Randomized Controlled Trials

RANDOMIZED
CONTROLLED TRIALS
PRESENTED BY:
DR. NABEELA BASHA

CONTENTS
 INTRODUCTION
 STEPS IN CONDUCTING RCT
 TYPES OF RCT
 ETHICAL CONSIDERATIONS
 CONCLUSIONS
 REFERENCES
 PREVIOUS YEAR QUESTIONS

Upon People Science
INTRODUCTION
 Epidemiology is derived from the word “epidemic”

• Epidemiology is the study of the distribution and
determinants of health-related states and events in
specified populations, and the application of this study to
the control of health problems. ( John M. Last in 1988 )

CLASSIFICATION
1. Observational studies
a. Descriptive studies
b. Analytical studies
(i) Ecological
(ii) Cross-sectional
(iii) Case-control
(iv) Cohort
2. Experimental/Intervention studies
a. Randomized controlled trials
b. Field trials
c. Community trials

EXPERIMENTAL STUDIES
• In the 1920s, “Experimental epidemiology” meant the study of
epidemics among colonies of experimental animals such as
rats and mice.
• In modern usage, experimental epidemiology is often equated
with “Randomized controlled trials”.
• Experimental or intervention studies are similar in approach to
cohort studies expecting that the conditions in which study is
carried out are under the direct control of the investigator.

• Thus experimental studies involve some action, intervention or
manipulation such as deliberate application or withdrawal of
the suspected cause or changing one variable in the causative
chain in the experimental group while making no change in the
control group, and observing and comparing the outcome of
the experiment in both the groups.
• This contrasts sharply with observational studies (descriptive,
case control, cohort studies), where the epidemiologist takes
no action but only observes the natural course of events or
outcome.

AIMS
• To provide “scientific proof” of etiological or risk factors
which may permit the modification or control of those
diseases.
• To provide a method of measuring the effectiveness and
efficiency of health services for the prevention, control and
treatment of diseases and improve the health of the
community.

ADVANTAGES OF EXPERIMENTAL
RESEARCH DESIGNS
• Researcher ‘control’ over the intervention and over which
subjects receive any intervention.
• Results are ensured.
• Reliable and well-respected research design
• Individual factors can be identified.

DISADVANTAGES OF EXPERIMENTAL
RESEARCH DESIGNS
• Problems in dealing with multiple causation; isolating
individual factors may over-simplify complex issues.
• Ethical issues.
• Researcher bias and subjectivity in research design, methods
and analysis.
• Hawthorne effect upon groups being researched.

RANDOMIZED CONTROLLED TRIALS
• 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.
• RCTs: Gold Standard

Definition: (Stedman’s medical dictionary)
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.

What is this method of carrying out scientific research,
and 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.
• Basically, scientific errors of the past have taught us where we
can go wrong, drawing false conclusions from our research.
RCTs are designed to eliminate these major errors.
• For new programmes or new therapies, the RCT is the No.1
method for evaluation.

Progression of Study Design:
Clinical Research
The role of oxygen in retrolental fibroplasia RLF
among premature infants.
 First Case - Feb. 14, 1941, Dr. Clifford, Boston
 Case Series - 1941 (Silverman 1980)
 Ca-Co Study (53 RLF Children, 298 Normal Children)
 Association was observed. Still, it was postulated that poor
health of infants necessitated longer hours of oxygen. Poor
health and no oxygen use caused RLF.

 I RCT: Gallinger Muncipal Hospital, Washington, DC
 II Collaborative Multi-centred Trial
 Confirmed the role of oxygen in the etiology of Retrolental
Fibroplasia

DESIGN OF RANDOMIZED CONTROLLED
TRIAL
Select suitable population
(reference or target)
Select suitable sample
(experimental or study)
Make necessary exclusions
Those not eligible
Those who do not
wish to give consent
Randomize
Experimental Control
Manipulation & Follow-up
Assessment

1. DRAWING UP A PROTOCOL
• Strict protocol
• Aims & objectives
• Questions to be answered
• Criteria of selection: Study & control groups
• Intervention to be applied
• Standardization of working procedures
• Schedules
Strictly followed through the study

Preliminary test runs:
• Sometimes, before a protocol is completed, 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.
• Sometimes it is useful to have a short test run of the protocol
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 : treatment of anemia.

