Randomised controlled trials : the basics
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Randomized controlled trials
The Basics
Definition
RCT is a study in which a group of investigators study an intervention in a series of individuals who receive the intervention in a random order.
Intervention to be tested is called the experimental group
The other group of participants is called the control group.
The control can be conventional practice, a placebo, or no intervention at all
Schema of a simple trial
Eligible patients
Rx group 1
Rx group 2
Randomize
Why Randomize?
We need to analyse groups at the end of the trial
To ensure that difference in groups is because of the Rx
For this you need comparable groups at the start of trial
Purpose of randomization is to make the treatment groups comparable
Value of randomization
it reduces the risk of serious imbalance in unknown but important factors that could influence the clinical course of the participants.
RCT
‘the most powerful tool in modern clinical research “– Prospective– Controlled– unbiased
What is wrong with non-randomized studies?
Two main types of studies, those with and those without concurrent control groups
Non-randomized studies II
Without concurrent controls Case series studies Historical controls
type of patient may change, due to eligibility criteria
environment changesdata quality often quite different between
groups
Non-randomized studies III
Controlled non-randomized studies Difficult to argue that one group is different from
another but allocation is predictable, so bias can arise from selection of patients
Randomization must be unpredictable
Random allocation
all participants have the same chance of being assigned to each of the study groups
the purpose is to keep both groups as similar to each as possible at the start of the trial.
Is coin tossing OK?
OK for big trials For small trials, such ‘simple randomization’
can lead to imbalance in group sizes
Example: trial with 30 patients
If 30 patients are in a trial randomized using coin tossing there is a 14% chance of 15:15 split
For 16:14 chance is 27% ‘Worse’ than 20:10 is 10% Why ‘worse’? Because imbalance leads to loss of power
We need randomization
to be done properly to ensure similar numbers in groups To combine with stratification -in large trials-
to ensure comparability
Pseudo-randomisation
Alternating record number Date of birth Geographical distribution
True randomization
Need to separate the person who generates allocation from those who assess eligibility
Third party schemesTelephone randomization servicePharmacy randomizationWeb-based service?
EnvelopesSealed envelopes (preferably opaque)
Blinding
The best way to protect a trial against bias is by keeping the people involved in the trial unaware of the identity of the interventions for as long as possible
Types of RCTs
RCTs according to whether the investigators and participants know which intervention is being assessed – Open trials – Single blind trials – Double blind trials – Triple blind trials
Blinding is difficult
Having placebo in the same shape , formula and taste is very costly, and time consuming.
The drug side effects e.g. local reaction at the site of injection would partially unblind .
Impossible if surgical and medical treatments are compared.
The need for urgent unblinding code in case of serious side effects
Other types of RCTs
RCTs according to how the participants are exposed to the interventions – Parallel trials – Crossover trials
Trials testing one variable or factorial design e.g (2 X2 X 2)
Follow up
During the trial– Adherence to the study protocol– Patients compliance with treatment
After finishing the intervention, follow up of participants should be sufficiently long and complete
Analysis of clinical trials
Analysis of clinical trials
Intension to treat analysis Per treatment analysis
Sub group analysis
Disadvantages of RCTs
expensive: time and money; volunteer bias; ethically problematic at times.
Interim Analysis
Done in large RCTs To explore the results after recruiting of half
of the participants If marked difference is recognized , then trial
should be stopped Examples: WHI trial Breech Trial
So, how to do RCT
Set up a protocol Recruit your patients Randomize (try to be blind) Follow up Analyze your data Publish
RCTs
The gold standard for therapeutic research
Basis for Meta-analysis
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