1. Reclassification of IIIA allergenic products

2. 2/53 Allergen Extracts pollens molds epidermoids insects foods

3. 3/53 Today ’ s presentation History of allergy and allergy treatment Allergen extract regulation Pre-FDA FDA 21 CFR 601.25 21 CFR 601.26 Completion of the 21 CFR 601.26 process

4. 4/53 History of allergy and allergy treatment 1819 – Dr. John Bostock first accurately describes hay fever as a disease affecting the upper respiratory tract 1869 – 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 fever http://www.allergyclinic.co.nz/guides/39.html

5. 5/53 History of allergy and allergy treatment 1911 - 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 immunotherapy http://www.allergyclinic.co.nz/guides/39.html

6. 6/53 History of allergy and allergy treatment First 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, 3 rd ed. 2004

7. 7/53 Allergen extract manufacturing Physicians began preparing extracts for others Sheldon et al. A Manual of Clinical Allergy (Saunders, 1953) contains detailed instructions (30 pages) for allergen extract production Practice evolved to independent laboratories preparing extracts Laboratories evolved into licensed manufacturers (first license issued in 1920 ’ s)

8. 8/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers

9. 9/53 Allergen extract regulation 1902: Hygienic Laboratory, Public Health and Marine Hospital Service 1930: National Institute (sic) of Health 1955-1972: 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 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/m iles.html/ http://www.history.nih.gov/exhibits/history

10. 10/53 Allergen extract regulation 1902: Hygienic Laboratory, Public Health and Marine Hospital Service 1930: National Institute (sic) of Health 1955-1972: 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 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 1987 http://www.fda.gov/opacom/backgrounders/m iles.html/ http://www.history.nih.gov/exhibits/history

11. 11/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA

12. 12/53 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)

13. 13/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1972 Bureau of Biologics FDA

14. 14/53 Members Classification panel 1974-1979 Paul Seebohm, MD Elliot Ellis, MD Ralph Hale, MD David Levy, MD Frank Perlman, MD Robert Reisman, MD Thomas Van Metre, MD Max Samter, MD (consultant)

15. 15/53 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

16. 16/53 Standards for Safety and Efficacy Classification panel 1974-1979 (601.25) Standards Defined for Safety in 601.25 “… relative freedom from harmful effect …” “ Proof shall consist of adequate tests by methods reasonably applicable … including results of significant human experience ”

17. 17/53 Standards for Safety and Efficacy Classification panel 1974-1979 (601.25) Standards Defined for Efficacy in 601.25 “ reasonable expectation that..the biological product … will serve a clinically significant function in the diagnosis … treatment … of disease ” “ Proof … shall consist of controlled clinical investigations … unless this requirement is waived ” because: “ Not reasonably applicable ” or Not “ essential to the investigation ” and An “ alternative methods of investigation is adequate to substantiate effectiveness ”

18. 18/53 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

19. 19/53 Immunotherapy evidence standards Classification panel 1974-1979 (601.25) Panel established criteria for evidence of immunotherapy efficacy Conclusive Acceptable Circumstantial Insufficient

20. 20/53 Immunotherapy evidence standards Classification panel 1974-1979 (601.25) Conclusive Evidence Effective in skin test diagnosis, and Placebo-controlled reduction in symptoms, and In vitro changes Specific IgG decreases Seasonal rise in IgE blunted Specific IgE decreases Histamine release decreases p. 3093

21. 21/53 Acceptable Evidence Effective in skin test diagnosis, and Long experience suggests reduction in symptoms, and In vitro changes Specific IgG decreases Seasonal rise in IgE blunted Specific IgE decreases Histamine release decreases p. 3093 Immunotherapy evidence standards Classification panel 1974-1979 (601.25)

22. 22/53 Circumstantial Evidence Effective in skin test diagnosis, and Long experience suggests reduction in symptoms Insufficient Evidence Not effective in skin test diagnosis Anecdotal reduction in symptoms No in vitro changes p. 3093 Immunotherapy evidence standards Classification panel 1974-1979 (601.25)

23. 23/53 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

24. 24/53 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

25. 25/53 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

26. 26/53 Panel recommendations Classification panel 1974-1979 (601.25) Manufacturing principles Studies for IIIA products Standardization

