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

2. 2/41 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. 3/41 Allergen extract regulation 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 http://www.fda.gov/opacom/backgrounders/ miles.html http://www.history.nih.gov/exhibits/history

4. 4/41 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA

5. 5/41 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. 6/41 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1972 Bureau of Biologics FDA

7. 7/41 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. 8/41 Product Classification Categories Defined 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. 9/41 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. 10/41 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. 11/41 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. 12/41 Panel recommendations Classification panel 1974-1979 (601.25) Diagnosis Therapy (foods not included) I26%1% II0% IIIA48%65% IIIB26%34%

13. 13/41 Panel recommendations Classification panel 1974-1979 (601.25) Manufacturing principles Studies for IIIA products Standardization

14. 14/41 Studies on IIIA products Classification 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. 15/41 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. 16/41 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1972 Bureau of Biologics FDA

17. 17/41 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. 18/41 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA 1982-1983 Reclassification Panel 601.26 IIIA I or II

19. 19/41 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. 20/41 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. 21/41 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. 22/41 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA 1982-1983 Reclassification Panel 601.26 IIIA I or II 2003-2006 Review and implementation IIIA I or II

23. 23/41 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. 24/41 Progress report Initial screening 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

25. 25/41 Progress report Database design 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

26. 26/41 Progress report Database design – main panel

27. 27/41 Progress report Database design – main panel

28. 28/41 Progress report Database design - document data panel

29. 29/41 Progress report Database design – main panel

30. 30/41 Progress report Database design – rationale panel

31. 31/41 Progress report Review statistics (as of 31 August 2006) Total entries: 1273 Individual reviews: 745 Committee reviews: 624

32. 32/41 Progress report (1) Reviews continue to be generic, not specific 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)

33. 33/41 Progress report (2) Information reviewed is from public sources Medline search English-language literature, 1972 to present ISI Google

34. 34/41 Progress report (3) Product safety 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.

35. 35/41 Progress report (4) Limited data may provide information on efficacy for certain products 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.

36. 36/41 Progress report (5) Food extracts placed in category I only based on studies in which an extract is used 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.

37. 37/41 Progress report (6) Products may be placed in category I based on cross-reactivity 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.

38. 38/41 Progress report (7) Specificity in source material nomenclature 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)

39. 39/41 Progress report (7) Specificity in source material nomenclature 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)

40. 40/41 Progress report (8) We encounter frequent examples of species synonymy General NCBI taxonomy database (www.ncbi.nlm.nih.gov/entrez)www.ncbi.nlm.nih.gov/entrez databases (http://www.mnh.si.edu/)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)www.itis.usda.gov Fish and seafood The Seafood List (www.cfsan.fda.gov/~frf/seaintro.html)www.cfsan.fda.gov/~frf/seaintro.html Regulatory Fish Encyclopedia (www.cfsan.fda.gov/~frf/rfe0.html)www.cfsan.fda.gov/~frf/rfe0.html FishBase (www.fishbase.org/)www.fishbase.org/ National Museum of Natural History - fish species (http://www.nmnh.si.edu/vert/fishes/fishcat/index.html) Molds (www.indexfungorum.org)www.indexfungorum.org

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