possible benefits, and minimize potential
harms

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Justice

Fair distribution of burdens and benefits of research
Respect for Persons
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Treat individuals as autonomous persons; allow
individuals to choose for themselves
Persons with limited autonomy need additional
protection, even to the point of excluding them from
activities that may harm them. The extent of
protection should depend upon the risk of harm, and
the likelihood of benefit.
The judgment that any individual lacks autonomy
should be periodically re-evaluated, and will vary
across situations.
Respect for Persons: Autonomy
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Subject must be capable of acting on personal
goals
Investigator must respect the considered opinions
of the subjects
Participation MUST be freely given. Cannot deny
medical care for decision not to participate in
research.
Respect for Persons: Protections

Those not fully capable of self determination
must be protected, including:
 The
very young, the cognitively impaired, some
physically incapacitated
 Those who are subject to coercion


staff and students of investigator
prisoners
Respect for Persons: Available
Protections
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Exclusion from study
Surrogate consent
Assent of minors age 7 or older
Prohibition on excessive inducements for
participation
Application of Respect for Persons

Informed Consent Process

Information - Does the consent form provide all the information
necessary for the individual to make a reasoned decision?

Comprehension - Is the consent form crafted in language
understandable to the potential participant?

Voluntariness - Does the consent form clearly indicate that
participation in the research is voluntary?

What additional protections can be in place to protect those with
limited autonomy?

How to determine whether one lacks the autonomy to make a
reasoned decision? (per study assessment, not a blanket decision)
Beneficence
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“First, do no harm.”
Maximize possible benefits and minimize
possible harms. Risk-benefit analysis
Unavoidable risks
Benefits may not accrue to research subject
Beneficence
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The IRB should determine whether the risks to subjects
are reasonable in relation to anticipated benefits
Obligations of beneficence affect both the researcher
and society –
 investigators are required to give forethought on
maximization of benefits and reduction of risk that
may be involved in the research

society should recognize the longer term benefits
and risk that may result from the improvement of
knowledge, and from the development of novel
medical, psychological, and social processes and
procedures
Applications of Beneficence

Assessment of Risks and Benefits

Risk refers to the probability of harm; when considering risk, one
should consider both the probability and the severity of the
envisioned harm; while the term, benefit refers to something that
promotes health, well-being, or welfare.

What are the risks of harm to the participants (consider physical,
psychological, social, and economic harms)? Are the risks justified?
Can they be minimized?

Can the research design be improved to minimize risk and maximize
benefit?

What are the benefits (to the participant; to society)?
Justice
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Treat people fairly
Do not exploit those who are readily available
or malleable
Fair distribution of the risks and the benefits of
research based upon the problem/issue under
investigation
Applications of Justice
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Selection of Subjects

Is the potential subject pool appropriate for the
research?

Is it appropriate to involve vulnerable populations
(e.g., economically disadvantaged; limited cognitive
capacity) in the research or are they being enrolled
because it is convenient or because they are easily
manipulated as a result of their situation?

Are the recruitment procedures fair and impartial?

Are the inclusion and exclusion criteria fair and
appropriate?
Implementation: Informed Consent
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Informed consent is a process, not a piece of
paper.
Consent for all full committee protocols must be
written and for clinical studies must be witnessed.
Verbal consent (a waiver of documentation) may
be possible for other kinds of research [using a
study information sheet]
Consent form must be understandable to the
subject and not excessively technical.
Informed Consent (con’t)
Consent must identify risks, benefits, and
possible outcomes.
 Consent must be obtained by an appropriate
member of the investigative team.
 The subject must have an opportunity to ask
questions and raise concerns.
 Financial interests must be disclosed.

Applications of the General
Principles

Consideration of the three general principles in
the conduct of research lead to the
consideration of:
 Informed
Consent process
 Risk/Benefits
 Selection
assessment
of research participants
Implementation: The IRB (Institutional Review
Board)
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Delegated to institution
 Federal-Wide
Assurance (FWA) in place with OHRP
 Reports to VC for Research
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UCI – 2 medical, 1 social-behavioral, 1 compliance, plus a
separate biomedical team for all expedited studies
Medical committee composed of physicians, scientists, other
medical personnel, pharmacists, community representatives.
Community member (non-scientific) must be present for IRB
to proceed.
IRB Responsibilities
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Safeguard rights, safety and well-being of all trial
subjects (with special attention to vulnerable
subjects)
Obtain the following documents:
 Trial
protocol and all amendments
 Informed consent and any updates
 Subject recruitment procedures, anything written to
subjects
 Investigator’s Brochure and applicable safety data
 Investigator’s qualifications
IRB Responsibilities
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Review of the proposed research
 Approval
/ favorable opinion
 Minor changes required to make it approvable
 Disapproval / negative opinion
 Termination / suspension of prior approval

