1. Ethical Legal/Issues in Human Subject Research II
ISD II – Infectious Diseases
Barbara Barrowman
Andrew Latus
March 7, 2003

2. Outline
Second of a two-part consideration of legal and ethical issues related to human subject research.
In the first session (during the GI course), we considered the following issues:
What is research?
Rationale for research ethics review
Ethical/legal/regulatory framework for human subject research in Canada

3. Outline (cont.)
We also identified a number of major ethical/legal issues in human subject research:
1. Scope of acceptable research
2. Conflicts of interest
3. Consent - informed, voluntary
4. Confidentiality, access to information
5. Children, mentally incompetent individuals
6. Justice in recruitment of subjects
Covered # 2 and 3 in the last session.
Today, we will cover the other issues, with an emphasis on #1 and 4.

4. The Tuskegee Syphilis Experiment
Clear example of ethically unacceptable research, at least by present standards
Some problems:
Lack of informed consent due to deception
Study was presented as treatment
Treatments for syphilis were available
Conflict of interest caused profound failure in duty to care
Injustice in selection of subject population
Unacceptable form of research
Clearly illustrates need for a focus on research ethics

5. Some History of Research Ethics
Early codes of medical ethics tended to treat research as part of overall code of medical ethics
Today, treated as a distinct area
Thomas Percival
first code of medical ethics to include requirements concerning research?
The use of experimental techniques on patients should be “scrupulously and conscientiously governed by sound reason” and undertaken only after consulting with other physicians
No mention of seeking the consent of the subject
Quotation is from (Beecher, 1970, 218)

6. Paternalistic Research Ethics
“It is our duty and our right to perform an experiment on a man whenever it can save his life, cure him or gain him some personal benefit. … So, among the experiments that might be tried on man, those that can only harm are forbidden. Those that are innocent are permissible, and those that may do good are obligatory.”
Claude Bernard, an influential French physiologist,
First quotation is from (Grodin, 1992, 125-6)
Second quotation is from

7. William Beaumont - Research Ethics Pioneer?
Some credit Beaumont with the “oldest … code” specifically focussed on human experimentation (1833):
“5. The voluntary consent of the subject is necessary…
“6. The experiment is to be discontinued when it causes distress to the subject…
7. The project must be abandoned when the subject becomes dissatisfied.”
Some dispute about whether code actually existed.
First quotation is from (Beecher, 1970)
Dispute is explained in (Numbers, 1979)

8. Policy vs. Practice
Ironically, some of the earliest and clearest pronouncements on the importance of consent in medical research are to be found in early 20th century Germany
Vaccination trials without consent on poor and vulnerable people (abandoned children, prostitutes) led to research regulations in Prussia in 1900
A 1931 directive from the German Reich Minister of the Interior forbids “innovative therapy” unless the “subject or his legal representative has unambiguously consented to the procedure in the light of relevant information provided in advance”
Quotation is from (Grodin, 1992, 130)

9. The Nuremberg Code
The modern era in research ethics begins with the Nuremberg Code (1947)
Produced as part of the “Doctors’ Trial,” part of the post-W.W.II war crimes tribunal
Response to research atrocities
Deliberate infection with malaria, smallpox, cholera
Sexual sterilization experiments
Cold temperature experiments

10. From the 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 … and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be known to him the nature, duration and purpose of the experiment; the methods and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.”

11. Not the End of Atrocities
Unfortunately, as already noted policy is one thing and practice another. Some examples:
Tuskegee Syphilis Experiment ( )
Willowbrook hepatitis vaccination experiments ( )
CIA funded LSD Experiments in Montreal (1950s & 1960s)
Brooklyn Jewish Chronic Disease Hospital cancer study (1963)
Note: all involved vulnerable participants
From 1963 to 1966, researchers deliberately infected newly admitted "mentally defective" children at the Willowbrook School, a State school in New York, with the hepatitis virus in order to study the natural history of the disease under controlled circumstances. In some cases, parents were not allowed to admit children to the institution unless they agreed to let them participate in the trials.
In 1963, physician-investigators at the Jewish Chronic Disease Hospital in Brooklyn, New York, injected cancer cells grown in the lab into people hospitalized with various chronic diseases without informing the people or gaining their consent. In review proceedings, the Board of Regents of the State University of New York found that the trial had not been presented to the hospital's research committee; the researchers were found guilty of fraud, deceit, and unprofessional conduct.
In 1970, came the revelation of the Tuskegee experiment. Starting in 1930 and continuing for four long decades, investigators began examining--but not treating--a group of 400 African-American men who had contracted syphilis. The researchers were interested in watching the natural course of the disease as it developed.

