Guideline for the testing and evaluation of the efficacy if antiparasitic substances for the treatment

12 Pages·2001·0.07 MB·English

TheEuropeanAgencyfortheEvaluationof Medicinal
Products
VeterinaryMedicinesandInformationTechnology
EMEA/CVMP/005/00-FINAL-Rev.1
COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS
GUIDELINE FOR THE TESTING AND EVALUATION OFTHE EFFICACY OF
ANTIPARASITIC SUBSTANCES FOR THE TREATMENT AND PREVENTION OF
TICK AND FLEA INFESTATION IN DOGS AND CATS
ADOPTION BY CVMP FOR RELEASE FOR 11 - 13 January2000
CONSULTATION
START OFCONSULTATION 14 January2000
END OFCONSULTATION 13 July2000
APPROVALBY EFFICACY WORKING PART 9 - 10 October 2000
ADOPTION BY CVMP 7 - 9 November 2000
MINOR MODIFICATIONS BY CVMP 15 February2001
DATE OFCOMING INTO EFFECT 9 May2001
Public 7WestferryCircus,CanaryWharf,London,E144HB,UK
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E-mail:[email protected] http://www.eudra.org/emea.html
EMEA2000Reproductionand/ordistributionofthisdocumentisauthorisedfornon-commercialpurposesonlyprovidedtheEMEAis
acknowledged
GUIDELINE FOR THE TESTING AND EVALUATION OFTHE EFFICACY OF
ANTIPARASITIC SUBSTANCES FOR THE TREATMENT AND PREVENTION OF
TICK AND FLEA INFESTATIONS IN DOGS AND CATS
1. INTRODUCTION
1.1 General
Thisnotefor guidanceisintendedasanadditiontothenotefor guidanceonthedemonstrationof
efficacyofectoparasiticidesdealingwithgeneralrequirementsfor theassessmentofefficacyofsuch
products.
Thisnoteprovidesspecialguidancewithrespecttothetestingandevaluationofefficacyofantiparasitic
productsthatareintendedfor externalusefor thetreatmentandpreventionoftickandflea infestations
indogsandcats.For productswithinsectgrowthregulatingproperties,somepartsofthisguideline
maynotbeapplicable.
Thisnoteshouldbereadalsotogether withDirective92/18/EECandtheCVMP/VICH-Guidelineon
GoodClinicalPractice(CVMP/VICH/595/98-FINAL).
1.2 Datarequirements
Inprinciple,thedemonstrationofefficacyincludesthefollowingtestphases:
- Descriptionofthemodeofaction
- Determinationofdose
- Doseconfirmationtrials,includingpersistentefficacytrials,whereapplicable
- Clinicalfieldtrials
Twotypesofstudiesshouldbeperformed:laboratorystudiestoestablishimmediateandpersistent
efficacyofa product,dependingontheclaim,andfieldstudiestoconfirmtheresultsoflaboratory
studies.
1.3 Ectoparasitespecies
Thechoiceoftickandflea speciestobetesteddependsontheir epidemiologicalstatusintheEuropean
member statewheretheveterinarymedicinalproductisintendedfor marketing.
Mostrelevanttickandflea speciesindogsandcatsinEurope:
Ticks:
Dermacentorreticulatus
Ixodeshexagonus
Ixodesricinus
Rhipicephalussanguineus
Fleas:
Ctenocephalidescanis
Ctenocephalidesfelis
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2. STUDYDESIGNFORTESTINGTHEEFFICACYOFPRODUCTSFORTHE
TREATMENTANDPREVENTIONOFTICKINFESTATION
Studiesfor eachtickspeciesandeachstageofthelife-cycleagainstwhichefficacyisclaimedshouldbe
provided. Theapplicantshouldjustifythetypeofstudies(invitroandinvivolaboratorystudiesand
fieldstudies)for eachspeciesandstage.
Asitisnotappropriatetofixbags,capsulesandtheliketocats,resultsoflaboratorystudiesindogsto
establishtheefficacyinthetreatmentandpreventionoftickinfestationsmaybeextrapolatedtocats.
However,a doseconfirmationstudyincatsshouldbeperformed.Inviewofthedifficultiesof
experimentalinfectionstudiesincats,pharmacokineticparametersmaybeusedinstead.Claimsfor
efficacyincatsshouldbesupportedbyfieldstudies.
