# Presentation: 323117

## Reclassification of IIIA allergenic products

## Allergen Extracts

- pollens
- molds
- epidermoids
- insects
- foods

## 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

## 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

## 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

## 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

## 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)

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

## 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.fda.gov/opacom/backgrounders/miles.html/)_
- _[http://www.history.](http://www.history.nih.gov/exhibits/history)__[nih](http://www.history.nih.gov/exhibits/history)__[.](http://www.history.nih.gov/exhibits/history)__[gov](http://www.history.nih.gov/exhibits/history)__[/exhibits/history](http://www.history.nih.gov/exhibits/history)_

**Notes:**
1901: thirteen children in St. Louis died after receiving diphtheria antitoxin contaminated with tetanus spores. Spurred Congress into passing the Biologics Control Act.

1906: Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.

1937:
ELIXIR OF SULFANILAMIDE, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law. 

## 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.fda.gov/opacom/backgrounders/miles.html/)_
- _[http://www.history.](http://www.history.nih.gov/exhibits/history)__[nih](http://www.history.nih.gov/exhibits/history)__[.](http://www.history.nih.gov/exhibits/history)__[gov](http://www.history.nih.gov/exhibits/history)__[/exhibits/history](http://www.history.nih.gov/exhibits/history)_

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

## 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 timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## MembersClassification 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)

## 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

## 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”

## 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”

## 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

## Immunotherapy evidence standardsClassification panel 1974-1979 (601.25)

- Panel established criteria for evidence of immunotherapy efficacy
- Conclusive
- Acceptable
- Circumstantial
- Insufficient

## Immunotherapy evidence standardsClassification 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

## 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

- 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)

## 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

- 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)

## 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)

- Manufacturing principles
- Studies for IIIA products
- Standardization

## Panel recommendationsClassification panel 1974-1979 (601.25)

- Manufacturing principles
- Studies for IIIA products
- Standardization

## Studies on IIIA productsClassification 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 cases

- p. 3116-3123

## 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 timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## 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 timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## MembersReclassification 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

## 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

## 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

## Fast forward (1983 to 2003)

## 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 timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB

## 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

## 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

## Categorization of papers 

- Study design
- Case report
- Number of cases
- Observational cohort
- Case-control
- Prospective
- Retrospective
- Placebo-controlled prospective

## 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

## Categorization of papers

- Diagnosis
- Prick
- ID
- Quantitative
- Immunotherapy
- Rush
- Conventional
- Oral
- Sublingual
- Parenteral

- Statistical analysis
- Valid
- Invalid
- None
- Analysis
- Validated
- Challenge
- Patient report
- Quantified

## 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

## 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

## 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

## 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

## Proposal (IV) - documentation

- All cited literature, PDF format
- All submitted manufacturer data
- All committee reports
- All committee discussion

## 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

## US allergen extract timeline

- 1900 +
- First extracts

- 1920 +
- Manufacturers

- 1974-1979
- Classification Panel
- 601.25
- I/II/IIIA/IIIB