Ethics in Clinical Research and Historical Perspective of Nazi Trials, Nuremberg Code, Thalidomide Study, Tuskegee Syphilis Study, The Belmont Report, The Declaration of Helsinki

Presented by :-
Mr. Shantanu S. Thakre
M-Pharm 1st – Year
Pharmaceutical Regulatory Affairs
JSS College of Pharmacy, Mysuru
Ethics in Clinical
Research

 Contents :-
 What is Ethics and Clinical Research?
 Importance of Ethics in Clinical Research
 Historical Perspectives of :-
• Nazis Trials
• Nuremberg Code
• Thalidomide Study
• Tuskegee Syphilis Study
• The Belmont Report
• The Declaration of Helsinki

 What is Ethics ?
The word ‘ethics’ is derived from the Greek word,
ethos, which means custom or character. Ethics is
the systematic study of values, so as to decide
what is right and what is wrong. Ethics is concerned
with what is good for individuals and society.
 What is Clinical Research ?
Clinical Research is a branch of healthcare science that determines the
safety and effectiveness of medications, devices, diagnostic products and
treatment regimens intended for human use. These may be used for
prevention, treatment, diagnosis or for relieving symptoms of a disease.

 Importance of Ethics in Clinical Research :-
• Ethics is important in clinical research because it keeps the researcher from
committing errors while seeking knowledge and truth.
• Ethical guidelines for clinical research were formulated only after discovery
of inhumane behavior with participants during research experiments.
• In clinical research human beings are involved, as opposed to animals,
atoms or asteroids, as the object of study.
• It focuses on improving human health and well-being, typically by identifying
better methods to treat, cure or prevent illnesses.

 The Ethics Committee stands as the bridge between the researcher and
the ethical guidelines of the country.

CLINICAL RESEARCH
HISTORICAL PERSPECTIVE
Nuremberg trials : 1945
Doctor`s trial : 1946
Nuremberg code : 1947
1964: Declaration of Helsinki
The Tuskegee Syphilis : 1972
Study ends (expose)
Belmont Report : 1979
1961: Thalidomide Study
1932: The Tuskegee Syphilis Study begins
The Nazi : 1942
Experiment

HISTORY
 Adolf Hitler, in 1919 organized the National Socialistic
German Workers Party, “NAZI”.
 A Nazi is a member of political party- like a Democrat or
Republican.
 Hitler used to fear people, he created a secret police force (S.S.)
Schutzstaffel known for its brutal tactics and having absolute power over
people.
 In 1933, the President of the German Republic Paul Von Hindenburg
appointed Hitler the position of Chancellor of Germany.
 Within weeks Germany changed from being republic to being dictatorship.

 Hitler opened the first concentration camp at “Dachau”.
 Harsh, discriminatory laws were intended to make Jews leave Germany,
but through the time laws summarized to the sentence “you have no right
to live”
 Over the next decade, these policies grew increasingly repressive and
violent and resulted, by the end of World War 2 (1939-1945), in the
systematic, state-sponsored murder of some 11 million peoples (before
and during world war 2), which was termed as “Holocaust”.
 The systematic killing of those they deemed “Unworthy of Life”. The
victims included mentally retarded, the institutionalized mentally ill, and the
physically impaired (aged) and the most numbers were of Jews peoples.

THE NAZI EXPERIMENT (1942)
 HOLOCAUST
 11 million people were killed.
o 6 million Jews (1.5 million children under 12)
o 5 million undesirables (old age or handicap or mentally disabled)
 Term comes from a Greek word that means burnt whole or consumed by fire.
 The term holocaust refers to the specific period in history dating from 1933 –
1945 and not any other mass murder or genocide.
 Concentration camps (Labor and death camps)
 Constant torture and starvation (Mass killing through gassing chambers)

MEDICAL EXPERIMENTS (Nazi Human Experimentation)
 Scores of Nazi doctors and medical researchers were
given permission to carry out medical experiments on
people in the camp including adults as well as children.
 Dr. Josef Mengele, “Angel of Death”, was in charge of the staff, which
performed the medical experiments in the name of “scientific research”.
 Experiments were in the form of torture because none were done using
anesthesia and resulted in death, trauma, disfigurement, or permanent
disability. Nazi physicians forced prisoners into participating, they did not
willingly volunteer and no consent was given for the procedures.

• Experiments on twin • Mustard gas experiment
• Bone, muscle and nerve
transplantation experiments
• Sulfonamide experiments
• Head injury experiments • Sea water experiments
• Freezing experiments • Sterilization and fertility
experiments
• Malaria experiments • Experiments with poison
• Immunization experiments • High Altitude experiments
• Epidemic experiments • Blood coagulation experiments
These are the medical experiments conducted by the Nazi Doctors, which are
as following :

1) Experiment on Twin :-
Infecting them with various diseases and injecting dyes into their eyes to change
their color. Physician also attempted to create Cojoined Twins by sewing twins
together, causing gangrene and eventually, death.
2) Bone, muscle and nerve transplantation experiments :-
Were conducted for the benefit of the German Armed Forces, to study bone,
muscle, and nerve regeneration, and bone transplantation from one person to
another. In these experiments, subjects had their bones, muscles and nerves
removed without anesthesia. As a result of these operations, many victims
suffered intense pain, mutilation, and permanent disability.

