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1 Report on the safety of non-standardized allergenic extracts Ronald L. Rabin, MD Chief, Laboratory of Immunobiochemistry Division of Bacterial, Parasitic.

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Presentation on theme: "1 Report on the safety of non-standardized allergenic extracts Ronald L. Rabin, MD Chief, Laboratory of Immunobiochemistry Division of Bacterial, Parasitic."— Presentation transcript:

1 1 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

2 2 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

3 3 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

4 4 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.

5 5 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

6 6 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)

7 7 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

8 8 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

9 9 AERS reports are submitted through MedWatch Forms 3500 (consumers) and 3500A (manufacturers) https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm

10 10 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

11 11 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).

12 12 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.

13 13 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

14 14 Types of reactions reported to AERS Reaction Categories (28%)(15%)

15 15 Product types reported to AERS n = 223 (some reports indicated more than one suspect product) (17%)(20%) Allergenic Product Type

16 16 Deaths associated with allergenic extracts reported to AERS 15 deaths: 10 females, 5 males Average age: 37 years (range 9-81) Deaths by Year

17 17 Reaction categories and product types in AERS death reports Reaction Categories and Product Types in Death reports Reaction Category Number of Reports Product Type Anaphylaxis5 Plant (5) Fungi (2), Unspecified (2), Food (1), Dust (1) Allergic5 Mite (2), Mold (2), Insect (1), Allergenic extract (2) Mixed2Mite (3), Insect (1) Cardiac1Plant (1) Unevaluable Event1Allergenic extract (1) No Adverse Event1Allergenic extract (1) Onset of symptoms known in eight reports Seven reports were “allergic reactions.” Onset within 5 minutes: 7 reports Onset within 20 minutes: 1 report

18 18 Hospitalizations associated with allergenic extracts reported to AERS Hospitalization: 35 of the 180 non-fatal reports (19.4%) Hospitalizations by Year

19 19 AERS: Hospitalization Reaction Categories Hospitalization Reaction Categories

20 20 AERS: Hospitalization Suspect Products n = 44 Hospitalization Suspect Products

21 21 AERS: Ingredients associated with hospitalization Ingredient# Reports Yellow Jacket Venom Protein3 Wasp Venom Protein1 Fire Ant1 Ragweed3 Weeds1 Hops1 “Grass Mix” or “Grass”3 Tree Mix2 Timothy Grass1 Bluegrass Kentucky June1 Birch1 Flaxseed or Linseed1 “Pollen”2 Mold2 Mite6 House Dust2 Ingredient# Reports Cat Hair2 Cattle Hair1 Unspecified Ingredient4 Allergenic Extracts18 Lobelia1 Lemon Balm1 Valerian Extract1 Calamus Oil1 Jimson Weed1 Honey1 Blueberry Leaf1 Lactobacillus acidophilus1 not allergenic products

22 22 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 FeaturesAsthma Severity

23 23 Products with non-allergenic related potential safety issues Monkey Dander, Rhesus Transmission of simian pathogens Monkey Hair, Rhesus Deer HairTransmission of TSE Dust, Autogenous Pathogens Toxins: synthetic and pathogen associated (APAC, October, 1986) Dust, Cotton Gin Dust, Grain Mill Dust, House Mixture Dust, Mattress Kissing BugsPathogen (T. cruzii) WormseedCalcium Oxalate crystals Rhubarb Toxin Castor Bean (2) Laburnum (Golden chain) Bracken Fern Mexican Tea 23

24 24 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

25 25 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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