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

TYPES OF RANDOMIZATION
1. RANDOM ASSIGNMENT:
 Flip a coin
o “Heads”—Tx A
o “Tails”—Tx B
 Roll a six-sided dice
o Even number—Tx A
o Odd number—Tx B

2. BLOCK RANDOMIZATION:
• Subjects are divided into ‘blocks’ and randomization is carried
out in each blocks.
• Ex; for two treatments and a block size of four, two of every
four consecutive patients would receive the experimental
therapy and the other two would receive control therapy.
EECC,ECEC, ECCE, CCEE, CECE,……..

3. STRATIFIED RANDOMIZATION:
• It may be important to ensure that the treatment and control
groups are balanced on important prognostic factors that can
influence the study outcome (e.g., gender, ethnicity, age,
socioeconomic status).
• Before doing the trial, the investigator decides which strata are
important and how many stratification variables can be
considered given the proposed sample size.

• A separate simple or blocked randomization schedule is
developed for each stratum.

4. MANIPULATION
• 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
dependant 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
The final step in the outcome of the trial is in terms of:
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.

• Errors in assessment can lead to “Bias”.
• 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 :
• Blinding can be done in three ways –
(a) SINGLE BLIND TRIAL : The trial is so planned that the
participant is not aware whether he belongs to the study group or
control group
(B) 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

(C) TRIPLE BLIND TRIAL : This goes one step further. The
participant, the investigator and the person analyzing the data are
all "blind". Ideally, of course, triple blinding should be used; but
double blinding is the most frequently used method when a blind
trial is conducted.

TYPES OF RANDOMIZED
CONTROLLED TRIALS
BASED ON RANDOMIZATION:
1. Randomized controlled trials: where randomization is used for
allocation of products and / or subjects.
2. Non-randomized or “non-experiment” or quasi-experiment:
those departing from strict randomization for practical
purposes in such a manner that non-randomization does not
seriously affect the theoretical basis of conclusions
e.g. natural experiments, water fluoridation studies

BASED ON 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:
• Factorial design study may be more efficient than a parallel
design if there is an interest in studying more than one
intervention at a time.
• 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 length of this interval is
determined by the pharmacologic properties of the drug being
tested), the two groups are switched. Those who received the
treatment under study are changed to the control group therapy
or placebo, 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.

• It is often seen in trials that evaluate dental filling materials;
subjects would require two similar cavities on the opposite
side before entering the trial.
• The test material can then be compared in the same
environment as the control material.

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 of a Clinical Trial:
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.

EARLY TRIALS
• 1747 - James Lind study on scurvy patients
• 1796 – Edward Jenner experiment with cow pox
• 1881-1900 – Finlay and Reeds experiment to elucidate
the mosquito-borne nature of yellow fever
• 1915 – Goldberger’s classical study inducing pellagra by
diet deficient in nicotinic acid

• 1945 – Water fluoridation study
• 1953 – first Randomized Controlled Trial on tuberculosis
patients

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.
• Phase 0 trials gives no data on safety or efficacy.
• 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 I (dose ranging / dose escalating/ safety trial)
• Phase I trials are the first-stage of testing in human subjects.
• 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.

MULTICENTER TRIALS
• A Multicenter research trial is a clinical trial conducted at
more than one medical centre or clinic.
• Reasons for Multi-center Trials :
1. To recruit necessary number of subjects within a reasonable
time.
2. May assure a more representative sample of the study or
target population
3. Enables investigators with similar interest and skills to work
together on a common problem

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.

• Communities selected for entry to the study have to be similar
as much as is possible, especially since only a small number of
communities will be entered.
• Very often, blinding is not possible in these types of studies,
and contamination and co-interventions become serious
problems.
• Contamination occurs when individuals from one of the
receive the intervention from the other experimental group.

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)

4. Evaluating the effectiveness and impact of the programme or
procedure (effectiveness or impact evaluation)
5. Relating the outcome to the input and constraints of the
programme (system evaluation) including cost-benefit
analysis.

OTHER TRIAL DESIGNS:
 Efficacy and Effectiveness trials:
• An efficacy trial answers the question: "Does this intervention
work under optimal conditions?" An effectiveness trial
answers the question: "Does this intervention work under
usual conditions?"
• Efficacy trials are sometimes called explanatory trials, whereas
effectiveness trials are also known as pragmatic trials.

 Explanatory and Pragmatic trials:
• Explanatory trials: main purpose is to provide biological
information ( about the way the drug acts and the way body
reacts to them).
• Pragmatic trials: which aims to test procedures under the
condition in which they would be applied in practice.

