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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first randomised trial was planned to test the value of a pertussis vaccine to prevent whooping-cough and the results of which were subsequently published by the Medical Research Council Whooping‐Cough Immunization Committee (1951). He later stated: ‘The aim of the controlled clinical trial is very simple: it is to ensure that the comparisons we make are as precise, as informative, and as convincing as possible’. This development by itself may not have led to more theoretically based statistical innovation directly, but was the foundation for the science of clinical trials.

      One of the most famous clinical trials was that conducted by James Lind (1716–1794) in 1747. He compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of sailors afflicted by scurvy and found that the group who were given oranges and lemons had largely recovered from their scurvy after 6 days. Somewhat later, Frederick Akbar Mahomed (1849–1884) founded the Collective Investigation Record for the British Medical Association. This organisation collated data from physicians practising outside the hospital setting and was an important precursor of modern collaborative clinical trials.

Tabular representation of Avicenna’s rules for the experimental use and testing of drugs

      It should not go unnoticed that David Roxbee Cox was one of the authors of the seminal papers referred to above although his paper describing the proportional‐hazards regression model appeared some 4 years earlier (Cox, 1972). His paper was presented at a discussion meeting of the UK Royal Statistical Society and subsequently published in Series B of the Society’s journals. This journal deals with the more theoretical aspects of statistical research and does not make easy reading for many statisticians and would not be one to which clinical teams might readily refer. Despite this, this particular paper is probably one of the most cited papers in the medical literature. In brief, the methodology leads to easier analysis of trials with survival time endpoints that include stratification in their design and/or baseline patient characteristics at the time of randomisation which may affect prognosis.

      As we have indicated, EBM requires that it is important to critically assess all the available evidence about whether an intervention works. Thus, systematic overviews have become a vital component of clinical trial research and are routinely applied before launching new trials as a means of confirming the need to carry out a clinical trial or after completing trials as a means of synthesising and summarising the current knowledge on the topic of interest. These reviews are the focal interest of the Cochrane Collaboration, and the associated handbook by Higgins, Thomas, Chandler, et al. (2019) provides the key to their implementation.

      Some developments have not depended on technical advancement (although there are always some) such as the now standard practice of reporting confidence intervals rather than relying solely on p‐values at the interpretation stage. Of major importance over this same time period has been the expansion in data processing capabilities and the range of analytical possibilities only made feasible by the amazing development in computer power. Despite many advances, the majority of randomised controlled trials remain simple in design – most often a two‐group comparison.

Schematic illustration of sequential phases of developing randomised controlled trials of complex interventions.

      Source: Campbell, Fitzpatrick, Haines, et al., (2000).

      The steps range from studies to determine the pharmacokinetic profile of a drug in healthy volunteers (Preclinical) to establishing the appropriate dosage for use in man (Phase I), then the establishment of indications of activity (Phase II). However, some of these steps may be taken in parallel and even simultaneously in the same subjects.

      These early studies are not usually randomised. However, studies conducted by Krishna, Anderson, Bergman, et al. (2007) on the effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia are described by them as ‘randomized’ and ‘phase I’. Randomised they undoubtedly are but their use of the Phase I nomenclature does not have an exact parallel in Figure 1.4. This highlights a difficulty when attempting to categorise trials using such a simple system. One may imagine that there will be clear stages in the development of a bioabsorbable coronary stent. These too will not exactly parallel those of drug development although they may well involve laboratory and animal studies. The single‐arm trial of Erbel, Di Mario, Bartunek, et al. (2007) may be considered as close to the Phase II type or a feasibility study of Chapter 19.