2.1 Laboratorystudies
2.1.1 Tickspecies
For demonstrationoftheefficacyinvivoitwillbesufficienttoperformtestinginadultticksonlysince,
ingeneral, larvaeandnymphshavea higher susceptibility. Nevertheless, thehigher drug-sensitivityof
larvaeandnymphsofa claimedtickspeciesshouldbecheckedinvitrobeforestartinginvivo
experiments,unlessitcanbedemonstratedbybibliographicdata.
Normally,atleast2establishedtickstrainsper indicationwillbesufficientfor laboratorytesting.
Whereefficacyisclaimedfor strainsofparasitesresistanttoe.g.organophosphates,definedresistant
laboratorystrainsshouldbeusedfor testing.
2.1.2 Selectionofanimals
Thechoiceofexperimentalanimalsshouldbejustifiedbytheapplicant.Itisdesirabletohaveanimals
ofa breedcharacterisedbya fur ofmoderatehair length,sothattheticksareoffereda chanceof
penetratingthroughthehair andbeingretainedontheanimals.
2.1.3 Allocation
Animalsshouldbemaintainedseparatedinindividualaccommodationduringthetrialtoensurethat
crosscontaminationdoesnotoccur.Itisrecommendedtoincludeatleast6animalsper
treatment/controlgroup.
2.1.4 Tickinfestation
Theinfestationlevelshouldbeapproximately50unfedadultticks(approximatelysexratioof1:1,
exceptfor Ixodesricinus)andofverysimilar ageper testanimalandinfestationtimepoint.Twentyfive
tofiftypercent(e.g.12-25ticks)oftheseticksshouldattachtotheanimalateachtimepointfollowing
infestationinthecontrolgroup.Thisdemonstratesthatthetickpopulationusedisvigorous.
Wholebodyinfestation
Ticksareappliedatoneor morepointsontheanimaltoallowthemtodistributeover theanimal.For
thisprocedure,theanimalsshouldbekeptquietfor approximately10minutesifpossible(e.g.bymild
sedation)sothatthetickscanattachfirmlytothefur withoutbeingremovedbytheanimal.
Siteinfestation
Thiscanbeusedasanalternativemethodfor testinganacaricidaleffectofa product.Infestationtakes
placewithina bag,capsuleor other device.Suchdevices,attachedtothebody,ear,pawor tail,can
alsobeutilisedtoexaminethelevelofactivesubstanceattheextremitiesoftheanimal.Theapplicant
shoulddescribeandjustifythemethodused.
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2.1.5 Criteriaofefficacy
2.1.5.1 Repellenteffect
Arepellenteffectmeansthatnotickswillattachtotheanimal.Ticksalreadyontheanimalwillleave
theanimalsoonafter treatment.
Ingeneral,noticksshouldbedetectableontheanimalafter 24hoursfollowingadministrationofthe
product.
2.1.5.2 Acaricidaleffect
Inevaluatingtheacaricidalefficacyofa product,thefeedingor engorgementofticksshouldbetaken
intoconsiderationinadditiontotherateatwhichticksarekilled.Itisrecommendedtoassessthe
acaricidaleffectonindividualticksaccordingtothefollowingparameters:
Definitionofparameters
Category Generalfindings Attachmentstatus Effect
1 live free no
2 live attached;unengorged no
(exceptsingleticks)
3 live attached;engorged no
(exceptsingleticks)*
4 killed free yes
5 killed attached;unengorged yes
6 killed attached;engorged no
(exceptsingleticks)*
*Note:Intheeventofanoccurrenceofsingleticksinthetreatmentgroupofcategories3and6,within
48hoursfollowinginfestation,a notecorrespondinginmeaningtothelinesproposedbelowshouldbe
includedintheSPCandpackageinsert:
Theremaybeanattachmentofsingleticks.Forthisreason,atransmissionofinfectious
diseasebytickscannotbecompletelyexcludedifconditionsareunfavourable.
Indicationssuchas„toprevent...“or „forprophylacticuse“shouldbeomittediftheeffectispurely
acaricidal,becauseasa rule,anattachmentoftheticksisnotpreventedbytheacaricidalsubstance.
Thus,a preventiveeffectisnotwarranted.Asa consequence,a notecorrespondinginmeaningtothat
proposedbelowshouldbeincludedintheSPCandpackageinsertifanacaricidaleffecthasbeen
claimed:
Tickswilldetachfromthehostwithin24to48hoursafterinfestationwithouthavinghada
bloodmeal,asarule.Anattachmentofsingleticksaftertreatmentcannotbeexcluded.
