Efficacy review of allergenic products

1
Efficacy review of allergenic products

• Progress report
• September 13, 2006

2
Todays presentation

• Review of prior efficacy reviews
• Panel I (1974-1979)
• Panel II (1982-1983)
• Current effort (2003)
• Initial screening
• Database
• Review issues
• Timeline

3
Allergen extract regulation

• The 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
4
US allergen extract timeline
1900 First extracts
1920 Manufacturers
5
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)

6
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
7
The Panels 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

8
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

9
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
10
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
11
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
12
Panel recommendationsClassification panel
1974-1979 (601.25)
13
Panel recommendationsClassification panel
1974-1979 (601.25)

• Manufacturing principles
• Studies for IIIA products
• Standardization

14
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 cases

p. 3116-3123
15
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

16
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
17
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

18
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
19
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

20
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

21
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

22
US allergen extract timeline
1974-1979 Classification Panel 601.25 I/II/IIIA/II
IB
1900 First extracts
1920 Manufacturers
23
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
• 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

24
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

25
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

26
Progress reportDatabase design main panel
27
Progress reportDatabase design main panel
28
Progress reportDatabase design - document data
panel
29
Progress reportDatabase design main panel
30
Progress reportDatabase design rationale panel
31
Progress reportReview statistics (as of 31
August 2006)

• Total entries 1273
• Individual reviews 745
• Committee reviews 624

32
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 companys licensed product was based upon
  information which applies to that product alone.
  (50 FR 3084)
• Most of Panel Is reviews were generic
• A few were product-specific
• for example, Dermatophytin (Hollister Stier) and
  Histamine Azoprotein (Parke Davis)

33
Progress report (2) Information reviewed is from
public sources

• Medline search
• English-language literature, 1972 to present
• ISI
• Google

34
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.

35
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.

36
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.

37
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.

38
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)

39
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 CFSANs
  list)

40
Progress report (8) We encounter frequent
examples of species synonymy

• General
• NCBI taxonomy database (www.ncbi.nlm.nih.gov/entre
  z)
• 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/f
  rf/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)

41
Summary completion of the 21 CFR 601.26 process

• 50 complete
• no broad safety issues identified
• evaluations are based on published data