**110**

**Guidance for Industry**

Effectiveness of Anthelmintics:

Specific Recommendations for Porcine

VICH GL16

**FINAL GUIDANCE**

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> 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>.

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######### U.S. Department of Health and Human Services

######### Food and Drug Administration

**Center for Veterinary Medicine**

**June 27, 2002**

**VICH GL16 [(Anthelmintics: Porcine)]{.smallcaps}**

**June 2002**

**For implementation at Step 7**

Effectiveness of Anthelmintics:

Specific Recommendations for Porcine

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 Porcine

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 porcine was developed by the Working Group
established by the Veterinary International Co-operation 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 porcine is part of this EAGR and the aim is (1) to be
more specific for certain issues for porcine 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.

It is also important to note that technical procedures to be followed in
the studies are not the aim of this guidance. We recommend to the
sponsors to refer to the pertinent procedures described in detail in
other published documents e.g., WAAVP Guidelines for Evaluating the
Effectiveness of Anthelmintics in Swine. Veterinary Parasitology
***21*** : 69 - 82, 1986.

## A. General Elements

### 1 - The Evaluation of Effectiveness Data

Only controlled tests are recommended both for the dose determination
and dose confirmation studies. Critical tests are generally considered
not to be very reliable for porcine.

Long-acting or sustained-release products should be subject to the same
evaluation procedures as other therapeutic anthelmintics. 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 should be conducted using naturally infected
animals. Induced infections with recent field isolates are also
acceptable, as well as natural infections which can have superimposed
induced infections of certain parasites. This procedure should allow a
wide range of parasites.

Persistent effectiveness studies should be conducted using induced
infections with recent field isolates.

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 that should be used is approximate and should depend on the
isolate that is used. The final number of larvae or eggs used in the
infection should be included in the final report. Table 1 shows the
range of viable L3 or eggs recommended.

Table 1 -- Range of viable L3 or eggs recommended to produce adequate
infections in porcine for anthelmintic evaluation.

  ------------------------------------------- ---------------------------
  Parasites                                   Range

  Stomach                                     

  *Ascarops strongylina*                      200

  *Hyostrongylus rubidus*                     1,000 -- 4,000

  *Physocephalus sexalatus*                   500

  Intestines                                  

  *Ascaris suum\**                            250 -- 2,500

  *Oesophagostomum* spp.                      2,000 -- 15,000

  *Strongyloides ransomi*                     1,500 -- 5,000

  *Trichuris suis*                            1,000 -- 5,000

  Lungs                                       

  *Metastrongylus* spp.                       1,000 -- 2,500

  Kidney                                      

  *Stephanurus dentatus*                      1,000 -- 2,000
  ------------------------------------------- ---------------------------

\* To maximize the establishment of adult worms a trickle infection with
a low number of eggs is recommended.

### 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) in each study;

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

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

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

#### 4.2 Number of Animals (dose determination, dose confirmation and persistency 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 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 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 statistical
and historical data, literature review, or expert testimony. The range
of porcine helminths (adults) that has been considered adequate to grant
a claim varies according to the species. Generally the minimal mean
number of nematodes recommended as adequate is 100. Lower mean counts
are to be expected with *A.suum, A. strongylina, P. sexalatus, S.
dentatus*, *Metastrongylus* spp. and *Fasciola* spp.

#### 4.4 Label Claims

For adult claims as a general rule the treatment should not be
administered earlier than 35 days for *A. strongylina,* 26 days for *H.
rubidus,* 55 days for *P. sexalatus*, 65 days for *A. suum,* 10 days for
*S. ransomi*, 28 to 45 days for *O. dentatum* and *O. quadrispinulatum*
, 50 days for *T. suis*, 35 days for *Metastrongylus* spp. and 10 months
for *S. dentatus*.

For L4 claims treatments should be given as general rule 7 to 9 days
days after infection with exceptions: 3 to 4 days for *S. ransomi* 11 to
15 days for *A. suum,* and 16 to 20 days for *T. suis.* The term
immature on the labelling is not recommended.

For claims against transmammary transmission of *S. ransomi* somatic
larvae, natural or artificially infected pregnant sows should be treated
at various times prior to parturition and the effectiveness checked by
counting the larvae in the sow milk and the adult worms in the small
intestine of the litter.

### 5 - Treatment Procedures

The method of administration (oral, parenteral etc), formulation and
extent of activity of a product will influence the protocol design.
Slow-release products should be tested over the entire proposed
effective time unless additional information suggests that this is
unnecessary, e.g., for systemically acting compounds blood levels
demonstrate steady state at all points of the proposed therapeutic
period. When the drug is to be administered in the water or via a
premix, it should be done following the labelling recommendations.
Palatability studies may be advisable for medicated feed. Samples of
medicated water or feed should be collected to confirm drug
concentration. The amount of medicated product consumed by each animal
or group of animals should be recorded to ensure that the treatment
satisfies the label recommendations.

### 6 - Animal Selection, Allocation and Handling

Test animals 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 the animals should be 2 to 6 months of age. Animals
should be assigned randomly to each treatment. Blocking in replicates by
weight, sex, age, and/or exposure to parasites may aid in reducing trial
variance. Faecal egg/larval counts are also an adequate method to
allocate the experimental animals.

For induced infections, the use of helminth naive animals is
recommended. Animals not raised in a helminth-free environment should be
treated with an approved anthelmintic drug to remove pre-existing
infections followed by faecal examination to determine that the animals
are helminth free.

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 seven-day
acclimatization period is recommended. Housing and feed/water supply
should be adequate according to the geographical location. 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

Confirmation studies are recommended to support each claim: adult and
larvae. For additional descriptions of the procedures refer to EAGR.

## 3. Field Effectiveness Studies

No species specific recommendations.

## 4. Persistent Effectiveness Studies

Two basic study designs have been used to pursue persistent
effectiveness claims: one using a single challenge, another using
multiple daily challenges following treatment. For consistency of
interpretation of results, a standardised study design is recommended
using multiple daily challenges, as this most closely mimics what occurs
in nature.

A minimum recommended for a persistent effectiveness claim (for each
duration and helminth claim) should include two trials (with worm
counts) each with a non-treated and one or more treated groups. At least
six animals in the control group should be adequately infected.
Persistent effectiveness claims should only be granted on a
species-by-species basis.

In the protocol using multiple daily challenges different groups of
animals should be treated and exposed to a daily natural or induced
challenge for 7, 14, 21 or more days after the treatment. Then at
approximately three weeks after the last challenge (or earlier) the
animals should be examined for parasite burden.

Persistent effectiveness claims should be supported by a minimum 90%
effectiveness based on geometric means.