Читать книгу Randomised Clinical Trials - David Machin - Страница 36

Control of the ‘experiment’ is clearly a desirable feature – perhaps easy to attain in the physics laboratory where experimental conditions are tightly controlled but not so easy with living material particularly if they are human. A good trial should answer the questions posed as efficiently as possible. In broad terms, this implies recruiting as few subjects as is reasonably possible for a reliable answer to be obtained.

Although good science may lead to an optimal choice of design, the exigencies of real life may cause these ideals to be modified. All the same, one can still keep in mind the hierarchy in the choice of designs of Figure 1.2, but where to enter this hierarchy will depend on circumstance. Thus, the investigators do not aim for the best design, but only the best realisable design in their context.

Technical (statistical) aspects of experimental design can be used in a whole variety of settings. Nevertheless, there are specific problems associated with implementing these designs in practice in the field of clinical trials. It is clear that trials cannot be conducted without human subjects (often patients); nevertheless, the constraints this imposes are not inconsiderable. Figure 1.3 illustrates some aspects that need to be considered when conducting such trials.

As we have indicated, the requirements for human studies are usually more stringent than in other research areas. For example, safety, in terms of the welfare of the experimental units involved, is of overriding concern in clinical trials, possibly of less relevance in animal studies and of no relevance to laboratory studies. In some sense, the laboratory provides, at least in theory, the greatest rigour in terms of the experimental design, and studies in human subjects should be designed (whenever possible) to be as close to these standards as possible. However, no consent procedures from the experimental units nor from animals, if they are involved, are required, whereas this is a very important consideration in all human experimentation even in a clinical trial with therapeutic intent.

Constraints may also apply to the choice of interventions to compare. For example, in certain therapeutic trials there may be little chance that a placebo option will bring any benefit (although this is certainly not the case in all circumstances) so comparisons may have to be made between two allegedly ‘active’ approaches despite little direct evidence that either of them will bring benefit. However, if, at the end of such a trial, a difference between treatments is demonstrated then activity for the better of the two is established so in one sense comparison with a placebo was not necessary. In contrast should the two treatments appear not to differ in their effectiveness then no conclusions can be drawn since one does not know whether both are equally beneficial or whether both are equally ineffective as compared to Placebo. Thus, an investigating team conducting this type of trial needs to be fully aware of the potential difficulties.

Figure 1.3 Special considerations for clinical trials in human subjects

Ethical considerations, as judged perhaps by a local, national or international committee, may also prevent the ‘optimal’ design being implemented. There are also issues related to patient data confidentiality which may, in the circumstances of a multicentre trial, make synthesis of all the trial data problematical. We address other components of Figure 1.3 in later sections of the book.