Human Subject Experimentation

1. Human Subject Experimentation The Nazis Lessons for Contemporary Research The Role of the Physician in Society Martin Donohoe

2. “When a doctor [goes] wrong, he is the first of criminals. He has nerve and he has knowledge.” - Sherlock Holmes to Dr. Watson, Arthur Conan Doyle

3. Nazi Medicine • Guiding philosophy = Hegelian (rational utility) • Social Darwinism - parallels in American and British Eugenics Movement • medical journals relatively silent • Ethics reduces morality to efficiency, economics, and aesthetics

4. Nazi Medicine • An arm of state policy • Focus on racial purity • from eugenic sterilization (370,000) • to involuntary euthanasia (70,000) • to large-scale genocide (over 6 million)

5. Nazi Medicine • Individual worth stated in economic terms; propaganda re obligations to the state • “I Accuse” • “Mathematics in the Service of Political Education”

6. Nazi Medicine • Doctoring the nation more important than doctoring individuals - Nazism as “applied biology” (Rudolph Hess) • Focus on preventive medicine and public health: anti-tobacco and anti-alcohol campaigns, environmental toxins, organic farming -to improve Aryan stock • Nazi soldiers given anabolic steroids to increase aggresiveness

7. Nazi Physicians • 52,000 physicians • National Socialist Party Members • Jews ostracized; replaced by young Aryans • today 0.2% of German physicians are Jews, c/w 17% pre-Nazis • 5% of non-Aryans committed suicide; 25% murdered

8. Nazi Physicians • Economic hard times, physicians salaries rise, academic perks • Blutkitt (“blood cement”) • Rare resistance • Catholics • Marxists • Dutch

9. Nazi “Physician-Researchers”(Torturers) • Dr. Sigmund Rascher - coagulation/amputation studies; hypothermia experiments • Dr. Karl Gebhart: heteroplastic transplantation experiments • c.f. Stalin’s attempts to create interspecies (half-men/half-apes) “super-warriors” • Drs. Karl Clausberg and Viktor Brack: X-irradiation/sterilization

10. Nazi “Physician-Researchers”(Torturers) • Drs. Joachim Mrugowsky, Erwin Ding-Schuler, and Waldemar Hoven: IV phenol and gasoline executions • Dr. Friedrich Wegener (“Wegener’s Granulomatosis”): German pathologist, Nazi party member, autopsied a prisoner with oxygen injected into his bloodstream in an embolism study; may have participated in experiments on concentration camp inmates

11. Nazi “Physician-Researchers”(Torturers) • Dr Hans Conrad Reiter (formerly “Reiter’s Syndrome”, now “reactive arthritis”): senior Nazi official • Dr. Joseph Mengele: Septicemia/twin vivisection studies • Dr. Hans Eppinger - “father of modern hepatology”

12. “Indirect Participants” • Prof. J Hallevorden: “Look here now, boys, if you are going to kill all these people at least take the brains out so that the material could be utilized … the more (brains) the better….I accepted these brains of course. Where they came from and how they came to me was really none of my business.”

13. Doctors and Resistance • German invasion of Poland (1939) • Drs Eugene Lazowski and Stanislaw Matulewicz created a fake typhus epidemic, using a harmless bacterium to innoculate non-Jews, knowing that infected Jews would be summarily executed • Germans fooled, quarantined area, many Jews escaped death

14. Nuremberg Doctors’ Trial • 23 German physicians tried • 16 found guilty • 7 hanged (incl. Gebhardt, Brack, Hoven, and Mrugowsky)

15. Nuremberg Doctors’ Trial • Rascher died before trial • Mengele fled for Argentina (remains verified 1985) • Hallevorden committed suicide before trial • Otto Ambros (chemist) – invented sarin (nerve gas), convicted of mass murder at Nuremberg Trials, later freed and worked with US chemical industry on thalidomide

17. Nuremberg Code • Voluntary consent is absolutely essential • Avoidance of unnecessary physical and mental suffering • Option to quit/responsibility to terminate • Other safeguards

18. Declaration of Geneva • “I will not permit considerations of religion, nationality, race, party politics or social standing to intervene between my duty and my patient” • “I will not use my medical knowledge contrary to the laws of humanity.” • “It is unethical for physicians to employ scientific knowledge to imperil health or destroy life.”

