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
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)
Number of ADE Reports
Adverse Drug Event Reports
45000
40000
35000
30000
Number
of Reports
25000
20000
15000
10000
5000
0
FY91 FY92 FY93 FY94 FY95 FY96 FY97 FY98 FY99 FY00 FY01 FY02 FY03 FY04 FY05 FY06 FY07 FY08
Year
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
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 20hrs/week
3/10 are current or previous practice owners
1/10 has lab animal experience
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
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.
Veterinary Drug
ADE Evaluation Scoring System
Amended Human System: 6-Part
Components of ADE Scoring System
(Modified Kramer Algorithm)
1. Previous Experience (-1, 0, +1)
2. Alternative Etiologic Candidate (-1, 0, +2)
3. Timing (-2, 0, +1)
4. Overdose (0, +1)
5. Dechallenge (-1, 0, +1)
6. Rechallenge (–1, 0, +1)
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
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
3 Ineffectiveness – Probably drug related
6 Ineffectiveness – Definitely drug related
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
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
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.
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
Reporting an ADE
1. a. Drug Company’s 800 #
b. FDA: 888-FDA-VETS
FORM 1932: Submitted by Sponsor
Helpful Information
Physical exam by veterinarian
Medical history
Diagnostic evaluation
Veterinarian’s opinion
Follow Up information
Reporting an ADE
1. a. Drug Company’s 800 #
b. FDA: 888-FDA-VETS
2. By Computer: www.fda.gov/cvm
download form 1932A
Form 1932A:
Mailed From The
Consumer
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
Reporting a nondrug adverse event
3. Vaccine Reaction: USDA
800-752-6255
4. Pesticide Reaction: EPA
800-858-7378
CVM does not:
Regulate the practice of veterinary
medicine
Report or judge off-label use
Advise on how to treat
animals with reactions
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.
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
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
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.
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.
FOI (Freedom of Information Act)
Reviewed ADE summaries are available to the public at
the FDA website.
http://www.fda.gov/AnimalVeterinary/SafetyHealth/P
roductSafetyInformation/ucm055394.htm
THIS SITE IS UPDATED MONTHLY
AMOXICILLIN
ORAL, CAT
Number of Animals Evaluated
90
Sign
HYPERESTHESIA
HYPERPNEA
HYPERSALIVATION
HYPOTHERMIA
HYPOTHERMIA, BODY
ICTERUS
INEFFECT, ANTIBIOTIC
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.
The Future For
Adverse Drug Event
Reviewing
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
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
CDRH
CBER
ORA/
OCM
CVM
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
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
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
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.
References
Bataller N, Keller WC., Monitoring
adverse reactions to veterinary drugs.
Pharmacovigilance. Vet Clin North Am
Food Anim Pract. 1999 Mar;15(1):1330, vii-viii.
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.
ADE algorithm
(if time allows)
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)
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)
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
Evidence of Overdose
For a score of +1
The clinical manifestation is clearly a doserelated 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 doserelated type of manifestation or there is no
evidence of an overdose.
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
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