Consider the qualifications of the investigator to
conduct the research
IRB Responsibilities
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May request additional information not supplied
by investigator and/or sponsor
Must conduct continuing review of protocol at
least once a year (time interval should be appropriate to
risk)
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Review the amount and method of payment
 No
coercion, pro-rated for partial completion
IRB Responsibilities
Require that information given to subjects as
part of informed consent is in accordance
with the regulations;
 Require documentation of informed consent
or may waive documentation in accordance
with the regulations;
 Notify investigators and the institution in
writing of its decision to approve or
disapprove proposed research or of
modifications required to secure IRB
approval of the research activity;
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Authority of the IRB
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Approve or disapprove research
Suspend or terminate approval that is not being
done in accordance with IRB requirements, or that
has resulted in unexpected harm to subjects
May observe or have a third party observe the
consent process and the research
May apply sanctions to investigators
No one can overturn IRB decision – not even
university administration
Boundaries between Practice and
Research
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The distinction between practice and research is
blurred; often because they occur together.
The IRB must ensure that the researcher (and the
participant) distinguishes practice from research in
both social science and biomedical research
Minimize the potential for therapeutic misconception –
when one believes the purpose of clinical research is to
treat rather then to gain knowledge
Investigator Responsibilities
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Obtain all required approvals prior to commencing
the research (CRFA, DSMB, IRB, CTPRMC, ICTS)
Obtain informed consent of all human subjects or
their legally authorized representatives (unless
waived) and use only the currently approved,
stamped consent form
Make no changes without prior review and approval
by the IRB
Obtain re-review at least every 365 days
Full Committee Review

Full Committee Research
 Most
common level of review
 Requires full committee vote (majority decides)
 2 reviewers plus staff are assigned to review
 Scientific review - IRB reviews the science as it
relates to risk/benefit ratio
Other Levels of Review

Expedited
 No
greater than minimal risk (e.g. blood samples from
healthy donors, hair or saliva specimens)
 Reviewed by one committee member or Chair unless
problems identified

No greater than minimal risk –
 Means
that 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
Other Levels of Review
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Exempt registration
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Exempt from federal regulations
Virtually no risk (e.g. retrospective data analysis,
discarded pathology materials – de-identified)
Investigator cannot decide if their research is exempt
– IRB must decide
3 year registration required at UCI
De Novo Review

Expedited and full committee research that extends
beyond 7 years must be submitted as a new protocol
Case study #1
Investigator X wants to do a study where cadavers
will be run through an x-ray machine to scan for
healed fractures. No information about the
cadavers or their living relatives is required.
Is this research?
Is this human subjects research?
Research or Not??
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Research means a systematic investigation,
including research development, testing and
evaluation, designed to develop or contribute to
generalizable knowledge (45CFR 46.102).
Human subject means a living individual about
whom an investigator (whether professional or
student) conducting research obtains:
 (1)
Data through intervention or interaction with the
individual, or
(2) Identifiable private information.
Case study #2
An Instructor wants to have all students in a class
interview each other to practice interviewing skills.
The results will not be written up or distributed
outside the classroom in any way.
Is this research?
Is this human subjects research?
Case study #3
A physician wants to compare Tylenol with Advil for
controlling headache. He plans to prescribe Tylenol
on odd days and Advil on even days. Then compare
the results. Both drugs already are approved by the
FDA to treat headache and are available over the
counter.
Is this research?
Is this human subjects research?
Does the physician automatically have access to his
patients’ medical records for research purposes
because of being the treating physician?
Case study #4
A Professor in a social science course includes 10% of
the course grade for participation in various
research projects within the school.
Is this educational practice allowable? Does this
violate anyone’s rights?
How could this requirement be structured so it doesn’t
violate any rights?
Advancement of IRB Processes

All IRB processes are now electronic:
 Reporting
of adverse events, unanticipated problems,
protocol violations, protocol deviations
 Modification requests (e-Mod)
 Continuing protocol applications (e-CPA)
 Initial IRB Application (e-APP)
 Non Human Subjects Determination form
Case Study #5
A patient with a rare form of incurable cancer is
offered a clinical trial opportunity at the
Comprehensive Cancer Center by his treating
physician. The clinical trial is testing whether two
medications that are FDA-approved for other forms of
cancer, are effective in this rare form of cancer.
Is this research?
What would be the level of review at the IRB?
Is it coercive to offer this trial to somewhat so
desperate?
Take Home Lessons
Human Subject Protection Rules
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The rules are there to protect the subjects from
excessive risk or exploitation.
The welfare and reputation of the institution and
the investigators are also at stake.
The investigator is responsible for knowing the
relevant regulations.
When in doubt, ask the IRB staff.
UCI IRB Accomplishments
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UCI achieved re-accreditation from AAHRPP in Fall
of 2011 - five-year accreditation
UCI is part of systemwide MOU for all UC
campuses – intent to rely on one IRB
UCI has MOU with CHOC for research
UCI has MOU with Miller’s Childrens, Memorial Med
Ctr, and CHOC
UCI has reliance agreements with commercial IRBs
http://www.rgs.uci.edu/ora/rp/hrpp/index.htm