FDACVMOSCDS

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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
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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)

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Number of ADE Reports
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• 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

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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

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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
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Adverse Drug Experience(ADE)

• An Adverse 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.

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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)

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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

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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

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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
• NSAIDs liver disease, perforations,
  aggression, vets failure to follow label
  precautions

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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

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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.

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New drugs (less than 3 yrs of marketing)

• Reporting of ADEs 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

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Reporting an ADE

• 1. a. Drug Companys 800
• b. FDA 888-FDA-VETS

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FORM 1932 Submitted by Sponsor
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Helpful Information

• Physical exam by veterinarian
• Medical history
• Diagnostic evaluation
• Veterinarians opinion
• Follow Up information

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Reporting an ADE

• 1. a. Drug Companys 800
• b. FDA 888-FDA-VETS
• 2. By Computer www.fda.gov/cvm
• download form 1932A

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• Form 1932A
• Mailed From The
• Consumer

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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

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Reporting a non-drug adverse event

• 3. Vaccine Reaction USDA 800-752-6255
• 4. Pesticide Reaction EPA 800-858-7378

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CVM does not

• Regulate the practice of veterinary medicine
• Report or judge off-label use
• Advise on how to treat
• animals with reactions

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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.

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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

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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/SafetyHealt
  h/ ProductSafetyInformation/ucm055433.htm

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Client Information Sheet (required for NSAIDs)

• 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.

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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.

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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

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

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The Future For Adverse Drug Event Reviewing
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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

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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

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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

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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

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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.

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References

• Bataller N, Keller WC., Monitoring adverse
  reactions to veterinary drugs. Pharmacovigilance.
  Vet Clin North Am Food Anim Pract. 1999
  Mar15(1)13-30, vii-viii.

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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 15213(2)208-11.Am Vet Med Assoc. 1998 Jul
  15213(2)208-11.

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ADE algorithm

• (if time allows)

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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)

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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)

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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

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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.

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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

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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