3) Head Injury Experiment :-
A young boy of eleven or twelve was strapped to a chair so he could not move.
Above him was a mechanized hammer that every few seconds came down upon
his head." The boy was driven insane from the torture.
4) Freezing experiments :-
Prisoners were forced to sit in tanks of freezing water for up to three hours. After
subjects were frozen, they then underwent different methods for rewarming.
Many subjects died in this process. The freezing/hypothermia experiments were
conducted for the Nazi high command to simulate the conditions the armies
suffered on the Eastern Front, as the German forces were ill-prepared for the
cold weather they encountered.

5) Malaria experiments :-
Healthy inmates were infected by mosquitoes or by injections of extracts of the
mucous glands of female mosquitoes. After contracting the disease, the subjects
were treated with various drugs to test their relative efficacy. Over 1,200 people
were used in these experiments and more than half died as a result. Other test
subjects were left with permanent disabilities.
6) Immunization experiments :-
At the German concentration camps of Dachau, scientists tested immunization
compounds and serums for the prevention and treatment of contagious diseases,
including malaria, typhus, tuberculosis, typhoid fever, yellow fever, and infectious
hepatitis

7) Epidemic experiments :-
Experimentation with epidemic jaundice was conducted. The test subjects were
injected with the disease in order to discover new inoculations for the condition.
These tests were conducted for the benefit of the German Armed Forces. Most
died in the experiments, whilst others survived, experiencing great pain and
suffering.
8) Mustard gas experiment :-
To investigate the most effective treatment of wounds caused by mustard gas.
Test subjects were deliberately exposed to mustard gas and other vesicants (e.g.
Lewisite) which inflicted severe chemical burns. The victims' wounds were then
tested to find the most effective treatment for the mustard gas burns.

9) Sulfonamide experiments :-
Experiments to investigate the effectiveness of sulfonamide, a synthetic
antimicrobial agent. Wounds inflicted on the subjects were infected with bacteria
such as Streptococcus, Clostridium perfringens (a major causative agent in
gas gangrene) and Clostridium tetani, the causative agent in tetanus
10) Sea water experiments :-
Experiments were conducted at the Dachau concentration camp to study various
methods of making sea water drinkable. These victims were subject to
deprivation of all food and only given the filtered sea water, which resulted in
Dehydration.

11) Sterilization and fertility experiments
The purpose of these experiments was to develop a method of sterilization which
would be suitable for sterilizing millions of people with a minimum of time and
effort. These experiments were conducted by means of X-ray, surgery and
various drugs.
12) Experiments with poison
Experiments were conducted at Buchenwald to investigate the effect of various
poisons. The poisons were secretly administered to experimental subjects in their
food. The victims died as a result of the poison or were killed immediately in order
to permit autopsies.

13) High Altitude experiments :-
In early 1942, prisoners at Dachau concentration camp were used by Sigmund
Rascher (was a German SS doctor)in experiments to aid German pilots who
had to eject at high altitudes. A low-pressure chamber containing these prisoners
was used to simulate conditions at altitudes of up to 68,000 feet (21,000 m). He
describes how the victim then lay unconscious, breathing only three times per
minute, until he stopped breathing 30 minutes after being deprived of oxygen.

14) Blood coagulation experiments :-
Sigmund Rascher experimented with the effects of Polygal, a substance made
from beet and apple pectin, which aided blood clotting. He predicted that the
preventive use of Polygal tablets would reduce bleeding from gunshot wounds
sustained during combat or surgery. Subjects were given a Polygal tablet, shot
through the neck or chest, or had their limbs amputated without anesthesia

Hypothermia (freezing) experiment
High Altitude Experiment
Racial Test
Twin Experiment
Romanic victim of Nazi
experiment
Head injury experiment
Nazi Human
Experiment

NUREMBERG TRIALS OR NAZIS TRIALS (1945 – 1949)
• The Nuremberg trials were a series of military tribunals held following World
War 2 by the Allied forces under international law and laws of war.
 Military tribunals – is a special court or committee that is appointed to deal
with particular problems. (Trials were held before an International Military
Tribunal (IMT).
 Allied forces – are two or more individuals,
organizations, or countries who are working
together towards the same purpose as a
result of a mutual agreement.

