Guideline No. 90
Guidance for Industry - Effectiveness of Anthelmintics: General Recommendations, Final Guidance - VICH GL7 (replaces 3/26/2001)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Guidance for Industry EFFECTIVENESS OF ANTHELMINTICS: FINAL GUIDANCE (THIS VERSION OF THE GUIDANCE REPLACES THE VERSION THAT WAS MADE AVAILABLE ON MARCH 26, 2001) 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 this document should be submitted to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Comments should be identified with the full title of the guidance document and the Docket No. 99D-2248. 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
General Recommendations
VICH GL7
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
October 11, 2001
G
ENERAL RECOMMENDATIONSRecommended for Consultation
at Step 7 of the VICH Process
on 16- 19 November 1999
by the VICH Steering Committee
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T HIS 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. |
E
FFECTIVENESS OF ANTHELMINTICS:GENERAL RECOMMENDATIONSEndorsed 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.
General Anthelmintic Guidance
Two sections have been identified in the guidance’s general elements, and specific evaluation studies. The General Elements section includes: good clinical practice, evaluation of effectiveness data, types of infection and parasite strains, product equivalence, recommendations for the calculation of effectiveness, standards of effectiveness and the definition of helminth claims. The Specific Evaluation Studies section describes dose determination, dose confirmation, field and persistent effectiveness studies.
A. General Elements
1 - Good Clinical Practice
The principles of Good Clinical Practice (GCP) should apply to all clinical studies and sponsors should work within the principles of the GCP recommendations. Non-GCP studies are considered as non-pivotal studies and may be used as supporting data.
2 - The Evaluation of Effectiveness Data, Use of Natural or Induced Infections, Definition of Laboratory and Field (Helminth) Strains
The evaluation of effectiveness data should be based on parasite counts (adults, larvae) in dose determination and dose confirmation studies; egg counts/larval identification is the preferred method to evaluate the effectiveness in field studies. Controlled and critical tests are acceptable both for the dose determination and dose confirmation studies. However, controlled tests are preferable, and the option to utilize critical tests should be supported with an explanation from the sponsor.
The use of natural or induced infections in effectiveness studies should be determined by the type of parasite and the claim proposed by the sponsor. In some rare, but epizootiologically important parasites, the use of induced infections is the only solution.
Recent field isolates generally are preferred to develop induced infections, although in some cases laboratory strains should be used (see glossary). Field strains are believed to reflect more accurately the current status of the parasite in nature. The characterization of each of the laboratory isolates used in the investigations should be included in the final report i.e. source, maintenance procedure, drug sensitivity, number of passages and expected establishment rates in the target host. For field isolates, characterization also needs to include source, date, location of isolation, previous anthelmintic exposure and maintenance procedure.
3 - Product Equivalence
The principle of product equivalence should be used for alternative formulations of the same approved drug, when used at the same dose, by the same route of administration and in the same host. For a formulation change to a product with the same approved drug the pharmacokinetic attributes of the drug should dictate the study type that should be conducted for product equivalence.
In either case for absorbed drugs that can be measured in the blood plasma, and for which a relationship with effectiveness can be correlated with pharmacokinetic parameters, a blood level bioequivalence study may be used. Alternatively and particularly where pharmacokinetic parameters cannot demonstrate a relationship with effectiveness, 2 dose confirmation studies using the dose-limiting parasite for therapeutic claims and/or 2 persistence effectiveness studies per species claimed may be needed.
4 - Recommendations for the Calculation of Effectiveness
The analysis of parasite data in support of effectiveness uses estimations of several parasitological parameters including faecal egg counts and worm counts, which may be a reflection of the success of the treatment. In most natural infections, and less in induced infections, large variations in data values between similarly treated animals have been observed. In this case, it may be recommended that additional studies be conducted to increase the number of observations.
4.1 Data Analysis Recommendations
The recommendations for approval of an anthelmintic product should be based on significant statistical differences between the treated and control groups and on calculated percent effectiveness of 90% or more.
