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ETHICS IN RESEARCH Evolution and Fundamentals
Primum non nocere(First, do no harm)-Hippocrates (in Epidemics)
It is not cruel to inflicton a few criminalssufferings which maybenefit multitudes ofinnocent          peoplethrough all c...
NAZI MEDICAL WAR CRIMES                            • The Medical Case, U.S.A. vs.                              Karl Brandt...
Nuremberg Trials: The Doctors Trial                     • Ignorance                     • Orders from superiors           ...
According to Hermann Goering (one of the defendants inthe Nuremberg Trial) the trial had been nothing morethan an exercise...
……. most Nuremberg defendants never aspired to bevillains.   Rather, they over-identified with anideological cause and suf...
Lack of:• Thinking:  …authentic inability to think. Thoughtlessness.  Inability to have an internal dialogue with oneself,...
THE TUSKEGEE SYPHILIS STUDY            •Initiated in the 1930s by US            Public Health Service (PHS)            •Ex...
• Nature of study not  disclosed• Treated for ‘bad blood’     Last Chance for  Special Free Treatment
• Penicillin was accepted as the treatment for syphilis  in 1943. Deliberately withheld from study subjects.• Story broke ...
• For the greater good of science• Were just carrying out orders, mere cogs in the  wheel of the PHS bureaucracy, exempt f...
• Public outrage prompted Congress to pass the National Research Act in 1974• The National Research Act also created the N...
The United States Government didsomething that was wrong, deeply,profoundly, morally wrong. It was anoutrage to our commit...
The people who ran the study at                  Tuskegee diminished the stature of                  man by abandoning the...
JEWISH CHRONIC DISEASE    HOSPITAL STUDY        • At New York’s Jewish Chronic          Disease Hospital        • In 1963 ...
Violations                 Defense• Consent oral, not      • Documentation  documented               unnecessary, much• Di...
• State of New York brought charges against Dr.  Chester M. Southam (investigator) and Dr.  Emmanuel E. Mandel (hospital’s...
WILLOWBROOK STUDY                    • From 1963 through 1966                    • Studies at the Willowbrook State       ...
Children were deliberately infected with the hepatitis virus• Early subjects were fed extracts of stools  from infected in...
• Claiming overcrowded conditions,  Willowbrook closed its doors to  new patients during the course of  these studies• The...
• Adequacy and freedom of consent• Inadequate disclosure of risk of later developing  chronic liver disease• Inadequate in...
RADIATION EXPERIMENTS• 1944-1974• To advance US national interests (Biomedical  sciences, defense, space exploration)• Mos...
• Eskimos in Alaska were given  radioactive iodine-131 by the Air Force  in the 1950s• To study thyroid activity in men  e...
• 1946 to 1956• Fernald State School in Massachusetts• Researchers from Harvard University and the  Massachusetts Institut...
• Issue of fairness of selection of participants• Participants not likely to derive any direct benefit• Research on partic...
• Advisory Committee on Human Radiation  Experiments created by President Clinton in  January 1994• Recommendations:    In...
MILGRAM’S OBEDIENCE STUDY                      • 1960-1964                      • Examine whether people will             ...
Study Set Up Electrical Control Panel    (115 V switch highest expected)Switches from 15-450 Volts
Violations                  Defense• Inadequate measures       • Participants could  to protect subjects         withdraw ...
JOHN HOPKINS ASTHMA STUDY                      • The study was described as a baseline                        physiologic ...
In its letter of findings OHRP cited multiple violations,  some as basic as:• Failure “to obtain published literature abou...
• Failure by the IRB to “receive or request from the  investigators any information regarding the  pharmacology and toxici...
• OHRP shut down all of Hopkins’ federally  funded human-subject protocols, some 2,800  studies• Although many ongoing stu...
CERVICAL DYSPLASIA STUDY• ICMR sposnored• 1976-1988• To observe the natural course of precancerous  uterine cervical lesio...
• Women with mild and moderate dysplasias at the  beginning of the study who developed severe  dysplasias were also observ...
Violations                  Defense• No written informed      • Most of the women in  consent                    the study...
• The controversy about the study became public in  1997• ICMR started developing ethical guidelines for  biomedical resea...
