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

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

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

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

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

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

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

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

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

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

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) 17025 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

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

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