Compliance and missing data

This section contains the following:

Introduction
Things to consider
Scenarios where special conditions apply
Additional resources
Further reading

Introduction

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.

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.

Things to consider

For a pragmatic trial, the intention to treat principle should in general be adhered to
Check the study protocol to find how missing data should be handled.
The CONSORT flow diagram used in the dummy tables should be used to illustrate the number of non-compliers and the number of missing data in the primary outcome(s)

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 will have defined 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 have been stated in the protocol.

Additional resources

Analysis 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.

ICH 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.