# Presentation: 527419

## 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