Compliance and missing data

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Deviations from the randomized treatment group happen in most trials.  For example, in a trial comparing placebo with antibiotics, some of those allocated to the antibiotics group might not take their medication.  In the analysis of a pragmatic trial, this non-compliance or protocol deviation should in general be handled using an ‘intention-to-treat’ principle – all participants enrolled should be included and analysed as part of the original group to which they were assigned.  The protocol should state what procedures will be adopted to minimise non-compliance and what procedures will be implemented to retain participants (see Post recruitment retention strategies).

Missing data will almost always occur in a randomised trial.  For example, participants may move away from the area or might refuse to continue participating in the trial.  There is no generally acceptable rate of loss to follow up (or missing data) but greater than 20% loss in the primary outcome(s) will pose a serious threat to the validity of the results.  In general, provided methods for dealing with missing data are sensible and pre-defined in the protocol, the trial results should be valid.   There is no consensus on which methods should be used for dealing with missing data so any investigation should include a sensitivity analysis of the assumptions used to handle the missing data.  Adjustment for loss to follow up should be made in the sample size calculation (see Sample size section)

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Things to consider when writing a protocol

Scenarios where special considerations apply
Cluster trials
In addition to possible missing patient data, cluster trials also have the potential for missing cluster level data.  For example, a whole hospital might decline to continue with the trial.  The protocol should define how this situation will be handled.

Equivalence trials
In trials that are designed to show equivalence, it is generally advocated that the groups are analysed on a ‘treatment received’ basis not by ‘intention to treat’.  The method of handling non-compliance should be stated in the protocol.

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Illustrative example - Magpie trial

All analyses will be based on the groups as randomly allocated, in other words this will be an intention-to-treat analysis. For the principal comparisons statistical significance will be taken as the 5% level, and for the subsidiary comparisons the 1% level. In addition to the prespecified sub-group analyses, sensitivity analyses will explore whether compliance with the allocated treatment influences the size of any effects on the primary outcomes. Good compliance, defined as loading dose plus 20-28 hours maintenance therapy, will be compared to both higher and lower doses. The effect of >12 hours treatment will be compared to <12 hours treatment. (Magpie trial - go to protocol)

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Additional resources

Trial protocol resource icon Checklist for compliance and missing data

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Trial Protocol Tool resource iconAnalysis and interpretation checklist

This checklist was developed by Dave Sackett, who prepared it for the forthcoming 3rd edition of Clinical Epidemiology; A Basic Science for Answering Questions about Health Care, to be published by Lippincott, Williams & Wilkins in 2004.

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Web resource iconICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials

This document provides guidance for the design, conduct, analysis, and evaluation of clinical trials of an intervention in the context of its overall clinical development.

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Further reading

Schulz KF, Grimes DA. Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet 2002; 359: 781-5.

Fergusson D, Aaron SD, Guyatt G, Hebert P. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis.  BMJ 2002; 325: 652-4.

Carpenter J, Pocock S, Lamm CJ. Coping with missing data in clinical trials: a model-based approach applied to asthma trials. Statistics in Medicine 2002; 21:1043-66.

Fayers PM, Machin D. Quality of Life: Assessment, Analysis and Interpretation.  Chichester: John Wiley & Sons, 2000.

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This page was last updated 19th October 2004.