Environmental AssessmentsHuman and Animal Drugs

Nancy SagerCenter for Drug Evaluation and Research

Food and Drug Administration

Statutory Framework

• Federal Food, Drug, and Cosmetic Act (FFDCA)

• National Environmental Policy Act (NEPA)– FDA regulations implementing NEPA (21 CFR Part 25) revised in 1997

• Human and animal drugs are exempt from EPA’s Toxic Substances Control Act (TSCA)

NEPA Process

• Categorical Exclusion (CE)– Extraordinary circumstances provision

• Environmental Assessment (EA)

• Environmental Impact Statement (EIS)

Categorical Exclusion Examples

• Investigational new (animal) drug applications (IND/INAD)

• Approval of natural substances when approval does not alter significantly the distribution of the substance, its metabolites or degradation products in the environment

Categorical ExclusionExamples

• Approval of a drug when the approval will not increase the use of the drug

• Withdrawal of approval of a drug

Categorical ExclusionExamples

• Human drugs: Approval of a drug when the concentration of drug expected to enter the aquatic environment (EIC) is less than 1 ppb

• Animal drugs: Approval of drugs intended for use in nonfood animals

Environmental Impact Statement

There are no categories of FDA actions that routinely significantly affect the quality of the human environment and that therefore ordinarily require the preparation of an EIS

– FDA has prepared only one EIS directly related to human/animal drug use (CFCs, 1978)

Environmental Assessment Issues Human Drugs

• EIC 1 ppb (ecotoxicity)

• Use of wild plants/animals (harvesting)

– extraordinary circumstances provision

Environmental Assessment Issues Animal Drugs

Ecotoxicity

• Feedlots/Poultry Houses/Swine Operations

– Confined animal feed operations (CAFOs)

• Aquaculture

• Pastured Animals

Ecotoxicity Evaluation

• Fate and Effects

• Follows standard approaches/test methods (OECD/EPA/VICH)

Fate: Physical/Chemical Characterization

• water solubility

• dissociation constant

• octanol/water partition coefficient

• vapor pressure

• sorption/desorption properties

Fate: Depletion Mechanisms

• photolysis

• hydrolysis

• biodegradation

Effects

• Tiered approach: Generally, acute toxicity testing then chronic if data indicate

• Typical number of effects studies

– Human drugs: 2-4

– Animal drugs: 4-5

Differences: Environmental Compartment

• EAs for human drugs normally focus on the aquatic environment

• EAs for animal drugs may evaluate fate and effects in the aquatic and terrestrial environments

Differences: Cut-offs

• Human drugs are categorically excluded (CE) if the EIC in the aquatic environment is less than 1 ppb (absent extraordinary circumstances)

• Animal drugs do not have a CE based on an EIC. However, less information can be provided if EICs are:

– less than 1 ppb released from aquaculture facility

– less than 100 ppb in soil

1 ppb (Aquatic)

• Data on human drugs routinely demonstrated no effects on relevant standard test organisms at concentration less than 1 ppb

• Approximately 90% of the toxicity results were 1 ppm or greater; 10% were between 1 ppb and 1 ppm)

6 4 51 3 4 0 2 0 1

95

32

12 9 7 610

26

20

53

0

20

40

60

80

100

120

0.001 0.1 0.2 0.03 0.4 0.5 0.6 0.7 0.8 0.9 1 100 200 300 400 500 600 700 800 900 1000

Toxicity test result (ppm)

Retrospective Review of Ecotoxicity DataCenter for Drug Evaluation and Research (CDER)

100 ppb (Soil)

100 ppb is below the level shown to have effects in ecotoxicity studies conducted on earthworms, microbes, and plants for animal drugs in the U.S

Sources of Information

• 21 CFR Part 25 (FDA regulations implementing NEPA)

• 40 CFR Parts 1500-1508 (NEPA regulations)

• Retrospective Review of Ecotoxicity Data Submitted in Environmental Assessments available under FOI from Public Docket No. 96N-0057

Sources of Information

• FDA’s guidance on Environmental Assessment of Human Drug and Biologics Applications (July 1998) available at http://www.fda.gov/cder/ guidance/index.htm

• FDA’s guidance on Environmental Impact Assessments (EIAs) for Veterinary Medicinal Products (VMPs); VICH GL6 (March 7, 2001) available at http://www.fda.gov/cvm/guidance/guide89.doc

Sources of Information

• After approval of the application, Environmental Assessments are available under the Freedom of Information Act