Randomised Clinical Trials. David Machin. Читать онлайн. Newlib. NEWLIB.NET

Автор: David Machin
Издательство: John Wiley & Sons Limited
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Жанр произведения: Медицина
Год издания: 0
isbn: 9781119524670
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education of staff or provision of three hip protectors per resident) of the intervention for elderly residents may not be essential to achieve the reduction in the hip fracture rates. As an extreme example, if cure can be achieved with dose d/2, then it would be foolish to give patients dose d. These issues have to be debated thoroughly by the trial design team.

      

      However, even within the structure of the simplest of all comparative trial designs, there are options that have to be considered. Although randomisation is mandatory for such a design, the choice of the allocation ratio of standard to test has to be agreed. Statistical considerations of efficiency usually favour a 1 : 1 allocation but other issues may predominate such as, for example, the availability of the test compound in a drug trial. The final choice of allocation ratio will influence the number of participants required to some extent and may complicate the informed consent process if (say) an option other than equal allocation is chosen and which may then be more difficult to explain or justify in lay terms.

      Further, as is suggested by the hierarchy of Figure 1.2, the options for presenting the interventions in a blinded or masked manner need to be discussed. In many circumstances, no blinding is possible so that an ‘open’ trial is conducted. In such cases, it is very important that the endpoint assessments are determined in as objective and reproducible manner as is possible.

      If more than two interventions are to be compared, then the number of design options increases and which to choose may crucially depend on the presence or absence of structure of the options under test. For example, if one is comparing three (or more) entirely different drugs none of which can be considered as standard, the chosen design may be quite obviously a parallel three‐group design with randomisation of equal patient numbers assigned to each, although how to determine the appropriate trial size is less clear. Alternatively, if one of the drugs can be considered a standard then strategies for sample size calculation tend to be more clear‐cut, as would be the case if the three drugs were in fact three different doses of the same drug. These issues are discussed in Chapter 12.

      In certain situations, it may be possible to ask two (therapeutic) questions within the same trial design rather than to conduct two separate two‐group trials. For example, in the trial conducted by Yeow, Lee, Cheng, et al. (2007), and which we describe in greater detail in Chapter 12, infants are randomised to one of two types of surgery and also to whether the operation should be undertaken at 6 months or 1 year of age. Thus, the two questions posed concern (i) the choice of surgery and (ii) when the surgery should be performed. The infants recruited to this so‐called 2 × 2 or 22, factorial design, are then randomised to one of the four options in equal proportions.

      However, obtaining the necessary regulatory approval of the trial may inhibit the choice of design that one may wish to conduct. For example, the committee may find unacceptable on ethical grounds the double‐placebo arm in a proposed 2 × 2 factorial design or may suggest that this makes obtaining consent difficult and could therefore compromise the ability to recruit the required numbers of patients. Thus, in some cases, the best experimental design may not be a practical option for the investigation and a balance has to be struck between what is statistically optimal and what is feasible.

      We discuss details of how the size of a trial is determined in Chapter 9.

      

      A crucial role of randomisation is to ensure that there are no systematic differences between the patient groups assigned to the different interventions. To preserve this situation, we need to, at all cost, avoid losing patients subsequent to randomisation, and we want to maximise the probability that the allocated treatment is indeed applied. Hence, it is extremely important to minimise the delays between consent, randomisation and the commencement of therapy.

      In an ideal setting, once a patient has consented to take part in a clinical trial, randomisation should take place immediately. Once the treatment allocation is known, therapy should begin immediately following that. This minimises delay and avoids the patient having the opportunity to change his or her mind before therapy begins. This helps to prevent the dilution that can occur if a patient refuses the allocated treatment or switches to the comparator option in the period between randomisation and starting treatment. As we will discuss later, for purposes of analysis, such patients are retained in the treatment group to which they were allocated. Consequently, for example, a patient who switches from intervention A to B will still be retained in A for analysis, and this will make the effect of B appear more similar to that of A than might truly be the case. Thus, the prospect of dilution should be anticipated at the design stage and all steps taken to reduce this possibility to a minimum.