RCC/JHU ORAL CANCER STUDY                    • Novemeber 1999- April2000                    • 25 oral cancer patients     ...
• Patients not informed of that drug was being  injected for the first time in humans• No warning of risks• Patients not i...
• JHU barred Dr. Huang from serving as principal investigator on any future research involving human subjects
RAGAGLITAZAR TRIAL• Discovered by DRL and licensed to Novo Nordisk• Phase III trials in 32 countries; >2000 patients• 130 ...
• Citing confidentiality no details of the 8 centers  given by the company• No patient details
LETROZOLE INFERTILITY TRIAL• Letrozole approved for treatment of breast cancer  in postmenopausal women• Sponsor: Sun Phar...
• Contraindicated in pre-menopausal women• Embryotoxic, fetotoxic, teratogenic• Schedule G drug; to be sold against prescr...
• Sponsor: Some marketing people went overboard.• Sponsor: Off-label prescription of drugs is a  common practice• Investig...
HISTORICAL DOCUMENTS
PRUSSIAN DIRECTIVE           (BERLIN CODE)• 29 December, 1900• First ever government issued directives on human  experimen...
Conditions of exclusion:• The human subject is a minor or not competent  due to other reasons• The human subject has not g...
REICH HEALTH COUNCIL           REGULATIONS• Regulation on New Therapy and Human  Experimentation• 28 Feb, 1931. Circular o...
NUREMBERG CODE(1946. Permissible Medical Experiments)1. Voluntary consent essential2. Experiment for fruitful results for ...
6. Risks not to exceed humanitarian importance of   problem7. Proper preparation and adequate facilities to   protect agai...
BELMONT REPORT   (National Commission for the Protection of Human Subjects of            Biomedical and Behavioral Researc...
Respect for Persons• Individuals should be treated as autonomous  agents (capable of self-determination)• Persons with dim...
Beneficence• Do no harm• Maximize possible benefits and minimize  possible harms• Application: Risk/Benefit assessment
Justice• Fairness in the distribution of the benefits  and burdens of research (distributive  justice)• Application:    Fa...
DECLARATION OF HELSINKI• Developed by the World Medical Association• As a statement of ethical principles to provide  guid...
• Research must be based on sound scientific  background• Considerations related to the well-being of the  human subject s...
ETHICAL REQUIREMENTS FOR A           RESEARCH TRIAL1.    Social or scientific value2.    Scientific validity3.    Fair sub...
• Compliance +                Conscience              • Active, dynamic•Compliance•Passive
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  1. 1. ETHICS IN RESEARCH Evolution and Fundamentals
  2. 2. Primum non nocere(First, do no harm)-Hippocrates (in Epidemics)
  3. 3. It is not cruel to inflicton a few criminalssufferings which maybenefit multitudes ofinnocent peoplethrough all centuries.-Aulus Cornelius Celsus (a 1stcentury Roman physicist,experimented on prisoners.De Medicina )
  4. 4. NAZI MEDICAL WAR CRIMES • The Medical Case, U.S.A. vs. Karl Brandt, et al. (also known as the Doctors Trial) • 1946-47 • Twenty-three doctors and administrators • Accused of organizing and participating in war crimes and crimes against humanityFreezing Water Experiment in the form of medical experiments and medical procedures inflicted on prisoners and civilians
  5. 5. Nuremberg Trials: The Doctors Trial • Ignorance • Orders from superiors • Medically justified • Others • 16 found guilty • Verdict contained a section “Permissible Medical Experiments” The 23 defendants • Nuremberg Code
  6. 6. According to Hermann Goering (one of the defendants inthe Nuremberg Trial) the trial had been nothing morethan an exercise of power by the victors of a war:justice, he said, had nothing to do with it.
  7. 7. ……. most Nuremberg defendants never aspired to bevillains. Rather, they over-identified with anideological cause and suffered from a lack ofimagination or empathy: they couldnt fully appreciatethe human consequences of their career-motivateddecisions.- Douglas O. Linder
  8. 8. Lack of:• Thinking: …authentic inability to think. Thoughtlessness. Inability to have an internal dialogue with oneself, which would permit self-awareness• Judgment: To exercise imagination, to contemplate the consequence of actions Hannah Arendt: Eichmann in Jerusalem. A Report On The Banality Of Evil.