 The decisions marked a turning part between classical and contemporary
international laws.
 The Nuremberg trials were conducted according to the laws of not only one
country, a group of four powers, (France, Britain, The Soviet Union and The
United States) with different legal traditions and practices.
 Nuremberg trials were held for the purpose of bringing Nazi war criminals to
justice; to force Nazi leaders to answer for war crimes.
 Nuremberg trials were a series of 13 trials
carried out in Nuremberg, Germany between
1945 – 1949.

War Crime Executive Committee
Evidence Room

NUREMBERG
 The city of Nuremberg is situated in the German state of Bavaria.
 Nuremberg was chosen as the site for two reasons,
o The Palace Of Justice was spacious and largely undamaged (one of the few
buildings that had remained largely intact through extensive Allied bombing
of Germany), and a large prison was also a part of the complex.
o Nuremberg was considered the ceremonial birthplace of the Nazi party. It
had hosted the Party`s annual propaganda rallies. Thus it was considered a
fitting place to mark the party`s symbolic demise.

THE MAJOR WAR CRIMINAL`S TRIAL (1945-1946)
 The famous, known and the first Nuremberg trails was
the trail of Major War Criminals, held from
November 20, 1945 to October 1, 1946.
 The chief American prosecutor was Robert H. Jackson,
an associate of the U.S. Supreme Court.
 Each of 4 allied powers supplied two judges- a main judge and an alternate.
 24 individuals were indicated along with 6 Nazi organizations determined to
be criminals.
 The defendants, who included Nazi party officials and high-ranking military
officers along with German industrialists, lawyers and doctors.

 They were included on such charges,
o Crimes committed before the war.
o Crimes against Peace : Including planning,
preparation, initiation and waging of wars of aggression. Were also wars in
violation of international treaties, agreements, and assurance.
o War crimes : including violation of the laws of war, including improper
treatment of prisoners of war, slave labor and use of outlaw’s weapons.
o Crime against humanity : This count involved the actions in concentration
camps and other death rampages, persecution on political, religious or racial
grounds.

 Hitler and two of his top associates, committed suicide in the spring of 1945
before they could be brought to trial.
 In the end, the international tribunal found all 24,
o Twelve were sentenced to death,
o Three were sentenced to life imprisonment
o Four received prison terms ranging from 10-12 years
o Three defendants were acquitted (found not guilty)
o Two committed suicide prior to trial
 Trial lasted 218 days and included testimony from 360 witness.
Defendants

SUBSEQUENT TRIALS (1946 – 1949)
 Following the war of Major War Criminals, there were 12 additional trails held
at Nuremberg.
 These proceedings lasting from December 1946 to April 1949, are grouped
together as the Subsequent Nuremberg Proceedings.
 They were different from the first trial in that they were conducted before
U.S. military tribunals.
 The subsequent trials were held in the same location at The Palace of
Justice in Nuremberg.

 The trials were as follows.,
1) Doctor`s trial
2) Milch trial
3) Judge`s trial
4) Pohl trial
5) Flick trial
6) IG Farben trial
7) Hostages trial
8) RuSHA trial
9) Einsatzgruppen trial
10) Krupp trial
11) Ministries trial
12) High Command trial

DOCTOR`S TRIAL (1946 – 1947)
 Doctor`s trial (officially United States of America v. Karl Brandt, et al.) was
the first of 12 trials for war crimes.
 This trial lasted from 9 December 1946 to 20 August 1947 but was held
before US military courts, and took place in the same rooms at The Palace
of Justice, Nuremberg.
 The trial described and documented some of the most gruesome and painful
medical experiments carried out by Nazi Doctors.
 The victims of these crimes are numbered in the hundreds of thousands. A
handful were alive; a few of the survivors appeared in the courtroom.

 After almost 140 days of proceedings, including the 85 witnesses and the
submission of almost 1500 documents, the American judges (3 judges and 1
alternate) pronounced punishment and were charged with murders, tortures.
 Among 23 defendants, 16 of the doctors were found guilty
7 were sentenced to death, 2 imprisonment for 25 years,1 imprisonment for 15
years,1 imprisonment for 10 years, 5 life imprisonment
 The judgment by the war crimes tribunal at Nuremberg laid down 10
standards to which physicians must confirm when carrying out experiments
on human subjects in a new code that is now accepted world wide.
 The judgment established a new standard of ethical medical behavior for the
post World War human rights era.

Defendants Court room during Doctor’s
Trial

NUREMBERG CODE (1947)
 The medical experiments conducted by German doctors and prosecuted in
the so called “Doctor`s trial” led to the creation of “The Nuremberg Code” to
control the future trials involving human subjects, a set of research ethics
principles for human experimentation.
 The Nuremberg code is a set of research ethics principles for human
experimentation set as a result of Subsequent Nuremberg Trials at the end
of The Second World War.
 The principles established by this code for medical practice now have been
extended into general codes of medical ethics.

