OVERVIEW of the ANIMAL DRUG APPROVAL PROCESS

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• OVERVIEW of theANIMAL DRUG APPROVAL PROCESS

Susan Storey, DVM FDA Center for Veterinary
Medicine Division of Therapeutic Drugs for Food
Animals Office of New Animal Drug
Evaluation Center for Veterinary Medicine
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FDA-CVMs Mission
The Center for Veterinary Medicine is a consumer
protection organization. We foster public and
animal health by approving safe and effective
products for animals and by enforcing other
applicable provisions of the Federal Food, Drug
and Cosmetic Act and other authorities.
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PRESENTATION TOPICS

• Background Information
• Investigational New Animal Drug (INAD) Process
• New Animal Drug Application (NADA) Technical
  Sections
• Administrative New Animal Drug Application

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• Law Federal Food, Drug and Cosmetic Act
  (FFDCA)
• Regulations - Code of Federal Regulations
• Policies and Guidelines/Guidances

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FFDCA

• Section 201 - Definition of a new animal drug
• articles intended for use in the diagnosis,
  cure, mitigation, treatment or prevention of
  disease in man or other animals and articles
  intended to affect the structure or any function
  of the body of man or any animals
• Section 512 - New Animal Drug Applications
• Section 512 (j) - Investigational New Animal Drug
  (INAD) Exemption

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Code of Federal Regulations

• Part 25 - Environmental Impact Considerations
• Part 58 - Good Laboratory Practice
• Part 201 - Labeling
• Part 511 - New Animal Drugs for Investigational
  Use
• Part 514 - New Animal Drug Applications
• Part 520-529 Approved Drugs/Dosage Forms
• Part 530 - Extra Label Drug Use in Animals
• Part 556 Tolerances for Residues
• Part 558 - Medicated Feeds

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What does an approved NADA mean?

• The product is safe and effective for its
  intended use.
• The methods, facilities and controls used for the
  manufacturing, processing and packaging of the
  drug are adequate to preserve its identity,
  strength, quality and purity.

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NADA

• NADA is a systematic approach to document
  evidence that drug products are safe and
  effective
• The traditional approval process is one
  submission with all the information for each of
  the technical sections
• Approved drug product consists of the drug, the
  packaging and the labeling

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NADA

• CVM describes the documented evidence in a
  Freedom of Information Summary, an Environmental
  Assessment, and in drug labeling.
• The approval is codified in the CFR via a Federal
  Register announcement.
• All of the above are accessible by the public
• Anyone can sponsor an NADA - U. S. Resident or
• a Foreign Firm
  with a U. S. Agent
• Usually pharmaceutical firms (monetary resources)

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Phased Review
Done under the regulations for Investigational
New Animal Drugs (INAD)

• Presubmission conferences
• Simultaneous work under each technical section
• Protocol reviews
• Study reviews
• Issue technical section complete letters

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INAD

• Sponsors propose the drug product and label
  indications
• Sponsors conduct the necessary research to
  support an approval
• Research conducted under an INAD exemption
• Legal requirements are described in 21 CFR Part
  511
• Allows shipment of the investigational drug via
  interstate commerce to investigators
• Allows authorization for the use of edible
  tissues from animals treated with the
  investigational drug

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INAD

• Research conducted under an INAD exemption (cont)
• Allows for the conduct of studies to collect data
  and document safety and effectiveness of the
  investigational drug
• Certain requirements for administering an INAD
  including labeling requirements, collection of
  data, maintenance of records, accountability of
  drug shipments, receipt and use, accountability
  of treated animals and their disposition,
  qualifications of investigators

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NADA Technical Sections

• Effectiveness
• Target Animal Safety
• Human Food Safety
• Environmental Impact
• Chemistry, Manufacturing and Controls
• Labeling
• Freedom of Information Summary
• All Other Information

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Demonstration Of Effectiveness

• one or more adequate and well-controlled studies

• a field investigation
• a study in a target species
• a study in laboratory animals
• a bioequivalence study
• an in vitro study

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Substantial Evidence 21 CFR 514.4
on the basis of which it could fairly and
reasonably be concluded by experts qualified by
scientific training and experience to evaluate
the effectiveness of the drug involved, on the
basis of which it could fairly and reasonably be
concluded by such experts that the drug will have
the effect it purports or is represented to have
under the conditions of use prescribed,
recommended or suggested in the labeling or
proposed labeling thereof.
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Demonstration Of Safety

• Adequate tests by all methods reasonably
  applicable show that the drug is safe for use
  under the conditions prescribed, recommended, or
  suggested in the proposed labeling.

• Target Animal Safety
• Human Food Safety
• User Safety
• Environmental Safety

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Target Animal Safety

• Tolerance study
• Margin of safety study
• Injection site irritation (injectables)
• Reproductive safety study
• Animal class safety study (e.g., young,
  geriatric)
• Special cases (specific breeds)

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Human Food Safety

• Meat, milk and eggs
• Drug residues-acute toxic response
• chronic exposure toxicity
• Antimicrobial resistance
• User Safety

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Human Food Safety
Sections

• Toxicology
• Residue Chemistry
• Antimicrobial Resistance

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Basic Toxicology Package

• Genetic toxicity tests
• 90-day feeding studies
• Two-generation reproduction study
• with a teratology component

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Additional Toxicology Studies

• Chronic bioassays for carcinogenicity
• One-year feeding studies
• Teratology in a second species
• Other specialized testing
• neurotoxicity
• immunotoxicity
• hormonal activity
• toxicity following in utero
  exposure

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Food Safety Decisions

• No Observable Effect Level (NOEL)
• Safety Factor

Acceptable Daily Intake NOEL
Safety Factor

Safe Concentration ADI X 60 kg
consumption factor
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Consumption Factors
Edible Product Muscle Liver Kidney Fat Milk Eggs
Grams Consumed/day 300 100 50 50
1500 mL 100
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Residue Chemistry

• Residue

Any compound present in the edible tissues of the
target animal that results from the use of the
compound, including the compound itself, its
metabolites, and any substance formed in or on
food as a result of the use of the compound.
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Residue Chemistry (cont)

• Total Residue and Metabolism Study
• Determines the marker residue
• Determines the target tissue

• Development and validation of methods to measure
  drug residues in edible tissues.

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Establishing a Withdrawal Time

• Objective Run a residue depletion study under
  field conditions to determine how long it takes
  marker residues to deplete to below the
  tolerance.

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100.0
99th Percentile with 95 Confidence
10.0
Drug Concentration
Actual Residue Values
Tolerance
0.1
1
2
3
4
5
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Withdrawal Time (days)
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Comparative metabolism study in the toxicological
species

• A model for human exposure

Development and validation of methods to measure
drug residues in edible tissues

• Determinative
• Confirmatory
• Screening

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Human Food Safety

• The withdrawal time is placed on the approved
  drugs label.
• The tolerance is published in 21 CFR 556.

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Human Food Safety Considerations for
Antimicrobial Resistance
Guidance for Industry Number 152 Evaluating the
Safety of Antimicrobial New Animal Drugs
with Regard to Their Microbiological Effects on
Bacteria Of Human Health Concern
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User Safety

• Potential hazards associated with
• manufacturing
• direct - occupational exposure at site
• indirect - manufacturing emissions
• administration to animals
• air, water and solid wastes contaminated
• via use and disposal of the drug

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Environmental Impact
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Chemistry, Manufacturing and Controls
The Division of Manufacturing Technologies
determines whether an animal drug will have and
maintain the necessary quality, strength, purity,
and identity. Quality cannot be inspected or
tested into a finished product. Each step of the
manufacturing process must be controlled to
provide assurance that the finished product will
be acceptable.
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Quality means

• The drug product has attributes that are the same
  or similar to the product demonstrated to be safe
  and effective in the target animal safety and
  efficacy studies and by analogy, that any copies
  of these products possess these same attributes
• The drug product does not contain microbiological
  or other extraneous contaminants

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Quality means (contd)

• The drug product does not contain impurities,
  degradants, manufacturing by-products or solvents
  in excess of levels demonstrated to be safe
• The drug product is formulated and manufactured
  by a process that consistently provides a product
  meeting predetermined quality attributes
• The drug product will maintain all necessary
  attributes throughout its marketed life

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Sterilization Process Validation

• Guidance for Industry No. 48 Submission
  Documentation for Sterilization Process
  Validation in Applications for Human and
  Veterinary Products

Analytical Controls
In-process and finished product
specifications Specifications include the tests,
methods, and acceptance criteria
Container/Closure
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Stability

• Stability studies are conducted on the drug
  product in the marketed container.
• Pre-approval stability studies provides evidence
  of potential environmental effects on the
  identity, strength, quality, purity and potency
  of new animal drug and medicated feed products.
• Stability studies are used to establish storage
  conditions and expiration dates

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Stability (contd)

• Post-approval stability studies provide assurance
  that the manufacturing of the new animal drug
  product provided batches that conform to the
  established specifications throughout its
  expiration dating period

Pre-Approval Inspection (PAI)
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LabelingFreedom of Information (FOI)
SummaryAll Other Information
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Administrative NADA Sponsors Submission

• New Animal Drug Application - Form 356V
• Technical Section Complete Letters
• Environmental Assessment
• Freedom of Information Summary
• Labeling

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OVERVIEW of theANIMAL DRUG APPROVAL PROCESS

• QUESTIONS?