RANDOMIZED CONTROLLED TRIAL

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RANDOMIZED CONTROLLED TRIAL

• DR. SANJAY P. ZODPEY, MD, PhD
• JULY 9-13, 2007
• MGIMS-SEWAGRAM, IAPSM -EPIDEMIOLOGY COMMITTEE
  MAHARASHTRA CHAPTER

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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

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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

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• 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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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.

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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
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• A clinical trial must employ one or more
  intervention techniques.
• These may be
• Prophylactic
• Diagnostic
• Therapeutic agents
• Devices
• Regimens
• Procedure

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• STEPS IN CONDUCT OF RCT
• The protocol
• Selecting reference and experimental populations
• Randomization
• Intervention
• Follow up
• Assessment

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CLINICAL TRIAL
Improved
INTERVENTION GROUP
Not Improved
Population - - - - Of patients - - - - With the
- - - - Condition - - - -
SAMPLE
-- ALLOCATION
Improved
CONTROL GROUP
Not Improved
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• 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

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• 2. Selecting Reference and Experimental
  Populations
• 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.
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• 3. Randomization
• Heart of the control trial
• Procedure Participants are allocated into study
  and control groups
• Eliminates bias and allows comparability

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• 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.
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• 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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• BLINDING
• UNBLINDED, OPEN TRIAL
• SINGLE BLIND
• DOUBLE BLIND
• TRIPLE BLIND

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• Some Study Designs
• Concurrent Parallel Study Designs
• 2. Cross Over Type of Study Designs

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PERIOD 1
PERIOD 2
INTERVENTION
RANDOM ALLOCATION
SUBJECTS
CONTROL
CROSS OVER DESIGN
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ETHICS IMPORTANT ISSUE IN CLINICAL TRIALS ETHICAL
CLEARANCE INSTITUTIONAL REVIEW BOARDS ETHICAL
COMMITTEES ICMR GUIDELINES FEDERAL/STATE
GUIDELINES INFORMED CONSENT
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• 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 refute 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.
• 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

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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

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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

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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

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PHASES OF TRIALS

• Phase IV Trials
• Post-marketing studies to delineate additional
  information including the drugs risks, benefits,
  and optimal use