Life is all about choices …

1. Life is all about choices … Human Subjects Research Ethics

2. Welcome to the Ethical Time Machine 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 All Aboard!

3. 1923 - 1952 Piaget describes stages of cognitive development First Human Heart Transplant Year - 1967 Penicillin - 1940 First Test Tube Baby Born 1978 sulfa drugs - 1932 First successful Open Heart Surgery - 1952 First Electrocardiogram 1903

4. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

5. 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

6. However … • The Nazis also … • exploited people’s trust in the medical community • by performing unethical experiments • on populations they discriminated against.

7. Nazi Battlefield Medicine Experiments • 1942: High altitude or low pressure experiments at Dachau • 1942-1943: Freezing experiments at Dachau • 1942-1945: Malaria experiments at Dachau • 1943-1944: Phosphorus burn experiments at Buchenwald • 1944: Seawater experiment at Dachau

8. 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.

9. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

10. 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.

11. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

12. 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 http://tis.eh.doe.gov/ohre/roadmap/achre/

13. ACHRE’S 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 …

14. 4000 human radiation experiments conducted • In a two prong effort by the US to • Provide for National Security • Provide medical studies to improve human health • Too often deceptively, secretly, and/or without informed consent

15. Testimony before ACHRE, 1995 • “My mother, Jan Stadt, had a number, HP-8. She was injected with plutonium March 9, 1946. 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

16. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

17. The Thalidomide Tragedy

18. Thalidomide was prescribed for morning sickness • Approved in Europe in late 1950’s 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.

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

20. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

21. 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

22. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

23. Socio-Behavioral Studies • Milgram’s 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? • http://www.prisonexp.org/ • Radiation experiments on soldiers • Fear

24. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

25. 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

26. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

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

28. 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

29. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

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

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

32. The 1920’s 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.

33. But in 1932, the funding for treatment ran out. • 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.

34. 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 study’s findings.

35. “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.

36. 399 Participants • None were ever told they had syphilis. • None were ever offered a cure • even when penicillin became available in 1943. • Researchers had even interfered • to keep subjects from getting penicillin • so the study could continue.

37. “Nothing Learned will Prevent, Find, or Cure a Single Case” • 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 people’s trust was shattered

38. “Bad Blood” • Macon county residents were very poor. • They lived and died without medical care • because they could not afford it. • They didn’t 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.”

39. “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

40. 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."

41. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

42. 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.

43. 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.”

44. The 3 Basic Ethical Principlesof the Belmont Report Respect for Persons Benefice Justice

45. 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

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

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

48. 20th Century Research Ethics Milestones ‘Back to the Future’ 1991 Common Rule Consolidated HHS/FDA Regulations 1981 Belmont Report 1979 1972Syphilis Study Exposed 1966 The Beecher Article (NEJM) Declaration of Helsinki 1964 Milgram Study Kefauver-Harris Amendments Food, Drug and Cosmetic Act 1962 The Thalomide Tragedy Nuremberg Code 1947 US Human Radiation Experiments The Nazi Experiments 1932 The Syphilis Study Begins Trigger Events

49. 1923 - 1952 Piaget describes stages of cognitive development First Human Heart Transplant Year - 1967 Penicillin - 1940 First Test Tube Baby Born 1978 sulfa drugs - 1932 First successful Open Heart Surgery - 1952 First Electrocardiogram 1903

50. ‘Home free’ in the 21st 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 …