“Primum, non nocere.” – Hippocrates (“First, do no harm.”)

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 Doctor’s 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 agent’s 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 physician’s 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 • Carleton’s 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.”