Treatment allocation treatments

As far as possible, the study should be conducted under double-blind conditions. Sometimes, pharmacological effects, desired or undesired, tend to unblind the study but even in these circumstances the identity of treatment will be unknown to subjects and observers at the time of dosing and before onset of effects, thereby minimising bias. Specified persoimel, such as the pharmacist, bioanalyst and pharmacokineticist, may need to know the treatment allocation code... 

Minimisation is based on the idea of biasing the treatment allocation so as to minimise the total imbalance between treatments according to some criterion. 

Ideally the trial should be double-blind with both the subject and the investigator being blind to the specific treatment allocation. If this is not possible for the investigator, for example, then the next best thing is to have an independent evaluation of outcome, both for efficacy and for safety. A single-blind trial arises when either the subject or investigator, but not both, is blind. 

Dynamic aibcation 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. ... 

Covariates affected by treatment allocation. Variables measured after randomisation (e.g. compliance, duration of treatment) should not be used as covariates in a model for evaluation of the treatment effect as these may be influenced by the treatment received. A similar issue concerns late baselines , that is covariate measures that are based on data captured after randomisation. The term time-dependent covariate is sometimes used in relation to each of the examples above. 

Blackburn et al. (1981) studied 49 patients with mild to moderately severe depressions in a psychiatric outpatient department and 39 patients from a general practice in Edinburgh, i.e. a total of 88 patients, of whom 64 (14 men, 50 women) completed the study. The patients were selected on the basis of the Research Diagnostic Criteria (Spitzer et al., 1978) as well as various rating and selfrating scales one-third of the patients each received one of the following, randomly allocated treatments for a maximum of 20 weeks ... 

It is important that the method of randomization is actually random. Treatment allocation according to day of the week, date of birth, date of admission or by alternate cases, is not random. The investigator will often know what treatment the patient will get if they enter the trial and so these methods are open to bias. Randomization must be based on tables of random numbers or computer-generated random allocation. It is also important that randomization is secure. Central telephone randomization is preferable to other methods, such as sealed envelopes containing the treatment allocation. 

By dynamic allocation, in which treatment allocation is influenced by the current balance of allocated treatments... 

Blinding should go beyond the observer and the observed. None of the investigators should be aware of treatment allocation, including those who evaluate endpoints, assess compliance with the protocol and monitor adverse events. Breaking the blind (for a single subject) should be considered only when the subject s physician deems knowledge of the treatment assignment essential in the subject s best interests. 

There are various levels of blinding, extending from open or open label (a term used by US investigators), where all concerned with the trial are aware of the identity of the trial medicine, to the other extreme of total blindness, in which everyone who interacts directly with the study subject or who comes into contact with the observations or data is unaware of treatment allocation statisticians, efficacy review committees, pathologists and experts invited to interpret objective endpoint criteria are unaware of treatment identity. In between there are various combinations of blindness, for example single... 

When there are several prognostic factors that can be determined before treatment allocation, the treatment groups can be balanced for these factors using a method known as minimisation .This method is particularly valuable in relatively small trials (say, 100 or fewer patients per treatment group) where simple randomised allocation may give substantial differences between the groups purely by chance. 

A difiSculty frequently arises in clinical trials because not all patients allocated to a treatment will complete the designated period of treatment or follow up. Non-completion may be a function of the particular treatment allocated, in that the reason for discontinuation of therapy may be inadequate efficacy or an adverse effect. If non-completing patients are omitted from fhe treatment comparison, bias may be introduced. Simply, if a treatment s failures are omitted from further consideration, the treatment will appear to be better than it really is. Thus, the primary efficacy analysis for the comparison of treatments must include all patients allocated to each treatment, whatever their ultimate fate. This is known as intention-to-treat (ITT) analysis. The implementation of an ITT analysis is not always easy, but usually either an endpoint analysis (in which the final assessment, whenever it was made, is used for fhe treatment comparison) or one of the strategies based on ranking the patients (from the best to the worst in the study) proposed by Gould. ... 

Crossover trial designs (Figure 31.2) are less often used in clinical practice and are implemented typically only in Phase 1 or 2 of development. Examples of these trials, such as bioequivalence and drug-drug interaction, commonly appear in the literature. In fact, numerous journal articles and textbooks are devoted to the formulation and analysis of these designs. In these trials, patients are allocated randomly to study arms (or sequences). Each patient within the sequence receives a treatment followed by one or more treatments these treatments can be replicated. The treatments can consist of single or multiple doses. 

Randomization is a word which is used to describe the allocation at random (using aleatory devices, such as, for example, dice, cards, lots or random number tables or generators) of treatments to the units in an experiment. In a clinical trial these units are most typically the patients, although occasionally a centre might be treated as a unit, and in cross-over trials, in which patients may receive two or more treatments, a treatment episode is the basic experimental unit. 

Senn SJ (1995) A personal view of some controversies in allocating treatment to patients in clinical trials. Statistics in Medicine 14 2661-2674. [See Comment in Statistics in Medicine 15(1) 113-116 (1996)]. 

Two approaches to randomization are common pre-allocation and post-allocation (Senn, 2004). In pre-allocation, treatment packs that are identical in appearance are prepared in random sequences and delivered to the centres. As each patient is recruited. 

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