# 5th lect clinical trial process

Clinical trial Process
Dr/ Eman M. Mortada
Professor
In public health and preventive medicine

1. Drawing a protocol
2. Selection of Participants
3. Randomization
4. Intervention
5. Regular Follow-up
6. Assessment and blinding
CONSORT
Lecture Outline

Steps of Conducting Trials
Design of a Randomized Controlled
Trial
Not eligible
Don’t
consent
1- Drawing up a protocol
2- Selecting participants
(reference and experimental
populations)
3- Randomization
4- Apply intervention
5- Follow-up and adherence to
protocol
6- Assessment of outcome

4
Assessment
Reference Population
Make necessary exclusions
RANDOMIZE
Experimental group Control group
Follow up
No Consent
Not Eligible
Protocol
Target Population
1
2
3
4
5 6

5
Assessment
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Follow up
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Protocol
Target Population
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2021/10/25
❑ One of the essential feature of RCT is that it is conducted under
a strict Protocol.

2021/10/25
❑ A research protocol is a detailed plan, like a roadmap. “ A
complete written description of, a research activity involving
human subjects.”
1. Drawing a
protocol

2021/10/25
❑ The protocol is the trial's 'operating manual' and ensures that
all researchers perform the trial in the same way on similar
patients and that the data is comparable across all patients.

Why is a research protocol needed for clinical
trial?
Because it involves human subjects
❑ The protocol designed to protect participants, ensures
rights and safety of the patients or who enrol for the trial
❑ Prevents bias and reduces source of errors in the study for
achieving high quality and reliable results

Functions of Clinical Trial Protocol
 Written agreement between:
➢ the investigator
➢ the participant,
➢ and the scientific community
 Legal documents for FDA and other regulatory
bodies
 To procure funding

❑ Once protocol is evolved, it should be strictly adhered to
throughout the study.
❑ Final version of protocol should be agreed upon by all
concerned before the trial begins.

How to write a protocol?
Rule of thumb: Include the right amount of
detail necessary for the reader of each section to be
able to understand exactly what is required to
conduct the study.
❑ Start with a hypothesis– must be in the form of
a statement
❑ Then turn it into a specific question
– the question must be “answerable”
– this forms the basis of the study “Objectives
❑ The type of question determines the study
design

The Protocol identifies
✓ Questions to be answered
✓ The aims and objectives
✓ Methods
❖ Criteria for the selection of study and control groups
❖ Size of the sample
❖ Procedures for allocation of subjects
❖ Treatments to be applied
Dose/dosing schedule, Route of delivery and method of preparation
❖ Standardization of working procedures
❖ Schedules
❖ Responsibilities of the parties

A. Clinical trial question
Every Clinical trial tries to answer specific scientific questions about
the tested treatment to find better ways to prevent, detect, or treat
diseases, or to improve care for people with diseases.

 In cancer research, for example, a clinical trial is designed to
show how a certain anticancer approach—for instance, a
promising drug, a new surgical procedure, a new diagnostic
test, or a possible way to prevent cancer—affects the people
who receive it.

 A research idea should be structured into a well-built
clinical research question with the following PICO
components:
 Population of interest
 Intervention to be tested
 Comparison strategy
 Outcome(s)
Stating the Question
P • Population
I • Intervention
C • Comparison
O • Outcome
For adult patients, will the use of a powered toothbrush,
compared to a manual toothbrush, result in reduction in
plaque and/or gingivitis?

A 28-year-old male presents with recurrent furunculosis
(skin boils) for past 8 months; these episodes have been
treated with drainage and several courses of antibiotics
but keep recurring. He asks if recurrences can be
prevented.
P Population/patient patients with recurrent furunculosis
I Intervention/indicator prophylactic antibiotics
C Comparator/control no treatment
O Outcome reduction in recurrence rate of
furunculosi

Form a Question
 For hospitalized patients are usual oral health
measures OR bundling more effective in reducing
the incidence of ventilator associated pneumonia?
Patient Hospitalized patients
Intervention Usual oral care
Comparison Bundling
Outcome Reduce VAP cases

B. Subject & Methods
• Target populations
• Inclusion /Exclusion
CRITEIA
• Sample size
Subject
• Research design
• Research intervention(s)
• Outcome (s) measurement
• Statistical analysis
Methods
• The type of question determines the study design
that should be used to answer the question.

