97 

 Guidance for Industry 

EFFECTIVENESS OF ANTHELMINTICS: 

Specific Recommendations for Caprine 

VICH GL14 

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 Division of Dockets 

Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, 

MD 20852. Submit electronic comments to http://www.regulations.gov. All comments should be 

identified with the Docket No. 99D-2248. 

For questions regarding this document, contact Janis Messenheimer, Center for Veterinary 

Medicine, (HFV-135), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 

240-276-8348, e-mail: janis.messenheimer@fda.hhs.gov. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

March 26, 2001
VICH GL14 (ANTHELMINTICS: CAPRINE ) 

EFFECTIVENESS OF ANTHELMINTICS: SPECIFIC RECOMMENDATIONS FOR CAPRINE

Recommended for Consultation 

at Step 7 of the VICH Process 

in February 1999 

by the VICH Steering Committee 

THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP AND IS 

SUBJECT TO CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7

OF THE PROCESS THE FINAL DRAFT WILL BE RECOMMENDED FOR ADOPTION TO THE REGULATORY 

BODIES OF THE EUROPEAN UNION, JAPAN, AND USA. 

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EFFECTIVENESS OF ANTHELMINTICS: 

SPECIFIC RECOMMENDATIONS FOR CAPRINE

Endorsed by the VICH Steering Committee at Step 7 of the VICH Process 

at its meeting from 16-19 November 1999 

This guidance represents FDA’s current thinking on this 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 

applicable statutes and regulations.

Introduction 

These guidances for caprine were developed by the Working Group established by the 

Veterinary International Cooperation on Harmonization (VICH), Anthelmintic Guidances. 

They 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 guidances for caprine are part of this EAGR and the aim is (1) to be more specific for 

certain specific issues for caprine not discussed in the overall guidances; (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 that the sponsors refer to the pertinent procedures 

described in detail in other published documents e.g. WAAVP Second Edition of Guidances 

for Evaluating the Effectiveness of Anthelmintics in Ruminants (Bovine, Ovine, Caprine) 

Veterinary Parasitology 58: 181-213, 1995. 

The cost of a full development program may preclude the development of products for this 

species, and since the helminth species of caprine are identical to those of ovine, it is 

recommended that consideration be given to an abbreviated schedule of studies to obtain 

approval. 

A. General Elements 

1 - The Evaluation of Effectiveness Data 

Only controlled tests based on parasite counts of adults/larvae are recommended both for 

the dose determination and dose confirmation studies, since critical tests generally are not 

considered to be reliable for ruminants. Egg counts/larval identification is the preferred 

method to evaluate the effectiveness in field studies. Long-acting or sustained-release 

products should be subjected 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. 

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2 - Use of Natural or Induced Infections 

Dose determination studies generally should be conducted using induced infections with 

either laboratory or recent field isolates. Limited experience exists with induced infection of 

Protostrongylidae, cestodes, Dicrocoelium spp. For these parasites, the use of natural 

infections instead of induced infections may be justified. 

Dose confirmation studies should be conducted using naturally infected animals however; 

induced infections or superimposed induced infections can also be used. 

This procedure will allow a wide range of parasites. For claims against 4th stage larvae, 

induced infections should be used. For claims against hypobiotic larvae, only natural 

infections should be considered. Sponsors should aim for a maximum period of 

accumulation of hypobiotic larvae for the particular parasite species being targeted in trial 

animals. This will be area or regionally dependent. Specific details on area or regional 

situations should be obtained from experts on a case by case basis, if needed. In all cases, 

animals should be housed (to preclude reinfection) for a minimum of 2 weeks before 

treatment. 

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 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 parasites with existing infection models. 

Table 1 - Number of infective stages recommended to produce adequate infections in 

caprine for anthelmintic evaluation 

Parasites VICH 

Abomasum

Haemonchus contortus 400 – 4,000 

Teladorsagia circumcincta 6,000 – 10,000 

Trichostrongylus axei 3,000 – 6,000 

Intestines 

Cooperia curticei 3,000 – 6,000 

T. colubriformis & T. vitrinus 3,000 – 6,000 

Nematodirus spp. 3,000 – 6,000 

Oesophagostomum spp. 500 – 1,000 

Chabertia ovina 800 – 1,000 

Bunostomum trigonocephalum 500 – 1,000 

Strongyloides papillosus 80,000 

Gaigeria pachyscelis 400 

Trichuris spp. 1,000 

Lungs 

Dictyocaulus filaria 1,000 – 2,000 

Liver 

Fasciola hepatica (metacercaria) 100 - 200 (chronic) 

1,000 – 1,500 (acute) 

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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 animals should be 

statistically significant (p<0.05); 

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

data; 

d) The infection of the animals in the study may be deemed adequate based on historical, 

parasitological and/or statistical criteria. 

