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  • Reclassification of IIIA allergenic products

  • Allergen Extractspollensmoldsepidermoidsinsectsfoods

  • Todays presentationHistory of allergy and allergy treatmentAllergen extract regulationPre-FDAFDA21 CFR 601.2521 CFR 601.26Completion of the 21 CFR 601.26 process

  • History of allergy and allergy treatment1819 Dr. John Bostock first accurately describes hay fever as a disease affecting the upper respiratory tract1869 In investigating his own hay fever, Dr. Charles Blakely performs the first skin test by applying pollen through a small break in his skin. He introduces concept that pollen causes hay feverhttp://www.allergyclinic.co.nz/guides/39.html

  • History of allergy and allergy treatment1911 - Noon and Freeman make sterile extracts of pollens and demonstrate that repeated injections improve clinical tolerance to allergen exposure, establishing the basis for allergen extract immunotherapyhttp://www.allergyclinic.co.nz/guides/39.html

  • History of allergy and allergy treatmentFirst aqueous extracts: Curtis (1900)Systematic investigations on extraction method: Wodehouse and Walker (1917) and Coca (1920s)Early allergists prepared extracts in their own offices for use with their patients

    Cohen and Evans, Allergen immunotherapy in historical perspective. In Lockey, et al. Allergens and allergen immunotherapy, 3rd ed. 2004

  • Allergen extract manufacturingPhysicians began preparing extracts for othersSheldon et al. A Manual of Clinical Allergy (Saunders, 1953) contains detailed instructions (30 pages) for allergen extract productionPractice evolved to independent laboratories preparing extractsLaboratories evolved into licensed manufacturers (first license issued in 1920s)

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers

  • Allergen extract regulation1902: Hygienic Laboratory, Public Health and Marine Hospital Service1930: National Institute (sic) of Health1955-1972: Division of Biologics Standards, NIH1972: Bureau of Biologics, FDA1982: Center for Drugs and Biologics, FDA1987: Center for Biologics Evaluation and Research, FDABiologics Control Act of 1902Food and Drugs Act of 1906Food Drug and Cosmetic Act of 1938Public Health Service Act of 1944Food and Drug Administration Modernization Act of 1997http://www.fda.gov/opacom/backgrounders/miles.html/http://www.history.nih.gov/exhibits/history

  • Allergen extract regulation1902: Hygienic Laboratory, Public Health and Marine Hospital Service1930: National Institute (sic) of Health1955-1972: Division of Biologics Standards, NIH1972: Bureau of Biologics, FDA1982: Center for Drugs and Biologics, FDA1987: Center for Biologics Evaluation and Research, FDABiologics Control Act of 1902Food and Drugs Act of 1906Food Drug and Cosmetic Act of 1938Public Health Service Act of 1944Food and Drug Administration Modernization Act of 1987http://www.fda.gov/opacom/backgrounders/miles.html/http://www.history.nih.gov/exhibits/history

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers

  • Classification panelConvened under 21 CFR 601.25: For purposes of reviewing biological products that have been licensed prior to July 1, 1972 that they are safe and effective and not misbrandedData requested from manufacturers in 39 FR 1082 (4 January 1974) and 39 FR 21176 (12 June 1974)Panel met from 24 May 1974 through 11 August 1979Panel report: submitted 13 March 1981; published in 50 FR 3082-3288 (23 January 1985)

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers1974-1979Classification Panel601.25I/II/IIIA/IIIB

  • MembersClassification panel 1974-1979Paul Seebohm, MDElliot Ellis, MDRalph Hale, MDDavid Levy, MDFrank Perlman, MDRobert Reisman, MDThomas Van Metre, MDMax Samter, MD (consultant)

  • The Panels Task Classification panel 1974-1979 (601.25)>1,500 extracted substances reviewedGoals:Evaluate safety and efficacy in accordance with 601.25Review labelingSubmit report on conclusions and recommendations

  • Standards for Safety and Efficacy Classification panel 1974-1979 (601.25)Standards Defined for Safety in 601.25relative freedom from harmful effectProof shall consist of adequate tests by methods reasonably applicableincluding results of significant human experience

  • Standards for Safety and Efficacy Classification panel 1974-1979 (601.25)Standards Defined for Efficacy in 601.25reasonable expectation that..the biological productwill serve a clinically significant function in the diagnosistreatmentof diseaseProofshall consist of controlled clinical investigationsunless this requirement is waived because:Not reasonably applicable orNot essential to the investigation andAn alternative methods of investigation is adequate to substantiate effectiveness

