RANDOMIZED

CONTROLLED TRIAL
CONTENTS
1. Introduction
2. Background
3. Types of RCT
4. Steps in conducting RCT
5. Validity of clinical trials
6. Nonrandomized interventional study designs (quasi-
experimental designs)
7. Advantages and disadvantages of RCT
8. References

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INTRODUCTION

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“Randomized Controlled Trials are quantitative, comparative,
controlled experiments in which investigators study two or
more interventions in a series of individuals who receive them
in random order”

Stedman’s medical dictionary

▷ “Gold standard”
▷ Patients are randomly assigned
▷ Differences between the groups can be attributed only to the
treatment(s) under study
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Hierarchy of evidence

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HISTORY OF RCT

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562 BC – 1537: Pre-James Lind Era

▷ “Book of Daniel” in The Bible

▷ King Nebuchadnezzar
▷ Meat and wine group
▷ Legume and water group
▷ 10 days

One of the first times in evolution of human species that an open

uncontrolled human experiment guided a decision about public
health
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1747: James Lind and scurvy trial

▷ Surgeon on a ship
▷ High mortality of scurvy amongst the sailors

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1800: Arrival of Placebo

▷ The word placebo first appeared in medical literature in the

early 1800s.
▷ Hooper's Medical Dictionary of 1811 defined it as “an epithet
given to any medicine more to please than benefit the patient.”
▷ 1863 -United States physician Austin Flint
▷ 13 patients suffering from rheumatism with an herbal extract
which was advised instead of an established remedy

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1946 First Randomized Curative Trial - The Randomized
Controlled Trial of Streptomycin

▷ Sir A. Bradford Hill, an epidemiologist for England's Medical

Research Council
▷ The trial, published in the British Medical Journal in 1948, tested
whether streptomycin is effective in treating tuberculosis.
▷ Alternated the assignment of hospital admissions to drug versus
control

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TYPES OF RANDOMIZED
CONTROLLED TRIALS

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1)Clinical Trial

2)Preventive Trial

3)Risk Factor Trial

4)Cessation experiments

5)Trial of etiologic agents

6)Evaluation of health system

7)Community intervention trials

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1)Clinical Trial

2)Preventive Trial

3)Risk Factor Trial

4)Cessation experiments

5)Trial of etiologic agents

6)Evaluation of health system

7)Community intervention trials

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Other designs:
According to the Different Aspects of Interventions Evaluated

Efficacy and Effectiveness trials

▷ Efficacy studies -benefits and harms of an intervention under

highly controlled conditions
▷ Multiple methodologic advantages, creates high internal validity
▷ Requires substantial deviations from clinical practice
▷ Effectiveness studies -more closely approach real-world practice,
with more heterogeneous patient populations, less-standardized
treatment protocols, and delivery in routine clinical settings
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Explanatory and Pragmatic trials

▷ Explanatory trials are optimized to demonstrate the efficacy of

an intervention in an ideal patient population. The real-world
effectiveness of an intervention is often not fully appreciated
through an explanatory trial.

▷ Pragmatic trial- first proposed by Schwartz and Lellouch in

1967.In a pragmatic clinical trial researchers attempt to
understand the real-world benefit of an intervention by including
a broad patient population, imposing fewer inclusion/exclusion
criteria, and choosing clinically relevant outcome measures

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Based on hypothesis
▷ Superiority trials
▷ Non-inferiority trials
▷ Equivalence trials

According to the number of participants

▷ N-of-one trials
▷ Mega Trial
▷ Sequential trials
▷ Fixed trials

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According to level of blinding
▷ The purpose of blinding is to reduce the risk of ascertainment and
observation bias. An RCT may be blinded by "procedures that
prevent study data collector, participants, or data observers from
knowing which intervention was received".

▷ Open RCT
▷ Single-blind
▷ Double-blind design
▷ Triple-blind

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Randomized Controlled Trials Classified According to
Participants’ Exposure and Response to the Intervention

▷ Parallel design
▷ Crossover design
▷ Factorial design
▷ Cluster design

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Parallel design

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Cross over designs

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Considerations

▷ Carryover and period effects on treatment outcomes

▷ Unless both carryover and period effects are known to be
negligible, a crossover design loses its advantages
▷ Ensure negligible carryover effects
▷ Treatment sequencing and patient assignment: Random
▷ Crossover rules and timing of measurements: time-dependent
and disease-state dependent.
▷ Dropouts, faulty data, and other data problems

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Stepped wedge design

▷ In a stepped wedge design, an intervention is rolled-out

sequentially to the trial participants (either as individuals or
clusters of individuals) over a number of time periods.
▷ The order in which the different individuals or clusters receive
the intervention is determined at random
▷ By the end of the random allocation, all individuals or groups
will have received the intervention

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Cluster
▷ Groups of participants
▷ Group randomized trials,Place randomized trials
Recommended Uses
▷ Cluster RCTs have commonly been used to evaluate the
delivery of healthcare services, the effects of educational
interventions, or the effects of organizational changes
▷ One reason to use cluster RCTs is to avoid “contamination”
between those patients receiving the intervention and those
who are not. Such contamination may weaken the estimate of
treat

