LAUSR

In the early days of randomised control trials the ability to reduce confounding fromknownand unknown confounders rightly underpinned their rapid rise in methodological popularity. Ever since, however, concerns have been expressed by the clinician community and others about the difficulty of applying estimates of effects derived from randomised control trials to settings and patient populations outside those in which randomised control trials have often been done. Applicability, also known as generalisability or external validity, is important because systematic reviews of randomised control trials are used to inform decisions about whether patients in the wider world, that is, outside the trials contributing to systematic reviews,would benefit from receiving the treatment evaluated in those systematic reviews. These decisions take for granted that random allocation is required to minimise confounding in making treatment comparisons. Rather, they consider the similarity or differences between patients, practitioners, settings and approaches between the care of the patients in the trials included in systematic reviews, and those of patients, settings and care of patients outside the trials. This article provides an account of how, since the 1960s, an unfolding understanding of the issue of applicability led to the recognition that there might be different purposes for different kinds of randomised trials. Following publication of the iconic report of the United KingdomMedical Research Council’s randomised trial of streptomycin for pulmonary tuberculosis in 1948, expository articles setting out the characteristics of and ground rules for randomised control trials began to appear, among which the best known are two articles by Austin Bradford Hill, a British statistician. By the end of the 1950s, the Council for International Organizations of Medical Sciences (established under the auspices of UNESCO and the WHO) had recognised that randomised control trials were of such importance that it convened an international conference to discuss them in Vienna, and asked Bradford Hill to organise it. All the formal presentations were by British investigators, and their papers were published in a book edited by Hill, Bird and Chalmers. The proceedings were also translated into French and published in a book edited by Daniel Schwartz – a French statistician – and three French statistician colleagues. At this early stage of its development, the purpose of a randomised trial was seen as singular and self-evident: to use randomisation to create groups comparable on known and unknown confounders, and thus obtain unbiased estimates of the effects of two or more interventions. In 1966, Marvin Schneiderman, a statistician at the US National Cancer Institute who had been involved in trials of cancer therapy in the early 1950s, summarised his thinking in a working paper prepared for a WHO Expert Committee on Cancer Treatment. His report noted that the singular purpose of randomised control trials had become dual: