Evidence for Frequency of Monitoring

The natural history of SMA in adults is that of a slowly progressive functional decline, where the common motor outcome assessment Hammersmith Functional Motor Scale Expanded (HFMSE) decreases by 0.5 points per year. ^{Reference Wadman, Wijngaarde and Stam8} Existing evidence and the marker of clinically meaningful change used in clinical trials for the HFMSE are 3 points. Based on the natural history and meaningful change on the HFMSE, this suggests patients not on therapy may require 6 years to demonstrate “statistically significant” decline. Recent evidence suggests that in response to nusinersen therapy for adult patients, clinically meaningful change on the HFMSE is seen in only 28%, 35%, and 40% of cases at 6, 10, and 14 months, respectively (Reference Hagenacker, Wurster and Günther5). Statistically significant changes were also observed for the Revised Upper Limb Module (RULM) and 6-minute-walk-test (6MWT) at these time points. This is consistent with the smaller prior observational study in adults demonstrating benefit of nusinersen at day 180 (6MWT and peak cough flow) and day 300 (6MWT and RULM). ^{Reference Walter, Wenninger and Thiele6} All motor outcome assessments currently used are expected to demonstrate clinically meaningful change only after a 1- to 2-year period. A concern is that a decline in outcome measures on treated patients in the span of 4 months is more likely to be secondary to inter- or intra-examiner variability or patient effort than a true effect. This potential artificial decline in outcome measure scores could lead to inappropriate termination of therapy provision based on stop criteria.

Human Resource Strain and Patient Burden

In certain jurisdictions where regular 4 monthly monitoring has been mandated, resource allocation is a concern as these motor outcome assessments are time-consuming and personnel intensive. Certain assessments must be performed by physical therapists, others by respiratory therapists; this coordinated assessment is not readily available outside of multidisciplinary motor neuron disease clinics or some rehabilitation center clinics for this population. Additionally, therapists must be trained in these measures to perform them accurately thus compounding limitations on personnel. There are ethical concerns when provincial governments mandate that scarce resources be utilized to provide frequent monitoring for largely stable patients for whom such frequent testing is not clinically relevant, nor evidence-based. This leaves fewer resources available for patients with other forms of motor neuron diseases or other neuromuscular conditions who may be rapidly progressing and in need of significant supports.

Additionally, frequent clinic visits can be challenging for patients; they are fatiguing, time-consuming, and sometimes costly depending on the degree of travel involved.

Collection of Real-World Evidence

Through the Canadian Neuromuscular Disease Registry (CNDR), an observational initiative to collect real-world evidence on SMA patients, both pediatric and adult SMA working groups comprised of expert investigators across the country have agreed to q6–q12 monthly monitoring of patients irrespective of therapeutic status. The registry is set up with a clear plan to assess effectiveness of novel therapies in a broad population.

The Canadian adult SMA physician working group are evaluating specific assessments by way of a Delphi model to incorporate best practices for the Canadian landscape (manuscript in preparation).

Proposition for Appropriate Monitoring

A recent CNDR meeting (January 20, 2020) convened adult experts in SMA from across Canada to agree on recommendations for frequency of monitoring. Final consensus included baseline visit, 6-months post-therapy initiation, and annually thereafter.

This proposed monitoring regimen allows for appropriate clinical monitoring, is congruent with the available evidence in treated adults, and does not put undue burden on provincial and clinic resources. Importantly, this standardized approach to SMA monitoring in Canada may prevent over-burdening patients and their families, for whom frequent clinic attendance is tiring, costly, and disruptive. The shared goal of the health care system is to provide a standard of care which is acceptable for patients, maintains appropriate resource allocation for all populations, and is feasible for the clinics. We believe our proposed monitoring system achieves these goals.

Declarations

Dr. Hodgkinson reports personal fees from Biogen, Roche, Sarepta outside the submitted work. Dr. Chapman reports personal fees from Biogen, Roche, outside the submitted work. Dr. Izenberg reports personal fees from Biogen, Roche, Akcea, Alexion, Takeda, Alnylam, Genzyme, outside the submitted work. Dr. Lochmuller reports grants and personal fees from Amplo Biotechnology, AMO Pharma, Biogen, Desitin, Fulcrum Therapeutics, GW Pharma, Milo Biotechnology, Pfizer, PTC Therapeutics, Roche, Santhera, Sarepta, Satellos, Ultragenyx, outside the submitted work, and Editor-in-chief, Journal of Neuromuscular Diseases (IOS Press). Dr. O’Connell reports personal fees from MT Pharma, grants and personal fees from Canopy Growth, personal fees from IPSEN, grants from Cytokinetics, grants from Mallinckrodt, grants from Orion, personal fees from Shoppers Drug Mart, outside the submitted work. Dr. O’Ferrall reports personal fees from PTC Therapeutics nmDMD Advisory Board; grants from Sanofi Genzyme, grants from Acceleron, grants from SAnofi Genzyme, grants from Grifols, outside the submitted work. Dr. Oskoui reports grants from Fonds de Recherche Sante du Québec, grants from Kids Brain Health Network, grants from Canadian Institutes of Health Research, grants from SickKids Foundation, grants from Cerebral Palsy Alliance Research Foundation, Fondation du Grand Defi Pierre Lavoie, outside the submitted work and served as site investigator on SMA clinical trials by Biogen, Roche, Cytokinetics. Dr. Pfeffer has nothing to disclose. Dr. Plamondon reports personal fees from Biogen, outside the submitted work. Dr. Rodrigue reports personal fees from Biogen, Roche outside the submitted work. Dr. Shoesmith reports other from Biogen, outside the submitted work, and Dr. Shoesmith’s spouse is employed by Roche. Dr. Warman Chardon has nothing to disclose. Dr. Brais reports other from Biogen, Roche, outside the submitted work. Dr. Korngut reports grants from Biogen, Sanofi Genzyme, Cytokinetics, personal fees from Alexion, Novartis, Mitsubishi Tanabe, Sarepta, Biogen, CSL Behring, outside the submitted work. Dr. Schellenberg reports grants from Allergan, Genzyme, Mitsubishi Tanabe, personal fees from Akcea, Genzyme, EMD Serono, Alexion, Biogen, Mitsubishi-Tanabe, Roche, outside the submitted work.