Randomised Controlled Trials

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Information about Randomised Controlled Trials
Health & Medicine

Published on January 27, 2009

Author: fovak

Source: slideshare.net

Randomised Controlled Trials (RCTs) Graeme MacLennan

James Lind Born Edinburgh 1716 On HMS Salisbury in 1747 he allocated 12 men with scurvy Cider Seawater Horseradish, mustard, garlic Nutmeg Elixir Vitriol Oranges and Limes

Born Edinburgh 1716

On HMS Salisbury in 1747 he allocated 12 men with scurvy

Cider

Seawater

Horseradish, mustard, garlic

Nutmeg

Elixir Vitriol

Oranges and Limes

Think about… Consider how you would go about evaluating the following interventions Surgical versus medical termination of pregnancy Referral guidelines for radiographic examination Paracetamol and/or ibuprofen for treating children with fever Nurse counsellors as an alternative to clinical geneticists for genetic counselling Single dose of chemotherapy versus radiotherapy treating testicular cancer http://news.bbc.co.uk/1/hi/health/7647007.stm Cervical cancer vaccine http://news.bbc.co.uk/1/hi/health/6223000.stm

Consider how you would go about evaluating the following interventions

Surgical versus medical termination of pregnancy

Referral guidelines for radiographic examination

Paracetamol and/or ibuprofen for treating children with fever

Nurse counsellors as an alternative to clinical geneticists for genetic counselling

Single dose of chemotherapy versus radiotherapy treating testicular cancer http://news.bbc.co.uk/1/hi/health/7647007.stm

Cervical cancer vaccine http://news.bbc.co.uk/1/hi/health/6223000.stm

The need to evaluate health care Variations in health care Unproven treatments Inadequacies in care Inaccurate medical models Limitation of resources New innovations … Crombie (1996)

Variations in health care

Unproven treatments

Inadequacies in care

Inaccurate medical models

Limitation of resources

New innovations



Crombie (1996)

Evaluation process Define research question What is already known? Identify appropriate study design Define population, intervention and criteria for evaluation How large a study? Consider measurement of evaluation criteria (“outcomes”) How often? Timing? Length of follow up? To whom? Who collects the data? What format? Analysis of data Dissemination and implementation

Define research question

What is already known?

Identify appropriate study design

Define population, intervention and criteria for evaluation

How large a study?

Consider measurement of evaluation criteria (“outcomes”)

How often?

Timing? Length of follow up?

To whom? Who collects the data? What format?

Analysis of data

Dissemination and implementation

Define research question and what is already known Research question (PICOT) Population Intervention Control/comparator Outcome Target Has the question already been answered? Conduct review to assess what is know about intervention

Research question (PICOT)

Population

Intervention

Control/comparator

Outcome

Target

Has the question already been answered?

Conduct review to assess what is know about intervention

Definition of population, intervention and “outcomes” Population Strict definition (explanatory) or flexible (pragmatic) Intervention Dose of drug, timing etc “ Outcomes” Health related Quality of Life Biochemical outcomes Symptoms Physical assessment Patient satisfaction Acceptability Cost-effectiveness

Population

Strict definition (explanatory) or flexible (pragmatic)

Intervention

Dose of drug, timing etc

“ Outcomes”

Health related Quality of Life

Biochemical outcomes

Symptoms

Physical assessment

Patient satisfaction

Acceptability

Cost-effectiveness

Measuring “outcome” Questionnaires, interview, medical notes etc Timing of questionnaires? Baseline (prior to treatment) Short term outcomes Long term outcomes Who collects the data?

Questionnaires, interview, medical notes etc

Timing of questionnaires?

Baseline (prior to treatment)

Short term outcomes

Long term outcomes

Who collects the data?

Sources of systematic errors Selection bias can be introduced by the way in which comparison groups are assembled Attrition bias systematic differences in withdrawal/follow up Performance bias Systematic differences in care provided Observation/detection bias systematic differences in observation, measurement, assessment

Selection bias

can be introduced by the way in which comparison groups are assembled

Attrition bias

systematic differences in withdrawal/follow up

Performance bias

Systematic differences in care provided

Observation/detection bias

systematic differences in observation, measurement, assessment

What is a randomised controlled trial? Simple Definition A study in which people are allocated at random to receive one of several interventions (simple but powerful research tool)

Simple Definition

A study in which people are allocated at random to receive one of several interventions

(simple but powerful research tool)

Simple RCT model RANDOMLY allocated to experimental or CONTROL group CONTROL EXPERIMENT Trial participants

What is a randomised controlled trial? Random allocation to intervention groups all participants have equal chance of being allocated to each intervention group why RCTs are referred to as randomised controlled trials

Random allocation to intervention groups

all participants have equal chance of being allocated to each intervention group

why RCTs are referred to as randomised controlled trials

Terminology Interventions are comparative regimes within a trial Prophylactic, diagnostic, therapeutic e.g. preventative strategies screening programmes diagnostic tests drugs surgical techniques

Interventions are comparative regimes within a trial

Prophylactic, diagnostic, therapeutic e.g.

preventative strategies

screening programmes

diagnostic tests

drugs

surgical techniques

What is a randomised controlled trial? One intervention is regarded as control treatment (the group of participants who receive this are the control group) NOTE: Contemporaneous (not historical controls) why RCTs are referred to as randomised controlled trials

One intervention is regarded as control treatment (the group of participants who receive this are the control group)

NOTE: Contemporaneous (not historical controls)

why RCTs are referred to as randomised controlled trials

Terminology Control Group can be conventional practice no intervention (this may be conventional practice) placebo Experimental Group receive new intervention (also called treatment group or intervention group interchangeably)

Control Group

can be

conventional practice

no intervention (this may be conventional practice)

placebo

Experimental Group

receive new intervention

(also called treatment group or intervention group interchangeably)

What is a randomised controlled trial ? RCTs are Experiments: investigators can influence number, type, regime of interventions Quantitative: measure events rather than try to interpret them in their natural settings Comparative: compare two or more interventions

RCTs are

Experiments: investigators can influence number, type, regime of interventions

Quantitative: measure events rather than try to interpret them in their natural settings

Comparative: compare two or more interventions

What is a randomised controlled trial? More Complex Definition Quantitative, comparative, controlled experiments in which a group of investigators study two or more interventions in a series of participants who are allocated randomly to each intervention group

More Complex Definition

Quantitative, comparative, controlled experiments in which a group of investigators study two or more interventions in a series of participants who are allocated randomly to each intervention group

Inclusion/exclusion criteria Decision rules applied to potential trial participants to judge eligibility for inclusion in trial See CONSORT statement www.consort-statement.org Important that they are applied identically to all groups in a trial!

Decision rules applied to potential trial participants to judge eligibility for inclusion in trial

See CONSORT statement

www.consort-statement.org

Important that they are applied identically to all groups in a trial!

What is randomisation? Randomisation is the process of random allocation Allocation is not determined by investigators, clinicians or participants Equal chance of being assigned to each intervention group Individual people patients caregivers (physicians, nurses etc) Groups of people, ‘cluster randomisation’ (Covered in more depth in later lecture)

Randomisation is the process of random allocation

Allocation is not determined by investigators, clinicians or participants

Equal chance of being assigned to each intervention group

Individual people

patients

caregivers (physicians, nurses etc)

Groups of people, ‘cluster randomisation’

(Covered in more depth in later lecture)

Pseudo-randomisation Other allocation methods include according to date of birth the number on hospital records date of invitation etc. These are NOT regarded as random These are called pseudo- or quasi-random

Other allocation methods include

according to date of birth

the number on hospital records

date of invitation etc.

These are NOT regarded as random

These are called pseudo- or quasi-random

Terminology Controlled clinical trials (CCTs) are not the same as randomised controlled trials Controlled clinical trials include non-randomised controlled trials and randomised controlled trials

Controlled clinical trials (CCTs) are not the same as randomised controlled trials

Controlled clinical trials include non-randomised controlled trials and randomised controlled trials

Why use randomisation? Characteristics similar across groups at baseline can isolate and quantify impact of interventions with effects from other factors minimised Risk of imbalance not abolished completely even if perfect randomisation To combat selection bias Unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials, Kunz and Oxman 1998 BMJ http://www.bmj.com/cgi/content/abstract/317/7167/1185

Characteristics similar across groups at baseline

can isolate and quantify impact of interventions with effects from other factors minimised

Risk of imbalance not abolished completely even if perfect randomisation

To combat selection bias

Unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials, Kunz and Oxman 1998 BMJ

http://www.bmj.com/cgi/content/abstract/317/7167/1185

Why do we need a control group? Don’t need a control group if completely predictable results Parachutes when jumping from plane New drug cures a few rabies cases But No intervention has 100% efficacy Many diseases recover spontaneously

