1. Different types of trial design
and implications for reporting
Alison Wearden

2. 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)

3. Methods of bias control Selection bias Randomized treatment assignment
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

4. 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?

5. 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?
Efficacy
Explanatory
Parallel arms/
factorial?
Effectiveness
Pragmatic
Patient
preference
Equivalence
Non-inferiority

6. Explanatory vs pragmatic Efficacy vs effectiveness
Explanatory, efficacy
Does this intervention work in people who receive it under carefully controlled conditions? How does it work?
Pragmatic, effectiveness
What would be the outcome if this intervention were implemented in usual clinical practice?
Broad, inclusive sample
More flexible
implementation
Qualitative studies, e.g. to
determine why people
dropped out
Tightly defined sample
Fixed protocol
Compliance measured
Process measures
See Zwarenstein et al., 2008, BMJ, 337,

7. 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

8. 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?

9. 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

10. 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)

11. 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
for B
3 =
A + control
4 =
Double
control
Eligible
Randomised to
A THEN B or
B THEN A A B B A

12. 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?

13. 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

14. Special considerations for reporting different types of trials
Standard CONSORT guidance is at
designated primary outcomes
sequence generation
allocation concealment ….
CONSORT guidelines have been elaborated for trials with complex interventions (cf. drug trials) and non-simple designs

15. 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,

16. 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,

17. 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
People may be carrying out equivalence trials without realising it.
Piaggio et al., 2006, JAMA,295,

18. 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