The multi-system involvement and heterogeneity that characterize myotonic dystrophy (DM) have fostered several efforts to design patient-reported outcome measures (PROMs) for clinical studies and trials. The intent of PROMs is to use patient feedback in design and implementation of validated questionnaires that can simultaneously capture changes across the challenging symptomology of DM while obtaining clinically meaningful information to support regulatory approval. While PROMs can prove insightful as an analytic tool for complex disorders, the potential barriers to PROM design, development, and interpretation are such that the Food and Drug Administration (FDA) developed a Guidance for Industry document (pdf) to aid in development of PROMs. Choice of PROMs for use in interventional trials must then be carefully informed.
Dr. Tara Symonds and her colleagues at Clinical Outcomes Solutions (COS) recently reported out a literature review of available PROMs that focus on type 1 myotonic dystrophy (DM1). COS a is health economics and outcomes research consulting group with considerable experience in understanding PROM design and implementation in clinical studies. Disclosure: The COS project was funded by Biogen, a company engaged in therapy development in DM1.
Dr. Symonds and her group evaluated a health status measure (MDHI), three activities of daily living scales (DM1-Activ, DM-Activc, and Life-H), two health related quality of life measures (INQoL & INQoL Serbian), and five sleep and fatigue measures (ESS, DSS, CFS, FSS, and FDSS) comparing their validity, reliability, and ability to detect change of each to guide choice of PROMs for use in DM1 studies.
MDHI was viewed as the only measure that attempted to capture all aspects of a DM1 patient's life that were impacted. Design of MDHI specifically for DM, internal consistency of the tool across domains assessed, test-retest reliability, and design in compliance with FDA’s Guidance for Industry were viewed as favorable traits. It was also noted that construct validity had been established for MDHI via comparison with a variety of existing functional measures (e.g., MMT, grip testing, and timed function tests).
DM1-Activ also was considered to have good validity and reliability and showed construct validity when compared to various manual testing measures and the Muscular Impairment Rating Scale (MIRS).
Most other PROMs assessed by the authors were viewed as more limited in capability and performance, and all PROMs were thought to require further assessment of responsiveness and meaningful change thresholds in interventional clinical trials. Dr. Symonds and team concluded that MDHI is arguably the best measure for use in clinical studies and trials provided that the critical areas of responsiveness and definition of meaningful change to patient are addressed. DM1-Activ also was deemed to have potential as a PROM in interventional trials, as long as content validity is explored further and the issues of responsiveness and meaningful change prove acceptable. Other measures were considered acceptable in evaluation of specific domains of the symptomatology of DM1.
FDA’s Guidance for Industry supports the use of well-designed and implemented PROMs as putative primary endpoint measures for clinical trials. Even as a secondary measure, a carefully selected PROM can bring considerable value to clinical trials, not the least is insight into meaningful benefit to the patient. The publication by Dr. Symonds and colleagues provides an evaluation of currently available tools by experts outside of the DM community. While current drug discovery and development efforts have focused on skeletal muscle function, desired treatments for DM will have to address a much wider disease burden. Validated and reliable PROMs with an ability to capture changes in multiple symptoms important to DM1 patients may prove to be a valuable tool in natural history studies and definitive clinical trials.
A Review of Patient Reported Outcome Measures for Use in DM1 Patients
Symonds T, Randall JA, Campbell P.
Muscle Nerve. 2016 Nov 11. doi: 10.1002/mus.25469.