Dr. Eman M. Mortada
Professor
In public health and preventive medicine
Basics of interventional
research
Phases and types

Historical aspects of the clinical trials
Drug Development Process
Phases of the clinical trials
Advantages and disadvantages of clinical trials
Types of Clinical Trials Based on the unit being
studied
Types of clinical research studies based on the
purpose
Lecture Outline

It is usually used to:
1- assess the efficacy of a new line of treatment (a new drug for example) or
2- to compare two types of treatments: surgical or medical
RECAP:
Clinical trials
❑ Clinical trials have the objective of finding the best intervention to
prevent, and treat diseases
Clinical trials are ”Gold standard”
in epidemiological research
&
the best epidemiological study design to
prove causation.
Dr. Eman Mortada

What are clinical trials?
*Clinical trials involve A carefully and ethically designed
prospective research study conducted on humans that is designed
to to find better ways to prevent, diagnose, or treat a disease and
add to medical knowledge
Clinical
Persons with clinical
disease or persons at risk
of clinical disease
Trial
An experiment
Dr. Eman Mortada

RECAP:
Randomized Trial Design
Time
Defined
Population
New
Treatment
Current
Treatment
Improved
Not Improved
Improved
Not Improved
R
A
N
D
O
M
I
Z
E
D
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Clinical Trials in History
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Significant Historical Events For Clinical Trials

Early clinical trial
James Lind’s
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Edward Jenner vaccinating for
prevention of Smallpox (1796)
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 Edward Jenner was an English country doctor who pioneered
vaccination.
 Jenner's discovery in 1796 that inoculation with cowpox gave
immunity to smallpox, was an immense medical breakthrough and
has saved countless lives.

Dr/ Eman Mortada
What is Smallpox?
 In the 18th century smallpox was a very common serious, contagious
disease and was a major cause of death.
 There is no specific treatment for smallpox, and the only prevention is
vaccination.

 Jenner was given the opportunity,
when a young milkmaid called
Sarah Nelmes came to see him
with sores on her hands like
blisters.
 Jenner identified that she had
caught cowpox from the cows she
handled each day.
 He carefully extracted some
liquid from her sores and
then took some liquid from
the sores of a patient with
mild smallpox.
 Jenner believed that if he
could inject someone with
cowpox, the germs from the
cowpox would make the
body able to defend itself
against the dangerous
smallpox germs which he
would inject later.

 Jenner approached a local farmer
called Phipps and asked him if he
could inoculate his son James
against smallpox.
 He explained to the farmer that if his
theory was correct, James would
never contract smallpox.
 Surprisingly, the farmer agreed.
 Jenner called his idea " vaccination"
 from the word vaccinia
 which is latin for
 cowpox.

 Clinical trials began in 1800 onward to proliferate and
more attention was paid to study design.
Lifespan Improvement
John Snow and Cholera (1850)
Dr. Eman Mortada

1- John Snow mapped cases
of cholera to help give him
clues about the cause.
2- Mapping of cases led John
snow to suspect water from
the Broad street pump as a
cause of cholera.
What did he do?

Dr / Eman Mortada
15
1- He used chlorine in an
attempt to clean the water
2- he removed the handle,
thus ending the outbreak.
Broad Street Pump

 Placebos were first use in 1863
 Goldberger relating pellagra to maize diet
(1915)
Pre-20th Century Medicine
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The story of pellagra
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What is pellagra?

What was the problem of pellagra?
In 1914, pellagra was a common disease in the United States.
It caused rashes, insanity and death.
The story of pellagra
An insect
Or Bacteria/germs
Dr/ Eman Mortada
What did people think cause of pellagra?

What evidence did Dr. Goldberger observe or collect about
pellagra?
Dr/ Eman Mortada
Pellagra was common in the South,
particularly in poor areas and institutions
(such as mental hospitals, orphanages, and
prisons).
Many people in the South ate a poor diet,
consisting of cornbread
Staff at institutions (such as mental hospitals,
orphanages, and prisons) did not have pellagra.
Descriptive study
Analytical study

He generated a Hypothesis
Pellagra might be a nutritional deficiency disease
He tested that hypothesis
Some prisoners fed a poor diet developed pellagra. When
provided a better diet, they recovered.
What did Dr. Goldberger conclude about the cause of
pellagra?
Dr. Goldberger concluded that pellagra was caused by a
nutritional deficiency (poor diet).
Dr/ Eman Mortada

 The first trial using properly
randomized treatment and control
groups also featured double blind
assessment was carried out in 1948 by
the Medical Research Council, and
involved the use of streptomycin to
treat pulmonary tuberculosis..
First large-scale clinical trial using a properly
designed randomized schema
New Era of Medicine
The idea of randomization was introduced in 1923.

