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 1

VICH Pharmacovigilance Harmonization Achievements International harmonization of reporting veterinary adverse events 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) ance.htm ance.htm 2

Save The Trees! 3

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 4

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 5

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 6

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 Health informatics – pharmacovigilance – individual case safety reports Unique descriptive wrappers needed to allow information acceptance by regionally different IT systems 7

Considerations for Harmonization Message Field Lengths and Data Types 8

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 9

Considerations for Harmonization Location Validations USA -States UK -Counties Japan -Prefectures Australia - Territories Canada – Provinces DECISION: leave the validation at the Regional level 10

Considerations for Harmonization Telephone Numbers Japan USA Germany England DECISION: simple text field with no validation. Format is to use a + before the country code and dashes in between numbers 11

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 12

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 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) 13

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 14

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 15

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 and break-out teleconferences as needed FDACVM Regional Implementation June

Number of Veterinary AE Reports Submitted to FDA CVM by Fiscal Year 17

Number of Companies Reporting Electronically (June 2013 Revision) 16 through Safety Reporting Portal 5 directly through Electronic Gateway 18

Percent of Veterinary AE Reports Submitted to FDA CVM Electronically 2011 –

Automatic population of database Identification of emerging problems More efficient data mining capabilities, even if the report has not yet been reviewed Electronic Submissions Gateway to Gateway 20

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 21

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 22

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 23

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 24

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 25

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 26

Some CVM Updates from 2011 Possible Danger with Animal Vaccine Device ( Caution to Pet Owners with the Use of an Unapproved Pet Shampoo Product ( Recall of Human Drug, Phenobarbitol ( 27

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 28

Safety Example: Estradiol – Secondary Exposures January 2007 to 2015 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!!) 29

Estradiol Secondary Exposure - Dogs LLTs reported January

Estradiol Secondary Exposure - Human LLTs reported January

Actions taken on Estradiol spray Medwatch Safety Alerts for Human Medical Products – July pdf pdf onforPatientsandProviders/ucm htm onforPatientsandProviders/ucm htm Label Change – Boxed Warning for unintentional secondary exposure added in 2011 CVM Updates for Pet Owners – July htm htm Animal Health Smart Brief disseminated information (in partnership with American Veterinary Medical Association) August

FDA CVM Reference Documents Regulation 21 CFR Definitions Regulation 21 CFR 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 33

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