reclassification of iiia allergenic products. 2/53 allergen extracts pollens molds epidermoids...

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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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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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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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


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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


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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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Manufacturers


601.25I/II/IIIA/IIIB


FDA

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Manufacturers


601.25I/IIII/IIIA/IIIBIIIB


FDA

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Manufacturers




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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Manufacturers




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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Manufacturers




FDA


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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Manufacturers




FDA


601.26IIIA I or II

2003-2006Review and

implementationIIIA I or II

reclassification of iiia allergenic products. 2/53 allergen extracts pollens molds epidermoids...

Documents

drugs act

cosmetic act

public health service

allergy treatment1819

processhistory of allergy

food drug

biologics evaluation

bureau of biologics