RANDOMIZED

CONTROLLED
TRIALS
Asha C S
First Year MDS
INTRODUCTON

◦ It is mainly in the last 35 to 40 years, determined efforts have been

made to use scientific techniques to evaluate methods of treatment
and prevention.
◦ An important advance in this field has been the development of an
assessment method, known as Randomized Controlled Trial(RCT).
◦ It is really an epidemiologic experiment.
What is a Randomized Controlled Trial?

◦ RCT is widely regarded as gold standard for evaluating health care

technologies as it allows us to be confident that a difference in
outcome can be directly attributed to a difference in the treatments
& not due to some other factor
 Definition
◦ RCTs are quantitative, comparative, controlled experiments in which
investigators study two or more interventions in a series of individuals
who receive them in random order.

◦ The RCT is one of the simplest and most powerful tools in clinical
research. (Stedman’s medical dictionary)
Why is it so highly valued?

◦ A Randomized Controlled Trial is an experiment or study

conducted in such a way that as many sources of bias as possible
are removed from the process.
◦ For new programs or new therapies, the RCT is the No.1 method
for evaluation.
 DESIGN OF RCT
Basic steps in conducting a RCT
include:

1. Drawing up a protocol
2. Selecting a reference and
experimental population
3. Randomization
4. Manipulation or intervention
5. Follow-up
6. Assessment of outcome
 1. DRAWING UP A PROTOCOL
◦ Strict protocol

◦ Specifies :
• Aims & objectives
• Questions to be answered
• Criteria of selection: Study & control groups
• Intervention to be applied
• Standardization of working procedures

◦ The protocol aims at preventing bias and to reduce the sources of error in
the study.
Preliminary test runs:

• Preliminary (pilot) studies have to be made to find out the feasibility or

operational efficiency of certain procedures or unknown effects or the
acceptability of certain policies.
• It is useful to see whether it contains flaws.
• It is important that the final version of the protocol should be agreed upon
by all concerned before the trial begins.
2. SELECTING REFERENCE AND
EXPERIMENTAL POPULATION
a) Reference or target population:
◦ It is the population to which the findings of the trial if found
successful, are expected to be applicable.
◦ It may be as broad as mankind or it may be geographically limited
or limited to persons in specific age, gender, occupational or social
groups. E.g.: population of the whole city, school children,
industrial workers etc
b) Experimental /Study Population:

• It is derived from the reference population.

• Ideally should be randomly chosen from the reference population.

• It should have the same characteristics as target population.

• It is also important to choose a stable population whose co-

operation is assured to avoid loses to follow-up.
◦ The participants should fulfill the following criteria:
• They must give informed consent.
• Should be representative of the population.
• Should be qualified or eligible for the trial. E.g.: new drug
3. RANDOMIZATION

• “Heart" of a control trial.

• It is the statistical procedure by which the participants are randomly

allocated into groups usually called the "study" and "control" groups.

• It is an attempt to eliminate "bias" and allow for comparability.

• Randomization is done only after the participant has entered the study and
it can be done by using table of random numbers.
• Every individual gets an equal chance of being allocated into either group.
• Randomization eliminates “selection bias”
• Finally, randomization guarantees that statistical tests of significance will
be valid.
CRITERIA FOR RANDOMIZATION

1. Unpredictability
• Each participant has the same chance of receiving any of the interventions.
• Allocation is carried out using a chance mechanism so that neither the
participant nor the investigator will know in advance which will be assigned.

2. Balance
• Treatment groups are of a similar size & constitution, groups are alike in all
important aspects and only differ in the intervention each group receives

3. Simplicity
• Easy for investigator/staff to implement
METHODS OF RANDOMIZATION

The common types of randomization include

(1) simple,
(2) block,
(3) stratified and
(4) unequal randomization
1. Simple Randomization

◦ This method is equivalent to tossing a coin for each subject that

enters a trial, such as Heads = Active, Tails = Placebo
◦ It is simple and easy to implement and treatment assignment is
completely unpredictable
◦ However, it can get imbalanced in treatment assignment, especially
in smaller trials.
 2. Block Randomization

◦ Simple randomization does not guarantee balance in numbers during

trial.

◦ Especially, if patient characteristics change with time, (e.g. early

patients sicker than later), early imbalances can't be corrected

◦ Block randomization is often used to fix this issue

• The basic idea of block randomization is to
divide potential patients into x blocks of
size 2n, then randomize each block such
that n patients are allocated to A and n to B.
then choose the blocks randomly

• This method ensures equal treatment

allocation within each block if the complete
block is used.
3. Stratified Randomization

◦ Stratification can balance subjects on baseline variables, tend to produce

comparable groups with regard to certain characteristics (e.g., gender, age,
race, disease severity), thus produces valid statistical tests.