2.1.6 Efficacytesting
Productswithrepellentor acaricidalpropertiesmaydemonstrateshortterm(<4weeks)or longterm(>
4weeks)persistenteffects.Productswithshort-termeffectstypicallyincludeshampoos,spraysand
spotons/pour ons. Productswithlong-termeffectsincludetypicallycollars. Efficacyshouldbe
establishedatintervalsthroughouttheperiodofeffectclaimed. Theapplicantshouldjustifythe
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methodsusedfor theassessmentofefficacy.Itisrecommendedthattickcountsaremadebypalpating
thedogandbyvisualassessment.Ticksshouldberemovedfromtestanimalsafter eachcounting.
2.1.6.1
For acaricidesthefollowingtimescheduleisrecommended:
Day -7: Examinationoftickstrainfor infestationrateandsuitabilityoftest
animals.
Day -2: Tickinfestation
Day 0: Applicationoftestsubstance.
Immediateefficacy Efficacytestingbypalpatingthedogandbyvisualassessmentaccordingto
thedefinitionsgivenunder 2.1.5.2atday0upto48hor longer if
appropriate(e.g.collars).
Short-termpersistent Preparationswitha claimedpersistentefficacyfor upto4weeks,e.g.
efficacy shampoo,spray,spotons,pour ons:
Weeklyinfestationofticks,efficacytestingupto48hfollowingeach
challengeasdescribedabove.
Long-termpersistent Preparationswitha claimedpersistentefficacyfor morethan4weeks,e.g.
efficacy collars:
Tickinfestationevery4weeksover theperiodofeffectivenessclaimed,
efficacytestingupto48hafter eachchallengeasdescribedabove.
Lastmonthoftheperiod
ofeffectivenessclaimed:
For reasonsofdecreasingefficacy,infestationevery2weeks.
2.1.6.2
For repellentsthefollowingtimescheduleisrecommended:
Day-7: Examinationoftickstrainfor infestationrateandsuitabilityoftest
animals.
Day 0: Applicationoftestsubstance.
Day 0 +24h* Tickinfestation.
Immediateefficacy Efficacytestingbypalpatingthedogandbyvisualassessmentupto24h
after challenge
Long-termpersistence Tickinfestationat4-weekintervalsover theperiodofeffectivenessclaimed
efficacy andefficacytestingupto24hafter challenge.
Lastmonthoftheperiod For reasonsofdecreasingefficacy,infestationevery2weeks.
ofeffectivenessclaimed:
* Theperiodoftimerequiredfor distributionoftheactivesubstancemayvarydependingonthe
productformulationandmaybelonger.
Note:Whereeffectivenessover severalmonthsisclaimed,theticksshouldbeappliedat4-week
intervalsover thefirstthreemonthsbecauseitshouldbetakenintoaccountthata toofrequent
applicationofticksmayinduceanindividuallyvaryingimmunitytoticksinthetestanimal.Inturn,this
mayadverselyaffecttheinfestationrate.Also,severereactionsatthesiteofapplicationshouldbe
reducedtoa minimum.
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2.1.7 Evaluationofefficacy
For calculationofefficacy(%),thefollowingformula (accordingtoAbbott’sformula)1is
recommended:
Efficacy(%)=100x (m –m )/m
C T C
Controlgroup(m ): Meannumber ofliveticksonthehostanimals
C
Treatmentgroup(m ):Meannumber oflive(categories1-3)or killed,engorgedticks(category6)on
T
thehostanimals.
Arithmeticmeansareusuallyacceptablefor thiscalculation.Ifgeometricmeansareused,the
transformationmustbejustifiedandthearithmeticmeansalsorecorded.
Theefficacyoftheproposedproductshouldbe>90%.
2.1.8 Testingforphotostability
For productsintendedfor externaluse,thefinalformulationintendedfor marketingshouldbetestedfor
itsphotostability,e.g.byUVradiationunder laboratoryconditions.
2.1.9 Testingforwaterstability
For productsintendedfor externaluse,thewater stabilityoftheformulationintendedfor marketing
shouldbedemonstrated,especiallyfor productswitha claimeddurationofefficacyfor 2or more
weeks.Theimpactofexposuretowater e.g.throughshampooing,swimming,rainwater onthe
acaricidal/repellenteffectshouldbeevaluatedatregular intervals(e.g.oncea week).Alternatively,data
ontheconcentrationtimecourseoftheactivesubstanceinthefur after single/repeatedwashingafter
treatmentcanbeprovided.Ifthewater stabilityoftheproductintendedfor marketingcouldnotbe
demonstrated,or data arenotavailable,thefollowingwarningshouldalwaysbeincludedintheSPC
andpackageinsert:
Avoidfrequentswimmingorshampooingtheanimalorremovecollarbeforehandbecause
theremaybeareductionoftheeffectiveness.
