Clinical outcome assessments in Pompe disease: a pragmatic review of their validity, concept coverage, and value in clinical practice and clinical research

Abstract Background Pompe disease is a rare, autosomal recessive, neuromuscular disorder caused by a deficiency in the acid alpha-glucosidase enzyme leading to the build-up of glycogen within lysosomes, which can result in severe cardiac, pulmonary, and skeletal disorders. The age of onset is variable, with phenotypes ranging from the rapidly progressive infantile-onset to the late-onset Pompe disease. Disease severity varies by age of onset, with progressive muscle weakness leading to diminished health-related quality of life. The introduction of enzyme replacement therapy has greatly improved prognosis for patients, but considerable morbidity and humanistic burden remain. Although symptoms and clinical signs are used to assess and aid treatment decisions, there is a need for sensitive clinical outcome assessments (COAs) that are patient relevant, valid, and reliable in order to provide evidence of treatment benefit. This research aimed to identify the optimal COAs for use in clinical research for the management of individuals with Pompe disease. Methodology A targeted literature search identified qualitative studies in Pompe disease populations, which formed the basis of a conceptual model and provided an overview of the patient experience. A second search resulted in a list of COAs used in Pompe disease research from published literature, regulatory submissions, health technology assessments, and clinical trials. A third literature search explored the psychometric validity of selected COAs that addressed the earlier concepts and were considered suitable for evaluating treatment outcomes in patients with Pompe disease. Results Based on the face and content validity of each COA identified in the searches, together with evidence of psychometric validity, six COAs that have concept coverage, validity, and sensitivity to change were considered suitable for assessing disease status and impact, and for guiding treatment decisions in adult patients with Pompe disease, and a further four for pediatric use. Conclusion Following rigorous pragmatic searches of the published literature, no single COA was identified that captures all the domains that are relevant to adults or infants with Pompe disease. The findings provide initial support for the use of the recommended COAs in Pompe disease, but additional research is needed to validate these findings.