A therapeutic trial is:
a carefully, and ethically, designed experiment with the aim of answering some precisely framed question. In its most rigorous form it demands equivalent groups of patients concurrently treated in different ways or in randomised sequential order in crossover designs. These groups are constructed by the random allocation of patients to one or other treatment... In principle the method has application with any disease and any treatment. It may also be applied on any scale; it does not necessarily demand large numbers of patients.23
22The Target Difference. Differences in trial outcomes fall into three grades (1) that the doctor will ignore, (2) that will make the doctor wonder what to do (more research needed), and (3) that will make the doctor act, i.e. change prescribing practice.
This is the classic randomised controlled trial (RCT), the most secure method for drawing a causal inference about the effects of treatments. Randomisation attempts to control biases of various kinds when assessing the effects of treatments. RCTs are employed at all phases of drug development and in the various types and designs of trials discussed below.
Fundamental to any trial are:
• An hypothesis
• Definition of the primary endpoint
• The method of analysis
Other factors to consider when designing or critically appraising a trial are the:
• Characteristics of the patients
• General applicability of the results
• Method of monitoring
• Use of interim analyses24
• Interpretation of subgroup comparisons.
The aims of a therapeutic trial, not all of which can be attempted at any one occasion, are to decide:
• Whether a treatment is of value
• The magnitude of that value (compared with other remedies)
• The types of patients in whom it is of value
• The best method of applying the treatment (how often, and in what dosage if it is a drug)
• The disadvantages and dangers of the treatment.
Dose-response trials. Response in relation to the dose of a new investigational drug may be explored in all phases of drug development. Dose-response trials serve a number of objectives, of which the following are of particular importance.
• Confirmation of efficacy (hence a therapeutic trial)
^Bradford Hill A1977 Principles of medical statistics. Hodder and Stoughton, London. If there is a 'father' of the modern scientific therapeutic trial, it is he.
24Particularly in large-scale outcome trials, a monitoring committee is given access to the results as these are accumulated; the committee is empowered to discontinue a trial if the results show significant advantage or disadvantage to one or other treatment.
• Investigation of the shape and location of the dose-response curve
• The estimation of an appropriate starting dose
• The identification of optimal strategies for individual dose adjustments
• The determination of a maximal dose beyond which additional benefit is unlikely to occur.
Superiority, equivalence and noninferiority in clinical trials. The therapeutic efficacy of a novel drug is most convincingly established by demonstrating superiority to placebo, or to an active control treatment, or by demonstrating a dose-response relationship (as above).
In some cases, however, the purpose of a comparison is to show not necessarily superiority, but either equivalence or noninferiority. The objectives of such trials are to avoid the use of a placebo, to explore possible advantages of safety, dosing convenience and cost, and to present an alternative or 'second-line' therapy.
Examples of possible outcome in a 'head to head' comparison of two active treatments appear in Figure 4.1.
There are in general, two types of equivalence trials in clinical development, bio- and clinical equivalence. In the former, certain pharmacokinetic variables of a new formulation have to fall within specified (and regulated) margins of the standard formulation of the same active entity The advantage of this type of trial is that, if bioequivalence is 'proven' then proof of clinical equivalence is not required. Proof of clinical equivalence of a generic product to the marketed product can be much more difficult to demonstrate.
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