19. Declaration of Helsinki • Patients’ rights to respect, self determination, informed decision-making • Investigators’ duties: primacy of subjects’ welfare, ethical considerations take precedence over laws and regulation • Allows for surrogate consent

20. Post-WW II • Over 700 Nazi rocket scientists and their families brought to the U.S. (including Werner von Braun) to help build nuclear missile program • Operation Paperclip • Japanese scientists brought to Fort Detrick, MD, to help establish U.S. biological/chemical weapons program

21. Post-WW II • German Medical Association unanimously issues blunt, straightforward apology for its role in the Holocaust (2012)

22. Post-WW II Human Subject Experimentation • James Ketchum (psychiatrist), L Wilson Green (scientist), Van Murray Sim – psychochemical warfare studies for US Army • Ketchum later joined faculty of University of Texas Medical School

23. Post-WW II Human Subject Experimentation • Tuskegee Syphilis Study • “The men’s status did not warrant ethical debate. They were subjects, not patients; clinical material, not sick people.” • Dr John Heller, Director of Venereal Diseases at PHS between 1943 and 1948 (interviewed in 1976)

24. Studies on Native Americans • Sterilizations • Radioactive iodine to study adaptation of thyroid gland to extreme cold • Forced removal of children to English language, religious schools (c.f., Australia) • Distrust and reluctance of minorities to participate in medical research

25. Research on Prisoners • 1905: cholera experiments on “volunteers” • 1915: Joseph Goldberger – pellagra studies • Parole in exchange for participation • 1941: Physician William Black infects children with herpes virus, paper published by J Peds

26. Post-WW II Human Subject Experimentation • Pharmaceutical and government sponsored studies on prisoners • 1940s and 1950s esp. • Halted in mid-1970s after drug company executives admitted prisoners were cheaper to use than chimpanzees • WW II: gonorrhea, gas gangrene, dengue fever, malaria

27. Post-WW II Human Subject Experimentation • Guatemala STD study (1946-8) • U.S. researchers deliberately infected 1,500 prisoners, military conscripts, prostitutes, orphans (provided by Sisters of Charity), and mental health patients with gonorrhea and syphilis • Scientists treated 87% of those infected (10% later required re-treatment), lost track of 13%

28. Post-WW II Human Subject Experimentation • Guatemala STD study (1946-8) • Wives, children, and grandchildren treated, but sexual contacts not traced • Study approved by Guatemalan government • Received material for resource-starved institutions in return • Subjects received cigarettes for participating

29. Post-WW II Human Subject Experimentation • Guatemala STD study (1946-8) • U.S. apologized (2010), has pledged $1 million to study research ethics, $775,000 to fight STDs in Guatemala • Class action lawsuit against U.S. government filed on behalf of 700 victims/relatives (2011)

30. Post-WW II Human Subject Experimentation • Guatemala STD study (1946-8) • Dr. John Cutler (research coordinator): “Unless the law winks occasionally, you have no progress in medicine” • In 1943, Cutler infected volunteer federal prisoners in Indiana with gonorrhea in exchange for cash

31. Post-WW II Human Subject Experimentation • Guatemala STD study (1946-8) • After Guatemala, Cutler oversaw the Tuskegee Syphilis Study • Was acting dean at University of Pittsburgh in 1960s

32. Post-WW II Human Subject Experimentation • University of Minnesota malaria study (1940s) • Drs. Thomas Francis, Jr. and Jonas Salk infect psychiatric hospital residents with influenza (?if consent adequate?)

33. Post-WW II Human Subject Experimentation • Atlanta prison gonorrhea study (1950s) • Patuxent prison Asian flu experiment (1957) • U.S. govt.-sponsored radiation, LSD (MK Ultra) experiments

34. Post-WW II Human Subject Experimentation • Pentagon/CIA experiments on soldiers and civilians • Edgewood Arsenal Experiments (involving more than 7,000 soldiers who were exposed to at least 250 biological and chemical agents) • Including sarin, VX, LSD, ritalin • Caused long-term health effects • Deliberate release of Serratia over San Francisco Bay; radioactive cadmium over St. Louis

35. Post-WW II Human Subject Experimentation • 1963: Dr. Chester Southam injects tumor cells into extremely infirm patients at Jewish Hospital for Chronic Disease in NY without informing them that the shots contain cancer cells • Southam later elected President of American Association for Cancer Research

36. Post-WW II Human Subject Experimentation • Willowbrook Hepatitis Experiments (1960s) • Pre-WW1: Joseph Goldberger’s pellagra experiments on Mississippi prisoners • Henry Beecher, NEJM (1966)

37. Post-WW II Human Subject Experimentation • Ongoing sterilization programs • Buck v. Bell (USSC, 1927) – 60,000 Americans sterilized • WI, NJ, CA, IN, NC, OR, others • Alabama’s Governor Graves vetoed law in 1930s law citing “hazard to personal rights” • Oregon governor Kitzhaber apologized in 2002 for the over 2500 state-forced sterilizations that occurred between 1917 and 1983 • 2012 – NC to compensate victims

38. Post-WW II Human Subject Experimentation • Iowa elementary school race experiment (1968; good or bad?) • Milgram’s obedience studies (1963); Milgram redux (2008) • Soviet psychiatry • US military/pharmaceutical vaccine and medication trials in the developing world

39. GM foods, biopharmaceuticals • Largest uncontrolled trial in history of humanity • E.g., Chinese children with vitamin A deficiency used for feeding trials of Golden Rice by Tufts University investigators • Without preceding animal studies • ? Nature of informed consent • May violate Nuremberg Code

40. Research on Prisoners • >90% of pharmaceutical industry research in early 1970s • Rapidly curtailed by state/federal laws and new university regulations • 2006: IOM approves with safeguards • 2009: 44% of jurisdictions allow compensation

41. Self-Experimentation • Albert Hoffman (LSD) • Werner Forssmann (right heart catheterization) • Barry Marshall (Helicobacter pylori) • Others

42. Disturbing Experiments • Inter-species breeding (ape-man, Ilya Ivanovich Ivanov, Guinea, 1927) • Two-headed dog (Vladimir Petrovich Demikhov, 1950s, Russia) • Monster Study (Wendell Johnson, 1939, University of Iowa) – deliberate induction of stuttering in orphan children

43. Contemporary Issues and Ethical Dilemmas • 90% of research dollars spent on diseases affecting 10% of the world’s population • Neglected tropical diseases • Research on special populations (cultural minorities, prisoners, developing world, etc.) • Ghostwriters • Contract Research Organizations • Role of institutional and for-profit IRBs

44. Contemporary Issues and Ethical Dilemmas • Use of placebo controls • Various drug trials • Anti-HIV medications and maternal-fetal transmission(sub-Saharan Africa) • Surfactant for neonatal RDS (Brazil, Bolivia) • Hep A vaccine (Thailand) • Trovan/meningitis/Nigeria (control = inadequate ceftriaxone dose)

45. Contemporary Issues and Ethical Dilemmas • 1/3 of phase 3 US drug company trials are conducted solely outside the US • Majority of phase 3 US drug company trial sites outside US, many in developing countries • Majority of developing nation trial sites without institutional review boards • Victims may seek redress under “Alien Torts Statute”

46. Contemporary Issues and Ethical Dilemmas • Nerve-sparing clitoroplasty as substitute for female genital cutting • AAP reversal of position (2010) • Kennedy Krieger Institute (Johns Hopkins) lead paint abatement study (1992)

47. Contemporary Issues and Ethical Dilemmas • Uninsured become research subjects to receive needed care • Human guinea pigs (professional lab rats) • Parent investigators • Neonatal analgesia • Under-representation of women and minorities in clinical trials

48. Contemporary Issues and Ethical Dilemmas • Informed consent for treatment – physician/patient negotiation vs. unilateral decision-making when treatment options limited • Relaxation of international research standards by eliminating Declaration of Helsinki standards (FDA, 2008)

49. Contemporary Issues and Ethical Dilemmas • 2003: Ban on industry experiments testing safety of pesticides/other potentially toxic chemicals in humans lifted by NAS and EPA • 2013 – EPA adds safeguards, issues regulations prohibiting studies on pregnant women and children • Monsanto’s Roundup purchased by US government for aerial spraying in Colombia as part of “War on Drugs”

50. Contemporary Issues and Ethical Dilemmas • 2008: Former director of UCLA School of Medicine’s donated body program pleads guilty to 5 year scheme to sell donated body parts to medical, drug, and research companies, netting more than $1 million • Clinical Trials Registry • Drug company noncompliance