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Protocol
Target Population
2

a. Selecting Reference Or Target Population
 It is the population to which the results of
the trial are applied and gets benefited
from the trial.
 It can be the whole or part of the country
 It can be any specific population like
school children, specific age groups, sex
groups or disease groups
2. Selection of Participants

Eligibility criteria
✓ In clinical trials, a set of eligibility criteria Consist of
Inclusion and/or exclusion criteria
✓ These criteria will have an impact on:
 Ability to generalize
 Participant recruitment

Participants Inclusion criteria
 Entry criteria, is intended to restrict the heterogeneity of
patients in the trial.
 Define main characteristics of target population that are
relevant to research question
 To specify who will be eligible to be included in the
study, based on demographic and clinical characteristics.
◼ Demographic characteristics
◼ E.g., adults, aged 20-69
◼ Clinical characteristics
◼ E.g., in good health

Participants Exclusion criteria
 To define who will not be eligible to be included in the study.
❑ Common exclusion criteria are atypical disease, the presence
of other diseases, an unusually poor prognosis (which may
cause patients to drop out of the assigned treatment group).
❑ Patients can refuse to participate in a trial.
Patients who refuse to participate are usually systematically
different—in socioeconomic class, severity of disease, other
health-related problems/ and other ways— from those who agree
to enter the trial.

More the exclusion criteria:
◼ More precise findings, and
lesser requirement of
sample size.
◼ More difficult to find
subjects and
generalizability will be
restricted

Eligibility Criteria
 Inclusion Criteria
Female
Age ≥ 21 years
BMI ≥ 25 kgm-2
REDUNDANT
• Exclusion Criteria
Male
Age < 21 years
BMI < 25 kgm-2

Eligibility Criteria
 Inclusion Criteria Exclusion Criteria
i. Female i. Male
ii. Age > 21 yrs ii. Age < 21
iii. BMI ≥ 25kgm-2 iii. BMI < 25
 Exclusion Criteria
i. Pregnant or breast feeding
ii. History of
…….
iii. Any other condition in the opinion of the
investigator (s) that would make the subject unsuitable for
the study

b. The Experimental or Study Population
❑ The study population is derived from the reference population, on
which the study is conducted..
 Actual participants on whom the trial will be conducted after
excluding the non- participants
Study Populations should be
1- Chosen randomly
2- Stable population (to avoid
losses)
3- Give “informed consent.”
4- Representative of the population
5- Eligible for the trial
Population At Large
Define Condition
Population With Condition
Entry Criteria
Study Population
Study Sample

Sample Size
❑ Clinical trials should have sufficient statistical power to
detect differences between groups considered to be of
clinical interest.
❑ Larger the sample size (the larger the n), the more confident
we will be in trusting the conclusion
❑ Effect of a particular intervention being studied is very
small, a large n would be needed to be certain of detecting it.
❑ Calculation of sample size-based on anticipated event rates
in study population and clinically relevant differences in
rates anticipated between two arms of trial.
❑ Therefore, calculation of sample size with provision for
adequate levels of significance and power is essential part of
planning.

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Assessment
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Follow up
No Consent
Not Eligible
Protocol
Target Population
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3. Randomization
❑ Randomization is the "heart" of a control trial.
❑ Randomization is a process by which each participant in the study
population has the same chance of being randomly assigned to
one of two or more groups e.g. Group A & Group B.

If, at the end of a clinical trial, a difference in outcomes occurs
between two treatment groups. The possible explanations for this
difference :
 the intervention exhibits a real effect;
 the outcome difference is solely due to chance
 there is a systematic difference (or bias) between the groups
due to factors other than the intervention.
Eligible
patients
Group A
Group B
Allocate Patients
Analysis
Why Randomise?
Is there a difference because:
- the treatment actually works

Patients
Less Severe
Patients
More Severe
Patients
Benefits of Randomization
❑ Randomization avoid selection bias and confounding
Allocation bias is minimized by randomization
This elimination of allocation bias will greatly enhance the validity
of the trial.