Austin Bradford Hill
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The father of modern RCTs

Clinical Trials recently
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Importance Of Clinical Trials
Registration
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All clinical trials should be registered
before the enrolment of the first
patient and all results made publicly
available
To ensure transparency,
accountability and to increase public
trust in the conduct of clinical
research.
Clinical trial registration and
results reporting would help ensure
unbiased public records on safety
and efficacy of drugs.

Drug Development Process
Phases of Clinical Trials
Dr. Eman Mortada

Phases in the Development of Drugs
Laboratory Research

Animal Studies

Clinical Trials
 Clinical trials that involve new
drugs go through a series of steps
are conducted in several phases and
each phase has a different purpose.
 The steps include:
 #1: Experiments in the laboratory
 #2: Once deemed safe, go through 4
phases
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Drug development timeline
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1- Preclinical trials
It is tested on animals before being tested
on human beings
 It takes about 2-5 years on the
average
 To test drug safety
 Pharmacokinetics and
pharmacodynamics are tested
➢ Preclinical testing by clinical Pharmacologist
Dr. Eman Mortada

Pharmacodynamics vs Pharmacokinetic
 What does the drug do to the
body?
 Investigate:
- Physiological effects (blood
glucose, electrolytes, kidney and
liver function)
- Mechanism of Drug action
(molecular and cellular responses to
drugs)
- Relationship between drug
concentration and effect (optimal
dose)
 What does the body do to the
drug?
 Investigate:
- Absorption (bioavailability)
- Distribution (circulation and
tissue)
- Metabolism (breakdown)
- Excretion (kidney and liver)
Pharmacodynamics studies Pharmacokinetic studies
Dr. Eman Mortada

Figure 1.1 Schematic representation of the pharmacokinetic and
pharmacodynamic processes that link the administration of drugs to its effects
Dose of drug
administered
Drug concentration
In systemic circulation
Drug in tissues or
distribution
Drug concentration
at site of action
Drug metabolized or excreted
Pharmacokinetics
Pharmacologic effect
Clinical response
Toxicity Efficacy
Pharmacodynamics
Absorption
Distribution
Elimination
Distribution
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 First in Man : Small number of healthy volunteers (20 to 25)
 Objective: dose finding (DF). Start with a dose of about 1/10 to 1/5
tolerated animal dose
 Slowly increase the dose to find a safe maximum tolerated dose or target
dose based on pre-clinical exposure
 If safe → try in a larger group of up to about 50 –75
 No blinding
 Performed by clinical pharmacologists
 Centre has emergency care & facility for kinetics study
 Takes 3 – 6 months [ 70% success rate]
2- Phase 1, Typical Characteristics
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3- Phase II
 Objective: Safety and Efficacy (SE) =To determine if new drug has any
beneficial activity and thus worthy of further testing / investment of resources.
 Once a drug has shown to be safe, then it must be tested for efficacy.
 First in patient [ different from healthy volunteer]
 Early phase [20 – 200 patients with relevant disease]
 Therapeutic benefits & ADRs evaluated
 Establish a dose range to be used in late phase
 Single blind, comparison with standard drug
 Late phase [ 50 – 500]
 Double blind
 Compared with a placebo or standard drug
 Takes 6 months to 2 years [ 35% success rate]
➢ Clinical testing by clinical Pharmacologist
Dr. Eman Mortada

3- Phase II
 Objective:
 Safety and Efficacy (SE)
 To determine if new drug has any beneficial activity and thus
worthy of further testing / investment of resources.
➢ Clinical testing by clinical Pharmacologist
Dr. Eman Mortada
Once a drug has
shown to be safe,
then it must be
tested for
efficacy.

3- Phase II
 Double blind
 Compared with a
placebo or standard
drug
Dr. Eman Mortada
First in patient [ different
from healthy volunteer]
Early phase
[20 – 200 patients with
relevant disease]
Late phase
[ 50 – 500]
❑ Therapeutic benefits & ADRs
evaluated
❑ Establish a dose range to be used
in late phase
❑ Single blind, comparison with
standard drug
 Takes 6 months to 2 years [ 35%
success rate]

4- Phase III
 Large scale, Randomised, Controlled trials
 Multiple arms: 2 (control vs intervention) or more
 Randomized treatment allocation
 Target population: 250 – 1000 patients
 Objective: to compare outcome to standard
[Comparative Treatment Efficacy]
 Takes a long time: up to 5 years [25% success]
➢ Clinical Trials by clinical Investigators
Dr. Eman Mortada

