Importance: Vitamin D deficiency increases the incidence of respiratory virus infections. More than 1 billion people worldwide are vitamin D deficient. If vitamin D deficiency is associated to incidence or severity of SARS-CoV-2 infection, a global call could be made for vitamin D supplementation to mitigate the pandemic. Objective: to determine if lower serum 25-hydroxyvitamin D (25(OH)D) levels are correlated to the risk for COVID-19 and its severity as measured by CT Design: single-center observational study Setting: AZ Delta general hospital Participants: 186 consecutive patients with PCR-confirmed SARS-CoV-2 infection hospitalized for COVID-19 from March 1, 2020 to April 7, 2020 Main outcome and measures: comparative analysis of 25(OH)D levels in patients hospitalized for COVID-19 at various radiological stages and a season/age/sex-matched diseased control population Results: we report on 186 SARS-CoV-2 infected patients requiring hospitalization for severe COVID-19: 109 males (median age 68 years, IQR 53-79 years) and 77 females (median age 71 years, IQR 65-74 years). At admission patients were screened by CT to determine temporal changes of COVID-19 lung disease and classified as stage 1 (ground glass opacities), 2 (crazy paving pattern) and 3 (consolidation). At intake, 25(OH)D levels were measured and compared to a season-matched population of 2717 diseased controls, consisting of 999 males (median age 69 years, IQR 53-81 years) and 1718 females (median age 68 years, IQR 43-83 years). Male and female COVID-19 patients combined showed lower median 25(OH)D than controls (18.6 ng/mL, IQR 12.6-25.3, versus 21.5 ng/mL, IQR 13.9-30.8; P=0.0016) and a higher fraction of vitamin D deficiency (58.6% versus 45.2%, P=0.0005). A strong sexual dimorphism was found: female patients had comparable vitamin D status as control females. Male COVID-19 patients, however, showed markedly higher percentage of vitamin D deficiency than controls (67.0% versus 49.2%, P=0.0006) and this effect was more pronounced with advanced radiological stage ranging from 55.2% in stage 1 to 74% in stage 3. Conclusions and relevance: vitamin D deficiency is a possible risk factor for severe SARS-CoV-2 infection in males. Vitamin D supplementation might be an inexpensive, accessible and safe mitigation for the SARS-CoV-2 pandemic.

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio™, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory.We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.