  9. 9. THE TUSKEGEE SYPHILIS STUDY •Initiated in the 1930s by US Public Health Service (PHS) •Examination of the natural history of untreated syphilis •Continued until 1972 •About 400 black men with syphilis participated •About 200 men without syphilis served as controls
  10. 10. • Nature of study not disclosed• Treated for ‘bad blood’ Last Chance for Special Free Treatment
  11. 11. • Penicillin was accepted as the treatment for syphilis in 1943. Deliberately withheld from study subjects.• Story broke in the Washington Star on July 25, 1972 (Article by Jean Heller of the Associated Press)• By the end of the experiment, 28 of the men had died directly of syphilis, 100 were dead of related complications, 40 of their wives had been infected, and 19 of their children had been born with congenital syphilis.
  12. 12. • For the greater good of science• Were just carrying out orders, mere cogs in the wheel of the PHS bureaucracy, exempt from personal responsibility.• The men had been ‘volunteers’ and ‘were always happy to see the doctors’• An Alabama state health officer who had been involved claimed ‘somebody is trying to make a mountain out of a molehill’
  13. 13. • Public outrage prompted Congress to pass the National Research Act in 1974• The National Research Act also created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research• This commission published the ‘Belmont Report’ in 1979
  14. 14. The United States Government didsomething that was wrong, deeply,profoundly, morally wrong. It was anoutrage to our commitment to integrityand equality for all our citizens.- President Clintons apology for the TuskegeeSyphilis Experiment to the eight remainingsurvivors, May 16, 1997
  15. 15. The people who ran the study at Tuskegee diminished the stature of man by abandoning the most basic ethical precepts. They forget their pledge to heal and repair.They had the power to heal the survivors and all theothers and they did not. Mr. Shaw, the others who arehere, the family members who are with us in Tuskegee,only you have the power to forgive. Your presencehere shows us that you have chosen a better path thanyour government did so long ago.
  16. 16. JEWISH CHRONIC DISEASE HOSPITAL STUDY • At New York’s Jewish Chronic Disease Hospital • In 1963 • To understand whether the body’s inability to reject cancer cells was due to cancer or debilitation • Studies involved the injection of foreign, live cancer cells into patients who were hospitalized with various chronic debilitating diseases
  17. 17. Violations Defense• Consent oral, not • Documentation documented unnecessary, much• Did not include more dangerous injection of cancer medical procedures cells were performed• Study had not been without consent presented to the hospital’s research • Would unnecessarily committee frighten the patients• Physicians responsible • Good science – for the patients’ care Cancer cells were had not been consulted going to be rejected
  18. 18. • State of New York brought charges against Dr. Chester M. Southam (investigator) and Dr. Emmanuel E. Mandel (hospital’s medical director)• Board of Regents of the University of the State of New York suspended the licenses of the doctors.Subsequently, subsequently stayed the suspension and placed the physicians on probation for one year
  19. 19. WILLOWBROOK STUDY • From 1963 through 1966 • Studies at the Willowbrook State School, a New York institution of "mentally defective persons" • Designed to gain an understanding of the natural history of infectious hepatitis and Investigator • Subsequently to test the effects of "gamma" globulin in preventing orDr. Saul Krugmann ameliorating the disease
  20. 20. Children were deliberately infected with the hepatitis virus• Early subjects were fed extracts of stools from infected individuals• Later received injections of more purified virus preparations.Defense by pointing out:• That the vast majority of them acquired the infection anyway while at Willowbrook, and• It would be better for them to be infected under carefully controlled research conditions.• Informed consent taken
  21. 21. • Claiming overcrowded conditions, Willowbrook closed its doors to new patients during the course of these studies• The hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients• Thus to get their children admitted parents had to agree to their participation in the studies
  22. 22. • Adequacy and freedom of consent• Inadequate disclosure of risk of later developing chronic liver disease• Inadequate information about dosages of gamma- globulin
  23. 23. RADIATION EXPERIMENTS• 1944-1974• To advance US national interests (Biomedical sciences, defense, space exploration)• Mostly radioactive tracers unlikely to cause harm
  24. 24. • Eskimos in Alaska were given radioactive iodine-131 by the Air Force in the 1950s• To study thyroid activity in men exposed to cold.• Government is negotiating compensation• Cancer patients at the University of Cincinnati College of Medicine were given full-body radiation• More than 60 percent of the patients were indigent African-Americans with low IQs
  25. 25. • 1946 to 1956• Fernald State School in Massachusetts• Researchers from Harvard University and the Massachusetts Institute of Technology• Fed radioactive forms of iron (n=17) and calcium (n =57) to mentally retarded boys from the school’s science club• To study the bodys ability to digest minerals.
  26. 26. • Issue of fairness of selection of participants• Participants not likely to derive any direct benefit• Research on participants without their awareness or (complete) consent
  27. 27. • Advisory Committee on Human Radiation Experiments created by President Clinton in January 1994• Recommendations: Individualized apology, financial compensation Elimination of all exemptions from informed consent requirements
  28. 28. MILGRAM’S OBEDIENCE STUDY • 1960-1964 • Examine whether people will follow orders under the presence of authority • Explore explanations for the atrocities of German soldiers during World War II Stanley MilgramSocial Psychologist • Deception: Effects of punishment on learning
  29. 29. Study Set Up Electrical Control Panel (115 V switch highest expected)Switches from 15-450 Volts
  30. 30. Violations Defense• Inadequate measures • Participants could to protect subjects withdraw at anytime from stress and the realization that they • Deception was were capable of brutal necessary and was actions explained at end of• Should have been study terminated at the first • Stress undertaken sign of discomfort in would have not have subjects lasting or injurious• Non-deceptive effects methods could have been used
  31. 31. JOHN HOPKINS ASTHMA STUDY • The study was described as a baseline physiologic test • Togias wanted to observe how normal lungs respond to irritants and asked healthy volunteers to inhale hexamethonium. • A volunteer, Ellen Roche was coughing, running a fever within days and had to be hospitalized for lungDr. Alkis G. Togias problems (May 2001) • She had to be put on a ventilator, and on June 2, she died.
  32. 32. In its letter of findings OHRP cited multiple violations, some as basic as:• Failure “to obtain published literature about the known association between hexamethonium and lung toxicity. Such data was readily available via routine MEDLINE and Internet database searches, as well as recent textbooks on pathology of the lung. ”• Failure “to obtain sufficient information regarding the source, purity, quality, and method of preparation and delivery of the hexamethonium used in the research" prior to approval.”
  33. 33. • Failure by the IRB to “receive or request from the investigators any information regarding the pharmacology and toxicity of inhaled hexamethonium in animals or sufficient information regarding the safety of inhaled hexamethonium in humans.”• “The informed consent document failed to indicate that inhaled hexamethonium was experimental and not approved by the FDA. Furthermore, hexamethonium was referred to as a "medication" in the informed consent document.”
  34. 34. • OHRP shut down all of Hopkins’ federally funded human-subject protocols, some 2,800 studies• Although many ongoing studies were quickly reinstated, about 1,700 were re-reviewed over the next several months before they could begin again
  35. 35. CERVICAL DYSPLASIA STUDY• ICMR sposnored• 1976-1988• To observe the natural course of precancerous uterine cervical lesions without treatment• 1158 women• End point: Development of carcinoma in situ
  36. 36. • Women with mild and moderate dysplasias at the beginning of the study who developed severe dysplasias were also observed until the lesions regressed or progressed to carcinoma in situ• In at least nine women the lesions progressed to invasive cancer, and 62 women developed carcinoma in situ of the cervix before they were treated
  37. 37. Violations Defense• No written informed • Most of the women in consent the study were• Allegations that the illiterate investigators had • Study helped India neither informed the evolve screening women that their guidelines for the lesions were known to progress to cancer nor national cancer control offered them treatment programme at the outset
  38. 38. • The controversy about the study became public in 1997• ICMR started developing ethical guidelines for biomedical research in humans, finalised in 2000
  39. 39. RCC/JHU ORAL CANCER STUDY • Novemeber 1999- April2000 • 25 oral cancer patients • M4N or G4N (could arrest growth of mouse tumours) • Regional Cancer Center, Thiruvananthapuram , Kerala • Ru Chih Huang, JHUDr. Ru Chih Huang
  40. 40. • Patients not informed of that drug was being injected for the first time in humans• No warning of risks• Patients not informed that they were being denied an established treatment.• Trial had not been approved by the Drugs Controller of India (approval was obtained retroactively)• No ethics clearance from JHU
