Randomized controlled trials. Aboubakr Elnashar

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Randomized Controlled Trials Prof. Aboubakr Elnashar Benha university Hospital, Egypt [email protected] ABOUBAKR ELNASHAR

Transcript of Randomized controlled trials. Aboubakr Elnashar

Page 1: Randomized controlled trials. Aboubakr Elnashar

Randomized Controlled Trials

Prof. Aboubakr ElnasharBenha university Hospital, Egypt

[email protected]

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CONTENTS

1.DEFINITION

2.ADVANTAGES AND DISADVANTAGES

3.STEPS IN CONDUCT OF RCT

4.TYPES OF RANDOMIZED CONTROLLED TRIALS

5.ETHICAL ISSUES IN CLINICAL TRIALS

6.QUALITY ASSESSMENT OF RCT

CONCLUSIONS

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1. DEFINITION

An epidemiological experiment in which

subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or

therapetuic procedure,

maneuver, or

interventition” (John M.Last, 2001)

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Randomized Controlled Trial (RCT)

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Patients are followed over time (prospective)

RCT:

evaluate effectiveness of drugs, exercise, diet, counseling, …………….

determine cause and effect.

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2. Advantages and Disadvantages

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RCT may not be possible or practical

1. Not ethical/possible to assign intervention

Cigarette smoking and lung cancer

H. pylori infection and ulcers

2. Impractically large sample size

Very low-incidence outcome

e.g., rare side effect of medication

3. Impractically long duration

Outcome requires many years to develop

e.g., development of cancer

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3. STEPS IN CONDUCT OF RCT

1. The protocol

2. Selecting reference and experimental populations

3. Randomization

4. Intervention

5. Follow up

6. Assessment of outcome

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1. The Protocol

1. Rationale

2. Aims & objectives, Questions to be answered

3. Design of the study:

1. Criteria of selection: Study & control groups

2. Intervention to be applied

3. Standardization of working procedures

4. Ethics:

patient consent, adverse events

5. Documentation

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2. Selecting Reference and Experimental Populations

a. Reference or target population

Population to which the findings of the trial are expected to be applicable (eg. drugs, vaccines, etc.)

b. Experimental or study population

It is derived from the reference population.

Ideally should be randomly chosen from the reference

population.

Sample size should be deermined:

sufficient statistical power to detect differences

between groups

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3. Randomization

Procedure:

Done only after the participant has entered the

study

Participants are allocated into study and control

groups

every individual gets an equal chance of being

allocated into either group.

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Goals of randomization

1. Equal Group Sizes for Adequate Statistical

Power

(Especially Subgroup Analyses)

2. Low selection bias

(investigator cannot predict the next subject's

group

assignment by examining which group has been

assigned the fewest subjects up to that point)

3. Low probability of confounding

(i.e., a low probability of "accidental bias"),

(i.e. a balance in covariates across groups).

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Methods

1. Random assignment

2. Table of random numbers

3. Computer generated list

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Types of randomization

1. Random (simple) assignment:

Flip a coin

o “Heads”—tx A

o “Tails”—tx B

Roll a six-sided dice

oEven number—tx A

oOdd number—tx B

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Alphabetical

Tx A = patients with last name A–M

Tx B = patients with last name N–Z

Telephone number/social security number

Tx A = last digit odd

Tx B = last digit even

Sequential

Tx A = morning patients

Tx B = afternoon patients

Bed number

Tx A = odd bed number

Tx B = even bed number

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Simple randomisation

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2. Block randomization:

Subjects are divided into ‘blocks’ and randomization is

carried out in each blocks.

Ex:

for two treatments and a block size of four, two of every four

consecutive patients would receive the experimental therapy

and the other two would receive control therapy.

EECC,ECEC, ECCE, CCEE, CECE,……..

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3. Stratified randomization:

Ensure that the treatment and control groups are balanced

on important prognostic factors that can influence the study

outcome (e.g., gender, ethnicity, age, socioeconomic status).

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Stratified randomization

• Stratify, then do block randomization

Male; 25-44 yrs ABBA BBAA BABA ABAB BAAB

Female; 45-60 yrs AABB ABBA BBAA BABA ABAB

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Stratified randomisation

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4. Manipulation/Intervention

Manipulation creates an independent variable:

drug, vaccine, new procedure, dietary

component, habit

whose effect is then determined by the

measurement of the final outcome, which

constitutes the dependant variable

incidence of disease, survival time, recovery

period.

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5. Follow Up

Examination of the experimental and control group

subjects at defined intervals of time

There may be loss of subjects from either group

due to a number of reasons. This is called as

“attrition”.

Death

Migration

Loss of interest

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6. Assessment

Positive results

Negative results

Errors in assessment can lead to “Bias”.

Bias can arise from three sources:

1. Subject variation

2. Observer bias

3. Evaluation Bias

Randomization cannot guard against these sort of bias.

To avoid the above situations, “Blinding” is done.

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Blinding can be done in three ways –

1. Single blind trial:

Participant is not aware whether he belongs to the

study group or control group

2. Double blind trial:

Neither the doctor nor the participant is aware of

the group allocation and the treatment received

3. Triple blind trial:

The participant, the investigator and the person

analyzing the data are all "blind".

Ideally, of course, triple blinding should be used;

but double blinding is the most frequently used

method when a blind trial is conducted.

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Design of RCT

Reference population

Experimental population

Exclusion criteria

Informed consentExcluded

Refused

Study population

Intervention group Control group

Outcome

Losses to follow-up Losses to follow-up

Random allocation

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Flowchart of 4 phases

(enrollment, intervention

allocation, follow-up, and

data analysis) of a

parallel randomized trial

of two groups, modified

from the CONSORT

(Consolidated Standards

of Reporting Trials) 2010

Statement[1]

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Trial registration

In 2004, the International Committee of Medical

Journal Editors (ICMJE) announced that all trials

starting enrolment after July 1, 2005 must be

registered prior to consideration for publication in one

of the 12 member journals of the committee.