The statistical analyses should be determined by the sponsor in the protocol stage prior to any data analyses. Nonparametric or parametric procedures are recommended. If the sponsor is able to demonstrate significant statistical differences between the treated and control groups, then percent effectiveness would be calculated using geometric means. For a product to be acceptable, the calculated percent effectiveness should be at least 90% (see Standards of Effectiveness).
4.2 Geometric Versus Arithmetic Means
Differences in effectiveness may be seen whether geometric or arithmetic means are used. However, in the context of harmonization, recommendations are needed for one method of calculating the means. Log-transformed parasite counts or egg-counts tend to follow a normal distribution more closely than do non-transformed parasite counts. The geometric mean is therefore a more appropriate estimate of central tendency and has less potential for misinterpretation. The use of arithmetic means to evaluate effectiveness has been considered to be a more stringent criterion reflected in a more conservative estimation of therapeutic activity of the product and may be acceptable in certain circumstances only.
For the calculation of percent of effectiveness geometric means are recommended for dose determination, dose confirmation, field trials and persistent effectiveness studies. In certain circumstances there may be conditions acceptable for the use of arithmetic means.
4.3 Number of Animals (Dose Determination, Dose Confirmation and Persistency Studies
)The minimum number of animals used per experimental group is a critical point. The number of animals will depend on the type of statistical analysis used, however, the inclusion of at least 6 animals in each experimental group is a minimum recommended.
4.4 Pooling Data
Pooling data is allowed when certain criteria are taken into account. For sponsors intending to pool data it is important to ensure that a general protocol is standardized for each type of study proposed, that is dose confirmation, field and persistency studies. There should be similarity among numbers of animals/group numbers of parasites, type of animals and experimental conditions. Where pooled data are used, any aberrant result should be explained to the regulatory authorities.
Pooling of data should only be considered where more than two studies (as defined in Section B-2 below) have been conducted and the majority of individual studies provide 90% or greater efficacy, i.e. minimally three studies with at least two of these demonstrating efficacy of 90% or greater are recommended to pool data. The overall efficacy of the pooled studies should demonstrate efficacy of 90% or greater.
In the case of rare parasites an alternative approach should be used (i.e. more trials may be recommended).
The geometric means should be calculated based on all control values, i.e. dropping zero counts in control groups and a corresponding number of zero treated animals are not recommended.
4.5 Adequacy of Infection
A universal definition of adequacy of infection should not be formulated because of the diversity of genera, species and strains of helminths subject to evaluation. Furthermore, each strain under test may have unique characteristics of infectivity and pathogenicity. However, in the development of study protocols the adequacy of infection should be addressed, especially in terms of the statistical, parasitological and clinical relevance of the infection level in individual control animals, as well as the number of control animals in which infections are established. The level of infection, and its’ distribution, among control animals should be adequate to permit the appropriate standards of effectiveness to be met with acceptable statistical and biological certitude/confidence. Multiple infections are acceptable, however, each helminth species should reach acceptable minimums of infection.
In cases where all animals in the control group are infected, then one possible statistical method involves the use of calculating the lower 95% confidence limit of the control group geometric mean burden. If this value is greater than 10% of the control group geometric mean burden, then the infection can be said to be adequate. In the case where some of the animals in the control group are not infected (counts=zero) then the geometric means should be replaced by the median and the 95% confidence limit should be based on the control group median burden. However, whatever statistical method may be recommended, adequate infections are still recommended in (a minimum of) six control animals.
4.6 Aliquot Size
Aliquot size to determine parasite burdens should be at least 2%. Smaller aliquot size may be used with justification.
5 - Standards of Effectiveness
A compound should be declared effective only when effectiveness against each parasite declared on the labeling stands at 90% or above, based on calculation of geometric means using pooled data (when appropriate), and there is a statistically significant difference in parasite numbers between control and treated animals. However, there are regional differences where the epizootiology of certain parasitic infections may recommend higher minimal effectiveness, especially when the aim for drug effectiveness is focussed specifically on preventing pasture contamination. These will be covered in the individual host species guidances. Effectiveness below 90% may be adequate when the claimed parasites do not have any other effective treatment.
