Objective: The objectives of this study were 1) to identify the medicines approved for the treatment of restless legs syndrome (RLS) by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA); 2) to find out about the use of clinical outcome assessments (COAs) in the approval process. COAs measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions. There are four types of COAs: patient-reported outcome (PRO), clinician-reported outcome (ClinRO), observer-reported outcome (ObsRO), and performance outcome (PerfO) measures; and 3) to identify the COAs endpoint positioning.

Background: RLS is a neurologic sensorimotor disorder characterized by an irresistible urge to move the legs when they are at rest. The urge to move is usually due to unpleasant feelings in the legs. Treatment includes lifestyle changes and use of medicines.

Methods: The EMA and FDA websites were explored to identify all medicines approved for RLS. The PROLabels database, through the ePROVIDE platform, was used for labeling claim identification. All corresponding labels were reviewed for endpoint positioning.

Results: The agencies approved nine products with RLS indication (representing four INN, i.e., gabapentin, pramipexole, rotigotine, ropinirole); four products were approved by the FDA, and five by the EMA, including one generic of pramipexole. For the products approved by both agencies (n=2), the sponsors submitted the same data for approval. All products were evaluated using the same PRO measure, i.e., the International Restless Legs Syndrome Study Group Rating Scale (IRLS), which assesses disease severity. All had a similar claim, i.e., improvement in baseline IRLS score. The mean change from baseline in IRLS was a co-primary efficacy endpoint. The other COA used to develop a co-primary efficacy endpoint was a ClinRO, either a Clinical Global Impression scale of Improvement (CGI-I) or a Clinical Global Impression scale of Illness Severity.

Conclusions: The patient’s perspective is of paramount importance in the evaluation of medicines approved for RLS. The clinician input is also considered as a valuable endpoint since all evaluations were based on the use of co-primary PRO/ClinRO.

References: Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Dec 13;87(24):2585-2593.

Food and Drug Administration. (2009). Guidance for Industry. Patient-reported outcome measures: Use in medical product development to support labeling claims. Federal Register, 74(35), 65132–65133.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-clinical-outcome-assessment-coa-data-in-the-drug-approval-process-of-medicines-for-the-treatment-of-restless-legs-syndrome-rls-a-review-of-the-labels-of-medicines-approved-by-the-fda/