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Environmental Safety Environmental Safety Assessment of New Animal Assessment of New Animal
DrugsDrugsWesley Hunter, Ph.D.Wesley Hunter, Ph.D.
U.S. Food and Drug AdministrationU.S. Food and Drug AdministrationCenter for Veterinary MedicineCenter for Veterinary Medicine
Environmental Safety TeamEnvironmental Safety Team
OutlineOutline
Legal mandates and implementationLegal mandates and implementationOverview of the CVM NEPA processOverview of the CVM NEPA processCategorical exclusionsCategorical exclusionsEnvironmental AssessmentsEnvironmental AssessmentsPoints to considerPoints to consider
Federal Food, Drug and Cosmetic ActFederal Food, Drug and Cosmetic Act
Target Animal SafetyTarget Animal Safety
Target Animal EffectivenessTarget Animal Effectiveness
Human Food SafetyHuman Food Safety
ManufacturingManufacturing
Other Public HealthOther Public Health
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National Environmental Policy Act National Environmental Policy Act (NEPA, 1969)(NEPA, 1969)
Basic national charter for the protection of the Basic national charter for the protection of the environmentenvironment
NEPA requires Federal Agencies consider NEPA requires Federal Agencies consider environmentenvironment
FDA Regulation: 21 CFR 25.15(a)FDA Regulation: 21 CFR 25.15(a)–– All applications or petitions requesting agency action All applications or petitions requesting agency action
require the submission of an require the submission of an Environmental Assessment Environmental Assessment (EA)(EA) or a or a claim of categorical exclusion (CE)claim of categorical exclusion (CE). .
FDA Role FDA Role -- ActionsActions
Examples of agency actions that require environmental Examples of agency actions that require environmental review:review:–– Allow investigations under INADAllow investigations under INAD–– Approval of NADA, ANADA, FAP, supplementsApproval of NADA, ANADA, FAP, supplements
Environmental review focuses on:Environmental review focuses on:–– UseUse–– ExcretionExcretion–– DisposalDisposal(not usually manufacturing)(not usually manufacturing)
from the need to from the need to prepare an EA or EISprepare an EA or EIS
Council on Environmental Quality (CEQ)Council on Environmental Quality (CEQ)Implement NEPAImplement NEPA
http://www.whitehouse.gov/ceq/http://www.whitehouse.gov/ceq/
CFR, Title 40, Part 1500 CFR, Title 40, Part 1500 -- 15081508
CategoricalExclusions
Environmental Assessments
(EA)
Environmental Impact
Statements (EIS)
Public document; Public document; determines whether to determines whether to prepare a finding of no prepare a finding of no
significant impact significant impact ((FONSIFONSI) or an ) or an EISEIS
Public document detailing Public document detailing the environmental impacts the environmental impacts
of actions, including of actions, including Record of Decision (ROD)Record of Decision (ROD)
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Overview of CVM NEPA ProcessOverview of CVM NEPA ProcessProposed Action
(new drug, indication, etc.)
