Treatment allocation

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. 

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. ... 

Senn SJ (2002) Ethical considerations concerning treatment allocation in drug development trials. 

Although the issues of missing data and intention to treat are closely related, they are not identical. Intention to treat analysis is possible provided outcome and randomization data are not missing and (in its strict sense) impossible if they are. If data are not missing, then even if patients are noncompliant it is possible to analyse them as randomized provided only that their original treatment allocation is known. A per-protocol analysis requires knowledge of compliance. Also, depending on what one means by per protocol, it may or may not require complete outcome data. For example, one could simply say for a per-protocol analysis that one is only interested in patients who not only took the medicine as instructed but also recorded their outcomes. 

Senn SJ (2001b) Two cheers for P-values. Journal of Epidemiology and Biostatistics 6 193-204. Senn SJ (2002) Ethical considerations concerning treatment allocation in drug development trials. 

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