1) The Voluntary Consent
• The voluntary consent of the human subject is absolutely essential.
• This means that the person involved should have legal capacity to give
consent; should be so situated as to be able to exercise free power of choice,
without the intervention of any element of force, fraud, deceit, duress,
overreaching, or other ulterior form of constraint or coercion; and should have
sufficient knowledge and comprehension of the elements of the subject
matter involved as to enable him to make an understanding and enlightened
decision.
• This latter element requires that before the acceptance of an affirmative
decision by the experimental subject there should be made known to him the

nature, duration, and purpose of the experiment; the method and means by
which it is to be conducted; all inconveniences and hazards reasonably to be
expected.
• The duty and responsibility for ascertaining the quality of the consent rests
upon each individual who initiates, directs, or engages in the experiment. It is
a personal duty and responsibility which may not be delegated to another
with impunity.

2) Beneficial to Human
• The experiment should be such as to yield fruitful results for the good of
society, unprocurable by other methods or means of study, and not random
and unnecessary in nature.
3) Prior Knowledge
• The experiment should be so designed and based on the results of animal
experimentation and a knowledge of the natural history of the disease or
other problem under study that the anticipated results will justify the
performance of the experiment.

4) Suffering and injury
• The experiment should be so conducted as to avoid all unnecessary physical
and mental suffering and injury.
5) Prior Risk
• No experiment should be conducted where there is an a prior reason to
believe that any risk as death or disabling injury will occur.

6) Risk and Benefit Analysis
• The degree of risk to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment.
7) Protection and Adequate Facilities
• Proper preparations should be made and adequate facilities provided to
protect the experimental subject against even remote possibilities of injury,
disability, or death.
8) Qualified Persons
• The experiment should be conducted only by scientifically qualified persons.
The highest degree of skill and care should be required through all stages of
the experiment of those who conduct or engage in the experiment.

9) Freedom to withdraw
• During the course of the experiment the human subject should be at liberty to
bring the experiment to an end if he has reached the physical or mental state
where continuation of the experiment seems to him to be impossible.
10) Termination of Studies
• During the course of the experiment the scientist in charge must be prepared
to terminate the experiment at any stage, if he has probable cause to believe,
in the exercise of the good faith, superior skill and careful judgment required
of him that a continuation of the experiment is likely to result in injury,
disability, or death to the experimental subject.

THE SIGNIFICANCE OF THE NUREMBERG CODE
 The Nuremberg code is one of several foundational documents that
influenced the principles of Good Clinical Practice (GCP).
 Good Clinical Practice is an attitude of excellence in research that provides a
standard for study design, implementation, conduct and analysis.
 More than a single document, it is a compilation of many thoughts, ideas and
lessons learned throughout the history of clinical research worldwide.
 Several other documents further expanded upon the principles outlined in the
Nuremberg Code,including the Declaration of Helsinki & The Belmont Report
 The goal has always been – and always will be – to conduct ethical clinical
trials and protect human subjects.

THE THALIDOMIDE STUDY
• In 1952, thalidomide was synthesised by Chemical Industry Basel (CIBA),
but was found "to have no effect on animals and was discarded" on that
basis. In 1957, it was acquired by Chemie-Grunenthal in Germany.
• The German company had been established as a soap maker after World
War II ended, to address the urgent market need for antibiotics. Heinrich
Mückter (Nazi Doctor, Pharmacologist, and chemist) was appointed to head
the discovery program based on his experience working with the German
army's antiviral research.

• While preparing reagents for the work, Muckter's assistant Wilhelm Kunz
isolated a by-product that was recognized by pharmacologist Herbert Keller
as an analog of Glutethimide, a Sedative. The medicinal chemistry work
turned to improving the lead compound into a suitable drug: the result was
Thalidomide. The toxicity was examined in several animals, and the drug
was introduced in 1956 as a sedative, but it was never tested on pregnant
women.
• Researchers at Chemie-Grünenthal found that thalidomide was a particularly
effective Antiemetic that had an inhibitory effect on Morning sickness. On
October 1, 1957, the company launched thalidomide and began marketing it
under the trade name Contergan.

• It was proclaimed a "wonder drug" for insomnia, coughs, colds and
headaches.
• Marketing of this drug was done in almost 46 countries.
• However, following its widespread use in Japan, Australia, and Europe,
practitioners began to notice links between mothers who had taken
thalidomide and the presence of Congenital Mutations in their children.
Congenital Mutations :- Structural or
functional anomalies (for example,
metabolic disorders) that occur during
intrauterine life and can be identified
prenatally, at birth, or sometimes may only
be detected later in infacy, such as hearing
defects.

