# Presentation: 530027

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

- Toby Silverman MD, LTC, USAR (Ret)
- Branch Chief, Clinical Review Branch
- Division of Hematology, Office of Blood
- December 14, 2006

## 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

## 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

## 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 administration
- 		Lack of preclinical/clinical dose response studies
- 3.	Mortality estimate
- 		Wide variability in projected mortality for individual 	subjects
- 4.	Magnitude of treatment effect
- 		Cannot be derived from animal data

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

## 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

## 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

## 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.

## 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

## 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

## 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)

## Data Pooling: Hypertension (Example)

## 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

## 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

## 1. Safety: AEs Stratified by Age

| Selected Treatment-Emergent AEs | Surgical 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

## 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

## 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 6 |
| CHF, 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 HTN
Drug 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

## 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

## 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

## 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

## 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*

## 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

## 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

## 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
*	**	**	**	*

## 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

## 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

**RTS = 0.9368 GCS + 0.7326 SBP + 0.2908 RR**

## 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

## 3. Mortality Estimate (2)

- www. Trauma .org

## 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

##  3. Mortality Estimate: NTDB

| Dead (%) |           55.8 |          67.6 |           56.8 |          44.1 |           29.7 |
| --- | --- | --- | --- | --- | --- |
| Alive (%) |           44.2 |          32.4 |           43.2 |          55.9 |           70.3 |

## 3. Mortality Estimate: NTDB

**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

## 3. Mortality Estimate: UAB/UMD

| Dead (%) |           58.1 |          88.6 |           57.9 |           45.5 |         42.5 |
| --- | --- | --- | --- | --- | --- |
| Alive (%) |           41.9 |          11.4 |          42.1 |           54.5 |         57.5 |

## Mortality Estimate: UAB/UMD

- 44

- 95

- 55

- 40

- N=234

## 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

## 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

## 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

## 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

## 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

## 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)

## 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

## 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

## 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 |

## 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

## 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%) |

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

- 2

- 1

- 3

- 4

- 1

- 0

- 9

- 2

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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](http://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

## 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

## 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

## Summary

- FDA asks the Advisory Committee to consider the following questions

## 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

## 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

## Question 3

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

## Question 4

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

## 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.