  • Product Classification Categories Defined in 21 CFR 601.25Category I: safe; effective; and not misbrandedCategory II: unsafe; ineffective; or misbrandedCategory III: data insufficient for classificationIIIA: thought to have favorable risk-benefit ratio; remain on the market pending completion of testingIIIB: thought to have unfavorable risk-benefit ratio; removal from the market pending completion of testing

  • Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)Panel established criteria for evidence of immunotherapy efficacy ConclusiveAcceptableCircumstantialInsufficient

  • Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)Conclusive EvidenceEffective in skin test diagnosis, andPlacebo-controlled reduction in symptoms, andIn vitro changesSpecific IgG decreasesSeasonal rise in IgE bluntedSpecific IgE decreasesHistamine release decreasesp. 3093

  • Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)Acceptable EvidenceEffective in skin test diagnosis, andLong experience suggests reduction in symptoms, andIn vitro changesSpecific IgG decreasesSeasonal rise in IgE bluntedSpecific IgE decreasesHistamine release decreases

    p. 3093

  • Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)Circumstantial EvidenceEffective in skin test diagnosis, andLong experience suggests reduction in symptoms

    Insufficient EvidenceNot effective in skin test diagnosisAnecdotal reduction in symptomsNo in vitro changesp. 3093

  • Category I(= safe; effective; and not misbranded)Classification panel 1974-1979 (601.25)Conclusive evidence; orAcceptable evidence, along withWidespread acceptance and useClinical syndrome documentedFavorable in vitro changesSystematic observation of possible AEs Natural history understood

    p. 3094

  • Category IIIA(= data insufficient for classification; favorable risk/benefit; may remain on market)Classification panel 1974-1979 (601.25)Acceptable evidenceCircumstantial evidencep. 3094

  • Category IIIB (= data insufficient for classification; unfavorable risk/benefit; may not remain on market)Classification panel 1974-1979 (601.25)Insufficient evidenceMay be assigned to II depending on Strength of dataLack of safetyRisk/benefitp. 3094

  • Panel recommendationsClassification panel 1974-1979 (601.25)Manufacturing principlesStudies for IIIA productsStandardization

  • Panel recommendationsClassification panel 1974-1979 (601.25)Manufacturing principlesStudies for IIIA productsStandardization

  • Studies on IIIA productsClassification panel 1974-1979 (601.25)Panel Recommendations:Design collaborative studiesAllow inference among related allergensObtain FDA approval for studiesSeparate protocols for Diagnosis and ImmunotherapyFor some extracts, these requirements may be modifiedIn vitro data may be acceptable in some cases

    p. 3116-3123

  • FDA responses to Panels recommendationsRecommendations regarding further testing of IIIA products superceded by a new rule (21 CFR 601.26) establishing a reclassification review panel47 FR 44062 (5 October 1982) Agency will publish a separate proposal regarding Category IIIA products

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers1974-1979Classification Panel601.25I/II/IIIA/IIIB

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers1974-1979Classification Panel601.25I/II/IIIA/IIIB

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers1974-1979Classification Panel601.25I/II/IIIA/IIIB

  • Todays presentationHistory of allergy and allergy treatmentAllergen extract regulationPre-FDAFDA21 CFR 601.2521 CFR 601.26Completion of the 21 CFR 601.26 process

  • Reclassification panelConvened under 21 CFR 601.26: IIIA products to be reclassified as I or IIPanel met from 19 November 1982 to 4 June 1983Panel report submitted December 1983

  • US allergen extract timeline1900 + First extracts1920 + Manufacturers1974-1979Classification Panel601.25I/II/IIIA/IIIB

  • MembersReclassification panel 1982-1983 (601.26)Paul Seebohm, MD*Elliot Ellis, MD*Clifton Furukawa, MDRalph Hale, MD*David Levy, MD*Floyd Malveaux, MDThomas Van Metre, MD** on previous panel

  • Panel Recommendations (diagnosis)Reclassification panel 1982-1983 (601.26)All Category IIIA products recommended for reclassification into Category I for diagnosis except:Certain pollens, molds, avian/mammalian, inhalants were recommended for reclassification as Category IIPanel stated that species definition required for reclassification into Category I

  • Panel Recommendations (therapy)Reclassification panel 1982-1983 (601.26)Pollen extracts, mammalian/avian extracts, many mold and insect extracts recommended for reclassification into Category ISpecies definition was required for reclassification into

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