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

Randomize

Rx group 1

Eligible patients
Rx group 2

?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 changes
data 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 trialsto 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 schemes
Telephone randomization service
Pharmacy randomization
Web-based service?
Envelopes
Sealed 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
Search for it first