Common randomization schemes
 Complete randomization
 Block randomization
 Stratified randomization
 Cluster randomization

❑ Individuals are assigned to control and intervention groups based on a
random event
❑ The event could be a coin toss for two groups of equal size or a more
complex computer generated algorithm
1. Complete Randomization

❑ Resulting group sizes may not be equal (or in the desired ratio) because
the process is truly random
1. Complete Randomization

Random assignment
 Flip a coin
 “Heads”—Tx A
 “Tails”—Tx B
 Roll a six-sided dice
 Even number—Tx A
 Odd number—Tx B
 Table of random numbers
 Computer generated list
Allocating subjects using Randomization

 Alphabetical
 Tx A = patients with last name A–M
 Tx B = patients with last name N–Z
 Telephone number/social security number
 Tx A = last digit odd
 Tx B = last digit even
 Sequential
 Tx A = morning patients
 Tx B = afternoon patients
 Bed number
 Tx A = odd bed number
 Tx B = even bed number
Allocating subjects using Randomization

❑ Ensures that the number of subjects assigned to treatment and
control groups is balanced
2.Block Randomization

❑ Creates the potential for bias because the assignment of certain block
members is determined by the assignment of others.
2.Block Randomization

3. Stratified Randomization
❑ This is done, when the study population is heterogeneous
consisting of men, women, patients with different levels of
severity of illness and suspected to give results of varying
frequency
❑ to guarantee that there is a balance of certain characteristics
in treatment and control groups

3. Stratified Randomization
❑ Individuals are separated into subgroups (strata) based on a
predetermined feature
❑ Randomly assigned to control and intervention groups using
one of the methods mention in previous slides

Allocation Ratio’s
1. Equal Allocation
Participants have the same chance
of being assigned to trial arms
◼ Easily accommodates multiple
arm studies
◼ Generally the most efficient
design
◼ Easy to implement
2. Unequal Allocation
• Assigns more participants to
intervention
• e.g. BEST – 2:1 allocation

Pros &Cons Of stratified randomization
Pros
 + Balance important variables between arms
 + Improves power by reducing variance
Cons
 − Complicates allocation process
 − Too many strata can lead to sparse data

4. Cluster Randomization
❑ Created in an attempt to deal with issues of contamination of
outcomes (exchange of information will bias the effect of the
intervention, and so it is easier to offer all of the patients of one
hospital counseling, while those in a similar, nearby hospital
receive no counseling)

4. Cluster Randomization
❑ Individuals are placed in subgroups
❑ The entire subgroup (cluster) is randomly assigned to be part of
a control or intervention group

Why do Cluster-Randomized Trials?
❖ „Nature of the intervention (e.g., mass media campaign,
population-level interventions) „
❖ Acceptability and reduced stigma (everyone gets the same
treatment within a cluster) „
❖ Can reduce participant self-selection → maximize
generalizability „
❖ Can get data on many nested population subgroups „
Allows assessment of population-level effects (Population
Attributable Fraction)

Alternatives to Randomization
 Randomization is not always possible due to ethical or
practical considerations
 Some alternatives:
 Historical controls
 Non-randomized concurrent controls
 Sources of bias for these alternatives need to be
considered

• A new treatment used in a series of
subjects
• Outcome compared with previous
series of comparable subjects
• go back to the records of patients
with the same disease who were
treated before the new therapy
became available
• Two sources of historical control
data:
✓Literature : Subject to publication bias
✓Data base
1-Historical Control Study

Studies using historical controls
Control arm
Subjects
Treatment arm
Studies conducted during different time periods
Subjects
Then
Now

• Rapid, inexpensive, good for initial testing of new treatments
• Vulnerable to biases
Different underlying populations
Criteria for selecting patients
Patient care
Diagnostic or evaluating criteria
1-Historical Control Study

Non-randomized Trials May Be Appropriate
❑ Early studies of new and untried therapies
❑ Uncontrolled early phase studies where the standard is
relatively ineffective
❑ Investigations which cannot be done within the current
climate of controversy (no “clinical equipoise”)
❑ Truly dramatic response

Baseline measurements
 Relevant baseline data should be measured in all study
participants before the start of intervention.
 Done immediately after randomization

EBMRC Dr.Soltani EMRC
Comparison of baseline data
Chan et al. Lancet 1997
Does P>0.05
indicate
comparability of
treatment groups?

