Jaro Vostal, MD, PhD Division of Hematology, OBRR,CBER, FDA Blood Products Advisory Committee

1. PRODUCT DEVELOPMENT PROGRAM FOR INTERVENTIONS INSEVERE BLEEDING DUE TO TRAUMA OR OTHER CAUSESco-sponsored by: DOD, FDA, HHS Office of the Assistant Secretary for Health and NHLBI Jaro Vostal, MD, PhD Division of Hematology, OBRR,CBER, FDA Blood Products Advisory Committee December 15, 2010

2. Development of products for treatment of severe bleeding due to trauma remains a major health issue • Despite major advances in therapies and medical practice, mortality due to severe trauma pre- and in hospital remains high • Severe bleeding associated with trauma contributes significantly to this high mortality • From both public health and military readiness perspectives, this is a major health issue

3. Our understanding of trauma physiology is still developing • Severe bleeding in trauma is associated with coagulopathy, tissue hypoperfusion and shock • Current treatments such as large volume transfusion may contribute to the coagulopathy and further complicate the pathophysiology of trauma • Evaluation of new treatments has been hampered, in part, by lack of consistent definitions of various trauma-associated pathologic states (e.g. moderate bleeding vs. severe bleeding) • A uniform approach is needed for evaluation of new therapies in this field

4. Current products for severe bleeding • Products used in current medical practice for treatment of severe bleeding have not been approved for this purpose • No systemic products for severe bleeding (CBER, CDER) • Some products for mild-moderate local bleeding (CDRH) • In current medical practice products such as Factor VIIa are used off-label for severe bleeding even without having this indication • Companies developing products for severe bleeding need a well defined pathway to evaluate their products

5. Workshop objectives • Gather information on evaluation of products intended to be used in patients with severe bleeding from trauma or other causes • Obtain practical information for the FDA that could be used by sponsors to support market applications • Develop uniform approach to facilitate research and development and ultimately lead to FDA approval of products for severe bleeding

6. Workshop Outline • Introduction of the issue • Overview of currently marketed products with bleeding indications (none for systemic agents, some for local agents) • Pathology of trauma • Statistics of clinical trials • Panel sessions (intro talk and panel discussion) • Definitions of Bleeding • Animal Models • Endpoints for clinical trials of a) local agents b) systemic agents • Ethics of clinical trials • Options for trauma clinical trials • Summary of panel session discussions

7. Session 1: Definitions of severe bleedingsummary • Based on existing data, it is difficult to identify a single criterion to define severe bleeding, • Obvious when seen but difficult to define prospectively • Combination of clinical biomarkers and physiological criteria may be useful • Modifying the existing trauma scales to fill the gaps may be useful • Rapid testing for biomarkers is needed e.g. Thromboelastogram (TEG)

8. Session 2: Animal Models summary The animal model should demonstrate the clinical hemostatic challenge for which the drug/device/biologic is to be used. • Reflect the coagulopathy and/or the vascular defect • Be severe enough be lethal • Be reproducible • Have ability to demonstrate the hemostatic efficacy • Ability to apply the hemostatic product as (potentially) indicated. • Prehospital considerations are distinct from intraoperative (large vessel injury vs. coagulopathy). • Hemostatic effects should not be considered separately from general systemic effects and/or safety • A polytrauma model in pigs with uncontrolled bleeding may be the best model at this time

9. Session 3: Clinical trial endpoints local agents summary 1) What local and or systemic factors should be taken into account to determine the severity of blood loss in a localized anatomic site? Anatomic Factors External bleeding vs. Internal bleeding Body Cavity (Chest, Abdomen, Pelvis) or Solid Organ (Liver, Spleen, Kidney, Lung): . Named vs. Non-Named Vessels or Artery vs. Vein: Patient Factors, Coagulopathic (any etiology) vs. Non-Coagulopathic: coagulopathy due to cancer vs trauma vs pharmaceuticals are different – can not extrapolate data from one group to another. History of Thrombo-emboli (DVT, PE, Cancer?): Emergency situation (trauma vs. elective): trauma is more heterogenous (e.g.: multiple & random bleeding sites) than elective (e.g.: fewer & more predictably located bleeding sites) Field vs. Hospital: civilian pre-hospital and military field data may be poolable. Rate of Bleeding (mild / moderate / severe / massive) was considered is important No consensus on objective measures of bleeding or method of assessment 2) What are clinically meaningful endpoints: change in parameters from baseline assessment (from before to after local agent use) to achieve hemostasis (complete cessation of bleeding) at the anatomic point of care? Time to 100% hemostasis: e.g.: 3 minutes. Incidence of 100% hemostasis: evaluate at 3 minutes

10. Session 4:Clinical endpoints systemic agentssummary • Hemodynamic instability • Panelists were not in favor of this endpoint • Criteria cannot be applied uniformly • Can be easily manipulated by routine clinical care • Transfusion • All thought it was clinically relevant but varied opinions about the magnitude of reduction required • Probably the best surrogate measurement for hemostasis • Avoidance of massive transfusion likely acceptable as an endpoint • Mortality • All agree acceptable endpoint • Most thought endpoint should be between 6-24 hours. • One person advocated for 28-30 day mortality • All agreed that a 5-10% reduction in mortality is clinically meaningful • Morbidity • All agree it is not a good endpoint • Perhaps acceptable for secondary endpoints • Composite endpoints • Not preferred for primary endpoint but acceptable for secondary endpoints

11. Session 5: Clinical trials in trauma patients vs. elective surgery patientsSummary • Trauma trials are difficult to conduct and costly • Patients are in the field, variable time before access to medical care • Extremely short period of time to decide if patients meet study criteria • Wide variety of injuries, co-morbidities, patient conditions • Unique ethical issues around obtaining consent • Elective surgery is a more controlled environment and clinical trials would be easier to conduct • However…. there are concerns that the physiologic response in trauma would be different than in elective surgery • Trauma induced shock/coagulopathy • Anesthetized surgical patients • Surgical trials could generate valuable information but would need further trials to verify results in a target population (trauma patients)

12. Session 6: Ethical considerations for clinical trials in trauma patientsSummary • Patients are frequently unable to consent to participate in a trial due to loss of consciousness or otherwise altered mental state • Clinical trials can be conducted on trauma patients under 21 CFR50.24 which allows whole community to consent to participate in a trial • Public has to be notified and have the option not to participate • Patients who will be enrolled should have the prospect of a benefit from the treatment based on previous studies • After enrollment the patient or LAR should be informed and given the opportunity to have treatment stopped.

13. Workshop Outcomes • Animal Studies • Polytrauma pig model of uncontrolled bleeding • Eligibility – not decided • trauma scores • Biomarkers • Endpoints • early mortality • Hemostasis • Trauma vs. non-Trauma studies • Pivotal study should be in trauma • Ethics (21CFR50.24) • possible but difficult in the civilian population • probably not acceptable in the military setting

14. FDA OBRR gratefully acknowledges… • the efforts of the steering committee, speakers, panel members and • panel chairs and the logistics staff • the funding for the workshop donated by DOD, NHLBI and HHS Office of the Assistant Secretary for Health