2. Background
How it All Began (1)
• Earliest recorded clinical trial:605-562 BC
- King Nebuchadnezzar II carries out the first clinical
trial when he orders that a strict diet of meat and
wine be followed for three years. However, four
children of royal blood convince Nebuchadnezzar to
allow them to exchange bread and water for the
required meal. After only ten days, those who have
switched to bread and water appear more
resplendent and well nourished than those who have
stuck to wine and meat.
3. Background
How it All Began (2)
• First clinical trial of a novel therapy:1537
- Renaissance surgeon Ambroise Parè mixes a concoction
of oil of rose, turpentine and egg yolk as a
replacement for the accepted medicament for
treating open wounds. One day after the unintentional
trial, Parè observes that the wounds treated with the
traditional formula are swollen and extremely painful,
while the wounds treated with the experimental
mixture are not painful. Parè deduces that the new
balm is more favorable than the oil usually applied.
4. Background
How it All Began (3)
• First use of control groups: 1747
-James Lind proves the effectiveness of lemon juice in
preventing scurvy. His experiment is known as one of
the first widely known controlled clinical trials: a trial
with a parallel control group that is given an
alternative treatment.
5. Background
How it All Began (4)
First use of a placebo:
- 19th century Trials utilizing the placebo emerge.
6. Background
How it All Began (5)
• First regulations against false therapeutic
claims: 1912
-USA Congress prohibits labeling medicines with
false therapeutic claims intended to defraud the
purchaser, a standard difficult to prove. However, it
acts as a stimulus to clinical studies.
7. Background
How it All Began (6)
First use of randomization: 1923
-20th Century Trials utilizing randomization develop.
Randomization is a process by which subjects in a
clinical trial are randomly assigned to receive one of the
treatments offered. In a 'blind' trial concerning the
effects of sanocrysin on tuberculosis, patients are
randomly divided into two separate groups of equal size.
One group receives the sanocrysin and the other
receives placebo. The patients do not know who is
getting the test drug.
8. Background
How it All Began (7)
• First body to manage clinical trials: 1930
- Therapeutic Trials Committee (UK)
- Experts from Great Britain establish a Therapeutic
Trials Committee with the idea of managing clinical
trials to study new drugs.
9. Background
How it All Began (8)
First US regulation to require drug safety:1938
- US Food, Drug, and Cosmetic Act
10. Background
How it All Began (9)
First multicenter studies employing the
same protocol: 1944
-Introduction of multicenter studies. These are
several studies conducted at different sites but
all using the same protocol; this allows the results
to be pooled, so that the greater numbers give
increased statistical 'power'.
-The UIS Public Health Service Act is passed,
encompassing a broad spectrum of health
concerns, in addition to regulation of biological
products and checks on infectious diseases.
11. Background
How it All Began (10)
• First properly randomized clinical trial with
control groups and blind assessment: 1948
- The British Medical Research Council (MRC) evaluated
the use of streptomycin to treat pulmonary
tuberculosis.
12. Background
How it All Began (11)
First strict, ethical regulations for medical
experimentation:
-1945 and onward - the Nuremburg Code (1948)
and the Declaration of Helsinki (1964,
amended in 1975, 1983, 1989,1996,2000,2008)
13. Background
How it All Began (12)
• First regulation for proof of efficacy: 1962
- Kefauver-Harris Drug Amendment (US) required
proof of efficacy required for new drug approval, in
addition to safety
14. US Food and Drugs Act of 1906
Evolution
Adulteration and misbranding of foods & drugs
have always been a problem in the U.S.
The problem increased by the late 19th C.
Sufferers of serious illnesses were sold worthless
drugs or therapies
Preservatives added to foods & drugs were useless
or worse toxic
15. Harvey Washington Wiley, chief chemist concerned
about chemical preservatives, initiated "poison squad"
experiments
Healthy volunteers consumed varying amounts of
questionable food additives to determine their impact
on health
Officially designated the “Hygienic Table.”
