FDA Presentation to BPAC:NMRC RESUS Protocol Using HBOC-201

Toby Silverman MD, LTC, USAR (Ret)Branch Chief, Clinical Review BranchDivision of Hematology, Office of Blood

December 14, 2006

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Oxygen Therapeutics in Trauma

FDA recognizes the important role that oxygen therapeutic agents might play in improving outcomes in traumatic hemorrhagic shock, and supports the development of safe and effective agents for use in resuscitation

FDA recognizes the unmet military and civilian need for improved outcomes in trauma

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RESUS Trial Protocol: Overview

HBOC-201 vs lactated Ringer’s solution (LR) for Rx of life-threatening post-traumatic hemorrhage in the urban-ambulance setting Pre-hospital use only Waiver from requirements for informed consent (21 CFR 50.24) Powered to detect 15% relative reduction in all-cause mortality at

28 days from estimated 58.1% to 49.4% (1130 subjects, p = 0.045)

Phase 2, 50-subject study to assess Feasibility and ability of study to answer efficacy and safety

outcome questions Appropriateness of entry criteria to target the desired population

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RESUS Trial Clinical Hold

1. Safety signals arising out of previous phase 2/3 studies

Excess clinically significant AEs (adverse events) in all analyses

2. Dosing and administrationLack of preclinical/clinical dose response studies

3. Mortality estimateWide variability in projected mortality for

individual subjects

4. Magnitude of treatment effectCannot be derived from animal data

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RESUS Trial Clinical Hold (2)

5. Benefit: Risk SAEs (serious adverse events) observed in

previous trials, uncertainty of the treatment effect, and wide variability in expected mortality for individual subjects preclude determination of a positive benefit:risk ratio.

6. Risk mitigation strategies proposed by NMRCMonitoring and therapeutic interventions may

not suffice to offset risks associated with use of HBOC-201

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Additional Concerns (Non-hold Items)

Restriction on age (exclusion of subjects ≥ 70 years old) Generalizability of data from RESUS to routine

prehospital emergency care Complexity of RESUS trial

Requirement for specialized EMT training Requirement for specialized training of in-hospital personnel Practicality of calculating RTS (Revised Trauma Score) under field

conditions Identification of patients for whom use of product may be

appropriate

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1. Safety: Data Limitations

Complete Review (CR) letter of July 30, 2003 to Biopure documented numerous deficiencies in the conduct of pivotal trial HEM-0115 Good Clinical Practice Data quality/completeness Difficulties assessing/verifying seriousness and

frequency of AEs Laboratory database issues due to co-mingling central

laboratory and site information

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1. Safety: Data Limitations (2)

Because of the limitations of the databases, the dataset provided represents a minimum estimate of adverse event information

For purposes of discussion, FDA will be presenting information on AEs derived from a consensus safety database

FDA and Biopure differ on adjudication of a few cases which are highlighted in the FDA tables.

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FDA Safety Analysis

Assumed a priori that a rigorous statistical assessment of differences between HBOC-201 and control for a particular AE would not be possible because of small sample size, even for HEM-0115 AEs/SAEs were expected to occur with low frequency

Data were pooled to achieve a larger sample size from which to estimate frequency of low-incidence events

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1. FDA Safety Analysis (2)

Subjects in previous studies, including HEM-0115, were Stable Medically cleared Judged not to be at particular cardiovascular risk Monitored and treated according to standard care

Study designs were generally similar Administration of HBOC-201 vs control (LR, HES (Hespan), RBC)

[Hb] < threshhold level with/without other signs/symptoms of anemia, or after fixed volume blood loss

RBC, crystalloid, and colloid available as needed Safety and tolerability vs control Effect on allogeneic RBC usage

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1. Outcome of Safety Analysis

Trends seen in the pooled database were also seen in the individual studies and across different types of studies (e.g. by control)

