A Brief History of Clinical Research

Department of Bioinformatics and

Biostatistics
 First Recorded “Experiment”

• The world's first clinical trial is recorded in the “Book of Daniel” in The
Bible.
• Nebuchadnezzar ( king of Babylon) Compared two diets, one with
meat and wine and one with vegetables and water
• After 10 days, those (Daniel and his three friends) with the vegetables
and water diet “appeared better nourished than the meat-eaters”

LOUISVILLE.EDU
 Rules for the testing of drugs

• Avicenna (1025 AD) in his encyclopedic ‘Canon of Medicine’

Proposed: that in the trial, a remedy should be used in its natural
state in disease without complications.
• He recommended that two cases of contrary types be studied, and
that study be made of the time of action and of the reproducibility of
the effects.

LOUISVILLE.EDU
 First Clinical Trial

• Ambroise Pere (1537), was responsible for the treatment of the

battlefield wounded soldiers.
• He compared a conventional treatment – oil with an
unconventional treatment, a digestive made of yolks of eggs, oil of
roses and turpentine.

LOUISVILLE.EDU
 First Clinical Trial

• Ambroise Pere (1537), was responsible for the treatment of the battlefield
wounded soldiers.
• He compared a conventional treatment – oil with an unconventional
treatment, a digestive made of yolks of eggs, oil of roses, and turpentine.
• He found that those who received the digestive medication “felt but little
pain, their wounds neither swollen nor inflamed, and having slept through
the night.
• Those who received the boiling oil were feverish with much pain and
swelling about their wounds.”

LOUISVILLE.EDU
 First Clinical Trial of the Modern Era

• Dr. Lind (1716-94), whilst working as a surgeon on a ship, was

appalled by the high mortality of scurvy amongst the sailors.
• He planned a comparative trial of the most promising cure for
scurvy.
• He had 12 individuals who were very sick, and he chose two of
each to receive different treatments.

LOUISVILLE.EDU
 First Clinical Trial of the Modern Era

• “The most sudden and visible good effects were perceived from the
use of oranges and lemons; one of those who had taken them,
being at the end of six days fit for duty.”
• The other sailor receiving this treatment was the best recovered of
any in his condition.
• Lind hesitated to recommend the use of oranges and lemons
because they were too expensive.

LOUISVILLE.EDU
 The First Placebo

• In 1863, Austin Flint planned the first clinical study comparing a dummy
remedy to an active treatment. The other sailor receiving this treatment was
the best recovered of any in his condition.
• He treated 13 patients suffering from rheumatism with an herbal extract
which was advised instead of an established remedy
• “This was given regularly and became well known in my wards as the
‘placeboic remedy’ for rheumatism. The favorable progress of the cases
was such as to secure for the remedy generally the entire confidence of the
patients.”

LOUISVILLE.EDU
 The First Double blind Controlled Trial

• The study was designed to investigate patulin treatment for (an

extract of Penicillium patulinum) the common cold.
• This was the first double-blind comparative trial with concurrent
controls.
• This nationwide study enrolled over a thousand British office and
factory workers suffering from colds.
• It was rigorously controlled by keeping the physician and the
patient blinded to the treatment.

LOUISVILLE.EDU
 First Randomized Curative Trial

• The idea of randomization was introduced in 1923.

• However, the first randomized control trial of streptomycin in
pulmonary tuberculosis was carried out in 1946.
• Determination of whether a patient would be treated by
streptomycin and bed-rest (S case) or by bedrest alone (C case)
was made by reference to a statistical series based on random
sampling numbers drawn.

LOUISVILLE.EDU
 Unethical Research - Johnson “Monster” Study

• The Monster Study was a stuttering experiment performed on 22

orphan children in Davenport, Iowa in 1939.
• Graduate student Mary Tudor conducted the experiment under the
supervision of Wendell Johnson at the University of Iowa.
• Half of the children received positive speech therapy, praising the
fluency of their speech, and the other half, negative speech
therapy, belittling the children for speech imperfections.

LOUISVILLE.EDU
 Unethical Research - Johnson “Monster” Study

• The study resulted in creating stuttering behavior in some of the

children who didn’t stutter and psychological conditions of some of
the children that lasted for several years.
• The University of Iowa searched for the children in the study and
provided compensation for their conditions.

LOUISVILLE.EDU
 Unethical Research - Tuskegee Study

• In 1932, the Public Health Service, working with the Tuskegee

Institute, began a study to record the natural history of syphilis in
hopes of justifying treatment programs for blacks. It was called the
“Tuskegee Study of Untreated Syphilis in the Negro Male.”
• African American men in rural Alabama with syphilis enrolled, and
given free examinations.
• The study was conducted without the benefit of patients’ informed
consent.

LOUISVILLE.EDU
 Unethical Research - Tuskegee Study

• By 1943, penicillin was the treatment of choice for syphilis and became
widely available, but the participants in the study were not offered
treatment.
• Although originally projected to last 6 months, the study went on for 40
years.
• An investigatory panel appointed by HEW (Department of Health,
Education, and Welfare) in August 1972 found the study “ethically
unjustified” and argued that penicillin should have been provided to the
men.

LOUISVILLE.EDU
 Unethical Research - Milgram Study

• Milgram (1963) was interested in researching how far people would

go in obeying an instruction if it involved harming another person.
• In a fake study of human “memory and learning” volunteer subjects
were asked to administer electric shocks as punishment to a
“learner” when the learner gave a wrong answer.
• The learner was not really being shocked, but this was not known
by the subject administering punishment.

LOUISVILLE.EDU
 Unethical Research - Milgram Study

The ethical issues involved with the Milgram experiment are as

follows:
• Use of deception
• Protection of participants involved
• The right to withdrawal.

LOUISVILLE.EDU
 Ethics and Regulation

In the 1940’s, after several recognized abuses of subjects in

research, in particular the experiments conducted by the Nazis,
ethical issues were raised, and processes set into motion to protect
human subjects for this abuse.

These are described in the Ethics and Regulation presentations.

LOUISVILLE.EDU
 Regulatory Events

• FDA was founded in 1862, Congress passed the Food and Drugs
Act in 1906 to be enforced by the FDA.
• After that, legislation progressively demanded greater
accountability for marketing food and drugs and the need for
testing drugs in clinical trials increased.

LOUISVILLE.EDU
 At the Present

• Now there are very strict guidelines for conducting clinical

research and monitoring the entire process to ensure protection of
human subjects and high scientific rigor.
• There are several resources for conducting clinical research
including: the Cochrane Collaborative and Library,
ClinicalTrails.gov, fda.gov, REDCap, and others.

LOUISVILLE.EDU
 At the Present

• There are many professional organizations that promote clinical

research including: Association of Clinical Research Professional
(ACRP), Society of Clinical Research Associates (SOCRA), and
many country based and international associations.
• These organizations are dedicated to promotion of moral and
ethical standards for conducting clinical research.

LOUISVILLE.EDU
 References

• Bhatt, Arun. Evolution of Clinical Research: A History Before and

Beyond James Lind. Perspectives in Clinical Research. 1(1) Jan-
Mar 2010, 6-10.
• Collier, Roger. Legumes, lemons and streptomycin: A short history
of the clinical trial. CMAJ, Jan 2009, 180(1) 23-24.

Both articles are posted on the course website as well as other

resources.

LOUISVILLE.EDU