Variability in Newborn Screening Across Canada: Spinal Muscular Atrophy and Beyond.

BACKGROUND: Newborn screening (NBS) identifies infants with severe, early-onset diseases, enabling early diagnosis and treatment. In Canada, decisions regarding disease inclusion in NBS programs occur at the provincial level, which leads to variability in patient care. We aimed to determine whether important differences exist in NBS programs across provinces and territories. Given that spinal muscular atrophy (SMA) is the most recent disease added to NBS programs, we hypothesized that its inclusion would show interprovincial variability and be more likely in provinces already screening for a greater number of diseases. METHODS: We conducted a cross-sectional survey of all NBS labs in Canada to understand: 1) what conditions were included in their program; 2) what genetic-based testing was performed and; 3) if SMA was included. RESULTS: All NBS programs (N = 8) responded to this survey by June 2022. There was a 2.5-fold difference in the number of conditions screened (N = 14 vs N = 36) and a 9-fold difference in the number of conditions screened by gene-based testing. Only nine conditions were common to all provincial NBS programs. NBS for SMA was performed in four provinces at the time of our survey, with BC recently becoming the fifth province to add SMA to their NBS on October 1, 2022. Currently, 72% of Canadian newborns are screened for SMA at birth. CONCLUSION: Although healthcare in Canada is universal, its decentralization gives rise to regional differences in NBS programs which creates inequity in the treatment, care, and potential outcomes of affected children across provincial jurisdictions.

Caregiver Burden of Spinal Muscular Atrophy: A Systematic Review.

OBJECTIVE: The objective of our study was to review, synthesize, and grade published evidence of caregiver burden of spinal muscular atrophy (SMA), a rare autosomal-recessive neuromuscular disease. METHODS: We searched Embase and PubMed for full-text articles published from inception up until 28 February, 2022, reporting results from studies of caregiver burden (i.e., negative aspects of providing informal care) in SMA. Two investigators independently screened article titles and abstracts for eligibility, reviewed full-text versions of selected records, extracted the data, and assessed risk of bias using the Newcastle-Ottawa Scale. The evidence was synthesized to answer the following questions: (1) In which geographical settings have the caregiver burden of SMA been studied? (2) What aspects of the caregiver burden of SMA have been investigated? (3) What instruments have been used to measure the caregiver burden of SMA? (4) What is known of the caregiver burden of SMA? (5) How is the caregiver burden of SMA impacted by available disease-modifying drugs? RESULTS: We identified 15 publications, covering samples from a total of ten countries (i.e., Australia, Canada, China, France, Germany, Romania, Spain, Turkey, the UK, and the USA), reporting estimates of caregiver burden derived using data recorded via surveys or interviews. The most common instruments used to measure caregiver burden were the Zarit Caregiver Burden Interview, the EQ-5D-5L, and the PedsQL Family Impact Model. Caregiving in SMA was found to be associated with reduced health-related quality of life, impaired family function, depression and anxiety, strain, and stress, as well as a substantial impact on work life and productivity. Evidence of the impact of disease-modifying drugs on caregiver burden in SMA was scarce. CONCLUSIONS: Caregivers to patients with SMA were found to be subject to a significant burden, including impaired health-related quality of life, reduced work ability and productivity, and financial stress, and many devote a substantial proportion of their time to provide informal care. Yet, the current body of literature is relatively scarce and more research is needed to better understand the clinical implications of informal caregiving in SMA and the relationship between caregiver burden and SMA types, as well as the impact of new disease-modifying treatments. Our synthesis will be helpful in informing clinical and social support programs (e.g., the routine screening of depression among caregivers, as well as financial support schemes to help manage the long-term day-to-day care) directed towards families caring for patients with SMA.

Costs of Illness of Spinal Muscular Atrophy: A Systematic Review.

OBJECTIVES: The objective of our study was to conduct a systematic literature review of estimates of costs of illness of spinal muscular atrophy (SMA). METHODS: We searched MEDLINE (through PubMed), CINAHL, Embase, Web of Science, National Health Service Economic Evaluation Database, and the National Health Service Health Technology Assessment Database for studies published from inception up until 31 August, 2020, reporting direct medical, direct non-medical, and/or indirect costs of any phenotype of SMA. Two reviewers independently screened records for eligibility, extracted the data, and assessed studies for risk of bias using the Newcastle-Ottawa Scale. Costs were adjusted and converted to 2018 US dollars. RESULTS: The search identified 14 studies from eight countries (Australia, France, Germany, Italy, Spain, Sweden, the UK, and the USA). The mean per-patient annual direct medical cost of illness was estimated at between $3320 (SMA type III, Italy) and $324,410 (SMA type I, USA), mean per-patient annual direct non-medical cost between $25,880 (SMA types I-III, Spain) and $136,800 (SMA type I, Sweden), and mean per-patient annual indirect cost between $9440 (SMA type I, Germany) and $74,910 (SMA type II, Australia). Most studies exhibited a risk of bias. CONCLUSIONS: The current body of evidence of costs of illness of SMA is relatively scarce and characterized by considerable variability across geographical settings and disease phenotypes. Our review provides data pertaining to the economic impact of SMA, which is of particular relevance in light of emerging treatments and ongoing research in this field, and underscores the substantial unmet medical need in this patient population.

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Medical students' perception of lesbian, gay, bisexual, and transgender (LGBT) discrimination in their learning environment and their self-reported comfort level for caring for LGBT patients: a survey study.

BACKGROUND: Historically, medical students who are lesbian, gay, bisexual or transgendered (LGBT) report higher rates of social stress, depression, and anxiety, while LGBT patients have reported discrimination and poorer access to healthcare. OBJECTIVE: The objectives of this study were: (1) to assess if medical students have perceived discrimination in their learning environment and; (2) to determine self-reported comfort level for caring for LGBT patients. DESIGN: Medical students at the University of Ottawa (N = 671) were contacted via email and invited to complete a confidential web-based survey. RESULTS: Response rate was 15.4% (103/671). This included 66 cis-gender heterosexuals (64.1%) and 37 LGBT students (35.9%). Anti-LGBT discrimination had been witnessed by 14.6% and heterosexism by 31.1% of respondents. Anti-LGBT discrimination most often originated from fellow medical students. Respondents who self-identified as LGBT were more likely to have perceived heterosexism (favoring opposite-sex relationships) (OR = 8.2, p < 0.001) or anti-LGBT discrimination (OR = 6.6, p = 0.002). While half of LGBT students shared their status with all classmates (51.4%), they were more likely to conceal this from staff physicians (OR = 27.2, p = 0.002). Almost half of medical students (41.7%) reported anti-LGBT jokes, rumors, and/or bullying by fellow medical students and/or other members of the healthcare team. Still, most respondents indicated that they felt comfortable with and capable of providing medical care to LGBT patients (≥83.5%), and were interested in further education around LGBT health issues (84.5%). CONCLUSION: Anti-LGBT discrimination and heterosexism are noted by medical students, indicating a suboptimal learning environment for LGBT students. Nonetheless, students report a high level of comfort and confidence providing health care to LGBT patients.