1. Recombinant allergens: what needs to come next?

2. Where we are with natural allergens n All natural, mixes based largely on an unselective extraction of source material Different diluentsDifferent diluents Varying potency and stabilityVarying potency and stability n Documented efficacy in the immunotherapy of allergic disease due to hymenoptera, ragweed, grass, cat, and dust mite allergen exposure

3. Where we are with natural allergens n Unitage for non-standardized products uninformative n Standardized products are controlled for potency and stability n Standardization is based on identity to US standard n Standardized products constitute a small minority of product number, but a greater percentage of product volume

4. Where we are with natural allergens n Allergenicity = immunogenicity = potency n Products may be used for diagnosis and immunotherapy (not all approved for both) n Production issues associated with certain products (e.g. precipitates)

5. Where we are with natural allergens - summary n A diverse group of products, many of which are of uncertain potency, but several of which are standardized and are of documented efficacy both for the diagnosis and treatment of allergic disease.

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

7. How can we improve the use of natural allergens? n Improve stability (glycerol, lyophilization, other) n Improve delivery systems n Better definition of indications n More consistent and rational applications

8. Where we are with recombinant allergens n Current: Potent research tools dissect immune responsesdissect immune responses modify immune responsesmodify immune responses study allergen structurestudy allergen structure determine structure-function relationshipsdetermine structure-function relationships generate novel productsgenerate novel products

9. Where we can be with recombinant allergens n Clinical opportunities (positive): Possible standardization toolsPossible standardization tools Allergenicity  immunogenicityAllergenicity  immunogenicity Greater purity and consistency of productGreater purity and consistency of product Greater product stability (both due to purity and engineering)Greater product stability (both due to purity and engineering) Improve delivery systems (in ways not possible using native proteins)Improve delivery systems (in ways not possible using native proteins)

10. Where we can be with recombinant allergens n Clinical opportunities (negative): Challenges to standardization (unique products with different biological features)Challenges to standardization (unique products with different biological features) Challenges to standardization (allergenicity  immunogenicity  potency))Challenges to standardization (allergenicity  immunogenicity  potency)) Indications will be very specificIndications will be very specific –IT products may be ineffective for diagnosis –Diagnostic products may be ineffective for IT –Usage may be population-specific

11. Where are we in the process? n Lab-based science n Clinical/financial interest n Preclinical safety and efficacy studies n Human studies Phase 1Phase 1 Phase 2Phase 2 Phase 3Phase 3 n Licensing n Post-licensing

12. How does the FDA decide? n The law Food Drug and Cosmetics Act of 1938 (FD&C Act)Food Drug and Cosmetics Act of 1938 (FD&C Act) –FDA Modernization Act of 1997 Public Health Service Act of 1944 (PHS Act)Public Health Service Act of 1944 (PHS Act) n The regulations Code of Federal Regulations (CFR)Code of Federal Regulations (CFR) n The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) n Guidance Documents

13. Guidance documents that apply to allergenic products n Guidance for Industry On the Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for an Allergenic Extract or Allergen Patch Test (1999) n Guidance for Industry: Testing Limits in Stability Protocols for Standardized Grass Pollen Extracts (2000) n Guidance for Reviewers: Potency Limits for Standardized Dust Mite and Grass Allergen Vaccines: A Revised Protocol (2000)

14. Guidance documents that apply specifically to recombinant products n (ICH) Quality of Biotechnology Products: Analysis of the Expression Construct in Cells Used for Production of R-DNA Derived Protein Products (1995) n (FDA) Guidance for Industry: Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In-Vivo Use (1996) n (ICH) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (1997) n (FDA) Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product (1999)

15. How to get there from here n Make a product that is safe and effectiveis safe and effective can be manufactured consistentlycan be manufactured consistently n Follow current Good Manufacturing Practices n Do the necessary studies

16. How to get there from here n Preclinical studies Product specific – efficacy, mechanism; choice of modelProduct specific – efficacy, mechanism; choice of model ToxicologyToxicology

