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
Bias in study
management
Standardized operating
procedures
Training of research personnel
Ascertainment bias Blinding of researchers to
treatment assignment
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
TRIALS

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?
Parallel arms/
factorial?
Equivalence
Non-inferiority
Effectiveness
Pragmatic
Patient
preference
Explanatory vs pragmatic
Efficacy vs effectiveness
Pragmatic, effectiveness
What would be the
outcome if this
intervention were
implemented in usual
clinical practice?

Explanatory, efficacy
Does this intervention
work in people who
receive it under carefully
controlled conditions?
How does it work?
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



See Zwarenstein et al., 2008, BMJ, 337, 1223-6
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:
Eligible
patients
Randomized
Novel
Treatment B
Consents
Receives B
Declines
Receives A
Standard
Treatment A
(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)
Eligible
Randomised to
A or control
A
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/consort-
statement/
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 non-
inferiority, 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