CVM GFI #97 (VICH GL14) Effectiveness of Anthelmintics: Specific Recommendations for Caprines

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#97
Effectiveness of Anthelmintics:
Specific Recommendations for Caprines
VICH GL14
Guidance for Industry
Final Guidance
This version of the guidance replaces the version made available August 2022.
Submit comments on this guidance at any time. Submit electronic comments to
https://www.regulations.gov. Submit written comments to the Dockets Management Staff
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD
20852. All comments should be identified with docket number FDA-2022-D-1494.
For further information regarding this document, contact Center for Veterinary Medicine, Food
and Drug Administration, 5001 Campus Drive, College Park, MD, email:
AskCVM@fda.hhs.gov.
Additional copies of this guidance document may be viewed on the Internet at
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or http://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine (CVM)
June 2026

VICH GL14 (A NTHELMINTICS : C APRINES )
October 2024
Revision at Step 9
For Implementation at Step 7
E FFICACY OF 	A NTHELMINTICS :
S PECIFIC 	R ECOMMENDATIONS
FOR 	C APRINES
(R EVISION 	1)
Revision at Step 9
Recommended for Adoption at Step 7 of the VICH Process
in October 2024
by the VICH Steering Committee
This Guidance has been developed by the appropriate VICH Expert Working Group and will be 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.

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Table of Contents
I. 	Introduction ............................................................................................................................. 1
A. General Elements .............................................................................................................. 2
1. 	The Evaluation of Effectiveness Data ....................................................................... 2
2. 	Use of Natural or Induced Infections ........................................................................ 2
3. 	Number of Infective Parasitic Forms Recommended for Induced Infections....... 2
4. 	Recommendations for the Calculation of Effectiveness .......................................... 3
4.1 	Factors to Support a Claim ............................................................................... 3
4.2 	Number of Animals (Dose Determination, Dose Confirmation, and
Persistency Studies) ........................................................................................... 4
4.3 	Adequacy of Infection ........................................................................................ 4
4.4 	Label Claims ....................................................................................................... 4
5. 	Treatment Procedures ................................................................................................ 5
6. 	Animal Selection, Allocation, and Handling............................................................. 5
B. Specific Evaluation Studies .............................................................................................. 6
1. 	Dose Determination Studies ....................................................................................... 6
2. 	Dose Confirmation Studies ........................................................................................ 6
3. 	Field Effectiveness Studies ......................................................................................... 6
4. 	Persistent Effectiveness Studies ................................................................................. 7

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Effectiveness of Anthelmintics: Specific Recommendations for
Caprines
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	Introduction
This caprine guidance was developed by the Working Group established by the International
Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary
Medicinal Products (VICH), Anthelmintic Guidances, and subsequently revised in 2024. It
should be read in conjunction with Guidance for Industry (GFI) #90 (VICH GL7), “Effectiveness
of Anthelmintics: General Recommendations,”1 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 GFI #90/VICH GL7 with the aim of simplicity for
readers comparing both documents.
The aim of the caprine guidance is: (1) to be more specific for certain specific caprine issues not
discussed in GFI #90/VICH GL7; (2) to highlight differences with GFI #90/VICH GL7 on
effectiveness data recommendations; and (3) to give explanations for disparities with GFI
#90/VICH GL7.
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 sponsors refer to the pertinent procedures described in
detail in other published documents, e.g., World Association for the Advancement of Veterinary
Parasitology (WAAVP) Third edition of the guideline for evaluating efficacy of anthelmintics in
ruminants (bovine, ovine, caprine) Veterinary Parasitology 329: 110187, 2024, and updated
versions as they are published.
The cost of a full animal drug development program may preclude the development of products
for this species, and since the helminth species of caprines are identical to those of ovines, it is
recommended that consideration be given to an abbreviated schedule of studies to obtain
approval.
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is
intended only to provide clarity to the public regarding existing requirements under the law.
FDA’s guidance documents should be viewed only as recommendations, unless specific
1 https://www.fda.gov/media/70349/download

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regulatory or statutory requirements are cited. The use of the word should in Agency guidances
means that something is suggested or recommended, but not required.
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 historical
data and/or statistical analysis.
2. 	Use of Natural or Induced Infections
Dose determination studies generally should be conducted using induced infections with either
laboratory strains or recent field isolates. Limited experience exists with induced infections of
Protostrongylidae, cestodes, and 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 to be present. For claims against 4 th stage larvae, induced
infections should be used. For claims against hypobiotic larvae, natural infections should be
used. Sponsors should aim for a maximum period of accumulation of hypobiotic larvae for the
particular parasite species being targeted in study 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.

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Table 1. Number of Infective Stages Recommended to
Produce Adequate Infections in Goats for Anthelmintic
Evaluation
Parasite Anatomical Location
Genus Species Range of
Eggs/Larvae
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)
Chronic 	100 – 200
Acute 	1,000 – 1,500
4. 	Recommendations for the Calculation of Effectiveness
4.1 Factors to Support a Claim
To support 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) in each study. The infection of animals in the
study will be deemed adequate based on historical, parasitological, and/or statistical
criteria;

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b. 	The differences in parasite counts between treated and control animals should be
statistically significant (p ≤ 0.05); and
c. 	Percent effectiveness should be 90% or higher and calculated and interpreted using
the procedures described in section A.4.5. Calculation and Evaluation of Percent
Effectiveness of GFI #90/VICH GL7.
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 has 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,
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
The minimum adequate number of helminths in individual control animals should be defined in
the protocol. However, final conclusions regarding adequacy of infection will be made as part of
the final report based on statistical analysis, 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, a minimum of 100 nematodes in individual control animals
is considered an adequate infection2. Lower individual counts are to be expected with
Bunostomum spp., Oesophagostomum spp., Trichuris spp., Gaigeria pachyscelis, and
Dictyocaulus filaria. Generally, for Fasciola spp., minimum counts of 20 adults are 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), C. ovina (49 days), Bunostomum spp. (52 to 56 days),
Strongyloides papillosus (14 to 16 days), and Fasciola spp. (see below).
For L4 claims, treatments should be given on the following days after infection: 3 to 4 days for
Strongyloides papillosus; 5 to 6 days for Haemonchus spp., Trichostrongylus spp., and Cooperia
spp.; 7 days for T. (O.) circumcincta; 8 to 10 days for Nematodirus spp. and D. filaria; and 15 to
2 The recommended minimum numbers are based on a review of published literature and data
from studies submitted for regulatory review.

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17 days for Oesophagostomum spp. The term “immature” on the labeling is not recommended
for these claims.
For Fasciola spp. treatment should be administered as follows:
a. 	Early immature stages: Treatment should be administered at 1 to 4 weeks post-infection
when flukes will be migrating in the liver parenchyma.
b. 	Late immature stages: Treatment should be administered at 6 to 8 weeks post-infection
when flukes are still immature but starting to enter the hepatic bile ducts.
c. 	Mature flukes: Treatment should be administered at 12 to 14 weeks post-infection when
all forms are in the bile ducts and gall bladder.
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. Slow-
release 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 medicated feed, it should be done
following the labeling recommendations. Palatability studies may be required for medicated
feeds. Samples of medicated water or medicated 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 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. Randomization to treatment group should be performed using an
adequate method that should be described in the protocol and final report. Blocking is only
recommended if it is expected to reduce residual error in the study. If blocking is used, blocks
should be included as a random effect in the statistical model. Nevertheless, blocking is not
always the most appropriate method for reducing residual error. Alternative methods may
therefore be considered, e.g., a suitably selected covariate.
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, chemically
not related to the test drug, to remove pre-existing infections followed by fecal examination to
determine that the animals are helminth-free. Extended-release anthelmintics should not be used.
If possible, treatment using anthelmintics with persistent activity should be avoided or the study
schedule adjusted to prevent interference of the treatment with the establishment of induced
infections.

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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 acclimatization period of 7 days is recommended. Housing, feed, and water should
be adequate according to the geographical location. Animals should be monitored daily for
adverse reactions.
B. Specific Evaluation Studies
1. 	Dose Determination Studies
A dose determination study and/or sheep/goat comparative pharmacokinetic studies where
appropriate, should verify if the dose selected is effective in goats.
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 sheep host.
3. 	Field Effectiveness Studies
The field studies should be replicated in different geographic locations and in animal/production
class(es) that represent the conditions of use for the indication being pursued. The protocol
should state the number of experimental units per treatment group (sample size), describe
allocation (proportion) to treatment groups, and include a brief description of how the sample
size was determined. The protocol should also describe procedures for random selection of
animals (number and percentage) to be sampled (if fecal samples will not be collected from all
available animals in the study), as appropriate, and the methods to be used for both fecal
collection and examination. Regardless of whether one or multiple parasites are being evaluated
within a study, an appropriate sample size calculation or justification is necessary prior to study
conduct.
Effectiveness against adult nematodes can be assessed by the reduction of fecal egg counts (or
larval counts for D. filaria) and should be performed using samples from the same animal before
and after treatment. Post-treatment counts are generally made 10-14 days after treatment, but the
timing of post-treatment counts will depend on the parasite species and class of anthelmintic
evaluated. For example, due to the known effects of macrocyclic lactones on nematode egg
suppression, post-treatment counts should be delayed until at least 14 days or longer. Unless
otherwise justified, effectiveness should be calculated using post-treatment fecal egg counts from
the treated and control (typically placebo or untreated control) groups. Additionally, a
calculation of effectiveness using pre- and post-treatment fecal egg counts from animals in the
treated group may provide further information on field effectiveness. Furthermore, additional
endpoints for evaluating field effectiveness should be considered as they are developed and
generally accepted by experts in veterinary parasitology.
See also sections A.4.4. Data Analysis Recommendations and A.4.5. Calculation and Evaluation
of Percent Effectiveness of GFI #90/VICH GL7.

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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 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-naive goats are
recommended for the studies. A study design is recommended using multiple daily challenges,
as this most closely mimics what occurs under field conditions. 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 3 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 and
should take into consideration the pharmacological properties of the product.
Persistent effectiveness claims should be supported by a minimum 90% effectiveness at each
time point, and calculated and interpreted using the procedures described in sections A.4.4. Data
Analysis Recommendations and A.4.5. Calculation and Evaluation of Percent Effectiveness of
GFI #90/VICH GL7. Persistent effectiveness claims should be granted for the longest period
between treatment and the last challenge where effectiveness criteria are met, and all preceding
time points tested meet the criteria as well.