1

• Primum,
• non nocere.
• Hippocrates
• (First, do no harm.)

2
Data Ethics

• One of the most serious ethical problems in
  clinical research is that of placing subjects at
  risk or injury, discomfort, or inconvenience in
  experiments where there are too few subjects for
  valid results, too many subjects for the point to
  be established, or an improperly designed random
  or double-blind procedure. Journal of Medical
  Ethics

3
Nuremberg code

• 1947 Doctors Trial at Nuremberg
• Atrocities in the name of research
• Sterilization experiments
• Dachau hypothermia/high altitude experiments
• Led to the Nuremberg Code
• 10 standards for research with
• human subjects
• Risk must be weighed against the
• expected benefit, and that unnecessary
• pain and suffering must be avoided.
• Doctors should avoid actions that
• injure human patients.
• Voluntary consent of patient is essential

4
Declaration of Helsinki

• 1964 Declaration of Helsinki of the World Medical
  Association issued a series of recommendations
  to guide research on human subjects
• Revised at regular intervals over many years
• The interests of the subject must always prevail
  over the interests of science and society.
• In any medical study, every patient--including
  those of a control group, if any--should be
  assured of the best proven diagnostic and
  therapeutic method."

5
Ethics in the U.S.

• Nuremberg and Helsinki had enormous moral force
  but not the force of law in the U.S.
• Provisions were largely ignored for many years
• In June 1966, Henry K. Beecher, an
  anesthesiologist at Harvard Medical School,
  published a highly influential article entitled
  "Ethics and Clinical Research" in the New England
  Journal of Medicine. He detailed 22 clinical
  trials that appeared to be highly unethical, in
  which researchers risked their patients' lives
  without fully informing them of the dangers and
  without obtaining their permission.

6
Willowbrook and Brooklyn Jewish hospital

• 1963-1966 hepatitis studies carried out at
  Willowbrook, a New York State institution for
  "mentally defective persons."
• Subjects, all children, were deliberately
  infected with the hepatitis virus
• During the studies, Willowbrook closed its doors
  to new inmates, claiming overcrowded conditions.
  But the hepatitis program was able to continue to
  admit new patients. In some cases, parents were
  unable to admit their child to Willowbrook unless
  they agreed to participate in the studies.
• 1963 Brooklyn Jewish Chronic Disease hospital
• Investigators injected live cancer cells into
  senile patients to observe their immunological
  responses. Subjects were never informed of the
  dangers.
• In neither case did the research have any
  potential therapeutic value to the patients under
  study.

7
Tuskegee syphilis experiment

• Study began in 1932 by the U.S. Public Health
  Service to determine the history of untreated
  syphilis
• Subjects were some 400 Black sharecroppers in
  Alabama diagnosed with syphilis
• Men were recruited without informed consent.
  Misinformed and told that some procedures (e.g.,
  spinal taps) were actually "special free
  treatment."
• By 1936, it was apparent that many more infected
  men than controls had developed complications.
  Death rate among those with syphilis was about
  twice as high as it was among the controls.
• In the 1940's, when penicillin, known to be
  effective in the treatment of syphilis, became
  available, the men were neither informed, nor
  treated with the antibiotic.
• Many died from untreated syphilis

8
Tuskegee syphilis experiment

• Study continued until it was exposed in the
  national press in 1972!
• 1996 review It has come to symbolize racism in
  medicine, ethical misconduct in human research,
  paternalism by physicians, and government abuse .
  . .
• President Clinton apologized to survivors in 1997
• U.S. government continues to pay millions of
  dollars yearly to surviving subjects and the
  families of deceased subjects.
• Read the book Bad Blood
• The Tuskegee Syphilis Study by James H. Jones
• and see the video The Deadly Deception (Nova).

9
Belmont Report

• Outrage over Tuskegee and Beecher article led to
  some reforms in the 1970s
• Congress created the National Commission for the
  Protection of Human Subjects of Biomedical and
  Behavioral Research which issued the influential
  Belmont Report in 1979
• Lays out 3 guiding ethical principles
• Respect for persons
• Beneficence
• Obligation to (1) Do no harm, and (2) Maximize
  benefits and minimize harms
• Justice
• Benefits of research should be distributed fairly

10
Ethics of clinical trials

• There is a delicate balance between when to do
  or not do a randomized trial. On the one hand,
  there must be sufficient belief in the agents
  potential to justify exposing half the subjects
  to it. On the other hand, there must be
  sufficient doubt about its efficacy to justify
  withholding it from the other half of subjects
  who might be assigned to placebos.
• Dr. Charles Hennekens, Harvard Medical School
  (who directed the physicians aspirin study)

11
Basic standards of data ethics for studies
involving human subjects

• Informed consent
• All individuals who are subjects in a study must
  give their informed consent before data are
  collected
• Subjects must be informed in advanced about the
  nature of a study and any risk of harm it may
  bring
• Confidentiality
• All individual data must be kept confidential
• Only statistical summaries for groups of subjects
  may be made public
• Not the same as anonymity where subjects names
  are not known, even to director of study (rarely
  the case)
• Institutional Review Boards
• Organization that carries out the study must have
  an institutional review board that reviews all
  planned studies in advance in order to protect
  subjects from possible harm
• Carletons IRB

12
Case Study 1

• Dr. W is a family practitioner with interest in
  the treatment of HIV infection and AIDS.
• He receives a letter from the coordinator of a
  study to evaluate a promising new treatment for
  the prevention of HIV-related dementia.
• The letter invites Dr. W to submit the names of
  potentially eligible patients.
• He will be paid 100 for each name provided.
• Is this ethically objectionable?

13
Case Study 2

• A highly respected medical institution keeps a
  vast amount of confidential medical data
• The institution has a rule that no employee can
  access this data for any personal or
  non-professional purpose
• A statistician employee, who has access to this
  data, recently had a physical check-up at the
  institution. Curious, he goes on-line to look up
  his own confidential medical records.
• When the institution found out about this, the
  statistician was immediately discharged.
• Is the institution justified in this action?

14
Case Study 3

• Dr. T, a psychiatrist, is asked to assist with a
  clinical trial to test a new drug in the
  treatment of psychosis.
• The study will enroll acutely psychotic patients
  with no history of psychosis or of treatment with
  antipsychotic drugs.
• Patients enrolled in the study will be randomly
  assigned to receive the new drug or a placebo and
  will remain in the hospital for 8 weeks. During
  this time they will not receive medications other
  than the study drug.
• Informed consent will be obtained from each
  participant or a proxy.
• Patients may be withdrawn from the study if their
  medical condition worsens substantially.

15
Is it ethical for Dr. T to enroll his patients in
this study?

• No! Consent alone is insufficient. The study must
  present a favorable balance of benefits and
  harms. (Canadian Med J, Bioethics for
  clinicians)
• The treatments being studied must be in a state
  of clinical equipoise, that is, there is
  genuine uncertainty within the expert clinical
  community about the comparative merits of the
  alternatives being tested.
• When effective standard treatment exists for a
  disease (as it does for schizophrenia) it is
  unethical to expose patients to the risk of
  treatment with placebo alone, since placebo is
  an inferior treatment.