Patient Reported Outcome (PRO) assessment in epilepsy: a review of epilepsy-specific PROs according to the Food and Drug Administration (FDA) regulatory requirements.

Annabel Nixon,Katie Breheny,Cicely Kerr,Diane Wild

doi:10.1186/1477-7525-11-38

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.

Highlights

Epilepsy is defined by the recurrence of spontaneous/unprovoked seizures and covers a range of clinical situations in terms of age of onset, type of seizures, aetiological background, resulting handicap, prognosis, and response to treatment [1]
Following instrument retrieval and initial review, 133 of these were excluded as they were found to be not epilepsy specific (n = 52), not for adult patient completion (n = 42), not to target a concept that could be potentially impacted by pharmacological treatment (n = 20) or instruments comprising single items that did not form a scale and/or for which no documentary evidence of validation could be located (n = 19)
This review identified that the Subjective Handicap of Epilepsy (SHE) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) met more of the regulatory requirements in terms of measurement properties, with both scales meeting four of the eight measurement properties evaluated

Summary

Introduction

Epilepsy is defined by the recurrence of spontaneous/unprovoked seizures and covers a range of clinical situations in terms of age of onset, type of seizures, aetiological background, resulting handicap, prognosis, and response to treatment [1]. The assessment of efficacy in clinical studies evaluating AEDs is generally focused on seizure frequency/occurrence in line with regulatory guidelines [1]. A PRO is defined as any report of the status of a patient’s health condition that comes directly from the patient without interpretation of the patient’s response by a clinician or anyone else [5]. Given that epilepsy is a complex disorder, which affects patients’ psychological health, independence, emotional adjustment and employment [6] there is a strong case for evaluating the impact of AEDs on broader aspects of patient’s lives, and previous studies have identified potential areas of patient’s lives that may be enhanced if epilepsy symptoms were improved [7]. It is unsurprising that PROs have been widely incorporated into clinical trials evaluating AEDs [8,9,10]

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