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Report on the safety of non-standardized allergenic extracts. Ronald L. Rabin, MD Chief, Laboratory of Immunobiochemistry Division of Bacterial, Parasitic and Allergenic Products Office of Vaccines Research and Review Center for Biologics Evaluation and Research, USFDA. Background

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report on the safety of non standardized allergenic extracts

Report on the safety of non-standardized allergenic extracts

Ronald L. Rabin, MD

Chief, Laboratory of Immunobiochemistry

Division of Bacterial, Parasitic and Allergenic Products

Office of Vaccines Research and Review

Center for Biologics Evaluation and Research, USFDA

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

Today’s presentations
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

Strategy of search for safety issues
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.

Definition of Adverse Event
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

Adverse Event Reporting System (AERS)

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

adverse event reporting system aers1
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)

Adverse Event Reporting System (AERS)
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

AERS: strengths of a passive surveillance system
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

AERS: limitations of a passive surveillance system
aers reports are submitted through medwatch forms 3500 consumers and 3500a manufacturers
AERS reports are submitted through MedWatchForms 3500 (consumers) and 3500A (manufacturers)

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

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

Office of Biostatistics/Division of Epidemiology
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).

Strategy of searching AERS for this report
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.

Summary of analysis from AERS database search
summary of aers data associated with allergenic extracts
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

types of reactions reported to aers
Types of reactions reported to AERS

(28%)

(15%)

Reaction Categories

product types reported to aers
Product types reported to AERS

(20%)

(17%)

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

Allergenic Product Type

deaths associated with allergenic extracts reported to aers
Deaths associated with allergenic extracts reported to AERS
  • 15 deaths: 10 females, 5 males
  • Average age: 37 years (range 9-81)

Deaths by Year

reaction categories and product types in aers death reports
Reaction categories and product types in AERS death reports

Onset of symptoms known in eight reports

Seven reports were “allergic reactions.”

Onset within 5 minutes: 7 reports

Onset within 20 minutes: 1 report

hospitalizations associated with allergenic extracts reported to aers

Hospitalizations by Year

Hospitalizations associated with allergenic extracts reported to AERS

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

literature reports of frequency of serious ae
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

summary of analysis from aers database search1
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

Summary of analysis from AERS database search
today s presentations1
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

Today’s presentations