Translation of HBOC Preclinical Data to Human Studies

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

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BPAC - Hauser

• Make outcome predictions
• Model /predict potential benefit to humans
• Model /predict potential harm to humans
• Predict AEs in RESUS trial
• Is (was) waiver of consent warranted?
• Examine /improve translational process

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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)

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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

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

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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

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BPAC - Hauser

• Immunol / pathology
• Lung pathology
• No difference in moderate HS
• Severe uncontrolled hemorrhage increased lung
  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

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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 dont bleed

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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

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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

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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

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BPAC - Hauser

• Concerns for AEs
• No obvious excess AEs 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
  (21 bias)
• EMS must titrate to effect in field trial

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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