The pooled analysis Showed safety signals already noted in the various

individual phase 2 studies leading up to pivotal HEM-0115

Identified new concerns for further analysis (e.g. MI, renal failure requiring dialysis, CVA)

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Data Pooling: Hypertension (Example)Pooling of individual coded categories into medically similar/related groups (Example) Crystalloid-colloid controlled

surgeries RBC-controlled surgeries Total HBOC-

201 AEs Total Control AEs

HBOC-201 N = 177

Control N = 131

HBOC-201 N = 531

RBC N = 487

N = 708

N = 618

HTN, BP increased, hypertensive crisis, malignant HTN, systolic HTN, etc

62 (35.0%) 17 (13.0%) 104 (19.6%) 42 (8.6%) 166 (23.4%) 61 (9.9%)

Hypertension 54 (30.6%) 15 (11.5%) 64 (12.1%) 32 (6.6%) 118 (16.6%) 47 (7.6%) BP increased 6 (3.4%) 2 (1.5%) 29 (5.5%) 5 (1.0%) 35 (4.9%) 7 (1.1%) Hypertensive crisis

0 0 1 (0.2%) 0 1 (0.1%) 0

Systolic hypertension

1 (0.6%) 0 1 (0.2%) 0 2 (0.3%) 0

SVR increased

0 0 1 (0.2%) 0 1 (0.1%) 0

Malignant hypertension

0 0 1 (0.2%) 0 1 (0.1%) 0

Systolic BP increased

1 (0.6%) 0 2 (0.4%) 1 (0.2%) 3 (0.4%) 1 (0.2%)

Post-op HTN 0 0 0 1 (0.2%) 0 1 (0.2%)

HTN-aggravated

0 0 5 (0.9%) 4(0.8%) 9 (1.3%) 4 (0.6%)

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1. Safety: AEs: All Clinical Trials

Treatment-emergent AE HBOC-201

N=797

Control (LR, HES, RBC)

N=661

Death 25 (3.1%) 14 (2.1%)CHF, heart failure, pulmonary edema, etc 54 (6.8%) 22 (3.3%)

Cardiac arrest, cardio-respiratory arrest, ventricular fibrillation

17* (2.1%) 6 (0.9%)

Myocardial infarction 14# (1.8%) 4 (0.6%)

Hypoxia, cyanosis, arterial desaturation 60 (7.5%) 26 (3.9%)

Pneumonia, aspiration pneumonia, pneumonitis 36 (4.5%) 24 (3.6%)

ARDS, respiratory distress/failure 22 (2.8%) 12 (1.8%)

CVA, TIA, RIND, cerebral infarction 16 (2.0%) 3 (0.5%)

Oliguria, anuria, acute/chronic renal failure, renal impairment

111 (13.9%) 55 (8.3%)

Dialysis, hemofiltration 7♠ (0.9%) 2 (0.3%)

FDA: *Study 0115-5405 and study 0107-0403; #Study 0101-725; ♠Study 0115-4308

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1. Safety: AEs by Type of Control Solution

Selected Treatment-Emergent AEs

RBC Controlled LR/HES Controlled

HBOC-201

N=547

Control

N=487

HBOC-201

N=177

Control

N=131

Death 21 (3.8%) 13 (2.7%) 4 (2.3%) 1 (0.8%)

CHF, heart failure, pulmonary edema, etc

38 (6.9%) 13 (2.7%) 16 (9.0%) 9 (6.9%)

Cardiac arrest, ventricular fibrillation 15* (2.7%) 5 (1.0%) 2 (1.1%) 1 (0.8%)

Myocardial infarction 8 (1.5%) 3 (0.6%) 6# (3.4%) 1 (0.8%)

Pneumonia 28 (5.1%) 19 (3.9%) 7 (4.0%) 3 (2.3%)

CVA 9 (1.6%) 1 (0.2%) 0 (0%) 0 (0%)

Acute renal failure 8 (1.5%) 4 (0.8%) 2 (1.1%) 0 (0%)

Dialysis 5♠ (0.9%) 2 (0.4%) 2 (1.1%) 0 (0%)

FDA: *Study 0115-5405 and study 0107-0403; #Study 0101-725; ♠Study 0115-4308

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1. Safety: AEs Stratified by AgeSelected Treatment-Emergent

AEsSurgical Studies Stratified by Age

<70 y/o ≥70 y/o

HBOC-201

N=476

Control

N=422

HBOC-201

N=222

Control

N=196

Death 9 (1.9%) 4 (0.9%) 16 (7.2%) 11 (5.6%)

CHF, heart failure, pulmonary edema, etc 26 (5.5%) 10 (2.4%) 28 (12.6%) 12 (6.1%)

Cardiac arrest, ventricular fibrillation 6* (1.3%) 2 (0.5%) 11* (5.0%) 4 (2.0%)

Myocardial infarction 6# (1.3%) 2 (0.5%) 8 (3.6%) 2 (1.0%)

Pneumonia 16 (3.4%) 6 (1.4%) 19 (8.6%) 7 (3.6%)

CVA 5 (1.1%) 2 (0.5%) 11 (5.0%) 1 (0.5%)

Acute renal failure 6 (1.3%) 3 (0.7%) 4 (1.8%) 1 (0.5%)

Dialysis 4 (0.8%) 0 (0%) 3♠ (1.4%) 2 (1.0%)

FDA: *Study 0115-5405 and study 0107-0403; #Study 0101-725; ♠Study 0115-4308

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Pivotal Trial HEM-0115 (48% of BLA)

Design: Multicenter, randomized, single-blind, RBC-controlled, parallel-group

Population: 693 subjects undergoing non-emergent orthopedic surgery

Randomization: at first transfusion decision HBOC-201 given as 60 g (2 x 30 g bags) to a maximum of

300 g (10 units) for low Hb (>6.5 but <10 g/dL) + at least one additional sign or symptom of anemia

Primary Endpoint: Avoidance of RBC transfusion during 6-week study period

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1.Safety: Clinically Important AEs in HEM-0115 Treatment-Emergent AE Aggregate

Population

N=353 vs 340

Stable “Trauma” Subgroup

N=34 vs 28

<70 y/o Subgroup

N=239 vs 227

≥70 y/o Subgroup

N=111 vs 111

Death 10 vs 6 0 vs 0 2 vs 0 8 vs 6CHF, heart failure, pulmonary edema 21 vs 5 1 vs 1 9 vs 2 12 vs 3

Cardiac arrest, ventricular fibrillation 9 vs 2 1 vs 0 3 vs 0* 6 vs 2

Myocardial infarction 4 vs 2 0 vs 0 0 vs 0 4 vs 2

↑Troponin (1/3 of population) 16 vs 2 0 vs 1 11 vs 2 5 vs 0

Hypertension, systolic HTN, post-op HTN, malignant HTNDrug Rx’ed (derived from CRFs by FDA)

60 vs 22

35 vs 7

3 vs 2 37 vs 7

22 vs 4

23 vs 15

13 vs 3

CVA, TIA 7 vs 2 0 vs 0 2 vs 2 5 vs 0

Hypoxemia, cyanosis, desaturation 19 vs 8 3 vs 1 14 vs 4 5 vs 4

Pneumonia, pneumonitis 15 vs 6 2 vs 1 8 vs 1 7 vs 5

Respiratory failure/distress 9 vs 5 4 vs 1 6 vs 0 3 vs 5

Oliguria, anuria, renal impairment 47 vs 25 2 vs 0 27 vs 16 20 vs 9

Dialysis, hemofiltration 3 vs 1 0 vs 0 2 vs 0 1 vs 1*

*Subject 5405 and 4308

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1. Safety: AEs in HEM-0115

Biopure hypothesized that: Inaccurate dosing guidelines led to over-infusion of the

product (e.g., pulmonary edema) More test subjects than control subjects had a history of

cardiac disease However, within HBOC-201 cohort, post hoc

stratification presence/absence of history of heart disease → no difference in incidence of AEs

