USPVeterinaryClinicalDrugInformationMonographDevelopmentProcess TheUnitedStatesPharmacopeia(USP)hasdevelopedclinicaldruginformation monographsthatprovideevidenceranked,speciesspecificextralabelrecommendations, withinaframeworkof compiledFDAapprovedproductlabelinformation,fortheuseof antibioticsinthemajorspecies,includingcatsanddogs. Thedevelopmentprocesswasa collaborativeeffortbetweentheUSPVeterinaryMedicineInformation Expert Committees(VMI) thatservedfrom1985tothepresentandstaffwithintheUSP VeterinaryGroup.

Committeememberswoulddecidewhich therapeuticcategories,and drugswithineachcategory,wereof greatestneed tothepractitioner.For the antimicrobials,22monographscovering63selectedmedicationswerecreated. OncedrugswereselectedbyVMIformonographdevelopment,astaff veterinarianobtainedpublicly availableinformationonthedrugsforreview,including USAandCanadianlabelinformation,FDAFreedomofInformationdocuments,foreign druglabels,andpeerreviewedjournalarticles.Carefulattention waspaidtospecies specificinformation.Thisinformation wasthenarrangedintoa common template containing:brandnames,categoryofdrug,indications,regulatoryconsiderations, chemistry,pharmacology andpharmacokinetics(i.e.,mechanismofaction/effect, absorption,distribution,proteinbinding,biotransformation,elimination),precautionsto consider,side/adverseeffects,overdoseinformation,clientconsultation,veterinary dosinganddosageformsinformation. Certain sections,suchaschemistryandregulatoryconsiderations,werenot contentious. Allreliablepharmacokineticinformationfoundwasadded,regardlessof species.Theindication anddosingrecommendations,however,requiredthegreatest

effort, andVMIappliedthemostintensiveevidencebasedapproachtoreachaconsensus onthesetwosections. Foreach extralabelindication,andanylabelindicationthatwasviewedas contentiousbyan ExpertCommitteemember,aspeciesspecificevidencetable summarizedallpertinentitemsofliterature. The tablewouldcontainthecitation information,thetypeofstudy[e.g.,casereport(s),clinicaltrial,diseasemodel,invitro study,metaanalysis,pharmacokineticstudywithoutsurrogateendpoints, pharmacokineticstudywithsurrogateendpoints], methodof randomization,typeof controlused(e.g.,positive,negative,uncontrolled),andthetypeofmaskingused(e.g., singlemasked,doublemasked,nonmasked).Asynopsisoftheclinicalmethodsused, dosesanddurationoftherapystudied,results,authorconclusions,andlimitationsnoted by theUSPstaff veterinarianwereincluded.Aportionofanexampleevidencetableis giveninFigure1. When all oftheevidencetablesforaparticulardrugorfamilyofdrugshadbeen constructed,theywereintegratedintoamonographballotprovidedtoVMIExpert Committeemembersandthirdparty adhocreviewersforinitial discussion.Therefore, reviewershadaccesstotheevidencetablesandallotherinformation compiledforthat drug(includinglabeledindications,pharmacokineticandsafetydata)duringthedecision makingprocess. Onceapreliminary consensusontheindicationsthatwouldbeincludedinthe monograph wasreached,aspeciesspecificstatementforeachindicationtobeincluded wasdraftedandplacedintooneofthreecategories.Acceptedindicationswerethose thathadsubstantialdatasupportingthemandwereincommonuse.Themajorityofthese

wereindicationsincludedincurrentproductlabeling,butextralabelindicationsalso wereincludediftheyrosetotherequiredlevelofevidence.ThePotentiallyeffective category (alsoknownasAcceptancenotestablishedintheolderUSPinformation monographs)includedindicationswithmoderateevidencetosupportaparticularuse, oftenaddressinganunmetclinicalneed.Lastly,anindicationmay havebeen deemed Unaccepted,meaningthedrugshouldnotbeusedforagivenpurpose.Thislatter categorization wasmostoftenappliedtoolderdrugsthatnewertreatmentshadrendered obsoleteduetoimprovedsafetyand/orefficacy.Inaddition,beginningin2005,allnew monographsandrevisionsofoldermonographsincludedevidenceratingsforeach indication.EachratingwascomposedofoneoverallEvidenceQualityindicatorandone ormoreEvidenceTypeindicators(seeExamples1and2).Themonographidentified intowhichofthethreecategoriesanindicationfell,combinedwiththedrugproducts evidenceratings,providinganevidentiarybasistosupportanindicateduse. Theevidencetablescreatedforextralabel indicationswerealsousedaspartof thediscussionsforcorrespondingdosagerecommendations.Inafewcases,tableswere specificallycreatedtoaddressadosagecontroversy.Bothextralabelindicationsand dosingwereassignedadesignationtodifferentiatethem fromlabeledrecommendations ineachmonograph. Theinitialballotallowedcommentsonanyportionofthemonograph,inaddition torequestingdecisionsonindicationsanddosing.Itwastypicallyfollowedbyatleast oneballotsummarizingtheinitialresponsestoissuesonwhichaconsensuswasnot reached. DraftmonographrevisionandExpertCommitteereviewcontinueduntila consensuswasreachedonallpreviouslycontentioussections. Themonograph wasthen

