1. Laboratory of Immunobiochemistry Site Visit
Ronald L. Rabin, MD
FDA/CBER/OVRR/DBPAP
November 4, 2010

2. Laboratory of Immunobiochemistry (LIB)
LIB supports the regulatory mission of CBER and FDA in assuring the safety and efficacy of allergenic products in the US
original research
directed research projects
expert advice
lot release data
BLA and IND review

3. History of LIB
Laboratory of Allergenic Products, Division of Bacterial Products
Laboratory of Immunobiochemistry, Division of Allergenic Products and Parasitology
Allergenic Products Testing Lab
Allergenic Products Research Lab
Laboratory of Immunobiochemistry, Division of Bacterial, Parasitic, and Allergenic Products

4. Natural allergen extracts
Complex mixtures of allergenic proteins, based largely on an unselective aqueous extraction of natural source material (pollens, insects, animals, foods, venoms)
Used for
Diagnosis (allergy skin testing) and
Allergen immunotherapy
Documented efficacy in the immunotherapy of allergic disease due to hymenoptera, ragweed, grass, cat, and dust mite allergen exposure

5. Natural allergen extracts
Non-standardized products (n > 1000)
Unitage uninformative (PNU/mL or w/v)
Standardized products (n = 19)
unitage correlates to biological potency
mass units, BAU/mL, specific allergen
controlled for potency and stability
based on identity to US standard
constitute a small minority of product number, but a greater percentage of product volume

6. How can we improve the use of natural allergen extracts?
Increase the number of standardized products
Improve the standardization of some current products by improving the definition of the measured allergens
Increase purity standards
selective extraction techniques, purification
Improve characterization methods

7. Recombinant / engineered allergens
Current: Potent research tools
dissect immune responses
modify immune responses
study allergen structure
determine structure-function relationships
generate novel products

8. Recombinant/engineered allergens
Opportunities (positive):
Allergenicity  immunogenicity
Possible standardization tools
Greater purity and consistency of product
Greater product stability (both due to purity and engineering)
Improve delivery systems (in ways not possible using native proteins)
Opportunities (negative):
Challenges to standardization
allergenicity  immunogenicity  potency
unique products with different biological features
Indications will be very specific
IT products may be ineffective for diagnosis
Diagnostic products may be ineffective for IT
Usage may be population-specific

9. The last dedicated site visit for LIB was in June 2006
relevant to the mission of the laboratory and deserved continued support from the agency

10. Staffing Ronald L. Rabin, MD – Lab Chief Philippa Hillyer, Ph.D.
Ashraf El Fiky MD, Ph.D.-Visiting Associate
Zeng Zhao, MD, Visiting Associate
Jay Slater, MD – Supervisory Medical Officer
Taruna Khurana, Ph.D.
Regulatory Staff
Sandra Menzies, MS–Consumer Safety Officer
Cherry Valerio
Katia Dobrovolskaia
Aaron Chen MS
Mona Febus

11. LIB regulatory activities (see Briefing Document, pp.12 - 13)
Lot release
US reference standards
distribution
maintenance
Regulatory review
IND applications
BLA applications and supplements
Implementation of category IIIA product reclassification to re-evaluate over 1200 non-standardized prodcuts for efficacy
ISO (International Standards Organization) compliance for accreditation to ensure stringent documentation and protocols for SOP
Replace RID for Fel d1 and Amb a1 (cat and ragweed) with ELISA
13th Int’l Paul-Ehrlich-Seminar: Regulatory Control and Standardization of Allergenic Extracts. Washington, D.C. September, 2011
Lot release: we are the product related lab that tests for lot release
IIIA: re-evaluate over 1200 products for efficacy
ISO17025: stringent documentation and SOP protocols

12. Endotoxins in allergen extracts
Scientific goals
Allergen structure and function
Biological activity and expression patterns of subtypes of types I and III IFN
Multiplex allergen extract potency assay
characterization of complex allergen extracts
Endotoxins in allergen extracts
Extract characterization
Modifying allergic responses

13. Regulatory responsibility
Regulatory correlates of LIB’s research program (see Briefing Document, p.15)
Regulatory responsibility
Research correlate
Improved lot release capabilities for current and future products
Allergen standardization
Immunomodulatory approach to inner city asthma
Multiplex allergen extract potency; cockroach allergen standardization
Allergenic extract safety and efficacy
Endotoxin
Parameters of effective immunomodulation
Types I and III IFN
Novel approaches to immunotherapy