Introduction to Clinical

Trials

Dr. Piyumi Wasana

 Objectives

• To define clinical trials

• To state the importance of clinical trials
• To identify different types of clinical trials
• To identify different phases of clinical trials
• To develop a clinical trial protocol
What are the Clinical Trials?

The studies performed with human subjects

to test new drugs or combination of drugs,
new approaches to surgery or radiotherapy
or procedures to improve the diagnoses of
diseases and the quality of life of the patient

Dr. James Lind

1747
20th May
 4 Questions of Clinical Trials
1. Does the study involve human
participants?

2. Are the participants prospectively

assigned to an intervention? If “Yes” to ALL
of these
questions, the
3. Is the study designed to evaluate the study is
effect of the intervention on the considered as a
participants? clinical trial

4. Is the effect that will be evaluated a

health-related biomedical or behavioral
outcome?
 Applied Basic research
Dependent variable

Safety
End points
Clinical Trial
Efficacy
Behavioral changes

Biochemical outcomes
About a problem or situation
Intervention because the person’s behaviour
is unreasonable or harmful
Importance of Clinical Trials
Evidence-Based Medicine:
Clinical trials provide robust scientific evidence regarding the safety and
efficacy of new medical interventions, allowing healthcare professionals to
make informed decisions about patient care based on empirical data.

Regulatory Approval:
Regulatory agencies such as the FDA and EMA require data from clinical trials
to evaluate the safety and efficacy of new drugs and medical devices before
approving them for use in the general population.

Improving Patient Outcomes:

By rigorously testing new treatments and therapies, clinical trials contribute
to the development of innovative medical interventions that can lead to
improved outcomes and quality of life for patients suffering from various
diseases and conditions.
Advancing Scientific Knowledge:

Clinical trials generate valuable data that contribute to a deeper understanding

of disease mechanisms, treatment approaches, and patient responses, thereby
advancing medical science and paving the way for future research and
discoveries.

Informed Decision-Making:

Participation in clinical trials empowers patients by providing access to cutting-

edge treatments and therapies, while also offering them the opportunity to
contribute to the advancement of medical science and potentially benefitting
from emerging treatments before they become widely available.
 Types of clinical trials
• Treatment
Test new approaches to treat a disease

• Prevention
What approaches can prevent disease

• Early-detection/screening
What are new ways to find hidden disease

• Diagnostic
How can new tests or procedures ID disease
 Phases of clinical trials

Phase 4
Phase 1 Phase 2 Phase 3 Studies are
• Small group of • 100-300 Patients • 300-3000 Patients conducted after the
healthy volunteers with a particular with a specific intervention has
(20 – 80) disease disease been marketed.
• First time to • To determine • To investigate the These studies are
evaluate safe efficacy and to efficacy by designed to monitor
dosage range and further evaluate the comparing the effectiveness of the
to identify side safety intervention to approved
effects other standard or intervention in the
experimental general population
interventions as and to collect
well as to monitor information about
adverse effects, and any adverse effects
to collect associated with
information that widespread use.
will allow the
intervention to be
used safely.
 According to epidemiological standpoint, there are
two major types of study designs,
• Observational

• Experimental Clinical Trail

Observational study Researchers watch what happens

naturally instead of intervening with specific treatments

Experimental study Researchers control the study by

controlling as many variables as possible
 Clinical Trails Study Designs
• Case control studies

• Cohort studies

• Case reports

• Randomized clinical trials

 Comparison of Study Design
Type of Study Design
Dimension Cross- Case-control Cohort Randomized
sectional clinical trial
Estimate A - B -
prevalence
Estimate - - A B
incidence
Prove C B- B+ A
Causality
Generalizability A B+ B+ B

Feasibility A A B C
 Randomized Clinical Trial
Target Population

Study Population

Randomized

Standard Treatment New Treatment

Disease Disease
Roadmap of a Clinical Trial

• Research Question
• Hypotheses
• Core Design
• Study Participants
• Recruitment
• Allocation
• Masking (Blinding)
• Treatment Groups
• Data
• Analytical Issues
• Interpretation of Results
 The Research Question

• Critical in the design of a trial

• Types of questions:
– Assessing efficacy of an intervention
– Assessing the effectiveness of an intervention

Efficacy trials (explanatory trials) determine whether an

intervention produces the expected result under ideal
circumstances. Effectiveness trials (pragmatic trials)
measure the degree of beneficial effect under “real world”
clinical settings.
 Types of Hypotheses
Comparative Trial (Superiority Trial)
– Objective: to demonstrate that a new therapy (n) is superior
to standard therapy (s) in terms of incident outcome (I)
HO: In = Is
HA: In < Is (one tailed) or HA: In ≠ Is (two tailed) at some
minimally detectable Δ judged to have clinical significance

Equivalence (non-inferiority trial)

– Objective: to demonstrate that a new therapy (n) is no worse
than standard therapy (s) in terms of incident outcome (I)
HO: In > Is
HA: In = Is at some Δ, the maximum tolerable difference
considered to be clinically acceptable
Basic Types of Study Design
Study participants
 Enrollment Criteria

• Inclusion Criteria
– characteristics of accessible population
• Exclusion Criteria
– considerations related to:
adherence to therapy
follow-up
safety
ethics
 Common Enrollment Criteria

