Parallel group design
This is the most common clinical trial design for confirmatory therapeutic (Phase 3) trials. Subjects are randomised, to one of two or more treatment 'arms'. These treatments will include the investigational drug at one or more doses, and one or more control treatments such as placebo and /or an active comparator. Parallel group designs are particularly useful in conditions that fluctuate over a short-term basis, e.g. migraine or irritable bowel syndrome, but are also used in chronic stable diseases such as Parkinson's disease and forms of cancer. The particular advantages of the parallel group design are simplicity, the ability to approximate more closely the likely conditions of use, and the avoidance of 'carry-over effects' (see below).
In this design, each subject is randomised to a sequence of two or more treatments, and hence acts as his/her own control for treatment comparisons. The advantage of this design is that subject-to-subject variation is eliminated from treatment comparison so that number of subjects is reduced.
In the basic crossover design each subject receives each of the two treatments in a randomised order. There are variations to this in which each subject receives a subset of treatments or ones in which treatments are repeated within the same subject (to explore the reproducibility of effects).
The main disadvantage of the crossover design is carry-over, i.e. the residual influence of treatments on subsequent treatment periods. This can be avoided to some extent by separating treatments with a 'washout' period and, more importantly, by selecting treatment lengths based on a knowledge of the disease and the new medication. The crossover design is best suited for chronic stable diseases e.g. hypertension, chronic stable angina pectoris, where the baseline conditions are attained at the start of each treatment arm. The pharmacokinetic characteristics of the new medication are also important, the principle being that the plasma concentration at the start of the next dosing period is zero and no dynamic effect can be detected.
In the factorial design, two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments. The simplest example is the 2x2 factorial design in which subjects are randomly allocated to one of four possible combinations of two treatments A and B. These are: A alone, B alone, A + B, neither A nor B (placebo). The main uses of the factorial design are to:
• make efficient use of clinical trial subjects by evaluating two treatments with the same number of individuals
• examine the interaction of A with B
• establish dose-response characteristics of the combination of A and B when the efficacy of each has been previously established.
Multicentre trials are carried out for two main reasons. First, they are an efficient way of evaluating a new medication, by accruing sufficient subjects in a reasonable time to satisfy trial objectives. Second, multicentre trials may be designed to provide a better basis for the subsequent generalisation of their findings. Thus they provide the possibility of recruiting subjects from a wide population and of administering the medication in a broad range of clinical settings. Multicentre trials can be used at any phase in clinical development, but are especially valuable when used to confirm therapeutic value in Phase 3.
The main potential problem with a multicentre clinical trial is that heterogeneity of treatment effects between centres may create difficulty in arriving at a single interpretation. This is not as big a problem as it sometimes painted, however, and large-scale multicentre trials using minimised data collection techniques and simple endpoints have been of immense value in establishing modest but real treatment effects that apply to a large number of patients e.g. drugs that improve survival after myocardial infarction.
Naturally there is a temptation simply to give a new treatment to all patients and to compare the results with the past, i.e. historical controls. Unfortunately this is almost always unacceptable, even with a disease such as leukaemia, for standards of diagnosis and treatment change with time, and the severity of some diseases (infections) fluctuates. The general provision stands that controls must be concurrent and concomitant. An exception to this rule is case-control studies (see p. 68)
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