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 Selection bias Bias in study management Ascertainment bias

Methods of bias control Randomized treatment assignment Concealment of assignment Standardized operating procedures Training of research personnel Blinding of researchers to treatment assignment

Bias introduced after Intention-to-treat analysis randomization 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? 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?

Effectiveness Pragmatic Patient preference Equivalence Non-inferiority

Explanatory Efficacy
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

vs vs

pragmatic effectiveness
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

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 Standard Treatment A Randomized Novel Treatment B Declines Receives A Consents Receives B (May be analysed as randomized)

Some trial designs

Simple, parallel design Is A better than control?
Eligible Randomised to A or control A control A 1= A+B 3= A + control Control for A 2= B + control 4= Double control

Factorial design Are effects of A and B additive or interactive? A & B each controlled

Randomized to 1,2,3 or 4 B Control for B

Cross-over design (Unlikely useful with small samples)

Eligible Randomised to A THEN B or B THEN 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-statem
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