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Potential Issues
▷ Design and analysis - complex
▷ Data points from patients within a cluster tend to be correlated, and
this correlation must be accounted for in both study design and
analysis
▷ There are also differences in the randomization

Strengths
▷ Evaluates the real-world effectiveness
▷ It provides an alternative methodology for assessing the
effectiveness of therapies in settings where randomization at the
individual level is inappropriate or impossible.
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Limitations
▷ Complex design - requires adequate understanding,
implementation, and proper reporting by researchers.
▷ Greater number of patients
▷ In order to obtain statistical power equivalent to that of individual
randomization designs, non standard sample size approaches
must be applied
▷ Autonomous patient decision-making can be jeopardized
▷ Informed consent
▷ Cluster designs should not be used- when reliable information
through individual RCT

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Factorial design

▷ A factor is a discrete variable used to classify experimental

units. Example
▷ A factorial design is one involving two or more factors in a
single experiment.
▷ Such designs are classified by the number of levels of each
factor and the number of factors.
▷ So a 2x2 factorial will have two levels or two factors and a 2x3
factorial will have three factors each at two levels

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STEPS IN CONDUCTING A RCT

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1. Drawing up a protocol
2. Selecting reference and experimental population - Causal
inference
3. Randomization
4. Intervention
5. Follow up
6. Assessment of outcome

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Types of controls :

▷ Placebo concurrent control

▷ Dose-comparison concurrent control
▷ Active treatment concurrent control
▷ Historical control

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3. Randomization
▷ Randomization was Contributed by statistician R.A. Fisher
in agriculture in 1923.
▷ Randomized plots of crops to receive different treatments

The basic benefits of randomization include

○ Eliminates selection bias.
○ Balances arms with respect to prognostic variables (known and
unknown).
○ Forms basis for statistical tests, a basis for an assumption-free
statistical test of the equality of treatments in advance which will be
assigned.

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Randomization Scheme

▷ Simple Randomization

▷ Restricted Randomization
○ Block Randomization
○ Stratification

▷ Adaptive Randomization

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Simple randomization

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Restricted Randomization

○ Block Randomization

▷ To ensure a balance in sample size across groups over time.

▷ Blocks are small and balanced with predetermined group
assignments, which keeps the numbers of subjects in each
group similar at all times.
▷ The block size is determined by the researcher and should be a
multiple of the number of groups

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▷ After block size has been determined, all possible balanced
combinations of assignment within the block must be calculated.
▷ Blocks are then randomly chosen to determine the patients’
assignment into the groups.
▷ May be generate groups that are rarely comparable in terms of
certain covariates

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Stratified randomization

▷ Control and balance the influence of covariates.

▷ Stratified randomization is achieved by generating a separate
block for each combination of covariates, and subjects are
assigned to the appropriate block of covariates.
▷ Stratified randomization can balance the control and treatment
groups for age or other identified covariates.
▷ Although stratified randomization is a relatively simple and useful
technique, especially for smaller clinical trials, it becomes
complicated to implement if many covariates must be controlled.

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Adaptive randomization

▷ Adaptive randomization refers to any scheme in which the

probability of treatment assignment changes according to assigned
treatments of patients already in the trial

Advantages
▷ Offers better balancing than standard randomization methods.
Treatment arms are balanced with respect to predefined patient
factors as well as for the number of patients in each group.
▷ It can incorporate a larger number of stratifying factors than
stratified randomization methods
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Allocation concealment

▷ SNOSE
▷ Sequentially numbered containers
▷ Pharmacy controlled
▷ Central randomization

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4. Intervention
▷ This refers to the deliberate application or withdrawal of the
suspected causal factor as laid down in the protocol.
▷ Eg : drug, vaccine, dietary component, habit
▷ Manipulation creates an independent variable (drug, vaccine,
new procedure) whose effect is then determined by the
measurement of the final outcome, which constitutes the
dependent variable (incidence of disease, survival time,
recovery period).

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5.Follow-up

▷ Examination of groups at defined intervals of time under the

same conditions, in a standard manner, with equal intensity,
same circumstances, same time frame.
▷ Follow-up can vary from a short period to many years.
▷ Over the years, there may be loss of subjects from either group
due to a number of reasons. This is called as “attrition”.

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▷ Attrition: refers to a rate of loss of participants from the study
that differs between the intervention and control groups.

It may compromise
○ internal validity by altering the random composition of groups
○ statistical validity by reducing sample size and power or by systematically
altering the variability within samples.
○ External validity due to the potential for attrition to limit the generalizability
of results to only those who are retained in a study.

