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Randomized controlled trials. Hilde Kløvstad Tallin, 6 September 2005 . Contents. Why randomized controlled trials? Design and conduct Selection of study population Allocation of study regimes Follow-up of participants Analysis and interpretation Publication.

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randomized controlled trials

Randomized controlled trials

Hilde Kløvstad

Tallin, 6 September 2005

contents
Contents
  • Why randomized controlled trials?
  • Design and conduct
    • Selection of study population
    • Allocation of study regimes
    • Follow-up of participants
    • Analysis and interpretation
    • Publication
question design
Question design
  • We need different studies to answer different study questions
  • The study question decides what design
key questions
Key questions
  • How many are (becoming) ill? (occurence)
  • Why do some people become ill why others stay healthy? (etiology/causiality)
  • How can we determine if somebody has a spesific health condition? (diagnostics)
  • What can we do to improve the health condition of individuals/populations? (effect of measures)
  • What will happen to those who are ill? (prognosis)
  • What is it like to use the health service? (experience)
intervention study important characteristic
Intervention study –important characteristic
  • Case – control study
    • Participants enrolled on basis of disease status
  • Cohort study
    • Participants enrolled on basis of exposure status
  • RCT
    • Investigator allocates the exposure
randomized controlled trials rct
Randomized controlled trials (RCT)

”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

why rct
Why RCT?
  • ”Gold standard” in epidemiological research
  • Makes study groups comparable
    • Controls for confounding (known and unknown)
    • Prevents selection bias
intervention studies
Therapeutic

Study population

Patients with disease

Objectives

Cure patients

Diminish symptoms

Prevent recurrence of disease/risk of death

Preventive

Study Population

Population at risk

Objectives

Reduce the risk of developing disease

Intervention studies
design conduct
Design - conduct

Different phases

  • Enrollment (selection of study population)
  • Allocation of study regimes
  • Follow-up
    • Maintainence and assessment of adherence
    • High and uniform rates of ascertainment
  • Analysis and interpretation
selection of study population 1
Selection of study population 1
  • Reference (source) population
    • The population to whom the results of the trial is applicable
    • Generalizability
  • Experimental population
    • The actual group in which the trial is conducted
    • Sample size
    • Sufficient number of outcome (endpoints)
    • Possibility for accurate follow up of information during the trial
selection of study population 2
Selection of study population 2
  • Participants must be fully informed
    • Risks
    • Benefits
    • Blinding/placebo
  • Willing to participate
    • Informed consent
  • Screened for eligibility
    • Inclusion criteria
    • Exclusion criteria
population hierarchy for intervention study
Population hierarchy for intervention study

