FDA/CVM/OSC/DS Adverse Drug Experience (ADE) Reporting System

1. FDA/CVM/OSC/DS Adverse Drug Experience (ADE) Reporting System Division Director: Dr. Lynn Post Team Leaders: Dr. John Baker, ADE Coordinator Dr. Dorothy McAdams Beth Anne Grove

2. History of ADE Program at CVM • Initially ADE reports were reviewed by Veterinary Medical Officers when they had time • 1998 – Pilot program started to have dedicated ADE reviewers; 4 reviewers were hired • Expanded in 2001(3 reviewers) and 2008(3 reviewers)

3. Number of ADE Reports

4. Safety Reviewers: Margarita Brown, DVM, MS (Coordinator) Priscilla Batten, DVM Lee Anne Palmer, VMD Tina Burgess, DVM Ame Walesby, DVM, MS, DACVS Sandi Ehnen, VMD Linda Walter-Grimm, DVM Jeanne Herring, VMD, ACLAM Roderick Hudson, DVM Teresa Koogler, DVM

5. Reviewers experience • 9/10 have between 8-30 years practice experience and hold current clinical licenses • 2/10 have large animal practice experience • 8/10 have companion animal and/or exotic experience • 7/10 still practice in local practices up to 20-hrs/week • 3/10 are current or previous practice owners • 1/10 has lab animal experience

6. Other ADE team members: Linda Kim-Jung, PharmD Renee Shibukawa-Kent, VMD, MPH, DACVPM Susan Bright, DVM Developing Positions: Liaison for pet food adverse events: Lee Anne Palmer Liaison for international adverse events: Margarita Brown

7. Adverse Drug Experience(ADE) AnAdverse Drug Experience is any adverse reaction that occurs following the use of a drug product. ADEs can be mild (itching, sneezing) to severe (death). ADEs include complaints of ineffectiveness, product defects and human safety associated with the handling of animal drugs products.

8. Veterinary Drug ADE Evaluation Scoring System Amended Human System: 6-Part Components of ADE Scoring System (Modified Kramer Algorithm) • Previous Experience (-1, 0, +1) • Alternative Etiologic Candidate (-1, 0, +2) • Timing (-2, 0, +1) • Overdose (0, +1) • Dechallenge (-1, 0, +1) • Rechallenge (–1, 0, +1)

9. Interpretation of Range • -9= not applicable to label instructions • -8, -7= not enough information; no conclusion • -6 to -1= remotely drug related • 0-2= possibly related to the drug • 3-5= probably related to the drug • 6= definitely drug related

10. Ineffectiveness Scoring -9 Ineffectiveness – Not Applicable (claim for ineffect for condition not on label) -1 Ineffectiveness – Remotely drug related 0-1 Ineffectiveness – Possibly drug related Ineffectiveness – Probably drug related 6 Ineffectiveness – Definitely drug related

11. Drug problems and interactions evaluated by CVM • Baytril – Blindness in cats • Etogesic – Keratoconjunctivitis sicca • Moxidectin – Overdoses from failure of syringe-locking device • Comfortis – interaction with ivermectin • NSAID’s – liver disease, perforations, aggression, vets failure to follow label precautions

12. Importance of knowing the label • Side effects and interactions – preapproval testing is limited • Precautions – which animals should not get the drug; follow up testing that should be done • Post-approval experience section • Client information sheet or consent

13. Purpose of ADE Reporting Data Collection: 1: Veterinary Adverse Drug Experiences (ADEs) 2: Suspected Product Failures (Ineffectiveness) 3: Product Defects 4: Human exposures Pre-testing by the manufacturer and review of the data by the government does not guarantee absolute safety and effectiveness of approved veterinary drugs due to the inherent limitations imposed by testing the product on a limited population of animals. Anyone with information to report is encouraged to contact the manufacturer of the suspect product.