Categorical Exclusion
Meets criteria
actions which the agency has predetermined actions which the agency has predetermined do notdo not individually or cumulativelyindividually or cumulatively have a have a significant effect on the human environment; significant effect on the human environment; and therefore, and therefore, ordinarilyordinarily do not require the do not require the preparation of an EA or EIS preparation of an EA or EIS
Generally based on limited use and/or Generally based on limited use and/or supplements to approved drugs that do not supplements to approved drugs that do not increase the useincrease the use
Categorical Exclusions
Categorical Exclusions forCategorical Exclusions forAnimal DrugsAnimal Drugs
21 CFR 25.3321 CFR 25.33(a) (1) (a) (1) –– (7) use does not increase; (7) use does not increase; (b) Reserved(b) Reserved(c) Naturally occurring(c) Naturally occurring(d) (1) (d) (1) –– (5) nonfood, anesthetic, (5) nonfood, anesthetic, nonsystemicnonsystemictopical and ophthalmic, minor species, prescription topical and ophthalmic, minor species, prescription for terrestrial animalsfor terrestrial animals(e) INAD(e) INAD(f) (f) no longer relevantno longer relevant(g) Withdrawal NADA or ANADA(g) Withdrawal NADA or ANADA(h) Withdrawal FAP(h) Withdrawal FAP
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Extraordinary CircumstancesExtraordinary Circumstances
21 CFR 25.21 21 CFR 25.21 –– FDA RegulationsFDA Regulations21 CFR 1508.27 21 CFR 1508.27 –– NEPA ExamplesNEPA Examples
FDA will require at least an EA for any FDA will require at least an EA for any specific action that ordinarily would be specific action that ordinarily would be excluded if extraordinary circumstances excluded if extraordinary circumstances indicate that the proposed action indicate that the proposed action maymaysignificantly affect the quality of the significantly affect the quality of the human environmenthuman environment
Extraordinary CircumstancesExtraordinary Circumstances
21 CFR 25.21 21 CFR 25.21 –– FDA RegulationsFDA Regulations
At the expected level of exposure there is At the expected level of exposure there is the the potentialpotential for serious harmfor serious harm to the to the environmentenvironment
Actions that adversely effect a species or Actions that adversely effect a species or the critical habitat of an the critical habitat of an endangered or endangered or threatened speciesthreatened species
21 CFR 25.15(d)21 CFR 25.15(d)Applicant:Applicant:
states that the action requested qualifies for a states that the action requested qualifies for a categorical exclusioncategorical exclusioncites the particular categorical exclusion that is cites the particular categorical exclusion that is claimed (only cite the most relevant if several apply)claimed (only cite the most relevant if several apply)verifies by statement that to the applicantverifies by statement that to the applicant’’s s knowledge (given a reasonable search for knowledge (given a reasonable search for information) no extraordinary circumstances existinformation) no extraordinary circumstances exist
The Agency:The Agency:agrees that the action qualifies and that no agrees that the action qualifies and that no extraordinary circumstances existextraordinary circumstances exist
Claiming a Categorical Claiming a Categorical ExclusionExclusion
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Environmental Assessment (EA)
Overview of CVM NEPA ProcessOverview of CVM NEPA ProcessProposed Action
(new drug, indication, etc.)
Categorical Exclusion
Meets criteria
Extraordinarycircumstances
Environmental AssessmentsEnvironmental Assessments
Environmental AssessmentsEnvironmental Assessments–– 21 CFR 25.40(a)21 CFR 25.40(a), , ……an EA is a concise an EA is a concise
public documentpublic document that serves to provide that serves to provide sufficient evidence and analysis for an sufficient evidence and analysis for an agency to determine whether to prepare an agency to determine whether to prepare an Environmental Impact Statement (EIS)Environmental Impact Statement (EIS) or a or a Finding of No Significant Impact (FONSI)Finding of No Significant Impact (FONSI)
–– FDA is ultimately responsible for the scope FDA is ultimately responsible for the scope and content of each EA (although they are and content of each EA (although they are usually prepared by the drug sponsor)usually prepared by the drug sponsor)
Preparing an Environmental Preparing an Environmental Assessment DocumentAssessment Document
Concise, objective, balanced documentConcise, objective, balanced documentFocus on relevant environmental issues Focus on relevant environmental issues relating to the use of the drug and its relating to the use of the drug and its disposal disposal Provide sufficient evidence and analysis to Provide sufficient evidence and analysis to determine the need for a determine the need for a FONSIFONSI or or EISEISDescription of potential risk mitigationsDescription of potential risk mitigations
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Format of an EAFormat of an EA
Generally follows a risk assessment processGenerally follows a risk assessment processHazard identificationHazard identificationExposure characterizationExposure characterizationEffects characterizationEffects characterizationRisk characterizationRisk characterizationConsequence assessmentConsequence assessmentMitigations/ managementMitigations/ management
–– appropriate for public display and allow the public appropriate for public display and allow the public to understand the agencyto understand the agency’’s decision (21 CFR s decision (21 CFR 25.40(a))25.40(a))
Guidance for Industry 61Guidance for Industry 61 gives general guidance gives general guidance on the content and format of an EAon the content and format of an EA
Overview of CVM NEPA ProcessOverview of CVM NEPA Process
Finding of No Significant Impact
(FONSI)
Risk Mitigation Options
Unacceptable risk
Environmental Impact Statement (EIS) &
Record of Decision (ROD)
Acceptable risk
Environmental Assessment (EA)
Proposed Action (new drug,
indication, etc.)