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Avoidance of bias

1. Use of a control group

• Placebo

• Most widely accepted treatment

• Most accepted prevention intervention

• Usual care

• Accepted means of detection

2. Blindness

3. Allocation concealment

4. Randomization

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4. TYPES OF RANDOMIZED CONTROLLED TRIALS

I. Based on randomization:

1. Randomized controlled trials:

where randomization is used for allocation of products and

/ or subjects.

2. Non-randomized or “non-experiment” or quasi-experiment:

those departing from strict randomization for practical

purposes in such a manner that non-randomization does not

seriously affect the theoretical basis of conclusions

e.g. natural experiments, water fluoridation studies

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II. Based on study designs:

1. Parallel study design:

Comparisons are made between two randomly

assigned groups, one group exposed to specific

treatment, and the other group not exposed.

Patients remain in the study group or the control

group for the duration of the investigation.

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2. Factorial Design:

more efficient than a parallel design if there is an

interest in studying more than one intervention at a

time.

Each participant is randomly assigned to a group

that receives a particular combination of

interventions or non-interventions

e.g:

group 1 receives vitamin X and vitamin Y

group 2 receives vitamin X and placebo Y,

group 3 receives placebo X and vitamin Y

group 4 receives placebo X and placebo Y.

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3. Cross-over study designs:

Each patient serves as his own control.

Patients are randomly assigned to a study group

and control group.

The study group receives the treatment under

consideration.

The control group receives some alternate form of

active treatment or placebo.

Two treatments, two period cross-overs

Must eliminate carryover effects

– Need sufficient washout period

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Cross over

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INTERVENTION

SUBJECTS

CONTROL

RANDOM

ALLOCATION

PERIOD 2

CROSS OVER DESIGN

PERIOD 1

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An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78%

were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster,

and 2% were factorial.[32]

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II. Based on hypothesis

which differ in methodology and reporting

1. Superiority

Most RCTs are superiority trials, in which one

intervention is hypothesized to be superior to

another in a statistically significant way

2. Noninferiority

To determine whether a new treatment is no worse

than a reference treatment.

3. Equivalence

the hypothesis is that two interventions are

indistinguishable from each other.

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1. superiority trials" (most)

– statistically significant

2. noninferiority trials”

– new treatment no worse than existing Rx

3. equivalence trials"

- x2 Rx indistiguishable

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III. Based on uses:

1. Clinical trials

2. Preventive trials

3. Risk factor trials

4. Cessation experiment

5. Trial of etiological agents

6. Evaluation of health services

7. Community intervention trials

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5. ETHICAL ISSUES IN CLINICAL TRIALS

Clinical trials should follow 3 principles:

1. Beneficence:

which require that good should result, harm should be

avoided, or that benefits should justify the expected risk

or harm

2. Respect for rights:

including the free choice of the subject and protection for

those diminished autonomy

3. Justice:

which require an equal distribution of burden and benefits

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How:

1. Proper information to all the study subjects

2. Informed consent

3. The trial is conducted ethically

4. Avoid bias in results

5. Sample size is adequate to give the results

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Informed consent:

• of all study participants

•The nature of informed consent may differ in different

countries and cultures, but the concept of individual

choice to join or not join a trial must be universal(Nuremberg Code 1949; World Medical Association 2000).

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Ethical clearance

1. Institutional review boards

2. Ethical committees

3. Indian Counsel Medical Research (ICMR)

guidelines

4. Federal/state guidelines

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Institutional review board/independent ethics committee

Safeguards the rights, safety, and well-being of all

trial subjects.

Should include:

at least 5 members

at least one member whose primary area of

interest is in non-scientific area

at least one member who is independent of the

institution/trial site

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Documents which should be submitted

1. Trial protocol with amendments

2. Written informed consent form

3. Subject recruitment procedure

4. Written information provided to the subjects

5. Investigator’s brochure

6. Available safety information

7. Information about payments and compensation

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6. QUALITY ASSESSMENT OF RCT

I. Checklist approach

II. Quality scoring system approach

Complicated

vary depending on the instrument used

not encouraged

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I. Checklist approach

1.

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2. Consolidated Standards of Reporting Trials

(CONSORT)

gold standard for reporting the results of RCTs.

alleviate the problems arising from inadequate

reporting of RCT.

standard way for authors to prepare reports of trial

findings

facilitating their complete and transparent reporting

aiding their critical appraisal and interpretation.

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Comprises

1. Checklist

25 items

focus on reporting how the trial was designed, analyzed,

and interpreted

2. Flow diagram

displays the progress of all participants through the trial.

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CONSORT: checklist and flow diagram

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Flow diagram of the progress through the phases of a randomized trial

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Flow diagram of the progress through the phases of a randomized trial

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Ii. Quality score approach

Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled

Clin Trials1996;17:1-12. URL: http://www.bmjpg.com/rct/chapter4.html

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CONCLUSIONS

“Gold standard” of research designs

Individual patients are randomly allocated to receive

the experimental treatment (intervention group) or the

standard treatment (control group)

Maximizes the potential for attribution

Good internal validity

May lack generalisability due to highly selected

participants

Can be costly to set up and conduct, ethical issues.

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ABOUBAKR ELNASHAR

You can get this lecture from:1.My scientific page on Face book:

Aboubakr Elnashar Lectures.

https://www.facebook.com/groups/2277

44884091351/

2.Slide share web site

[email protected]

4.My clinic: Elthwara St. Mansura