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Safety: AEs in HEM-0115 (2)

HH = HBOC-201 subjects who did not receive RBC HR = HBOC-201 subjects who also received RBC R- = RBC subjects who received ≤ 3 units R+ = RBC subjects who received > 3 units

Medical History in HH, HR, R-, and R+ Subgroups of HEM-0115 HH Subgroup

N (%) HR subgroup N (%)

R- Subgroup N (%)

R+ Subgroup N (%)

Total 211 139 231 107 Cardiovascular 139 (66.5) 96 (69.1) 173 (74.9) 77 (72.0)

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1. Safety: AEs in HEM-0115 (2)

Biopure hypothesized that: Total [Hb] lower in HBOC-201 arm - ↑ risk of

ischemia However,

Mean 1.23 g/dL difference between HBOC-201 and RBC in total [Hb] for lowest recorded value probably does not explain the excess of AEs for HBOC-201

Within HBOC-201 cohort, post hoc stratification by nadir total [Hb] < 8 g/dL or ≥ 8 g/dL → no difference in incidence of high frequency AEs such as hypertension, elevated troponin levels, or oliguria

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1. Safety Conclusions

Excess adverse events are consistently associated with use of HBOC-201 RBC-controlled surgery studies Crystalloid/colloid controlled surgery studies Age stratification in surgery studies Total [Hb] and history of heart disease do not appear to be

independent predictors of adverse event imbalances when assessed in post hoc stratification of HBOC-201 cohort in HEM-0115

FDA considers these AEs important to consider when thinking about RESUS

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2. Dosing and Administration

Default administration rate = 50 mL/min (actual rate determined by judgment of EMS provider) Preclinical animal studies of hemorrhagic shock

Range: gravity infusion (not otherwise quantified) to 10 mL/kg/min

No dose-ranging studies Limited clinical data

Infusion rate 3.8 mL/min in Phase 2 crystalloid/colloid studies

Mean infusion rate 5.5 mL/min in HEM-0115 4/ 353 subjects at rates ≥ 40 mL/min

No dose-ranging studies

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2. Dosing and Administration (2)

Limited safety data for product administration at higher dosing rates and doses is a principal concern given the known intrinsic properties of HBOCs (vasoactivity and vascular injury) and the AE profile of HBOC-201 in previous trials

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3. Mortality Estimate Challenges

Wide variability in projected mortality for individuals based on proposed RESUS entry criteria

Proportion of trauma population who can potentially benefit from any life-saving therapy is a very small subset of the total trauma population RESUS represents <1% of total trauma population

Information on proportion of serious trauma patients alive at the scene who expire before reaching the ER is not readily available

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3. Basis for Mortality Estimate in RESUS

Enrollment of subjects at higher risk of dying from hemorrhagic shock SBP <90 mm Hg Weighted Revised Trauma Score (RTS, full

range 0-7.84) Enrollment criteria ranging from 1 to < 5

Exclusion of subjects for whom blood is readily available within 10-15 minutes

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3. Mortality Estimate

The Revised Trauma Score is calculated based on three parameters — Glasgow Coma Score, systolic blood pressure, and respiratory rate

GCS has 3 components- eye opening, verbal response, motor response

Glasgow Coma Scale (GCS)

Systolic Blood Pressure (SBP)

Respiratory Rate (RR)

Coded Value

13-15 >89 10-29 4 9-12 76-89 >29 3 6-8 50-75 6-9 2 4-5 1-49 1-5 1 3 0 0 0

RTS = 0.9368 GCS + 0.7326 SBP + 0.2908 RR

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Revised Trauma Score Issues

RTS cannot be computed unless data from all three components captured

Glasgow Coma Score (GCS) heavily confounded by intubation, severe facial injury, intoxication, etc. No consensus in literature for allocating verbal response scores

for intubated or pharmacologically paralyzed patients

Studies report a loss of cases for analysis of 3-28% Usually it is the GCS that is missing

