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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. The agencies

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Efficacy review of allergenic products

Efficacy review of allergenic products

Progress report

September 13, 2006


Today s presentation
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

Allergen extract regulation

http://www.fda.gov/opacom/backgrounders/miles.html

http://www.history.nih.gov/exhibits/history


Us allergen extract timeline

1972

Bureau of Biologics

FDA

US allergen extract timeline

1900 +

First extracts

1920 +

Manufacturers


Classification panel
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 timeline1

1972

Bureau of Biologics

FDA

US allergen extract timeline

1974-1979

Classification Panel

601.25

I/II/IIIA/IIIB

1900 +

First extracts

1920 +

Manufacturers


The panel s task classification panel 1974 1979 601 25
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
Product Classification CategoriesDefined 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
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
Panel recommendationsClassification panel 1974-1979 (601.25)


Panel recommendations classification panel 1974 1979 601 251
Panel recommendationsClassification panel 1974-1979 (601.25)

  • Manufacturing principles

  • Studies for IIIA products

  • Standardization


Studies on iiia products classification panel 1974 1979 601 25
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 cases

p. 3116-3123


Fda responses to panel s recommendations
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 timeline2

1972

Bureau of Biologics

FDA

US allergen extract timeline

1974-1979

Classification Panel

601.25

I/II/IIIA/IIIB

1900 +

First extracts

1920 +

Manufacturers


Reclassification panel
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 timeline3

1982-1983

Reclassification Panel

601.26

IIIA I or II

1972

Bureau of Biologics

FDA

US allergen extract timeline

1974-1979

Classification Panel

601.25

I/II/IIIA/IIIB

1900 +

First extracts

1920 +

Manufacturers


Panel recommendations diagnosis reclassification panel 1982 1983 601 26
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
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
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 timeline4

1982-1983

Reclassification Panel

601.26

IIIA I or II

2003-2006

Review and

implementation

IIIA I or II

1972

Bureau of Biologics

FDA

US allergen extract timeline

1974-1979

Classification Panel

601.25

I/II/IIIA/IIIB

1900 +

First extracts

1920 +

Manufacturers


The process 2003 2006
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 reportInitial screening


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 reportDatabase design


Progress report database design main panel
Progress reportDatabase design – main panel


Progress report database design main panel1
Progress reportDatabase design – main panel


Progress report database design document data panel
Progress reportDatabase design - document data panel


Progress report database design main panel2
Progress reportDatabase design – main panel


Progress report database design rationale panel
Progress reportDatabase design – rationale panel


Progress report review statistics as of 31 august 2006

Total entries: 1273

Individual reviews: 745

Committee reviews: 624

Progress reportReview statistics (as of 31 August 2006)


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 (1) Reviews continue to be generic, not specific


Progress report 2 information reviewed is from public sources

Medline search

English-language literature, 1972 to present

ISI

Google

Progress report (2) Information reviewed is from public sources


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 (3) Product safety


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 (4)Limited data may provide information on efficacy for certain products


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 (5)Food extracts placed in category I only based on studies in which an extract is used


Progress report 6 products may be placed in category i based on cross reactivity

If an extract is shown 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 – 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 (6)Products may be placed in category I based on cross-reactivity


Progress report 7 specificity in source material nomenclature

Specific designations/names 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 – 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


Progress report 7 specificity in source material nomenclature1

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 (7)Specificity in source material nomenclature


Progress report 8 we encounter frequent examples of species synonymy

General Several issues quickly arose:

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)

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


Summary completion of the 21 cfr 601 26 process
Summary: completion of the 21 CFR 601.26 process Several issues quickly arose:

  • 50% complete

  • no broad safety issues identified

  • evaluations are based on published data


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