◦ Large clinical trials don’t use stratification. It is unlikely to get imbalance in

subject characteristics in a large randomized trial.
4. Unequal Randomization

◦ The most statistically efficient

randomization allocates equal
numbers of patients to experimental
and control groups.

◦ However, this may not be the most

economically efficient or
ethically/practically feasible.
4. MANIPULATION/INTERVENTION

◦ This refers to the deliberate application or

withdrawal of the suspected causal factor as
laid down in the protocol. E.g. : 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).
 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”.
◦  Death  Migration  Loss of interest
 6. ASSESSMENT
a) Positive results: that is, benefits of the experimental measure such as
reduced incidence or severity of the disease, cost to the health service or
other appropriate outcome in the study and control groups.
b) Negative results: that is, adverse effects, severity and frequency of side
effects and complications, if any including death.
 BLINDING :
◦ Refers to a practice where study participants are prevented from
knowing certain information that may somehow influence them—
thereby tainting the results.

• Bias can arise from three sources:

◦ Subject variation
◦ Observer bias
◦ Evaluation Bias
• Randomization cannot guard against these sort of bias.
• To avoid the above situations, “Blinding” is done.
Blinding can be done in three ways :–
SINGLE BLIND TRIAL : The trial is so planned that the participant is
not aware whether he belongs to the study group or control group
DOUBLE BLIND TRIAL : The trial is so planned that neither the
doctor nor the participant is aware of the group allocation and the

treatment received
TRIPLE BLIND TRIAL
• The participant, the investigator

and the person analyzing the

data are all "blind".

Types Of Randomized Controlled Trials Based On
Study Designs:

◦ Concurrent parallel study design

◦ Factorial Design
◦ Cross-over type of study designs
1.Concurrent parallel study design:
• In this design, comparisons are made between two randomly assigned
groups, one group exposed to specific treatment, and the other group not
exposed.
• Patients remain in the study group or the control group for the duration
of the investigation.
2 .Factorial Design:
• refers to an experimental design that consists of two or more factors, with
each factor having multiple discrete possible values or “levels”.
• Using this design, all the possible combinations of factor levels can be
investigated in each replication
• In addition to efficiency, an advantage to this design is that one might
derive suggestions of differential effect of treatment in the presence or
absence of the other treatment.
3. Cross-over type of study designs:
• With this type of study design, each patient serves as his own
control.

• As before, the patients are randomly assigned to a study group and

control group. The study group receives the treatment under
consideration. The control group receives some alternate form of
active treatment or placebo.
• The two groups are observed over time. Then the patients in each group
are taken off their medication or placebo to allow for the elimination of the
medication from the body and for the possibility of any "carry over" effect.

• After this period of medication, the two groups are switched. Those who
received the treatment under study are changed to the control group, and
vice versa.
Split mouth design:
•Dental arches, quadrants,
sextants, or individual teeth
within patients are randomized
for treatment.
•Not applicable for systemic
therapies, only to evaluate site-
specific therapies.
Types Of RCT Based On Uses:
1. Clinical trials

2. Preventive trials

3. Risk factor trials

4. Cessation experiment

5. Trial of etiological agents

6. Evaluation of health services

7. Community intervention trials

1.CLINICAL TRIALS
(WHO definition) :

◦ Any research study that prospectively assigns human participants or

groups of humans to one or more health-related interventions to
evaluate the effects on health outcomes. Health outcomes include any
biomedical or health-related measures obtained in patients or
participants, including pharmacokinetic measures and adverse events .
PHASES OF CLINICAL TRIAL :

Traditionally, clinical trials of new therapies or devices pass through the

following phases:
1. Phase I clinical trial
2. Phase II clinical trial
3. Phase III clinical trial
4. Phase IV clinical trial
PHASE 0 ( Human microdosing studies):

• Phase 0 is a recent designation for exploratory, first-in-human trials, also

known as human microdosing studies.
• Distinctive features include administration of single subtherapeutic doses of
the study drug to a small number of subjects (10 to 15) to gather data on
agent’s Pharmacodynamics and Pharmacokinetics.
• Phase 0 trials gives no data on safety or efficacy.
PHASE I (dose ranging / dose escalating/ safety trial)

• Phase I trials are the first-stage of testing with therapeutic dose.