This recommended effectiveness standard (= 90% or higher) is based on helminth removal 

from the host. If, however, the focus of regional anthelmintic treatment is to target prevention 

of pasture contamination due to the epizootiology of gastrointestinal helminth parasites, then 

a higher minimum effectiveness standard may be applied. Sponsors should discuss such 

situations with the regulatory authorities prior to commencement of trial work. 

4.2 Number of Animals (Dose Determination, Dose Confirmation and Persistency 

Studies) 

The minimum number of animals used per experimental group is a critical point. Although the 

number of animals will depend on the possibility 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 calculated. If the 

differences are significant (p<0.05), effectiveness may be calculated and if the infection is 

deemed adequate in each study, 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 

Concerning minimum adequate number of helminths, the decision will be made when the 

final report is submitted based on statistical and historical data, literature review, or expert 

testimony. The range of caprine 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 

Bunostomum spp, Oesophagostomum spp., Trichuris spp., Gaigeria pachyscalis and 

Dictyocaulus filaria. For Fasciola spp., minimal mean counts of 20 adults is considered 

adequate. 

4.4 Label Claims 

For adult claims as a general rule the treatment should not be administered earlier than 21 to 

25 days after infection; optimum for most species are 28 to 32 days. Major exceptions are 

Oesophagostomum spp. (34 to 49 days), C. ovina (49 days) Bunostomum spp. (52 to 56 

days), Strongyloides papillosus (14 to 16 days) and Fasciola spp. (8 to 12 weeks). 

For L4 claims, treatments should be given on the following days 3 to 4 days for Strongyloides 

papillosus, 5 to 6 days for Haemonchus spp., Trichostrongylus spp. and Cooperia spp., 7 

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days for T.(O.) circumcincta, 8 to 10 days for Nematodirus spp. D. filaria, and 15 to 17 days 

for Oesophagostomum spp. The term immature on the labeling is not recommended. For 

early immature Fasciola spp., treatments should be given 1 to 4 weeks after infection and for 

late immatures at 6 to 8 weeks. 

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. It is advisable to consider the 

weather and animal relationship with regard to effectiveness of topical formulations. Slowrelease products should be tested over the entire proposed effective time unless additional 

information suggests that this is unnecessary. e.g. blood levels demonstrate steady state at 

all points of the proposed therapeutic period. 

When the drug is to be administered in the water or in a premix, it should be done following 

the labeling recommendations. Palatability studies may be required 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. For products used topically, the impact of 

weather (e.g. rainfall, UV light), and coat length impact should be included in the evaluation 

of the effectiveness of the product. 

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 

ruminating, and older than 3 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 useful 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 strict requirements of 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, feed, and 

water 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 

A dose determination trial and/or caprine/ovine comparative pharmacokinetic studies where 

appropriate, should verify if the dose selected is effective in caprine. 

2 - Dose Confirmation Studies 

Confirmation studies including at least the dose limiting helminth(s) and stages in each study 

are recommended. If effectiveness is demonstrated for the test parasites a claim can be 

supported for all the helminth species claimed for the ovine host. 

3 - Field Effectiveness Studies 

No species specific recommendations 

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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 

both procedures, no standardized protocol has been developed. When conducting studies, 

protocol details should include among other things: determination of larval viability 

throughout the study, rationale for larval challenge and justification for slaughter time. 

Parasite naïve goats are recommended in these studies. A study design is recommended 

using multiple daily challenges, as this most closely mimics what occurs in nature. Two 

studies (with parasite counts) each with a non-treated and one or more treated groups, are 

recommended for a persistent effectiveness claim (for each duration and helminth claim). 

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 

are examined for parasite burden. The challenge interval and schedule may vary for longer 

acting products. 

Persistent effectiveness claims should be supported by a minimum 90% effectiveness based 

on geometric means.