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Translation of HBOC Pre-clinical Data to Human Studies

Translation of HBOC Pre-clinical Data to Human Studies . BPAC Dec 14, 2006 Carl J. Hauser MD. BPAC - Hauser. Mandate Assess HBOC efficacy as resuscitation fluid in animal models tested Volume expander Oxygen carrier Assess for harmful effects in animal models Hemodynamic Immune

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Translation of HBOC Pre-clinical Data to Human Studies

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  1. Translation of HBOC Pre-clinical Data to Human Studies BPAC Dec 14, 2006 Carl J. Hauser MD

  2. BPAC - Hauser • Mandate • Assess HBOC efficacy as resuscitation fluid in animal models tested • Volume expander • Oxygen carrier • Assess for harmful effects in animal models • Hemodynamic • Immune • Coagulation • Other / Unforseen

  3. BPAC - Hauser • Make outcome predictions • Model /predict potential benefit to humans • Model /predict potential harm to humans • Predict AE’s in RESUS trial • Is (was) waiver of consent warranted? • Examine /improve translational process

  4. BPAC - Hauser • What patient population should be tested? • Most benefit / least risk • Pre-clinical modeling parameters • Controlled vs uncontrolled hemorrhage • Variable depth / duration of shock • Inclusion of associated tissue trauma • Reproducing clinical resuscitation protocols • Undesirable effects (inevitable)

  5. BPAC - Hauser • How should humans be tested? • Clinical studies should reflect animal data • Not marketing / client concerns • Populations • Applications • Urban, rural, hospital, ‘far forward’ uses different • What are appropriate comparator therapies? • Endpoints of therapy (BP, lactate, ?O2 based) • Assessing NO-vasoconstriction side-effects • Specific subpopulations suffer or benefit • Focus on most successful animal protocols

  6. BPAC - Hauser Using Pre-clinical Data to Model Human Responses

  7. BPAC - Hauser • Physiology • HBOC  higher BPs than LR/HEX but • CI / DO2 often lower • SVR often unreported (back calculate) • Uniformly higher SVR (vasoconstriction) • Effect on hepatic bleeding • Uniformly better volume resuscitation • expected at 2/1 vs 4/1 v/v resuscitation • No real indication of benefit

  8. BPAC - Hauser • Mortality • Mortality differences in severe shock preps • Mortality does depends on Hgb • One model stands out (Carolina) • Constant blood loss /fluid replacement • Replicates long-distance (rural / military) scenario • HBOC clearly allows survival as Hct nears zero • May be crucial in long clinical transports

  9. BPAC - Hauser • Immunol / pathology • Lung pathology • No difference in moderate HS • “Severe uncontrolled hemorrhage” increasedlung injury in HBOC • ? earlier death in comparators • “Vent free days” is the relevant human outcome • Hepatic pathology • HBOC clear transaminasemia, cholestatis • Hepatic dysfunction rarely determines outcome • Significant differences in post-injury inflammatory events unlikely

  10. BPAC - Hauser • Coagulation and hemostasis • TEG, PFA100 show signif HBOC effect • Will effect control of primary injury • Comparators always HEXTEND • Known thrombopathy • Straw man • Might be significant issue in clinical use • But….corpses don’t bleed

  11. BPAC - Hauser • Tissue oxygenation • Sophisticated, complex studies • HBOC likely does improve tissue pO2 • Regional differences • Hepatic worse • Brain better • Injured brain better still • No obvious lactic acidosis or increased BD • Suggests possible advantage – esp. in TBI

  12. BPAC - Hauser • NO metabolism • Sophisticated, complex studies • HBOC does ‘sump’ NO • Assay based differences • Systemic nitrites / nitrates • Tissue s-nitrosylation by IHC • SMA ring responses to ACh • Vasoconstriction seems less than prior Hgbs • Human response can only be assessed clinically

  13. BPAC - Hauser • Predicted benefits of HBOC-201 • HBOC-201 is a potentially useful resuscitation fluid in extreme anemia • Volume expansion / BP effects may be useful • Benefits most likely in prolonged transports / TBI • No clear excessive NO-sump effect • Likely to cause coagulopathy, but comparable to other fluids • Exemption from consent IS WARRANTED

  14. BPAC - Hauser • Concerns for AE’s • No obvious excess AE’s in animal trials • Some NO sumping / vasoconstriction • Must watch for acidosis, • Distribution of MOF events • Coagulopathy in trauma will be difficult to distinguish from existing processes • Preclinical resuscitation protocols favor HBOC (2:1 bias) • EMS must titrate to effect in field trial

  15. BPAC - Hauser • Process • Sponsors played to “clients” (FDA, DOD) • Data was only interpretable by true experts • FDA should reward “un-spun” data • Outsource scientific expertise • Broad-based teams of unbiased experts • Outsource ethical expertise • Similar deliberative body(s) • Waiver of consent must be readily available where preclinical data warrants or acute care research in the USA will die

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