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88th Meeting 14 December 2006




Topic: Review of a proposed clinical trial of HBOC-201 in trauma


Following opening remarks by the Chairman of BPAC, Dr. Frederick Siegal, and the Director of the Office of Blood Research and Review, Dr. Jay Epstein, the Committee listened to several FDA presentations. Dr. Toby Silverman presented an overview of federal regulation 21CFR50.24, which discusses the requirements for conducting trials with exception from informed consent.  Diane Maloney, Esq. summarized the October 11, 2006 Public Hearing on Emergency Research. This presentation was followed by Dr. Abdu Alayash, who gave an overview of hemoglobin-based oxygen carriers. Next, Dr. Laurence Landow introduced the RESUS trauma trial and the reasons why the trial was placed on clinical hold by FDA. These reasons included: (i) a safety profile showing excess deaths and adverse events in subjects receiving HBOC-201 compared to control subjects in non-trauma studies, (ii) insufficient safety information regarding dosing and rate of administration as proposed in RESUS, (iii) inability to derive the magnitude of the treatment effect from animal data, and (iv) heterogeneity of the expected mortality rate for individuals in the target population.


The Committee next heard presentations by the sponsor, Naval Medical Research Center. Dr. Daniel Freilich gave introductory remarks. He was followed by Admiral John Mateczun who discussed the importance of the RESUS trial to the Department of Defense. Dr. Lewis Kaplan discussed the pathophysiology and current treatment for hemorrhagic shock and Dr. Rick Dutton provided a more detailed overview of the proposed study protocol. Dr. Susan Stern presented an overview of preclinical studies of hemorrhagic shock and traumatic brain injury, after which Dr. Gerson Greenburg analyzed the results of Biopure’s clinical studies using HBOC-201. Dr. Freilich completed the sponsor’s presentation with an overview of the RESUS trial and a discussion of benefit:risk.


The Committee next heard from three Special Government Employees engaged by FDA as outside consultants who presented their analyses of published preclinical studies using HBOC-201 in animal models of hemorrhagic shock with or without traumatic brain injury.


Dr. Toby Silverman concluded FDA’s presentations by providing an assessment of the proposed trauma protocol.


The Committee then discussed and voted on the following questions:


1.      Please discuss the following safety concerns raised by FDA

a.       Safety signals and adverse events in previous clinical studies

b.      Demonstrated vasoactivity of the product

c.       Limited safety data for higher doses and rates of administration


The Committee noted that based on the totality of data from controlled studies in subjects undergoing elective surgery, an excess number of clinically meaningful adverse events was apparent in the HBOC-201 treatment arm. However, some committee members remarked that the safety signals observed in non-trauma studies were not relevant to RESUS, whereas one member indicated that these safety signals did suggest that the product was vasoactive and may have induced adverse events seen with other products of this class. Excluding subjects from the proposed RESUS protocol aged 70 years or over, as proposed by the sponsor, would not be expected to change this imbalance. The Committee also remarked on the paucity of clinical data from the field trauma population and the fact that the safety profile of HBOC-201 observed in animal models of hemorrhagic shock inaccurately predicted the safety profile observed in clinical trials of the product. Another concern expressed was whether results from the RESUS civilian trauma trial could be generalized to the battlefield setting. Some Committee members stated they were not overly concerned about the product’s vasoactivity and its potential to worsen outcome due to rebleeding. However, two Special Government Employees who were unable to attend the meeting expressed the opposite opinion in written commentaries provided to the Committee.  Their statements also noted that use of a vasoactive resuscitation fluid prior to surgical control of bleeding could increase uncontrolled hemorrhage and worsen mortality.         


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.


Although the Committee indicated that animal studies showed proof of concept, it did not agree with the extrapolation of animal data to provide a reliable treatment effect.  The Committee stated it did not necessarily accept that results from the animal studies of hemorrhagic shock were relevant to the clinical setting because of confounding factors, such as use of general anesthesia, and that only clinical data from studies in the intended population would be truly informative.   


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


The Committee voted 11 to 8 that the benefits of the trial, as proposed, do not outweigh the risks for individual subjects.  One member abstained.


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


It was remarked by a Committee member that it would be very unusual to go from animal data (there being no relevant clinical trauma data) directly to a Phase III trial.  It was suggested, instead, that FDA and the sponsor negotiate an acceptable Phase 1 or 2 trial of 200-300 trauma subjects to obtain safety information and preliminary efficacy data before considering a Phase 3 trial.  General discussion by the Committee supported this concept.


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.


The Committee stressed that results from a Phase 2 trial could provide information to answer this question. Regarding the alternative possibility for an adaptive trial design, it was suggested that results from a Phase 2 trial should be reviewed publicly, before a large Phase 3 trial is permitted under 21CFR50.24.  A public process would not take place if a Data Monitoring Committee alone were making that decision as part of an interim analysis in a single, staged trial.  The Committee indicated that including subjects 70 years old and older would make it possible to generalize the trial to both the civilian and military settings.