1W.S.Abbott(1987)
Abbott’sFormula-AMethodofComputingtheEffectivenessofanInsecticide
JournalofTheAmericanMosquitoControlAssociation,Vol.3,2,302-303
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2.2 Fieldstudies
2.2.1 General
Fieldstudiesshouldtakeplacewhentherelevanttickspeciesareabundantandshouldbeperformedin
atleast2differentgeographicregions.Theresultsofthefieldstudyshouldlargelyconfirmthoseofthe
laboratorystudy.Fieldstudiesshouldbeperformedfor eachanimalspecies(dog/cat)claimed.
2.2.2 Selectionofanimals
Thestudyshouldincludeanimalsconfirmedtobeinfestedwithticksbyanappropriatelyqualified
personwhoshouldrecordtheinitiallevelofinfestationinthequestionnaire.Thetickspeciesshouldbe
identified.
Atleasta totalof50casesineachregionshouldbeavailablefor efficacyevaluation.Theanimals
shouldbelongtoa varietyofbreedsofdifferenthair lengthandtodifferenthusbandries.Furthermore,
animalsexposedtoa highriskofinfection(e.g.hounds)shouldbeincludedifpossible.
2.2.3 Counting
Countsshouldbeundertakenatweeklyintervals.
2.2.4 Treatment
Thefinalformulationintendedfor marketingshouldbeusedattherecommendeddoseandroute.Any
deviationshouldbejustifiedbytheapplicant.Thestudyshouldincludea controlgroup.
2.2.5 Studyprotocol
Anexamplestudyprotocolisattachedtothisguideline.
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3. STUDYDESIGNFORTESTINGTHEEFFICACYOFPRODUCTSFORTHE
TREATMENTANDPREVENTIONOFFLEAINFESTATION
Bothlaboratoryandfieldstudiesshouldbeperformedfor eachanimalspeciesclaimed(dog/cat).
3.1 Laboratorystudies
3.1.1 Fleaspecies
Laboratorystudiesfor eachflea speciesandeachstageofthelife-cycleagainstwhichefficacyis
claimedshouldbeprovided.Thetypeofstudies(invitroandinvivolaboratorystudies)for eachspecies
andstageshouldbejustified.Ifthelaboratorystudieshaveincludedtheflea speciescommonly
identifiedonthehostspeciesthenspecificationoffleasisnotusuallyrequiredinthefieldstudies.
Whereefficacyisclaimedfor strainsofparasitesresistanttoe.g.organophosphates,definedresistant
laboratorystrainsshouldbeusedfor testing.
3.1.2 Allocationoftestanimals
Thechoiceofexperimentalanimalsshouldbejustified.Itisdesirabletoincludeanimalsofa breed
characterisedbya fur ofmoderatehair length,sothatthefleasareoffereda chanceofpenetratingthe
hair andbeingmaintainedontheanimal.
Animalsshouldbemaintainedseparatedinindividualaccommodationduringthetrialtoensurethat
crosscontaminationdoesnotoccur. Itisrecommendedtoincludeatleast6animalsper
treatment/controlgroup.
3.1.3 Fleainfestation
Studiestosupportclaimsforthetreatmentofadultfleas:
Itisrecommendedtoinfestthetestanimalswith50-100unfedadultfleasofverysimilar agefor each
infestation.Eachanimalshouldbeinfestedwiththesamenumber offleas.Fleasshouldbedistributed
over theentirehostanimal.Approximately50%ofthesefleasshouldbepresentonthecontrolanimals
ateachtimepointfollowinginfestation.
Studiestosupportclaimsforthepreventionoffleainfestations:
Dependingonthespecificnatureoftheclaim,alternativestudydesignsmaybeapplicable,for example,
usingenvironmentsabletosupportflea infestations.Theapplicantshouldjustifythechoiceofstudy
design.
3.1.4 Testingforefficacy
Insecticidalproductsmaydemonstrateshortterm(<4weeks)or longterm(>4weeks)persistent
effects.Productswithshort-termeffectstypicallyincludedusts,spraysandspotons/pour ons.Products
withlong-termeffectstypicallyincludecollars.
Efficacyshouldbeestablishedatintervalsthroughouttheclaimedtime.
Theapplicantshouldjustifythemethodsusedfor assessmentofefficacyandthetimefromtreatmentto
assessmentofefficacy.Wherepossibleflea countsshouldbemadebycombing.However itisimportant
todemonstratethatreproducibleresultscanbeachievedbycombing.
