This marginally housed cohort had greater than expected mortality and high levels of multimorbidity with adverse associations with role function and likelihood of treatment for psychosis. These findings may guide the development of effective health care delivery in the setting of marginal housing.

Background The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli‐derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low‐middle‐income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure Seven biogeneric EcASNases (P1–P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2/dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug‐related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high‐risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch‐to‐batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high‐quality asparaginases remains an unmet therapeutic need.

Our study shows no evidence that total intravenous anesthesia is superior to inhaled anesthesia or vice versa during endoscopic transsphenoidal sinus surgery with regard to relevant clinical outcome parameters.

We thank Drs. Cecconello and Michalowski for their comments.We acknowledge the exceptional efforts of Brazil's physicians and scientists to identify and address the problem of inferior quality asparaginase in their country. 1 We share their concern that the asparaginase experience is potentially representative of a wider global problem of access to quality-assured generic cancer medicines. 2 This concern must be balanced against the requirement of generic products and biosimilars to meet the need for off-patent essential medicines at affordable cost. 3 As observed with generic imatinib, not all generic products are substandard. 4 This then behoves us to identify products suitable for therapeutic use among the variety of generic options in the market. We believe three approaches allow us to address this challenge. The first approach is to establish collaborative multi-institutional clinical groups to standardise disease management and evaluate treatment strategies systematically. 5 As shown by Dr.Cecconello and colleagues, 1 this enables us to begin addressing unmet needs in access to cancer medicines that are safe, suitably tolerated, effective, available in child-friendly formulations and at affordable cost. The second approach is to develop partnerships with pharmaceutical companies to evaluate pharma products, including conducting clinical studies to monitor drug safety and efficacy. This requires companies to recognise the long-term advantages of such a partnership, which includes developing the evidence base for product use in clinical practice and identifying opportunities for innovation. 6 The third approach is to engage patient advocacy groups to raise awareness and support for clinical studies that evaluate generic medicines and to identify generic products suitable for therapeutic use. This latter approach has received a fillip with launch of the World Health Organisation's Global Initiative for Childhood Cancer in 2018. 7 Collectively, we believe these approaches bear the promise of ensuring access to high-quality generic medicines for paediatric cancers.

No abstract