title: Current practices in preclinical drug development: gaps in hemostasis testing to assess risk of thromboembolic injury.
abstract: The Health and Environmental Sciences Institute Cardiac Biomarkers Working Group surveyed the pharmaceutical development community to investigate practices in assessing hemostasis, including detection of hypocoagulable and hypercoagulable states. Scientists involved in discovery, preclinical, and clinical research were queried on laboratory evaluation of endothelium, platelets, coagulation, and fibrinolysis during safety assessment studies. Results indicated that laboratory assessment of hemostasis is inconsistent among institutions and not harmonized between preclinical and clinical studies. Hemostasis testing in preclinical drug safety studies primarily focuses on the risk of bleeding, whereas the clinical complication of thrombosis is seldom assessed. Our results reveal the need for broader utilization of biomarkers to detect altered hemostasis (e.g., endothelial and platelet activation) to improve preclinical safety assessments early in the drug development process. Survey respondents indicated a critical lack of validated markers of hypercoagulability and subclinical thrombosis in animal testing. Additional obstacles included limited blood volume, lack of cross-reacting antibodies for hemostasis testing in laboratory species, restricted availability of specialized hemostasis analyzers, and few centers of expertise in animal hemostasis testing. Establishment of translatable biomarkers of prothrombotic states in multiple species and strategic implementation of testing on an industry-wide basis are needed to better avert untoward drug complications in patient populations.
authors.affiliation: Department of Pathology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: A Eric
authors.initials: AE
authors.lastname: Schultze
authors.forename: Dana B
authors.initials: DB
authors.lastname: Walker
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tarrant
authors.forename: Marjory B
authors.initials: MB
authors.lastname: Brooks
authors.forename: Syril D
authors.initials: SD
authors.lastname: Pettit
mesh_terms: D000818:Animals; D035843:Biomedical Research; D001780:Blood Coagulation Tests; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards*; D004345:Drug Industry / Q000458:organization & administration*; D006487:Hemostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D012107:Research Design; D018570:Risk Assessment / Q000379:methods / Q000592:standards; D011795:Surveys and Questionnaires; D013923:Thromboembolism / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis