Reclassification of IIIA allergenic products

1
Reclassification of IIIA allergenic products
2
Allergen Extracts

• pollens
• molds
• epidermoids
• insects
• foods

3
Todays 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

4
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

5
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

6
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
7
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 1920s)

8
US allergen extract timeline
1900 First extracts
1920 Manufacturers
9
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
10
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
11
US allergen extract timeline
1900 First extracts
1920 Manufacturers
12
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)

13
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
14
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)

15
The Panels Task Classification panel 1974-1979
(601.25)

• gt1,500 extracted substances reviewed
• Goals
• Evaluate safety and efficacy in accordance with
  601.25
• Review labeling
• Submit report on conclusions and recommendations

16
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 applicableincluding results of
  significant human experience

17
Standards for Safety and Efficacy Classification
panel 1974-1979 (601.25)

• Standards Defined for Efficacy in 601.25
• reasonable expectation that..the biological
  productwill serve a clinically significant
  function in the diagnosistreatmentof disease
• Proofshall consist of controlled clinical
  investigationsunless 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

18
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

19
Immunotherapy evidence standardsClassification
panel 1974-1979 (601.25)

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

20
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
21
Immunotherapy evidence standardsClassification
panel 1974-1979 (601.25)

• 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
22
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

p. 3093
23
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
24
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
25
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
26
Panel recommendationsClassification panel
1974-1979 (601.25)

• Manufacturing principles
• Studies for IIIA products
• Standardization

27
Panel recommendationsClassification panel
1974-1979 (601.25)

• Manufacturing principles
• Studies for IIIA products
• Standardization

28
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 cases

p. 3116-3123
29
FDA responses to Panels 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

30
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
31
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
32
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
33
Todays 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

34
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

35
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
36
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
37
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

38
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

39
Fast forward (1983 to 2003)
40
Task at hand 2003-2006

• Review the 601.26 Reclassification Panels
  recommendations regarding Category IIIA products
• Review data published since 1972
• Determine FDA position on Reclassification
  Panels recommendations based upon additional
  data

41
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
42
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
• FDAs 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

43
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

44
Categorization of papers

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

45
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

46
Categorization of papers

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

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

47
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

48
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

49
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

50
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 

51
Proposal (IV) - documentation

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

52
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

53
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers