Life is all about choices … Human Subjects Research Ethics

Join me as we journey back to an age where The field of Medicine comes into its own, and Optimism, Progress, and Science sit on the Throne of GOD Welcome to the Ethical Time Machine All Aboard!

Piaget describes stages of cognitive development First Test Tube Baby Born 1978 First Human Heart Transplant Year First successful Open Heart Surgery Penicillin sulfa drugs First Electrocardiogram 1903

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Nazi Germany at beginning of World War II Was the most scientifically and technologically advanced country in the world, Had a proposed code of research ethics, Supported midwifery, nutrition programs, ecology, public health, human genetics, cancer, radiation, and asbestos research

However … The Nazis also … exploited peoples trust in the medical community by performing unethical experiments on populations they discriminated against.

Nazi Battlefield Medicine Experiments 1942: High altitude or low pressure experiments at Dachau : Freezing experiments at Dachau : Malaria experiments at Dachau : Phosphorus burn experiments at Buchenwald 1944: Seawater experiment at Dachau

At Ravensbruck women were shot or slashed on the legs. The wounds stuffed with glass, dirt, and bacteria cultures and sewn shut then treated with experimental anti-infective agents.

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

The Nuremberg Code Key Ideas –Voluntary Informed Consent –Right of the Subject to Withdraw from the Experiment at any Time –A Human Subject Cannot be Sacrificed for the Greater Good of Science –Investigator must terminate the experiment at any time the well-being of his/her subjects is threatened.

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Human Radiation Experiments In 1994, President Clinton appointed the Advisory Committee on Human Radiation Experiments (ACHRE) To investigate unethical experiments conducted by our government during WWII and the Cold War Era

ACHRES Investigation Revealed … testing on soldiers feeding radioactive cereal to teenagers at a school for the mentally retarded, irradiating the testicles of prison inmates, injecting plutonium into hospital patients, intentional releases of radiation into the environment …

4000 human radiation experiments conducted In a two prong effort by the US to –P–Provide for National Security –P–Provide medical studies to improve human health Too often deceptively, secretly, and/or without informed consent

Testimony before ACHRE, 1995 My mother, Jan Stadt, had a number, HP-8. She was injected with plutonium March 9, She was 41 years old, and I was 11 years old at the time. My mother and father were never told or asked for any kind of consent to have this done to them. My mother went in (to the hospital) for scleroderma...and a duodenal ulcer, and somehow she got pushed over into this lab where these monsters were. Milton Stadt Son of subject in the Rochester University experiments

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

The Thalidomide Tragedy

Thalidomide was prescribed for morning sickness Approved in Europe in late 1950s but not in US due to diligent efforts by one USDA doctor. However as was common practice among pharmaceutical companies … some U.S. doctors were supplied samples and paid to study its safety and efficacy.

It was subsequently discovered that … Thalidomide causes severe deformities in babies and its effects are even passed on to later generations.

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

1962 Kefauver-Harris Amendments Food, Drug and Cosmetic Act Looked at practices of pharmaceutical companies Required more testing before widespread use Informed consent from patients receiving experimental drugs

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Socio-Behavioral Studies Milgrams Study of Obedience to Authority –Subjects coerced into feeling they had seriously injured somebody The Stanford Prison Experiment –What happens when you put good people in an evil place? – Radiation experiments on soldiers –Fear

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Declaration of Helsinki 1964 Research with humans should be based on the results from laboratory and animal experimentation Research protocols should be reviewed by an independent committee prior to initiation Informed consent from research participants is necessary Research should be conducted by medically/scientifically qualified individuals Risks should not exceed benefits

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Dr. Beecher began his famous article in the NEJM by stating: … medicine is sound, and most progress is soundly attained …

He then went on to describe … 22 examples of research studies with controversial ethics conducted by reputable researchers and published in major journals. "Until this article we assumed that unethical research could only occur in a depraved regime like the Nazis. Robert J. Levine, MD

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Syphilis the AIDS of an earlier time Untreated, it can lead to –s–severe heart disease, –b–brain damage, –p–paralysis, and –d–death. The problem was, until 1907, no one could treat it.

Then Nobel Prize-winning microbiologist Paul Ehrlich discovered Salvarsan an arsenic-based compound. It was the first chemotherapy.

The 1920s was a progressive era in medicine Armed with confidence and the Scientific Method, Public Health Service officials were determined to control syphilis in their time. They set up free treatment clinics throughout the south, including Macon county, Alabama, home to the Tuskegee Institute.

While writing the final report, Dr. Taliaferro Clark, head of the PHS Venereal Disease Division conceived an idea to salvage the study … Macon county offered an unparalleled opportunity for the study of the effect of untreated syphilis in the Negro male. But in 1932, the funding for treatment ran out.