Categorical Exclusion
Meets criteria
Extraordinarycircumstances
Environmental AssessmentEnvironmental AssessmentHarmonized GuidanceHarmonized Guidance
Phase I (March 7, 2001)Phase I (March 7, 2001)–– Guidance for Industry 89Guidance for Industry 89
((http://www.fda.gov/downloads/AnimalVeterinary/GuidanceCompliancehttp://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnEnforcement/GuidanceforIndustry/UCM052424.pdfforcement/GuidanceforIndustry/UCM052424.pdf) )
Phase II (January 9, 2006)Phase II (January 9, 2006)–– Guidance for Industry 166Guidance for Industry 166
((http://www.fda.gov/downloads/AnimalVeterinary/GuidanceCompliancehttp://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnEnforcement/GuidanceforIndustry/UCM052500.pdfforcement/GuidanceforIndustry/UCM052500.pdf))
These These guidancesguidances have been developed by an have been developed by an international group (VICH) to harmonize the data international group (VICH) to harmonize the data requirements for approval of veterinary drug requirements for approval of veterinary drug products in the U.S., European Union, Australia products in the U.S., European Union, Australia and Japan.and Japan.
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Unacceptable risk
Unacceptable risk
Does not meet criteria
Phase I analysis – (Exposure)
Phase II analysis - Tier A(Acute)
Phase II analysis - Tier B(Chronic/reproductive)
Phase II analysis - Tier C(Further analysis)
Overview of CVM NEPA ProcessOverview of CVM NEPA ProcessProposed Action (e.g., new drug
or use)
Categorical Exclusion
Finding of No Significant Impact
(FONSI)
Risk Mitigation Options
Unacceptable risk
Meets criteria
Environmental Impact Statement (EIS) &
Record of Decision (ROD)
Acceptable risk
Extraordinarycircumstances
Environmental Assessment (EA)
Unacceptable risk
Unacceptable risk
Does not meet criteria
Phase I analysis – (Exposure)
Phase II analysis - Tier A(Acute)
Phase II analysis - Tier B(Chronic/reproductive)
Phase II analysis - Tier C(Further analysis)
Overview of CVM NEPA ProcessOverview of CVM NEPA Process
Finding of No Significant Impact
(FONSI)
Risk Mitigation Options
Unacceptable risk
Environmental Impact Statement (EIS) &
Record of Decision (ROD)
Acceptable risk
Veterinary ScenariosVeterinary Scenarios
Intensively reared animals Pasture animals
Aquaculture
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Phase I GuidancePhase I GuidanceA limited exposure assessment– Uses a pre-determined environmental
concentrationRecommended Predicted Environmental Concentration (PEC) values
≥100 ppb in soil≥1 ppb in water
Phase II analysis
Phase II GuidancePhase II Guidance
Focus on ecosystem protection Laboratory studies on properties, environmental fate, and effects on invertebrates, fish, plants Measurement endpoints: mortality, immobilization, reproduction, growthBiogeochemical cycling (nitrogen and carbon transformation)
Predicted No Effect Concentration (PNEC)
Predicted Environmental Concentration (PEC)
RQ = PEC/PNEC
Environmental release
Fate/Distribution
Proposed Use
Single speciestoxicity data
Extrapolation (AF)
Exposure Exposure AssessmentAssessment
Effects Effects AssessmentAssessment
Risk CharacterizationRisk Characterization
Phase IIRisk-Quotient Method
≥1 move to next tier
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Exposure AssessmentExposure Assessment
Chemical & environmental fate properties
(metabolism, excretion, storage time, degradation in storage, adsorption, etc.)
