Safe and Effective Whole Blood ID/AST Device for Use in Neonatal ICU Settings

Abstract The key objective of this proposed Phase IIB SBIR Competing Renewal effort is to continue the process of developing pediatric products of the ongoing SBIR Fast Track R44HD084033 that require approval of a federal regulatory agency (FDA), and this Phase IIB stage research and development is necessary to move closer to commercialization as stated for NICHD IIB requirements in PHS 2018-2 Omnibus Solicitation for SBIR/STTR Grant Applications and PA- 18-573.In addressing NICHD Pregnancy and Perinatology Branch’s (PPB) top priority topic of “Rapid methods for diagnosis of bacterial infections and inflammation; antibiotic sensitivity,” and PPD’s supported research area of “diagnostics, monitoring, and therapeutic devices and instruments for newborn infants in the nursery and in Neonatal ICU (NICU) setting,” we add Gram positive pathogens to the current Gram negative pathogen identification (ID) panel and additional first line empirical antibiotics to antimicrobial susceptibility testing (AST) panel to address healthcare associated infections (HAIs) in nursery and NICU settings.The proposed hypothesis-driven, milestone driven IIB study is based on the analytical and clinical testing plans and protocols negotiated with FDA through pre-sub meetings for 510(k) de novo submission for in vitro diagnostics (IVD) devices as outlined in the CLINICAL REGULATORY PROGRESS section of COMMERCIALIZATION PLAN. The scope of work of this IIB study on NicuMax® is to carry out analytical validation and non-interventional clinical testing required by FDA to demonstrate safety and effectiveness of the pediatric ID/AST system developed to address two major challenges of blood culture for neonatal sepsis listed below through the current NICHD SBIR Fast Track project. Major challenges of current FDA cleared blood culture systems using pediatric bottles Progress from current SBIR Fast Track for neonatal sepsis in NICU settings 1. Procurement of insufficient blood volume (less than 1-3 mL as needed) for blood culture system designed for adults Blood collection tube and system designed to take blood volume of 200 uL to 2 mL. 2. Long blood-to-result time (andgt;24 hours) for culture-positive, culture-negative and antimicrobial susceptibility. Traditional AST is still needed for PCR-based system. Pathogen ID (6 hours) + AST (2 hours) = 8 hours from blood to complete ID/AST before the 2nd administration of empirical antibiotic The current Fast Track R44HD084033 project does not include FDA analytical and clinical demonstration of substantial equivalency to FDA cleared devices, since it’s not a research topic covered by Phase I/II effort and there is not a predicate device cleared by FDA specifically for infants in NICU and nursery settings. Based on the close communications with FDA, this Phase IIB effort focuses on three major criteria outlined by FDA: Top Priority Risk Factors Risk Management and Mitigation Recommended by FDA Effectiveness and safety of testing limited blood volume (200µL – 2 mL) from infants Aim 1a: Species-specific pathogen recovery, Aim 1b: Confirmed LOD with various blood volumes (0.2 – 2 mL) benchmarked with BacT/Alert PF Pediatric FAN bottle. Effectiveness and safety of direct whole blood ID in 6 hours and AST in 2 hours Aim 2a: Fully automated whole blood ID/AST with random access, Aim 2b: Species-specific sensitivity, specificity, PPV, and NPV with whole blood matrix management Effectiveness and safety demonstration of reproducibility over broad range strains Aim 3a: Species-specific ID and antibiotic-specific CA, vmj, maj, and min Aim 3b: Precision/reproducibility with internal and external quality controlsNarrative The main goal of this Phase IIB project is to accelerate the commercialize of the ongoing SBIR Fast Track program outcome that integrates lab automation, rapid molecular analysis, genotypic pathogen quantification and phenotypic antibiotic conditions to dramatically improve the sensitivity and specificity of rapid, evidence- based pathogen identification (ID) and antimicrobial susceptibility testing (AST) directly from limited whole blood volume of infants in nursery and NICU settings.