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

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

Potential Plasma-Derived Products

Polyclonal antibodies from hyperimmune donors (IGIV products) Human vaccinees Animals immunized

Human Plasma (high titer) Interim procedure – safety concerns

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

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

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

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

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

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)

Current Thinking: Clinical Trials for Licensure of VIGIV

New product indications limited to treatment of life-threatening smallpox vaccinations Eczema vaccinatum Progressive vaccinia

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)

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

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

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

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

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

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

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

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

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

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)

Unresolved Issues

Funding Coordination and prioritization Control of product distribution