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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
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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.
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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@[email protected]
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