MARKETING
• In the UK, the British pharmaceutical company The Distillers Company
(Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of Diageo
plc), marketed thalidomide throughout the UK, Australia and New Zealand,
under the brand name Distaval, as a remedy for morning sickness.
• Their advertisement claimed that "Distaval can be given with complete
safety to pregnant women and nursing mothers without adverse effect
on mother or child ... Outstandingly safe Distaval has been prescribed for
nearly three years in this country." Globally, more pharmaceutical companies
started to produce and market the drug under license from

Chemi-Grünenthal. By the mid-1950s, 14 pharmaceutical companies were
marketing thalidomide in 46 countries under at least 37 different trade names.

THALIDOMIDE DISASTER
• In the 1960s, two medical professionals; Dr Widukind Lenze and Dr
William McBride, observed an association between the use of thalidomide in
expecting mothers and congenital malformations.
• First affected child girl born on 25 December 1957, she was the daughter of
employee of Grunenthal.
• It was seen that the baby took birth was without developed limbs.
• On December 1961, McBride wrote letter in The Lancet that congenital
abnormalities are present in approximately 1-5 % of babies.

• In recent months he observed that the incidence of multiple severe
abnormalities in babies delivered of women who were given the drug
thalidomide during pregnancy, as an anti-emetic or as a sedative during
pregnancy is to be almost 20%.
• These abnormalities are present in structures developed from mesenchyme
i.e., the bones and musculature of the gut. Bony development seems to be
affected in a very striking manner, resulting in polydactyly, syndactyly, and
failure of development of long bones (abnormally short femora and radii).
• Once publicized, these findings were further backed by several cases across
the globe with a reported 10,000 children thought to have been born with
phocomelia.

SYMPTOMS PATTERN
• Phocomelia : abnormal limbs
• Amelia : missing limbs
OTHER TERATOGENIC EFFECTS
• Abnormal number of digits
• Missing/ malformed eye(s) and ears(s)
• Anal atresia
• Brain damage/ autism
• Spinal cord defect
• Cleft lip or palate
• Heart, kidney, GIT and genital defects
Abnormal number of
Digits
Missing Limbs
Abnormal Eyes Abnormal Ears

DAMAGE
• 10,000-12,000 thalidomide babies were born with this defect in almost 46
affected countries.
• 40% of victims died within a year of birth.
• Today there are approximately 5000 thalidomide survivor.

REMOVAL FROM MARKET
• When a German newspaper published that 161 babies were adversely
affected by thalidomide, it marked the beginning of END, leading the makers
of the drug to finally stop distribution within Germany.
• As a consequence, thalidomide was removed from the market in the majority
of countries, with some still offering the drugs several years after.
• In addition to these abnormalities, there was an increase in the number of
miscarriages reported by women during the same period of time.
• By 1962, the drug was banned in most countries where it was previously
sold.

• In the US, representatives from Chemie-Grünenthal approached Smith, Kline
& French (SKF) (was an American Pharmaceutical Company) now
GlaxoSmithKline (GSK),(British Multinational Pharmaceutical Company
headquartered in London, England) with a request to market and distribute
the drug in North America. A memorandum, rediscovered in 2010 in the
archives of the FDA, shows that in 1956–57, as part of its in-licensing
approach, Smith, Kline and French conducted animal
tests and ran a clinical trial of the drug in the US
involving 875 people, including pregnant women.

FDA REFUSAL
• The US FDA refused to approve thalidomide for marketing
and distribution. However, the drug was distributed in large
quantities for testing purposes, after the American
distributor and manufacturer Richardson-Merrell had
applied for its approval in September 1960.
The official in charge of the FDA review, Frances Oldham Kelsey, (was a
Canadian-American Pharmacologist and Physician. As a reviewer of the
USFDA she refused to authorize thalidomide for market because she had
lack of concern about evidence) did not rely on information from the company,
which did not include any test results.

 Leprosy Treatment :-
 In 1964, Israeli physician Jacob Sheskin administered thalidomide to
a patient critically ill with leprosy. The patient exhibited Erythema
Nodosum Leprosum (ENL), a painful skin condition, one of the
complications of leprosy. The treatment was attempted despite the
ban on thalidomide's use, and results were favourable: the patient
slept for hours and was able to get out of bed without aid upon
awakening. A clinical trial studying the use of thalidomide in leprosy
soon followed

 Thalidomide has been used by Brazilian physicians as the drug of
choice for the treatment of severe ENL since 1965, and by 1996, at
least 33 cases of thalidomide embryopathy were recorded in people
born in Brazil after 1965 Since 1994, the production, dispensing, and
prescription of thalidomide have been strictly controlled.
 Despite this, cases of thalidomide embryopathy continue, with at least
100 cases identified in Brazil between 2005 and 2010. 5.8 million
thalidomide pills were distributed throughout Brazil in this time period
largely to poor Brazilians in areas with poor access to healthcare, and
these cases have occurred despite the controls.