Chemicals fed to the young men included borax,
salicylic, sulfurous, and benzoic acids, & formaldehyde
16. Wiley became convinced that chemical
preservatives should be used in food only when
necessary
That the burden of proving safety should fall on the
producer
That none should be used without informing the
consumer on the label
Wiley unified a variety of groups behind a federal
law to prohibit the adulteration and misbranding
of food and drugs
18. US Food and Drugs
Act of 1906
First nationwide consumer protection law made it
illegal to distribute misbranded or adulterated
foods, drinks and drugs across state lines
Offending products could be seized & condemned;
persons could be fined & jailed
Drugs had either to abide by standards of purity
and quality set forth in the UNITED STATES
PHARMACOPEIA & the NATIONAL FORMULARY
Presence & quantity of alcohol or certain narcotic
drugs had to be stated on proprietary labels
19. Sulfanilamide Tragedy
A disaster in 1937 prompted Congress to act
A Tennessee drug company marketed a form of the
new sulfa wonder drug that would appeal to
pediatric patients, Elixir Sulfanilamide
The solvent in this untested product was
diethylene glycol
Over 100 people died, many of whom were children
20. Elixir Sulfanilamide
It tasted just fine: flavor
Never tested for toxicity
No regulation regarding safety
Removed for mislabeling
21. US Food, Drug, and
Cosmetic Act 1938
• Required pre-market review of safety in a New Drug
Application (NDA) and specified labeling requirements
• It also began marking study drugs with the phrase, “for
investigational use.”
• It also gave the FDA the authority to inspect sponsor
drug manufacturing plants and gave them more
enforcement power.
• The requirement of proving effectiveness was still
missing.
22. NAZI MEDICAL EXPERIMENTS
The “Nazi Doctors Trial”
• Nazi human experimentation was a series of
controversial medical experiments on large
numbers of prisoners by the German Nazi regime
in its concentration camps during World War II.
• Prisoners were coerced into participating: they did
not willingly volunteer and there were no informed
consent.
23. • Typically, the experiments resulted in death,
disfigurement or permanent disability.
• At Auschwitz and other camps, under the
direction of Dr. Eduard Wirths, selected inmates
were subjected to various experiments which were
supposedly designed to help German military
personnel in combat situations, develop new
weapons, aid in the recovery of military personnel
that had been injured, and to advance the racial
ideology.
24. • Dr. Aribert Heim conducted similar medical
experiments at Mauthausen. After the war, these
crimes were tried at what became known as the
Doctors' Trial, and revulsion at the abuses
perpetrated led to the development of the
Nuremberg Code of medical ethics.
25. Nuremberg Code -1948
• First formal statement on medical ethics
• 10 standards for physicians to conform to when
carrying out experiments on human participants.
• The result of judgment by an American military
war crimes tribunal conducting proceedings
against 23 Nazi physicians and administrators for
their willing participation in war crimes and
crimes against humanity.
26. Nuremberg Code -1948
Was developed in response to the judicial
condemnation of the acts of Nazi physicians, and
did not specifically address human subject
research in the context of the patient-physician
relationship.
Nuremberg Code establishes the need for informed
consent in human research
27. Nuremberg Code -1948
Briefly the 10 standards of the Nuremberg Code:
1. ICF
2. Experiment should be useful and necessary
3. Previous animal experiments before human
4. No physical and mental sufferings
5. No Death and disability outcome
6. Degree of risk not to exceed humanitarian
importance
28. Nuremberg Code -1948
7. Qualified researchers conduct the study
1. Human protection from any possibilities
of HARM.
2. Any time Quit from the study.
10. Preparation to stop the study at any
moment
29. Thalidomide tragedy-
1957 to 1961
• Thalidomide – the active ingredient of an hypnotic
agent which was sold in Germany
• Under the trademark CONTERGAN – triggered a
global tragedy & remains part of the corporate
history of Grünenthal.
• Thalidomide was developed by Grünenthal in
1954.
• The substance had a sedative effect and was used
to promote sleep was prescribed to women in early
pregnancy to overcome the unpleasantness of
morning sickness
30. Thalidomide tragedy-
1957 to 1961
• Unlike other hypnotics of that period it was not
associated with dependency and
• It appeared to be particularly well tolerated. In line
with the pharmacological and toxicological
investigations carried out in rodents
33. Thalidomide tragedy
• Thalidomide, the nightmare drug responsible for
over 10,000 human birth deformities and many
more-born throughout the world as
• Phocomelics, deformed, some with fin-like hands
grown directly on the shoulders; with stunted or
missing limbs;
• deformed eyes and ears; ingrown genitals; absence
of a lung; a great many of them still-born or dying
shortly after birth; parents under shock, mothers
gone insane, some driven to infanticide
34. Kefauver-Harris Drug
Amendment (1962)
• The earlier law (the Federal Food, Drug, and
Cosmetic Act of 1938) was passed in response to a
tragic error made in formulating a cough syrup for
children
• In the USA, proof of efficacy of pharmaceuticals
was required for the first time with the passage of
the Kefauver- Harris Drug Amendment
35. Kefauver-Harris
Amendments
(1962)
• Efficacy as well as safety must be demonstrated in
studies before a drug is marketed
• First US law requiring researchers
to:
– Inform subjects of experimental nature of a drug
– Obtain consent before starting the trial.