Difficulty in coding GCS portion of RTS can lead to large variation in the RTS

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3. Mortality Estimate (2)

www. Trauma .org

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3. Mortality Estimate: RTS Issues

Number of subjects and number of deaths are not equally distributed throughout the range of RTS scores

Greatest potential benefit to offset risk is distributed predominantly to those with lower proposed RTS scores Least potential benefit to offset risk is distributed to those with

higher proposed RTS scores

Small imbalances in RTS scores can have greater effect on outcome than the therapeutic intervention

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3. Mortality Estimate: NTDB

1078

379 223 218 258

1363

789

293 172 109

0

500

1000

1500

2000

2500

3000

Overall 1-<2 2-<3 3-<4 4-<5

Dead

Alive

Mortality and N in hypotensive subjects < 70 y/o admitted to US trauma centers with/without TBI (NTDB hospital arrival data)

Dead (%) 55.8 67.6 56.8 44.1 29.7

Alive (%) 44.2 32.4 43.2 55.9 70.3

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3. Mortality Estimate: NTDB

0

10

20

30

40

50

60

70

80

1-<2 2-<3 3-<4 4-<5

% of NAlive %

Mortality and N in hypotensive subjects < 70 y/o admitted to US trauma centers with/without TBI (NTDB Hospital Arrival Data)

N=2441

1168 516 390 367

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3. Mortality Estimate: UAB/UMD

98

540 30 23

136

39

55

2517

0

50

100

150

200

250

Overall 1.1-2 2.1-3 3.1-4 4.1-5

DeadAlive

Mortality and N in hypotensive subjects < 70 y/o admitted to US trauma centers with/without TBI (prehospital data)

Dead (%) 58.1 88.6 57.9 45.5 42.5

Alive (%) 41.9 11.4 42.1 54.5 57.5

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Mortality Estimate: UAB/UMD

0

10

20

30

40

50

60

70

1.1-2 2.1-3 3.1-4 4.1-5

% of N

Alive %

44 95 55 40

Mortality and N in hypotensive subjects < 70 y/o admitted to US trauma centers with/without TBI (prehospital data)

N=234

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3. Mortality Estimate Conclusions:

The patient population is likely to be heterogeneous

While ranges for mortality differ in the three available databases, all indicate a very wide range of survival probabilities

While the overall average mortality rate is ~ 58%, many subjects will have a probability of death that is much lower than the average

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4. Treatment Effect

There is no clinical or preclinical basis to allow the numerical estimate of treatment effect for HBOC-201 in pre-hospital trauma resuscitation Not possible to estimate the potential magnitude of the

treatment effect from clinical trials using HBOC-201 in elective surgery

No prospective, randomized, controlled Phase 2 studies in consenting trauma subjects with/without TBI have been conducted/completed with HBOC-201

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4. Treatment Effect (2):

Sponsor bases its estimate of treatment effect and its assessment of likely safety for RESUS on results of a subset of preclinical animal models of trauma and hemorrhagic shock

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4. Treatment Effect: Limitations of Models

Limitations inherent to the animal models that preclude direct extrapolation of results to humans. Models of hemorrhagic shock

Basic physiology vs survival Controlled vs uncontrolled hemorrhage Vascular vs parenchymal organ hemorrhage With/without TBI

Resuscitation strategies Fixed volume vs fixed BP vs BP/HR-controlled Periods of observation Hypotensive vs normotensive resuscitation Volume ratios of resuscitation fluids Short vs long “transit” times

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4. Treatment Effect (3):

Preclinical tests are not intended to supplant data derived from adequate and well-controlled trials in humans, nor is safety information derived from animal studies intended to supplant safety data derived from clinical trials performed in humans

