1. 1/22 Potential Next Steps Jay E. Slater, MD Director, DBPAP

2. 2/22 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. 3/22 Internal review determinations Table 1. Use in Diagnosis and Treatment Addressed in Literature (n = 480) Table 2. Foods: Use in Diagnosis Addressed in Literature (n = 134) Table 3. Non-food: Use in Diagnosis Addressed in Literature (n = 73) Table 4. Minimal or No Literature Relating to Use in Diagnosis and Treatment (n = 566) Table 5. Potential Safety Issues (n = 16)

4. 4/22 Documents available Review panel reports –http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm Tables –http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/BloodVaccinesandOtherBiologics/AllergenicProductsAdvisory Committee/UCM274718.pdf FR notice (instructions for comments) –http://www.gpo.gov/fdsys/pkg/FR-2011-09-26/pdf/2011-24598.pdf

5. 5/22 Discussion points Comments on –the review process so far; –the decision to list non-standardized allergenic products in five tables according to the evidence collected; and –the possible disposition of the categories of products identified in the Tables

6. 6/22 Paths forward 21 CFR 601.25 and 601.26 Other approaches

7. 7/22 Paths forward 21 CFR 601.25 and 601.26 Established approach Basis for previous efficacy/safety reviews But - it is difficult to assess non-standardized products using data that relate to “general” product type. (For a new approval today, we would require individualized showing for a manufacturer’s product.) These regulations apply to products licensed before 1 July 1972 – and not to those licensed after that date.

8. 8/22 Assessing non-standardized products “generally” The “general” data are comprised of: –Conclusions from case reports, not studies –Interpretation and application of cross- reactivity data –Conclusions applied “generally” to multiple manufacturers

9. 9/22 Non-standardized allergenic products licensed after 1 July 1972 Three of seven manufacturers obtained their licensed for non-standardized allergenic extracts late 1972 to 1974. http://www.fda.gov/downloads/BiologicsBloodVaccines/UCM149969.pdf

10. 10/22 Paths forward 21 CFR 601.25 and 601.26 Other approaches: –Use other regulations to address evidence of efficacy issues (Tables 4 and 5) along with safety issues (Table 5)

11. 11/22 Paths forward Reasons to take action on the basis of efficacy evidence –Both advisory panels concluded that many allergenic extracts lack sufficient evidence of efficacy –In our current review, FDA failed to identify supportive efficacy data for hundreds of products

12. 12/22 Panel recommendations Classification panel 1974-1979 (601.25) Diagnosis Therapy (foods not included) I26%1% II0% IIIA48%65% IIIB26%34%

13. 13/22 Panel recommendations Reclassification panel 1982-1983 (601.26) Diagnosis Therapy (foods not included) I83%67% II17%33% excludes IIIB foods/insects

14. 14/22 Panel recommendations Reclassification panel 1982-1983 (601.26) Diagnosis Therapy (foods not included) I73%59% II27%41% includes IIIB foods/insects

15. 15/22 Paths forward Reasons to take action on the basis of efficacy evidence –Both advisory panels concluded that many allergenic extracts lack sufficient evidence of efficacy –In our current review, FDA failed to identify supportive efficacy data for hundreds of products

16. 16/22 Paths forward Other approaches –Action under other regulations 21 CFR 601.5 This regulation is applicable to all licensed products; unlike 601.25 and 601.26, its application is not limited to products licensed before 1 July 1972.

17. 17/22 21 CFR 601.5 § 601.5 Revocation of license. …(b)(1) The Commissioner shall notify the licensed manufacturer of the intention to revoke the biologics license, setting forth the grounds for, and offering an opportunity for a hearing on the proposed revocation if the Commissioner finds any of the following: …(vi) The licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use.

18. 18/22 FDA would focus on products where there are safety concerns and where product efficacy is not supported by data FDA could bring actions to revoke licenses under §601.5, for allergenic extracts in Tables 4 and 5 21 CFR 601.5

19. 19/22 Other potential actions for products in Tables 1-3 Nomenclature corrections: work with manufacturers to –Rename ambiguous products –Eliminate redundancies based on nomenclature –Eliminate mixes Indication corrections –Some extracts in Table 3 need to be relabeled “for diagnostic use only”

20. 20/22 Paths forward 21 CFR 601.25 and 601.26 Other approaches: –use 21 CFR 601.5 to address evidence of efficacy along with safety issues (Tables 4 and 5) –work with manufacturers to address and correct nomenclature issues and indications (Tables 1-3)

21. 21/22 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

22. 22/22 Discussion points Comments on –the review process so far; –the decision to list non-standardized allergenic products in five tables according to the evidence collected; and –the possible disposition of the categories of products identified in the Tables