Clinical practice and the development of evidence

Abstract

Editorial: “There is little robust empirical evidence on which to base treatment recommendations for fatty acid oxidation disorders. While consensus guidelines are important, understanding areas where there is a lack of consensus is also critical to inform priorities for future evaluative research.” This is the opening sentence of the paper by Potter and colleagues (doi:10.1007/ s10545-011-9352-2) describing the practice of Canadian metabolic physicians treating fatty acid oxidation defects. It is certainly true that research in this area is badly needed, especially now, since the advent of newborn screening, as many more patients are diagnosed than formerly, and a goodly proportion are asymptomatic – some perhaps never needing any intervention at all. The problem of finding evidence of effectiveness of treatment for rare disorders is well recognised, and is particularly relevant to inborn errors of metabolism. Various consensus-based methods have been developed which make use of all existing empirical evidence, combined with expert opinion, in a systematic way. Best known is perhaps the Delphi method in which a panel of experts respond to a questionnaire. The responses and commentaries are collated by a moderator, who resends this to panel members. They may then reconsider and perhaps alter their original responses. This may happen more than once. The iterative process, ideally carried out anonymously, aims to achieve consensus. There is a problem with this as with other consensus methods, as findings may be translated, either formally or informally, into a standard of practice, but without any extra evidence. The consensus practice might be plain wrong, or at the least, not beneficial. The paper published here (Potter et al. 2011) is different: it was not designed to point the way to a consensus on treatment, but rather to underline what was the variation of views on the desirable treatment. In their study, they asked physicians how certain conditions would be treated in their centres, and identified areas of difference. Is knowledge of lack of consensus helpful in pointing the way to future research? Certainly, as the authors suggest, it may show areas of clinical equipoise, allowing the establishment of a formal randomised controlled trial of treatment versus no treatment for one individual element of management. The opinions were those of only a small number of metabolic physicians, not all with great experience. However, experience and knowledge of the literature does not always translate into practice: a meeting of internationally known metabolic physicians agreed that there was no evidence for the use of carnitine in MCAD deficiency, but most indicated that they would prescribe it if circulating levels were shown to be very low (Spiekerkeoetter et al. 2010). At present we are stuck for the most part with opinion and a few papers offering guidance based on practice. For very-longchain acyl CoA dehydrogenase deficiency, for example, substituting some dietary long-chain fat by medium-chain triglyceride (MCT) was thought to be indicated (Spiekerkoetter et al. 2009) but recently work with mouse models indicates that MCT used chronically, as opposed to episodically before excercise, may not be helpful, but instead be significantly harmful (Tucci et al. 2011). Well-designed trials are badly needed. For those situations where there is clinical uncertainty these could indeed be multicentred randomised controlled trials, a challenge, considering especially the problem of endpoints, but one that must be taken up. Communicated by: Verena Peters