17. How to get there from here n IND submission To show that the product is safe and effectiveTo show that the product is safe and effective To support the labeled indications and dosingTo support the labeled indications and dosing

18. IND process n Investigational New Drug n Section 262 of the PHS Act n Section 505 of the FD&C Act n http://www.fda.gov/cber/ind/ind.htm

19. n FDA’s objectives in reviewing an IND: to assure the safety and rights of subjectsto assure the safety and rights of subjects in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety (21 CFR 312.22(a))in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety (21 CFR 312.22(a))

20. IND - Phase 1 n initial introduction into humans n dose ranging n closely monitored n safety n activity

21. Reasons for “hold” on Phase 1 study n unreasonable and significant risk of illness or injury n clinical investigator is not qualified n Investigator’s Brochure is misleading, erroneous or materially incomplete n insufficient information to assess risk

22. IND - Phase 2 n controlled clinical trials n effectiveness (preliminary) n closely monitored n relatively small numbers (100’s)

23. IND - Phase 3 n evaluate efficacy n larger studies (100’s - 1000’s) n controlled n pivotal

24. Reasons for “hold” on Phase 2/3 study n All the Phase 1 reasons unreasonable and significant risk of illness or injuryunreasonable and significant risk of illness or injury clinical investigator is not qualifiedclinical investigator is not qualified Investigator’s Brochure is misleading, erroneous or materially incompleteInvestigator’s Brochure is misleading, erroneous or materially incomplete insufficient information to assess riskinsufficient information to assess risk n protocol or plan is deficient in design to meet its stated objectives

25. IND process n Protects human subjects safetysafety civil rightscivil rights n Improves the science rigorous study designrigorous study design n Facilitates product approval design previeweddesign previewed

26. How to get there from here n General hurdles for new allergens Biological justificationBiological justification Manufacturing practicesManufacturing practices –Lot to lot consistency Good potency assayGood potency assay –if you can’t measure it, how can you study it? Study powerStudy power

27. Study power n The study needs to be of adequate size to support the stated study objectives n The failure to demonstrate a difference is not sufficient to demonstrate equivalence  = 0.05;  = 0.2  = 0.05;  = 0.2

28. How to get there from here n Specific hurdles for new recombinant allergens character and stability of gene constructcharacter and stability of gene construct if cell line is used, the cell line needs to be extensively tested for absence of adventitious agents (such as retroviruses, EBV, SV40)if cell line is used, the cell line needs to be extensively tested for absence of adventitious agents (such as retroviruses, EBV, SV40) fermentation/growth media/growth conditionsfermentation/growth media/growth conditions purificationpurification characterization/proof of structurecharacterization/proof of structure

29. How to get there from here n More specific hurdles for new recombinant allergens study design must target the appropriate patient population (may be different from the natural counterpart)study design must target the appropriate patient population (may be different from the natural counterpart) indications must be carefully considered prior to study design (may be different from the natural counterpart)indications must be carefully considered prior to study design (may be different from the natural counterpart)

30. How to get there from here n Unitage will have to be biological unless purity is assuredpurity is assured correlation of biological activity to mass unitage is constantcorrelation of biological activity to mass unitage is constant stability of biological activity is assured under conditions under which the product will be shipped, stored and usedstability of biological activity is assured under conditions under which the product will be shipped, stored and used

31. But it has been done before... n Antihemophilic factor n Coagulation Factor VIIa n Coagulation factor IX n Etanercept n Epoetin alfa n Filgrastim n Hepatitis B vaccine n Infliximab n Interferon alfacon-1 n Oprelvekin n Palivizumab n Sargramostim n Trastuzumab n Pegfilgrastim n Peginterferon alfa-2b n Alemtuzumab n Anakinra n Darbepoetin alfa n Drotrecogin alfa

32. Resources n http://www.fda.gov/cber/ind/ind.htm n AAAAI Future Immunomodulation Initiative n pre-IND meeting