12. The Helsinki Declarations
1964 – World Medical Associations Declaration of Helsinki ‘replaces’ the Nuremberg Code
Since revised in 1975, 1983, 1989, 1996 and 2000
2000 version is contained in handout
Less stringent on consent, allows for proxy consent
Most other national and international codes now share this approach

13. Some Major Ethical/Legal Issues in Medical Research
Scope of acceptable research
Conflicts of interest
Consent - informed, voluntary
Confidentiality, access to information
Children, mentally incompetent individuals
Justice in recruitment of subjects

14. Scope of Acceptable Research
Two issues:
Is there some research which should never be done even if the other concerns on our list can be met
Xenotransplantation?
Embryonic stem cell research?
Cloning?

15. Scope of Acceptable Research
2. What do we do with the results of immoral research?
“good science is incompatible with bad ethics”?
“the Tuskegee study was and remains a key source of information about … syphilis.” (Caplan, 419)
“The immorality of research methods should not blind us to the importance of noting and discussing them.” (Caplan, 423)

16. Confidentiality
General obligation of confidentiality owed by physicians to patients extends to researchers
Embodied in research codes, guidelines
Research Ethics Board’s (REB’s) typically require policies re. storage and destruction of data and samples, anonymization of data
Should also be addressed in consent forms

17. Confidentiality
Tension between need to share data and privacy of subjects
Beware of over-promising confidentiality:
Access to data for safety and ethics monitoring
Health Protection Branch, Health Canada
Periodic review by REB’s
General legal/ethical obligations to break confidentiality
E.g., child abuse revealed during interview
Will be discussed in more detail in subsequent session

18. Confidentiality in Genetic Research
Genetics raises problems in that the information gathered through genetic research is not only information about an individual, but also about those to whom the individual is related
Is there a duty to warn family members of being at risk?

19. Research Involving Children
Application of ‘mature minor’ principle to research?
Substitute consent by parents?
Parents may consent to child’s participation in research that offers reasonable hope of benefiting child
What about research that has no intended benefit for the child?
Unclear

20. Research Involving Mentally Incompetent Individuals
Significance - research into Alzheimer’s, stroke, emergency department research, etc.
Substitute consent?
Advance directives?
e.g. NF Advance Health Care Directives Act

21. The TCPS ( )
Research on incompetent subjects may be acceptable provided that:
Consent is sought from the appropriate 3rd party
The subject’s wishes are sought and the subject does not dissent from the research
Using incompetent subjects is necessary in order for the research question to be addressed
The subjects are not exposed to more than minimal risks without the potential for benefits to the subject
U.S. will allow research which poses a greater than minor increase over minimal risk provided that:
It presents a ‘reasonable’ opportunity to study a serious problem affecting the health and welfare of children
The study is approved by the secretary of the Department of Health and Human Services after consultation with experts.
(Kopelman, 2000, )

22. Justice in the Recruitment of Research Subjects
So why do research on children & incompetent subjects?
Clinical research has potential to offer significant individual benefit
treatment only available through trial, most up-to-date, financial coverage for new medications, etc.
Also potential future benefit for class of patients
Historically medications/interventions predominantly tested on narrow segment of population - young-middle aged white males (“the 70 kg man”)

23. Justice in Recruitment of Research Subjects
Optimally, clinical trial sample population should mirror patient population in clinical practice
Inclusion of women, the elderly, individuals of Aboriginal, Asian or African heritage, etc
Tri-Council Statement 1998
Anti-discrimination provision, importance of research on children and elderly