The document summarizes key historical events in medical research ethics and the development of protections for human subjects. It describes atrocities like the Nazi experiments and Tuskegee Syphilis Study that lacked informed consent. This led to regulations like the Nuremberg Code and Belmont Report, which established ethical principles of respect for persons, beneficence, and justice. The Belmont Report specifically aimed to provide guidelines for research ethics through its principles and considerations for informed consent, risk-benefit assessments, and fair subject selection.

1. The Belmont Report

2. Historical Perspective
• Nuremberg War Tribunal (1947) - Criminal proceedings against
23 leading German physicians and administrators for their willing
participation in war crimes and crimes against humanity. Horrifying
procedures were conducted for research purposes on thousands of
concentration camp prisoners without their informed consent
(consent is permission or agreement).
• Syphilis Study in Tuskegee, GA (1932-1972) – As part of a
research project conducted by the U.S. Public Health Service, 600
low-income African-American males, 400 of whom were infected
with syphilis, were monitored for 40 years. Free medical
examinations were given; however, participants were not told about
their disease. Even though a proven cure (penicillin) became
available in the 1950s, the study continued until 1972 with
participants being denied treatment. In some cases, when
participants were diagnosed as having syphilis by other physicians,
researchers intervened to prevent treatment. Many participants died
of syphilis during the study. The study was stopped in 1973 by the
U.S. Department of Health, Education, and Welfare only after its
existence was publicized and it became a political embarrassment.

3. Historical Perspective
• Thalidomide use - Thalidomide was used in the 1950s to combat
unpleasant symptoms associated with pregnancy. At the time it was
being used it was not usually disclosed to patients that the drug was
investigational and still in the testing phase of the regulatory process.
After women in Europe, Canada, and the U.S. were treated with the
drug it was discovered that the drug had teratogenic effects, causing
severe deformities in the fetus. Thalidomide was soon banned
worldwide. Unfortunately, approximately 12,000 babies were born
with severe deformities due to thalidomide.
• Radiation experiments (1940s – 1960s) - U.S. officials studied
the effects of radiation through experiments on hospital patients,
pregnant women, mentally disabled children, and enlisted military
personnel. Few of the participants of the experiments gave informed
consent; most had no knowledge that they were being subjected to
radioactive materials. Manhattan Project officials authorized the
wartime experiments to establish health and safety standards for the
thousands of workers in atomic bomb plants.

4. Response to Research Abuses
• Nazi atrocities in World War II drew attention to the lack of
international standards on research with human participants and led
to the formulation of the Nuremburg Code (1948).
• The thalidomide disaster led to the adoption of the "Kefauver
Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring
drug manufacturers to prove to the FDA the safety and effectiveness
of their products and physicians to obtain informed consent from
potential subjects before administering investigational medications.
• The Declaration of Helsinki drafted by the world Medical Association
in 1964 (most recently updated in 2000) builds on the Nuremberg
Code and is the basis for Good Clinical Practices used today.
• The National Research Act (1974) passed primarily in response to the
syphilis study, codified the requirement that human participants in
research must be protected and set the stage for the issuance of the
Belmont Report.

5. National Research Act (1974)
• Due to the publicity from the Syphilis Study, the
National Research Act of 1974 was passed.
• The National Research Act created the National
Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research.
• The Commission charge was to identify the basic
ethical principles that should underlie the conduct of
biomedical and behavioral research involving human
participants and to develop guidelines which should be
followed to assure that such research is conducted in
accordance with those principles.

6. Willowbrook:
From 1963 to 1966, the Willowbrook Study
involved a group of children diagnosed with
mental retardation, who lived at the
Willowbrook State Hospital in Staten Island,
New York.

7. Willowbrook:
These innocent children were deliberately
infected with the hepatitis virus; early subjects
were fed extracts of stools from infected
individuals and later subjects received
injections of more purified virus preparations.