  41. 41. • JHU barred Dr. Huang from serving as principal investigator on any future research involving human subjects
  42. 42. RAGAGLITAZAR TRIAL• Discovered by DRL and licensed to Novo Nordisk• Phase III trials in 32 countries; >2000 patients• 130 patients from 8 centres in India• Trial initiated without full animal testing• Stopped on reports of urinary bladder tumours in rats and mice
  43. 43. • Citing confidentiality no details of the 8 centers given by the company• No patient details
  44. 44. LETROZOLE INFERTILITY TRIAL• Letrozole approved for treatment of breast cancer in postmenopausal women• Sponsor: Sun Pharmaceuticals Limited• 2003• Research cum promotion: Use of letrozole for inducing ovulation (infertility)• >430 women
  45. 45. • Contraindicated in pre-menopausal women• Embryotoxic, fetotoxic, teratogenic• Schedule G drug; to be sold against prescriptions of oncologists only
  46. 46. • Sponsor: Some marketing people went overboard.• Sponsor: Off-label prescription of drugs is a common practice• Investigator(s): Did not realize that the company had not received approval from the DCGI for this indication• Patients’ protection: Approval of IEC; Information that the trial was for an unapproved indication
  47. 47. HISTORICAL DOCUMENTS
  48. 48. PRUSSIAN DIRECTIVE (BERLIN CODE)• 29 December, 1900• First ever government issued directives on human experimentation• Conditions for exclusion ‘under all circumstances’ of ‘all medical interventions for other than diagnostic, healing and immunization purposes, regardless of other legal or moral authorization’
  49. 49. Conditions of exclusion:• The human subject is a minor or not competent due to other reasons• The human subject has not given his unambiguous consent• The consent is not preceded by a proper explanation of the possible negative consequences of the intervention
  50. 50. REICH HEALTH COUNCIL REGULATIONS• Regulation on New Therapy and Human Experimentation• 28 Feb, 1931. Circular of the Reich Minister of the Interior• Acknowledge need for human experimentation• Focuses on the consent and the well-being of the subjects• Responsibility of medical profession
  51. 51. NUREMBERG CODE(1946. Permissible Medical Experiments)1. Voluntary consent essential2. Experiment for fruitful results for the good of society and should be necessary3. Animal experiments first and human study in anticipation of scientific benefits4. Avoid physical and mental suffering and injury5. No intentional death or disability
  52. 52. 6. Risks not to exceed humanitarian importance of problem7. Proper preparation and adequate facilities to protect against even remote possibilities of injury8. Study only by qualified persons9. Subject at liberty to discontinue10. Investigator to stop if harm occurs or is anticipated
  53. 53. BELMONT REPORT (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979)• A. Boundaries between research and practice• B. Ethical principles underlying the conduct of research: Respect for persons Beneficence Justice
  54. 54. Respect for Persons• Individuals should be treated as autonomous agents (capable of self-determination)• Persons with diminished autonomy deserve protection• Application: Informed consent
  55. 55. Beneficence• Do no harm• Maximize possible benefits and minimize possible harms• Application: Risk/Benefit assessment
  56. 56. Justice• Fairness in the distribution of the benefits and burdens of research (distributive justice)• Application: Fair procedures and outcomes in the selection of subjects Protection of vulnerable subjects
  57. 57. DECLARATION OF HELSINKI• Developed by the World Medical Association• As a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects• First adopted in 1964 (Helsinki, Finland). Has undergone 5 revisions; the most recent in October 2000
  58. 58. • Research must be based on sound scientific background• Considerations related to the well-being of the human subject should take precedence over the interests of science and society
  59. 59. ETHICAL REQUIREMENTS FOR A RESEARCH TRIAL1. Social or scientific value2. Scientific validity3. Fair subject selection4. Favourable risk-benefit ratio5. Independent review6. Informed consent7. Respect for potential and enrolled subjects
  60. 60. • Compliance + Conscience • Active, dynamic•Compliance•Passive

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