1. 1 INTRODUCTION: Proposed Use of HBOC-201 * in the RESUS (Restore Effective SUrvival in Shock) Trauma Trial Laurence Landow MD, FRCPC Medical Officer, Clinical Review Branch Division of Hematology, OBRR/CBER December 14, 2006 *Hemopure R [hemoglobin glutamer-250 (bovine)]

2. 2 HBOC-201 Regulatory History July 2002: BLA for anemia in orthopedic surgery submitted by Biopure July 2003: Complete Review letter sent to Biopure - Biopure is no longer pursuing licensure for this indication June 2005: RESUS IND submitted by NMRC — placed on hold mainly for –Safety –Inability to derive the magnitude of the treatment effect from animal data –Heterogeneity of the expected mortality rate for individuals in the target population

3. 3 RESUS Trial Protocol Setting: uncontrolled hemorrhagic shock in urban trauma subjects, of whom 33% are expected to have concomitant non-penetrating traumatic brain injury (TBI) Inclusion criteria: –SBP <90 mmHg –Revised Trauma Score 1 to <5 –18 – <70 y/o “Accounts for 0.56% of admissions at large trauma centers” (page 121, RESUS protocol)

4. 4 RESUS Trial Protocol Clinical Trial Material (CTM): HBOC-201 or LR CTM Dosing in the ambulance: –Most subjects expected to require 500 mL (2 units) of HBOC-201 (or 1000 mL of LR) over 10 min — actual rate determined by EMS provider –Remaining subjects expected to require additional CTM for BP 100), with a maximum dose of 1500 mL CTM will be permanently halted in any subject with BP ≥120 mmHg

5. 5 RESUS Trial Protocol Standard of care solutions in the ambulance: –Subjects with BP 100) after 1500 mL of CTM can receive standard of care solutions –Subjects with BP >99 but believed by EMS personnel to be volume under-resuscitated can receive standard of care solutions if two or more signs of “occult shock” are present

6. 6 RESUS Trial Protocol Overview In-Hospital Care: no new bags of HBOC-201 will be hung in the ER – all subjects will receive RBCs Primary endpoint: powered to detect a 15% relative reduction in 28-day all cause mortality –From estimated control mortality rate of 58.1% to 49.4% –α=0.045 Consent: waiver from requirement for informed consent [21CFR 50.24]

7. 7 FDA Concerns with RESUS Design: Safety and Dosing Increased AEs, including SAEs and deaths, observed in clinical studies with product –Excess AEs noted in HBOC-201 treatment arm in elective surgery studies could potentially be greater in critically ill trauma subjects Minimal evidence provided to FDA to support safety of 50 mL/min default infusion rate –HEM-0115: mean rate=5 mL/min (only 4 subjects with rate >40 mL/min)

8. 8 FDA Concerns with RESUS Design: Safety and Dosing Safety concerns over using a long-acting, vasoactive product such as HBOC-201 in the ambulance –Infusion of CTM will be titrated against BP — HBOC-201 subjects could be at risk of fluid under-resuscitation –Effect on BP can last hours — simply stopping the infusion may not prevent BP from continuing to rise –Acute BP elevations cannot be medically controlled in the ambulance — hypertension triggered by the product could exacerbate bleeding in subjects with uncontrolled hemorrhage

9. 9 FDA Concerns with RESUS Design: Safety and Dosing South African study HEM-0125 –~ 10 trauma subjects admitted to the ER have received HBOC-201 –Study is small and, in addition, may not tell us what might occur with this vasoactive product when administered to trauma subjects in the field/urban ambulance setting –Study excludes subjects with TBI in whom BP elevations could exacerbate intracranial bleeding and result in a rapidly expanding space-occupying lesion

10. 10 FDA Concerns with RESUS Design: Efficacy Numerical estimate of survival benefit is based entirely on data from animals Relatively short time-to-definitive care leaves narrow window to show benefit Mandated termination of HBOC-201 for BP ≥120 –Could result in subjects receiving too little product –Pivotal trial HEM-0115: 36% vs. 10 % of subjects with BP 130 mmHg (HBOC-201 vs. RBC)

11. 11 Questions for BPAC

12. 12 Question 1 Please discuss the following safety concerns raised by FDA –Safety signals and adverse events in previous clinical studies –Demonstrated vasoactivity of the product –Limited safety data for higher doses and rates of administration

13. 13 Question 2 Please discuss whether the available preclinical and clinical data are sufficient to estimate a treatment benefit for all-cause mortality at 28 days in the proposed RESUS trial.

14. 14 Question 3 After considering all available data, do the potential benefits outweigh the potential risks for individual subjects in the RESUS trial?

15. 15 Question 4 Are there additional data that could help inform an assessment of benefit:risk in the RESUS trial?

16. 16 Question 5 Please comment on any modifications to the study design that might improve the benefit:risk ratio in the RESUS trial –For example, a trial targeting a group with higher predicted mortality.

17. 17 Thank you

18. 18