**111**

**Guidance for Industry**

Effectiveness of Anthelmintics:

Specific Recommendations for Canine

VICH GL19

**FINAL GUIDANCE**

####  {#section .ZUT}

####  {#section-1 .ZUT}

> 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. Submit electronic comments
to <http://www.fda.gov/dockets/ecomments>. All comments should be
identified with the Docket No. 00D-1532.

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 27, 2002**

**VICH GL19 [(Anthelmintics: Canine)]{.smallcaps}**

**June 2002**

**For implementation at Step 7**

Effectiveness of Anthelmintics:

Specific Recommendations for Canine

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 Canine

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 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 canine 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 with the aim of simplicity for readers comparing both
documents.

The guidance for canine is part of the EAGR and the aim is: (1) to be
more detailed for certain specific issues for canines 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 pertinent procedures described in detail in other published
documents, e.g., WAAVP Guidelines for Evaluating the Effectiveness 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 effectiveness in field studies.

The controlled test is the most widely accepted of the testing
procedures for 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; however, at least one study should be
conducted in naturally infected animals for each parasite claimed on the
label. *Echinococcus* spp. 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 *Echinococcus*
spp. trials conducted using this genus 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 difficulties
in obtaining a sufficient number of infected animals*: Filaroides
milksi*, *F. hirthi, Dioctophyma renale, Capillaria aerophila, C. plica,
Spirocerca lupi, Physaloptera* spp*, Mesocestoides* spp*.* and
*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. 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 canines for anthelmintic evaluation.

+-------------------------------------+--------------------------------+
| Parasites                           | Range                          |
+-------------------------------------+--------------------------------+
| Small Intestine                     | 100 - 500 \*                   |
|                                     |                                |
| *Toxocara canis*                    | 200 - 3,000                    |
|                                     |                                |
| *Toxascaris leonina*                | 100 - 300                      |
|                                     |                                |
| *Ancylostoma caninum*               | 100 - 300                      |
|                                     |                                |
| *Ancylostoma braziliense*           | 1,000 -- 1,500                 |
|                                     |                                |
| *Uncinaria stenocephala*            | 1,000 - 5,000                  |
|                                     |                                |
| *Strongyloides stercoralis*         | 20,000-40,000                  |
|                                     |                                |
| *Echinococcus granulosus*           | 5 - 15                         |
|                                     |                                |
| *Taenia* spp.                       |                                |
+-------------------------------------+--------------------------------+
| **Large Intestine**                 | 100 - 500                      |
|                                     |                                |
| *Trichuris vulpis*                  |                                |
+-------------------------------------+--------------------------------+
| Heart                               | 30 -- 100 \*\*                 |
|                                     |                                |
| *Dirofilaria immitis*               |                                |
+-------------------------------------+--------------------------------+

> \* In suckling canine or canine less than 5 months of age.
>
> \*\* 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. granulosus* 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 *Echinococcus* spp. 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; statistical significance could then 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 canine recommended as adequate is in the range of
5 to 20. Higher counts are to be expected with *A. caninum* and *U.
stenocephala*.

### 

### *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. vulpis*       | 84 days       |                                  |
+-------------------+---------------+----------------------------------+
| *A. caninum*      | \> 21 days    | 6 to 8 days \* (L4)              |
+-------------------+---------------+----------------------------------+
| *A. braziliense*  | \> 21 days    | 6 to 8 days (L4)                 |
+-------------------+---------------+----------------------------------+
| *U. stenocephala* | \> 21 days    | 6 to 8 days (L4)                 |
+-------------------+---------------+----------------------------------+
| *T. canis*        | 49 days       | 3 to 5 days (L3/L4)              |
|                   |               |                                  |
|                   |               | 14 to 21 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)                  |
+-------------------+---------------+----------------------------------+
| *E. granulosus*   | \> 28 days    |                                  |
+-------------------+---------------+----------------------------------+
| *Taenia* spp.     | \> 35 days    |                                  |
+-------------------+---------------+----------------------------------+
|                   |               |                                  |
+-------------------+---------------+----------------------------------+

\* For somatic larvae, treat within 2 days prior to parturition.

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

\- *Physaloptera* spp., *S. lupi, C. plica, D. renale, E. granulosus,
Taenia* spp., *D. caninum, Mesocestoides* spp.: 10 to 14 days;

\- *C. vulpis*: 14 days;

\- *F. milksi, F. hirthi*: 42 days;

\- *F. osleri*: one-half of the animals at 14 days and the other half at
28 days;

-   *D*. *immitis*: varies by trial design.

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

## 5 - Treatment Procedures

The method of administration (oral, parenteral, topical), formulation
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 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 canine are suitable for effectiveness
studies.

However, there are exceptions:

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

\- *A*.*caninum, A. braziliense, A. tubaeforme, U. stenocephala* : six
to 12 weeks;

\- *T. canis, T. leonina* : two to six weeks;

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

*- Mesocestoides* spp.: eight weeks or older;

*- U. stenocephala* and *T. vulpis* : older canines can be used.

Naturally infected animals should be selected based on egg output or
expelled proglottids for 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 canines. 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 recommendation.

## 2 - Dose Confirmation Studies

No species-specific recommendation.

## 3 - Field Effectiveness Studies

Field (clinical) studies should not be conducted with canine infected
with *Echinococcus* spp*.*

## 4 - Persistent Effectiveness

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