6 - Definition of Helminth Claims
Parasite identification will determine the type of claim proposed on the labeling. A species claim is highly recommended. However, a genus claim should be acceptable on the assumption that generally speaking there is more than one species in that genus. If species claims are to be made then the presence of each should be confirmed including two dose confirmation studies for each parasite.
B. Specific Evaluation Studies
Three types of studies should be used in the evaluation of all new anthelmintics: dose determination, dose confirmation and field effectiveness studies. Special studies may also be used to determine the persistent effectiveness of an anthelmintic.
1 - Dose Determination Studies
Dose titration trials should from now on be referred to as dose determination studies, their purpose being to determine the dose rate to be recommended for the particular target animal. The studies may or may not be conducted using the final formulation. However, if not, any changes in the formulation should be scientifically justified. Some regulatory authorities may waive the requirement for a dose determination study where alternative data are presented to support the intended dosage. For generic products, where the optimum dose of the active ingredient has already been generally adopted, dose determination studies are not necessary.
When broad spectrum activity is claimed for an anthelmintic preparation, dose determination studies should contain a dose-limiting species within the claimed spectrum, and should be independent of whether the dose limiting species is a high or a low (= rare) prevalence species. The sponsor should select the parasites taking into consideration their impact on animal health. Confirmation of effectiveness against the species for which a claim is made, should be completed in the dose confirmation studies.
When only one parasite is claimed (e.g. Dirofilaria immitis), the discussion on the number of species and the dose limiter becomes irrelevant.
One internationally accepted design includes a minimum of three groups receiving different levels of anthelmintic treatment e.g., 0, 0.5, 1 and 2x the anticipated dose together with a group of untreated controls. It is suggested that the range of doses should be selected on the basis of preliminary studies to encompass the approximate effective dose. The reason for the dose selected should be explained. For each selected parasite, groups of treated and untreated controls should consist of at least six (= recommended) adequately infected animals, but if there is any doubt about the level of infection then the number should be increased accordingly (see data analysis).
This phase of the testing should be conducted using adult parasites unless there is information that larvae of a particular parasite could be a dose-limiting stage or the proposed product claim is only targeting a specific parasite at the larval stage (e.g. Dirofilaria immitis). Dose determination studies may be conducted using natural infections, however induced infections are preferred. Both laboratory strains and recent field isolates (see glossary) can be used to develop induced infections.
2 - Dose Confirmation Studies
These studies should be conducted using the final formulation of the drug to be commercialized. The dose confirmation work should not be conducted on known drug resistant strains of parasites. To investigate effectiveness against adult parasites, naturally infected animals are preferred. However, induced infections using recent field isolates in one of the studies are acceptable. For rare parasite species, laboratory strains may be used and they may be conducted outside the geographic location in which the product will be authorized for marketing. Dose confirmation for larval stages should be conducted using induced infections. The sponsor should explain deviations from this recommendation. Against inhibited stages only natural infections are recommended.
At least two controlled or, when appropriate, critical dose confirmation studies per individual claim are recommended (single or multiple infections). Two studies are the minimum suggested to verify that effectiveness can be achieved against various helminth strains in animals raised in disparate regions and climates and under respective husbandry conditions. At least one of the studies should be conducted in the geographic location where registration is being pursued and both studies should be conducted under conditions that are sufficiently representative of the various conditions under which the product will be authorized. In the event that in certain locations parasites are particularly rare then two trials from outside the location should be acceptable. Since the sensitivity of the parasites to treatment should be independent of the geographical location, additional confirmation studies from local regions are not justifiable. Such considerations should be addressed in the confirmatory field trials. A dose determination study can be used in place of one of the confirmation studies, if the final formulation was used and administered under label recommendations.
For each study, it is recommended that at least six animals per treatment group should be adequately infected. The adequacy of the infection should be defined in the protocol phase. A sufficient number of infected animals should be examined before treatment to ensure that at least 6 (= recommended) adequately infected animals for the parasite or life stage of a parasite are present at the start of the trial (see recommendations for the calculation of effectiveness).
