Ethical Issues for Human
Subjects Research
Role of IRBs
I. Purpose of Human Subjects
Research
 Understand Disease
 Validate New Therapies
 Understand Physiological Processes
 Study Human Behavior
 Evaluate Curricular Changes
 Evaluate New Teaching Methods
Ethical Issues in Research
 When using humans or animals for
research, important ethical issues must be
addressed
 Historically,
these issues were addressed by the
professional code of ethics
 Codes of conduct have evolved and now have
been codified into law.
Ethical Issues in Research
 World War II—The Nuremburg Trial
 Joseph
Mengele and unethical experiments
performed by Nazi doctors
Ethical Issues in Research
 World War II-The Nuremburg Trial
 20
doctors were charged with War Crimes and
Crimes against humanity
 Joseph Mengele fled and was not tried
 Lead to Nuremburg Code of 10 Principles
Nuremburg Code
 Requires voluntary consent
 Experiments must be rational
 Experiments must be based on animal studies and
knowledge of the disease
 Experiments should avoid suffering
 No experiment should involve excessive risks,
except in those studies where physical
experimental physicians also serve as subjects
Nuremburg Code
 Degree of risks should be determined by importance of the
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problem
Precautions should be taken to avoid against even remote
possibilities of injury, disability, or death
Experiment should be conducted only by scientifically
qualified persons
Subjects should be able to end experiment at any time
The scientist in charge must be prepared to terminate the
experiment at any stage, if they believe the experiment is
likely to result in injury, disability, or death to the subject
Ethical Issues in Research
 Unfortunately, codes were not always
followed:
 Tuskegee

Not treated even after penicillin discovered
 Jewish

Syphilis Study-USPHS-1930’s
Chronic Disease Hospital
Patients injected with cancer cells
 Midgeville State

Hospital
Investigational drugs used without consent
Ethical Issues in Research
 Willowbrook State Hospital-1970
 Retarded injected with viral hepatitis
 US Department of Energy-1950s-60s
 Studies on radioactive fallout
 University of Iowa-1940s
 Research on stuttering in orphans home
 Johns Hopkins-2001
 Asthma study with hexamethonium
National Research Act
 Increased Public concern led to congressional action and
National Research Act of 1974

President Nixon then established National Commission for the
Protection of Human Subjects of Biomedical and Behavioral
research
 Commission charged to consider:
 Boundaries between practice and research
 Assessment of role of risk vs. benefit in research
 Guidelines for selection of subjects
 Informed Consent
Belmont Report
 National Commission submitted the Belmont
Report to President in 1979
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Led to 1981 revision of 1974 guidance (45 CFR 46) for
human research committees
45 CFR 46-has become the bible for reviewing research
funded by DHHS
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Required appointment of Institutional Review Boards or IRB’s
to review human subject studies
Provided standards for appointment of IRBs, record-keeping
and oversight in research
45 CFR 46
 Revised in 1983 and 1991
 In

1991 revisions referred to as Common Rule
Adopted by 15 federal agencies, not just DHHS
 Institutions with
NIH funding must submit
assurance of compliance to OHRP, DHHS

After February 28, 2001-assurances must cover all
research at institution, not just NIH
II. Institutional Review Boards
 Makeup of IRB
 At
least 5 members
 Male/Female
 Professionals/laypersons
 External “non-affiliated” member
 Must represent community
 Lay person must be at meeting for reviews
II. Institutional Review Boards
 IRB’S must be guided by principles
outlined in Belmont Report:
 Respect
for persons: respect for patient
autonomy
 Beneficence: maximize benefits and minimize
harm
 Justice: Equitable distribution of research
burdens and benefits
III. IRB Review of Research
 Three categories of Review:
 Exempt
 Expedited
 Full
Review
IRB Review of Research
 Exempt-by Chair or Administrator
 Research
in educational settings involving
normal educational practices
Instructional strategies
 Effectiveness of instructional techniques
 Comparison of techniques or curricula, etc.

