# Presentation: 663339

## Efficacy review of allergenic products

- Progress report
- September 13, 2006

## 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

## 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.fda.gov/opacom/backgrounders/miles.html)_
- _[http://](http://www.history.nih.gov/exhibits/history)__[www.history.nih.gov](http://www.history.nih.gov/exhibits/history)__[/exhibits/history](http://www.history.nih.gov/exhibits/history)_

**Notes:**
1901: thirteen children in St. Louis died after receiving diphtheria antitoxin contaminated with tetanus spores. Spurred Congress into passing the Biologics Control Act.

1906: Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.

1937:
ELIXIR OF SULFANILAMIDE, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law. 

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

## 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)

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## 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

## 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

## 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

## 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

## Panel recommendationsClassification panel 1974-1979 (601.25)

|  | Diagnosis | Therapy
 (foods not included) |
| --- | --- | --- |
| I | 26% | 1% |
| II | 0% | 0% |
| IIIA | 48% | 65% |
| IIIB | 26% | 34% |

## Panel recommendationsClassification panel 1974-1979 (601.25)

- Manufacturing principles
- Studies for IIIA products
- Standardization

## 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

## 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

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## 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

## 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

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## 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

## 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

## Progress reportDatabase design – main panel

## Progress reportDatabase design – main panel

## Progress reportDatabase design - document data panel

## Progress reportDatabase design – main panel

## Progress reportDatabase design – rationale panel

## Progress reportReview statistics (as of 31 August 2006)

- Total entries: 			1273
- Individual reviews:		 745
- Committee reviews:		 624

## 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)

## Progress report (2) Information reviewed is from public sources

- Medline search
- English-language literature, 1972 to present
- ISI
- Google

## 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.

## 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.

## 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.

## 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.

## 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)

## 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)

## Progress report (8) We encounter frequent examples of species synonymy

- General
- NCBI taxonomy database (_[www.ncbi.nlm.nih.gov/entrez](http://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](http://www.itis.usda.gov/)_)
- Fish and seafood
- The Seafood List (_[www.cfsan.fda.gov/~frf/seaintro.html](http://www.cfsan.fda.gov/~frf/seaintro.html)_)
- Regulatory Fish Encyclopedia (_[www.cfsan.fda.gov/~frf/rfe0.html](http://www.cfsan.fda.gov/~frf/rfe0.html)_)
- FishBase (_[www.fishbase.org/](http://www.fishbase.org/)_)
- National Museum of Natural History - fish species (http://www.nmnh.si.edu/vert/fishes/fishcat/index.html)
- Molds (_[www.indexfungorum.org](http://www.indexfungorum.org/)_)

## Summary: completion of the 21 CFR 601.26 process

- 50% complete
- no broad safety issues identified
- evaluations are based on published data