 In 1998, the FDA approved the drug's use in the treatment of ENL.
Because of thalidomide's potential for causing birth defects, the drug
may be distributed only under tightly controlled conditions. The FDA
required that “Celgene Corporation’’ (a Pharmaceutical company
that makes Cancer and Immunology drugs) which planned to market
thalidomide under the brand name “Thalomid”.
 In 2010, the World Health Organization (WHO) stated that it did not
recommend thalidomide for leprosy due to the difficulty of adequately
controlling its use, and due to the availability of Clofazimine

 Cancer treatment :-
 Shortly after the teratogenic properties of thalidomide were recognized
in the mid-1960s, its anti-cancer potential was explored and two clinical
trials were conducted in people with advanced cancer, including some
people with multiple myeloma; the trials were inconclusive.
 Judah Folkman pioneered studies into the role of Angiogenesis (the
proliferation and growth of blood vessels) in the development of
cancer, and in the early 1970s had shown that
solid tumors could not expand without it.

 In 1993 he surprised the scientific world by hypothesizing the same was
true of blood cancers, and the next year he published work showing that
a biomarker of angiogenesis was higher in all people with cancer, but
especially high in people with blood cancers, and other evidence
emerged as well. Meanwhile, a member of his lab,
Robert D'Amato, who was looking for
Angiogenesis inhibitors, discovered in 1994
that thalidomide inhibited angiogenesis and
was effective in suppressing tumor growth in rabbits.

 Around that time, the wife of a man who was dying of multiple
myeloma and whom standard treatments had failed, called Folkman
asking him about his anti-angiogenesis ideas. Folkman persuaded the
patient's doctor to try thalidomide, and that doctor conducted a clinical
trial of thalidomide for people with multiple myeloma in which about a
third of the subjects responded to the treatment. The results of that
trial were published in the New England Journal of Medicine in 1999.

 After further work was done by Celgene and others, in 2006 the
U.S. Food and Drug Administration granted accelerated approval for
thalidomide in combination with Dexamethasone for the treatment
of newly diagnosed multiple myeloma patients.
 It was also evaluated whether thalidomide can be combined with
Melphalan and Prednisone for patients with multiple myeloma.
This combination of drugs probably results in an increase of the
overall survival.

WHAT IS SYPHILIS ?
 Syphilis is a sexually transmitted disease (STD) caused by a type of bacteria
known as Treponema pallidum.
 It is a highly contagious disease that`s mostly spread through sexual activity.
Three stages of syphilis are :
o Primary – Development of sore ; Secondary – Development of rash
Latent or hidden stage – primary and secondary symptoms disappear, and
there wont be any noticeable symptoms at this stage. However bacteria
remain in the body. ; Tertiary – Damage of internal organs leading to death

1905: Bacterium
causing syphilis
isolated
1926: 35% prevalence of
syphilis in African American
1931: Rosenwald fund
discontinuous funding
1945: Penicillin accepted
as treatment of choice
1973: Congress holds
hearing and lawsuit on
behalf of participants
2004: Last
participant dies
1907: Blood test for
syphilis developed
1929: Mercury and
bismuth treatment <30%
effective
1932: PHS follow up
studies commenced.
Interns/nurses from
Tuskegee Institute get
involved.
1972: First news articles
condemn studies.
Study ends.
1974: Participants receive
$10 million settlement
SYPHILIS AND STUDY TIMELINE

ORIGIN OF THE STUDY
 The research was intended
o to test whether syphilis caused cardiovascular damage more often than
neurological damage
o to determine if the natural course of syphilis in black men was significantly
different from that in whites.
 U.S. Public Health Service (PHS) conducted follow up studies led by :
o Tuskegee Institute – provided resources and interns (for training)
o Dr. Taliaferro Clark – formulation of study
o Dr. Raymond Vonderlehr – selected the participants
 Started in 1932

THE TUSKEGEE SYPHILIS EXPERIMENT (1932 – 1972)
 The study was also called “The Tuskegee Study of Untreated Syphilis in the
Negro Male”.
 The study included
o 600 African American men
- 399 infected African American men
- 201 uninfected African American men
 These men were promised to give incentives,
- Medical care - Free meals - Free treatment
- Rides to and from the clinic - Survivors insurance

 The men enrolled in the study were never told they had syphilis or that the
disease could be transmitted through sexual intercourse.
 Instead, researchers kept this information from them and told the patients
that they were being treated for “bad blood” (a local term used to describe
several aliments, including syphilis, anemia and fatigue).
 Treatment was initially part of the study, but after the original study failed to
produce any useful data, it was decided to follow the subjects until their
deaths (instead the government was purposely letting their disease progress
for the study), and all treatments were halted.
 They were monitored by health workers, but only giving placebos such as
aspirin and mineral supplements men thought that they were been treated.

