A clinical trial is a controlled experiment conducted in humans to test new interventions such as drugs or devices. James Lind conducted the first systematic clinical trial in 1747 to test treatments for scurvy. Since then, clinical trials have evolved to their modern form involving control groups, randomization, and different phases. Clinical trials are conducted in four phases - Phase I tests safety in small groups, Phase II explores efficacy and optimal dosing, Phase III tests efficacy in large groups, and Phase IV occurs after approval to further monitor safety. Clinical trials are needed to develop and regulate new medical interventions and provide high-quality evidence on benefits and risks.

1. Chapter 1: Introduction to Clinical
Trials
Topics to be covered
Fundamental Points
What is a clinical trial?
Historical examples of clinical tria
Why Are Clinical Trials Needed?
Problems in the Timing of a Trial
Phases of Clinical Trials

2. What is a ‘clinical trial’?
• A trial is an experiment
• An experiment is a series of observations made under
conditions controlled by the scientist.
• A clinical trial is a controlled experiment having a
clinical event as an outcome measure, done in a
clinical setting, and involving persons having a specific
disease or health condition.
• The distinction of a clinical trial from other types of
medical studies is the experimental nature of the trial
and its occurrence in humans.

3. History
• The concepts behind clinical trials are ancient. The
Book of Daniel, for instance, describes a planned
experiment with both baseline and follow-up
observations of two groups who either partook of, or
did not partake of, "the King's meat" over a trial period
of ten days.
• Experiments performed by Edward Jenner over his
smallpox vaccine etc.
• Although early medical experimentation was often
performed, the use of a control group to provide an
accurate comparison for the demonstration of the
intervention's efficacy, was generally lacking

4. First Systematic Clinical Trial
• The first proper clinical trial was conducted by the physician James
Lind]
• The disease scurvy, now known to be caused by a Vitamin C
deficiency, would often have terrible effects on the welfare of the
crew of long distance voyages

5. Lind’s trial
• Lind conducted the first systematic clinical trial in 1747.
• Lind selected 12 men in a ship, all suffering from scurvy,
and divided them into six pairs, giving each group
different additions to their basic diet.
– Group 1 were given a quart of cider daily,
– Group 2 twenty-five drops of elixir of vitriol (sulfuric acid),
– Group 3 six spoonfuls of vinegar,
– Group 4 half a pint of seawater,
– Group 5 received two oranges and one lemon,
– Group 6 a spicy paste plus a drink of barley water.
• After six days Group 5 almost recovered.

6. Modern Clinical Trial
• After 1750 clinical trial began to take its modern shape John
Haygarth demonstrated the importance of a control group for
the correct identification of the placebo effect
• Further work in that direction was carried out by the eminent
physician Sir William Gull, 1st Baronet in the 1860s.
• Sir Ronald A. Fisher, developed his Principles of experimental
design in the 1920s as an accurate methodology for the proper
design of experiments.
• Austin Bradford Hill was a pivotal figure in the modern
development of clinical trials who had been involved in the
streptomcyin trials.
• He became famous for a landmark study carried out in
collaboration with Richard Doll on the correlation between
smoking and lung cancer.

7. The 1954 Salk Polio Vaccine Trial
• The Biggest Public Health Experiment Ever:
The 1954 Field Trial of the Salk Poliomyelitis
Vaccine,”
– Reference: Meier, P. (1972), In: Statistics: A Guide
to the Unknown, J. Tanur (Editor) Holden-Day.
Features of the Polio Trial

9. Why Are Clinical Trials Needed?
• Clinical trials are used to develop and test interventions in nearly all
areas of medicine and public health.
• In many countries, approval for marketing new drugs hinges on
efficacy and safety results from clinical trials.
• In addition to testing novel therapies, clinical trials frequently are
used to confirm findings from earlier studies.
• When the results of a study are surprising or contradict biological
theory, a confirmatory trial may follow.
• Medical practice generally does not change based upon the results of
one study.
– Design flaws, methodological errors, problems with study
conduct, or analysis and reporting mistakes can render a clinical
trial suspect.
– Hence, confirmation of results in a study, or a trial extending the
use of the therapy to a different population, is often warranted.

10. Trials must have
• A rationale based on prior observational data
or biologic evidence
• An explicit, testable and potentially falsifiable
hypothesis
• An uncertainty as to whether an intervention is
efficacious (“equipoise”)
• Reasonable expectation that benefits will
exceed risk
• An intervention that potentially can be
randomized

11. Purpose of a Clinical Trial
• Assessment of efficacy, safety, or benefit:risk
– To protect the public health by assuring their safety
and efficacy
– Goal may be superiority, non-inferiority, or
equivalence
• To regulate medical products
– To apply standards to quality, purity, and potency
– In a regulatory setting: The goal may be to “show
that the drug has the effect it purports to have”

12. Trials can Evaluate
• New drugs and new treatment of diseases
• New medical and health care technology
• New methods of primary prevention
• New programs for screening
• New ways of organizing and delivering health
services
• New community health programs
• New behavioral intervention programs

13. Problems in the Timing of a Trial
• Clinical trials are time-consuming, labor-intensive, and
expensive.
• They require the cooperative effort of physicians, patients,
nurses, data managers, methodologists, and statisticians.
• Patient recruitment can be difficult.
• Some multi-center (across institutions) clinical trials cost up to
hundreds of million of dollars and take five years or more to
complete.
• Prevention trials, conducted in healthy subjects to determine
if treatments prevent the onset of disease, are important but
the most cumbersome, lengthy, and expensive to conduct.

14. • Many studies have a “window of opportunity” during which
they are most feasible and will have the greatest impact on
clinical practice.
• For comparative trials, the window usually exists relatively early
in the development of a new therapy.
• If the treatment becomes widely accepted or discounted based
on anecdotal experience, it may become impossible to formally
test the efficacy of the procedure.
• Even when clinicians remain unconvinced of efficacy or relative
safety, patient recruitment can become problematic.
• Some important medical advances have been made without the
formal methods of controlled clinical trials, i.e., without
randomization, statistical design, and analysis. Examples include
the use of vitamins, insulin, some antibiotics, and some
vaccines.

15. Phases of Clinical Trials
• Historically, developing new treatment or drug has
been a very “step-by-step” approach
Give the drug to a few healthy volunteers and see how they
tolerate it
Try it in patients; explore different doses and dose-regimens
Confirm what we think we have discovered (“learn and
confirm” principal)
Expand knowledge of drug once it is on the market
• Food and Drug Administration (FDA) and World Health
Organization (WHO) classified clinical trials during
course of drug or device testing in four phases I-IV.

16. Pre-clinical
• Pri-clinical phase study is conducted to test
new drug or treatment in experimental
animals
• Purpose
– to check the safety if used in human biengs

17. Phase I
• Sometimes called “Clinical pharmacologic studies”
• Test new drug or treatment in a small group of people
(20–80 healthy volunteers) for the first time to
evaluate its safety and preliminary evidence of effect
• Purposes
– Determine levels of toxicity, metabolism,
pharmacological effect, and safe dosage range
– Identify side effects
– Determine optimal or tolerable dose
– Describe adverse event
– Establish feasibility of treatment approach

18. Phase II
• The drug or treatment is given to a larger group of people (100–
300 patients) for efficacy and to further evaluate its safety
• Purposes
– Assess safety, acceptability/tolerance, and probable effective
dose
– Estimation of activity
– Comparison of doses or schedules
– Estimation of factors for Phase III
• A Phase II trial may be the first time that the agent is given to
patients with the disease of interest to answer questions such as:
– What is the correct dosage for efficacy and safety in patients
of this type?
– What is the probability a patient treated with the compound
will benefit from the therapy or experience an adverse effect?

19. Phase III
• Is a rigorous clinical trial with randomization, one or more control
groups and definitive clinical endpoints.
• Often multi-center, accumulating the experience of thousands of
patients.
• Address questions of comparative treatment efficacy which involves a
placebo and/or active control group so that precise and valid
estimates of differences in clinical outcomes attributable to the
investigational therapy can be assessed.
• Sometimes called “Effectiveness studies”
• Purposes
– Confirm effectiveness, compare it to commonly used treatments
– Monitor acceptability, side effects and complications
– Demonstrate superiority or non-inferiority
– Estimate rates of adverse events

20. Phase IV
• A phase IV trial occurs after regulatory approval of the
new therapy.
• Sometimes called an expanded safety (ES) study can
provide important information that was not apparent
during the drug development.
– For example, a few thousand patients might be involved
in all of the phase III trial for a particular therapy. An ES
study, however, could involve >10,000 patients. Such
large sample sizes can detect more subtle safety
problems for the therapy, if such problems exist.
• Some Phase IV studies will have a marketing objective for
the company as well as collecting safety data.

21. Note : The terminology of phase I, II, III, and IV trials does not work well for
non-pharmacologic treatments and does not account for translational trials.
E.g. community interventions, process of care, diagnostic procedures,
dietary supplementations, etc.