title: Patient Reported Outcome (PRO) assessment in epilepsy: a review of epilepsy-specific PROs according to the Food and Drug Administration (FDA) regulatory requirements.
abstract: Despite collection of patient reported outcome (PRO) data in clinical trials of antiepileptic drugs (AEDs), PRO results are not being routinely reported on European Medicines Agency (EMA) and Food and Drug Administration (FDA) product labels. This review aimed to evaluate epilepsy-specific PRO instruments against FDA regulatory standards for supporting label claims. Structured literature searches were conducted in Embase and Medline databases to identify epilepsy-specific PRO instruments. Only instruments that could potentially be impacted by pharmacological treatment, were completed by adults and had evidence of some validation work were selected for review. A total of 26 PROs were reviewed based on criteria developed from the FDA regulatory standards. The ability to meet these criteria was classified as either full, partial or no evidence, whereby partial reflected some evidence but not enough to comprehensively address the FDA regulatory standards. Most instruments provided partial evidence of content validity. Input from clinicians and literature was common although few involved patients in both item generation and cognitive debriefing. Construct validity was predominantly compromised by no evidence of a-priori hypotheses of expected relationships. Evidence for test-retest reliability and internal consistency was available for most PROs although few included complete results regarding all subscales and some failed to reach recommended thresholds. The ability to detect change and interpretation of change were not investigated in most instruments and no PROs had published evidence of a conceptual framework. The study concludes that none of the 26 have the full evidence required by the FDA to support a label claim, and all require further research to support their use as an endpoint. The Subjective Handicap of Epilepsy (SHE) and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) have the fewest gaps that would need to be addressed through additional research prior to any FDA regulatory submission, although the NDDI-E was designed as a screening tool and is therefore unlikely to be suitable as an instrument for capturing change in a clinical trial and the SHE lacks the conceptual focus on signs and symptoms favoured by the FDA.
authors.affiliation: Oxford Outcomes, an ICON Plc. Company, Seacourt Tower, West Way, Oxford, OX2 0JJ, UK. annabel.nixon@oxfordoutcomes.com
authors.forename: Annabel
authors.initials: A
authors.lastname: Nixon
authors.forename: Cicely
authors.initials: C
authors.lastname: Kerr
authors.forename: Katie
authors.initials: K
authors.lastname: Breheny
authors.forename: Diane
authors.initials: D
authors.lastname: Wild
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D033161:Government Regulation; D006801:Humans; D007880:Legislation, Drug / Q000592:standards; D017063:Outcome Assessment, Health Care / Q000331:legislation & jurisprudence / Q000592:standards; D015203:Reproducibility of Results; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence*
chemical_list: D000927:Anticonvulsants