95 

 Guidance for Industry 

EFFECTIVENESS OF ANTHELMINTICS: 

Specific Recommendations for Bovine 

VICH GL12 

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 GL12 (ANTHELMINTICS: BOVINE) 

EFFECTIVENESS OF ANTHELMINTICS: SPECIFIC RECOMMENDATIONS FOR BOVINE

Recommended for Consultation 

at Step 7 of the VICH Process 

in November 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 BOVINE

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

certain specific issues for bovine 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. 

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 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. Limited experience exists with induced infections of 

Toxocara vitulorum, cestodes and Dicrocoelium dendriticum. For these parasites the use of 

natural infections instead of induced infections may be justified. 

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Dose confirmation studies should be conducted using naturally infected animals which can 

have superimposed induced infections of certain parasites that will not interfere with the 

resident intestinal population. This procedure will allow a wide range of parasites. 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. 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 cattle 

for anthelmintic evaluation. 

Parasites VICH 

Abomasum 

Haemonchus placei 5,000 - 10,000 

Ostertagia ostertagi 10,000 - 30,000 

Trichostrongylus axei 10,000 - 30,000 

Intestines 

Cooperia oncophora 10,000 - 30,000 

C. punctata 10,000 - 15,000 

T. colubriformis 10,000 - 30,000 

Nematodirus spathiger 

N. helvetianus 

N. battus

3,000 - 10,000 

3,000 - 10,000 

3,000 - 6,000 

Oesophagostomum radiatum 

O. venulosum

1,000 - 2,500 

1,000 - 2,000 

Chabertia ovina 500 - 1,500 

Bunostomum phlebotomum 500 - 1,500 

Strongyloides papillosus 1,000 - 200,000 

Trichuris spp. 1,000 

Lungs 

Dictyocaulus viviparus 500 - 6,000 

Liver 

Fasciola hepatica (metacercaria) 

 Adult cattle 1,000 

 Young cattle 500-1,000 

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: 

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a) Two dose confirmation studies conducted with a minimum of six adequately infected nonmedicated 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) 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 

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 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 bovine 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., and Dictyocaulus spp. For 

Fasciola spp. minimal mean counts of 20 adults may be 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 is 28 to 32 days. Major exceptions are 

Oesophagostomum spp. (34 to 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 as a general rule 7 days after infection with the 

following recommended exceptions: 3 to 4 days for Strongyloides papillosus., 5 to 6 days for 

Haemonchus spp., Trichostrongylus spp. and Cooperia spp., 8 to 10 days for Nematodirus

spp. 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 

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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 

No species specific recommendations 

2 - Dose Confirmation Studies

Confirmation studies are recommended to support each claim: adult, larvae and when 

applicable hypobiotic larvae.

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 is 

using a single challenge, another using multiple daily challenges following treatment. For 

both procedures, no standardized protocols have 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 cattle are recommended in these studies. A study design is recommended 

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

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(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.