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
 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 Descriptive studies

Observational Experimental
studies studies

Ex. Case –control

Ex. RCT
Cohort
 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 Preventive
• Study population • Study Population
– Patients with disease – Population at risk

• Objectives • Objectives
– Cure patients – Reduce the risk of
– Diminish symptoms developing disease
– Prevent recurrence of
disease/risk of death
 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
– 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 Excluded
Informed consent 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:
– 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
– ………..
 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
– 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 Excluded
Informed consent 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