Division of Hematology Emergency Preparedness Action Initiatives Prepared

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

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

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

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

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

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

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

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

Current Thinking: Clinical Trials for Licensure of VIGIV w Licensure based upon PK equivalence and safety data. PK not inferior (> 0. 8) to VIG given I. M. w Accelerated Approval designation desirable (21 CFR 601. 40 – 601. 46) n n expedited availability of product Phase IV commitments to study human surrogate markers (e. g. influence of VIGIV on vaccine take, lesion size)

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

Vaccinia Immune Globulin: Current DH Research w Developing and Testing Potency assays for VIG Products n SCID mouse model l l n n 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)

Vaccinia Immune Globulin: Current DH Research w Determining levels of anti-vaccinia antibodies in licensed IGIV products n n 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

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

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

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

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

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

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

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

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

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

Unresolved Issues w Funding w Coordination and prioritization w Control of product distribution