Human Research Ethics
Roger L. Bertholf, Ph.D.
Associate Professor of Pathology
Chief of Clinical Chemistry & Toxicology
University of Florida Health Science Center/Jacksonville
The Nuremberg Trials
• The International Military Tribunal (1945)
• The Doctors Trial (1946)
• The Nuremberg Code (August, 1947)
Defendants and Defense Counsel
15 of 23 guilty, 7 hanged, 5 life sentences
The Nuremberg Code
• Established necessity of informed consent
• Introduced concept of beneficence
• Introduced the notion of proportionality
between risk and benefit
“Before IRBs, the only consent required
was that of a researcher's department
head. The Nuremberg Code was ignored
in practice. As I look back on it, the
interpretation of these codes was that
they were necessary for barbarians, but
not for fine upstanding people . . .”
Dr. William Silverman, Columbia
pediatrician, on the postwar mentality
Jewish Chronic Disease Hospital
Brooklyn, 1963
• Elderly debilitated patients injected with live
cancer cells to study immunologic response
(per transplant rejection)
• Patients not informed of cancer cells
– investigators did not wish to frighten
unnecessarily
– a priori hypothesis that cells would be readily
rejected
“ . . . the judgment of the investigator is not
sufficient as a basis for reaching a conclusion
concerning the ethical . . . set of questions.”
NIH panel that investigated studies at
Jewish Chronic Disease Hospital
“The investigator’s judgment must be subject to
prior peer review to ensure an independent
determination of risks and benefits and . . .voluntary
informed consent.”
NIH Director James Shannon, endorsed by
Surgeon General William Steward, Feb 1966
The Declaration of Helsinki
• Adopted by the World Medical Association in
1964
• Provided guidelines for the conduct of human
subjects research
– Institutional Review Boards
– “generally accepted scientific principles”
– Distinction between clinical and basic research
– Placebo controversy
The Tuskegee Syphilis Study
• PHS initiated syphilis treatment program in
1928
• Discovered 35 – 40% infection rate in
Macon County, AL
• Revised study to observation only
• Enlisted help of the Tuskegee Institute
• Terminated in 1972
Philadelphia Enquirer, 1972
“Ethical lapses are almost never
cases of bad people, doing bad
things, for no good reason. Rather,
they are good people, doing bad
things, for good reasons.”
Loosely quoting Marcia Angell, MD
former Editor-in-Chief, NEJM
US National Research Act (1974)
• Established National Commission for Protection of
Human Subjects
– The Belmont Report, 1979
• Code of Federal Regulations, 1974, 1981
– Institutional Review Boards (IRBs)
• Common Rule, 1991
The Belmont Report
• Drafted by the National Commission for the
Protection of Human Subjects in
Biomedical and Behavioral Research
• Final version adopted in 1979
• Three sections:
– Clinical practice vs. research
– Three guiding principles of ethical research
– Application of the three principles
Clinical practice vs. research
• What is the purpose of the activity?
• Are results generalizable?
• Example
Three Guiding Principles of
Ethical Research
• Respect for Individuals
• Beneficence
• Justice
Respect for Individuals
• Individuals act as autonomous agents
• Individuals who are not capable of acting as
autonomous agents are entitled to special
protections
– Minors
– Mentally incapacitated persons
– Prisoners
Beneficence
• Guided by two basic principles:
– Do no harm
– Maximize benefits and minimize potential
harms
• Risks should be in proportion to potential
benefits
• Research design should ensure valid results
Justice
• Benefits and risks of human research should
be fairly distributed
• Social vs. individual justice
Federal Regulations
• 45 CFR 46
– The Common Rule (Part A)
– Subparts B, C, and D
• 21 CFR 50 and 56
– 50 includes rules for clinical trials
– 56 describes IRB responsibilities
Oversight of human research
GAO, OIG, OHRP, DHHS, NIH, FDA, AAMC, AAU, NBAC, Congress, media…
INSTITUTIONS SANCTIONED
BY FEDERAL AGENCIES
• Univ of Minnesota • VCU/MCV
• UCLA • UA-Birmingham
• Univ of Rochester • Univ of Pennsylvania
• Rush Presbyterian • Univ of Oklahoma
• West LA, VA Hosp • UTMB-Galveston
• Duke Univ • Johns Hopkins
• Univ of Ill - Chicago
• U Colorado
Case #1:
The Academic Pathologist
A pathologist submits a protocol that would
involve saving surgical specimens submitted
from prostate surgeries for future studies using
a new immunohistochemical method that may
help predict the long term survival of prostate
cancer patients. She believes her research is
exempt from IRB review, since it does not put
subjects at any risk, and involves tissues that
would be discarded anyway.