DOCTOR`S ENVOLVED
• Oliver C. Wenger was the director of the regional PHS
Venereal Disease Clinic in Hot Springs, Arkansas. He
and his staff took the lead in developing study
procedures. Wenger continued to advise and assist the
study when it was adapted as a long-term, no-treatment
observational study after funding for treatment was lost.
• Raymond A. Vonderlehr was appointed on-site
director of the research program and developed the
policies that shaped the long-term follow-up section of
the project.

• Robert Russa Moton, then president of Tuskegee
Institute, and Eugene Dibble, head of the
Institute's John A. Andrew Memorial Hospital, both lent
their endorsement and institutional resources to the
government study.
• Nurse Eunice Rivers, who had trained at Tuskegee
Institute and worked at its hospital, was recruited at the
start of the study to be the main point of contact with
the participants.

PENICILLIN
 Penicillin came into use in 1947, which could be cure syphilis.
 It is a antibiotic, specifically the type known as penicillin G benzathine. It
has proven to be effective at killing Treponema pallidum.
 Had penicillin been administrated to the syphilitic men in the study, many
would have lead longer and more comfortable lives. However, the
government did not treat them.

THE STUDY BECOME PUBLIC
 The story finally broke in “Washington Star” on July 25, 1972, in an article by
Jean Heller of the Associated Press and its unethical methods were
exposed in the Washington Star.
 By the time 28 men had died of syphilis, 100 others were dead of related
complications, at least 40 wives had been infected and 19 children had
contracted the disease at birth.
 Under the glair of publicity, the government ended
their experiment, and the first time provided the
men with effective medical treatment for syphilis.

THE END OF THE STORY
 After the Tuskegee study become public, it caused a public outcry that led the
Assistant Secretary for Health and Scientific Affairs to appoint an Ad Hoc
Advisory Panel to review the study.
 The panel had nine members from the fields of medical, law, religion, labor,
education, health administration and public affairs.
 The Advisory Panel concluded that The Tuskegee Study was “ethically
unjustified” – the knowledge gained was sparse when compared with the risks
the study posed for its subjects. In October 1972, the panel advised stopping
the study at once. A month later, The Assistant Secretary for Health and
Scientific Affairs announced the end of The Tuskegee Study.

OUTCOMES
 Tuskegee study made major changes in federal rules governing medical
research were established.
 National Research Act Law created to protect human subject in research
passed in 1974.
 National Commission for the Protection of Human subjects of Biomedical
and Behavioral Research was created as a result.
 The Belmont Report summarized the basic ethical issues that needed to be
followed when doing research.

 As part of the settlement in 1973, the U.S. government promised to give
lifetime medical benefits and burial services to all living participants. The
Tuskegee Health Benefit Program (THBP) was established to provide the
services.
 In 1974 participants received $10 million settlement.
 President Clinton apologized to those involved and had a ceremony for
them in 1997

 The report was issued on September 30, 1978 and published in the Federal
Register on April 18, 1979. The report took its name from the Belmont
Conference Center where the document was drafted in part. The Belmont
Conference Center, once a part of the Smithsonian Institution, is in
Elkridge, Maryland, 10 miles south of Baltimore, and until the end of 2010 was
operated by Howard Community College.[3]

 History:
 The Belmont Report was first written by the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research
(was the first public national body to shape bioethics policy in the United
state) Prompted in part by problems arising from the Tuskegee Syphilis
Study (1932–1972) and based on the National Commission for the Protection
of Human Subjects of Biomedical and Behavioral Research (1974–1978), the
Department of Health, Education and Welfare (HEW) revised and expanded its
regulations for the protection of human subjects i.e 45 CFR part 46 in the late
1970s and early 1980s.

 In 1978, the Commission's report Ethical Principles and Guidelines for the
Protection of Human Subjects of Research was released, and it was
published in 1979 in the Federal Register. It was named the Belmont Report,
for the Belmont Conference Center, where the National Commission met when
first drafting the report. The Belmont Report is one of the leading works
concerning ethics and health care research. It allows for the protection of
participants in clinical trials and research studies.

 The Belmont Report explains the unifying ethical principles that form the
basis for the National Commission's topic-specific reports and the regulations
that incorporate its recommendations.

 The three fundamental ethical principles for using any human subjects
for research are:
Respect for persons: protecting the autonomy of all people and treating them
with courtesy and respect and allowing for informed consent. Researchers
must be truthful and conduct no deception;
Beneficence: the philosophy of "Do no harm" while maximizing benefits for the
research project and minimizing risks to the research subjects; and
Justice: ensuring reasonable, non-exploitative, and well-considered procedures
are administered fairly — the fair distribution of costs and benefits to potential
research participants — and equally.

 These principles remain the basis for the United States Department of Health
and Human Services (HHS) human subject protection regulations.
 Applications of these principles to conduct research requires careful
consideration of i) informed consent, ii) risks benefit assessment, and
iii)selection of subjects of research.

