Risk Analysis for Veterinary Biologics: Case Studies Richard E. HILL, Jr., Patricia FOLEY Center for Veterinary Biologics Veterinary Services Animal and Plant Health Inspection Service United States Department of Agriculture Ames, Iowa USA Center for Veterinary Biologics United States Department of Agriculture Animal and Plant Health Inspection Service
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Risk Analysis for
Veterinary Biologics:
Case Studies
Richard E. HILL, Jr., Patricia FOLEY
Center for Veterinary Biologics Veterinary ServicesAnimal and Plant Health Inspection ServiceUnited States Department of AgricultureAmes, Iowa USA
Center for
Veterinary Biologics
United States Department of Agriculture
Animal and Plant Health Inspection Service
Topics
► Risk Analysis for Biotechnology-
derived Biologics (brief summary)
► Case Studies
► Vectored vaccines (review of risk
decisions and mitigations)
► Transgenic Plant-derived Vaccines
(additional considerations and example)
► Emerging Issues and Unique
Biologics
Risk Review of
Biotech-derived Applications
► Data: Summary Information Format (SIF)
– The biologics firm provides the requested information
using the pertinent SIF, reviewed by USDA
► Risk Assessment (RA) outline
– Completed by the firm, evaluated by USDA
► Risk analysis by USDA of proposed field safety trials
– Environmental assessment (EA) of any potential effects
• On animal safety, public health, or the environment
Biotech Risk Assessment
Objective of Studies: ID Hazards
► Examine genotypic and phenotypic stability in target
host animals (reversion to virulence?)
► Evaluate changes in tissue tropism
► Assess shed/spread capabilities
► Assess host range specificity
► Consider recombination potential and consequences
► Identify effect of overdosing
► Assess survivability in environment
► Expected risk: Risk Rating = [(L) x (D)] x [(C) x (D)]
Formal Risk Review of
Biotechnology-Derived Products
► USDA conducts Master Seed & prelicense serial testing
► The firm provides to USDA
– Confidential business information-deleted SIF/RA
► For live vaccines: Federal Register Notice of pending
trials
– CBI-deleted SIF/RA & EA available to the public
– Public comment period
– Finding of No Significant Impact (FONSI)
– Approval of field trials if no issues arise
► Licensure
– If the field trials showed the product to be safe and all
other requirements are met
Request to Ship + Test
an Experimental Biologic – 9 CFR 103.3
Analysis of pre-license data & information
Hazard Identification &
Release Assessment
Risk Characterization
Low:
Acceptable Risk
Approve Request
Medium:
Unacceptable Risk
Satisfactory
Mitigation
Yes: Approve Request No: Deny Request
High:
Unacceptable Risk
Deny Request
Environmental Considerations
► Deliberate release of any organism containing
recombinant DNA into the environment is subject to
review and approval by appropriate Federal
agencies.
► Under normal husbandry and laboratory practices,
injected veterinary biologicals are not considered to
be released into the environment if testing shows the
agents are not shed.
Overview
► Each biotech product is evaluated individually
to determine the appropriate requirements to
establish purity, safety, potency, and efficacy.
► Replication proficient products must undergo
an environmental risk assessment.
► Killed or inactivated (non-replication
competent) biotechnology products must
undergo an abbreviated risk assessment.
Case Studies
► Vaccinia-vectored oral baited rabies vaccine
(V-RG) for wildlife
► Canarypox-vectored vaccines
► Transgenic plant-derived vaccines
► Risks
– < 1960, mostly domestic animals
– Now: > 90% of animal cases in
wildlife (carnivores, bats)
– Livestock: most often cattle & horses
► Costs
– > $300 million/year in US for oral rabies vaccine (ORV)
– FY2007: 11,361,002 ORV baits in 17 states
► Need new ORVs, baits & biomarkers
– Current ORV effective in raccoon, coyote, gray fox
– Need vaccines for use in skunk, bat, mongoose
Rabies
U. S. Risks and Costs
Rabies
Domestic Animals
Rabies
Wild Animals
Licensed Global Vaccines
►ORV - attenuated strains (various SAD vaccine
viruses, ERA G 333) – red foxes, raccoons
► ORV - freeze-dried or encapsulated SAG2 – dogs,
red foxes, raccoons
► Cell culture or nerve-tissue KV for use in dogs,
cats, ferrets, horses, cattle, or sheep
► Live poxvirus vectored vaccines, per WHO, 2004:
● > 75 million doses of V-RG – red foxes
(Belgium, France, Israel, Luxemburg, Ukraine);
raccoons (Republic of Korea); coyotes,
raccoons, grey foxes (Canada, US), domestic
dogs (Sri Lanka)
Rabies Virus
V-RG Oral Rabies Vaccine
Case Study
►1983: Vaccinia-vectored vaccine developed containing
Rabies glycoprotein G – unique, baited, oral use in wildlife
►Extensive studies in containment, then in the field (Belgium,
France): contact with baits in a wide variety of species
►Safe in rabbits, various spp. mice + voles, woodchucks,