Comparison between centralized and decentralized supply chains of autologous chimeric antigen receptor T-cell therapies: a UK case study based on discrete event simulation

Background aimsDecentralized, or distributed, manufacturing that takes place close to the point of care has been a manufacturing paradigm of heightened interest within the cell therapy domain because of the product's being living cell material as well as the need for a highly monitored and temperature-controlled supply chain that has the potential to benefit from close proximity between manufacturing and application.MethodsTo compare the operational feasibility and cost implications of manufacturing autologous chimeric antigen receptor T (CAR T)-cell products between centralized and decentralized schemes, a discrete event simulation model was built using ExtendSIM 9 for simulating the patient-to-patient supply chain, from the collection of patient cells to the final administration of CAR T therapy in hospitals. Simulations were carried out for hypothetical systems in the UK using three demand levels—low (100 patients per annum), anticipated (200 patients per annum) and high (500 patients per annum)—to assess resource allocation, cost per treatment and system resilience to demand changes and to quantify the risks of mix-ups within the supply chain for the delivery of CAR T treatments.ResultsThe simulation results show that although centralized manufacturing offers better economies of scale, individual facilities in a decentralized system can spread facility costs across a greater number of treatments and better utilize resources at high demand levels (annual demand of 500 patients), allowing for an overall more comparable cost per treatment. In general, raw material and consumable costs have been shown to be one of the greatest cost drivers, and genetic modification-associated costs have been shown to account for over one third of raw material and consumable costs. Turnaround time per treatment for the decentralized scheme is shown to be consistently lower than its centralized counterpart, as there is no need for product freeze-thaw, packaging and transportation, although the time savings is shown to be insignificant in the UK case study because of its rather compact geographical setting with well-established transportation networks. In both schemes, sterility testing lies on the critical path for treatment delivery and is shown to be critical for treatment turnaround time reduction.ConclusionsConsidering both cost and treatment turnaround time, point-of-care manufacturing within the UK does not show great advantages over centralized manufacturing. However, further simulations using this model can be used to understand the feasibility of decentralized manufacturing in a larger geographical setting.     

Childhood cancer and residential radon exposure – results of a population-based case-control study in Lower Saxony (Germany)

A population-based case-control study on risk factors for childhood malignancies was used to investigate a previously reported association between elevated indoor radon concentrations and childhood cancer, with special regard to leukaemia. The patients were all children suffering from leukaemia and common solid tumours (nephroblastoma, neuroblastoma, rhabdomyosarcoma, central nervous system (CNS) tumours) diagnosed between July 1988 and June 1993 in Lower Saxony (Germany) and aged less than 15 years. Two population-based control groups were matched by age and gender to the leukaemia patients. Long-term (1 year) radon measurements were performed in those homes where the children had been living for at least 1 year, with particular attention being paid to those rooms where they had stayed most of the time. Due to the sequential study design, radon measurements in these rooms could only be done for 36% (82 leukaemias, 82 solid tumours and 209 controls) of the 1038 families initially contacted. Overall mean indoor radon concentrations (27 Bq m^–3) were low compared with the measured levels in other studies. Using a prespecified cutpoint of 70 Bq m^–3, no association with indoor radon concentrations was seen for the leukaemias (odds ratio (OR): 1.30; 95% confidence interval (95% CI): 0.32–5.33); however, the risk estimates were elevated for the solid tumours (OR: 2.61; 95% CI: 0.96–7.13), mainly based on 6 CNS tumours. We did not find any evidence for an association between indoor radon and childhood leukaemia, which is in line with a recently published American case-control study. There is little support for an association with CNS tumours in the literature. Received: 14 December 1998 / Accepted in revised form: 10 June 1999