**113**

**Guidance for Industry**

Effectiveness of Anthelmintics:

Specific Recommendations for Feline

**VICH GL20**

**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 GL20 [(Anthelmintics: Feline)]{.smallcaps}**

**June 2002**

**For implementation at Step 7**

Effectiveness of Anthelmintics:

Specific Recommendations for Feline

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 Feline

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 feline was developed by the Working Group that
was established by the Veterinary International Cooperation on
Harmonization (VICH), Anthelmintic Guidances. It should be read in
conjunction with the "VICH Effectiveness of Anthelmintics: 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 guidance with the aim of simplicity for readers comparing
both documents.

The guidance for feline is part of the EAGR and the aim is: (1) to be
more detailed for certain specific issues for feline not discussed in
the EAGR; (2) to highlight differences with the EAGR on data
recommendations, and (3) to give explanations for disparities with the
EAGR guidance.

It is important to note that technical procedures to be followed in the
studies are not the aim of this guidance. We recommend that the sponsors
refer to the pertinent procedures described in detail in other published
documents e.g., WAAVP Guidelines for Evaluating the Efficacy of
Anthelmintics for Dogs and Cats, Veterinary Parasitology ***52***:
179-202, 1994.

# A. General Elements

## 1- The Evaluation of Effectiveness Data

The evaluation of effectiveness data is based on parasite counts
(adults, larvae) in dose determination and dose confirmation studies;
egg counts/larval identification should be the preferred method to
evaluate the effectiveness in field studies.

The controlled test is the most widely accepted of the testing
procedures for the evaluation of anthelmintic drug effectiveness.
However, the critical test may be appropriate for some intestinal
species of parasites, e.g., ascarids.

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 should be conducted using induced infections
with either laboratory or recent field isolates.

Dose confirmation studies should be conducted using naturally or
artificially infected animals. Generally, when induced infections are
used, at least one study should be conducted in naturally infected
animals for each parasite claimed on the labelling. *Echinococcus
multilocularis* and *Dirofilaria* spp. testing may be conducted using
animals harbouring induced infections due to public health
considerations for echinococcosis and the complexity of the claims for
heartworm. Due to the zoonotic potential of *E. multilocularis* trials
conducted using this parasite should be carried out under high
biosecurity provisions.

For the following helminths, induced infections may also be the only
method to determine effectiveness of the product because of the
difficulties in obtaining a sufficient number of infected animals:
*Capillaria aerophila, Physaloptera* spp.*, Crenosoma* *vulpis.* For
claims against larval stages, only studies with induced infections
should be used.

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

## 3 - Number of Infective Parasitic Forms Recommended for Induced Infections

The number to be used is approximate and will depend on the isolate that
is used. The final number of larvae used in the infection should be
included in the final report. Table 1 shows the range of numbers
recommended for common helminths.

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

+-------------------------------------+--------------------------------+
| Parasites                           | Range                          |
+-------------------------------------+--------------------------------+
| **Small Intestine**:                | 100 - 500                      |
|                                     |                                |
| *Toxocara cati*                     | 200 - 3,000                    |
|                                     |                                |
| *Toxascaris leonina*                | 100 - 300                      |
|                                     |                                |
| *Ancylostoma tubaeforme*            | 100 -- 300                     |
|                                     |                                |
| *Ancylostoma braziliense*           | 1,000 -- 5,000                 |
|                                     |                                |
| *Strongyloides stercoralis*         | 5 -- 15                        |
|                                     |                                |
| *Taenia taeniaeformis*              | 100 - 500                      |
|                                     |                                |
| **Large Intestine**                 |                                |
|                                     |                                |
| *Trichuris campanula*               |                                |
+-------------------------------------+--------------------------------+
| **Heart**                           | 30 -- 100\*                    |
|                                     |                                |
| *Dirofilaria immitis*               |                                |
+-------------------------------------+--------------------------------+

\* For adulticidal or microfilaricidal testing 5 to 15 pairs of adult
worms can be transplanted.

## 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 non-medicated animals (control group) and six
adequately infected medicated animals (treated group);

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

c\) Effectiveness should be 90% or higher calculated using transformed
(geometric means) data. For some parasites with public health or animal
welfare/clinical implications e.g., *E. multilocularis* and *D.
immitis*, respectively, higher effectiveness standards (i.e., up to
100%) may be appropriate. The regulatory authority of the region in
which the product is intended to be registered should be consulted;

d\) The infection of the animals in the study may be deemed adequate
based on historical, parasitological and/or statistical criteria;

e\) Effectiveness against helminths should be evaluated by examining for
the presence or absence of parasitic elements in faecal material or
blood. An *E.* *multilocularis* claim does not need field studies due to
public health concerns.

### *4.2 Number of Animals (Dose Determination and Dose Confirmation Trials)*

The minimum number of animals used per experimental group is a critical
point. Although the number of animals will depend on the ability to
process the data statistically according to the adequate statistical
analysis it has been recommended, to achieve harmonization, that the
inclusion of at least six animals in each experimental group is a
minimum.

