1/22 Efficacy Review of Allergen Extracts (2003 – Present) Jay E. Slater, MD Director, DBPAP

2/22 Today’s presentations Background Allergenics efficacy reviews –Panel 1, 21 CFR ( ) –Panel 2, 21 CFR ( ) Current evaluation process ( ) Safety of allergenic extracts Assessments Next steps

3/22 Standardized products are controlled for potency and stability, and are not subject to this review D. farinae D. pteronyssinus Cat hair Cat pelt Short ragweed pollen Hymenoptera –Honey bee –Wasp –Yellow jacket –Yellow hornet –White-faced hornet –Mixed vespid Grass pollens –Bermuda grass –Red top –June (Kentucky blue) –Perennial rye –Orchard –Timothy –Meadow fescue –Sweet vernal

4/22 Internal review: Review Panel 2 recommendations regarding Category IIIA products Review data published since 1972 Determine FDA position on Panel 2 recommendations based upon additional data

5/22 CBER/FDA internal review participants Marc Alston Jennifer Bridgewater Richard Capek Aaron Chen Bo Chi Nicolette deVore Ekaterina Dobrovolskaia Ashraf El Fiky Phillipa Hillyer Jason Humbert Sandra Menzies Martha Monser Vada Perkins Ronald Rabin Paul Richman Tina Roecklein Jennifer Ross Jay Slater Colleen Sweeney Elizabeth Valenti Cherry Valerio Leslie Wagner

6/22 Review process Internal review: Data to be collected –Pubmed, ISI and Google searches English-language literature, 1972 to present –Files submitted to docket –MedWatch

7/22 Panel 1: “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) –Nearly all of Panel 1’s reviews were “generic” –A few were product-specific for example, Dermatophytin (Hollister Stier) and Histamine Azoprotein (Parke Davis) Our reviews continued to be “generic” Review process Internal review:

8/22  All allergen extracts to be reviewed separately for their use as diagnostic and therapeutic reagents [50 FR 3124]  For each indication, an extract would be considered to be in category I only if it was judged to be both safe and effective [§601.25(e)(1)] Review process Internal review:

9/22  Food allergen extracts are not labeled for therapy [Panel 1, 50 FR 3247]  For all other allergen extracts, the product is considered safe unless there is evidence to the contrary  See, for example, Panel 1, 50 FR 3097: “Allergenic extracts used in accordance with generally accepted principles of diagnostic skin testing are associated with minimal acceptable risks…[and] used in accordance with accepted principles of immunotherapy are safe…” Review process: safety Internal review:

10/22 Rationale, safety review Panels 1 and 2 classified nearly all products as safe. Negative safety data sufficient –Baseline of adverse events for both skin tests and immunotherapy with all extracts –Higher-than-baseline adverse events typical for the most potent extracts associated with patient and practice risk factors

11/22  As discussed before this Committee in 2005 and 2006, the working threshold for efficacy would be:  Two or more valid and reviewed clinical case reports, or  One valid and reviewed clinical case report that included supportive challenge data (oral, bronchial, nasal, conjunctival), or  Cross reactivity of the reviewed extract with another allergenic extract considered to be effective, supported by  immunologic data that support the cross reactivity, or  membership of the reviewed extract in the same genus or tribe as the other extract (“tribe” applies to grass pollens only)  [Note: if multiple species within a genus are shown to be cross reactive, the entire genus would be considered to be cross reactive]  For studies evaluating the efficacy of food extracts, the material used in the study must be produced using a method comparable to the commercial product. For example, studies using fresh food, unfiltered pulp, juice, or slurries would not be considered supportive.  An allergenic product could be considered effective for therapy on the basis of its effectiveness in diagnosis, if that extract is made from a pollen or animal (non-food) source material Review process: efficacy Internal review:

12/22 Positive data on efficacy required Well-described case reports would be sufficient; controlled trials not necessary. –It is often difficult to determine with precision the causes of allergic symptoms. –Allergic diseases can vary by season and location, and are subject to spontaneous remissions and exacerbations. –In the case of most allergenic extracts it is not possible with existing technology to identify and quantify active ingredients. –Allergies to many of the >1000 individual allergens are uncommon Rationale, efficacy review

13/22 For grass pollen, tree pollen, weed pollen and animal dander extracts, the preponderance of data supports the efficacy and safety of immunotherapy. Therefore, those allergens placed in category I for diagnosis would be placed in category I for therapy as well. Rationale, efficacy review

14/22 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, the material used in the study must be produced using a method comparable to the commercial product. Rationale, efficacy review

15/22  Nomenclature would be considered unacceptable if:  product species could not be identified  product name contained the word ‘mixed’  there were multiple listings of the same product Review process Internal review:

16/22 Panel 1: specific designations/names – not necessarily genus/species – were required Panel 2: genus/species required for pollen, mold and plant extracts Current review: technology is now readily available for scientifically accurate species identification of all source materials Rationale, nomenclature review

17/22 Mixes are ambiguous –Does “genus only” mean that all species within the genus are included? In what proportion? Naming needs to be correct and consistent among manufacturers to avoid errors. Rationale, nomenclature review

18/22 Report format Internal review: 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 Literature retrieved since 1972 (include search strategy) Assessment

19/22 Documentation Internal review: All cited literature, PDF format All committee reports All committee discussion

20/22 Initial screening Internal review: Initial database contained over 1500 extracts Removal of obviously duplicate and obsolete entries Resulting list: 1269 entries –Animals: 48 –Dusts: 6 –Foods: 277 –Insects: 34 –Molds: 180 –Plants: 16 –Pollens: 708

21/22 Database design Internal review: 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

22/22 Today’s presentations Background Allergenics efficacy reviews –Panel 1, 21 CFR ( ) –Panel 2, 21 CFR ( ) Current evaluation process ( ) Safety of allergenic extracts Assessments Next steps