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Thefollowingtimescheduleisrecommended:
Day -2: Flea infestation, 2daysbeforetreatment.
Day 0: Applicationoftestsubstance.
Immediateefficacy Efficacytestingwitha recognisedmethod,e.g.countingbycombing,atday
0upto48hfollowingtreatmentor longer ifappropriate(e.g.collars).
Short-term Preparationswitha claimedpersistentefficacyfor upto4weeks,e.g.
persistentefficacy shampoo,spray.
Weeklyinfestation,efficacytestingupto48hfollowingeachchallenge.
Long-term Preparationswitha claimedpersistentefficacyfor morethan4weeks,e.g.
persistentefficacy collars.
Flea infestationevery4weeksover theperiodofeffectivenessclaimed,
efficacytestingupto48hafter eachchallenge.
Lastmonthofperiodof
effectivenessclaimed: For reasonsofdecreasingefficacy,infestationevery2weeks.
Other effectssuchasrepellent,insectgrowthregulatoryor insectdevelopmentinhibitoryeffectsarenot
consideredinthisguidelinebutwillbedealtwithata lager stage. Ifclaimedtheseeffectsmustbe
demonstratedaccordingtoa recognisedscientificstandard.
3.1.5 Evaluationofefficacy
For calculationofefficacy(%),thefollowingformula (accordingtoAbbott’sformula)isused:
Efficacy(%)=100x (m –m )/m
C T C
Controlgroup(m ): Meannumber oflivefleasonthehostanimals.
C
Treatmentgroup(m ):Meannumber oflivefleasonthehostanimals.
T
Arithmeticmeansareusuallyacceptablefor thiscalculation.Ifgeometricmeansareused,the
transformationmustbejustifiedandthearithmeticmeansalsorecorded.
Theefficacyoftheproposedproductshouldbeapproximately100%.
3.1.6 Testingforphotostability
For productsintendedfor externaluse,thefinalformulationintendedfor marketingshouldbetestedfor
itsphotostability,e.g.byUVradiationunder laboratoryconditions.
3.1.7 Testingforwaterstability
For productsintendedfor externaluse,thewater stabilityoftheformulationintendedfor marketing
shouldbedemonstrated,especiallyfor productswitha claimeddurationofefficacyfor 2weeksor
more.Theimpactofexposuretowater e.g.throughshampooing,swimming,rainwater onthe
insecticidaleffectshouldbeevaluatedatregular intervals(e.g.oncea week). Alternatively,data onthe
concentrationtimecourseoftheactivesubstanceinthefur after single/repeatedwashingcanbe
provided.
Ifwater stabilityofthefinalproductcouldnotbedemonstrated,or data arenotavailable,thefollowing
warningshouldalwaysbeincludedintheSPCandpackageinsert:
Avoidfrequentswimmingorshampooingtheanimalorremovecollarbeforehandbecause
theremaybeareductionoftheeffectiveness.
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3.2 Fieldstudies
3.2.1 General
Fieldstudiesshouldbeperformedwhenfleasareabundant,inatleasttwodifferentgeographicregions.
Specificationoffleasisnotusuallyrequiredinfieldstudies. Theresultsofthefieldstudyshould
confirmthoseofthelaboratorystudy. Fieldstudiesshouldbeperformedfor eachanimalspecies
(dog/cat)claimed.
3.2.2 Selectionofanimals
Thestudyshouldincludeanimalsconfirmedtobeinfestedwithfleasbyanappropriatelyqualified
personwhoshouldrecordtheinitiallevelofinfestationinthequestionnaire. Atleasta totalof50cases
ineachregionshouldbeavailablefor efficacyevaluation.Thehostanimalsshouldbelongtoa variety
ofbreedsofdifferenthair lengthandtodifferenthusbandries.Furthermore,animalsexposedtoa high
riskofinfestationshouldbeincludedifpossible.Treatmentofthehomeenvironmentwithpesticides
(e.g.InsectGrowthRegulators)shouldbeavoidedduringthestudy.
3.2.3 Counting
Actualflea countse.g.throughcombingshouldbeperformedeverytwoweeks. However,for products
witha shorttermresidualactivitymorefrequentcountsshouldbeperformed.Themethodofflea
countingusedshouldbejustified.
3.2.4 Treatment
Thefinalformulationintendedfor marketingshouldbeusedattherecommendeddoseandroute.Any
deviationshouldbejustified.Thestudyshouldincludea controlgroup.
3.2.5 Studyprotocol
Anexamplestudyprotocolisattachedtothisguideline.
EMEA2001 10