IRB Review of Research
 Exempt-by Chair or Administrator
 Research
involving educational tests (cognitive,
diagnostic, aptitude)

Unless
– Names or identifiers are recorded and
– Disclosure could put subject at risk of criminal liability or
affect employability
IRB Review of Research
 Exempt-by Chair or Administrator
 Survey
research without identifiers; interviews,
observation of public behavior

Unless
– Names or identifiers are recorded and
– Disclosure could put subject at risk of criminal liability or
affect employability
IRB Review of Research
 Exempt-by Chair or Administrator
 Collection
or study of existing data, documents,
records, pathological or diagnostic specimens
If the sources are publicly available, or
 If information is recorded so that the subject cannot
be identified, directly or indirectly

IRB Review of Research
 Exempt-by Chair or Administrator
 Research and demonstration projects conducted
by or subject to approval by DHHS to study,
evaluate or examine:
Public benefit or service programs
 Procedures for obtaining benefits or services from
these programs
 Other changes in these programs

– Taste and food quality evaluation and consumer
acceptance studies
IRB Review of Research
 Expedited Review
 Research activities reviewed by Chair or designee
 Two cautions however:
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Only for activities involving minimal risk-i.e., no more risks
than those in everyday life
Cannot be used if subject responses might pose civil or
criminal risk to subject, unless
– Reasonable protections can be implemented so that risks related
to invasion of privacy and breach of confidentiality are minimal
IRB Review of Research
 Expedited Review-Categories eligible
 Some
studies of approved drugs or devices
 Collection of blood from adults
Not to exceed 550mL in 8 weeks
 Not more often than 2 times per week
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 Collection
of specimens by non-invasive
means: sweat, excreta, amniotic fluid, hair,
teeth, plaque
IRB Review of Research
 Expedited Review-Categories eligible
 Collection of data through non-invasive means,
excluding X-ray and microwave
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EKG, ECG, MRI, weighing, thermography, ultrasound,
doppler blood flow, exercise, flexibility testing, etc.
Research involving data, records, specimens collected,
or that will be collected solely for non-research
purposes
Collection of voice, video, digital, or images made for
research purposes
IRB Review of Research
 Expedited Review-Categories eligible
 Research on individual or group characteristics or behavior
including:

