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

Search for it first