randomised controlled trials
TRANSCRIPT
Randomized controlled trials
The Basics
Definition
RCT is a study in which a group of investigators studies two interventions in a series of individuals who receive them in a random order.
Intervention to be tested is called the experimental group
The other intervention is regarded as a standard of comparison or control, and the group of participants who receive it 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?
Compare groups at the end of the trial Difference is because of the Rx For this you need comparable groups Purpose of randomization is to make the
treatment groups comparable Ensures that only difference in groups is due
to trial treatments
RCT
‘the most powerful tool in modern clinical research “
Prospective Controlled unbiased
What is wrong with non-randomized studies?
Two main types of study, those with and those without concurrent control groups
Non-randomized studies II
Without concurrent controls Uncontrolled
cannot really make much of such studies if there is any variation in outcomes.
Historical controls type of patient may change, due to eligibility
criteriaenvironment changes, due to trialdata quality often quite different between
groups
Non-randomized studies III
Non-randomized concurrent controlsAlternationOdd/Even hospital no. or date of birthFirst letter of surname
Difficult to argue that one group is different from another but allocation is predictable, so bias can arise from selection of patientsso 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
But we need randomization
to be done properly to ensure similar numbers in groups To combine with stratification -in large trials-
to ensure comparability for prognostic factors
Pseudo-randomisation
Alternating record number Date of birth Geographical distribution Open list
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)
Value of randomization
it reduces the risk of serious imbalance in unknown but important factors that could influence the clinical course of the participants.
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
RCTs according to how the participants are exposed to the interventions
Parallel trials Crossover trials Trials with factorial design
Blinding
The best way to protect a trial against is by keeping the people involved in the trial unaware of the identity of the interventions for as long as possible
Blinding
Could be single Could be double Could be triple
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
Follow up
Adherence to the study protocol Patients compliance with treatment and
follow up sufficiently long and complete
Analysis of clinical trials
Analysis of clinical trials
Intension to treat analysis Per protocol analysis
Sub group analysis
Disadvantages of RCTs
expensive: time and money; volunteer bias; ethically problematic at times.
Interim Analysis
Done in large multicenter 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 AIDS trial
RCTs
The gold standard for therapeutic research
Basis for Meta-analysis
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