Perception, cognition, motivation, identity, language,
communication, beliefs or practices, etc.
 Research involving surveys, interview focus groups,
program evaluations, or quality assurance methods
 Continuing reviews for previously approved projects
 Minor changes in previously approved research
IRB Review of Research
 Full Review-Full Committee
 Investigational
drugs, devices, invasive
techniques (PET scan), implants, etc.
 Higher risk research
 NOTE-research not approved by IRB cannot be
approved by higher authorities, however
approved research may be disapproved by
higher authorities
IV. IRB Approval
 To be approved:
 Risks
must be minimized by sound research
design
 Risks must be reasonable in relation to benefits
 Selection of subjects must be equitable
 Informed consent will be sought from each
subject
IRB Approval
 To be approved-continued:
 Informed consent will be appropriately
documented
 When appropriate, research plan must ensure
continued safety of subjects
 Where appropriate, provisions made to protect
privacy of subjects and data
 When working with subjects vulnerable to
coercion, must consider added safeguards
Continuing Review
 For research continuing more than one year,
an annual review is required
 New standards under review:
 Will
probably require IRB monitoring of some
clinical trials
 Constant assessment of conflict of interest of
the investigators
Informed Consent
 Not needed for exempt studies
 Required for Expedited Review-but may be
simplified for low risk studies
 Rigorous consent for Full Review projects
 May be waived by IRB for emergency
Medicine research-controversial issue
Informed Consent
 Consent must address critical elements or
points outlined by Federal Law
 Consent signed by subject or legal
representative and investigator
 Subject must be given copy of consent
 No exculpatory language may be used in the
written consent
Basic Elements of Consent
 Explanation of purpose and duration
 Description of risks
 Description of benefits
 Disclosure of alternatives to participation
Basic Elements of Consent
 Explanation of Confidentiality of Records
 Who to contact regarding patient rights
 For
research with more than minimal risks,
comment on compensation and care for injury
 Right to withdraw without prejudice
 Statement regarding unforeseen risks,
especially to unborn child
Additional Elements for Consent
 Statement that investigator may terminate
patient participation
 Information regarding any costs
 Statement regarding consequences of
withdrawing-especially for drug studies
 Number of subjects in study
Special Populations-Children
 Special Considerations
 Children
are persons who have not attained the
legal age for consent to treatments or
procedures involved in research
 Research not involving greater than
minimal risk may be approved:
 With
assent of the child and permission of
parents
Special Populations-Children
 Special Considerations
 Research
involving greater than minimal risk
and the prospect of direct benefit to the child
may be approved:
If the risk is justified by the anticipated benefit
 The relation of the benefit to risk is at least as
favorable to subjects as the alternative approaches
 With assent of the child and permission of parents
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Special Populations-Children
 Special Considerations
 Research involving greater than minimal risk and no
prospect of direct benefit to the child may be approved:
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If the risk represents a minor risk over minimal risk
If the intervention presents experiences that are reasonably
similar to those in actual medical, dental, social, psychological,
or educational situations
If the intervention is likely to yield generalizeable knowledge
about the disorder or condition
With assent of the child and permission of parents
Special Populations-Children
 Special Considerations
 Assent of the child
 Usually
verbal-confirmed by parents
 “Assent” cam usually be provided by children
over six years of age-but varies based on
maturity and psychological state
 Failure to object should not, absent affirmative
agreement, be construed as assent
Special Populations-Prisoners
 Special Considerations
 IRB membership
 Majority
of members must have no association
with the prison
 Must include a prisoner, or prisoner
representative with experience to serve in this
capacity
Special Populations-Prisoners
 Special Considerations
 The
research may be approved if:
The advantages of participation are not “enticing” or
prohibit good judgment
 Risks are similar to those for non-prisoner research
 Consent is understandable to prison population
 Decision to participate will not affect parole
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Special Populations-Prisoners
 Special Considerations
 Permitted
Research:
Study of causes, effects, or processes involving
incarceration
 Study of prisons as institutional structures or of
prisoners as incarcerated persons
 Study of conditions affecting prisoners as a class
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– Vaccine trials for diseases prevalent in prisons
– Study of social behavior of prison population
VI. Federal Oversight
 FDA spot checks IRBs to monitor
compliance with drug and device studies
 Recent problems at Rush, Duke, UIC, U of
Colorado, U of Oklahoma, and Hopkins
have prompted calls for greater scrutiny of
IRBs
VI. Federal Oversight
 New 2000/2001 DHHS guidelines require:
 Training
of investigators and “key” personnel
in human research protection
 Certification by investigators that they have
received training (NIH offers on web)
 Certification that investigator has no conflict of
interest
 Monitoring of clinical trials by IRB
VI. Federal Oversight
 Education on “Responsible Conduct of
Research”
 Nine
Areas:
Data acquisition, management, sharing, ownership
 Mentor, trainee practices and responsibilities
 Publication practices and responsible ownership
 Peer review
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VI. Federal Oversight
 Education on “Responsible Conduct of
Research”
 Nine
Areas:
Collaborative science
 Human subjects
 Research involving animals
 Research misconduct
 Conflict of interest and commitment
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VII. New HIPAA regulations
 Health Insurance Portability and
Accountability Act of 1996
 Privacy
Rules effective April 14th, 2001
Health insurers must safeguard personal health
information
 May not disclose to employers for employmentrelated decisions
 However, information can be used for research
approved by a properly convened IRB