Reference population

Experimental population

Exclusion criteria

Informed consent

Excluded

Refused

Study population

Random allocation

Intervention group

Control group

Losses to follow-up

Losses to follow-up

Outcome

selection of study population 3
Selection of study population 3
  • The actual study population = selected subgroup of the experimental population
    • Generalizability
    • Volunteerism
  • Obtain baseline data and/or ascertain outcome for subjects eligible, but unwilling to participate
    • Study results generizable beyond trial group
allocation of study regimes 1
Allocation of study regimes 1
  • After eligible and willing
  • Different comparisons:
    • Another dosage of same drug
    • Another therapy or program
    • Continuation of standard medical practise
    • Placebo
    • Nohting …….
  • Allocation by randomization
allocation of study regimes 2 randomization
Allocation of study regimes 2-randomization
  • Random = governed by chance
  • Randomization = allocation of individuals to groups by chance
  • Each sampling unit has the same chance of selection
  • Makes intervention and control group comparable at the start of the investigation
  • Favourable effect on those reading the published result
allocation of study regimes 3 randomization
Allocation of study regimes 3-randomization
  • Simple randomization
    • First option
  • Stratified randomization
    • Classified into subgroups before randomization
    • Randomize within subgroups
    • (if sample size is limited)
      • blocking
  • Methods:
    • Table of random numbers
    • Computer generated randomization-list
    • Sealed envelopes
    • Telephone lists
    • ………..
allocation of study regimes 4 potential bias
Allocation of study regimes 4-potential bias
  • Knowledge on study regimes might influence the evaluation of the outcome
  • Blinding
    • Hiding information about the allocated study regimes from key participants in a trial
    • Depending on outcome of interest
    • Ethics, feasibility, compromise
allocation of study regimes 5 potential bias
Allocation of study regimes 5- potential bias
  • Placebo
    • Inert medication or prosedure, i.e
    • No effect
    • Intended to give the patient the perception they are receiving treatment
  • Single – blind
    • Observer or subject are kept ignorant about allocated study regime
  • Double blind
    • Both observer and the subject are kept ignorant about allocated study regime
follow up of participants 1 adherence
Follow-up of participants 1- adherence
  • Adherence = Health related behaviour that abides by the recommendations from the investigator
  • Possible reasons for non-adherence
    • Developing side effects
    • Forgetting to take medication
    • Withdrawing consent
    • Decide alternative treatment
    • Health issues: treatment contraindicated
  • Extent of non-adherence is related to length of study time
follow up of participants 2 adherence
Follow-up of participants 2-adherence
  • Non-adherence will decrease the statistical power to detect the true effect of the study intervention
  • Strategies to enhance adherence
    • Selection of interested/reliable study population (generelizability)
    • Frequent contact with participants
  • Monitoring adherence (difficult to measure)
    • Self report
    • Pill counts
    • Biochemical parameters
follow up of participants 3 ascertainment of outcome of interest
Follow-up of participants 3ascertainment of outcome of interest
  • Uniform ascertainment – all study groups
  • Complete follow-up of all study participants
  • Keep number of individuals lost to

follow-up an aboslute minimun

factorial design
Factorial design
  • Advantage
    • Answer two or more questions in a single trial for only a marginal increase in cost
  • Should not
    • Complicate trial operation
    • Affect eligibility reqirements
    • Cause side effects – poor adherence
    • Interaction between study regimes
early termination of a trial stopping rules
Early termination of a trial- stopping rules
  • Possible reasons for early termination/modifcation
    • Data indicates clear benefit from intervention
    • Intervention is harmful
  • Develop guidelines before trial begins
    • Statistical tests
    • Interim data
  • Interim results to be modified by independent body
analysis and interpretation
Analysis and interpretation
  • Compare baseline characteristics in study groups to assess balance
    • If imbalance, control for known confounding factors
  • Inclusion or exclusion of non-adherent participants in analysis?
    • Randomization is done on the basis of OFFERING intervention
      • analysis on the same basis
    • Non-adherence may be related to factors that also affect the risk of outcome under study
    • Failure to include all subjects allocated to one study regime will lead to biased results
  • Intention to treat analysis
    • All subjects allocated to one study regime are analyzed together
population hierarchy for intervention study26
Population hierarchy for intervention study

Reference population

Experimental population

Exclusion criteria

Informed consent

Excluded

Refused

Study population

Random allocation

Intervention group

Control group

Losses to follow-up

Losses to follow-up

Outcome

unique problemes of intervetion studies
Unique problemes of intervetion studies
  • Ethics
    • Sufficients doubts to withold from half the population
    • Sufficient believes to expose half the population
    • Requires high scientific standards
  • Feasibility
    • Widespread adaption of measures by community
    • Problems of finding sufficiently large eligeble sample size
  • Costs
    • Expensive
publication
Publication
  • Ensure a comprehensive, publically available database on RCTs
  • International Committée of Medical Journals Editors (ICMJE)
    • Registration of all clinical trials (1July, 2005)
    • Registration before enrollment of participants
    • Only registered trials will be published
  • Consort statement
    • Checklist
    • Flow chart
summary
Summary
  • Gold standard in epidemiological research
  • Makes study groups comparable
    • Random allocation
    • Sufficient sample size
  • Unique problems of ethics, feasibility and costs
  • Ensure transparancy of all trials
ad