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Different types of trial design

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Different types of trial
design
and implications for reporting
Alison Wearden
Uncontrolled trials
• Test feasibility and acceptability of an
intervention, and whether there are
adverse effects
• May allow preliminary examination of
mechanisms of change
• N-of-1 designs, randomized schedule, can
be used to test theory (cause and effect)
Types of BIAS
Methods of bias control
Selection bias
Randomized treatment assignment
Concealment of assignment
Standardized operating
procedures
Training of research personnel
Blinding of researchers to
treatment assignment
Bias in study
management
Ascertainment bias
Bias introduced
after randomization
Intention-to-treat analysis
Publication bias
Prospective registration of trials
Publication of negative trials
From D. Wang & A Bakhai (Eds) Clinical Trials. A Practical Guide
to Design, Analysis and Reporting. 2006, Remedica: London, pp 57
The hegemony of pharmacological
trials
• Blinded randomised controlled trials
considered gold standard for testing drugs
• Heavily influenced guidelines for RCTs
• Are drug-RCT issues always appropriate
for complex behavioural interventions?
• Can attempts to eliminate bias distort
implementation and assessment of
intervention?
Efficacy
Explanatory
Types of
CONTROLLED
Parallel arms/ TRIALS
factorial?
Effectiveness
Pragmatic
Patient
preference
Equivalence
Non-inferiority
What factors do you need to
take into account choosing
a trial type and design?
What is your research
question?
Are there ethical
constraints?
Where might you want to
publish your trial?
Explanatory
Efficacy
vs
vs
pragmatic
effectiveness
Explanatory, efficacy
Pragmatic, effectiveness
Does this intervention
work in people who
receive it under carefully
controlled conditions?
How does it work?
What would be the
outcome if this
intervention were
implemented in usual
clinical practice?
•Tightly defined sample
•Fixed protocol
•Compliance measured
•Process measures
•Broad, inclusive sample
•More flexible
implementation
•Qualitative studies, e.g. to
determine why people
dropped out
Intention to treat analysis
• Preserves the benefits of randomization, ie
minimizes bias. Withdrawals may be more
common in one arm of trial
• Ecological validity (people do drop out)
• It gives a pragmatic estimate of the
effectiveness of a treatment, rather than just
a report of the efficacy of the treatment
• It requires a method for dealing with missing
data
Equivalence trials
• Instead of having a “no treatment” control,
equivalence trials test whether a new
intervention is as good as (or not worse
than) an established treatment with proven
efficacy
• New intervention may have some
advantage (convenience, cost) over
established, but is it at least as efficacious?
Randomisation issues
• Unit of randomisation (individual, group)
• Simple or block design (to even up group
numbers)
• Stratification or minimisation to achieve groups
balanced on key baseline characteristics
• Patient preference designs
– Zelen
– Wennberg
• Rucker
– Comprehensive cohort
Preference designs
• Patient preference may be an issue
– refusal to participate
– reduced compliance with non-preferred arm
• Consent may be taken AFTER
randomization, e.g. Zelen design:
Standard
Treatment A
Eligible
patients
Declines
Receives A
Randomized
Novel
Treatment B
Consents
Receives B
(May be
analysed as
randomized)
Some trial designs
Simple, parallel design
Is A better than control?
Factorial design
Are effects of A and B
additive or interactive?
A & B each controlled
Cross-over design
(Unlikely – useful with
small samples)
A
Eligible
Randomised to
A or control
control
Randomized
to 1,2,3 or 4
A
Control
for A
B
1=
A+B
2=
B + control
Control
for B
3=
A + control
4=
Double
control
Eligible
Randomised to
A THEN B or
B THEN A
A
B
B
A
Analysis issues
• Pre-specification of primary outcomes if
there are multiple measures
• Analysis plan pre-specified and published
• Intention to treat vs per protocol analysis
• How are missing data dealt with?
Where do you want to publish?
• Which audience do you want to reach?
• Does impact factor matter?
• Uniform requirements for “prestigious”
medical journals
– Trial must be registered
– Protocol must be published
– CONSORT guidelines must be adhered to
• Important issue of publication bias
Special considerations for reporting
different types of trials
• Standard CONSORT guidance is at
http://www.consort-statement.org/consortstatement/
– designated primary outcomes
– sequence generation
– allocation concealment ….
• CONSORT guidelines have been elaborated
for trials with complex interventions (cf. drug
trials) and non-simple designs
Reporting of psychological trials
should include
• Components of the intervention(s), how they
were individualised (if applicable), how they
were standardized
• How therapist fidelity to treatment assessed
• How experimental intervention and
comparator(s) were implemented
• Description of therapists (specialism,
experience etc) and setting
Boutron et al., 2008, Ann Int Med, 148, 295-309
Reporting pragmatic trials
• Explanatory vs pragmatic “attitude”
• Sample description and eligibility criteria –
is sample typical? Is setting typical?
• CONSORT diagram should explain
reasons for non-participation if known
• Particular attention to clinical interest of
findings
• Description of key aspects of setting which
affected findings
Zwarenstein et al., 2008, BMJ, 337, 1223-6
Issues with equivalence, or noninferiority, trials
• People may be carrying out equivalence
trials without realising it.
• Analysis with respect to a pre-stated
margin of non-inferiority (smallest clinically
interesting difference)
• ITT analysis may increase risk of type 1
error
• Choice of outcomes important
Piaggio et al., 2006, JAMA,295,1152-1160
Reporting equivalence trials
• Need to reference established efficacy of
“standard” treatment
• Hypotheses should be framed in terms of
non-inferiority
• “Margins of equivalence” should be
reported
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