Environmental Assessment for Environmental Assessment for Pharmaceuticals - Pharmaceuticals - FDA Perspective

Charles E. Eirkson IIICenter for Veterinary Medicine

U.S. Food and Drug Administration

NCAC SOT: Emerging Issues in Water Contamination

April 15, 2010

TopicsTopics

LegalLegal

RegulatoryRegulatory

ScienceScience

Risk ManagementRisk Management

Wrap-up/summaryWrap-up/summary

Agency’s Roles and PrioritiesAgency’s Roles and Priorities

Primary Federal agency for regulating Primary Federal agency for regulating pharmaceuticals and personal care pharmaceuticals and personal care productsproducts

FoodsFoods Human DrugsHuman Drugs Animal DrugsAnimal Drugs CosmeticsCosmetics Medical DevicesMedical Devices

Statutes & RegulationsStatutes & Regulations

Primary Statutory authoritiesPrimary Statutory authorities Food, Drug, & Cosmetic Act of 1938Food, Drug, & Cosmetic Act of 1938 Public Health Service Act of 1944Public Health Service Act of 1944

Supplemental authoritySupplemental authority National Environmental Policy Act National Environmental Policy Act

(NEPA) of 1969(NEPA) of 1969

Regulatory responsibilitiesRegulatory responsibilities Title 21 Code of Federal RegulationsTitle 21 Code of Federal Regulations

FDA Implementation of NEPAFDA Implementation of NEPA

Council on Enviromental Quality Council on Enviromental Quality

40 CFR, Part 1500 - 1508 40 CFR, Part 1500 - 1508

1) Categorical Exclusions1) Categorical Exclusions2) Environmental Assessments (EA) 2) Environmental Assessments (EA) 3) Environmental Impact Statements (EIS)3) Environmental Impact Statements (EIS)

FDA Regulations FDA Regulations

NEPA regs -- 21 CFR Part 25NEPA regs -- 21 CFR Part 25

Categorical ExclusionCategorical Exclusion

Classes of actions that individually Classes of actions that individually or cumulatively do not significantly or cumulatively do not significantly affect the quality of the human affect the quality of the human environment are ordinarily environment are ordinarily excluded from the requirement to excluded from the requirement to prepare an EA or EISprepare an EA or EIS

Categorical ExclusionsCategorical Exclusions

Action on original and abbreviated new human Action on original and abbreviated new human and animal drug if there is no increase in use of and animal drug if there is no increase in use of the active moietythe active moiety

Action on a human and animal drug for a Action on a human and animal drug for a naturally occurring substance if no significant naturally occurring substance if no significant change in environmental exposurechange in environmental exposure

Investigation of a new human and animal drugInvestigation of a new human and animal drug

Categorical exclusions con’t Categorical exclusions con’t

Human approvalHuman approval

Predicted WWTP effluent introductory Predicted WWTP effluent introductory concentrations (EIC) of < 1 ppbconcentrations (EIC) of < 1 ppb

• Estimate based on high-end projected sales Estimate based on high-end projected sales and worse-case, end-of-pipe effluent dischargesand worse-case, end-of-pipe effluent discharges

• Based upon retrospective analysis of EAsBased upon retrospective analysis of EAs

Categorical Exclusion con’tCategorical Exclusion con’t

Veterinary approvalsVeterinary approvals

non-food animalsnon-food animals Rx drugs for therapeutic use in Rx drugs for therapeutic use in

terrestrial speciesterrestrial species

Extraordinary circumstances Extraordinary circumstances trump a claim of categorical trump a claim of categorical exclusion.exclusion.

Extraordinary circumstancesExtraordinary circumstances

At the expected level of exposure At the expected level of exposure there is the potential for serious there is the potential for serious harm to the environmentharm to the environment

Adverse effect on species or the Adverse effect on species or the critical habitat of an endangered or critical habitat of an endangered or threatened speciesthreatened species

FDA Actions that may* need EAFDA Actions that may* need EA

Approval of:Approval of: New Drug Application (NDA),New Drug Application (NDA), Biologics License Application (BLA),Biologics License Application (BLA), New Animal Drug Application (NADA)New Animal Drug Application (NADA) Device Pre-Market Approval (PMA) Device Pre-Market Approval (PMA)

Action on:Action on: Investigational New Drug Application (IND)Investigational New Drug Application (IND) Investigational New Animal Drug Investigational New Animal Drug

Application (INAD)Application (INAD) Investigational Device Exemption (IDE)Investigational Device Exemption (IDE)