▷ Reasons:
○ Death
○ Migration
○ Loss of interest

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6. Assessment

The final step in the outcome of the trial is in terms of:

a. Positive results
b. Negative results
c. Bias- “any systematic error in the design, conduct or analysis
of a study that results in a mistaken estimate of an
exposure’s effect on the risk of disease”

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ANALYSIS OF THE DATA

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Intention to treat analysis

▷ Basic Principle - “As randomized, so analyzed”

▷ Includes all randomized patients in the groups to which they were
randomly assigned, regardless of their adherence with the entry
criteria, regardless of the treatment they actually, and regardless
of subsequent withdrawal from treatment or deviation from the
protocol…..(Lloyd) Fisher et al., 1990.
▷ Addresses the question of pragmatic hypothesis– the
effectiveness of therapy

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Per protocol analysis

▷ The opposite end of the spectrum from ITT analysis includes

in the analysis only those cases who completed treatment.
▷ Its results represent the best case treatment results that
could be achieved if the study sample were retained and
remained compliant with treatment.
▷ Should not be used alone/main analysis

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Subgroup analysis

▷ Planned subgroup analyses.

▷ Exploratory subgroup analyses.

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VALIDITY OF CLINICAL TRIALS

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Internal validity

▷ High internal validity means that the differences observed

between groups are related to the intervention tested in the
trial.
▷ The two main threats to internal validity are bias and random
error
▷ Although bias can be voluntarily reduced by appropriate study
design and good clinical practice, the chance of random error
remains due to the intrinsic variability of the measured data by
pure chance.

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External validity

▷ External validity describes the extent to which the results of an

RCT can be generalized into clinical practice and the general
population.
▷ It is worth noting that internal validity of a study is the prerequisite
of its external validity since incorrect data due to missing internal
validity can, per se, not be applied to the general population

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NON RANDOMIZED
INTERVENTIONAL STUDY
DESIGNS (QUASI-EXPERIMENTAL
DESIGNS)

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▷ Nonequivalent Groups Design – similar to RCT

▷ Pretest-Posttest Design - the dependent variable is

measured once before the treatment is implemented and
once after it is implemented

▷ Interrupted time series study - uses observations at

multiple time points before and after an intervention (the
‘interruption’). The design attempts to detect whether the
intervention has had an effect significantly greater than
any underlying trend over time.
▷ . 57
ADVANTAGES AND
DISADVANTAGES OF RCT

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Advantages

▷ Comparative:
○ One treatment is directly compared to another to establish
superiority

▷ Minimises bias:
○ Randomisation - allocation bias and selection bias
○ Blinding - performance bias
○ Double-blinding - assessment bias
○ Allocation concealment - performance and assessment bias
○ Prospective design - recall error

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▷ Statistical reliability
▷ Minimises confounding factors:

○ minimises confounding due to unequal distribution of

prognostic factors
○ makes groups comparable according both known and
unknown factors
○ Blocked randomisation makes groups comparable
within known confounding factors

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Disadvantages
▷ Logistics:
○ Power calculation - vast samples size
○ Validity requires multiple sites
○ Long trial run time may result in the loss of relevance as
practice may have moved on by the time the trial is
published
▷ Statistics
○ A disadvantage of block randomization is that the allocation
of participants may be predictable and result in selection
bias when the study groups are unmasked

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▷ Applicability
○ Efficacy and effectiveness
○ Results may not always mimic real life treatment situation
(e.g. inclusion / exclusion criteria; highly controlled setting)

▷ Ethical limitations
○ Randomization requires clinical equipoise

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 REFERENCES
▷ Park K. Park's textbook of preventive and social medicine.
▷ Fletcher RH, Fletcher SW, Fletcher GS. Clinical epidemiology: the
essentials. Lippincott Williams & Wilkins; 2012
▷ Bhatt A. Evolution of clinical research: a history before and beyond James
Lind. Perspectives in clinical research. 2010 Jan;1(1):6
▷ Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy
trials. Clinical and translational gastroenterology. 2014 Jan;5(1):45.
▷ Wasan AD. Efficacy vs effectiveness and explanatory vs pragmatic: where
is the balance point in pain medicine research?.

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▷ Witt CM. Efficacy, effectiveness, pragmatic trials–guidance on terminology
and the advantages of pragmatic trials. Complementary Medicine Research.
2009;16(5):292-4.
▷ Suresh KP. An overview of randomization techniques: an unbiased
assessment of outcome in clinical research. Journal of human reproductive
sciences. 2011 Jan;4(1):8.
▷ Machin D, Fayers PM. Randomized clinical trials: design, practice and
reporting. John Wiley & Sons; 2010 May 20.
▷ US Food and Drug Administration. CFR-code of federal regulations title 21.
Current good manufacturing practice for finished pharmaceuticals Part.
2017;211.
▷ Schulz KF, Grimes DA. Allocation concealment in randomised trials:
defending against deciphering. The Lancet. 2002 Feb 16;359(9306):614-8.
▷ Nardini C. The ethics of clinical trials. cancermedicalscience. 2014;8.
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▷ Spieth PM, Kubasch AS, Penzlin AI, Illigens BM, Barlinn K, Siepmann T.
Randomized controlled trials–a matter of design. Neuropsychiatric disease
and treatment. 2016;12:1341.
▷ Rothwell PM. External validity of randomised controlled trials:“to whom do
the results of this trial apply?”. The Lancet. 2005 Jan 1;365(9453):82-93.
▷ Thorlund K, Haggstrom J, Park JJ, Mills EJ. Key design considerations for
adaptive clinical trials: a primer for clinicians. bmj. 2018 Mar 8;360:k698

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