RANDOMIZED CONTROL TRIALS

Kinza WaqarAssisitant Clinical Research AssociateShifa Clinical research Center (SCRC)

CONTENTS:What are RCTs?

General Principals of RCTs

Randomization: The strength of RCTs

Allocation concealment

Bias in randomization

Blinding

Inclusion and exclusion criteria

Baseline data

Intent to treat

Types of RCTs

Ethics of RCTs

Clinical equipoise

Reporting of RCTs

PICK A SHAPE!

Choose a shape, anyone you like.

Wait till the next 6 slides to find out the purpose.

WHAT IS RCT Randomized control trial is a study in which people are allocated at random to receive one of several clinical interventions.

(Jadad AR, 1980) Intervention = Any maneuver that improves health status. Can be:a. Diagnostic testb. Treatmentc. Prevention strategyd. Intervention procedure

(DeVore GR,1994)

RANDOMIZATION:

All participants should have same chance of being assigned to a particular study group.

The allocation, therefore, is not determined by the investigators, the clinicians, or the study participants

If randomization is done properly, it reduces the risk of a serious imbalance

(Altman DG, 1991)

ALLOCATION CONCEALMENT To prevent selection bias.

Allocation concealment refers to the technique used to implement the sequence, not to generate it

Methods:

1. SNOSE sequentially numbered, opaque, sealed envelopes

2.pharmacy controlled numbered or coded containers

3. central randomization— eg, by telephone to a trials office—or other method whose description contained elements convincing of concealment—eg, a secure computer-assisted method

BIAS IN RCT

In statistics it means a tendency of an estimate to deviate in one direction from a true value.

Why does it matter: true outcomes are unknown. Bias should be eliminated in concluding research results

BIAS IN RCT

Types: Selection bias: if some potentially eligible individuals are selectively excluded from the study

Ascertainment bias: occurs when the results of a trial are distorted by knowledge of which intervention each participant is receiving.

IMPORTANT SOURCES OF BIAS Bias during the planning phase of an RCT

oChoice-of-question bias: hidden agenda

oRegulation bias: IRB bias or the Bureaucracy bias.

oWrong design bias: wrong research design can produce misleading answers.

oPopulation choice bias: gender bias, age bias, literacy bias

Bias During reporting:

oSelective reporting bias

oFraud bias

opublication bias

oTime lag bias

(Jadad AR, Rennie D., 1998)

BLINDING

The purpose of blinding is to reduce the risk of ascertainment and observation bias

ParticipantLess likely to :-leave trial without providing outcome data, leading to lost to follow-up-biased psychological or physical responses to intervention-to seek additional adjunct interventionsMore likely to:-comply with trial regimens

Trial Investigator

Less likely to: -transfer their inclinations or attitudes to participants-differentially administer co-interventions-differentially adjust dose-differentially withdraw participants-encourage or discourage participants to continue trial

Assessors

Less likely to: -have biases affect their outcome assessments, especially with subjective outcomes of interest

(Kenneth F Schulz, David A Grimes, 2002)

WHAT SHAPE YOU CHOSE?

c Types of RCTs c Types of RCTsTreatment group

Control group

Square Triangle = Placebo

Circle

It was :RandomizedUnbiasedSingle – blinded/double blinded

TYPES OF RCT:

Different Aspects of Interventions Evaluated

Explanatory and pragmatic trials: Does it work, to what extent.

Efficacy or effectiveness trial: everyday vs. ideal conditions

Phase 1, 2, 3 and 4 trials

Phase 1:Healthy volunteers

Phase 2:Focus on efficacyStill Evaluating safety

Phase 3:Effectiveness trialsMostly RCTs

Phase 4:Post marketingMonitor possible adverse events

TYPES OF RCT: According to Participants’ Exposure and Response to the Intervention

Parallel design: each group of participants is exposed to only one of the study interventions

Crossover design: each of the participants is given all of the study interventions in successive periods.

Factorial design: when two or more experimental interventions are not only evaluated separately but also in combination and against a control.

TYPES OF RCT:

According to the Number of Participants:

N-of-one trials: with only one participant

Megatrials: 1000+ patients, worldwide, multicenter

Sequential trials: Number of participants is not specified

Fixed trials: Pre-defined sample size

TYPES OF RCT:

With reference to blinding:

Open RCT: Everyone involved in trial knows

Single-blinded RCT:

Blinding of patients

Double Blinded RCT: Blinding of patients and treating physicians

Triple blinded RCT: blinding of patients, treating physicians, and study investigators

TYPES OF RCT:

According to Nonrandomized Participant Preferences

Preference trials:

These are called preference trials because they include at least one group in which the participants are allowed to choose their preferred treatment from among several options offered

(Till JE, Sutherland HJ, Meslin EM., 1992)

ETHICS OF RCT:

It is not ethical to build a trial in which, before enrollment, evidence suggests that patients in one arm of the study are more likely to benefit from enrollment than patients in the other arm.

Randomized controlled trials can be planned only in areas of uncertainty and can be carried out only as long as the uncertainty remains

for example, the effect of a risk factor such as smoking cannot ethically be addressed with randomized controlled trials.

(Hellman S, Hellman DS., 1991)

CLINICAL EQUIPOISE

The principle of equipoise, provides the ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. 

i. A trial should begin with a null hypothesis

ii. here should exist no decisive evidence that the intervention or drug being tested will be superior to existing treatments or effective at all

INCLUSION CRITERIA

Specific inclusion criteria are used to optimize the following:

1. Recruitment, compliance and follow-up of patient

2. generalizability of results

3. expected efficacy of treatment

4. the rate of primary outcome

EXCLUSION CRITERIA

Some valid reason for excluding participants are:

1. When the risk of treatment (or placebo) is unacceptable

2. When the treatment is unlikely to be effective, disease is too mild or too severe or patient already failed the treatment.

3. When the patient has other conditions (co-morbidity).

4. When the patient is unable or unlikely to adhere to precool and follow ups

5. Other constraints; language, cognitive impairment, no phone at home etc.

BASELINE MEASUREMENTS

At baseline, collect information about:

1. Demographics

2. Contact details; to help in tracking subject during study.

Includes Name, email, address, tel/fax, contact info of friends or family

3. Major clinical characteristic and prognostic factors.

INTENT TO TREAT

Intent to Treat:

A method to correct for differential dropout rates between patients from one arm of the study and another is to analyze data by the intent to treat—that is, data are analyzed in the way patients were randomized, regardless of whether or not they received the intended intervention.

(Huwiler-Müntener K, Jüni P, Junker C, Egger M., 2002)

REPORTING OF RCTS

CONSORT (Consolidated Standards of Reporting Trials)

Standard format of reporting an RCT

Following slides show that CONSORT checklist

You can find the Consort Checklist on SCRC official website:

http://www.int.shifa.com.pk/video/web/scrc/article2/CONSORT%202010%20Checklist/