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Efficacy review of allergenic products

Efficacy review of allergenic products. Progress report September 13, 2006. Today ’ s presentation. Review of prior efficacy reviews Panel I (1974-1979) Panel II (1982-1983) Current effort (2003+) Initial screening Database Review issues Timeline. The agencies

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Efficacy review of allergenic products

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  1. Efficacy review of allergenic products Progress report September 13, 2006

  2. Today’s presentation • Review of prior efficacy reviews • Panel I (1974-1979) • Panel II (1982-1983) • Current effort (2003+) • Initial screening • Database • Review issues • Timeline

  3. The agencies 1902: Hygienic Laboratory, Public Health and Marine Hospital Service 1930: National Institute (sic) of Health 1955: Division of Biologics Standards, NIH 1972: Bureau of Biologics, FDA 1982: Center for Drugs and Biologics, FDA 1987: Center for Biologics Evaluation and Research, FDA The laws Biologics Control Act of 1902 Food and Drugs Act of 1906 Food Drug and Cosmetic Act of 1938 Public Health Service Act of 1944 Food and Drug Administration Modernization Act of 1997 Allergen extract regulation http://www.fda.gov/opacom/backgrounders/miles.html http://www.history.nih.gov/exhibits/history

  4. 1972 Bureau of Biologics FDA US allergen extract timeline 1900 + First extracts 1920 + Manufacturers

  5. Classification panel • Convened 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 misbranded…” • Data 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 1979 • Panel report: submitted 13 March 1981; published in 50 FR 3082-3288 (23 January 1985)

  6. 1972 Bureau of Biologics FDA US allergen extract timeline 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1900 + First extracts 1920 + Manufacturers

  7. The Panel’s Task Classification panel 1974-1979 (601.25) • >1,500 extracted substances reviewed • Goals: • Evaluate safety and efficacy in accordance with 601.25 • Review labeling • Submit report on conclusions and recommendations

  8. Product Classification CategoriesDefined in 21 CFR 601.25 • Category I: safe; effective; and not misbranded • Category II: unsafe; ineffective; or misbranded • Category III: data insufficient for classification • IIIA: thought to have favorable risk-benefit ratio; remain on the market pending completion of testing • IIIB: thought to have unfavorable risk-benefit ratio; removal from the market pending completion of testing

  9. Category I(= safe; effective; and not misbranded)Classification panel 1974-1979 (601.25) • Conclusive evidence; or • Acceptable evidence, along with • Widespread acceptance and use • Clinical syndrome documented • Favorable in vitro changes • Systematic observation of possible AEs • Natural history understood p. 3094

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

  11. Category IIIB (= data insufficient for classification; unfavorable risk/benefit; may not remain on market)Classification panel 1974-1979 (601.25) • Insufficient evidence • May be assigned to II depending on • Strength of data • Lack of safety • Risk/benefit p. 3094

  12. Panel recommendationsClassification panel 1974-1979 (601.25)

  13. Panel recommendationsClassification panel 1974-1979 (601.25) • Manufacturing principles • Studies for IIIA products • Standardization

  14. Studies on IIIA productsClassification panel 1974-1979 (601.25) • Panel Recommendations: • Design collaborative, FDA-approved studies • Separate protocols for Diagnosis and Immunotherapy • Allow inference among related allergens • In vitro data may be acceptable in some cases p. 3116-3123

  15. FDA responses to Panel’s recommendations • Recommendations regarding further testing of IIIA products superceded by a new rule (21 CFR 601.26) establishing a reclassification review panel • 47 FR 44062 (5 October 1982) • Agency will publish a separate proposal regarding Category IIIA products

  16. 1972 Bureau of Biologics FDA US allergen extract timeline 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1900 + First extracts 1920 + Manufacturers

  17. Reclassification panel • Convened under 21 CFR 601.26: IIIA products to be reclassified as I or II • Panel met from 19 November 1982 to 4 June 1983 • Panel report submitted December 1983

  18. 1982-1983 Reclassification Panel 601.26 IIIA I or II 1972 Bureau of Biologics FDA US allergen extract timeline 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1900 + First extracts 1920 + Manufacturers

  19. 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 II • Panel stated that species definition needed for reclassification into Category I

  20. Panel Recommendations (therapy)Reclassification panel 1982-1983 (601.26) • Pollen extracts, mammalian/avian extracts, many mold and insect extracts recommended for reclassification into Category I • Species definition was needed for reclassification into Category I • Miscellaneous inhalant and all food extracts recommended for reclassification into Category II

  21. Task at hand: 2003-2006 • Review the 601.26 Reclassification Panel’s recommendations regarding Category IIIA products • Review data published since 1972 • Determine FDA position on Reclassification Panel’s recommendations based upon additional data

  22. 1982-1983 Reclassification Panel 601.26 IIIA I or II 2003-2006 Review and implementation IIIA I or II 1972 Bureau of Biologics FDA US allergen extract timeline 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1900 + First extracts 1920 + Manufacturers