– http://www.hipadvisory.com/regs/finaladvisory/gresearch.htm
HIPAA allows research with
conditions
 If material has been or can be de-identified,
no conflict with HIPAA regulations
 Appropriate
if records custodian uses data
 Often not practical to disclose since records
custodian may simply state this is too difficult
HIPAA allows research with
conditions
 To use or disclose data without patient
authorization:
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Discloser (records custodian) must document that
waiver (of consent) has been obtained from an IRB
or
Researcher must represent in writing or orally, that
disclosure is preparatory to research, and no records
will be removed
or
Researcher must represent in writing or orally that the
disclosure is for research on decedents
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Document of death may be required by disclosure
Laboratory Research Animals
Laboratory Research Animals
 All NIH funded research with animals
requires IACUC approval
 IACUC
or Institutional Animal Care and Use
Committee must meet NIH standards
Scientist
 Non-scientist
 Non-affiliated member
 Veterinarian
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Laboratory Research Animals
 Functions of the IACUC
 Review animal care and use program every six months
 Inspect facilities for housing animals every six months
 Prepare reports o reviews for Institutional Official
 Review concerns involving animals at institution
 Make recommendations regarding program to Official
Laboratory Research Animals
 Functions of the IACUC
 Review,
approve, require modifications in
applications for animal use
 Review, approve, require modifications of
proposed changes in approved animal projects
 Suspend activities not adhering to approved
uses
Laboratory Research Animals
 To approve animal use:
 Procedures
must avoid pain or discomfort and
have sound research design
 Procedures involving minor discomfort or pain
must include sedation, analgesia, or anesthesia
 Animals that would experience chronic pain
must be euthanized at the end of the procedure
Laboratory Research Animals
 To approve animal use:
 Living conditions must be appropriate for species
 Medical care must be available from veterinarian
 Personnel conducting procedures must be qualified
 Methods of euthanasia must abide by AVMA rules
 Studies approved by IACUC may be disapproved by
Institutional offices, however, unapproved studies may
not be approved by higher officials
Laboratory Research Animals
 USDA and NIH have oversight
 NIH
does not have inspection arm
 USDA makes periodic, unannounced visits to
assess compliance for “covered” species
Case Number 1
 Social scientist
 Observing 1st
grade play activities
 What level of review?
Exempt
 Expedited
 Full Review
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Case Number 2
 Psychologist
 Interviewing 1st

Benign questions: no names or identifiers
 What
level of review
Exempt
 Expedited
 Full Review
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graders
Case Number 3
 Behavioral Scientist
 Interviewing 3rd
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Questions regarding sexual behavior, parental
handling of bad behavior, etc.
 What
level of review?
Exempt
 Expedited
 Full Review
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graders
Nuremburg Code
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The voluntary consent of the human subject is absolutely essential
The experiment should be such as to yield fruitful results for the
good of society, unprocurable by other methods or means of study,
and not random and unnecessary in nature.
The experiment should be so designed and based on the results of
animal experimentation and a knowledge of the natural history of
the disease or other problem under study, that the anticipated results
will justify the performance of the experiment.
The experiment should be so conducted as to avoid all unnecessary
physical and mental suffering and injury.
Nuremburg Code
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No experiment should be conducted, where there is an a priori
reason to believe that death or disabling injury will occur; except,
perhaps, in those experiments where the experimental physicians
also serve as subjects.
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The degree of risk to be taken should never exceed that determined
by the humanitarian importance of the problem to be solved by the
experiment.
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Proper preparations should be made and adequate facilities provided
to protect the experimental subject against even remote possibilities
of injury, disability, or death.
Nuremburg Code

The experiment should be conducted only by scientifically qualified
persons. The highest degree of skill and care should be required through all
stages of the experiment of those who conduct or engage in the experiment.
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During the course of the experiment, the human subject should be at liberty
to bring the experiment to an end, if he has reached the physical or mental
state, where continuation of the experiment seemed to him to be impossible.
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During the course of the experiment, the scientist in charge must be
prepared to terminate the experiment at any stage, if he has probable cause
to believe, in the exercise of the good faith, superior skill and careful
judgment required of him, that a continuation of the experiment is likely to
result in injury, disability, or death to the experimental subject.