27. 27/53 Panel recommendations Classification panel 1974-1979 (601.25) Manufacturing principles Studies for IIIA products Standardization

28. 28/53 Studies on IIIA products Classification panel 1974-1979 (601.25) Panel Recommendations: Design collaborative studies Allow inference among related allergens Obtain FDA approval for studies Separate protocols for Diagnosis and Immunotherapy For some extracts, these requirements may be modified In vitro data may be acceptable in some cases p. 3116-3123

29. 29/53 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

30. 30/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1974-1979 Classification Panel 601.25 I/II/IIIA/IIIB 1972 Bureau of Biologics FDA

31. 31/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA

32. 32/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA

33. 33/53 Today ’ s presentation History of allergy and allergy treatment Allergen extract regulation Pre-FDA FDA 21 CFR 601.25 21 CFR 601.26 Completion of the 21 CFR 601.26 process

34. 34/53 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

35. 35/53 US allergen extract timeline 1900 + First extracts 1920 + Manufacturers 1972 Bureau of Biologics FDA 1982-1983 Reclassification Panel 601.26 IIIA I or II

36. 36/53 Members Reclassification panel 1982-1983 (601.26) Paul Seebohm, MD* Elliot Ellis, MD* Clifton Furukawa, MD Ralph Hale, MD* David Levy, MD* Floyd Malveaux, MD Thomas Van Metre, MD* * on previous panel

37. 37/53 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 required for reclassification into Category I

38. 38/53 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 required for reclassification into Category I Miscellaneous inhalant and all food extracts recommended for reclassification into Category II

39. 39/53 Fast forward (1983 to 2003)

40. 40/53 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

41. 41/53 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

42. 42/53 The process: 2003-2006 Establish a provisional process by which Category IIIA products will be reclassified and implement the process Collect data on products since 1972 Establish criteria to be applied when reviewing data 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

43. 43/53 Provisional review process (I) Data to be collected Medline search English-language literature, 1972 to present Manufacturer data, if available Files submitted to docket Medwatch and VAERS

44. 44/53 Categorization of papers  Study design  Case report  Number of cases  Observational cohort  Case-control  Prospective  Retrospective  Placebo-controlled prospective

45. 45/53 Categorization of papers  Species  Human  Veterinary  Vehicle  Aqueous  Glycerine  Alum  Not specified  Potency test  None  protein  w/v  Biological  Antibody-based  Lot  Single  Multiple, identified  neither

46. 46/53 Categorization of papers  Diagnosis  Prick  ID  Quantitative  Immunotherapy  Rush  Conventional  Oral  Sublingual  Parenteral  Statistical analysis  Valid  Invalid  None  Analysis  Validated  Challenge  Patient report  Quantified

47. 47/53 Provisional review process (II) Criteria for reclassification into category I Efficacy – two or more well-described case reports, uncontradicted. Safety – absence of species-specific SAE reports from any source greater than case reports; will consider risk-benefit for case reports

48. 48/53 Rationale for CBER Review Committee criteria Positive data on efficacy required Well-described case reports are sufficient; controlled trials NOT necessary. Although there are many controlled efficacy trials for allergen immunotherapy, these have only been performed using few highly prevalent extracts

49. 49/53 Rationale for CBER Review Committee criteria Negative safety data sufficient Baseline of AEs for both skin tests and immunotherapy with all extracts Higher-than-baseline AEs typical for the most potent extracts Higher-than-baseline AEs associated with patient and practice risk factors

50. 50/53 Provisional review process (III) Report format Extract name Alias Group Manufacturers Category, according to Panel Reclassification category Citation in original Panel report Specific literature cited in Panel report, with brief summaries (if possible, separate by diagnosis, therapy and cross-reactivity) Literature retrieved since 1972 (include search strategy) Assessment and reclassification All cited literature, in digital format

51. 51/53 Proposal (IV) - documentation All cited literature, PDF format All submitted manufacturer data All committee reports All committee discussion

52. 52/53 Reclassification of IIIA allergenic products Completion of review/regulatory process started in 1972 Approximately 1200 products to review Extensive documentation of review materials and deliberations Will report progress to Advisory Committee

53. 53/53 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