Guidance for Industry: Effectiveness of Anthelmintics: Specific Recommendations for Poultry-Gallus Gallus - VICH GL21 - Final Guidance

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

Guidance for Industry

Effectiveness of Anthelmintics:
Specific Recommendations
for Poultry-GALLUS GALLUS
VICH GL21

FINAL GUIDANCE

This final guidance is intended to standardize and simplify methods used in the evaluation of new anthelmintics submitted for approval to the European Union, Japan, and the United States.

Comments and suggestions regarding the document should be submitted to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the Docket No. 00D-1629. 

For questions regarding this document, contact Thomas Letonja, Center for Veterinary Medicine, (HFV-135), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7576, e-mail:  tletonja@cvm.fda.gov.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
June 19, 2002

VICH GL21 (ANTHELMINTICS: POULTRY – GALLUS GALLUS)
June 2002
For implementation at Step 7

EFFECTIVENESS OF ANTHELMINTICS:
SPECIFIC RECOMMENDATIONS FOR
POULTRY - GALLUS GALLUS

Recommended for Implementation
on June 2001
by the VICH Steering Committee

THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP AND WAS SUBJECT TO CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7 OF THE PROCESS THE FINAL DRAFT IS RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES OF THE EUROPEAN UNION, JAPAN AND USA.

EFFECTIVENESS OF ANTHELMINTICS:
SPECIFIC RECOMMENDATIONS FOR POULTRY - GALLUS GALLUS

Endorsed by the VICH Steering Committee at Step 7 of the
VICH process at its meeting from June 2001

This guidance represents the agency's current thinking on the subject matter and does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  An alternative method may be used as long as it satisfies the requirements of the applicable statutes and regulations.

Introduction
The present guidance for poultry (Gallus gallus) was developed by the Working Group established by the Veterinary International Cooperation on Harmonization (VICH), Anthelmintic Guidances. It should be read in conjunction with the VICH Effectiveness of Anthelmintic: General Recommendations (EAGR) which should be referred to for discussion of broad aspects for providing pivotal data to demonstrate product anthelmintic effectiveness. The present document is structured similarly to the EAGR with the aim of simplicity for readers comparing both documents.

This guidance for poultry is part of this EAGR and the aim is (1) to be more specific for certain specific issues for poultry not discussed in the EAGR; (2) to highlight differences with the EAGR on effectiveness data recommendations and (3) to give explanations for disparities with the EAGR. Although technical procedures to be followed are not the aim of this guidance, some details are given as until now the pertinent procedures have not been described elsewhere.

A. General Elements

1- The Evaluation of Effectiveness Data
Only controlled tests based on parasite counts of adults/larvae should be acceptable both for the dose determination and dose confirmation studies, since critical tests generally are not considered to be reliable for chickens. Egg counts with identification of the genus should be the preferred method to evaluate the effectiveness in field studies. Adequate parasite infection should be defined in the protocol according to regional prevalence or historic and/or statistical data.

2- Use of Natural or Induced Infections
Dose determination studies generally should be conducted using induced infections with either laboratory or recent field isolates.

Dose confirmation studies could be conducted using naturally infected birds which can have superimposed induced infections. This procedure should allow a wide range of parasites to be present in the experimental birds. Also, induced infections in one of the studies should be acceptable. Studies for larval stages should be conducted with induced infections only.

The history of the parasites used in the induced infection studies should be included in the final report.

3- Number of Infective Forms Recommended for Induced Infections
Table 1 indicates the number of eggs/cysticercoids recommended to be used and will depend on the isolate that is used. The final number of eggs/cysticercoids used in the infection should be included in the final report.

Table 1. Range of infective stages recommended to produce adequate infections in chickens for anthelmintic evaluation.

Parasites	Range
Ascaridia galli	200-500
Capillaria obsignata	100-300
Heterakis gallinarum	200-300
Raillietina cesticillus Syngamus trachea	50-100  200 - 600

Some factors to consider for induced infections in chickens are:

a) Young birds should be used in the studies;

b) To maximize the establishment of adequate infections it is recommended to use low numbers of infective stages;

c) Stress (e.g., poor diets) is not recommended to generate helminth infections;

d) Housing conditions should not allow accidental infections.

4- Recommendations for the Calculation of Effectiveness

4.1 Criteria to grant a claim
To be granted a claim, the following pivotal data should be included:

a) Two dose confirmation studies conducted with a minimum of six adequately infected birds in each of the non-medicated group and the treated group;

b) The differences in parasite counts between treated and control birds should be statistically significant (p<0.05);

c) Effectiveness should be 90% or higher calculated using transformed (geometric means) data of worm counts;

d) The infection of the birds in the study should be deemed adequate based on historical, parasitological and/or statistical criteria.

4.2 Number of Animals (Dose Determination and Dose Confirmation Trials)
The minimum number of birds used per experimental group is a crucial point. Although the number of birds will depend on the ability to process the data according to the adequate statistical analysis, it has been recommended, to achieve harmonization, that the inclusion of at least six birds in each experimental group is a minimum.

4.3 Adequacy of Infection
Concerning the minimum adequate number of helminths, the decision should be made when the final report is submitted based on statistical and historical data, literature review, or expert testimony. The range of chicken helminths (adults) considered adequate to grant a claim will vary according to the species. Generally a mean number of 20 adult A. galli is considered to be adequate. Lower counts may be expected with H. gallinarum, C. obsignata and R. cesticellus.  Necropsies should be conducted within 10 days of treatment.

4.4 Label Claims
For adult claims, as a general rule, the treatment should not be administered earlier than 28 days after infection. It is recommended to include at least six sentinel birds for helminth characterization and quantification before treatment is initiated. For L4 claims, treatments should be given, as a general rule, seven days after infection, except for A. galli and H. gallinarum which should be 16 days after infection.

5 - Treatment Procedures
The method of administration (oral, parenteral, topical, slow release, etc.), formulation and extent of activity of a product will influence the protocol design.

When the drug is to be administered in the water or in a premix, it should be done as much as possible following the labelling recommendations. Palatability/consumption studies may be recommended for medicated premixes. Samples of medicated water or feed should be collected to confirm drug concentration. The amount of medicated product provided to each animal should be recorded to ensure that the treatment satisfies the label recommendations.

6 - Bird Selection, Allocation and Handling
Test birds should be clinically healthy and representative of the age, sex, and class for which the claim of the test anthelmintic is to be made. In general, birds should be young and from a breed that is susceptible to helminth infections. Birds should be randomly assigned to each group. Blocking in replicates by weight, sex, age, and/or exposure to parasites may aid in reducing trial variance. Faecal egg counts are also acceptable to allocate the experimental birds.  Control birds should be of the same weight, age, breed, sex and history as the treated group. For induced infections, the use of helminth naive birds is recommended.

Animal housing, feeding and care should follow recommendations for welfare, including vaccination according to local practices.  This information should be provided in the final report. A minimum 10-day acclimatization period is recommended. Housing and feed/water should be adequate according to the geographical location. Birds should be monitored daily to determine adverse reactions.

B.  Specific Evaluation Studies

1- Dose Determination Studies
If the treatment recommends extended administration, one or more studies are recommended to determine the minimum treatment period for effectiveness.

2 - Dose Confirmation
No species specific recommendations.

3 - Field Effectiveness Studies
Due to commercial constraints the experimental unit in these studies invariably should be the shed/house. A shed/house should receive only one treatment, i.e., control or medicated.

Clinical observations, production variables, and records of mortality should be maintained and compared to historical data of the commercial establishment. Slaughterhouse inspection reports should be included in the final report, when the number of test animals can not be confirmed.

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