environmental safety assessment of new animal drugs · finding of no significant impact (fonsi) –...

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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.)


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


Proposed Action (new drug,

indication, etc.)


Meets criteria


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)



(FONSI)


Unacceptable risk

Meets criteria



Acceptable risk



Unacceptable risk

Unacceptable risk








(FONSI)


Unacceptable risk



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








(FONSI)


Unacceptable risk



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]

environmental safety assessment of new animal drugs · finding of no significant impact (fonsi) –...

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