Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease

Abstract

Background Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective. Methods We used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2). Results Findings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures. Conclusions The MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

Effect of efgartigimod on muscle group subdomains in participants with generalized myasthenia gravis: post hoc analyses of the phase 3 pivotal ADAPT study

“…Patient-reported outcomes are becoming increasingly important for both regulatory authorities (for approval considerations) and payors (for considerations of treatment utilization) [21,23]. With the emphasis shifting toward patient-reported outcomes, several tools sensitive to the domains of ocular, bulbar or generalized weakness have been developed [21,24]. The patient's perspective of gMG is important [23], and thus utilization of a patient-reported scale (e. independently validated.…”

Measuring Overall Severity of Myasthenia Gravis (MG): Evidence for the Added Value of the MG Symptoms PRO

“…In addition to these widely used outcome measures, the MG Symptoms Patient-Reported Outcome (PRO) is a novel PRO measure specific to MG which was developed using the current best standards, which build on extensive direct input from patients [ 11 , 12 ], and which has demonstrated promising psychometric performances [ 13 ]. Integrating the patient voice in clinical decision-making, through PRO measures, has been identified as critical in many contexts, from clinical research [ 14 – 16 ] to routine clinical practice [ 17 , 18 ], and even more specifically in rare diseases [ 19 ].…”

Addressing Outcome Measure Variability in Myasthenia Gravis Clinical Trials

“…1,6,24 More holistic assessments may be needed that measure aspects of the disease not currently captured and that are developed with extensive patient input. 25 A potential limitation of our approach was the lack of a formal consensus process. We did, however, take several steps to ensure the rigor of our process which included multiple and overlapping opportunities for broad stakeholder input, both in the presence of peers (e.g., during symposium) and anonymously (e.g., online surveys).…”

“…1,6,24 More holistic assessments may be needed that measure aspects of the disease not currently captured and that are developed with extensive patient input. 25…”