1. Efficacy Review of Allergenic Extracts: Background (1972 – 1985) Jay E. Slater, MD Director, DBPAP

2. 2/35 Today’s presentations Background Allergenics efficacy reviews –Panel 1, 21 CFR 601.25 (1974-1979) –Panel 2, 21 CFR 601.26 (1982-1983) Current evaluation process (2003-2011) Safety of allergenic extracts Assessments Next steps

3. 3/35 Allergen extracts aqueous extract products derived from several natural source materials: Pollens Mold spores Animal skin and hair Insects Foods They may be used for the the diagnosis and treatment of allergic diseases, including allergic rhinitis, allergic conjunctivitis, asthma, and – in some cases – anaphylaxis.

4. 4/35 History of allergen extracts 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, 3rd ed. 2004

5. 5/35 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 1920s)

6. 6/35 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 Kefauver Harris Drug Amendments of 1962 Food and Drug Administration Modernization Act of 1997 http://www.fda.gov/opacom/backgroun ders/miles.html/ http://www.history.nih.gov/exhibits/hist ory

7. 7/35 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 May 1974 to August 1979 Panel report: submitted March 1981; published in 50 FR 3082-3288 (23 January 1985) http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm Classification panel

8. 8/35 Members Classification panel 1974-1979 Paul Seebohm, MD –Associate Dean, College of Medicine, University of Iowa Elliot Ellis, MD –Chair, Pediatrics, SUNY Buffalo Ralph Hale, MD –University of Kansas School of Medicine David Levy, MD –Johns Hopkins University Frank Perlman, MD –University of Oregon Medical School Robert Reisman, MD –SUNY Buffalo Thomas Van Metre, MD –Johns Hopkins University Max Samter, MD (consultant) –Director, Institute of Allergy and Clinical Immunology, Grant Hospital, Chicago

9. 9/35 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

10. 10/35 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”

11. 11/35 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 as described in §314.126…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”

12. 12/35 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

13. 13/35 Immunotherapy evidence standards Classification panel 1974-1979 (601.25) Panel established the following criteria for evidence of immunotherapy efficacy –Conclusive –Acceptable –Circumstantial –Insufficient 50 FR 3093

14. 14/35 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 50 FR 3093

15. 15/35 Immunotherapy evidence standards Classification panel 1974-1979 (601.25) 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 50 FR 3093

16. 16/35 Immunotherapy evidence standards Classification panel 1974-1979 (601.25) 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 50 FR 3093

17. 17/35 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 50 FR 3094

18. 18/35 Category IIIA (= data insufficient for classification; favorable risk/benefit; may remain on market) Classification panel 1974-1979 (601.25) Acceptable evidence Circumstantial evidence 50 FR 3094

19. 19/35 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 50 FR 3094

20. 20/35 Skin test diagnosis ImmunotherapyIn vitro changes Panel I classification ConclusiveEffectivePlacebo-controlled reduction in symptoms YesI AcceptableEffectiveReduction in symptoms, “long experience” YesI or IIIA CircumstantialEffectiveReduction in symptoms, “long experience” NoIIIA InsufficientNot effectiveAnecdotal evidence onlyNoII or IIIB

21. 21/35 Panel recommendations Classification panel 1974-1979 (601.25) Diagnosis Therapy (foods not included) I26%1% II0% IIIA48%65% IIIB26%34%

22. 22/35 Panel recommendations Classification panel 1974-1979 (601.25) Manufacturing principles Studies for IIIA products Standardization 50 FR 3116-3123

23. 23/35 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 50 FR 3116-3123

24. 24/35 FDA responses to Panel’s recommendations on IIIA products 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)

25. 25/35 Today’s presentations Background Allergenics efficacy reviews –Panel 1, 21 CFR 601.25 (1974-1979) –Panel 2, 21 CFR 601.26 (1982-1983) Current evaluation process (2003-2011) Safety of allergenic extracts Assessments Next steps

26. 26/35 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 http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm

27. 27/35 Members Reclassification panel 1982-1983 (601.26) Paul Seebohm, MD* –Associate Dean, College of Medicine, University of Iowa Elliot Ellis, MD* –Chair, Pediatrics, SUNY Buffalo Clifton Furukawa, MD –University of Washington Ralph Hale, MD* –Kansas University Medical Center David Levy, MD* –Johns Hopkins University Floyd Malveaux, MD –Chair, Allergy, Howard University Hospital Thomas Van Metre, MD* –Johns Hopkins University Robert Reisman, MD* (consultant) –SUNY Buffalo * on previous panel

28. 28/35 Guidelines for reclassification of a Category IIIA product to Category I Reclassification panel 1982-1983 (601.26) Accumulated evidence indicates that the extract is safe Derived from well-defined source material Definable or measurable constituents and is capable of being standardized Demonstrated to be effective by skin testing in allergic and non-allergic subjects and/or RAST or is closely analogous to products shown to be effective Properly labeled [For IT, valid clinical study of product or analogous product] Page 7, at http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM271333.pdf

29. 29/35 Skin test diagnosis ImmunotherapyIn vitro changes Panel I classification ConclusiveEffectivePlacebo-controlled reduction in symptoms YesI AcceptableEffectiveReduction in symptoms, “long experience” YesI or IIIA CircumstantialEffectiveReduction in symptoms, “long experience” NoIIIA InsufficientNot effectiveAnecdotal evidence onlyNoII or IIIB

30. 30/35 Skin test diagnosis ImmunotherapyIn vitro changes Panel I classification ConclusiveEffectivePlacebo-controlled reduction in symptoms YesI AcceptableEffectiveReduction in symptoms, “long experience” YesI CircumstantialEffectiveReduction in symptoms, “long experience” NoI InsufficientNot effectiveAnecdotal evidence onlyNoII or IIIB

31. 31/35 Panel recommendations Reclassification panel 1982-1983 (601.26) (excludes former IIIB insects/foods) Diagnosis Therapy (foods not included) I83%67% II17%33%

32. 32/35 Panel recommendations Diagnosis Therapy, foods not included I83%67% II17%33% Diagnosis Therapy, foods not included I26%1% II0% IIIA48%65% IIIB26%34% Classification panel 1974-1979 Reclassification panel 1982-1983 (601.25)(601.26) (excludes former IIIB insects/foods)

33. 33/35 This bar graph shows how Panel 2 assessed allergen extracts according to their classification by Panel 1. For products found by Panel 1 to be category 1, Panel 2 reclassified nearly all into category I as well. For category IIIA, about 90% were reclassified into category I. And for IIIB, about half were placed in category I.

34. 34/35 Follow-up to the activities of the efficacy review panels Panel 1 report (issued January 1985): –Category IIIB allergenic products were voluntarily removed from the market Panel 2 report for allergenics not published or implemented

35. 35/35 Today’s presentations Background Allergenics efficacy reviews –Panel 1, 21 CFR 601.25 (1974-1979) –Panel 2, 21 CFR 601.26 (1982-1983) Current evaluation process (2003-2011) Safety of allergenic extracts Assessments Next steps