Statistical Principles for Clinical Trials
number. The logistics of some trials, such as those with a screening phase, may make
matters more complicated, but the unique pre-planned assignment of treatment, or
treatment sequence, to subject should be clear. Different trial designs will require
different procedures for generating randomisation schedules. The randomisation
schedule should be reproducible (if the need arises).
Although unrestricted randomisation is an acceptable approach, some advantages can
generally be gained by randomising subjects in blocks. This helps to increase the
comparability of the treatment groups, particularly when subject characteristics may
change over time, as a result, for example, of changes in recruitment policy. It also
provides a better guarantee that the treatment groups will be of nearly equal size. In
crossover trials it provides the means of obtaining balanced designs with their greater
efficiency and easier interpretation. Care should be taken to choose block lengths that
are sufficiently short to limit possible imbalance, but that are long enough to avoid
predictability towards the end of the sequence in a block. Investigators and other
relevant staff should generally be blind to the block length; the use of two or more
block lengths, randomly selected for each block, can achieve the same purpose.
(Theoretically, in a double-blind trial predictability does not matter, but the
pharmacological effects of drugs may provide the opportunity for intelligent
guesswork.)
In multicentre trials (see Glossary) the randomisation procedures should be organised
centrally. It is advisable to have a separate random scheme for each centre, i.e. to
stratify by centre or to allocate several whole blocks to each centre. More generally,
stratification by important prognostic factors measured at baseline (e.g. severity of
disease, age, sex, etc.) may sometimes be valuable in order to promote balanced
allocation within strata; this has greater potential benefit in small trials. The use of
more than two or three stratification factors is rarely necessary, is less successful at
achieving balance and is logistically troublesome. The use of a dynamic allocation
procedure (see below) may help to achieve balance across a number of stratification
factors simultaneously provided the rest of the trial procedures can be adjusted to
accommodate an approach of this type. Factors on which randomisation has been
stratified should be accounted for later in the analysis.
The next subject to be randomised into a trial should always receive the treatment
corresponding to the next free number in the appropriate randomisation schedule (in
the respective stratum, if randomisation is stratified). The appropriate number and
associated treatment for the next subject should only be allocated when entry of that
subject to the randomised part of the trial has been confirmed. Details of the
randomisation that facilitate predictability (e.g. block length) should not be contained
in the trial protocol. The randomisation schedule itself should be filed securely by the
sponsor or an independent party in a manner that ensures that blindness is properly
maintained throughout the trial. Access to the randomisation schedule during the
trial should take into account the possibility that, in an emergency, the blind may
have to be broken for any subject. The procedure to be followed, the necessary
documentation, and the subsequent treatment and assessment of the subject should
all be described in the protocol.
Dynamic allocation is an alternative procedure in which the allocation of treatment to
a subject is influenced by the current balance of allocated treatments and, in a
stratified trial, by the stratum to which the subject belongs and the balance within
that stratum. Deterministic dynamic allocation procedures should be avoided and an
appropriate element of randomisation should be incorporated for each treatment
allocation. Every effort should be made to retain the double-blind status of the trial.
For example, knowledge of the treatment code may be restricted to a central trial
office from where the dynamic allocation is controlled, generally through telephone
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