listedforpublicreviewonUSPswebsite,duringwhichtimecopiesofdrafttextwere madeavailabletothemanufacturersofthedrug,theCenterforVeterinaryMedicine/U.S. FoodandDrugAdministration,andall otherinterestedpartiesforreviewandcomment. Followingpublicreviewthemonograph wasfinalized,becamepartof USPsauthorized text(notFDAenforceable),andwaspublished.Monographsunderwentperiodic updates,asneeded. USP monographsweretheonlydruginformationsourcein veterinarymedicinewhichunderwentsuchextensiveevidencebasedevaluationcoupled withexpertpanelreview,aprocessbywhichthescientificcredibilityoftheinformation wasmaintained. InDecemberof2008,USPunderwentasignificantstaffreductionwitha concomitantreductionoreliminationofcertaininformationprograms,duetothe worldwideeconomicdownturn.Thereisnolongeraveterinarianonstafftoworkwith theVMIExpertCommitteetodevelopandupdatethemonographsandevidencetables. Mostofthemorethan100evidencetablescreatedduringdevelopmentofthisevidence basedinformationarenotpubliclyavailable.InSeptember2009,theVeterinaryClinical DrugInformationmonographsweretransferredtotheAmericanAcademyofVeterinary PharmacologyandTherapeuticsandcanbeaccessedonthewebsiteat http://www.aavpt.org/USPmonographs.shtml.Thefuturedevelopmentofthisdrug informationresourceisbeingdiscussedwithintheAAVPTandtheAmericanCollegeof VeterinaryClinicalPharmacology.

Example1.Evidencetable Cefazolininthe preventionof perioperativeinfectionsindogs.

Revisiondate:June16,2008 Study1of 1:WhittemTL,JohnsonAL,SmithCW,etal.Effectofperioperativeprophylactic antimicrobialtreatmentindogsundergoingelectiveorthopedicsurgery.JournaloftheAmerican VeterinaryMedicalAssociation1999July15215(2):2126. Goal:Toinvestigatewhetherperioperativeantibioticadministrationreduces Limitations: theriskofdevelopingpostoperativeinfectionafterelectiveorthopedicsurgery. Nonewere noted. Methods: Dogspresentedforelectiveorthopedicsurgery.Exclusionsincludedsurgery requiringinternalfixationdevices,dentalproceduresalsoperformed, antibioticgivenwithintheprevious30days,openfractures,multiplelimb trauma,infectionneartheincisionsite,andseveregingivitisorotitisexterna. Onlythepharmacistwhomadeupthetreatmentsknewwhichmedication N=126total wasgiventoeachsubject.Justbeforethesurgeryincisionwasclosed,a cases cultureswabwastakenfromtheincisionsite.Specificcriteriaweresetto enrolled evaluatewhetherpostoperativeinfectionhadoccurred. Theauthorsexpectedtoneed201casestohavesufficientdataforevaluation. Design: Random ized, blinded, controlled clinicaltrial Doseandduration: Medicationswereadministered30minutesbeforethefirstincisionand,if surgerylastedmorethan90minutes,aseconddosewasgiven.Dogswere monitoredfor10to14daysaftersurgery. Group1(48dogs)Intravenouscefazolin,20mgperkgofbodyweight (mg/kg) Group2(43dogs)IntravenouspenicillinG,40,000unitsperkgofbody weight Group3(35dogs)Intravenoussaline Results: Thestudywasendedearly,basedonthedatafromthefirst112dogs significantlymoreinthecontrolgroupdevelopedinfections(15.6%)than dogstreatedwitheitherantibiotic(3.8%).Nosignificantdifferencein infectionratewasfoundbetweenthetwogroupsreceivingantibiotics. Usingtheinfectionratesfound(6.3%forcefazolintreated,2.3%for penicillinGtreated,14.3%fornoantibiotic),5,000MonteCarlosimulations wererun.Theresultssuggesteddogsthatreceivednoantibioticdeveloped infectionsignificantlymorefrequentlythanthosegivenantibiotics.No statisticallysignificantdifferencecouldbefoundbetweenthetwogroups treatedwithantibiotics. Conclusions: CefazolinorpenicillinGshouldbeequallyeffectiveinpreventing postoperativeinfectionfromelectiveorthopedicsurgery.

Example2.EvidenceratingsandIndicationStatement EvidenceQuality A.Goodevidencetosupportarecommendationforuse B.Moderateevidencetosupportarecommendationforuse C.Insufficientevidencetosupportarecommendationforuse D.Moderateevidencetosupportarecommendationagainstuse E.Goodevidencetosupportarecommendationagainstuse EvidenceType 1. Speciesspecificevidencefromatleastonelargerandomizedandcontrolledtrial (RCT)ormultiplesmallRCTs 2. SpeciesspecificevidencefromasmallRCT,diseasemodels,largecasestudies, pharmacokineticstudiesusingsurrogateendpoints,orevidencefromwelldesigned trialsinadifferentspeciesthatisconsideredappropriateforcomparison. 3. Dramaticresultsfromeitherwelldesigned,speciesspecifictrialswithoutcontrols, controlledtrialswithoutrandomization,orsmallcasestudies. 4. Pharmacokineticstudieswithoutsurrogateendpointsorwelldesigned pharmacodynamicstudiesinhealthyanimals 5. Invitrostudies 6. Opinionsofrespectedauthoritiesonthebasisofclinicalexperienceorreportsof expertcommittees.

Exampleofanindicationstatementinthemonograph Dogs Accepted US,CAN EL EL *Perioperativeinfections(prophylaxis) Cefazolinis usedinthepreventionofinfectionsassociatedwithsurgery, includingbonesurgery,andcausedbysusceptibleorganisms, whentheriskofinfectionishighorpotentiallyseverelydamaging (Evidencerating:A1,2).{R1268283} *ELUS,CAN indicatesanextralabelindicationintheU.S.andCanada.