1. Division of Hematology Emergency Preparedness Action Initiatives Prepared by Mark Weinstein, Ph.D., Dorothy Scott M.D. and Basil Golding M.D. Division of Hematology FDA/CBER/OBRR

2. Strategic Plans  Form working groups within CBER; liaison with CDC, NIH and DoD to address:  Category A Anthrax Smallpox Botulism Plague Hemorrhagic Fever Viruses Tularemia

3. Potential Plasma-Derived Products  Polyclonal antibodies from hyperimmune donors (IGIV products) Human vaccinees Animals immunized  Human Plasma (high titer) Interim procedure – safety concerns

4. Production of Immune Globulins  Donors of plasma for hyperimmune globulin Identification through OVRR, NIH and DoD of vaccinees to be recruited as potential donors Collection of plasma suitable for initial development and large-scale manufacturing Meets FDA requirements for recovered or source plasma

5. Product Status  Assessment of Currently Available Treatments How much product is currently available? What is known about product efficacy?  Estimation of Need number of affected individuals anticipated dose by weight availability and preparedness of supportive care

6. Product Development  Assays for assigning potency: research and development binding assays in vitro neutralization and in vivo protection  Potency standards  IND(s) from CDC, DoD, or industry identification of potential sponsors and/or manufacturers facilitate submission and expedite review funding

7. Vaccinia Immune Globulin (VIG): Issues  Used to treat smallpox vaccination complications  Supplies for massive vaccination campaign are insufficient  VIG effectiveness is based on uncontrolled studies

8. Challenges in Development and Use of VIG Intravenous (VIGIV)  Determining optimal clinical study; real treatment studies not possible  Monitoring effects of treatment; ascertaining efficacy, determining effective serum levels of antibodies for treatment  Assuring adequate supplies for possible scenarios; assuring delivery of VIGIV where needed

9. Current Thinking: Clinical Trials for Licensure of VIGIV  Licensure based upon PK equivalence and safety data. PK not inferior (> 0.8) to VIG given I.M.  Accelerated Approval designation desirable (21 CFR 601.40 – 601.46) expedited availability of product Phase IV commitments to study human surrogate markers (e.g. influence of VIGIV on vaccine take, lesion size)

10. Current Thinking: Clinical Trials for Licensure of VIGIV  New product indications limited to treatment of life-threatening smallpox vaccinations Eczema vaccinatum Progressive vaccinia

11. Vaccinia Immune Globulin: Current DH Research  Developing and Testing Potency assays for VIG Products SCID mouse model In vivo neutralization assay Immune deficient mice (systemic spread of virus) Comparison to in vitro plaque reduction neutralization assays Comparison to novel high-throughput in vitro vaccina virus replication assay (collaboration with OVRR)

12. Vaccinia Immune Globulin: Current DH Research  Determining levels of anti-vaccinia antibodies in licensed IGIV products IGIV product testing suggests that some products may be useful in treatment Certain IGIV products may serve as a potential second-line agent if VIG/VIGIV products are not in sufficient supply

13. Vaccinia Immune Globulin: Planned DH Research  Evaluating Potency Assays – relevance to in vivo situation; ease of use; validation  Establishment of VIG working standard  Correlates of VIG product potency immune globulin structure and subclass manufacturing effects improvements for future products  Studies of high-titer IGIVs in SCID mice Vacccinia protection Prophylaxis and treatment of disseminated infection

14. Botulinum Immune Globulin (BIG) Assess current supplies –Licensed product (equine) –IND products (equine and human) Facilitate accessibility of supplies for civilians Discussions with CDC, DoD and NIH IND drafted and sponsored by CDC –Olympic Games 1996, modified for 2002

15. BIG: Future Plans Discussions with CDC and DoD to make additional human product from vaccinees Facilitate potency testing by contract labs. and FDA Establish potency standards

16. Anthrax: Background  Treatment/Prevention Antibiotics (5/11 patients with IA died) Vaccines (mainly against PA, low titers) Antibodies?  Evidence for Antibody Role In vitro neutralization Animal challenge

17. Anthrax Immune Globulin  Identify vaccinees treated under IND (OVRR reviewers)  Discussions with CDC, DoD and NIH  IND drafted and sponsored by CDC with advice from FDA  Research plan to provide basis for development of a sheep AIG

18. Current Status: Anthrax High titer FFP units available for life- threatening anthrax and for production of a pilot lot of AIG Plan to test animals with human high titer AIG “Consensus” of AIGWG to plasmapherese vaccinees for manufacture of an AIG product

19. AIG: DH Research Plan  Study different vaccines/immunogens in animals  Choose immunogen that elicits highest titer  Identify manufacturer/sponsor to make product in animals  Facilitate pre-clinical testing – mice, rabbits and possibly monkeys  Develop standards and assays  Facilitate IND submission and product approval

20. AIG: Assays and Standards  Develop and validate in-house standard and assays (OVRR)  Alternatively work with other govt. agencies or contractors to ensure that standards and validated assays are available  Correlate assay to in vivo effects in animals and humans

21. AIG: Assays - available or under development  Binding assays: ELISA (NIH, FDA)  In vitro Toxin Neutralization Assay (CDC, USAMRIID, FDA)  Rodent challenge (CDC, USAMRIID, FDA)  Monkey challenge (USAMRIID)

22. Unresolved Issues  Funding  Coordination and prioritization  Control of product distribution