* Unless Excluded by 21 CFR 25.31* Unless Excluded by 21 CFR 25.31

Agency’s Roles and PrioritiesAgency’s Roles and Priorities

Review claims for categorically Review claims for categorically exclusionexclusion

Review the EA submitted by the Review the EA submitted by the sponsorsponsor

Determine appropriate actionDetermine appropriate action• Finding of No significant Impact (FONSI) Finding of No significant Impact (FONSI) • Environmental Impact Statement (EIS)Environmental Impact Statement (EIS)

FDA EAFDA EA

Concise public documentConcise public document Use and Disposal (not manufacturing)Use and Disposal (not manufacturing) Sufficient evidence and analysis Sufficient evidence and analysis

• FONSI or EISFONSI or EIS Aids an agency's compliance with NEPA Aids an agency's compliance with NEPA Facilitates preparation of EISFacilitates preparation of EIS Includes:Includes:

• need for the actionneed for the action• alternativesalternatives• list of agencies and personslist of agencies and persons

Identifies potential mitigationsIdentifies potential mitigations

EA AvailabilityEA AvailabilityMost actions are categorically excludedMost actions are categorically excluded

published in the published in the Federal RegisterFederal Register

Many actions have EAsMany actions have EAs

published in the published in the Federal RegisterFederal Register public display/available in FDA Document public display/available in FDA Document

Management BranchManagement Branch 113 + EAs for new animal drugs and feed 113 + EAs for new animal drugs and feed

additives on line at:additives on line at:

www.fda.gov/AnimalVeterinary/DevelopmentApprovalwww.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/EnvironmentalAssessments/default.htmProcess/EnvironmentalAssessments/default.htm

FDA ScenariosFDA Scenarios

Risk = Hazard x Exposure

Current and Future Environmental Assessments

Risk = exposure to a Risk = exposure to a chance of loss chance of loss

(or of losing something(or of losing something we value) we value)

EA FocusEA Focus

Ecosystem protection Ecosystem protection

Laboratory studies on invertebrates, Laboratory studies on invertebrates,

fish, plants at different trophic levelsfish, plants at different trophic levels

Measurement endpoints: mortality, Measurement endpoints: mortality,

immobilization, reproduction, immobilization, reproduction,

growth, functional responsesgrowth, functional responses

Biogeochemical cycling (nitrogen, Biogeochemical cycling (nitrogen,

carbon transformation)carbon transformation)

GuidanceGuidanceCDER guidanceCDER guidance

Environmental Assessment of Human Drug and Biologics Environmental Assessment of Human Drug and Biologics Applications (July 1998)Applications (July 1998) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070561.pdfegulatoryInformation/Guidances/ucm070561.pdf

CVM guidanceCVM guidance

Environmental Impact Assessment for Veterinary Medicinal Environmental Impact Assessment for Veterinary Medicinal Products (VMP)Products (VMP)

Phase I (Sept. 1998)Phase I (Sept. 1998)http://www.fda.gov/downloads/AnimalVeterinary/http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052424.pdfUCM052424.pdf

Phase II (January 2006) Phase II (January 2006) http://www.fda.gov/downloads/AnimalVeterinary/GuidanceChttp://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/omplianceEnforcement/GuidanceforIndustry/UCM052500.pdfUCM052500.pdf

Figure 1Tiered Approach to Fate and Effects Testing

Determine environments of Potential ConcernAtmospheric, Aquatic and/or Terrestrial

Investigate DepletionMechanism(s)

MicrobialInhibition Test STOP

rapid

complete

MicrobialInhibition Test

No rapid, completedepletion mechanism

Log Kow > 3.5 CONSIDER initiatingchronic toxicity testing

Tier 3

Log Kow <3.5 or Log Kow > 3.5 with justification

TIER 1Acute Toxicity1 species

LC or EC < 100050 50

MEEC

STOP

Tier 3

No Observed Effectsat MEEC

Observed Effectsat MEEC

TIER 2Acute ToxicityBase SetAquatic &/orTerrestrial

LC or EC > 100050 50

MEEC

LC or EC > 10050 50

MEEC

STOP

Tier 3

No Observed Effectsat MEEC

Observed Effectsat MEEC

LC or EC < 10050 50

MEEC

TIER 3Chronic ToxicityAquatic &/orTerrestrial

LC or EC > 10 & No observed Effects at MEEC50 50MEEC

STOP

LC or EC < 10 or Observed Effects at MEEC50 50

MEEC

Consult CDER

Note: MEEC = EEC or EIC whichever is greater

Veterinary Phase I Veterinary Phase I GuidanceGuidance

harmonized - EU, Japan, US, Australiaharmonized - EU, Japan, US, Australia

legal and exposure criterialegal and exposure criteria

exempt from full risk analysisexempt from full risk analysis

extensive extensive in vivoin vivo metabolism metabolism

aquaticaquatic introduction concentrationintroduction concentration < 1 < 1 g/Lg/L

terrestrial introduction concentrationterrestrial introduction concentration < 100 < 100 g/Kgg/Kg