Use pattern
PECManure loading rate, water use and management
Exposure AssessmentExposure Assessment
Dose
Duration Frequency
Seasonal Distribution
Number of Animals Treated
Species & Diseases
Chemical Use
Administration (e.g., feed, injection, bath)
Effects AssessmentEffects AssessmentLaboratory tests (single species; standardized tests)Laboratory tests (single species; standardized tests)
Acute tests in Tier AAcute tests in Tier A
Chronic tests in Tier BChronic tests in Tier B
algae
+ +
crustacea fish
Model Aquatic EcosystemModel Aquatic Ecosystem
Terrestrial as wellTerrestrial as well
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TIER A StudiesTIER A StudiesPhysicalPhysical--chemical Studieschemical Studies
• Water Solubility• Dissociation Constant• UV-Visible Absorption Spectrum• Melting Temperature• Vapour Pressure • Octanol/Water Partition Coeff.
Environmental Fate Studies
• Soil adsorption/desorption• Degradation in soil • Degradation in aquatic systems• Photolysis (optional)• Hydrolysis (optional)
Aquatic Effects Studies
• Algae growth inhibition• Daphnia acute immobilization• Fish acute toxicityIncludes testing of saltwater species
if relevant for drug use
Terrestrial Effects Studies
• Terrestrial plant growth • Microorganisms (N transform)• Earthworm subacute/reprod.• Dung fly and beetle larvae (for
certain ectoparasiticides)
Tier B StudiesTier B StudiesEnvironmental Fate
Study• Bioconcentration in fish
Aquatic Effects Studies• Daphnia or crustacean reproduction
• Fish, early-life stage
• Sediment invertebrate toxicity
Includes testing of saltwater species if relevant to drug use/disposal pattern
Terrestrial Effects Studies• Earthworm chronic
• Terrestrial plants growth – 2 additional species + sensitive spp. from Tier A
• Nitrogen fixation - extension of Tier A study for an additional 100 days
Aquatic Effects Studies• Daphnia or crustacean reproduction
• Fish, early-life stage
• Sediment invertebrate toxicity
Includes testing of saltwater species if relevant to drug use/disposal pattern
Risk CharacterizationRisk screening based on a risk quotient (RQ)
PNEC = Effects endpoint ÷ Assessment Factor (AF)Lab to field extrapolationInterspecies and intraspecies differences in sensitivityAcute to chronic extrapolation
Predicted No Effect Concentration (PNEC)
Predicted Environmental Concentration (PEC)
RQ = PEC/PNEC
Risk CharacterizationRisk Characterization
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Surface water Surface water EndpointEndpoint AFAF•• algae (96 h)algae (96 h) EC50EC50 100 100 •• invertebrate (48 h)invertebrate (48 h) EC50EC50 10001000•• fish (96 h)fish (96 h) LC50LC50 10001000
PNECs for TIER APNECs for TIER A
SoilSoil•• earthworm (chronic)earthworm (chronic) NOECNOEC 10 10 •• higher plants (3 species)higher plants (3 species) EC50EC50 100100•• microorganisms (28 days)microorganisms (28 days) << 25% of control25% of control
Dung (pasture animals)Dung (pasture animals)•• dung fly dung fly EC50EC50 100 100 •• dung beetle dung beetle EC50EC50 100 100
Surface waterSurface water EndpointEndpoint AFAF•• algae (96 h)algae (96 h) NOECNOEC 10 10 •• invertebrate (21 d)invertebrate (21 d) NOEC NOEC 1010•• fish (28 d)fish (28 d) NOEC NOEC 1010•• sediment species (varies)sediment species (varies) NOECNOEC 1010
Soil Soil •• earthworm earthworm no recommendation no recommendation •• higher plants (more species) higher plants (more species) NOECNOEC 10 10 •• microorganisms (100 days)microorganisms (100 days) < 25% of control< 25% of control
BioaccumulationBioaccumulation•• BCF > 1000 l/kg BCF > 1000 l/kg investigate investigate secondary poisoningsecondary poisoning
PNECs for TIER BPNECs for TIER B
Tier C Tier C –– Further AnalysisFurther Analysis
Specialized Laboratory and/or Field TestingSpecialized Laboratory and/or Field Testing–– Pulsed exposure studiesPulsed exposure studies–– Microcosm and mesocosm studiesMicrocosm and mesocosm studies–– InIn--stream studiesstream studies–– Test additional speciesTest additional species
Refined Risk AnalysisRefined Risk Analysis–– Species sensitivity distribution analysis Species sensitivity distribution analysis –– Probabilistic exposure analysesProbabilistic exposure analyses–– Specialized environmental fate modelingSpecialized environmental fate modeling
