efficacy review of allergenic extracts: background (1972 – 1985) jay e. slater, md director, dbpap

Efficacy Review of Allergenic Extracts: Background (1972 – 1985)

Jay E. Slater, MD

Director, DBPAP

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Today’s presentations

• Background• Allergenics efficacy reviews

– Panel 1, 21 CFR 601.25 (1974-1979)– Panel 2, 21 CFR 601.26 (1982-1983)

• Current evaluation process (2003-2011)• Safety of allergenic extracts• Assessments• Next steps

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Allergen extractsaqueous extract products derived from several natural source materials:

• Pollens• Mold spores• Animal skin and hair• Insects• FoodsThey may be used for the

the diagnosis and treatment

of allergic diseases, including

allergic rhinitis, allergic

conjunctivitis, asthma, and –

in some cases – anaphylaxis.

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History of allergen extracts

• 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 1920s)

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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• Kefauver Harris Drug

Amendments of 1962• Food and Drug Administration

Modernization Act of 1997

http://www.fda.gov/opacom/backgrounders/miles.html/http://www.history.nih.gov/exhibits/history

http://www.fda.gov/opacom/backgrounders/miles.html/




http://www.history.nih.gov/exhibits/history



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• 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 May 1974 to August 1979• Panel report: submitted March 1981; published in 50

FR 3082-3288 (23 January 1985)

http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm

Classification panel

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MembersClassification panel 1974-1979

• Paul Seebohm, MD– Associate Dean, College of Medicine, University of Iowa

• Elliot Ellis, MD– Chair, Pediatrics, SUNY Buffalo

• Ralph Hale, MD– University of Kansas School of Medicine

• David Levy, MD– Johns Hopkins University

• Frank Perlman, MD– University of Oregon Medical School

• Robert Reisman, MD– SUNY Buffalo

• Thomas Van Metre, MD– Johns Hopkins University

• Max Samter, MD (consultant)– Director, Institute of Allergy and Clinical Immunology, Grant Hospital, Chicago

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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 as described in §314.126…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 the following criteria for evidence of immunotherapy efficacy – Conclusive– Acceptable– Circumstantial– Insufficient

50 FR 3093

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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

50 FR 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

50 FR 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

50 FR 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

50 FR 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

50 FR 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

50 FR 3094

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Skin test diagnosis

Immunotherapy In vitro changes

Panel I classification

Conclusive Effective Placebo-controlled reduction in symptoms

Yes I

Acceptable Effective Reduction in symptoms, “long experience”

Yes I or IIIA

Circumstantial Effective Reduction in symptoms, “long experience”

No IIIA

Insufficient Not effective Anecdotal evidence only No II or IIIB

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Panel recommendationsClassification panel 1974-1979 (601.25)

DiagnosisTherapy

(foods not included)

I 26% 1%

II 0% 0%

IIIA 48% 65%

IIIB 26% 34%

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Panel recommendationsClassification panel 1974-1979 (601.25)

• Manufacturing principles

• Studies for IIIA products

• Standardization

50 FR 3116-3123

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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 cases

50 FR 3116-3123

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FDA responses to Panel’s recommendations on IIIA products

• 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)

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Today’s presentations• Background• Allergenics efficacy reviews



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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

http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm272115.htm

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MembersReclassification panel 1982-1983 (601.26)• Paul Seebohm, MD*

– Associate Dean, College of Medicine, University of Iowa• Elliot Ellis, MD*

– Chair, Pediatrics, SUNY Buffalo• Clifton Furukawa, MD

– University of Washington• Ralph Hale, MD*

– Kansas University Medical Center• David Levy, MD*

– Johns Hopkins University• Floyd Malveaux, MD

– Chair, Allergy, Howard University Hospital• Thomas Van Metre, MD*

– Johns Hopkins University• Robert Reisman, MD* (consultant)

– SUNY Buffalo * on previous panel

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Guidelines for reclassification of a Category IIIA product to Category I Reclassification panel 1982-1983 (601.26)

• Accumulated evidence indicates that the extract is safe• Derived from well-defined source material• Definable or measurable constituents and is capable of

being standardized• Demonstrated to be effective by skin testing in allergic

and non-allergic subjects and/or RAST or is closely analogous to products shown to be effective

• Properly labeled• [For IT, valid clinical study of product or analogous

product]Page 7, at

http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM271333.pdf

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Skin test diagnosis




Yes I


Yes I or IIIA


No IIIA


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Skin test diagnosis




Yes I


Yes I


No I


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Panel recommendations Reclassification panel 1982-1983 (601.26)

(excludes former IIIB insects/foods)

DiagnosisTherapy

(foods not included)

I 83% 67%

II 17% 33%

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Panel recommendations

DiagnosisTherapy,

foods not included

I 83% 67%

II 17% 33%

DiagnosisTherapy,

foods not included

I 26% 1%

II 0% 0%

IIIA 48% 65%

IIIB 26% 34%

Classification panel 1974-1979 Reclassification panel 1982-1983

(601.25) (601.26) (excludes former IIIB insects/foods)

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This bar graph shows how Panel 2 assessed allergen extracts according to their classification by Panel 1. For products found by Panel 1 to be category 1, Panel 2 reclassified nearly all into category I as well. For category IIIA, about 90% were reclassified into category I. And for IIIB, about half were

placed in category I.

Panel 2 evaluations of Panel 1 products

0%

20%

40%

60%

80%

100%

I II IIIA IIIB

Panel 1 category

Per

cen

t p

lace

d in

ca

teg

ory

I b

y P

anel

2

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Follow-up to the activities of the efficacy review panels

• Panel 1 report (issued January 1985):– Category IIIB allergenic products were

voluntarily removed from the market

• Panel 2 report for allergenics not published or implemented

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Today’s presentations

• Background• Allergenics efficacy reviews



efficacy review of allergenic extracts: background (1972 – 1985) jay e. slater, md director, dbpap

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