14. New drugs (less than 3 yrs of marketing): Reporting of ADE’s is very important for new drugs: Since pre-approval data is limited, once new drugs are used in thousands of animals – new side effects can show up

15. Reporting an ADE 1. a. Drug Company’s 800 # b. FDA: 888-FDA-VETS

16. FORM 1932: Submitted by Sponsor

17. Helpful Information • Physical exam by veterinarian • Medical history • Diagnostic evaluation • Veterinarian’s opinion • Follow Up information

18. Reporting an ADE 1. a. Drug Company’s 800 # b. FDA: 888-FDA-VETS 2. By Computer: www.fda.gov/cvm download form 1932A

19. Form 1932A: Mailed From The Consumer

20. ADEs • Most of ADEs reported come from the manufacturer on FDA Form 1932 • Reports from owners and veterinarians on FDA Form 1932a account for less than 1% of reported ADEs

21. Reporting a non-drug adverse event 3. Vaccine Reaction: USDA 800-752-6255 4. Pesticide Reaction: EPA 800-858-7378

22. CVM does not: • Regulate the practice of veterinary medicine • Report or judge off-label use • Advise on how to treat animals with reactions

23. Use of Data: Evaluate Trends and relative frequencies of clinical signs and lack of efficacy. Initiate label revisions, formulation changes, product packaging alterations or further clinical studies for investigation In rare circumstances this information may lead to removal of the drug from the market. Monitor off label uses of products including wildlife and human user safety issues.

24. Communication of our information • JAVMA Articles • Freedom of Information (FOIA) requests • Dear Doctor letters • Client information sheets • Informed consent • Cumulative ADE summaries webpage • Post approval label changes • Outreach

25. Dear Doctor Letter • After a label is revised to include new safety information, the drug company generally will send a letter to all practitioners describing the label changes and other important prescribing information. http://www.fda.gov/AnimalVeterinary/SafetyHealth/ ProductSafetyInformation/ucm055433.htm

26. Client Information Sheet (required for NSAID’s) • Similar to the Patient Prescribing Information (PPI), which is commonly distributed with human pharmacy prescriptions. • Written in “consumer-friendly” language and provides information about the benefits and side effects associated with the use of the prescribed drug in easily understandable Q & A format. • Supplements the information provided in the Package Insert; some Client Information Sheets are printed on the reverse side of the Package Insert.

27. Informed Consent • Remember to discuss possible side effects with the client before you dispense the drugs. Consider pre-administration blood work especially with long term administrations. • Supply the associated Client Information Sheets when dispensing drugs to the client. • Computer programs are now available that print out information sheets for other drugs similar to ones we get at a pharmacy.

28. FOI (Freedom of Information Act) Reviewed ADE summaries are available to the public at the FDA website. http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055394.htm THIS SITE IS UPDATED MONTHLY

30. AMOXICILLIN ORAL, CAT Number of Animals Evaluated 90 Sign HYPERESTHESIA HYPERPNEA HYPERSALIVATION HYPOTHERMIA HYPOTHERMIA, BODY ICTERUS INEFFECT, ANTIBIOTIC

31. Post-approval ADE section for labels: • After a drug has been on the market for 1 to 2 years, the primary reviewer does an analysis of the information to see if there are signs that need to be added to the Adverse Reaction section. • It is good to regularly review the labels for drugs to see if there have been any changes.

32. The Future For Adverse Drug Event Reviewing

33. Current Workflow • ADE report received • Triaged for review • Newly approved drugs (prior to 1 year anniversary) within 1 week (prior to 3 years) within 1 month • Hot topics as presented • ADE report entered into current database for review • Summary report updated monthly on CVM website

34. Owner/Vet/Drug company reports case Medwatch Plus Portal Call FDA if no Web-access Web-access Voluntary/ Mandatory Gateway Report coded, triaged, and sent to appropriate Center CDER CFSAN CBER ORA/ OCM CDRH CVM

35. New Reporting Form • Electronic format • Also available as paper until submission requirements change at Agency level Compatible with VICH reporting form Accompanying Guidance helps explain how to fill out the form

36. Electronic Submissions • Automatic population of the database • Workflow management • Identification of emerging problems • More efficient data mining capabilities, even if the report has not yet been reviewed

37. VICH International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Products • International harmonization of reporting adverse events • USA, EU, Japan • Canada, Australia • standardize definitions • standardize data elements • standardize dictionaries • electronic submission

38. References • Hampshire VA, Doddy FM, Post LO, et al., Adverse drug event reports at the United States Food and Drug Administration Center for Veterinary Medicine. J Am Vet Med Assoc., 2004 Jan 15; 224(2):177.