36. research1966
rewrite:
– Consent required except in cases of emergency or
experimental therapeutic treatment with children
or similar situations
– Documentation of consent in writing Inform
subjects that they may receive a placebo
37. The consequences
• Comprehensive medical act 1976
• an amendment to the Medicines Act of the Federal
Republic of Germany in 1964, the comprehensive
Medicines Act of 1976
• Act made it compulsory for new medicines to
undergo astringent licensing and assessment
procedure.
• Since that time companies have to submit to the
regulatory authorities extensive experimental
results
38. The consequences
• confirming the efficacy, safety and sufficient
quality of medicinal products before a medicine
can be licensed for sale for the first time.
• Special tests to detect any risk of malformation
have become standard practice.
39. Tuskegee Institute
Syphilis Study
1932 Study the natural course of untreated syphilis:
– Was originally scheduled to end after assessing what
health effects had occurred
– In the beginning, there was no intent to deny anyone
treatment on a long term basis.
399 African-American men matched against 201
uninfected subjects (controls)
Men were not informed about their disease
Were not informed that the research would not benefit
them
40. Tuskegee Institute
Syphilis Study
• they did not receive the proper treatment needed to
cure their illness. In exchange for taking part in
the study, the men received free medical exams,
free meals, and burial insurance.
41. Syphilis Study
• 1943- penicillin accepted as treatment for syphilis
• 1951- Penicillin was widely available but was
withheld from the subjects.
• Subjects were never given the choice about
continuing once penicillin became available
• 1972- Study exposed. Public outcry
• March 1973- Study Stopped
• 1997- President Clinton apologizes to subjects and
their families
42. • The American people are sorry – for the loss, for
the years of hurt. You did nothing wrong, but
you were grievously wronged. I apologize and I
am sorry that this apology has been so long in
coming.
-- President William J. Clinton, May 16, 1997
43. National Research Act 1974(1)
• Direct result of the Syphilis study
• Due to the publicity from the Syphilis Study, the
National Research Act of 1974 was passed.
• The National Research Act created the National
Commission for the Protection of
Human Subjects of Biomedical and Behavioral
Research.
44. National Research Act
1974(2)
• The Commission charge was to identify the basic
ethical principles that should underlie the conduct
of biomedical and behavioral research involving
human participants and to develop guidelines
which should be followed to assure that such
research is conducted in accordance with those
principles.
45. National Commission for the
Protection of Human Subjects of
Biomedical and Behavioral
Research
• Carrying out its charge, the Commission prepared
the Belmont Report in 1979.
The Belmont Report is a statement of basic ethical
principles and guidelines that provide “an
analytical framework to guide the resolution of the
ethical problems arising from research with human
subjects.”
46. National Commission for the
Protection of Human Subjects of
Biomedical and Behavioral
Research
• The framework of the Belmont Report is presented
in three discussion topics:
– Boundaries between practice and
research;
– Basic ethical principles,
– Applications.
47. Boundaries between
Practice and Research
The distinction between practice and research is
blurred; often because they occur together.
The IRB must ensure that the researcher (and the
participant) distinguishes practice from research in
both social science and biomedical research
Minimize the potential for therapeutic
misconception – when one believes the purpose of
clinical research is to treat rather then to gain
knowledge
48. Belmont Report
Basic Ethical Principles
Respect for Persons
– Individuals should be treated as autonomous agents
– Individuals with diminished autonomy are entitled to
protections
Beneficence
Do not harm
Maximum possible benefits, and minimize potential
harms
Justice
Fair distribution of burdens and benefits of research
49. Respect for Persons
• Treat individuals as autonomous persons; allow
individuals to choose for themselves
• Persons with limited autonomy need additional
protection, even to the point of excluding them
from activities that may harm them. The extent of
protection should depend upon the risk of harm,
and the likelihood of benefit.
