Guidelines in the JIMD: Evidence-based practice for inherited metabolic disease

Since Sackett et al. stated that ‘Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’, randomised clinical trials (RCTs) and meta-analysis have become established as the cornerstone of evidence-based practice.1 However, such studies remain challenging for ultra-rare disorders including the 1500 or so known inherited metabolic diseases (IMDs).2 RCTs in such patient populations are frequently underpowered3 and are also confounded by genetic variability between affected individuals, variable pre-treatment manifestations, a lack of standard of care comparators and dearth of clinically relevant outcome measures.4 Frequently, treatment effects can be assessed through comparisons with well-characterised historical cases, and the JIMD is dedicated to publishing comprehensive cohort studies for IMDs with detailed clinical, functional and genetic data. In the absence of data from RCTs, clinical practice guidelines established by experts in the field using standardised methodology can help to guide evidence-based practice. Guidelines are important tools for our care of, and advocacy for, children and adults with (ultra)rare IMDs. In contrast to more common disorders, for which there is often a wealth of data from clinical studies, the evidence base for IMDs is limited, and recommendations for diagnosis and management are often based on expert consensus. Increasingly, such consensus is accomplished using methodology, such as the Delphi approach, although this is by no means uniform.5 The more recent GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation6) may be more suitable for the rare disease field, as it partially accounts for the above described challenges. Recognising the variable limitations, guidelines published in peer-reviewed journals set a standard for multiple stakeholders, including clinicians, researchers, health services, regulatory agencies and patient advocacy groups. A published guideline can facilitate access to services or therapies, provide directions for clinical researchers and be accepted as standard of care by agencies. In a special online issue of the journal accompanying this editorial, we bring together a collection of guidelines and position papers published in the Journal of Inherited Metabolic Disease. These include guidelines for the management of organic acidurias,7-9 urea cycle disorders,10 cobalamin-related remethylation disorder,11 galactosaemia,12 congenital disorders of glycosylation,13-16 acute porphyria,17 phenylketonuria,18 pyridoxine-dependent epilepsy19 and mitochondrial neurogastrointestinal encephalomyopathy,20 as well as guidelines for neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy21 and for safe drug prescribing in primary mitochondrial disorders.22 We hope that collating these high-quality clinical practice guidelines will be an invaluable resource to aid our readership in improving the diagnosis and treatment of patients with IMDs and help them to optimise care pathways. Guidelines must be dynamic; recommendations must be amended to reflect the growth in our understanding of the disorder. It must always be borne in mind that guidelines are intended as a tool to provide direction to their readers based on the sum of knowledge and experience at the time of publication. They are neither set in stone, nor immutable, and should not replace clinical judgement, or responsibility. ‘It's about integrating individual expertise with the best external evidence’—Sackett's words of wisdom from almost three decades ago continue to resonate.1 The authors declare no conflicts of interest.