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Recombinant allergens: what needs to come next?

Recombinant allergens: what needs to come next?. Where we are with natural allergens. All natural, mixes based largely on an unselective extraction of source material Different diluents Varying potency and stability

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Recombinant allergens: what needs to come next?

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  1. Recombinant allergens: what needs to come next?

  2. Where we are with natural allergens • All natural, mixes based largely on an unselective extraction of source material • Different diluents • Varying potency and stability • 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 • Unitage for non-standardized products uninformative • Standardized products are controlled for potency and stability • Standardization is based on identity to US standard • Standardized products constitute a small minority of product number, but a greater percentage of product volume

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

  5. Where we are with natural allergens - summary • 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? • 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. How can we improve the use of natural allergens? • Improve stability (glycerol, lyophilization, other) • Improve delivery systems • Better definition of indications • More consistent and rational applications

  8. Where we are with recombinant allergens • Current: Potent research tools • dissect immune responses • modify immune responses • study allergen structure • determine structure-function relationships • generate novel products

  9. Where we can be with recombinant allergens • Clinical opportunities (positive): • Possible standardization tools • Allergenicity  immunogenicity • 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)

  10. Where we can be with recombinant allergens • Clinical opportunities (negative): • Challenges to standardization (unique products with different biological features) • Challenges to standardization (allergenicity  immunogenicity  potency)) • Indications 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? • Lab-based science • Clinical/financial interest • Preclinical safety and efficacy studies • Human studies • Phase 1 • Phase 2 • Phase 3 • Licensing • Post-licensing

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

  13. Guidance documents that apply to allergenic products • 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) • Guidance for Industry: Testing Limits in Stability Protocols for Standardized Grass Pollen Extracts (2000) • 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 • (ICH) Quality of Biotechnology Products: Analysis of the Expression Construct in Cells Used for Production of R-DNA Derived Protein Products (1995) • (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) • (ICH) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (1997) • (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 • Make a product that • is safe and effective • can be manufactured consistently • Follow current Good Manufacturing Practices • Do the necessary studies

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

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

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

  19. FDA’s objectives in reviewing an IND: • to 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))

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

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

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

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

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

  25. IND process • Protects human subjects • safety • civil rights • Improves the science • rigorous study design • Facilitates product approval • design previewed

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

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

  28. How to get there from here • Specific hurdles for new recombinant allergens • character 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) • fermentation/growth media/growth conditions • purification • characterization/proof of structure

  29. How to get there from here • More specific hurdles for new recombinant allergens • 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)

  30. How to get there from here • Unitage will have to be biological unless • purity is assured • correlation 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 used

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

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

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