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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