Randomized Controlled Trials

RANDOMIZED CONTROLLED TRIAL

Objectives
• To understand the design issues related to
RCTs
• To know various steps involved in conduct of
RCTs
• To know various types of clinical trials
RANDOMIZED CONTROLLED TRIAL
• Earlier public health measures were
introduced on the basis of assumed benefits
without subjecting them to rigorous testing
Last 30 to 40 years.
• Evolution of Randomized Controlled Trials
 CLINICAL TRIALS
• Prospective study comparing the effect and
value of one of more interventions against a
control in human subjects with a given medical
condition.
• Measures causality in terms of the effect of an
intervention: If one alters the risk factor, does
one alter the occurrence of the event/injury?
•"...the most definitive tool for evaluation of the
applicability of clinical research.“
RANDOMIZED CONTROLLED TRIAL
• A true experiment, in which the researcher randomly
assigns some patients to at least one maneuver
(treatment) and other patients to a placebo, or usual
treatment.
• Key features
• the classic way to evaluate efficacy or effectiveness of
drugs (or exercise, diet, counseling)
• patients are followed over time (prospective)
• Properly done, an RCT can be used to determine cause
and effect.
• The ideal clinical trial is one that is randomized and
 double-blind. “RANDOMIZED, DOUBLE-BLIND,
CONTROLLED TRIAL” is considered as research design
par excellence and “GOLD STANDARD” amongst
research designs with which results of other studies
are often compared.
• Deviation from this standard has potential drawbacks
• A clinical trial must employ one or more intervention
 techniques. These may be :

• Prophylactic
• Diagnostic
• Therapeutic agents
• Devices
• Regimens
• Procedure
 STEPS IN CONDUCT OF RCT
• The protocol
• Selecting reference and experimental populations
• Randomization
• Intervention
• Follow up
• Assessment
CLINICAL TRIAL
 1. The Protocol 
• Aims and objectives, Research questions,
Selection criteria, Sample size, procedures up
to the evaluation of outcome
• Prevents bias and reduces the sources of
errors
• Preliminary test runs – feasibility or
operational efficiency
2. Selecting Reference and Experimental Pop
ulations
 
a. Reference or target population - population to
which the findings of the trial, if found
successful, are expected to be applicable (eg.
drugs, vaccines, etc.)
b. Experimental or study population - actual
population that participates in the
experimental study
Participants must fulfill the followi
ng criteria:
• Must give informed consent
• Should be representative of the population
• Should be qualified or eligible for the trial
 SAMPLE SIZE 
• Clinical trials should have sufficient statistical
power to detect differences between groups
considered to be of clinical interest.
• Therefore, calculation of sample size with
provision for adequate levels of significance
and power is essential part of planning
 3. Randomization 

• Heart of the control trial

• Procedure: Participants are allocated into
study and control groups
• Eliminates bias and allows comparability
• Both
groups should be alike with regards to certain
 variables that might affect the outcome of the
experiment - Best done by using table of
random numbers.
 RANDOMIZATION
 
• Randomization tends to produce study groups
comparable with respect to known as well as
unknown risk factors, removes investigator bias
in the allocation of subjects and guarantees that
statistical tests will have valid significance levels.
• 4. Manipulation / Intervention 
• Deliberate application or withdrawal or
reduction of a suspected causal factor
• It creates an independent variable
 5. Follow Up 
• Implies examination of the experimental and
control group subjects at defined intervals of
time, in a standard manner, with equal
intensity, under the same given circumstances.

• Attrition: Inevitable losses to follow up

 6. Assessment 
• Positive results
• Negative results
• Biases: Subject variation, Observer bias,
Evaluation bias
• Can be corrected by blinding
 BLINDING

• UNBLINDED, OPEN TRIAL

• SINGLE BLIND
• DOUBLE BLIND
• TRIPLE BLIND
• Some Study Designs: 

1. Concurrent Parallel Study Designs

2. Cross Over Type of Study Designs
 ETHICS

• IMPORTANT ISSUE IN CLINICAL TRIALS

• ETHICAL CLEARANCE
– INSTITUTIONAL REVIEW BOARDS
– ETHICAL COMMITTEES
– ICMR GUIDELINES
– FEDERAL/STATE GUIDELINES

“INFORMED CONSENT”
Types of Randomized Controlled T
rials:
1. Clinical Trial
• Concerned with evaluating therapeutic agent,
mainly drugs eg. Evaluation of beta-blockers in
reducing cardiovascular mortality
• Not all clinical trials are susceptible to being
blinded
2. Preventive Trials: 
Trial of primary preventive measures eg.
Vaccines
- Analysis of preventive trials must result in clear
statement about benefits to community, risk
involved and cost to health
• 3. Risk Factor Trials: 

• Investigator intervenes to interrupt the usual sequence

in the development of disease for those individuals
who have risk factor for developing the disease
• Primary prevention of CHD using clofibrate to lower
serum cholesterol
4. Cessation Experiment:

 • An attempt is made to evaluate the

termination of a habit which is considered to
be causally related to disease
• Cigarette smoking and lung cancer
5. Trials of Etiological Agents: 
• To confirm or refute an etiological hypothesis
6. Evaluation of Health Services:
• Domiciliary treatment of PTB was as effective
as more costlier hospital or sanatorium
treatment
• MULTICENTER TRIALS 

• Reasons for Multi-center Trials :

• 1. To recruit necessary number of subjects within a reasonable
time.
• May assure a more representative sample of the study or
target population
• Enables investigators with similar interest and skills to work
together on a common problem
• PHASES OF TRIALS 
• Phase I Trials:
• Initial studies to determine the metabolism and
pharmacologic actions of drugs in humans, the
side effects associated with increasing doses, and
to gain early evidence of effectiveness; may
include healthy participants and / or patients
• PHASES OF TRIALS 
• Phase II Trials:
• Controlled clinical studies conducted to evaluate
the effectiveness of the drug for a particular
indication or indications in patients with disease
or condition under study and to determine the
common short-term side effects and risks
• PHASES OF TRIALS 
• Phase III Trials:
• Expanded controlled and uncontrolled trials after
preliminary evidence suggesting effectiveness of
the drug has been obtained, and are intended to
gather additional information to evaluate the
overall benefit-risk relationship of the drug
• PHASES OF TRIALS 
• Phase IV Trials:
• Post-marketing studies to delineate additional
information including the drug’s risks,
benefits, and optimal use