  23. The process: 2003-2006 • Establish a provisional process by which Category IIIA products will be reclassified and implement the process • Publish a Proposed Order – Federal Register • FDA’s reclassification of IIIA products into Category I or II • Period for public comment after issuance of Proposed Order • Consider public responses, and revise order as necessary • Publish a Final Order – Federal Register • Classification • Revoke licenses for products reclassified into Category II

  24. Initial database contained over 1500 extracts Removal of duplicate and obsolete entries Current list: 1273 entries Animals: 46 Dusts: 6 Foods: 278 Insects: 34 Molds: 180 Plants: 17 Pollens: 714 Progress reportInitial screening

  25. Microsoft Access Provision for Records for each extract Simultaneous access by committee members of all records Filing and organization of all data retrieved and saved Final reports Progress reportDatabase design

  26. Progress reportDatabase design – main panel

  27. Progress reportDatabase design – main panel

  28. Progress reportDatabase design - document data panel

  29. Progress reportDatabase design – main panel

  30. Progress reportDatabase design – rationale panel

  31. Total entries: 1273 Individual reviews: 745 Committee reviews: 624 Progress reportReview statistics (as of 31 August 2006)

  32. Panel I: “A generic recommendation relied on the accumulated evidence and indicates the status of information about the substance. A recommendation for a company’s licensed product was based upon information which applies to that product alone.” (50 FR 3084) Most of Panel I’s reviews were “generic” A few were product-specific for example, Dermatophytin (Hollister Stier) and Histamine Azoprotein (Parke Davis) Progress report (1) Reviews continue to be generic, not specific

  33. Medline search English-language literature, 1972 to present ISI Google Progress report (2) Information reviewed is from public sources

  34. Panels I and II classified nearly all products as safe. Unless there are data suggesting safety issues, we have inferred that the product is safe for diagnosis and (other than foods) for immunotherapy. Progress report (3) Product safety

  35. For Grass, Tree and Weed Pollens and Animals, the preponderance of data supports the efficacy and safety of immunotherapy. Therefore, those allergens placed in category I for diagnosis should be placed in category I for therapy as well. For case reports for Foods, a single case report may suffice for skin test diagnosis if it has supportive oral challenge data as well. For case reports for other allergens, a single case report may suffice for skin test diagnosis if it has supportive nasal or bronchial or conjunctival challenge data as well. Progress report (4)Limited data may provide information on efficacy for certain products

  36. Specifics of extraction techniques for skin testing materials generally not reviewed. The underlying assumption is that most allergens are water-soluble and stable when properly stored. This assumption is not valid for food allergens. Therefore Data will be considered supportive of the efficacy of a food allergen extract for diagnosis only if the allergen extract was prepared by a method comparable to commercial methods. Data using fresh and/or unfiltered pulp, juice, or slurries are not considered supportive. Progress report (5)Food extracts placed in category I only based on studies in which an extract is used

  37. If an extract is shown – using in vitro or in vivo data – to be cross-reactive to another extract for which adequate efficacy data exist, then the cross-reactive extract may be considered to be effective as well. Partial cross-reactivity is acceptable. When quantitative cross-reactivity data are provided, the degree of cross-reactivity should be no less than 20% for allergens of the same genus. For allergens of different genera, the minimum level of cross-reactivity should be higher. When cross-reactivity data among two or more extracts of the same genus are especially convincing, then additional members of the same genus may be determined to be cross-reactive. Progress report (6)Products may be placed in category I based on cross-reactivity

  38. Specific designations/names – not necessarily genus/species – were required by Panel I Genus/species required by Panel II for “pollen, mold and plant extracts” (p. 13) Progress report (7)Specificity in source material nomenclature

  39. Current review initiated with genus/species designations. Several issues quickly arose: Multiple beans (Navy, pinto, red kidney, green yellow wax) share single genus/species: Phaseolis vulgaris Flounder: three genera designated (Pectinidea, Platichthys, Pleuronectes) but no species Catfish articles do not designate genus/species Lobster articles do not identify genus/species (Homarus americanus +35 other species in CFSAN’s list) Progress report (7)Specificity in source material nomenclature

  40. General NCBI taxonomy database (www.ncbi.nlm.nih.gov/entrez) databases (http://www.mnh.si.edu/) Mammals National Museum of Natural History - mammal species (http://nmnhgoph.si.edu/msw/) Plants and pollens PLANTS (http://plants.usda.gov) Integrated Taxonomic Information System (www.itis.usda.gov) Fish and seafood The Seafood List (www.cfsan.fda.gov/~frf/seaintro.html) Regulatory Fish Encyclopedia (www.cfsan.fda.gov/~frf/rfe0.html) FishBase (www.fishbase.org/) National Museum of Natural History - fish species (http://www.nmnh.si.edu/vert/fishes/fishcat/index.html) Molds (www.indexfungorum.org) Progress report (8) We encounter frequent examples of species synonymy

  41. Summary: completion of the 21 CFR 601.26 process • 50% complete • no broad safety issues identified • evaluations are based on published data

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