1 / 15

Translation of HBOC Pre-clinical Data to Human Studies

This review discusses the pre-clinical evaluation of Hemoglobin-based Oxygen Carriers (HBOC) as resuscitation fluids. It explores efficacy, potential benefits, and risks based on animal model data. Highlights include assessing hemodynamic stability, immune responses, coagulation effects, and modeling human outcomes. Key considerations for clinical trials such as patient populations and ethical implications, including the need for waivers of consent, are addressed. The findings stress the importance of aligning human studies with pre-clinical data to enhance patient safety and therapeutic effectiveness.

rocco
Download Presentation

Translation of HBOC Pre-clinical Data to Human Studies

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related