The Iowa State University Model Bioethics Institute

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Use of humans and animals in research
Gary Comstock Director, Ethics Program
gcomstock_at_ncsu.edu
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A survey of college students routine behaviors,
such as a questionnaire that asks them to
describe the amount of time they spend studying
and their use of alcoholic beverages, is exempted
from review by our Institutional Review
Board.A. True, because surveys that ask routine
questions need not be reviewed.B. False,
because the use of alcohol by students not yet 18
is illegal, and any questionnaire that asks about
illegal behavior must be reviewed by our IRB.C.
False, because although such surveys are exempt
at other institutions, NC States specific
institutional guidelines explicitly require IRB
review for surveys that ask about illegal
behavior.
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A survey of college students routine behaviors,
such as a questionnaire that asks them to
describe the amount of time they spend studying
and their use of alcoholic beverages, is exempted
from review by our Institutional Review
Board.A. True, because surveys that ask routine
questions need not be reviewed.B. False,
because the use of alcohol by students not yet 21
is illegal, and any questionnaire that asks about
illegal behavior must be reviewed by our IRB.C.
False, because although such surveys are exempt
at other institutions, NC States specific
institutional guidelines explicitly require IRB
review for surveys that ask about illegal
behavior.
4
As of 1985, evidence showed that institution
review boards were biased against studies of
unusual or politically sensitive
subjects.True or false?
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As of 1985, evidence showed that institution
review boards were biased against studies of
unusual or politically sensitive
subjects.True. Ceci, Peters, and Plotkin
(1985, American Psychologist) found that IRBs
were inconsistent in their judgments of many
types of studies, and were biased against studies
of unusual and politically sensitive subjects.
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Topics for this session 1. Use of
humans a. A history of abuse -
Nuremberg - US Public Health
Service - Belmont b. Protection c.
Conflict of interest d. Justice 2. Use of
animals
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History of scandals Nuremberg Third Reich
medical experiments
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Germany, 1930s - 40s
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International response Nuremberg War
Criminal Trials 1947
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The voluntary informed consent of the human
subject is absolutely essential.

• Legal capacity to give consent
• Free of force, fraud, deceit, duress,
  constraint or coercion
• Sufficient comprehension to make an
  enlightened decision

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The duty for ascertaining the quality of consent
rests upon each individual who initiates, directs
or engages in the experiment.
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A history of abuse, 1932 1974, US
US Public Health Service syphilis study,
Tuskegee, AL
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Herman Shaw White House May 16, 1997
Tuskegee study participant
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Radiation, 1940s -- Soldiers, journalists sent
into radioactive wake of atomic bomb
trials.Thalidomide, 1950s -- Pregnant women
given a drug not approved by FDA to control sleep
and nausea. Severe birth deformities.Willowbro
ok State School for the Retarded, 1960s
--Experimental hepatitis serum injected into
mentally retarded children. Parents unable to
enroll children in school unless they consented
to trial.
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The National Commission (1974-78)

• National Commission for the Protection of
  Subjects of Biomedical and Behavioral Research
• Charge
• recommend to DHEW guidelines to protect the
  rights and welfare of human subjects of
  research, particularly those with disabilities
  and develop principles to govern the ethical
  conduct of research
• Reports
• Fetal research, children, prisoners,
  institutionalized mentally infirm, psychosurgery,
  IRBs, The Belmont Report

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US response, 1979
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- The Belmont Report

• Ethical principles to protect human subjects
• 1. Respect for persons
• 2. Beneficence
• 3. Justice

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• 1. Respect for persons
• Each human being is an autonomous individual.
• Each should be free to make decisions about
  their own welfare.

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• 2. Beneficence
• Researchers have a social duty to do good and
  improve the world by maximizing the ratio of good
  research consequences over bad consequences.

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• 3. Justice
• Researchers are bound by considerations of
  fairness to distribute the risks and benefits of
  research justly.

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Belmont emphasis

• Protect humans from exploitation
• Special protection for most vulnerable
  (children, pregnant women, prisoners)

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Research ethics emphasis, 1980s 90s

• Experimental trials constitute health care
• (AIDs trials, ACT-UP)
• Who has access to the trials? (Answer
• everyone should have access)
• Should subjects be paid? (Answer yes, but
  only enough to compensate them
• for their time)

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SurveysExempt from review Surveys asking
about routine behaviors (e.g., how much time
students spend studying).Inconsistent IRBs do
not always make consistent judgments (e.g.,
suggestion of bias against studies of unusual or
politically sensitive subjects Ceci, Peters,
and Plotkin, 1985, American Psychologist).
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Research ethics emphasis, 2000s

• Conflict of interests

Researcher's personal financial interests,
personal relationships, job security Institution'
s financial interests, desire to participate in
technology transfer What to do?
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Disclose!

