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Reclassification of IIIA allergenic products
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Allergen ExtractsAllergen Extracts
pollens molds epidermoids insects foods
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Today’s presentation History of allergy and allergy
treatment Allergen extract regulation
Pre-FDA FDA
21 CFR 601.25 21 CFR 601.26 Completion of the 21 CFR 601.26 process
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History of allergy and allergy treatment
1819 – Dr. John Bostock first accurately describes hay fever as a disease affecting the upper respiratory tract
1869 – In investigating his own hay fever, Dr. Charles Blakely performs the first skin test by applying pollen through a small break in his skin. He introduces concept that pollen causes hay fever http://www.allergyclinic.co.nz/guides/
39.html
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History of allergy and allergy treatment 1911 - Noon and Freeman make
sterile extracts of pollens and demonstrate that repeated injections improve clinical tolerance to allergen exposure, establishing the basis for allergen extract immunotherapy
http://www.allergyclinic.co.nz/guides/39.html
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History of allergy and allergy treatment
First aqueous extracts: Curtis (1900) Systematic investigations on
extraction method: Wodehouse and Walker (1917) and Coca (1920s)
Early allergists prepared extracts in their own offices for use with their patients
Cohen and Evans, Allergen immunotherapy in historical perspective. In Lockey, et al. Allergens and allergen immunotherapy, 3rd ed. 2004
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Allergen extract manufacturing Physicians began preparing extracts for
others Sheldon et al. A Manual of Clinical Allergy
(Saunders, 1953) contains detailed instructions (30 pages) for allergen extract production
Practice evolved to independent laboratories preparing extracts
Laboratories evolved into licensed manufacturers (first license issued in 1920’s)
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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
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Allergen extract regulation 1902: Hygienic Laboratory,
Public Health and Marine Hospital Service
1930: National Institute (sic) of Health
1955-1972: 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
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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Allergen extract regulation 1902: Hygienic Laboratory,
Public Health and Marine Hospital Service
1930: National Institute (sic) of Health
1955-1972: 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
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 1987
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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MembersClassification panel 1974-1979
Paul Seebohm, MD Elliot Ellis, MD Ralph Hale, MD David Levy, MD Frank Perlman, MD Robert Reisman, MD Thomas Van Metre, MD Max Samter, MD (consultant)
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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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Standards for Safety and Efficacy Classification panel 1974-1979 (601.25)
Standards Defined for Safety in 601.25 “…relative freedom from harmful
effect…” “Proof shall consist of adequate tests
by methods reasonably applicable…including results of significant human experience”
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Standards for Safety and Efficacy Classification panel 1974-1979 (601.25)
Standards Defined for Efficacy in 601.25 “reasonable expectation that..the biological
product…will serve a clinically significant function in the diagnosis…treatment…of disease”
“Proof…shall consist of controlled clinical investigations…unless this requirement is waived” because:
“Not reasonably applicable” or Not “essential to the investigation” and An “alternative methods of investigation is
adequate to substantiate effectiveness”
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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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Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)
Panel established criteria for evidence of immunotherapy efficacy Conclusive Acceptable Circumstantial Insufficient
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Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)
Conclusive Evidence Effective in skin test diagnosis, and Placebo-controlled reduction in
symptoms, and In vitro changes
Specific IgG decreases Seasonal rise in IgE blunted Specific IgE decreases Histamine release decreases
p. 3093
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Acceptable Evidence Effective in skin test diagnosis, and Long experience suggests reduction in
symptoms, and In vitro changes
Specific IgG decreases Seasonal rise in IgE blunted Specific IgE decreases Histamine release decreases
p. 3093
Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)
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Circumstantial Evidence Effective in skin test diagnosis, and Long experience suggests reduction in
symptoms
Insufficient Evidence Not effective in skin test diagnosis Anecdotal reduction in symptoms No in vitro changes
p. 3093
Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)
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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)
Manufacturing principles Studies for IIIA products Standardization
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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 studies Allow inference among related allergens Obtain FDA approval for studies Separate protocols for Diagnosis and
Immunotherapy For some extracts, these requirements may
be modified 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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US allergen extract timeline
1900 + First extracts 1920 +
Manufacturers
1974-1979Classification Panel
601.25I/IIII/IIIA/IIIBIIIB
1972Bureau of Biologics
FDA
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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
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Today’s presentation History of allergy and allergy
treatment Allergen extract regulation
Pre-FDA FDA
21 CFR 601.25 21 CFR 601.26 Completion of the 21 CFR 601.26 process
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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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MembersReclassification panel 1982-1983 (601.26)
Paul Seebohm, MD* Elliot Ellis, MD* Clifton Furukawa, MD Ralph Hale, MD* David Levy, MD* Floyd Malveaux, MD Thomas Van Metre, MD*
* on previous panel
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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 required 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 required for reclassification into Category I
Miscellaneous inhalant and all food extracts recommended for reclassification into Category II
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Fast forward (1983 to 2003)
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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
Collect data on products since 1972 Establish criteria to be applied when reviewing data
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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Provisional review process (I) Data to be collected
Medline search English-language literature, 1972 to
present Manufacturer data, if available Files submitted to docket Medwatch and VAERS
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Categorization of papers Study design
Case report Number of cases
Observational cohort Case-control
Prospective Retrospective
Placebo-controlled prospective
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Categorization of papers Species
Human Veterinary
Vehicle Aqueous Glycerine Alum Not specified
Potency test None protein w/v Biological Antibody-based
Lot Single Multiple, identified neither
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Categorization of papers Diagnosis
Prick ID Quantitative
Immunotherapy Rush Conventional Oral Sublingual Parenteral
Statistical analysis Valid Invalid None
Analysis Validated
Challenge Patient report
Quantified
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Provisional review process (II)
Criteria for reclassification into category I Efficacy – two or more well-described
case reports, uncontradicted. Safety – absence of species-specific
SAE reports from any source greater than case reports; will consider risk-benefit for case reports
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Rationale for CBER Review Committee criteria
Positive data on efficacy required Well-described case reports are
sufficient; controlled trials NOT necessary. Although there are many controlled efficacy trials for allergen immunotherapy, these have only been performed using few highly prevalent extracts
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Rationale for CBER Review Committee criteria
Negative safety data sufficient Baseline of AEs for both skin tests and
immunotherapy with all extracts Higher-than-baseline AEs typical for the
most potent extracts Higher-than-baseline AEs associated with
patient and practice risk factors
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Provisional review process (III) Report format
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 (if possible, separate by diagnosis, therapy and cross-reactivity)
Literature retrieved since 1972 (include search strategy)
Assessment and reclassification
All cited literature, in digital format
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Proposal (IV) - documentation All cited literature, PDF format All submitted manufacturer data All committee reports All committee discussion
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Reclassification of IIIA allergenic products Completion of review/regulatory
process started in 1972 Approximately 1200 products to
review Extensive documentation of review
materials and deliberations Will report progress to Advisory
Committee
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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
Recommended