3 - Field Effectiveness Studies
These studies should be conducted using the final formulation of the drug product to be commercialized to confirm effectiveness and safety. The number of field trials to be conducted and animals involved in each trial should depend on (1) the animal species, (2) the geographic location and (3) local/regional situations. The controls i.e. non treated animals or animals treated with a registered anthelmintic with a known profile, should equal a minimum of 25% of the treated animal numbers. Local/regional implies within a country and/or association with a climatic and/or management area (see also glossary). To achieve the requested numbers it is also acceptable to conduct multi-center studies with sub-trials in each local/region. The request for additional (or fewer) studies, and/or animals (animal welfare considerations) by local regulatory authorities should be fully justified. The product should always be tested in the breed/age range/class/production type of animal intended to be treated as indicated on the labeling.
4 - Persistent Effectiveness Studies
Modern broad spectrum anti-parasitic compounds may show persistent effectiveness due to the presence of residual activity of either the parent compound, or the metabolites, in the treated animal. These claims should be based on actual worm counts and not on number of eggs per gram of faeces. Claims of activity of less than seven days should not be considered a persistent effect and claims should mention persistent effectiveness for a certain number of days. The type of protocol depends on the animal species and will be discussed under the specific target species guidance.
As described for dose confirmation, a persistence claim (for each duration and parasite claim) should include two trials (with worm counts) each with a non-treated and treated group. It is recommended that at least six animals per treatment group should be adequately infected. The adequacy of the infection should be defined in the protocol phase. Persistence claims should be in terms of a species-by-species basis.
GLOSSARY
ADEQUATE INFECTION:
ALIQUOT SIZE
CLAIM
CONTROLLED TEST
CRITICAL TEST: A procedure whereby the number of parasites recovered from an animal after the treatment is added to the number counted in the intestine at necropsy which are considered to be the total number of parasites in the animal at the time of treatment. The effectiveness is calculated as follows: [Nº of parasites expelled] divided by [(Nº of parasites expelled) plus (Nº of parasites remaining)] X100 is equal to % effectiveness in the individual animal.
DOSE CONFIRMATION STUDY:
In-vivo study to confirm the effectiveness of a selected drug dose and formulation; may be conducted in the laboratory or in the field.
DOSE DETERMINATION STUDY: In-vivo
study conducted to determine the most appropriate dose or range of effectiveness of a veterinary drug.
DOSE-LIMITING PARASITE:
A parasite that will be identified during dose determination studies that will identify the dosage of the drug at which it shows 90% effectiveness. Any lower concentration of the product will show an effectiveness below 90% for the doselimiting parasite even though it will adequately treat other parasites (90% or better effectiveness) in the host.
EFFECTIVENESS:
The degree to which the manufacturers claims on the labeling have been supported by adequate data i.e. providing control of at least 90% on the basis of the calculation of geometric means using pooled data from controlled studies.
FIELD EFFECTIVENESS STUDY:
Larger scale study to determine effectiveness and safety of a veterinary drug under actual use conditions.
GCP:
Good Clinical Practice: A set of recommendations intended to promote the quality and validity of test data. It covers the organizational process and the conditions under which studies are planned, performed, monitored, recorded and reported.
GEOGRAPHICAL LOCATION:
A subdivision where the guidances will be implemented: Japan, European Union, USA and Australia/New Zealand.
FIELD ISOLATE:
A collection of a sub-population of helminths for the conduct of drug effectiveness tests isolated from the field less than 10 years ago. The helminths are considered representative of current parasitic infections in the field and have been characterised (source, date, location, previous anthelmintic exposure and maintenance procedures).
LABORATORY STRAIN:
A sub-population of helminths that has been isolated from the field at least 10 years ago, characterised and has been segregated in the laboratory based on a particular property which makes it unique for research areas such as resistance to certain antiparasitic compounds.
RARE PARASITE
: Low prevalence parasite species which may or may not be able to produce significant morbidity and clinical symptoms, usually limited to certain geographic locations.
REGION:
An area within a geographical location defined by climatic conditions, target animal husbandry, and parasite resistance prevalence.
VICH:
Veterinary International Cooperation on Harmonization. |
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