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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. Background

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Report on the safety of non-standardized allergenic extracts

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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 and Allergenic Products Office of Vaccines Research and Review Center for Biologics Evaluation and Research, USFDA

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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)

  7. 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

  8. 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

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

  10. 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

  11. 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

  12. 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

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

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

  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. 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

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

  19. Hospitalization Reaction Categories AERS: Hospitalization Reaction Categories

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

  21. AERS: Ingredients associated with hospitalization not allergenic products

  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 Features Asthma Severity

  23. Products with non-allergenic related potential safety issues 23

  24. 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

  25. 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

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