 The Declaration of Helsinki (DoH) is the World Medical Association’s
(WMA) best-known policy statement. The first version was adopted in 1964
and has been amended seven times since, most recently at the General
Assembly in October 2013. The current (2013) version is the only official
one; all previous versions have been replaced and should not be used or
cited except for historical purposes.
 Today, the Declaration of Helsinki continues as an essential reference for
Institutional Review Report (IRB) that review HHS-conducted or -
supported human subjects research proposals involving human subjects, in
order to ensure that the research meets the ethical foundations of the
regulations.

 History
 The Declaration was originally adopted in June 1964 in Helsinki, Finland,
and has since undergone seven revisions (the most recent at the General
Assembly in October 2013) and two clarifications, growing considerably in
length from 11 paragraphs in 1964 to 37 in the 2013 version. The
Declaration is an important document in the history of research ethics as it
is the first significant effort of the medical community to regulate research
itself, and forms the basis of most subsequent documents.

 Prior to the 1947 Nuremberg Code there was no generally accepted code of
conduct governing the ethical aspects of human research, although some
countries, notably Germany and Russia, had national policies. The
Declaration developed the ten principles first stated in the Nuremberg Code,
and tied them to the Declaration of Geneva (1948), a statement of
physicians' ethical duties

 I Basic Principles
1) Clinical research must conform to the moral and scientific principles that justify
medical research and should be based on laboratory and animal experiments
or other scientifically established facts.
2) Clinical research should be conducted only by scientifically qualified persons
and under the supervision of a qualified medical man.
3) Clinical research cannot legitimately be carried out unless the importance of
the objective is in proportion to the inherent risk to the subject.
4) Every clinical research project should be preceded by careful assessment of
inherent risks in comparison to foreseeable benefits to the subject or to others.

5) Special caution should be exercised by the doctor in performing clinical
research in which the personality of the subject is liable to be altered by
drugs or experimental procedure.

II. CLINICAL RESEARCH COMBINED WITH PROFESSIONAL CARE
1. In the treatment of the sick person, the doctor must be free to use a new
therapeutic measure, if in his judgment it offers hope of saving life, re-
establishing health, or alleviating suffering.
If at all possible, consistent with patient psychology, the doctor should obtain
the patient’s freely given consent after the patient has been given a full
explanation. In case of legal incapacity, consent should also be procured from
the legal guardian; in case of physical incapacity the permission of the legal
guardian replaces that of the patient.

2. The doctor can combine clinical research with professional care, the objective
being the acquisition of new medical knowledge, only to the extent that clinical
research is justified by its therapeutic value for the patient.
III. NON-THERAPEUTIC CLINICAL RESEARCH
1. In the purely scientific application of clinical research carried out on a human
being, it is the duty of the doctor to remain the protector of the life and health of
that person on whom clinical research is being carried out.
2. The nature, the purpose and the risk of clinical research must be explained to
the subject by the doctor.

3a. Clinical research on a human being cannot be undertaken without his free
consent after he has been informed; if he is legally incompetent, the consent of
the legal guardian should be procured.
3b. The subject of clinical research should be in such a mental, physical and
legal state as to be able to exercise fully his power of choice.
3c. Consent should, as a rule, be obtained in writing. However, the responsibility
for clinical research always remains with the research worker; it never falls on the
subject even after consent is obtained.
4a. The investigator must respect the right of each individual to safeguard his
personal integrity, especially if the subject is in a dependent relationship to the
investigator.

4b. At any time during the course of clinical research the subject or his
guardian should be free to withdraw permission for research to be continued.
1975: First revision. 29th Meeting, Tokyo
1983: Second revision. 35th Meeting, Venice
1989: Third revision. 41st Meeting, Hong Kong
1996: Fourth revision. 48th Meeting, Somerset West (South Africa)
2000: Fifth revision. 52nd Meeting, Edinburgh
2002: First clarification, Washington
2004: Second clarification, Tokyo
2008: Sixth revision, 59th Meeting, Seoul
2013: Seventh revision, 64th Meeting, Fortaleza

 REFERENCE
• https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/
• https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-
belmont-report/index.html
• https://en.wikipedia.org/wiki/Nuremberg_Code
• https://research.unc.edu/human-research-ethics/resources/ccm3_019064/
• https://www.icj-cij.org/public/files/library-of-the-court/library-of-the-court-
en.pdf

• https://www.mcgill.ca/oss/article/history/40-years-human-experimentation-
america-tuskegee-study
• https://biotech.law.lsu.edu/cphl/history/reports/tuskegee/complete%20report.
pdf
• https://en.wikipedia.org/wiki/Belmont_Report
• https://en.wikipedia.org/wiki/Declaration_of_Helsinki
• https://www.wma.net/publications/wma-doh-1964-2014/

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