Essential elements of a clinical trial
1. Prospective
 Subjects followed forward
2. Intervention
 Prophylactic, diagnostic or therapeutic
3. Control
 Compared to intervention group
4. Randomized
 Equality of baseline characteristics
5. Blinded
 Systematic bias
Controlled
Randomized
Dr. Eman Mortada

Approval must be gained:
 Once a drug has proven satisfactory after Phase III trials, the trial
results are usually combined into a large document containing a
comprehensive description of the methods and results of human
and animal studies, manufacturing procedures, formulation
details, and shelf life.
 This collection of information makes up the "regulatory
submission" that is provided for review to the appropriate
regulatory authorities like the U.S. Food And Drug
Administration (FDA) so they can then grant the sponsor
approval to market the drug, device or treatment.
Dr. Eman Mortada

New Drug Application (NDA)
 By law, the FDA has 60 days to decide
if there is enough information to
continue with the NDA review.
 By law, the FDA is required to make a
final decision within 180 days.
 In practice this timeframe often is
lengthened (considerably) by mutual
agreement.

Thalidomide:
 German pharmaceutical company Grünenthal.
 Sold from 1957 to 1961 (40 different brands) in almost
50 countries.
 To pregnant women, as an antiemetic to combat morning
sickness and as an aid to help them sleep.
 Inadequate tests were performed to assess the drug's
safety, with catastrophic results for the children of
women who had taken thalidomide during their
pregnancies.
 Approximately 10,000 children (1956-1962) were born
with severe malformations, including Phocomelia
(presents at birth very short or absent long bones and
flipper-like appearance of hands and sometimes feet).
Why so strict?

5- Phase IV
✓ Starts immediately after marketing
✓ Phase four studies are frequently observational
✓ Report all ADRs (Adverse Drug Reactions)
✓ Helps to detect
 rare ADRs
 Drug interactions
 Also new uses for drugs [Sometimes called Phase V]
➢ Post marketing Surveillance by Practicing Clinicians
Pharmacovigilance: the science of collecting, monitoring,
researching, assessing and evaluating information from healthcare
providers and patients on the adverse effects of medicines, biological
products, herbals and traditional medicines Dr. Eman Mortada

Summary of phases
Summary of phases
Dr. Eman Mortada

Timeline of Clinical Trials
A typical timetable from test tube to patient
 R&D and pre-clinical 5 years
 Phase 1 6 months
 Phase 2 2.0 years
 Phase 3 5 years
 NDA evaluation ongoing
 Total 12.5 years
Dr. Eman Mortada

Intervention Trials
 Gold standard for evaluating
efficacy of therapeutic or
preventive measures.
 Provides strongest evidence for
causality.
 Reduces influence of other
determinants of exposure and
outcome (confounding) due to
randomization.
 Expensive, time-consuming.
 Loss-to-follow up of patients
and non-compliance might
constitute major biases
 Often based on volunteer
samples, results may not be
generalizable to the wider
population
 Ethical considerations
(equipoise necessary) –
believe new treatment is at
least as good as old treatment
or placebo.
Advantages Disadvantages
Dr. Eman Mortada

✓The principle of equipoise, provides the
ethical basis for medical research that
involves assigning patients to different
treatment arms of a clinical trial.
✓Clinically, we define equipoise as a
lack of consensus within the expert
clinical community on the preferred
therapy. = equal ignorance of certainity
Clinical equipoise

Dr. Eman Mortada

Types of Clinical Trials
Dr. Eman Mortada

Depending on:
Community
trials
The community is
the unit of study
Field
trials
Healthy people are
the unit of study
Clinical
trials
Patients are the
unit of study
Types of Experimental Studies
Unit of Study
Dr. Eman Mortada

1- Community trials:
Intervention directed at entire community :
 Start by determining eligible communities and their willingness to
participate.
 Communities are randomized into two groups
 Collect baseline measures of the problem to be addressed in the
intervention and control communities.
 The experimental group (will take the new vaccine) and the the
control group (will not take the vaccine).
 The participants will be followed to compare the level of
occurrence of the disease in both groups.
 Therefore, these groups should be similar as much as possible in all
aspects except the treatment /intervention received.
Dr. Eman Mortada

