Intervention studies:

Clinical Trial
Learning Objectives
1. Explain the distinguishing features of a clinical trial
(intervention study).
2. Recognize the differences between phase I, II, III, & IV
clinical trials.
3. Recognize the aim of randomization.
4. Define blinding with its types and explain its purpose .
5. Explain different types of clinical trial
6. Explain the purpose and design of community trials
7. Understand statistical measures in clinical trials
 Categories of Clinical Studies

• Studies answer one of 4 types of

questions:
Therapy (efficacy)
Harm
Diagnosis
Prognosis
Clinical Trial: Definition

A clinical trial is a prospective study

comparing the effect and value of an
intervention(s) against a placebo or
conventional treatment (control) in
human beings.
Phases of clinical trials
• Phase I: Pharmacology and toxicology
• Drug safety, not effectiveness
• Small number of healthy humans
• Phase II: Initial investigation of treatment effect
• Efficacy and safety
• Small scale of affected humans
• Phase III: Clinical evaluation of treatment
• Large scale “effectiveness” under field conditions
• Dose – response
• Side effects
• Phase IV: Post marketing Surveillance
• Monitoring long-term adverse effects (disease, death)
• Observational studies
Clinical Trials For Treatment: Objective
• To assess the efficacy (therapeutic effect under
optimum/ideal clinical trial conditions) and
effectiveness (therapeutic effect under medical
practices and marketing situations) of a new
intervention or drug
• To assess the side effects and tolerance of
patients to the new drug or intervention
• This would help establishing the role of the new
drug or intervention in clinical practice.
 General Design of Clinical Trial
Parallel Design
Intervention Outcome
PAR Study T
S R
Group No No
Intervention Outcome

PAR = Population at Risk

S = Sampling design
R = Randomize intervention
T = Elapsed time
 One armed clinical trial

Interferon A
Proportion
HCV case S Sample + HCV cleared
Adjuvant
TIME

S = Sampling design
Compare with historical data of interferon only
 General Design of Clinical Trial
Radical 5 years survival
mastectomy
+ radiotherapy Quality of life
Breast
Cancer S Sample R
Lumpectomy 5 years survival
+ Radiotherapy
+
Chemotherapy Quality of life

TIME

S = Sampling design
R = Randomize intervention
 General Design of Clinical Trial

Diet A Weight loss

Overweight
and obese S Sample R

Diet B Weight loss

TIME

S = Sampling design
R = Randomize intervention
 General Design of Clinical Trial

Proportion
Interferon A
HCV cleared

HCV case S Sample R

Interferon A
+ Proportion
Adjuvant HCV cleared

TIME

S = Sampling design
R = Randomize intervention
 Cross-over Design
Group A Group B
Population
Intervention Intervention

Sample R Washout
period
Group B Group A
Placebo Placebo

Outcome Outcome
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Statistical issues
6. Ethical considerations
Clinical Trials: Selection of Subjects

• Target population, must be defined

The intervention is intended to benefit this population
• Criteria must be explicitly stated that capture the
population at risk
Inclusion criteria – identifies the target population
Exclusion criteria – excludes people from target
population for safety reasons
Who can participate in clinical trials?
• All clinical trials have guidelines about who can
participate. Exclusion/inclusion criteria help
produce reliable results
• Criteria based on factors such as
• Age / Gender
• Type and stage of disease
• Previous treatment
• Medical conditions
• Feasibility of Enrollment
• Ease /Difficulty of Follow Up
• Some ethical considerations:
• Involvement of children (<18 years)
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Statistical issues
6. Ethical considerations
Clinical Trials: Randomization
Assignment of experimental units to either
treatment or control by a random process such that
neither investigator nor patient decides the
treatment to be assigned at the time the patient is
registered.
Clinical Trials: Randomization
Randomization will, on average,
balance the known and unknown risk
factors for the outcome under study.

Control Group 9
7
1

1 2 3
3 4 1
0

5 6 7 8

9 1 5
0 8
6
2 4

Intervention group
Key Points
• A random process should be used to generate treatment
allocations or assignments
• Every participant has an equal chance to receive either the
intervention or the control treatment
• Treatment allocations should be concealed until the time of
randomization – “Allocation Concealment” is critical to
prevent selection bias -- some refer to this as “blinded
randomization”. (It should not be confused with blinding of
treatments).
• Do not use LISTs but Closed envelopes!!!
Stratification

• A procedure in which factors known to be

associated with the response (prognostic factors)
are taken into account in the allocation process /
randomization).

• Pre-stratification refers to a stratified design;

post-stratification refers to the analysis
 Two Important Methods for
Removing Bias in Clinical Trials

1. Randomization

2. Blinding
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Statistical issues
6. Ethical considerations
Clinical Trials: Blinding

• Masking individuals participating in the

trial from the treatment assignment
• Levels of blinding
Individual

Investigators

Analyst
 Examples of Studies Where Blinding of
Treatment is Difficult / Impossible

• Surgical (e.g. device) vs. medical treatment

• Non-pharmacologic and behavioral

interventions (e.g. diet, rehabilitation)
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Statistical issues
6. Ethical considerations
 Clinical Trials: Placebo

• Placebo is an inert compound given to

subjects in a clinical trial.
• Placebo arm is a true control for an
intervention.
• Assess relative effect of intervention - relative risk
• Assess risk for adverse events
• Placebo arms are not ethical if there is an
established intervention (only with a state of
equipoise)
 RCT Endpoints (types)
• Primary endpoint (e.g. HCV patient becomes PCR free after 3
months constitutes the end of the trial, e.g. Hypertensive patient
showing systolic blood pressure ≤ 140 mmHg for three successive
months…)
• Surrogate endpoints which is "a biomarker intended to
substitute for a clinical endpoint" ( decrease in the PCR count in
HCV patients or CD4+ count for progression to AID)
• Composite endpoints where the intervention is considered a
“success” or a “failure” with any of many outcomes (death or a
second myocardial infarction attack in treatment of acute
myocardial infarction)
• Safety outcomes rate of adverse events
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Ethical considerations
6. Statistical issues
Ethical issues
• In 1964 the eighteenth World Medical Association (WMA)
meeting in Helsinki, Finland, adopted a formal code of ethics for
physicians engaged in clinical research (World Medical
Association, 1964).

