Division of Hematology Emergency Preparedness Action Initiatives

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 HematologyFDA/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