The Study of Untreated Syphilis in the Negro male (1932 – 1972) was only supposed to last a year … but then Dr. Raymond Vondelehr advocated continuing the study to get autopsies. Autopsies would confirm clinical observation and therefore greatly contribute to the scientific reliability of the studys findings.

Bringing them to Autopsy By the time Jean Heller broke the story in the Washington Star in 1972 The experiment had gone on for 40 years. During all this time, it was no secret to the wider medical community. Results of the study had been published in well known medical journals. Yet no one ever questioned the study.

399 Participants None were ever told they had syphilis. None were ever offered a cure even when penicillin became available in Researchers had even interfered to keep subjects from getting penicillin so the study could continue.

28 men died of syphilis 100 men died from related complications at least 40 wives were infected 19 children had contracted the disease at birth a whole peoples trust was shattered Nothing Learned will Prevent, Find, or Cure a Single Case

Bad Blood Macon county residents were very poor. They lived and died without medical care because they could not afford it. They didnt distinguish between syphilis and a host of other maladies which they called bad blood. They trusted the government doctors and they traveled great lengths to get a little free medical care. They were told they were being treated for bad blood.

I, like most everybody else, was horrified at the things that were practiced upon these Jewish people, such as doing experiments while the patients were not only alive but doing such things as would cause their deaths. All these sorts of things were horrendous to me and I, like most everyone else, deplored them. Dr. John R. Heller, Researcher, Tuskegee Syphilis Study

Final Report of Tuskegee Syphillis Study "Society can no longer afford to leave the balancing of individual rights against scientific progress to the scientific community."

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

In 1974 at Belmont, the National Commission for the Protection of Human Subjects began deliberations … Kenneth John Ryan, M.D., Joseph V. Brady, Ph.D., Robert E. Cooke, M.D., Dorothy I. Height, President, NCNW, Albert R. Jonsen, Ph.D., Patricia King, J.D., Karen Lebacqz, Ph.D., David W. Louisell, J.D., Donald W. Seldin, M.D., Eliot Stellar, Ph.D., Robert H. Turtle, LL.B., Attorney.

Which led in 1978 to the opening words of the Belmont Report Scientific Research has produced substantial social benefits. It has also posed some troubling ethical questions.

The 3 Basic Ethical Principles of the Belmont Report Respect for Persons Benefice Justice

Respect for Persons Definition: Individuals should be treated as autonomous agents Persons with diminished autonomy are entitled to protection Application: Voluntary Informed Consent Belmont Report

Benefice Definition: Do not harm Maximize possible benefits Minimize possible harms Application: Assessment of risks and benefits Belmont Report

Justice Definition: Who ought to receive the benefits of research? Who ought to bear its burdens? Application: Equitable Selection of Subjects Belmont Report

Syphilis Study Exposed The Beecher Article (NEJM) 1932 The Syphilis Study Begins Trigger Events Nuremberg Code Kefauver-Harris Amendments Food, Drug and Cosmetic Act Declaration of Helsinki Belmont Report Consolidated HHS/FDA Regulations Common Rule The Nazi Experiments US Human Radiation Experiments The Thalomide Tragedy Milgram Study 20 th Century Research Ethics Milestones Back to the Future

Piaget describes stages of cognitive development First Test Tube Baby Born 1978 First Human Heart Transplant Year First successful Open Heart Surgery Penicillin sulfa drugs First Electrocardiogram 1903

Home free in the 21 st Century? Research is still Risky –Gene Therapy Trials Death of 18 year old Jesse Gelsinger in 1999 Conflict of interest –Cloning –Nanotechnology –Internet Research –Artificial Intelligence –Chemical and Biological terrorism –Space travel …

Institutions where Studies have been temporarily suspended July 1998 – July 2001 Rush Presbyterian – St. Lukes Medical Center Friends Research Institute Veteran Affairs Greater LA Virginia Commonwealth University John Hopkins

Questions to Consider Why should we be concerned about Human Subject Research? Do you think another Tuskegee could happen in the future? Do you think a Tuskegee could ever happen to you? Can you envision yourself ever being faced with an ethical dilemma in Human Subjects research? What are some guidelines or resources you could turn to? And finally, The Tuskegee Study started in the United States in 1932 and continued for 40 years, well past the Nuremberg trials. It was also no well kept secret. Research articles were published in major medical journals during this time. Why do you think nobody saw a connection between Nuremberg and the Tuskegee Syphilis Study?

The 1997 Presidential Apology to Tuskegee Participants

choices have consequences Now its your turn - how will YOU choose? Life is all about choices …