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Assessment
RANDOMIZE
Follow up
No Consent
Not Eligible
Protocol
Target Population
4

 After random allocation into arms,
 The intervention (new drug or new procedure) is
applied to the one group and placebo or old procedure to
the latter group.
# Comparison Groups in clinical trials
❑ Therapy vs. no therapy
❑ Therapy vs. placebo or sham
❑ Therapy A vs. Therapy B (conventional practice)
4. Applying Intervention

Fundamentals of the experimental Treatment
Choice of treatment:
 Must be medically justifiable
 Must be in a state of clinical equipoise
 Must be used in compatibility with health care needs of
study patients
 Must be acceptable to patients and persons administering it

Types of RCT in Surgery
Three types of RCTs are commonly described “surgical”
 Type I –comparison of medical treatments in surgical
patients – traditional clinical trials
 Type II – comparison of a surgical technique with a
medical treatment or no treatment
 Type III – comparison of two surgical techniques

Allocation concealment
 A technique used to prevent selection bias by concealing the
allocation sequence from those assigning participants to
intervention groups, until the moment of assignment.
 Allocation concealment prevents researchers from
(unconsciously or otherwise) influencing which participants are
assigned to a given intervention group.
Unclearly concealed and inadequately concealed trials, compared to
adequately concealed trials, exaggerated the estimates of an
intervention’s effectiveness by 30% to 40%, on average

X
Less Severe
Patients
More Severe
Patients

Generally done using SNOSE
 SNOSE: Sequentially numbered opaque sealed
envelope.
 Each envelope is sequentially numbered with
Group A or Group B card placed alternatively
inside the envelopes and sealed.
 Each participant is allotted group according to
card in the envelope he/she sets for his/her
sequence.

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Follow up
No Consent
Not Eligible
Protocol
Target Population
5

This implies examination of the experimental and control
groups:
 at defined intervals of time,
 in a standard manner, with equal intensity,
Both groups are similarly followed in all aspects like duration,
type of follow-up

 Routine Procedures (report forms)
➢ Interviews
➢ Examinations
➢ Laboratory Tests
 Adverse Event Detection/Reporting
 Quality Assurance

Usefulness of Follow-up visits :
Treatment
administration and
treatment adjustment
Evaluate response to
treatment
Collect information on
the outcome and other
secondary data
Assess adherence to the
assigned treatment

Loss to follow-up (Attrition)
✓ Some losses to follow-up are inevitable due to factors, such as:
 Death
 Migration
✓ During the trial subjects may deviate from the protocol for
various reasons including:
❑ Developing side effects.
❑ Forgetting to take their medication.
❑ Simply withdrawing their consent after randomization
❑ Loss of interest
So, every effort should be made to minimize the losses to follow
up and increase the compliance of the study participants.

Maintenance Of Compliance
 Frequent contacts with the
participants through phone calls, home
visits, clinic visits
 Providing calendar packs to the
participants and asking them to stick
on to calendar packs without fail.
 Giving incentives like free medical aid
in future, giving some gifts.
Compliance will lead to better validity
which in turn enables for better
generalizability

Non-compliance
 Non-compliance decreases the statistical power of the trial
which speaks about the validity (truth of the results)
 Extent of non-compliance is directly proportional to the
duration and complexity of the trial.
 Compliance is difficult when the end –points are time taking
like incidence of cancers or death

Factors that minimize compliance problems :
• Study design; the shorter the study, the more likely subjects
are to comply with the intervention;
• Simplicity of the intervention; for example, single dose drug
regimens are preferable to multiple dose regimens;
• Subject selection; people likely to follow the study protocol
(run-in period can be used);
• A truly informed subject is likely to be better complier
(provider-patient interactions are the most consistent
determinants).

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6

6. Assessment
➢ The final step is assessment of the outcome of the trial
(a) Positive results
Benefits of the
experimental measure
Reduced incidence
Reduced Severity of the
disease
(b) Negative results
Severity
Frequency of side-effects
and complications
Death

❑ Incidence of results compared rigorously and differences
are tested for significance.
❑ Data analysis may be done sequentially or at the end of
trial (more useful).
❑ Errors of assessment of outcomes may give rise to Bias.