• To IRB, to subjects
• COI committee to review appeals and monitor
  project management
• No participation allowed if financial stake
  is larger than stipulated level

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• Goals for this session
• History of scandals
• 2. Use of humans
• 3. Use of animals

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Headless MiceW. Shawlot and R.R.
Behringer (1995)Nature vol. 374pp. 425-430
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Genetic engineering

• takes mankind into realms that belong to God
  and God alone
• - Prince Charles

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IACUC

• History of animal abuse
• Potential COI of individual investigators
  with using animals
• Anyone using animals in research is
• legally obligated to care for them

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POLICY Animals should be used only as
required to achieve results which will
ultimately benefit society.Whenever feasible,
mathematical models, in vitro biological systems,
and computer and audiovisual aids should
augment, complement, or possibly replace animal
use entirely
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CASETesting pesticides on humans Food
Quality Protection Act (FQPA) 1996 requires US
Environmental Protection Agency (EPA) to
establish No Observable Effect Level (NOEL) for
all chemicals suspected of developmental
toxicity.
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"A NOEL is defined as an exposure level at which
there is no statistically or biologically
significant increase in the frequency or severity
of any effect between the exposed population and
its appropriate control (U.S. EPA 1999a). Two
10-fold safety factors are then applied. First,
the NOEL observed in rodents is divided by a
factor of 10 to account for the extrapolation
from rodent to human. All texts quoted are
from "Pesticide Testing in Humans Ethics and
Public Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
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"Then that number is divided by a second factor
of 10 to account for variation among humans.
Thus, the traditional practice had been to
determine the NOEL in animals, divide that number
by 100, and on that basis calculate the pesticide
standard, termed a "reference dose" or
"tolerance" (EWG 1999). All texts quoted are
from "Pesticide Testing in Humans Ethics and
Public Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
40
"Then that number is divided by a second factor
of 10 to account for variation among humans.
Thus, the traditional practice had been to
determine the NOEL in animals, divide that number
by 100, and on that basis calculate the pesticide
standard, termed a "reference dose" or
"tolerance" (EWG 1999). All texts quoted are
from "Pesticide Testing in Humans Ethics and
Public Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
41
in certain instances--especially where
developmental toxicity is suspected or where data
on developmental toxicity are lackingEPA is
required to apply a third child-protective
safety factor of up to 10-fold and thus to divide
the NOEL obtained in animals by a factor of as
much as 1,000 (103) in setting human standards
(U.S. EPA 2003b). All texts quoted are from
"Pesticide Testing in Humans Ethics and Public
Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
42
in certain instances--especially where
developmental toxicity is suspected or where data
on developmental toxicity are lackingEPA is
required to apply a third child-protective
safety factor of up to 10-fold and thus to divide
the NOEL obtained in animals by a factor of as
much as 1,000 (103) in setting human standards
(U.S. EPA 2003b). All texts quoted are from
"Pesticide Testing in Humans Ethics and Public
Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
43
Some pesticide manufacturers have increasingly
undertaken testing in humans, thus bypassing the
need for the first 10-fold safety factor. Testing
in humans may render unnecessary the safety
factor that accounts for the extrapolation from
animals to humans. The net effect is that the
NOELs determined in humans must be divided by a
factor of only up to 100 to comply with the FQPA
(U.S. EPA 2003b)." All texts quoted are from
"Pesticide Testing in Humans Ethics and Public
Policy," Christopher Oleskey, et al.
Environmental Health Perspectives Volume 112,
Number 8, June 2004 http//www.ehponline.org/membe
rs/2004/6522/6522.html
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• Dr. Sinbad wants you to help him test a new
  chemical on humans in a developing country. Is
  his research proposal ethical?
• What are the facts who are the stakeholders
  potential harms?
• Facts He wants to get the grant.
• Using humans in this way is not
  contrary to his professional code, because
• Not contrary to the laws of the country
• Stakeholders Experimental subjects, Sinbad,
  others?
• Potential harms
• Subjects could be harmed.
• Sinbad could lose standing in field.
• You could be tainted by association with him.

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• Assume that these are facts
• Sinbad will not get the results without using
  the human subjects
• Other researchers have used private grant
  monies
• on human subjects in developing countries
• Subjects are paid a sum equal to 2 months
  salary in their economy
• No subject has ever been, and never will, be
  harmed.

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• Assume these are also facts
• Sinbads course gets him the results he needs, SO
  his course is in his own best long-term
  self-interests.
• Sinbads course is not contrary to his
  professional code nor illegal in the country in
  which it is being conducted, SO it is in the
  interests of those in his profession
• Sinbads course is in the interests of those
  supporting him and those on whom hes
  experimenting because it leads to very useful
  results, SO it is in the interests of all human
  beings and does maximize happiness.
• Sinbads course does not inform the experimental
  subjects of the risks associated with the
  procedure SO it does not respect the subjects
  right to informed consent.

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Four ethical principles 1. Self-interest I
ought always to do what is in my own long-term
best self-interests. 2. Virtue I ought
always to do what my profession regards as
virtuous being honest, treating persons
fairly, not harming persons or property, giving
due credit, etc. 3. Maximize happiness and
minimize risk I ought always to try to make
the world a better place, by maximizing the
amount of happiness (pleasure, interests
satisfied, utilities achieved) in the world
while minimizing the amount of unhappiness
(harms, risks, disutilities). 4. Respecting
rights I ought always to do my duty and respect
each individual persons basic rights (the right
to life, liberty, the pursuit of happiness,
informed consent, etc).
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Use the principles to assess whether this course
of events is ethical. 1. Self-interest
Sinbads conduct will produce results he needs
to produce food efficiently and save lives. 2.
Virtue Sinbads professional code does not
prohibit research that is illegal in the US but
legal in other countries. 3. Maximizing
happiness and minimizing risk Sinbads work
will lead to far more human lives being saved
than are put at risk by the research. 4.
Respecting rights Experimental subjects have an
ethical right to be fully informed about the
procedures. Sinbads subjects rights are not
being respected.
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Is this course of events ethically justified? 1.
Self-interest Sinbads conduct will produce
results he needs to produce food efficiently and
save lives. 2. Virtue Sinbads professional
code does not prohibit research that is illegal
in the US but legal in other countries. 3.
Maximizing happiness and minimizing risk
Sinbads work will lead to far more human lives
being saved than are put at risk by the
research. 4. Respecting rights Experimental
subjects have an ethical right to be fully
informed about the procedures. Sinbads subjects
rights are not being respected.
YES
YES
YES
NO
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• Problem The 4 principles do not agree on the
  answer.
• How do we decide which is the correct answer?
• Count? (no)
• We analyze the arguments given for each answer,
  and
• Determine which answer has the best reasons
• to support it.
• Most weighty, convincing, plausible, true,
  justifiable

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• A Method for Ethical Decision - Making
• Fix the facts, stakeholders, and harms.
• Assess the course of events and decisions from
  each of the 4 ethical perspectives.
• Assign a value (a weight) from each of the 4
  ethical perspectives to the course of events.

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A Sinbad uses subjects legally but without
getting informed consent. Profession is mute on
the subject.
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Assign a value 1 point if the action is in
his best long-run self-interests - 1 point if
action is not in his best long-run self-interests.
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A Sinbad uses subjects legally but without
getting informed consent. Profession is mute on
the subject. Procedure Give Sinbad 1
point if the action is in his self-interest -
1 point if action is not in his self-interest.
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4 points if Course A is in his professions
interests - 4 points if Course A is against his
professions interests
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5 points if Course A is in everyones
interests - 5 points if Course A is against
everyones interests.
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5 points if Course A respects human
rights - 5 points if Course A disrespects human
rights.
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Total Add up all the points in the row.
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Lowest score ( - 15 ) -- least possible
rational support for Course A Highest
score ( 15 ) -- strongest possible rational
support for Course A
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• How did we determine the numbers?
• Moral intuitions screened for bias
• Ethical judgments critically examined
• Inter-cultural comparisons of judgments
• Logical assessments of argumentative validity
  and soundness
• Empirical research into how moral judgments are
  formed (psychologically, socially)
• Study of which judgments lead to overall
  long-term
• individual and collective happiness (objective
  indicators and subjective indicators)
• Informal unscientific survey of how professional
• ethicists rank the various considerations.

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What assumptions did we make in assigning
values? 1. Self-interest Lowest possible score
- 1 , highest 1 Self-interest should
count least because of the ease of
self-deception and the potential unfairness of
only taking ones own interests into
account. 2. Professional codes Lowest
possible -4 , highest 4 Such codes
should count much more than ones
self-interested judgments because they are the
outcome of a deliberative critical process in
which a community of inquirers pools its
knowledge to distill its best practices.
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Assumptions in assigning values 3. Interests
of all Lowest possible - 5 , highest
5 Making the world a better place by maximizing
the ratio of happiness over unhappiness, and of
benefits over risks should more than
professional codes because professional codes
may be biased slightly toward the interests of
the profession. Utilitarianism requires taking
all interests equally.
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Assumptions in assigning numbers 4. Human
rights Lowest possible - 5 , highest
5 Same justification as for interests of all.
Since rights theories often define themselves in
opposition to utilitarian theories, I assume the
weight of a rights argument must be able to
cancel out, at least, utilitarian arguments.
Thus, rights and utilitarian arguments have the
same highest possible weighting.
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Obviously, the numbers are critical. How do we
justify the ranges we chose? A question for
researchers in ethics
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Acknowledgments

• Jeffrey Kahn, University of Minnesota,
  Protecting Human Subjects Where We Are and How
  We Got Here
• David Resnik, East Carolina University, Research
  Ethics Across the Curriculum What Needs to Be
  Done?