Results of preclinical studies do not establish a quantitative estimate of treatment effect

and do not negate safety findings in completed clinical trials in

humans

48 FR 26720; IND Regulation Rewrite: See preamble

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4. Conclusions About Treatment Effect

Proof of concept that HBOC-201 might sustain life in trauma has been shown by animal studies in narrowly defined models of lethal hemorrhagic shock

Nevertheless, preclinical data could potentially support studies of HBOC-201 in settings where an extremely high mortality rate is expected (e.g. massive hemorrhage with/without prolonged delay to definitive care, TBI)

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5. Potential Concerns Using HBOC-201 for Uncontrolled Hemorrhage in the Ambulance

Risk of fluid under-resuscitation Limitations inherent to the ambulance setting Risk of increased bleeding or re-bleeding due

to hypertension- of concern in all trauma patients but especially those with head trauma

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5. Potenial Concerns Using HBOC-201 for Uncontrolled Hemorrhage in the Ambulance

Fluid under-resuscitation BP used as a surrogate for perfusion BP > 100 mm Hg using vasoactive HBOC-201 could

mislead healthcare providers to withhold needed crystalloid, resulting in tissue underperfusion

Unclear how to interpret classic signs of occult shock (e.g. thready pulse, cool extremities) when using HBOC-201

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5. Limitations of the Ambulance

Elective Surgery

Field Trauma

Medically optimized Yes No

Monitoring of vital organ function Advanced (real time)

Extremely limited

Rx of ↑BP Drugs immediately available

None

Rx of hypothermia Fluid warmers Blankets

Extra personnel immediately available Yes No

Definitive control of uncontrolled bleeding

Yes No

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5. Potential Concerns Using HBOC-201 for Uncontrolled Hemorrhage in the Ambulance

Increased bleeding and re-bleeding “Although thrombus after an arterial injury is formed

almost immediately…it is initially “soft and jelly-like” …Transformation to a more rigid hemostatic plug requires …at least 20-30 minutes following injury”

“Resuscitation strategies which cause abrupt increase in blood pressure and flow may increase hemorrhage volume.”

Stern, S. Low-volume fluid resuscitation for presumed hemorrhagic shock: helpful or harmful? Curr Opin Crit Care 2001; 7: 422-430

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5. Vasoactivity of HBOC-201

Trial Population(HBOC-201 vs. Control)

Frequency of Rx-Emergent HT (%)

BLA

Elective Surgery

Aggregate

N=708 vs. 618

166 vs. 48

(23% vs. 8%)

Age <70 Subgroup

N=476 vs. 422

98 vs. 37

(21% vs. 9%)

HEM-0115

Elective Orthopedic Surgery

Aggregate

N=350 vs. 338

Requiring Rx Subgroup

60 vs. 22

(17% vs. 6%)

35 vs 7

(11% vs. 2%)

Age <70 Subgroup

N=244 vs 227

Requiring Rx Subgroup

37 vs 7

(15% vs. 3%)

22 vs 4

(9% vs 2%)

COR-0001*

Elective PCI

Elective PCI

N=31 vs. 15

9 vs. 0

(29% vs. 0%)

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5. Percent of Hypotensive (SBP ≤ 90 mm Hg) HEM-0115 Subjects With SBP Responses > 130 mm Hg

0

5

10

15

20

25

30

35

40

131-140 mmHg

141-150 mmHg

151-160 mmHg

131-160

HBOC-201 (N= 25)RBC (N= 20)

21

34

1 0

9

2

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5. Potential Safety Concerns in the Ambulance: Summary HBOC-201 is a vasoactive product with a

duration of action lasting hours BP can continue to increase after HBOC-201 is

stopped at 120 mm Hg BP elevations cannot be treated in the ambulance Abrupt BP elevations can increase bleeding Increased bleeding is problematic for all subjects

with uncontrolled bleeding in the ambulance, but especially for subjects with TBI