In experimental study bias may arise
from different sources:
Bias
Subjects
observer
investigator
Selection bias
Placebo effect
Hawthorne Effect
Detection Bias
Observer Bias.
Performance bias
Attrition bias

Bias on part of participant
✓ 1- Selection bias: Systematic difference in the way the
subjects selected for the study
✓ 2- Subject variation: who may feel better if they knew they
are receiving a new form of treatment.
Hawthorne Effect– Sometimes the participants in
comparison group may exaggerate the effects/outcomes to
please the investigator
Placebo effect – Psychological relief of symptoms, not true
biological relief, is often reported
✓ 3-Attrition bias= dropout and loss to FU

Bias
✓ Performance bias
Systematic difference in the care provided to the participants
(in interview or physical examination) if clinician knows beforehand
the particular procedure.
✓ Detection Bias = Observer Bias.
Systematic difference in assessment of the outcome
Observer may subconsciously give a favorable report.
 Randomization can’t guard against these bias, nor the size of sample.
 In order to reduce these problems, a technique known as “Blinding” is
adopted.

 Blinding means Keeping people unaware of treatment
group assignment after randomization
 Masking the identity of the assigned interventions
 Blinding is done to reduce bias in outcome
✓ Minimizes subject variation
✓ Minimizes performance bias
✓ Minimizes detection bias
Blinding= Masking Treatment
hiding who got what

Classification of Randomised Trials
By blinding
 Open trials
 Single blind trials
 Double blind trails
 Triple blind trials

1. Single Blind: (subject)
 The patient is unaware of which treatment they are taking, while the
investigators are aware of whether the treatment is new, standard, or
placebo.
 Evaluate surgical interventions
 To “blind” patients, can use a placebo or sham
Often used when double blinding is impractical for reason such as
❑Need to adjust medication
❑Potential side effects
– PLACEBO:is an inactive agent made to seem identical to the active
agent in terms of appearance and mode of administration.
– SHAM: something applied (ex. Surgery)_not fully masked
➢ sham operation (anesthesia and incision)
➢ sham device such as sham acupuncture

2. Double Blind(subject and investigator )
Neither the participant nor the investigator
conducting the study knows which treatment
is being given to the participant
Should be used whenever possible
Problems With Double Blinding
❑ side effects (observable by patient) are much harder to
blind in general
❑ If treatment truly effective can be recognized by its
efficacy in patients

In triple-blinded studies, as well as the investigators and
participants, all members of the sponsor’s project team (e.g., the
project clinician, statistician, and data manager) are blinded.
Disadvantage:
Lessens the chance that the trial may stop early to favor either
treatment, and makes evaluation of results more objective.
Lessens investigator’s ability to monitor safety and efficacy.
Use:
Appropriate for studies in which the risk of adverse events due
to the new or standard treatment is low
3. Triple-blinded (subject, investigators, and
data reviewer)
Triple blinding is considered best, while
double blinding is used most.

 If the new intervention is a surgical treatment and is being compared with
tablets then the difference between the two is difficult to hide, it may be
difficult to blind the physician in a surgery or device study
4. Un-blinding (avoid masking)

 In some studies it may be impossible (or unethical) to blind
 The masking involves risk to patient
✓ a treatment may have characteristic side effects
✓ In emergencies and life threatening situations for participants,
unblinding can be done.
 Procedures for unmasking are lacking
4. Un-blinding (avoid masking)

Do Not Confuse Allocation Concealment with
Blinding
 Allocation concealment seeks to prevent selection bias,
occurs BEFORE randomisation protects assignment sequence
before and until allocation, and can always be successfully
implemented
 In contrast, blinding seeks to prevent Performance bias,
protects sequence after allocation, and cannot always be
successfully implemented. Blinding occurs AFTER
randomisation
 Complete blinding cannot be achieved without allocation
concealment

Time
Randomisation
Concealment
of allocation Blinding
Selection bias Performance bias
Allocation concealment vs blinding

Study sample
Control
Intervention
Experimental
Intervention
Allocation of subjects
Outcomes
Follow up
Selection bias
• Randomisation
• Concealment
Performance bias
• Standardisation of care
protocol
• Blinding of care providers
and patients
Detection bias
Blinding of outcome assessors
and patients
Follow up
Attrition bias
Drop-outs?
Cross-over?
• Is everyone accounted for?
Outcomes

Flow diagram of the progress through the phases of a
randomized trial

CONSORT: checklist and flow diagram

# 5th lect clinical trial process

# 5th lect clinical trial process

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