Efficacy review of allergenic products Progress report September 13, 2006.

Efficacy review of allergenic products

Progress reportSeptember 13, 2006

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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

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Allergen extract regulationThe 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.history.nih.gov/exhibits/history

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US allergen extract timeline

1900 + First extracts 1920 +

Manufacturers

1972Bureau of Biologics

FDA

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Classification panelClassification 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)

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Manufacturers

1974-1979Classification Panel

601.25I/II/IIIA/IIIB


FDA

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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

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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

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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

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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

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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

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Panel recommendationsClassification panel 1974-1979 (601.25)

DiagnosisTherapy

(foods not included)

I 26% 1%

II 0% 0%

IIIA 48% 65%

IIIB 26% 34%

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Panel recommendationsClassification panel 1974-1979 (601.25)

Manufacturing principles Studies for IIIA products Standardization

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Studies on IIIA productsClassification 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 casesp. 3116-3123

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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

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Manufacturers


601.25I/II/IIIA/IIIB


FDA

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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

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Manufacturers


601.25I/IIII/IIIA/IIIBIIIB


FDA

1982-1983Reclassification Panel

601.26IIIA I or II

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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

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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

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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

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Manufacturers


601.25I/IIII/IIIA/IIIBIIIB


FDA

1982-1983Reclassification Panel

601.26IIIA I or II

2003-2006Review and

implementationIIIA I or II

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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

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Progress reportInitial 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

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Progress reportDatabase 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

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Progress reportDatabase design – main panel

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Progress reportDatabase design - document data panel

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Progress reportDatabase design – rationale panel

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Progress reportReview statistics (as of 31 August 2006)

Total entries: 1273

Individual reviews: 745

Committee reviews: 624

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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)

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Progress report (2) Information reviewed is from public sources

Medline search English-language literature, 1972 to

present ISI Google

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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.

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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.

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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.

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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.

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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)

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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)

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

NCBI taxonomy database (www.ncbi.nlm.nih.gov/entrez) databases (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) Fish and seafood

The Seafood List (www.cfsan.fda.gov/~frf/seaintro.html) Regulatory Fish Encyclopedia (

www.cfsan.fda.gov/~frf/rfe0.html) FishBase (www.fishbase.org/) National Museum of Natural History - fish species

(http://www.nmnh.si.edu/vert/fishes/fishcat/index.html) Molds (www.indexfungorum.org)

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Summary: completion of the 21 CFR 601.26 process

50% complete

no broad safety issues identified

evaluations are based on published data

Efficacy review of allergenic products Progress report September 13, 2006.

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