Randomized

Controlled Trial
Isolated Case Reports
Case Series
Cross-Sectional study
Case-Control Study
Cohort Study
Randomized Clinical Trial
Meta-Analysis

EXAMPLE:
The role of oxygen in retrolental fibroplasia RLF among
premature infants.



Progression of Study Design:
Clinical Research
Randomized controlled trials
An epidemiological experiment in which
subjects in a population are randomly
allocated into groups, usually called study
and control groups to receive and not receive
an experimental preventive or therapetuic
procedure, maneuver, or interventition

John M.Last, 2001
Randomized Controlled Trial
A true experiment
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.

Why RCT?
Gold standard in epidemiological research

Makes study groups comparable
Controls for confounding (known and unknown)
Prevents selection bias


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ETHICS
IMPORTANT ISSUE IN CLINICAL TRIALS
ETHICAL CLEARANCE
* INSTITUTIONAL REVIEW BOARDS
* ETHICAL COMMITTEES
* ICMR GUIDELINES
* FEDERAL/STATE GUIDELINES
Ethical Considerations
Major issue for Randomized Controlled Trial
Proper information to all the study subjects
Informed consent
The trial is conducted ethically
Avoid bias in results
Sample size is adequate to give the results
What if, before the study is completed, there is
evidence that one treatment is better than the
other one
1. Clinical Trial:
Diagnostic, Therapeutic, Prophylactic, Devices,
Procedures, Regimens, Protocols
2. Preventive Trial
3. Risk Factor Trial
4. Cessation experiments
5. Trial of etiologic agents
6. Evaluation of health system

Types of Randomized Controlled Trials
Types of Randomized Controlled Trials:

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

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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
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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

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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

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5. Trials of Etiological Agents:
- To confirm or disprove an etiological
hypothesis

6. Evaluation of Health Services:
- Domiciliary treatment of PTB was as effective
as more costlier hospital or sanatorium
treatment

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MULTICENTER TRIALS
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
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.

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1. The protocol
2. Selecting reference and experimental
populations
3. Randomization
4. Intervention
5. Follow up
6. Assessment


Steps in conduct of RCT
1. The Protocol
- Rationale
- Aims and objectives, Research questions
- Design of the study: selection of patients, drugs
and doses, assessment, withdrawals, data analysis,
data discharge
- Ethics: patient consent, adverse events
- Documentation
- Procedure
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2. Selecting Reference and Experimental
Populations

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



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Participants must fulfill the following criteria:

- Must give informed consent

- Should be representative of the population

- Should be qualified or eligible for the trial



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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
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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

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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

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6. Assessment
- Positive results
- Negative results

- Biases: Subject variation, Observer bias,
Evaluation bias

- Can be corrected by blinding
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Avoidance of bias
Use of a control group
Blindness
Randomization
Consent before randomization
Control group
Placebo
Most widely accepted treatment
Most accepted prevention intervention
Usual care
Accepted means of detection
Randomization: Definition
Not a random sampling
Random allocation
Known chance receiving a treatment
Cannot predict the treatment to be given
Eliminates selection bias
Similar treatment groups
Only one factor is different
Randomization tries to ensure that ONLY ONE
factor is different between two or more
groups
Observe the consequences
Attribute Causality
Randomization
We want to assign a group of subjects to one
of two groupsTreatment A or Treatment B
How can we do this in a random manner?
Randomization
Random assignment
Flip a coin
HeadsTx A
TailsTx B
Randomization
Random assignment
Roll a six-sided dice
Even numberTx A
Odd numberTx B
Randomization
Random assignment
Table of random numbers
Computer generated list
Almost Random assignments
Random assignment
Alphabetical
Tx A = patients with last name AM
Tx B = patients with last name NZ
Telephone number/social security number
Tx A = last digit odd
Tx B = last digit even
Sequential
Tx A = morning patients
Tx B = afternoon patients
Bed number
Tx A = odd bed number
Tx B = even bed number
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BLINDING
UNBLINDED, OPEN TRIAL
SINGLE BLIND
DOUBLE BLIND
TRIPLE 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

Double-Blinded Single-Blinded