**114**

**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*)]{.smallcaps}**

**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]{.smallcaps} 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*            | 50-100                        |
|                                      |                               |
| *Syngamus trachea*                   | 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.