Quick Summary
BLOOD PRODUCTS ADVISORY COMMITTEE
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,
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.