111 

Guidance for Industry 

Effectiveness of Anthelmintics: 

Specific Recommendations for Canine 

VICH GL19

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 00D-1532. 

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 

June 27, 2002 
Page 2 

VICH GL19 (ANTHELMINTICS: CANINE) 

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 USA. 
Page 3 

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. 
Page 4 

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 

Toxocara canis 

Toxascaris leonina 

Ancylostoma caninum 

Ancylostoma braziliense 

Uncinaria stenocephala 

Strongyloides stercoralis 

Echinococcus granulosus 

Taenia spp. 

100 - 500 * 

200 - 3,000 

100 - 300 

100 - 300 

1,000 – 1,500 

1,000 - 5,000 

20,000-40,000 

5 - 15 

Large Intestine 

Trichuris vulpis 100 - 500 

Heart 

Dirofilaria immitis 30 – 100 ** 

* 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. 
Page 5 

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 nonmedicated 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. 
Page 6 

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. 
Page 7 

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.