Case #1 Questions
• Does this protocol need to be submitted for
IRB review?
– YES! All research involving human subjects
must be submitted for IRB review.
• What criteria must be met in order for
research to be exempted from IRB review?
Criteria for Exemption from IRB
review
• “Research involving the collection or study of
existing data, documents, records, pathological
specimens, or diagnostic specimens, if these
sources are publicly available or if the information
is recorded by the investigator in such a manner
that subjects cannot be identified, directly or
through identifiers linked to the subjects.” 45 CFR
46.101(b)(4)
Exemption from IRB review
• One of the key words in the statute is “existing.”
Why does it make a difference if the data already
exists or not?
– Does the existence of the research protocol affect the
collection of the specimen (the intervention)?
• Can the project be carried out without identifying
the subjects?
– Protocols that do not record any subject identifiers can
often be exempted from IRB review
Assessing Risk
• Do you agree that the project does not put
the subjects at any risk whatsoever?
• If not, then what is the risk to subjects?
– Risk of discovering a prognostic marker
– Violation of of a subject’s autonomy, by
including them in a research project without
their knowledge or consent
Expedited Review
• If this project is not exempted from IRB
review, can its review be expedited?
• What are the criteria that must be met for
expedited review?
– “Research involving materials (data, documents,
records, or specimens) that have been collected,
or will be collected solely for non-research
purposes (such as medical treatment or
diagnosis).” 63 FR 60364-60367, November 9, 1998.
Case #2:
A Deal You Can’t Refuse
A local biotechnology company is developing a test
for genetic markers of asthma. As part of their
validation protocol, the company needs to
correlate the presence of the markers with asthma.
They have offered your lab $150 for each blood
specimen from a patient with the diagnosis of
asthma. To protect themselves in case their
records are audited, the company will require you
to maintain a “key” that can be used to identify the
source of each specimen, if necessary.
Questions for Case #2:
• Does this protocol need to be submitted for
IRB review?
• Does this research involve any risk for the
subjects?
• Is payment for research specimens (or
subjects) legal and/or ethical?
• What are the principal concerns an IRB
should have with this protocol?
Is the research exempt from review,
or eligible for expedited review?
• It is not exempt
– Because patient identifiers will be maintained,
it does not qualify for exemption
• It may qualify for expedited review
– Only if the risk is deemed minimal
Does the research involve risk for
the subjects?
• A genetic predisposition to asthma may
affect a subject’s insurability
– Does it make any difference that the patients
have already been diagnosed with asthma?
Is payment for research subjects
legal and/or ethical?
• In some cases, it would be unethical not to
pay subjects
– The principle of justice requires that burdens
and benefits of research are fairly distributed
– However, money should not be used as an
incentive to participate
• Are patients entitled to be informed when
their blood is sold to private research
companies?
Summary of IRB concerns
• Is there a potential for future harm to
subjects based on the information produced
by the research?
• Is the method for obtaining specimens fair
and ethical?
• Can the research be carried out if informed
consent is required?
Case #3:
Who’s the research subject?
The manufacturer of a new birth control device
wants to determine whether use of the device
causes any side effects in women. Previous studies
have demonstrated that the device is about 85%
effective. Subjects must be fertile, discontinue any
other form of birth control, and be involved in a
monogamous sexual relationship. The purpose of
the study and potential risks are adequately
explained in the consent form, which the subject
must sign to enroll. The device is free to
participants, but no other payment is offered.
Questions for Case #3:
• What are the risks and potential benefits of
this study?
– The IRB must ensure that any risks associated
with participation in research are balanced by
potential benefit
• Should the sexual partner be considered a
research subject also, and sign a consent?
Does the study have a favorable
risk/benefit ratio?
• How does a 15% failure rate compare to
standard birth control methods?
• What are the benefits of the new birth
control device?
Should the sexual partner’s
consent be required?
• Is the sexual partner considered a “research subject?”
– The statutes define human subject as:
“. . .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.”
– Intervention is further clarified as including:
“. . .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.”
Human Protections Rubrick
• Does the research involve human subjects?
• Does the research involve risk to participating
human subjects?
• Do the potential benefits of the research
justify the risk involved?
• Has the protocol been designed to minimize
risk to participants?
Case #4: Heroic Measures
An ED physician wants to determine whether
massive doses of TPA can help revive patients
who have not responded to conventional
resuscitative measures. He will only use this
therapy in patients who otherwise would be
pronounced dead. He submits a protocol that
defines explicitly the circumstances under
which a patient will become a candidate for the
protocol, and requests a waiver of informed
consent.
Case #4 Questions
• What are the risks to subjects in this
project?
• Should informed consent be required?
• Do you think the IRB should approve this
protocol?
– If so, should a signed informed consent be
required?