Veterinary Phase IIVeterinary Phase II Guidance Guidance

Risk-quotient method = PEC : PNEC.Risk-quotient method = PEC : PNEC.

Predicted environmental concentration Predicted environmental concentration (PEC) (PEC)

Predicted no effect concentration (PNEC) Predicted no effect concentration (PNEC)

Assessment Factor (AF)Assessment Factor (AF)

Three Tiers (A,B,C) as neededThree Tiers (A,B,C) as needed

Base Set Data RequirementsBase Set Data Requirements

Physical-chemical studies

- Water Solubility - Dissociation Constant - UV-Visible Absorption Spectrum - Melting Temperature - Vapour Pressure - Octanol/Water Partition

Environmental fate studies

- Soil adsorption/desorption- Degradation in soil - Degradation in aquatic systems- Photolysis (optional)- hydrolysis (optional)

Aquatic effect studies

- Algae- Daphnia- Fish

Terrestrial effect studies - Micro-organisms - Terrestrial plants- Earthworm

Surface water Surface water EndpointEndpoint AFAF• algae (96 h)algae (96 h) EC50 EC50 100 100 • invertebrate (48 h)invertebrate (48 h) EC50 EC50 10001000• fish (96 h)fish (96 h) LC50 LC50 10001000

Veterinary TIER A AssessmentVeterinary TIER A Assessment

SoilSoil• earthworm (chronic)earthworm (chronic) NOECNOEC 10 10 • higher plants (3 species)higher plants (3 species) EC50EC50100100• micro-organisms (28 days)micro-organisms (28 days) < 25% of control< 25% of control

Dung (pasture animals)Dung (pasture animals)• dung fly dung fly EC50EC50100 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 • micro-organisms (100 days)micro-organisms (100 days) < 25% of < 25% of controlcontrol

BioaccumulationBioaccumulation• BCF > 1000 l/kg BCF > 1000 l/kg investigate secondary investigate secondary poisoning poisoning

Veterinary TIER B AssessmentVeterinary TIER B Assessment

Veterinary TIER C AssessmentVeterinary TIER C Assessment

Refined Risk AnalysisRefined Risk Analysis• Specialized environmental fate modelingSpecialized environmental fate modeling• Probabilistic exposure analysesProbabilistic exposure analyses

Specialized Laboratory and/or Field TestingSpecialized Laboratory and/or Field Testing• Pulsed exposure studiesPulsed exposure studies• Microcosm and mesocosm studiesMicrocosm and mesocosm studies• In-stream studiesIn-stream studies

Risk ManagementRisk Management• Use restrictionsUse restrictions• Mandatory treatment requirementsMandatory treatment requirements• Effluent discharge limitsEffluent discharge limits

Potential Risk Mitigation OptionsPotential Risk Mitigation Options

Use limitations on drug label (e.g., Use limitations on drug label (e.g., limit frequency or site of use; specify limit frequency or site of use; specify minimum dilution prior to discharge)minimum dilution prior to discharge)

Effluent treatment stipulated on the Effluent treatment stipulated on the drug product label (e.g., settling drug product label (e.g., settling ponds, activated carbon)ponds, activated carbon)

““No discharge” to surface watersNo discharge” to surface waters Water quality benchmark Water quality benchmark

development and reportingdevelopment and reporting

Possible Data for Application to Possible Data for Application to Human ExposureHuman Exposure

Human Drug Development Human Drug Development Nonclinical Data CollectedNonclinical Data Collected

Safety PharmacologySafety Pharmacology

Toxicokinetics and PharmacokineticsToxicokinetics and Pharmacokinetics Repeated Dose ToxicityRepeated Dose Toxicity

Genotoxicity (Genotoxicity (in vitroin vitro; ; in vivoin vivo)) CarcinogenicityCarcinogenicity Reproductive and Developmental ToxicologyReproductive and Developmental Toxicology ImmunotoxicityImmunotoxicity Other Studies: Other Studies:

• Phototoxicity, antigenicity, juvenile animal Phototoxicity, antigenicity, juvenile animal toxicity, mechanistic studies, studies on toxicity, mechanistic studies, studies on metabolites and impuritiesmetabolites and impurities

Guidance Document: ICHM3(R2): Nonclinical Safety Studies for the Guidance Document: ICHM3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Conduct of Human Clinical Trials and Marketing Authorization for PharmaceuticalsPharmaceuticals

28

Nonclinical StudiesNonclinical Studies

• Characterize potential toxic effects prior to Characterize potential toxic effects prior to clinical studies:clinical studies:

Pediatric PatientsPediatric Patients Peri- and Postnatal PopulationPeri- and Postnatal Population Pregnant Women/Women of Childbearing AgePregnant Women/Women of Childbearing Age

• Estimate the maximum recommended Estimate the maximum recommended starting dose (MRSD) and dose range for starting dose (MRSD) and dose range for first-in-human clinical trials.first-in-human clinical trials.

• Identify parameters for clinical monitoring Identify parameters for clinical monitoring of potential adverse effects.of potential adverse effects.

29

Studies to Evaluate the Safety of Residues of Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human FoodVeterinary Drugs in Human Food

Repeat-Dose (90-Day) Toxicity TestingRepeat-Dose (90-Day) Toxicity Testing

Repeat-Dose (Chronic) Toxicity TestingRepeat-Dose (Chronic) Toxicity Testing

Developmental Toxicity TestingDevelopmental Toxicity Testing

Reproductive Toxicity TestingReproductive Toxicity Testing

Microbiological AnalysisMicrobiological Analysis

Genotoxicity TestingGenotoxicity Testing

Carcinogenicity TestingCarcinogenicity Testing

Veterinary Food Safety Veterinary Food Safety Acceptable Daily Intake (ADI) Acceptable Daily Intake (ADI)

Consider all available oral toxicity dataConsider all available oral toxicity data Select Select most appropriate NOAELmost appropriate NOAEL from from

the most appropriate studythe most appropriate study Benchmark Dose Lower BoundBenchmark Dose Lower Bound – BMDL – BMDL

also also a a possiblepossible point of departure point of departure Select appropriate safety factorSelect appropriate safety factor

Safe Disposal of MedicinesSafe Disposal of Medicines

SummarySummary

FDA continues to work with its federal partners - EPA, USGS, CDC - FDA continues to work with its federal partners - EPA, USGS, CDC - and the regulated industry to address the ecological and human and the regulated industry to address the ecological and human health implications of pharmaceutical residues in the environmenthealth implications of pharmaceutical residues in the environment

FDA has human preclinical and clinical data that should be useful FDA has human preclinical and clinical data that should be useful for determining safety of pharmaceuticals in waterfor determining safety of pharmaceuticals in water

The FDA has extensive risk assessment experience in setting safe The FDA has extensive risk assessment experience in setting safe concentrations for ‘microconstituents’ in foods and beveragesconcentrations for ‘microconstituents’ in foods and beverages

The ADI approach is internationally recognized and can be used in The ADI approach is internationally recognized and can be used in risk assessments for pharmaceuticals in drinking waterrisk assessments for pharmaceuticals in drinking water

For a limited number of high risk products, product labeling For a limited number of high risk products, product labeling includes specific drug disposal methods designed to improve includes specific drug disposal methods designed to improve risk/benefit balancerisk/benefit balance

FDA promotes the safe disposal methods as described in the FDA promotes the safe disposal methods as described in the Federal Drug Disposal GuidelinesFederal Drug Disposal Guidelines

Thank YouThank You

Charles E. Eirkson IIICharles E. Eirkson IIIFDA, CVM , Environmental Safety TeamFDA, CVM , Environmental Safety Team240-276-8173240-276-8173charles.eirkson@fda.hhs.govcharles.eirkson@fda.hhs.gov

Acknowledge:Acknowledge:

Suzanne Fitzpatrick, Ph.D. Suzanne Fitzpatrick, Ph.D. FDA, Office of the CommissionerFDA, Office of the Commissioner

Ranaan Bloom, Ph.D. andRanaan Bloom, Ph.D. and Emily A. McVey, Ph.D.Emily A. McVey, Ph.D.FDA, CDER, FDA, CDER, Office of Pharmaceutical ScienceOffice of Pharmaceutical Science