In cases where there are several studies none of which have six
adequately infected animals in the control group (for example, important
rare parasites), the results obtained could be pooled to accumulate 12
animals in the studies and statistical significance could be calculated.

If the differences are significant (p\<0.05), effectiveness may be
calculated and if the infection is deemed adequate, the claim may be
granted. Sampling techniques and estimation of worm burden should be
similar among laboratories involved in the studies to allow adequate and
meaningful extrapolation of the results to the population.

### *4.3 Adequacy of Infection*

With respect to the minimum adequate number of helminths, the decision
should be made when the final report is submitted based on historical
data, literature review, or expert testimony. Generally, the minimal
number of nematodes in feline considered to be adequate is in the range
of 5 to 20. Higher counts are to be expected with *A. tubaeforme*.

### *4.4 Label Claims*

A claim for effectiveness against life stages of each parasite should
refer to each stage in the case of natural infections, or age in days in
the case of induced infection. Table 2 is provided as a guide for the
recommended time of treatment of induced infections.

Table 2. Recommended time of treatment after infection

+-------------------+---------------+----------------------------------+
| Parasite          | Adult Stages  | Larval Stages                    |
+-------------------+---------------+----------------------------------+
| *S. stercoralis*  | 5 to 9 days   |                                  |
+-------------------+---------------+----------------------------------+
| *T. campanula*    | 84 days       |                                  |
+-------------------+---------------+----------------------------------+
| *A. tubaeforme*   | \> 21 days    | 6 to 8 days (L4)                 |
+-------------------+---------------+----------------------------------+
| *A. braziliense*  | \> 21 days    | 6 to 8 days (L4)                 |
+-------------------+---------------+----------------------------------+
| *T. cati*         | 60 days       | 3 to 5 days (L3/L4)              |
|                   |               |                                  |
|                   |               | 28 days (L4/L5)                  |
+-------------------+---------------+----------------------------------+
| *T. leonina*      | 70 days       | 35 days (L4)                     |
+-------------------+---------------+----------------------------------+
| *D. immitis*      | 180 days      | 2 days (L3), 20 to 40 days (L4)  |
|                   |               |                                  |
|                   |               | 70 to 120 days (L5), 220 days    |
|                   |               | (microfilariae)                  |
+-------------------+---------------+----------------------------------+
| *T.               | \> 35 days    |                                  |
| taeniaeformis*    |               |                                  |
+-------------------+---------------+----------------------------------+
|                   |               |                                  |
+-------------------+---------------+----------------------------------+

With the majority of parasites approximately seven days is a sufficient
time period from the termination of treatment until the test animals are
necropsied. The following parasites are the exception to the above
general recommendation:

*Physaloptera* spp.*, C. aerophila, E. multilocularis, T.*
*taeniaeformis*, *Dipylidium caninum*: 10 to 14 days;

*C. vulpis:* 14 days;

*D. immitis:* varies by trial design.

For claims against transmammary transmission of *T. cati* somatic larvae
of natural or artificially infected pregnant queens should be treated
prior to or just after parturition and the effectiveness checked by
counting the larvae in the queen milk and/or the adult worms in the
small intestines of the litter.

## 5 - Treatment Procedures

The method of administration (oral, parenteral, and topical) and extent
of activity of the product will influence the protocol design. It is
advisable to consider the weather and animal relationship and bathing
with regard to effectiveness of topical formulations.

For oral formulations, palatability studies should always be included in
the evaluation of the effectiveness of the product. For products
administered topically, the impact of weather (e.g., rainfall, UV
light), bathing and coat length should be included in the evaluation of
the effectiveness of the product.

## 6 - Animal Selection, Allocation and Handling

Approximately six-month-old feline are generally suitable for controlled
studies, however, older and younger animals can also be used and the
following exceptions should be taken into account:

\- *S. stercoralis*: less than six months;

\- *A. braziliense, A. tubaeforme six* to 16 weeks;

\- *T. cati, T. leonina:* four to 16 weeks;

\- *D. caninum:* three months or older.

Naturally infected animals should be selected based on egg output or
expelled proglottids in gastrointestinal parasites, and parasitological
and/or immunological methods for *D. immitis*. They should be assigned
to each group and replicated using an adequate method that should be
described in the final report. Replications should cover each factor
that may have an impact on the final evaluation of the effectiveness of
the formulation. Animal housing, feeding and care should follow
recommendations for welfare for felines. Animals should be acclimatized
for at least seven days to the experimental facilities and personnel.
Animals should be monitored daily to determine adverse reactions.

# B. Specific evaluation studies

## 1- Dose determination studies

No species specific recommendations.

## 2- Dose confirmation studies

No species specific recommendations.

## 3 - Field Effectiveness studies

Field (clinical) studies should not be conducted with feline infected
with *E. multilocularis* and *D. immitis.*

## 4 - Persistency Effectiveness studies

Due to the differing biology of helminths in feline and the lack of
experience with persistent effectiveness for these parasites, no
recommendations can be provided.