Transcript Reference documents (FDA CVM)

VICH Pharmacovigilance Guidelines
GL35 Development and Harmonization
Center for Veterinary Medicine (CVM)
Food and Drug Administration
Margarita Brown, DVM MS
FDA Center for Veterinary Medicine
Office of Surveillance and
Compliance
[email protected]
240-276-9048
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VICH Pharmacovigilance Harmonization
Achievements
International harmonization of reporting veterinary
adverse events
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GL24 AE Terms, Definitions, Management
GL29 PSUR Standardization, Management
GL42 Data Elements for Submission of AE
GL30 Controlled Lists of Terms (24 lists!)
GL35 Electronic Standards (Data Transfer)
http://www.vichsec.org/guidelines/pharmacovigil
ance.htm
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Save The Trees!
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Information in ADE Report
 Trade & Generic Name of Product
 Dosage Information (route, date and amount
administered, reason for use, etc.)
 Patient(s) Signalment, Overall State of Health
 Concomitant Drugs Administered
 Description of Adverse Reaction
 Animal Outcome
 Veterinarian’s opinion
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GL 35 Electronic Standards for Transfer
of Data
 Recommendation to ensure secure transmission
 Definition of electronic message structure
 Relationships between the data elements
 Establishment of additional vocabularies
 Business and schema validation rules and field
descriptors specifications for AER data and
wrapper information
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Considerations for Harmonization
Scope
 EMA – drugs and biologics
 Japan MAFF – drugs and biologics
 FDA CVM – drugs and product problems
 USDA CVB – biologics
 Canada VDD – drugs
 Canada CCVB - biologics
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Considerations for Harmonization
Standardized Message Format
Provide electronic standards to consider a single message
to transmit GL 42 content to all regions
 Format free and available to all users
 Decision – must be in line with ISO 27953-1 Health
informatics – pharmacovigilance – individual case
safety reports
 Unique descriptive wrappers needed to allow
information acceptance by regionally different IT
systems
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Considerations for Harmonization
Message Field Lengths and Data Types
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Considerations for Harmonization
Regional Registrations
FDA CVM
 Product has same registration number regardless of varying
strength of tablet
EMA
 Product has different registration number with different strength
of tablet
DECISION: use of “Cannot Be Determined” if insufficient
information
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Considerations for Harmonization
Location Validations
 USA 
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States
UK Counties
Japan Prefectures
Australia - Territories
Canada – Provinces
DECISION: leave the validation at the Regional level
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Considerations for Harmonization
Telephone Numbers
 Japan
+81-3-2364-7781
 USA
+1-240-276-9048
 Germany
+49-2173-38-4163
 England
+44-0-20-7523-7504
DECISION: simple text field with no validation. Format is to
use a + before the country code and dashes in between
numbers
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Considerations for Harmonization
Time Zones
How to accept a report that is submitted “tomorrow”??
 Valid date and timestamp of YYYYMMDDHHMMSS+/-
ZZZZ
 **NOTE: HHMMSS represents hours, minutes, and
seconds, and +/-ZZZZ represents GMT offset**
 Date of Message creation
 Date of Batch creation
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Harmonized Vocabularies (GL30)
 Use a common language for submission
 It can be mapped to another language for display in the
individual backend system
 Breed examples:
 Great Dane vs Deutsche Dogge
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Dog124 Deutsche Dogge, Great Dane
 Pomeranian vs German Spitz
 Dog334 Spitz – German Pomeranian
 Mixed breed vs Crossbred
 Dog 88 Crossbred Canine/dog
 Dog 196 Mixed(Dog)
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Harmonized Vocabularies
(VeDDRA)
Veterinary Dictionary for Drug Related Affairs
(VeDDRA) terminology for documenting clinical signs
 System Organ Class (SOC)
• High Level Term (HLT)
•
Preferred Term (PT)
• Low Level Term (LLT)
 Low Level Terms (LLT) are submitted
 Allows collection of reported LLT by into higher
category (PT) on searches
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Preferred Term: Lethargy
Can be reported as several different Low Level Terms:
Decreased activity
Depression
Devitalisation
Dull
Fatigue
Feelings of weakness
Generalized weakness
Lack of awareness
Lack of Response to
owner
Lethargy
Listless
Loss of strength
Reluctant to move
Tiredness
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Timeline
 GL35 basis signed June 2010
 Annexed with suggested field lengths and data types
 Working Group reviewed documents and comments
 Teleconferences June 2011 to June 2012
• Monthly 3 hour teleconferences for 10 months
• One face-to-face meeting to finalize
• Email and break-out teleconferences as needed
• FDACVM Regional Implementation June 2013
