Proceedings of the Food and Drug Administration public workshop on pathogen reduction technologies for blood safety 2018 (Commentary, p. 3026)

Atreya, Chintamani; Glynn, Simone; Busch, Michael; Kleinman, Steve; Snyder, Edward; Rutter, Sara; AuBuchon, James; Flegel, Willy; Reeve, David; Devine, Dana; Cohn, Claudia; Custer, Brian; Goodrich, Raymond; Benjamin, Richard J.; Razatos, Anna; Cancelas, Jose; Wagner, Stephen; Maclean, Michelle; Gelderman, Monique; Cap, Andrew; Ness, Paul

rt or pediatric patients where cost-benefit and risk-benefit calculations are likely to have their most favorable outcomes. 143 Providing products to regions with high endemic disease rates can greatly improve cost-benefit analyses but will require partnerships with nongovernmental organizations and longer-term considerations of sustainability in these environments when supplementation of costs is no longer feasible. 144 Clinical experience with pathogen reduction for red blood cells: completing the triad-Richard J. Benjamin, MD, PhD, FRCPath Speaker's summary: Unique technologies are needed to adequately balance the need for robust, broad-spectrum PI and the disparate characteristics of RBCs, PLTs, and plasma proteins. INTERCEPT RBCs incorporate treatment of RBCs in AS with 0.2 mmol/L amustaline (S-303) in the presence of 20 mmol/L glutathione (GSH), in a closed system. 135 Amustaline rapidly crosslinks and/or forms adducts with nucleic acids to prevent pathogen replication without generating reactive oxygen species (ROS), while the active compound degrades to undetectable concentrations (<0.75 nmol/L) during processing. An exchange step into a licensed storage solution removes the majority of the breakdown products, resulting in treated RBCs with a 35-day shelf life. 145 Extensive testing confirmed a lack of neonatal and reproductive toxicity, carcinogenicity, genotoxicity, and acute and chronic toxicity, while confirming potent inactivation of a broad range of enveloped and nonenveloped viruses, bacteria, protozoa, and WBCs. 146 Animal models confirmed a lack of immunogenicity. Treated RBCs demonstrate reduced hemolysis and increased ATP levels compared to conventional irradiated RBCs. A similar closed-system process is in development for WB collections in collaboration with the Swiss Red Cross for use in austere environments. 147 INTERCEPT RBCs were successfully evaluated in a series of clinical trials demonstrating the safety, efficacy, and the performance of the system (Table 4 ). Radiolabeled recovery and survival studies in healthy volunteers confirm acceptable RBC recovery and life span, exceeding FDA requirements. 120, 148 A Phase III randomized controlled study (STARS) involving 51 complex cardiac surgery patients in Germany demonstrated that treated RBCs met the predetermined noninferiority margin for hemoglobin (Hb) content (mean treatment difference [test-control] of 2.27 g/unit [95% CI, −2.61 to −1.92 g/unit), within the prespecified equivalence margins (AE5 g/unit) and with reduced hemolysis at the end of storage. 149 Subjects received a mean of 2.9 (range, 1-8) test or control RBC components during surgery or within 7 days of surgery. Exploratory clinical endpoints, including renal and hepatic insufficiency and the 6-minute walk test, as well as adverse events, were not different, and no patients had antibodies specific for INTERCEPT RBCs.