Post on 25-Dec-2015
transcript
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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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
1974-1979Classification Panel
601.25I/II/IIIA/IIIB
1972Bureau of Biologics
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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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
1974-1979Classification Panel
601.25I/II/IIIA/IIIB
1972Bureau of Biologics
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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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
1974-1979Classification Panel
601.25I/IIII/IIIA/IIIBIIIB
1972Bureau of Biologics
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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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
1974-1979Classification Panel
601.25I/IIII/IIIA/IIIBIIIB
1972Bureau of Biologics
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 – main panel
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Progress reportDatabase design - document data panel
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Progress reportDatabase design – main 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