• James Penston.
• Consultant Physician/Gastroenterologist, Scunthorpe General Hospital, Cliff Gardens, Scunthorpe, North Lincolnshire DN15 7BH, UK. james.penston@nlg.nhs.uk
• Med. Hypotheses. 2005 Jan 1; 64 (3): 651-7.

AbstractLarge-scale randomised trials influence the clinical management of millions of patients throughout the world and are believed to be the most reliable source of evidence on which to base therapeutic decisions. But do they really deserve the accolades bestowed upon them? The decision to perform these studies implies that the treatment difference is expected to be small and, thus, that large numbers of patients are required to achieve statistical significance. This small treatment difference is a direct consequence of limited knowledge of the subject matter which precludes the formation of homogeneous classes of patients with respect to the outcome. In fact, the majority of patients recruited are redundant in the sense that they would not develop the outcome regardless of treatment and, hence, could not participate in testing the efficacy of the drug in question. The conventional view is that randomisation satisfactorily addresses the issues resulting from heterogeneous study populations. However, the statistical approach to causation--which ignores the fundamental features of causal inference characteristic of both everyday discourse and the scientific method--that is used in large-scale randomised trials fails to deliver reliable generalisations even if the many potential obstacles to internal validity are set aside. Moreover, the results of large-scale randomised trials are not open to independent verification. Given the enormous profits to be made from the long-term treatment of common chronic diseases, the absence of any satisfactory method to detect research fraud is of some concern. Fewer than 5% of patients given treatment on the basis of large-scale randomised trials derive any benefit whatsoever. Arguments based on the benefits of such treatment to the wider community of patients are weakened by the dubious external validity of these studies but, in any case, cannot be used to promote the treatment of individual patients. Interestingly, when patients are provided with detailed information about the size of the benefits, most decline treatment. This is hardly surprising as it is debatable whether or not such meagre treatment effects could have any meaning to an individual patient. Large-scale randomised trials continue to be regarded as the gold standard of clinical research. This, of course, merely reflects the ability of powerful vested interests--in particular the pharmaceutical industry--to defy the sound arguments which demonstrate that the methodology of these studies is deeply flawed. Sooner or later, though, common sense must prevail.

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