Don’t need a control group if completely predictable results

Parachutes when jumping from plane

New drug cures a few rabies cases

But

No intervention has 100% efficacy

Many diseases recover spontaneously

Regression to the mean Occurs when an intervention aimed at a group or characteristic that is very different from average For example selecting people because they have high blood pressure then measuring them in future will see the blood pressure measurements closer to the mean of the population Morton and Torgerson BMJ 2003 326:1083-4 Bland and Altman BMJ 1994 308:1499 and 309:780

Occurs when an intervention aimed at a group or characteristic that is very different from average

For example selecting people because they have high blood pressure then measuring them in future will see the blood pressure measurements closer to the mean of the population

Morton and Torgerson BMJ 2003 326:1083-4

Bland and Altman BMJ 1994 308:1499 and 309:780

DISTRIBUTION OF RESULTS threshold measurement 1 measurement 2

Hawthorne Effect Experimental effect in the direction expected but not for the reason expected Essentially studying/measuring something can change what you studying/measuring

Experimental effect in the direction expected but not for the reason expected

Essentially studying/measuring something can change what you studying/measuring

Placebo Effect Effect (usually, but not always positive) attributed to the expectation that a therapy will have an effect The effect is due to the power of suggestion A placebo is an inert medication or procedure Waber et al 2008 JAMA Commercial Features of Placebo and Therapeutic Efficacy http://jama.ama-assn.org/cgi/content/full/299/9/1016

Effect (usually, but not always positive) attributed to the expectation that a therapy will have an effect

The effect is due to the power of suggestion

A placebo is an inert medication or procedure

Waber et al 2008 JAMA Commercial Features of Placebo and Therapeutic Efficacy

http://jama.ama-assn.org/cgi/content/full/299/9/1016

EFFECT OF AN INTERVENTION Effect size Experimental group Control group Hawthorne E. R. mean Placebo E. Therapeutic E. Real difference Noise Signal

Minimising bias in RCTs Blinding Single blind – participants are unaware of treatment allocation Double blind – both participants and investigators are unaware of treatment allocation Requires use of placebos in drug trials Schulz and Grimes (2002)

Blinding

Single blind – participants are unaware of treatment allocation

Double blind – both participants and investigators are unaware of treatment allocation

Requires use of placebos in drug trials Schulz and Grimes (2002)

Concealment of random allocation list “ Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment” Schulz KF (1995). Subverting randomisation in controlled trials. JAMA, 274, 1456-8

“ Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment”

Schulz KF (1995). Subverting randomisation in controlled trials. JAMA, 274, 1456-8

Blinding, placebos RCTs should use the maximum degree of blinding that is possible Placebo is a ‘dummy’ treatment given when there is no obvious standard treatment needed as the act of taking a treatment may have some effect -need to attribute double blind treatments must be indistinguishable to those affected

RCTs should use the maximum degree of blinding that is possible

Placebo is a ‘dummy’ treatment given when there is no obvious standard treatment

needed as the act of taking a treatment may have some effect -need to attribute

double blind treatments must be indistinguishable to those affected

Empirical evidence of bias

‘ Explanatory’ and ‘Pragmatic’ questions Explanatory Can it work in an ideal setting …..? Efficacy Hypothesis testing Placebo controlled Double blind Pragmatic Does it work in the real world …..? Effectiveness Choice between alternative approaches to health care Standard care Open

Explanatory

Can it work in an ideal setting …..?

Efficacy

Hypothesis testing

Placebo controlled

Double blind

Pragmatic

Does it work in the real world …..?

Effectiveness

Choice between alternative approaches to health care

Standard care

Open

Key differences between explanatory and pragmatic trials (1) Explanatory Pragmatic Question efficacy effectiveness Setting ‘laboratory’ normal practice Participants strictly defined broader, clinically indicated (uncertainty) Interventions strictly defined as clinical practice

Explanatory Pragmatic

Question efficacy effectiveness

Setting ‘laboratory’ normal practice

Participants strictly defined broader, clinically indicated (uncertainty)

Interventions strictly defined as clinical practice

Key differences between explanatory and pragmatic trials (2) Explanatory Pragmatic Outcomes short-term long-term, patient- surrogates centered and resource orientated Size small (usually larger single centre) (often multi-centre) Analysis treatment received intention to treat Relevance indirect direct to practice

Explanatory Pragmatic

Outcomes short-term long-term, patient- surrogates centered and resource orientated

Size small (usually larger

single centre) (often multi-centre)

Analysis treatment received intention to treat

Relevance indirect direct

to practice

Example of selection bias for PP in an open trial Exp Ctrl None None White(2005) E E Worse prognosis

Terminology: explanatory versus pragmatic Explanatory trials estimates efficacy - that is the benefit the treatment produces under ideal conditions Pragmatic trials estimates effectiveness - that is the benefit the treatment produces under routine clinical practice Roland M, Torgerson D. What are pragmatic trials? BMJ 1998;316:285

Explanatory trials

estimates efficacy - that is the benefit the treatment produces under ideal conditions

Pragmatic trials

estimates effectiveness - that is the benefit the treatment produces under routine clinical practice

Roland M, Torgerson D. What are pragmatic trials? BMJ 1998;316:285

RCT as the Gold Standard The randomised controlled trial is widely regarded as the gold standard for evaluating health care technologies because it allows us to be confident that a difference in outcome can be directly attributed to a difference in the treatments and not due to some other factor

The randomised controlled trial is widely regarded as the gold standard for evaluating health care technologies because it allows us to be confident that a difference in outcome can be directly attributed to a difference in the treatments and not due to some other factor

RCT strengths Confounding variables minimised Only research design which can in principle yield causal relationships can clarify the direction of cause and effect Accepted by EBM school Don’t have to know everything about the participants

Confounding variables minimised

Only research design which can in principle yield causal relationships

can clarify the direction of cause and effect

Accepted by EBM school

Don’t have to know everything about the participants

RCT limitations Contamination of intervention groups Comparable controls Problems with blinding What to do about attrition? Are patients/professionals willing to be in trial different from ‘refusers’?- external validity Cost!

Contamination of intervention groups

Comparable controls

Problems with blinding

What to do about attrition?

Are patients/professionals willing to be in trial different from ‘refusers’?- external validity

Cost!

Other issues in RCTs (1) Ethics Management issues Interim analysis and ‘stopping rules’ part of ethical concern mechanisms to avoid patient harm Data Monitoring and Safety Committee required for trials Clemens F et al Data monitoring in randomised controlled trials: surveys of recent practice and policies. Clin Trials 2005;2(1):22-33.

Ethics

Management issues

Interim analysis and ‘stopping rules’

part of ethical concern

mechanisms to avoid patient harm

Data Monitoring and Safety Committee required for trials

Clemens F et al Data monitoring in randomised controlled trials: surveys of recent practice and policies. Clin Trials 2005;2(1):22-33.

Other issues in RCTs (2) A power calculation is essential for the validity of a trial and will always be necessary for grant applications and in publications of the trial (later lecture) The methods of randomisation should always be reported. It is not enough to say that the patients were randomly allocated to the treatments. (see CONSORT)

A power calculation is essential for the validity of a trial and will always be necessary for grant applications and in publications of the trial (later lecture)

The methods of randomisation should always be reported. It is not enough to say that the patients were randomly allocated to the treatments. (see CONSORT)

Parallel group (simple) RCT design in practice Patient eligible for either treatment Patient gives informed consent Yes No Randomise Exclude from trial Experimental treatment Standard treatment Standard treatment

Summary “ Gold standard” of research designs Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group) Maximises the potential for attribution Randomisation guards against selection bias between the two treatment groups Standard statistical analysis Good internal validity May lack generalisability due to highly selected participants Can be costly to set up and conduct, ethical issues

“ Gold standard” of research designs

Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group)

Maximises the potential for attribution

Randomisation guards against selection bias between the two treatment groups

Standard statistical analysis

Good internal validity

May lack generalisability due to highly selected participants

Can be costly to set up and conduct, ethical issues

Good study design General considerations maximise attribution Ensure no factor other than the intervention differs between the intervention and control group Random allocation, if adequately carried out, will in the long run ensure comparable groups with respect to all factors minimise all sources of error systematic error (bias) random error (chance) be practical and ethical

General considerations

maximise attribution

Ensure no factor other than the intervention differs between the intervention and control group

Random allocation, if adequately carried out, will in the long run ensure comparable groups with respect to all factors

minimise all sources of error

systematic error (bias)

random error (chance)

be practical and ethical

Minimise sources of error Systematic errors (bias) “ inaccuracy which is different in its size or direction in one of the groups under study than the others ” Minimise bias by ensuring that the methods used are applied in the same manner to all subjects irrespective of which group they belong to. Random errors (chance) “ Inaccuracy which is similar in the different groups of subjects being compared” Adequate sample size, accurate methods of measurement Elwood (1998)

Systematic errors (bias)

“ inaccuracy which is different in its size or direction in one of the groups under study than the others ”

Minimise bias by ensuring that the methods used are applied in the same manner to all subjects irrespective of which group they belong to.

Random errors (chance)

“ Inaccuracy which is similar in the different groups of subjects being compared”

Adequate sample size, accurate methods of measurement

Elwood (1998)

Study designs Experimental (Randomised controlled trial) A new intervention is deliberately introduced and compared with standard care Quasi-experimental (non-randomised, controlled before and after) Researchers do not have full control over the implementation of the intervention (“opportunistic research”) Observational (Cohort, case-control, cross-sectional) describes current practice observed differences cannot be attributed solely to a “treatment” effect

Experimental (Randomised controlled trial)

A new intervention is deliberately introduced and compared with standard care

Quasi-experimental (non-randomised, controlled before and after)

Researchers do not have full control over the implementation of the intervention (“opportunistic research”)

Observational (Cohort, case-control, cross-sectional)

describes current practice

observed differences cannot be attributed solely to a “treatment” effect

Evaluation of health care interventions Randomised controlled trials are considered as the “gold standard” However, some debate over the advantages and disadvantages of different research designs for assessing the effectiveness of healthcare interventions Polarised views “ observational methods provide no useful means of assessing the value of a therapy” (Doll, 1993) RCTs may be unnecessary, inappropriate, impossible or inadequate (Black, 1996) Approaches should be seen as complementary and not as alternatives (Black, 1996) Interpretation of RCTs in terms of generalisability

Randomised controlled trials are considered as the “gold standard”

However, some debate over the advantages and disadvantages of different research designs for assessing the effectiveness of healthcare interventions

Polarised views

“ observational methods provide no useful means of assessing the value of a therapy” (Doll, 1993)

RCTs may be unnecessary, inappropriate, impossible or inadequate (Black, 1996)

Approaches should be seen as complementary and not as alternatives (Black, 1996)

Interpretation of RCTs in terms of generalisability

Useful/interesting links www.jameslindlibrary.org (History) www.consort-statement.org (CONSORT) www-users.york.ac.uk/~mb55/pubs/pbstnote.htm (All the stats notes from BMJ) www.ctu.mrc.ac.uk (MRC CTU) www.rcrt.ox.ac.uk (under construction) Doll R. Clinical Trials the 1948 watershe BMJ 1998;317:1217-1220 The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials Regina Kunz and Andrew D Oxman BMJ 1998 317: 1185-1190

www.jameslindlibrary.org (History)

www.consort-statement.org (CONSORT)

www-users.york.ac.uk/~mb55/pubs/pbstnote.htm (All the stats notes from BMJ)

www.ctu.mrc.ac.uk (MRC CTU)

www.rcrt.ox.ac.uk (under construction)

Doll R. Clinical Trials the 1948 watershe BMJ 1998;317:1217-1220

The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials Regina Kunz and Andrew D Oxman BMJ 1998 317: 1185-1190

References Black. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996 : 312;1215-8 Crombie. Research in Health Care. 1996 Doll. Doing more good than harm: the evaluation of health care interventions. Ann NY Acad Sci 1993:703;310-13 Elwood M. Critical appraisal of epidemiological studies and clinical trials. 1998 OUP; Oxford. Greenhalgh T. How to read a paper. 2001 BMJ; London Schulz and Grimes. Lancet Epidemiology series. 2002

Black. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996 : 312;1215-8

Crombie. Research in Health Care. 1996

Doll. Doing more good than harm: the evaluation of health care interventions. Ann NY Acad Sci 1993:703;310-13

Elwood M. Critical appraisal of epidemiological studies and clinical trials. 1998 OUP; Oxford.

Greenhalgh T. How to read a paper. 2001 BMJ; London

Schulz and Grimes. Lancet Epidemiology series. 2002

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