• The judgment that any individual lacks autonomy
should be periodically re-evaluated, and will vary
across situations.
50. Beneficence
The IRB should determine whether the risks to
subjects are reasonable in relation to
anticipated benefits
Obligations of beneficence affect both the
researcher and society –
investigators are required to give forethought on
maximization of benefits and reduction of risk that may be
involved in the research
society should recognize the longer term benefits and risk
that may result from the improvement of knowledge, and
from the development of novel medical, psychological, and
social processes and procedures
51. Food and Drug Administration
1977
• The Code of Federal Regulations of the USA
• Establishes the regulations for clinical research in
the USA.
• Introduces the concepts of “Good Clinical
Practice”and “Data Integrity
52. Declaration Of Helsinki(1)
Developer :World Medical Association
Statement of Ethical Principles for Medical
Research Involving Human Subjects
First adopted in 18th WMA General Assembly,
Helsinki, Finland, June 1964
53. Declaration Of Helsinki(2)
Amended by:
29th WMA General Assembly, Tokyo, Japan, October
1975
35th WMA General Assembly, Venice, Italy, October
1983
41st WMA General Assembly, Hong Kong, September
1989
48th WMA General Assembly, Somerset West,
Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland,
October 2000
59th WMA General Assembly, Seoul, October 2008
54. Declaration Of Helsinki(3)
Aim
A distinction between Scientific and Clinical
Research
The need for informed consent
Statement of ethical principles for medical research
involving human subjects, including research on
identifiable human material and data.
Addressed primarily to physicians
Potential benefits must outweigh hazards
55. Declaration Of Helsinki(4)
• Ethical Pillars of Clinical Research:
Autonomy (Consent)
Beneficence
Non malfeasance (Misconduct)
Fidelity (Duty of Care)
Truthfulness (Honesty)
Confidentiality
Justice
56. ICH-GCP(1)
• Early 1960s : Widespread concern about the safety
and control of investigational drugs and the clinical
research process developed among member of the
medical profession, the scientific community,
regulatory authorities, and general public.
57. ICH-GCP(2)
1968 : WHO convened a Scientific Group on
Principles for Clinical Evaluation of Drugs
The Scientific Group was charged with reviewing and
formulating principles for clinical evaluation of drug
products.
1975 : Another WHO Scientific Group was convened
to specifically consider all aspects of the evaluation
and testing of drugs and to formulate proposals and
guidelines for research in the field of drug
development.
58. ICH-GCP(3)
Background
Need for safe and efficient products for various
health problems
Drug development is expensive and time
consuming
Need for efficient quality systems
Global drug market
Existence of national laws and regulations for drug
development
59. ICH-GCP(4)
Full form- International Conference on
Harmonization of Technical Requirements for
Registration of
Pharmaceuticals for Human Use
Primary participants
USA, European Union, Japan
Regulatory and industry representatives
60. ICH Categories
Quality (24 guidelines) - related to chemical and
pharmaceutical quality assurance
Safety (15 guidelines) - related to pre-clinical
studies
Efficacy (18 guidelines) - related to clinical
research in human subjects
Multidisciplinary (5 guidelines) – i.e., Medical
Terminology (MedDRA)
61. Efficacy Guidelines
E2 - Clinical Safety Data Management
E3 - Structure and Content of Clinical Study Reports
E6 - Good Clinical Practice(ICH-GCP)
E7 - Studies in Support of Special
Populations/Geriatrics
E8 - General Consideration of Clinical Trials
E9 - Statistical Principles for Clinical Trials
E11 - Clinical Investigation in the Pediatric
Population
E12 - Clinical Evaluation of New Antihypertensive
Drugs
62. Good Clinical Practice
(E6)
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance
that the data and reported results are credible and
accurate, and that the rights, integrity, and
confidentiality of trial subjects are protected.”
ICH GCP Glossary 1.24
63. GCP Objective
International ethical and scientific quality standard for
designing, conducting, recording and reporting trials that
involve the participation of human subjects.
Compliance with this standard provides public assurance
that the rights, safety and well-being of trial subjects are
protected, consistent with the principles that have their
origin in the Declaration of Helsinki.
Clinical trial data are credible.
Primary reason is:
Protection of Human Rights
– clinical trial subjects
– future patients who may receive approved product based
on study results in the marketing application.