• This became known as the Helsinki Declaration, which has

been revised by the WMA many times up to 2000. This
declaration is intended to be reviewed and updated periodically.
Investigators planning to do clinical trials should consult
these documents for ethical considerations.
Selected items
• Stopping rules or when to stop the trial:
• (i) if severe and unexpected side effects or complications occur, e.g.,
development of polio and death of some participants of the Salk polio
vaccine trial in 1954 or
• (ii) if the benefit from the intervention becomes evident and undeniable. A
well-known example is the early discontinuation of the trial on Sabin polio
oral vaccine after the results of the first year proved almost 100% protection.
• Standard of care protocol should be applied to all participants of
a clinical trial.
• Informed consent should be read, agreed upon and signed by
each participant. The rationale of the informed consent is to
safeguard the individual and to ensure that patients play an active
role in decisions about their treatments.
Key Elements of a Clinical Trial

1. Selection of subjects
2. Randomization: Allocation of exposure
3. Blinding
4. Data collection
5. Ethical considerations
6. Statistical issues
Clinical Trials: Statistical Issues
• Sample Size
• Determined for primary study outcome
• Must account for multiple comparisons
• Often requires statistical consultation
• Monitoring of events
• Interim analyses are performed to determine whether to stop the study
earlier than planned for.
• Sample size must be adjusted for the number of interim analyses
• Data and Safety Monitoring Board (DSMB) is an independent
committee set up specifically to monitor data throughout the duration
of the study to determine if continuation of the study is scientifically
and ethically appropriate.
• Analysis
Intent-to-treat vs. Per Protocol analysis
• Intent to treat (ITT) analysis involves ALL participants that are
enrolled in the trial regardless they completed the study or not.
• Per Protocol analysis includes only those who completed the
trial
• ITT analysis is intended to avoid various misleading artifacts that
can arise in intervention research. Those dropping from the study
may have some problems,
• ITT has usually lower efficacy than per protocol analysis
Clinical Trials: Analysis

Fundamental measure of association: Relative Risk – Absolute Risk

Reduction

How to calculate risk?

AR (absolute risk) = the number of events (good or bad) in
treated or control groups, divided by the number of people in that
group.
ARC = the AR of events in the control group.
ART = the AR of events in the treatment group.
ARR (absolute risk reduction) = ARC – ART.
RR (relative risk) = ART / ARC.
Clinical Trials: Analysis
Efficacy
Incidenceplacebo - Incidencetreatment
Efficacy =
Incidenceplacebo

Incidencetreatment
Efficacy = 1 - = 1 - Relative Risk
Incidenceplacebo
Clinical Trials: Analysis
• Survival, or failure-time, curves
• Number Needed to Treat (NNT)
1
NNT =
Incidencecontrol - Incidencetreated
 Clinical Trials: Analysis
• Survival, or failure-time, curves
• Number Needed to Treat (NNT)
1
NNT =
ARR

The Number Needed to Treat (NNT) is the number of patients you need to treat
to prevent one additional bad outcome (death, stroke, etc.). For example, if a drug
has an NNT of 5, it means you have to treat 5 people with the drug to prevent one
additional bad outcome.
NNT = 1/Absolute Risk Reduction
• First described in 1988: the number of patients that need
to be treated in order for one to benefit.
• An attractive means of summarising the results of a
clinical trial in a single figure,
• The meaning of a sentence such as ‘20 patients need to be
treated to avoid one additional death over a five-year
period’ is easily understood by both doctors and patients.
• Similar measures are reported in vaccination and screening
studies (number needed to vaccinate/screen) and their
values are derived in a similar fashion to the NNT.
 Folic acid to prevent Neural Tube Defects
ITT analysis
Group TTT NTD/All Cases/100 RR (95% CI)
Folic acid Other vitamins
A + - 2/258 5/514 0.28
B + + 3/256 1%
(0.11-0.75)
C - - 11/260 18/517
D - + 7/257 3.5%

• Incidence in TTT = 1%
• Incidence in Comparative = 3.5%
𝟑.𝟓−𝟏
• Efficacy = = (1-RR) = 71%
𝟑.𝟓
𝟏𝟎𝟎
• NNT = = 40
𝟑.𝟓−𝟏
NNH = 1/Absolute Risk Increase
• A measure of how many people need to be treated (or exposed
to a risk factor) in order for one person to have a particular
adverse effect.
• For example, March et. al showed that the antidepressant sertraline
had an NNH of 64 for suicidal thoughts when used in children
and adolescents.
• This means that for every 64 patients given sertraline, one will
experienced suicidal thoughts.
• The lower the NNH, the more risk of harm; An NNH of 1 would
mean that every patient treated is harmed.
 Community trials
• Community trials are usually preventive in nature
(sometimes termed Preventive Trials) e.g., vaccines and
chemo-prophylactic drugs.
• e.g., the oral polio vaccine in the early 1950s in USA.
• Community trial that has been conducted to evaluate the
effect of adding fluorides to the drinking water to
prevent dental caries.
• Randomization can be done but the unit of
randomization is “a cluster” or a group of people rather
than individuals, called randomized cluster trials