• Normally a small group of 20-100 healthy volunteers will be recruited.
• These trials are conducted in an inpatient clinic, where the subject can be
observed by full-time medical staff until several half-lives of the drug
have passed.
PHASE II (Safety and intervention tolerance trial):

• Phase II trials are performed on larger groups (100-300) and are designed to
assess the activity of the therapy, as well as to continue Phase I safety
assessments in a larger group of volunteers and patients.

• Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase
IIA is specifically designed to assess dosing requirements, whereas Phase IIB
is specifically designed to study efficacy.
PHASE III
• Phase III studies are randomized controlled trials on large patient groups
(300–3,000 or more) and are aimed at being the definitive assessment of the
efficacy of the new therapy.
• They are the most expensive, time-consuming and difficult trials to design
and run.
• Phase III should be designed and conducted to a high standard, with
precise quantitative results on efficacy and safety.
PHASE IV ( Post-marketing or surveillance studies):

• Phase IV trials involve the post-launch safety surveillance and ongoing

technical support of a drug.
• This is designed to detect any rare or long-term adverse effects over a
much larger patient population and timescale than was possible during the
clinical trials.
• Such adverse effects detected by Phase IV trials may result in the
withdrawal or restriction of a drug.
2. PREVENTIVE TRIALS

• To prevent or eliminate disease on an experimental basis.

• The most commonly occurring trials are that of vaccines and chemo
prophylactic drugs. Eg: Trial of whooping cough vaccines, Caries vaccine.
• Preventive trials involve larger number of subjects and long span of time
to obtain results, hence are associated with greater number of practical
problems in their organization and execution
3. RISK FACTOR TRIALS
• It is a preventive trial of risk factors in which the investigator intervenes to
interrupt the usual sequence in the development of disease for those
individuals who have “risk factor” for developing the disease; often this
involves risk factor modification.
• Can be either “single factor” or “multi factor”.
• E.g.: The WHO promoted trial on primary prevention of coronary heart
disease was largest preventive trial.
4. CESSATION EXPERIMENTS

• An attempt is made to evaluate the termination of a habit, which is

considered to be causally related to a disease.
• If it results in significant reduction of the disease, the hypothesis of cause
is strengthened. E.g. Smoking & lung cancer
5. TRIAL OF ETIOLOGICAL AGENTS

• To confirm or refute an etiological hypothesis.

• Since most diseases are fatal, disabling or unpleasant human
experiments to confirm etiological hypothesis are rarely possible.
Ex: Development of retrolental fibroplasia (RLF) in premature babies
exposed to oxygen
6. EVALUATION OF HEALTH SERVICES

• To assess the effectiveness and efficiency.

• Since resources are limited and priorities must be set for the
implementation of a large number of activities.
• Eg: TB regimen in India – which demonstrated that “domiciliary
treatment” of pulmonary tuberculosis was as effective as the more
costlier “hospital treatment”.
7. COMMUNITY INTERVENTION TRIALS (CITs)

• CITs are usually carried out in hospitals or clinics, and are usually
directed at a patient group with specific health conditions.
• However, randomized experiments are also sometimes done in the
community.
• In these types of studies, the major difference from the RCT is that the
randomization is done on communities rather than individuals
Typical examples of such trials include:

1. Evaluating the need for a service, i.e. Community

diagnosis(assessment or evaluation of needs)
2. Evaluating the design of a health service (design evaluation)
3. Evaluating the performance or efficiency of the process of delivery of
the services (efficiency or process evaluation)
CONCLUSION
◦ Randomized controlled trials are the most rigorous way of determining
whether a cause-effect relation exists between treatment and outcome and for
assessing the cost effectiveness of a treatment

◦ Randomization ensures no systematic differences between intervention

groups in factors, known and unknown, that may affect outcome

◦ Double blinding ensures that the preconceived views of subjects and

clinicians cannot systematically bias the assessment of outcomes.

• Although randomized controlled trials are powerful tools, their use is
limited by ethical and practical concerns.

• In other circumstances a randomized controlled trial may be ethical but

infeasible(difficulties with randomization and recruitment) .

• Another limiting factor is that RCTs are generally more costly and time
consuming than other studies.
 REFERENCE
◦ Park’s Textbook of Preventive And Social Medicine, K. PARK . 24th EDN

◦ Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled

trials important?. BMJ: British Medical Journal. 1998 Jan 17;316(7126):201.

◦ [Internet].Lexjansen.com.2022. Available from:

https://www.lexjansen.com/pharmasug/2006/Posters/PO06.pdf

◦ Aryal S. Randomized Controlled Trial (RCTs)- Definition, Features, Principle, Steps

[Internet]. The Biology Notes.2022 Available from:
https://thebiologynotes.com/randomized-controlled-trial-rcts/#6-assessment