Life is all about choices

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

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However

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

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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

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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.

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

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

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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

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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

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

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It was subsequently discovered that

• Thalidomide causes severe deformities in babies
• and its effects are even passed on to later
  generations.

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

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

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

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

• medicine is sound, and most progress is
  soundly attained

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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

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

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Then Nobel Prize-winning microbiologist Paul
Ehrlich discovered Salvarsan

• an arsenic-based compound.
• It was the first chemotherapy.

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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.

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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.

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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.

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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.

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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.

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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 peoples trust was shattered

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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.

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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

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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."

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

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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.

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

• Definition
• Do not harm
• Maximize possible benefits
• Minimize possible harms
• Application
• Assessment of risks and benefits

Belmont Report
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Justice

• Definition
• Who ought to receive the benefits of research?
• Who ought to bear its burdens?
• Application
• Equitable Selection of Subjects

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

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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

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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?

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The 1997 Presidential Apology to Tuskegee
Participants
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Life is all about choices
choices have consequences
Now its your turn - how will YOU choose?
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