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6. Benefit and Risk

1999- Workshop on Safety and Efficacy evaluation of oxygen therapeutics when used as red blood cell substitutes and as resuscitation fluids

2004- Draft guidance Hierarchical approach to evaluation of safety

Initial evaluation in situations where AEs expected to be uncommon to facilitate detection of potential safety problems Subjects medically cleared, carefully monitored, medically managed according to

in-hospital standard of care guidelines RBC control

Demonstration of adequate safety profile when compared with RBC allows evaluation in less stable trauma subjects able to provide consent, or unstable trauma subjects unable to provide consent

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6. Benefit and Risk (2)

In field setting, oxygen therapeutic should have superior survival outcome when compared to an asanguinous solution

Possible for oxygen therapeutic to have an inferior safety profile when compared with blood, and yet reduce mortality in trauma in the field when compared with asanguinous solutions Very difficult to design clinical trial

Not easy to weigh relative importance of observed safety signals and AEs vs. potential benefit in terms of lives saved, particularly if findings suggesting clinical benefit have not been observed in other settings

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6. Benefit and Risk (3)

Wide variability in projected mortality for individual subjects means that benefits to offset risks are not evenly distributed

Magnitude of treatment effect cannot be estimated from animal studies

Prior studies in humans do not provide a basis for estimating treatment effect in trauma

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6. Benefit and Risk- Challenges

HBOC-201 was associated with ~ 50% increase (~1% absolute excess) deaths due to SAEs Additional deaths due to SAEs will offset

potential benefit in terms of lives saved with HBOC-201

Reduce power of study to detect a beneficial effect

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6. Benefit and Risk Challenges

Victims of trauma, even young ones, may not have a lower risk for AEs, but rather, may have a higher risk than older, medically cleared subjects undergoing elective surgeries Excess AEs noted in HBOC-201 treatment arm in

elective surgery could potentially be greater in critically ill trauma subjects

Transport times in urban ambulance setting are short and window of opportunity for benefit is small

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6. Benefit and Risk: Conclusions

FDA performed an extensive sensitivity analysis, varying assumptions for deaths due to SAEs, effect size, and the underlying mortality rate

FDA found that the trial, as designed, is very sensitive to small fluctuations in the assumptions and is not robust

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Risk:Benefit Analysis # 3 by NMRC

The detailed methods and other information underlying the NMRC risk assessment in the Issue Summary have not been submitted to FDA and therefore could not be reviewed adequately.

However, FDA has preliminary concerns with the model as presented: Documentation on validation of the model is lacking Sensitivity analyses performed are incomplete and do not take

power of the study for each scenario into account Analysis using retrospective post hoc subsetting of patient groups in

HEM-0115 is problematic and may not be valid

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7. Risk Mitigation: Restrictions on Age

FDA’s position is that the trial should not have an upper age limit

Fastest growing segment of trauma population is population > 50 years old and more particularly, > 70 years old (www.cdc.gov/ncipc/wisqars/default/htm)

Distinguishing subjects above or below a particular age, under field conditions, likely to be difficult

Older subjects may be at greater risk of ischemic consequences of severe hemorrhage and therefore might also potentially benefit more from administration of an oxygen-carrying resuscitation fluid

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Summary

FDA has a number of concerns about RESUS

1. Excess clinically significant AEs in all analyses

2. Lack of preclinical/clinical dose response studies to support proposed dosing

3. Wide variability in projected mortality for individual subjects

4. Magnitude of treatment effect cannot be derived from animal data

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Summary

5. SAEs observed in previous trials, uncertainty of the treatment effect, and wide variability in expected mortality for individual subjects preclude determination of a positive benefit:risk ratio.

6. Monitoring and therapeutic interventions may not suffice to offset risks associated with use of HBOC-201

7. Excluding the elderly may not reduce risks associated with use of HBOC-201

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Summary

FDA asks the Advisory Committee to consider the following questions

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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

59

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

60

Question 3

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

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Question 4

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

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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.