Examples of community-level interventions
 Immunization campaigns
 Screening programmes delivered to residents of a geographic area
 Mass educational programs
 Health promotion programmes delivered to towns, schools
 Services provided to primary care practice populations
 Nutritional, environmental sanitation interventions:
 dietary supplements
Dr. Eman Mortada

e.g.: Vitamin A Community Trial
 450 Sumatran villages with high childhood mortality
rates
 Exposure = Vitamin A supplementation program vs. no
intervention
 Random allocation of intervention: 229 treatment
villages, 221 control villages
1
Childhood mortality rate in exposed village
53
4.9 per 1000
10,919
R = =
0
Childhood mortality rate in control villages
75
7.3 per 1000
10,231
R = =
Dr. Eman Mortada

Limitations of Community Trials
 Random allocation of communities is not practical
 Only a small number of communities can be included
 Other methods are needed to ensure any difference
found can be attributed to the intervention rather than
to any inherent differences between the communities
studied
Dr. Eman Mortada

Field trial Clinical trial
In healthy population On patients
Often prophylactic Often therapeutic (including
prevention of sequelae)
For primary prevention For secondary and tertiary
prevention
2- Field trials
❑ Involve people who are disease-free but presumed to be at risk
❑ Data collection – “in the field” in the general population
Dr. Eman Mortada

Dr. Eman Mortada
Real examples: CATCH -Coordinated Approach To Child Health
(formerly known as the Child and Adolescent Trial for
Cardiovascular Health)
The largest school-based field trial ever sponsored by the National
Institutes of Health. Designed to prevent sedentary behavior, poor
dietary choices, and tobacco use through changes at the
elementary school level
The trial demonstrated positive changes in the school food service
and physical education program, as well as in students'
cardiovascular health behaviors.
Examples of field trial
Go to the readings for details

Caries Fluoride Study
Dr. Eman Mortada
 This was a controlled trial conducted to determine
if increasing fluoride levels in drinking water
would reduce children's dental caries. Two
experimental units, the towns of Newburgh and
Kingston in New York State, were assigned to a
treatment (fluoridation) arm and a control
(unfluoridation) arm, respectively.
What is the IV, DV &type of this trial
IV: fluoridation
DV: dental caries
&type of this trial: community trial

Bicycle helmet campaign
You want to test whether a public awareness campaign
about bicycle safety at elementary schools will increase
bicycle helmets use among school-aged children. To test
this intervention, you identify 12 elementary schools,
half of which will be randomly assigned to participate in
a school-wide bicycle helmet awareness program. The
other 6 schools will serve as controls and will receive no
special intervention. Research assistants will determine
the percentage of bicyclists wearing helmets at standard
locations in neighborhoods of each of the schools before
and after the intervention.
Dr. Eman Mortada
What is the IV, DV &type of this trial
IV: bicycle helmet awareness program
DV: percentage of bicyclists wearing helmets
&type of this trial: community trial

 One of the largest trial ever conducted was the MRFIT Study
in the US
 It was a primary prevention trial to test the effect of multiple
interventions to reduce the risk of premature coronary heart
disease (CHD)
 in 12,866 men, age 35–57, with one or more of three risk
factors (hypertension, hyperlipidemia, or cigarette smoking)
without a prior history of CHD.
Dr. Eman Mortada
The Multiple Risk Factor Interventional Trial
(MRFIT)
What is the IV, DV & unit of study?

 The trial was conducted in 22 clinical centers in the United
States, screening 356,222 men for the desired study
population.
 Six thousand four hundred and twenty eight participants were
assigned to the intervention group, and 6,438 were assigned to
the usual care group. Active follow-up was obtained for
6 years, and more than 25 years of surveillance has occurred.
Dr. Eman Mortada
IV: bicycle helmet awareness program
DV: risk of premature coronary heart disease
&type of this trial: field trial

Test new treatments,
combinations of drugs,
surgical approaches, or
radiation therapy
Find ways to prevent
diseases; include medicines,
vaccination, or lifestyle
change
Test the best way to
detect specific diseases or
health conditions
Come up with better tests or
procedures for diagnosing a
disease or health condition
Explore ways to improve the comfort
and quality of life of people with a
chronic illness (also known as
supportive care trials)
Types of Clinical Trials
Based on the purpose

1. Treatment Trials
They test
 New treatments
 New combination of drugs
 New approaches to Surgery
 New Radiation therapy
Possible benefit:
Early access to new treatments
Possible risk:
Occurrence of unknown side effects
For the most part, "clinical trials" have
been concerned with evaluating
therapeutic agents, mainly drugs.
Dr. Eman Mortada

Types of Treatment Trials
Pharmaceutical (treatment, biological, synthetic).
Device (prosthesis, sensory aids).
Procedure (surgery, laser, radiological).
Behavior change (smoking cessation, dietary
modification, exercise).
Other (counseling, information provision).
Dr. Eman Mortada

2. Prevention Trials
They try to find better ways to prevent disease in
people and to prevent disease recurrence using
 Medicines
 Vaccines
 Vitamins
 Minerals
The most frequently occurring type of
preventive trials are the trials of vaccines
and chemo-prophylactic drugs.
Dr. Eman Mortada

➢ A type of preventive trial is the trial of risk factors in
which the investigator intervenes to interrupt the usual
sequence in the development of disease for those
individuals who have "risk factor" for developing the
disease.
➢ For example
the major risk factors of coronary heart disease are elevated
blood cholesterol, smoking, hypertension and sedentary
habits.
Risk Factor Trial
Dr. Eman Mortada

3. Screening Trials
 To find out the best way to detect certain diseases
or conditions
Possible benefit:
Detecting disease at an earlier stage, resulting in
improved outcomes
Possible risks:
Discomfort
Dr. Eman Mortada

Screening can be defined as:
The early detection of disease in individuals who do not show any
signs of disease (preclinical) to prevent worsening of the existing
disease.
Dr / Eman Mortada 10/25/2021
Screening is an important aspect of secondary prevention.

Benefits of screening
1. Magnitude of disease can be precisely assessed,
where pre-symptomatic cases are not missed.
.
Dr / Eman Mortada
10/25/2021

Benefits of screening
2. Early detected cases can be effectively controlled, with
better prognosis, no or minimal consequences and less
burden on health services.
Dr / Eman Mortada
Important assumption in epidemiology:
The Earlier the diagnosis the better the prognosis
10/25/2021

Common screening Tests
General medical examination ( check ups)
 Blood cholesterol for heart disease
 Fasting blood sugar for diabetes
 Blood pressure for hypertension
e.g.: Preemployment medical examination
Tuberculin test to screen for exposure to tuberculosis
Dr / Eman Mortada 10/25/2021

Cancer screening
1. Pap smear to detect potentially precancerous lesions and
prevent cervical cancer
2. Mammography and breast self examination to detect
breast cancer
3. Colonoscopy and fecal occult blood test to detect
colorectal cancer
4. One is the digital rectal examination (DRE), in which the
examiner inserts a gloved, lubricated finger into the
rectum to examine the adjoining prostate. The other is the
prostate-specific antigen (PSA) blood test, which
measures the concentration of this molecule in the blood
Dr / Eman Mortada 10/25/2021

Disadvantages of screening
Screening is not always free of risk
Dr / Eman Mortada
Not 100% accurate
test.
Detected cases may be
actually free of the disease
False positive
Test may misdiagnose
actually diseased persons
False
negative
10/25/2021

False Positives
 Stress and anxiety caused by a “False Positive”
screening result.
 Unnecessary investigation and treatment
 Monetary expense
Risk in Screening
Dr / Eman Mortada 10/25/2021
False Negatives
• A false sense of security caused by false
negatives, which may even delay final diagnosis
and delayed intervention

10/25/2021
Dr / Eman Mortada
71

4. Diagnostic Trials
 To find better tests for diagnosis of a disease
 To find better procedures for diagnosis of a
disease
Dr. Eman Mortada

5. Quality of Life Trials
 Also called Supportive care trials
 Often employed for the chronically ill patients
 They explore the ways to improve the quality of life
Dr. Eman Mortada

Examples of clinical trials
 Physicians Health Study (PHS)
 Risks and benefits of aspirin and beta carotene in the
prevention of cardiovascular disease and cancer
 Started recruitment of US male physicians in 1982
 2x2 factorial structure
 Primary endpoint: total mortality
 Secondary endpoint: myocardial infarction
Dr. Eman Mortada

❑ Approval of relevant
governing and ethical
committees is essential
❑ Clinical trials are
research studies
involving people
❑ Constitute the last
step of the research
process includes
preliminary
laboratory
research and
animal testing
Lecture Summary
❑ Used to find better
ways to prevent,
detect, and treat
disease
Dr. Eman Mortada

Recommended readings
 1. Friedman LM, Furberg CD, and DeMets DL.
Fundamentals of Clinical Trials.
4th Edition. http://tinyurl.com/n7t6bcx 2010. Chapter 1.
 2. http://en.wikipedia.org/wiki/Randomized_controlled_trialA
straightforward and useful overview of randomized controlled
trial, including details of different randomization methods
Dr. Eman Mortada

Dr / Eman Mortada

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Dr. Eman Mortada