CVM GFI #49 Evaluating Target Animal Safety and Effectiveness of Antibacterial New Animal Drugs for Bovine Mastitis

Description

This guidance provides target animal safety and effectiveness study design considerations and recommendations for sponsors of bovine mastitis drug products with antibacterial activity that are administered by intramammary infusion. This guidance replaces the original guidance for industry (GFI) #49, issued in April 1996, entitled “Target Animal Safety and Drug Effectiveness Studies for Anti-Microbial Bovine Mastitis Products (Lactating and Non-Lactating Cow Products).” Sponsors may propose alternatives, with appropriate justification, to the study designs described in this guidance. CVM encourages sponsors to meet with us early in their investigational product development timeline to propose and agree on the appropriate study designs for their specific project.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

4

Antibacterial New Animal Drugs

Subject of the guidance for bovine mastitis; Evaluating Target Animal Safety and Effectiveness of Antibacterial New Animal Drugs for Bovine Mastitis.; Subject of the safety and effectiveness evaluation; Evaluating safety and effectiveness for bovine mastitis.

Lactating Cow Products

Drugs administered to dairy cows in active lactation; Data to demonstrate mammary gland safety for a lactating cow product typically should be collected by conducting a safety study.; Effectiveness – Lactating Cow Products

Dry Cow Products

Drugs administered to dairy cows at or after dry-off; Safety data generated in lactating dairy cows typically is not sufficient to demonstrate mammary gland safety for dry dairy cow products.; Products for mastitis in dry dairy cows should be evaluated for treatment and prevention.

Dry Cow Product

demonstrate mammary gland safety for a dry cow product

Stakeholders

2

Sponsor

Entity responsible for submitting applications under section 524B

Masked Veterinarian

Role responsible for performing physical examinations; Performs physical examinations at enrollment and study end.; Should perform a physical examination at enrollment and end of study.

Regulatory Context

Regulatory Activities

3

Effectiveness Study

sponsor may collect the safety data as part of an effectiveness study

Labeled indication

Pathogens included in the indication based on study results.

Safety Study

A sponsor should conduct a safety study

Document Types

2

Protocol

Defines the standard of veterinary practice and limits for anesthetic regimens

Proposed Labeling

Required information to be submitted as part of the AFIC process.

Attributes

5

Systemic absorption

Level at which ingredients enter the bloodstream

Bacterial Cure

Negative culture results in post-treatment milk samples; Defined as negative culture results in both post-treatment milk samples.; Defined as a quarter with negative results in both post-treatment milk samples.

Clinical Cure

Normal milk quality and normal quarter health at post-treatment points

Withdrawal Time

Unless a sponsor demonstrates the absence of any visible lesions... a trim loss statement may be included on the labeling.

QSCC

Have a QSCC less than 200,000 cells/mL

Technical Details

Substances

9

Active pharmaceutical ingredient

Substance intended for incorporation into a finished drug product

Streptococcus uberis

Pathogen acceptable for inclusion in the labeled indication.

Streptococcus dysgalactiae

Pathogen acceptable for inclusion in the labeled indication.

Klebsiella spp.

Target environmental bacterial pathogen.; Coliform pathogen acceptable for inclusion in the labeled indication.

Escherichia coli

species that should not be used in dietary supplements

Streptococcus agalactiae

Pathogen acceptable for inclusion in the labeled indication; Target contagious bacterial pathogen.; Pathogen acceptable for inclusion in the labeled indication.

Staphylococcus aureus

bacteria that causes TSS

Excipients

Differences in excipients may affect product stability

Antibacterial New Animal Drugs

Evaluating Target Animal Safety and Effectiveness

Testing Methods

6

Quantitative Somatic Cell Count

Have a recent (within 30 days) quantitative somatic cell count (QSCC) less than 200,000 cells/mL.

Statistical Analysis

plan for evaluating equivalent or improved performance

Mass Spectrometry

Used for comparing separated molecules

Bacterial Culture

Bacterial culture results should be summarized for each treatment group.; Method used to identify pathogens in milk samples; Milk samples collected for identification of isolates.; Used to identify isolates from milk samples.

Bacterial Milk Cultures

evaluate treatment success in lactating dairy cows with positive bacterial milk cultures

Somatic Cell Count

SCC samples should be collected and evaluated

Processes

5

Systemic margin of safety study

Study to evaluate safety when drugs enter systemic circulation

Mammary gland safety study

Study required depending on the dosage form

Reproductive safety study

Study to address safety in breeding/pregnant dairy cows

Intramammary Infusion

For bovine mastitis products administered by intramammary infusion, sponsors should address the safety to the mammary gland.

Injection

For bovine mastitis products administered by injection, sponsors should address the safety to the target animal.

Clinical Concepts

5

Bovine Mastitis

Target disease for the antibacterial drugs; Evaluating Target Animal Safety and Effectiveness of Antibacterial New Animal Drugs for Bovine Mastitis.; Target disease for the antibacterial new animal drugs.; The primary disease state being evaluated in the guidance.

Clinical Mastitis

Condition in lactating dairy cows requiring effectiveness studies; Have no recent (within 30 days) history of clinical mastitis.; treatment of clinical mastitis; Condition characterized by abnormal milk or quarter health; Visible signs of mastitis used as exclusion criteria.; Condition leading to removal from the study if developed in enrolled quarters.

Subclinical Mastitis

Condition in lactating or dry cows requiring effectiveness studies; treatment of subclinical mastitis; Condition with positive bacterial cultures but no clinical signs; Assessment of treatment success for this condition.; Assessment of treatment success in each enrolled quarter.

Adverse drug reactions

Information to be included in labeling for the neonate.

Udder Irritation

sponsors should address the safety to the mammary gland (udder irritation) of the target animal.

Standards & References

External Standards

1

National Mastitis Council

Source of methods for collecting milk samples to prevent contamination; Methods for collecting milk samples to prevent contamination.; Provides methods for milk sample collection to prevent contamination.

ICH References (2)

VICH GL43

Study design considerations for injection site safety studies are provided in GFI #185 (VICH GL43).; Harmonized guideline for Target Animal Safety.

VICH GL9

Good Clinical Practice guideline referenced for study conduct; Harmonized guideline for Good Laboratory Practice.

Related CFR Sections (1)

21CFR514.1§ 514.1 Applications.
(a) Applications to be filed under section 512(b) of the act shall be submitted in the form and contain the information described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign language, an accurate and complete ERead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure of the study director to assure protocol compliance and accurate data recording

1

Failure of the study director to assure experimental data are accurately recorded and verified

1

Failure to properly identify specimens

1

Failure to assure experimental data were accurately recorded and verified

1

Failure to authorize and document deviations from standard operating procedures

1

QAU failed to assure reported results accurately reflect raw data

1

Failure to maintain a Quality Assurance Unit

1

Study director failed to assure protocol compliance and data accuracy

1

Fabrication of animal weight data

1

Failure to establish procedures for handling test and control articles

1