 Equivalency and Non – inferiority trials:
• Equivalence trial: A randomized clinical trial in which two
distinct agents are compared head-to-head against each other,
and sometimes, but not always, against an inert agent (a
placebo) as well. If two agents work equally well, the
treatment that is less expensive, better tolerated, or more easily
administered, may be preferable to use.
• Non – inferiority trial: A clinical trial that shows that a new
treatment is as good as the standard treatment.

QUALITY ASSESSMENT OF RCT
• Various approaches used:
 Checklist approach
 Quality scoring system approach
• Quality scores are complicated and tend to vary depending on
the instrument used –so, not encouraged

QUALITY SCORE APPROACH
Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled
Clin Trials1996;17:1-12. URL: http://www.bmjpg.com/rct/chapter4.html
59

INITIATIVE TO IMPROVE QUALITY OF
REPORTING TRIALS
• The Consolidated Standards of Reporting Trials (CONSORT)
has become the gold standard for reporting the results of
RCTs.
• CONSORT encompasses various initiatives developed by the
CONSORT Group to alleviate the problems arising from
inadequate reporting of randomized controlled trials.

• The main product of CONSORT is the CONSORT Statement,
which is an evidence-based, minimum set of recommendations
for reporting randomized trials. It offers a standard way for
authors to prepare reports of trial findings, facilitating their
complete and transparent reporting, and aiding their critical
appraisal and interpretation.

• The CONSORT Statement comprises a 25-item checklist and a
flow diagram. The checklist items focus on reporting how the
trial was designed, analyzed, and interpreted; the flow diagram
displays the progress of all participants through the trial.

CONSORT: checklist and flow diagram

ETHICAL ISSUES IN CLINICAL
TRIALS
Clinical trials should follow 3 principles:
• Beneficence: which require that good should result, harm
should be avoided, or that benefits should justify the expected
risk or harm
• Respect for rights: including the free choice of the subject and
protection for those diminished autonomy
• Justice: which require an equal distribution of burden and
benefits

CLINICAL EQUIPOISE (Freedman 1987):
There must be uncertainty as to the usefulness of the intervention
among those knowledgeable about the intervention.
Individual investigators or doctors may have personal beliefs about
the benefits of a new intervention. Those beliefs may prevent those
investigators from participating in or entering into a clinical trial.

INFORMED CONSENT:
• Informed consent of all study participants is essential.
The nature of informed consent may differ in different countries
and cultures, but the concept of individual choice to join or not
join a trial must be universal (Nuremberg Code 1949; World
Medical Association 2000 etc).

INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE
• Safeguards the rights, safety, and well-being of all trial
subjects.
• Composition:
• Should include:
at least five members
at least one member whose primary area of interest is in
non-scientific area
at least one member who is independent of the
institution/trial site

• Documents which should be submitted to a IRB/IEC:
 Trial protocol with amendments
 Written informed consent form
 Subject recruitment procedure
 Written information provided to the subjects
 Investigator’s brochure
 Available safety information
 Information about payments and compensation

CONCLUSIONS
• “Gold standard” of research designs
• Individual patients are randomly allocated to receive the
experimental treatment (intervention group) or the standard
treatment (control group)
• Maximizes the potential for attribution
• Good internal validity
• May lack generalisability due to highly selected participants
• Can be costly to set up and conduct, ethical issues.

REFERENCES
• Park’s Textbook of Preventive And Social Medicine, K.
PARK . 23rd EDN
• Oxford Textbook of Public Health Vol 2. – The Methods of
Public Health. Fifth Edn. Detels, Beaglehole, Lansang,
Gulliford.
• Essentials of Public Health Dentistry (Community Dentistry),
Soben Peter. 5th EDN
• Essentials of Dental Public Health. Daly, Batchelor, Treasure,
Watt. 2nd EDN

• http://annals.org/article.aspx?articleid=745807
• http://www.consort-statement.org/consort-statement/flow-
diagram
• http://www.ebbp.org/course_outlines/randomized_controlled_t
rials/
• http://medical-
dictionary.thefreedictionary.com/equivalence+trial

PREVIOUS YEAR QUESTIONS
• How will you assess the quality of a randomized controlled
trial. (20 marks) (RGUHS SEPTEMBER-2005)
• Clinical trials. (10 marks) (M.D.S Degree examination, 2000)
• Double blind trials. (10 marks) ( M.D.S.Degree examination,
1995)

Randomized Controlled Trials

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