39. References Bataller N, Keller WC., Monitoring adverse reactions to veterinary drugs. Pharmacovigilance. Vet Clin North Am Food Anim Pract. 1999 Mar;15(1):13-30, vii-viii.

40. References • Keller WC, Bataller N, Oeller DS, Processing and evaluation of adverse drug experience reports at the Food and Drug Administration Center for Veterinary Medicine. J Am Vet Med Assoc. 1998 Jul 15;213(2):208-11.Am Vet Med Assoc. 1998 Jul 15;213(2):208-11.

41. ADE algorithm (if time allows)

42. Previous Experience • For a score of +1 • The clinical manifestation is generally recognized to occur in this species at the dosage received (from label adverse warnings; or appearing in the STARS updated database more than 10% of the time or in published veterinary literature. • For a score of 0 • The clinical manifestation is not generally recognized to occur in this species at the dosage received but has been previously reported in veterinary and/or human medicine or: • The drug has limited accumulated clinical experience (time and/or quantity marketed) • For a score of –1 • The clinical manifestation is previously unreported and the drug has substantial accumulated clinical experience (time and/or quantity marketed)

43. Alternative Etiologic Candidate • For a Score of +2 • There is no good candidate or no change in a candidate which can explain the clinical manifestation, exclusive of drug administration • For a score of 0 • An alternative candidate(s) exists, but not a good one(s) which can well explain the clinical manifestation or: • The clinical manifestation commonly occurs spontaneously in this type of patient and situation, usually in the absence of any recognizable alternative candidate(s) • For a score of –1 • There is a good candidate or a change in a candidate which can well explain the clinical manifestation, exclusive of drug administration. (usually identified by a DDX in the comments section of the final report)

44. Timing of Events • For a score of +1 • Timing was consistent and as expected for this type of clinical manifestation to this drug • For a score of 0 • Do not know what timing to expect • For a score of –2 • The timing was inconsistent for this type of clinical manifestation to this drug

45. Evidence of Overdose • For a score of +1 • The clinical manifestation is clearly a dose-related type of manifestation , and there is unequivocal evidence that the amount of drug received was an overdose for this animal • For a score of 0 • The clinical manifestation is not a dose-related type of manifestation or there is no evidence of an overdose.

46. Dechallenge • For a Score of +1 • The clinical manifestation disappeared after discontinuation of the suspect drug or administration of a specific antidote • For a Score of 0 • Dechallenge difficult, impossible, or inappropriate to assess • A non-specific agent or maneuver (non-antidotal) was administered that was directed against the clinical manifestations and that usually produces the degree and rate of improvement observed in this case • The clinical manifestation is characteristically transient and episodic, and there is no established pattern of the episodes regardless of what occurs after discontinuing the drug • The clinical manifestation is known to be dose-related and the clinical manifestation did not diminish or disappear after the dosage was reduced For a score of –1 • The clinical manifestation did not diminish or disappear after discontinuation of suspect drug • The clinical manifestation improved without Dechallenge and the improvement cannot be attributed to the development of tolerance

47. Rechallenge • For a score of +1 • The clinical manifestation unequivocally recurred or exacerbated after Rechallenge • For a score of 0 • There was no Rechallenge attempted • The clinical manifestation failed to recur or exacerbate on Rechallenge, but the dosage or duration of drug administration on Rechallenge was substantially less than that suspected of causing the original clinical manifestation • Recurrence or exacerbation of the clinical manifestation was impossible to assess because it was progressing or was at a level of severity that any further increase would be difficult to appreciate • For a score of –1 • The clinical manifestation failed to recur or exacerbate on Rechallenge