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Report on the safety of non-standardized allergenic extracts

Ronald L. Rabin, MDChief, Laboratory of Immunobiochemistry

Division of Bacterial, Parasitic and Allergenic ProductsOffice of Vaccines Research and Review

Center for Biologics Evaluation and Research, USFDA

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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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Strategy of search for safety issues

• Search for safety issues related to their properties as allergens– Pubmed– Google and other lay sources– FDA Adverse Event Reporting System (AERS)

• Search for safety issues unrelated to their properties as allergens (e.g. pathogens, toxins)– Fifteen potential issues that will be addressed in this

presentation

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Definition of Adverse Event

Any undesirable experience associated with the use of a medical product

— “associated with the use” refers to a temporal relationship

— may or may not be causally related to the product

Serious:

Death, hospitalization, life-threatening, disability, congenital anomaly and/or other serious outcome.

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Adverse Event Reporting System (AERS)

Collects reports of AEs from: – drugs– therapeutic biologics– allergenic extracts – blood and blood products

• Does not include preventative vaccines• Data are collected through MedWatch (Form 3500 or 3500A)

• Since 1969, >4 million reports

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm

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Adverse Event Reporting System (AERS)

Passive surveillance system– voluntary for providers, consumers to report to FDA or

manufacturers

• Mandatory for manufacturers (CFR 600.80)– Submit adverse event report within 15 days if serious and

unexpected.– Submit other reports within 1 year.– Periodic adverse experience/Safety Update Report

(Quarterly if product is <3 years old)

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AERS: strengths of a passive surveillance system

• Open-ended for hypothesis generation

• Potential detection of new or rare adverse events

• Timeliness

• Geographic diversity

• Capability to monitor production lots

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AERS: limitations of a passive surveillance system

• Cannot calculate incidence rates– Under-reporting– Absence of denominators

• Reporting bias – Publicity or litigation may stimulate reporting– Newer products are more likely to be reported than older ones

• No control group

• Missing and inaccurate data

• Reported diagnoses not verified

• Lack of consistent diagnostic criteria

• No reports of concomitant medications

• Low likelihood of detection of long latency events

• Often unable to assess causation

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AERS reports are submitted through MedWatchForms 3500 (consumers) and 3500A (manufacturers)

https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm

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Office of Biostatistics/Division of Epidemiology

• CBER/OVRR requested an analysis of AE reports in AERS for allergenic extracts

• The analysis was provided to CBER on 09 July 2010

• Analysis report authors:

– Alexis Mosquera, RN

– Craig Zinderman, MD, MPH

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Strategy of searching AERS for this report

• Reviewed all AERS reports that identified an allergenic extract as a suspect product and received by FDA from 1987-2010.

• Each report was classified into one of 24 AE categories based on the Medical Dictionary for Regulatory Affairs (MedDRA) reaction Preferred Terms (PT).

• Reaction PT of anaphylaxis, anaphylactic reaction, or anaphylactic shock were placed in reaction category of “anaphylaxis.”

• All other AEs (e.g. edema, urticaria, hives, dyspnea, wheezing) were classified as “allergic.”

• Reaction from multiple body systems were referred to as “mixed.”

• Each report was also categorized according to the type of allergenic product: animal, dust, fungi, food, insect, mite, mold, plant, or pollen.

• Reports associated with more than one category were counted once for EACH category on the report (# reports > # patients).

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Summary of analysis from AERS database search

• Serious AEs to allergen extracts are relatively rare; consistent with the medical literature.

• Reported AEs are not associated with any one product or class of extracts (standardized or non-standardized).

• Therefore, these AEs are associated with the procedure of immunotherapy which, when performed in accordance with generally accepted principles, is safe.

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Summary of AERS data associated with allergenic extracts

• 195 AEs

• Gender (n = 157): 86 females (55%), 71 males (45%)

• Age: mean 39 years (range 7-83)

Reports by Year

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Types of reactions reported to AERS

Reaction Categories

(28%) (15%)

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Product types reported to AERS

• n = 223 (some reports indicated more than one suspect product)

(17%)(20%)

Allergenic Product Type

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Deaths associated with allergenic extracts reported to AERS

• 15 deaths: 10 females, 5 males

• Average age: 37 years (range 9-81)

Deaths by Year

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Reaction categories and product types in AERS death reports

Reaction Categories and Product Types in Death reports

Reaction CategoryNumber

of Reports

Product Type

Anaphylaxis 5Plant (5) Fungi (2), Unspecified (2), Food (1), Dust (1)

Allergic 5Mite (2), Mold (2), Insect (1), Allergenic extract (2)

Mixed 2 Mite (3), Insect (1)

Cardiac 1 Plant (1)

Unevaluable Event 1 Allergenic extract (1)

No Adverse Event 1 Allergenic extract (1)

Onset of symptoms known in eight reportsSeven reports were “allergic reactions.”Onset within 5 minutes: 7 reportsOnset within 20 minutes: 1 report

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Hospitalizations associated with allergenic extracts reported to AERS

Hospitalization: 35 of the 180 non-fatal reports (19.4%)

Hospitalizations by Year

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AERS: Hospitalization Reaction Categories

Hospitalization Reaction Categories

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AERS: Hospitalization Suspect Products

n = 44

Hospitalization Suspect Products

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AERS: Ingredients associated with hospitalization

Ingredient # Reports

Yellow Jacket Venom Protein 3

Wasp Venom Protein 1

Fire Ant 1

Ragweed 3

Weeds 1

Hops 1

“Grass Mix” or “Grass” 3

Tree Mix 2

Timothy Grass 1

Bluegrass Kentucky June 1

Birch 1

Flaxseed or Linseed 1

“Pollen” 2

Mold 2

Mite 6

House Dust 2

Ingredient # Reports

Cat Hair 2

Cattle Hair 1

Unspecified Ingredient 4

Allergenic Extracts 18

Lobelia 1

Lemon Balm 1

Valerian Extract 1

Calamus Oil 1

Jimson Weed 1

Honey 1

Blueberry Leaf 1

Lactobacillus acidophilus 1

not allergenicproducts

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Literature: Reports of frequency of serious AE

Report* extracted from surveys in U.S. of fatal and near-fatal serious AE 1973-2001.The surveys were conducted through AAAAI.Fatal reactions: 76 (~1 per 2.5-3.0 x 106 injection visits)Near-fatal reactions: 273 (~1 per 1.0 x 106 injection visits)

*Bernstein, DI and Epstein T. Immunol Clin N Amer 31:241; 2011

Clinical Features Asthma Severity

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Products with non-allergenic related potential safety issues

Monkey Dander, RhesusTransmission of simian pathogensMonkey Hair, Rhesus

Deer Hair Transmission of TSE

Dust, AutogenousPathogens

Toxins: synthetic and pathogen associated

(APAC, October, 1986)

Dust, Cotton Gin

Dust, Grain Mill

Dust, House Mixture

Dust, Mattress

Kissing Bugs Pathogen (T. cruzii)

Wormseed Calcium Oxalate crystals

Rhubarb

Toxin

Castor Bean (2)

Laburnum (Golden chain)

Bracken Fern

Mexican Tea 23

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Summary of analysis from AERS database search

• Serious AEs to allergen extracts are relatively rare; consistent with the medical literature.

• Reported AEs are not associated with any one product or class of extracts (standardized or non-standardized).

• Therefore, these AEs are associated with the procedure of immunotherapy which, when performed in accordance with generally accepted principles, is safe.

• There are, however, 16 products with potential safety issues that are not associated with the allergenic activity of those products

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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