8. Willowbrook:
Investigators defended the injections by
pointing out that the vast majority of them
acquired the infection anyway while at
Willowbrook, and it would be better for them
to be infected under carefully controlled
research conditions.

9. Willowbrook:
The study's purpose was to study the history
of the disease when left untreated and later to
assess the effects of gamma globulin as a
therapeutic intervention.

10. Willowbrook:
This study generated a variety of concerns,
such as the deliberate infection of the children
and the attempts to convince the parents to
enroll them in the study in exchange for
admission to the hospital (which was
deliberately short of space).

11. Fernald School Study:
The Fernald School was the site of the 1946–
53 joint experiments by Harvard University
and MIT that exposed young male children to
tracer doses of radioactive isotopes.

12. Fernald School Study:
The experiment was conducted in part by a
research fellow sponsored by the Quaker Oats
Company. MIT Professor of Nutrition Robert S.
Harris led the experiment, which studied the
absorption of calcium and iron.

13. Fernald School Study:
The boys were encouraged to join a "Science
Club", which offered larger portions of food,
parties, and trips to Boston Red Sox baseball
games. The 57 club members ate iron-
enriched cereals and calcium-enriched milk for
breakfast.

14. Fernald School Study:
In order to track absorption, several
radioactive calcium tracers were given orally
or intravenously. Radiation levels in stool and
blood samples would serve as dependent
variables.

15. Fernald School Study:
Neither the children nor their parents ever
gave adequate informed consent for
participation in a scientific study.

16. Protection of Human Subjects:
•Nuremburg Code (1947)
•Declaration of Helsinki (1964)
•The Belmont Report (1978)
•FDA (Food-drug administration) Regulations
and the Common Rule (1979, etc.)

17. Nuremberg Code
The voluntary consent of the human subject is
absolutely essential. This means that the person involved:
•should have legal capacity to give consent;
should be so situated as to be able to exercise free power of
choice, without the intervention of any element of force, fraud,
deceit, duress, over-reaching, or other ulterior (existing beyond
what is obvious or admitted; intentionally hidden) form of
constraint or coercion (the action or practice of persuading
someone to do something by using force or threats);
•and should have sufficient knowledge and comprehension of
the elements of the subject matter involved as to enable him/her
to make an understanding and enlightened decision.

18. The Belmont Report, 1978
Basic Ethical Principles:

19. National Commission for the Protection
of Human Subjects of Biomedical and
Behavioral Research
• Carrying out its charge, the Commission prepared the
Belmont Report in 1979.
• The Belmont Report is a statement of basic ethical
principles and guidelines that provide “an analytical
framework to guide the resolution of the ethical problems
arising from research with human subjects.”
• The framework of the Belmont Report is presented in
three discussion topics: boundaries between practice and
research; basic ethical principles, and applications.

20. Boundaries between
Practice and Research
• The distinction between practice and research is
blurred; often because they occur together.
• The IRB (Institutional Review Board) 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

21. 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
• Justice
– Fair distribution of burdens and benefits of research

22. Respect for Persons
• 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.

23. Beneficence
• The IRB (Institutional Review Board) 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

24. Justice
• 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

25. 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 assessment
 Selection of research participants

26. IRB
Members
should
consider
the
following…

27. 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 and 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?

28. 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 (imagine as a future possibility; visualize) 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)?

29. Applications of
Justice
• 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?

30. The Belmont Report
• Although never officially adopted or endorsed by Congress
or DHEW (now DHHS), the Belmont Report has served as
an ethical framework for protecting human subjects for
over 25 years. Many of it recommendations have been
incorporated into DHHS Title 45 CFR Part 46 and FDA Title
21 CFR Part 50.
• To obtain a full appreciation of the Belmont Report, IRB
Members are strongly encouraged to read it in its
entirety. The report can be found @
http://www.fda.gov/oc/ohrt/IRBS/belmont.html

31. Questions?
Please contact:
 Karen Allen
Director of Research Protections
@ kallen@uci.edu or 949-824-1558