Statistical Methods in Medical Research 4ed

might, for example, be thought that a drug cannot take effect before at least a
week has elapsed, and that therefore any adverse events occurring during the first
week can be discounted. These events should be omitted only if the underlying
assumption is universally accepted; otherwise, the possibility of bias again arises.
Similarly, adverse events (such as accidental deaths) believed to be unrelated to
the disease in question should be omitted only if their irrelevance is beyond
dispute (and this is rarely so, even for accidental deaths). However, events
especially relevant for the disease under study (such as cardiovascular events in
a trial for treatments for a cardiovascular disease) should be reported separately
and may well form one of the primary endpoints for the trial.
The policy of including in the analysis, where possible, all patients in the
groups to which they were randomly assigned, is called the intent(ion)-to-treat
(ITT) or as-randomized approach. It follows the pragmatic approach to trial
design (§18.3), in that groups receive treatments based on ideal strategies laid
down in the protocol, with the recognition that (as in routine medical practice)
rigidly prescribed regimens will not always be followed. In a modified form of
ITT it is occasionally thought reasonable to omit a small proportion of patients
who opted out of treatment before that treatment had started. In a doublemasked
drug trial, for instance, it may be clear that the same pressures to opt out
apply to all treatment groups. This would not be so, however, in a trial to
compare immediate with delayed radiotherapy, since the group assigned delayed
treatment would have more opportunity to opt out before the start of radiotherapy.
If a high proportion of patients abandon their prescribed treatment regimen,
perhaps switching to an alternative regimen under study, the estimates of differences
in efficacy between active agents will be biased, probably towards zero. In
a later subsection we discuss whether adjustments can be made to allow for this
incomplete compliance.
Withdrawals and missing data
18.6 Protocol departures 607
An ITT analysis may be thwarted because response variables, or other relevant
information, are missing for some patients. These lacunae can arise for various
reasons. The patient may have withdrawn from the investigator's care, either
because of dissatisfaction with the medical care or because of removal to another
district. In a follow-up study, information may be missing for some prescribed
visits, because the patient was unwell. Technical equipment may have failed,
leading to loss of test results, or other administrative failures may have
occurred.
In such situations it may be possible to retrieve missing information by
assiduous enquiry at the medical centre. In trials for which mortality is the
primary endpoint, it is possible in some countries (such as the UK) to determine