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Number of Veterinary AE Reports Submitted
to FDA CVM by Fiscal Year
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Number of Companies Reporting Electronically
(June 2013 Revision)
• 16 through Safety Reporting Portal
• 5 directly through Electronic Gateway
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Percent of Veterinary AE Reports Submitted to
FDA CVM Electronically 2011 – 2014
http://www.accessdata.fda.gov/FDATrack
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Electronic Submissions
Gateway to Gateway
 Automatic population of database
 Identification of emerging problems
 More efficient data mining capabilities, even if the
report has not yet been reviewed
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Advantages
 Workflow
 Periodic cases in real time
 Case quality
 Closer working relationship with PV partners
 Data available for rapid recovery
 Data available for data mining and statistics
 PV Analyser
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Quality Assurance Review Sample
(Program began at CVM in October 2013)
Goals:
• Standardized, impartial review of electronically submitted
cases and VedDRA coding
• Maximize receipt of complete and usable case information
• Identify knowledge gaps (such as coding) for evaluation
• Address gaps in future workshops or revisions
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FDA CVM Pharmacovigilance Scope
• Animal safety
• Drugs and devices (approved or unapproved)
• Serious and non-serious adverse events
• Lack of expected effectiveness
• Off label use/misuse
• Humans reacting after exposure
• Violations of residue levels
• Product problems
• Medication errors
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• Evaluate signals and trends
•Develop Case Series
• Monitored Adverse Reaction Committee
•Interactive cross center pharmacovigilance forum for discussion of
safety and effectiveness issues of concern
•Label revisions
•Formulation changes
•Product packaging alterations
•Further clinical studies for investigation
•Inform public of perceived risks
•examples: CVM Updates/Dear Doctor letters
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What Data Mining Can Do:
 Signal potential problems quickly
 Generate hypotheses regarding potential drug safety
problems
 Signal events that might be missed if a pattern is not
expected
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What Data Mining Cannot Do:
 Data mining cannot prove or refute causal associations
between drugs and events.
 Data mining simply identifies disproportionality of drug-
event reporting patterns
 Data mining cannot replace hands-on clinical review
 Individual review of cases is always necessary to explore
data mining signals
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Some CVM Updates from 2011
 Possible Danger with Animal Vaccine Device
(http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm270642.htm)
 Caution to Pet Owners with the Use of an Unapproved
Pet Shampoo Product
(http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm255384.htm)
 Recall of Human Drug, Phenobarbitol
(http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm246624.htm)
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Safety example:
Vaccine Device – LLTs reported
 Two reports of adverse events:
 LLT – Fracture
 LLT – Injection site erythema
 LLT - Syringe, abnormal (2)
 Eight reports of product defect only:
 LLT – Syringe, abnormal
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Safety Example:
Estradiol – Secondary Exposures
January 2007 to 2015
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Search Brand Name
Search active ingredient(s) – estradiol
Search SOC – Reproductive system disorders
Recovered 18 dogs (1 case also involved 2 children with
secondary exposure)
 Breed only known for 6 of the 18 dogs – small breed
dogs (Yorkie, Poodle, Chihuahua, Pug)
 Weight only reported for 8 of the 18 dogs:
 2.27 kg to 4.5 kg (and one 11 kg Pug!!)
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Estradiol Secondary Exposure - Dogs
LLTs reported January 2007-2015
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Estradiol Secondary Exposure - Human
LLTs reported January 2007-2015
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Actions taken on Estradiol spray
 Medwatch Safety Alerts for Human Medical Products – July 2010
 http://www.fda.gov/downloads/forconsumers/consumerupdates/ucm22
0544.pdf
 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformati
onforPatientsandProviders/ucm220185.htm
 Label Change – Boxed Warning for unintentional secondary exposure
added in 2011
 CVM Updates for Pet Owners – July 2010
 http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm2
20420.htm
 Animal Health Smart Brief disseminated information (in partnership
with American Veterinary Medical Association) August 2010
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FDA CVM Reference Documents
 Regulation 21 CFR 514.3 - Definitions
 Regulation 21 CFR 514.80
 Records and reports concerning experience with
approved new animal drugs
 Guidance for Industry – Implemented
 GFI#188 – VICH GL42 – Data Elements for Submission
 GFI#143 – VICH GL30 – Controlled Lists of Terms
 GFI#214 – VICH GL35 – Electronic Standards for
Submission
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