Transcript Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005 Contents • Why randomized controlled trials? • Design and conduct – – – – – Selection of study population Allocation of study.

Randomized controlled trials
Hilde Kløvstad
Tallin, 6 September 2005
Contents
• Why randomized controlled trials?
• Design and conduct
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Selection of study population
Allocation of study regimes
Follow-up of participants
Analysis and interpretation
Publication
Question
design
• We need different studies to answer
different study questions
• The study question decides what design
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)
Different study designs
Epidemiological
studies
Analytical studies
Observational
studies
Descriptive studies
Experimental
studies
Ex. Case –control
Cohort
Ex. RCT
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)
”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?
• ”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
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
• Reference (source) population
– The population to whom the results of the trial is
applicable
– Generalizability
• Experimental population
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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
• 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
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
• 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
• After eligible and willing
• Different comparisons:
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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
• 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
• 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
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………..
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
• 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
• 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
• 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
• 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
• Advantage
– Answer two or more questions in a single trial
for only a marginal increase in cost
• Should not
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Complicate trial operation
Affect eligibility reqirements
Cause side effects – poor adherence
Interaction between study regimes
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
• 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 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
• 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
• 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
• 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