Risk Mitigation and Management (Labeling)Risk Mitigation and Management (Labeling)–– Use and/or disposal restrictionsUse and/or disposal restrictions–– Mandatory treatment requirementsMandatory treatment requirements–– Water quality benchmarks for use in NPDESWater quality benchmarks for use in NPDES
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Study DesignStudy Design
Adequate and wellAdequate and well--controlled studiescontrolled studiesFollow FDA and/or OECD GLP standardsFollow FDA and/or OECD GLP standardsOECD guidelines are generally accepted OECD guidelines are generally accepted and recommendedand recommendedMethods should be adequately validatedMethods should be adequately validated
Use of peerUse of peer--reviewed journal reviewed journal articles to support key dataarticles to support key data
Acceptable approach for some endpointsAcceptable approach for some endpointsStudies must be adequate and wellStudies must be adequate and well--controlledcontrolledWell documented and corroboratedWell documented and corroboratedSee Guidance for Industry 106 for more See Guidance for Industry 106 for more informationinformation
Unacceptable risk
Unacceptable risk
Does not meet criteria
Phase I analysis – (Exposure)
Phase II analysis - Tier A(Acute)
Phase II analysis - Tier B(Chronic/reproductive)
Phase II analysis - Tier C(Further analysis)
Overview of CVM NEPA ProcessOverview of CVM NEPA Process
Finding of No Significant Impact
(FONSI)
Risk Mitigation Options
Unacceptable risk
Environmental Impact Statement (EIS) &
Record of Decision (ROD)
Acceptable risk
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Following approval, the EA is put on public display:Following approval, the EA is put on public display:http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalhttp://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/EnvironmentalAssessments/default.htmProcess/EnvironmentalAssessments/default.htm
Environmental Assessment Environmental Assessment DocumentDocument
Points to ConsiderPoints to Consider
Points to ConsiderPoints to ConsiderCE submissionsCE submissions
Applicant should:Applicant should:
Ensure that the submission Ensure that the submission includes the correct and includes the correct and complete CFR citationcomplete CFR citation
If no extraordinary circumstances exist, ensure that If no extraordinary circumstances exist, ensure that submissionsubmission includes a statement certifying that to the includes a statement certifying that to the sponsorsponsor’’s knowledge, no extraordinary circumstances s knowledge, no extraordinary circumstances existexist
Ensure that the submission Ensure that the submission includes basic informationincludes basic informationabout the drugabout the drug (e.g., dose, dosage form, species, (e.g., dose, dosage form, species, indications for use, etc.)indications for use, etc.)
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Points to ConsiderPoints to ConsiderEA submissionsEA submissions
Applicant should:Applicant should:Ensure that the public EA does not contain any proprietary information
Ensure that studies referred to in the EA are summarizedin the EA
Ensure that important scientific statements contain reference citations
Ensure that metabolites and/or degradates are adequately considered
CommunicationCommunication
We encourage communication early and We encourage communication early and often.often.If you have an alternative approach or If you have an alternative approach or unique situation that differs from our unique situation that differs from our current guidance, please let us know. We current guidance, please let us know. We are open to considering other approaches. are open to considering other approaches.
Thank YouThank You
Wesley Hunter, Ph.D.Wesley Hunter, Ph.D.FDA/CVMFDA/CVMEnvironmental Safety Team, HFVEnvironmental Safety Team, HFV--1621627500 Standish Place7500 Standish PlaceRockville, MD 20855Rockville, MD 20855240240--276276--95489548wesley.hunterwesley.hunter@[email protected]