CVM GFI #229 Evaluating the Effectiveness of New Animal Drugs for the Reduction of Pathogenic Shiga Toxin-Producing E. coli in Cattle

Description

This guidance provides recommendations to industry relating to study design and describes criteria that the Center for Veterinary Medicine (CVM) thinks are the most appropriate for the evaluation of the effectiveness of new animal drugs that are intended to reduce pathogenic Shiga toxin-producingEscherichia coli(STEC) in cattle.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

1

New Animal Drugs

Products subject to clinical investigation guidance.

Stakeholders

2

Sponsor

Entity responsible for submitting applications under section 524B

Clinical Investigator

Veterinarian responsible for selecting anesthetic regimens and conducting field studies

Regulatory Context

Regulatory Activities

1

Combination New Animal Drug Application

Submission for approval of two or more previously approved drugs

Document Types

3

Protocol

Defines the standard of veterinary practice and limits for anesthetic regimens

Final Study Report

Data presentation requirements; Comprehensive document providing evaluation of study results

Final report

required as part of the premarket submission

Attributes

5

Substantial Evidence of Effectiveness

The legal standard for proving a drug works; Legal standard required for drug approval

Permissible Analytical Variation

Relates to a single application of the assay method

Pre-slaughter withdrawal period

Time period used to demonstrate drug effectiveness

Fecal pen prevalence

Primary response variable for effectiveness evaluation

Fecal pen quantity

Primary response variable for concentration reduction indication

Technical Details

Substances

2

Shiga Toxin-Producing E. coli

Pathogenic bacteria targeted for reduction in cattle

E. coli O157:H7

Pathogen that triggers corrective action if detected in sprouts or irrigation water.; primary consideration given to reduction of Salmonella spp. and E. coli O157:H7; Pathogen tested for in spent sprout irrigation water.; Pathogen associated with radish and alfalfa sprouts

Testing Methods

7

Drug Assays

Assessment of drug concentrations in experimental diets; Used to verify drug concentration in feed or water

Multi-location field study

Recommended study design to establish effectiveness

Challenge model studies

Acceptable for demonstrating effectiveness for non-O157 STEC serotypes

Proximate and Chemical Analyses

Conducted on basal diet samples to ensure proper nutrient densities

Culture technique

Appropriate and sensitive method to measure prevalence of E. coli O157:H7

Confirmatory genetic methods

Used to confirm suspect colonies of E. coli O157:H7

Immunologic methods

Used to confirm suspect colonies of E. coli O157:H7

Processes

1

Fecal grab samples

Method of collecting samples from the rectum of live cattle

Identified Hazards

Hazards

2

Cross-contamination

Risk associated with construction, traffic flow, and shared equipment.; Risk from raw food to RTE food or from insanitary objects; Personnel handling RTE foods touch contaminated surfaces

Induced Resistance

Potential for the drug to engender resistance in E. coli O157:H7

Standards & References

External Standards

1

National Research Council

Source for nutrient recommendations for food-producing animals

Specifications

2

Colony-forming units (CFU) per gram

Unit of measurement for fecal concentration of the pathogen

α=0.05

Statistical significance level for effectiveness criteria

ICH References (1)

VICH GL9

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

Related CFR Sections (3)

21CFR514.117§ 514.117 Adequate and well-controlled studies.
(a) Purpose. The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. OnRead full regulation →
21CFR511.1§ 511.1 New animal drugs for investigational use exempt from section 512(a) of the Federal Food, Drug, and Cosmetic Act.
(a) New animal drugs for tests in vitro and in laboratory research animals.Read full regulation →
21CFR558.4§ 558.4 Requirement of a medicated feed mill license.
(a) A feed manufacturing facility must possess a medicated feed mill license in order to manufacture a Type B or Type C medicated feed from a Category II, Type A medicated article.Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to evaluate raw materials for mycotoxins

3

Super-potent concentration of monensin

3

Failure to sufficiently assess the probability that a hazard will occur

2

Failure to implement a written food safety plan

2

Failure to sufficiently assess the probability that a hazard will occur in the absence of preventive controls

1

Failure to conduct a hazard analysis to identify and evaluate known or reasonably foreseeable hazards

1

Failure to report a reportable food to the RFR within twenty-four hours

1

Misbranded animal food

1

Failure to properly identify drugs in the mixing areas

1

Adulterated animal food

1