• General mailings • Screenings

– Licensed drivers – Worksite
– Voters – Community
– Employee paychecks • Physician Referral
• Targeted mailings • Medical Record Review
– HMO enrollees • Internet / WWW
– AARP members – Clinical trial registries
• Mass media – Banner ads
– Radio – Social networks
– TV ads
– Newspapers
– Posters/flyers
 Comments on Recruitment
• Recruitment begins with design

• Response rate is always lower than expected

• Required resources are more than expected

• Dedicated personnel are necessary

• Recruitment period is often longer than expected

• Implement several strategies to identify best source

• Prepare back-up strategies

 Allocation
• Random
 Simple - The subjects are randomly allocated to one of intervention group
based on a constant probability
 Stratified - The subjects are defined based on certain levels, which are
covariates
 Blocked- The subjects having similar characteristics are classified into
blocks
• Non-Random
 Haphazard
 Systematic

Why Randomized Trials?

• To eliminate selection BIAS

• To reduce/avoid CONFOUNDING from known and,
more importantly, unknown confounders
 Blinding (masking)
Single Blind
– Observers (persons who collect outcome variable) do not
know treatment assignment

Double Blind
– Study participants AND observers do not know treatment
assignments

Triple Blind
– Data interpreters, study participants, and observers do not
know treatment assignments
 Single Double Triple
masked masked masked

Outcome
Assessor(s) × × ×

Participant
× ×

Data
Interpreter ×
 Selection of Groups
• Active Treatment Group

• Comparison Group
– Placebo (no active therapy)

– Usual care (referral back to personal MD)

– Active control group (provision of standard therapy)

 Data
• Baseline data
– Determine eligibility
– Describe study participants
– Define subgroups
– Address confounding
• Measures of Adherence
• Outcome Variables Outcome Variables
• Principal outcome
– most important variable after
randomization code
– specified in hypothesis
– determinant of sample size
• Secondary Outcomes
– relevant to research question
 Analytical Issues
• Sample Size (Power Calculations)

• Analytical Approach (a priori)

• Intention-to-treat or per protocol

• Analysis depends on the type of outcome data

• Basic tests
- Continuous outcome variable: t-test
Examples: Blood pressure, serum cholesterol
- Dichotomous or categorical data: chi-squared,
logistic regression, cox modeling for time to event
 Interpretation of Results

• Internal Validity
– conclusions correctly describe what happened in the study

• External Validity (‘generalizability’)

– the degree to which the conclusions apply to the study
population
Why randomized clinical trials can
be difficult?
• Hard to find and recruit the right people
– Many don’t want to be “guinea pigs”

• Greater responsibility, documentation

• May take years for outcomes to develop

• People are free to do as they please

– Some assigned to treatment don’t adhere
– Some assigned to control seek treatment
– Some drop out of the trial completely
 Adherence (compliance)
• Difficult to measure
• Difficult to promote
• Must be promoted and measured, at least in efficacy
or explanatory trials
• Measurement
– self report
– pill count
– blood levels of drug
– biological changes (urine or blood)
• Promotion
– exclude poor candidates before randomization
– keep intervention simple
– respond to evidence of inadequate adherence
 How To Handle Participants Who
Don’t Adhere to Trial Assignment?
Gold standard in the analysis
• Intention-to-Treat Approach
of data in randomized clinical
trials
– Least optimistic
– Maintains initial balance from randomization
– Highlights problems from adverse effects
Imputation techniques to address the missing observations

• Complete case analysis

• Single imputation methods (last observation carried forward,
baseline observation carried forward or putting reasonable estimates)
• Estimation-equation methods
• Methods based on a statistical model
 • Per protocol Approach

– Most optimistic

– Upsets initial balance from randomization

– Downplays problems from adverse effects

• Per protocol alone Estimate the true efficacy of an

intervention

• Both intention – to –treat and per protocol Furnish

a beneficial picture of the outcome of randomized
clinical trials by means of efficacy and effectiveness
 Theoretical example

A study will design and implement a workplace mindfulness

program, enrolling employees of a company - randomizing
them to experience the program vs not. At baseline and
again in one month they will measure blood pressure,
cortisol levels, and administer a survey about stress.

1. Does the study involve human participants?

YES - Employees of the company

 Theoretical example…..

A study will design and implement a workplace mindfulness

program, enrolling employees of a company - randomizing
them to experience the program vs not. At baseline and
again in one month they will measure blood pressure,
cortisol levels, and administer a survey about stress.

2. Are the participants prospectively assigned

to an intervention?
YES - Participants are prospectively
assigned to participate in a workplace
mindfulness program.
 Theoretical example…..
A study will design and implement a workplace mindfulness
program, enrolling employees of a company - randomizing
them to experience the program vs not. At baseline and
again in one month they will measure blood pressure,
cortisol levels, and administer a survey about stress.

3. Is the study designed to evaluate the effect

of the intervention on the participants?
YES – They will measure the effect of the
program on blood pressure, cortisol
levels, and stress levels as measured by
surveys
 Theoretical example…..
A study will design and implement a workplace mindfulness
program, enrolling employees of a company - randomizing
them to experience the program vs not. At baseline and
again in one month they will measure blood pressure,
cortisol levels, and administer a survey about stress.

4. Is the effect that will be evaluated a

health-related biomedical or behavioral outcome?

YES – Blood pressure, cortisol levels, and

stress levels are health related
biomedical outcomes
Thank you