Randomized controlled trials

The Basics

DefinitionRCT 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 trialEligible patientsRx group 1Rx group 2Randomize

Why Randomize?We need to analyse groups at the end of the trialTo ensure that difference in groups is because of the RxFor this you need comparable groups at the start of trialPurpose of randomization is to make the treatment groups comparable

Value of randomizationit reduces the risk of serious imbalance in unknown but important factors that could influence the clinical course of the participants.

RCTthe most powerful tool in modern clinical research ProspectiveControlledunbiased

What is wrong with non-randomized studies?

Two main types of studies, those with and those without concurrent control groups

Non-randomized studies IIWithout concurrent controlsCase series studies Historical controls type of patient may change, due to eligibility criteriaenvironment changesdata quality often quite different between groups

Non-randomized studies IIIControlled non-randomized studiesDifficult to argue that one group is different from another but allocation is predictable, so bias can arise from selection of patientsRandomization 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 trialsFor small trials, such simple randomization can lead to imbalance in group sizes

Example: trial with 30 patientsIf 30 patients are in a trial randomized using coin tossing there is a 14% chance of 15:15 splitFor 16:14 chance is 27%Worse than 20:10 is 10%Why worse?Because imbalance leads to loss of power

We need randomizationto be done properlyto ensure similar numbers in groupsTo combine with stratification -in large trials- to ensure comparability

Pseudo-randomisationAlternating record numberDate of birthGeographical distribution

True randomizationNeed to separate the person who generates allocation from those who assess eligibilityThird party schemesTelephone randomization servicePharmacy randomizationWeb-based service?EnvelopesSealed envelopes (preferably opaque)

BlindingThe 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 RCTsRCTs 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 difficultHaving 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 RCTsRCTs 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 upDuring the trialAdherence to the study protocolPatients compliance with treatmentAfter finishing the intervention, follow up of participants should be sufficiently long and complete

Analysis of clinical trials

Disadvantages of RCTs expensive: time and money; volunteer bias; ethically problematic at times.

Interim AnalysisDone in large RCTsTo explore the results after recruiting of half of the participantsIf marked difference is recognized , then trial should be stoppedExamples: WHI trial Breech Trial

So, how to do RCTSet up a protocolRecruit your patientsRandomize (try to be blind)Follow upAnalyze your dataPublish

RCTs

The gold standard for therapeutic research

Basis for Meta-analysis

Search for it first