美国植物药研究指南

GuidanceforIndustry

BotanicalDrugProducts

U.S.DepartmentofHealthandHumanServices

FoodandDrugAdministration

CenterforDrugEvaluationandResearch(CDER)

June2004

Chemistry

Chemistry

GuidanceforIndustry

BotanicalDrugProducts

CopiesofthisGuidanceareavailablefrom:

DivisionofDrugInformation(HFD-240),

OfficeofTrainingandCommunications,

CenterforDrugEvaluationandResearch(CDER),

FoodandDrugAdministration

5600FishersLane,Rockville,MD20857,(Tel)301-827-4573

Internetat

/cder/guidance/index.htm

U.S.DepartmentofHealthandHumanServices

FoodandDrugAdministration

CenterforDrugEvaluationandResearch(CDER)

June2004

TABLEOFCONTENTS

I.INTRODUCTION 1

II.BACKGROUND 2

III.GENERALREGULATORYAPPROACHES 3

A.MarketingUnderOTCDrugMonographVersusApprovedNDA 4

B.CMCInformationforBotanicalDrugProducts 5

C.CMCandToxicologyInformationtoSupportInitialStudies 5

D.ApplicabilityofCombinationDrugRegulations 6

IV.MARKETINGABOTANICALDRUGUNDERANOTCDRUGMONOGRAPH 6

V.MARKETINGABOTANICALDRUGUNDERANNDA 7

VI.INDSFORBOTANICALDRUGS 7

A.INDInformationforDifferentCategoriesofBotanicals 7

B.BasicFormatforINDs 9

1.CoverSheet(see§312.23(a)(1)) 9

2.TableofContents(see§312.23(a)(2)) 9

3.IntroductoryStatementandGeneralInvestigationalPlan(see§312.23(a)(3)) 9

4.Investigator′sBrochure(see§312.23(a)(5)) 9

5.Protocols(§312.23(a)(6)) 9

6.Chemistry,Manufacturing,andControls(§312.23(a)(7)) 10

7.PharmacologicalandToxicologicalInformation(§312.23(a)(8)) 13

8.PreviousHumanExperienceWiththeProduct(§312.23(a)(9)) 13

VII.INDSFORPHASE1ANDPHASE2CLINICALSTUDIESOFLAWFULLY

MARKETEDBOTANICALPRODUCTSWITHOUTSAFETYCONCERNS 13

A.DescriptionofProductandDocumentationofHumanUse 13

1.DescriptionofBotanicalsUsed(§312.23(a)(3)(i)) 14

2.HistoryofUse(§312.23(a)(3)(ii),(a)(9)) 14

3.CurrentMarketedUse(§312.23(a)(3)(ii),(a)(9)) 14

B.Chemistry,Manufacturing,andControls 14

1.BotanicalRawMaterial(§312.23(a)(7)(i)) 14

2.BotanicalDrugSubstance(§312.23(a)(7)(iv)(a)) 15

3.BotanicalDrugProduct(§312.23(a)(7)(iv)(b)) 15

4.AnimalSafetyTest(§312.23(a)(8)) 16

5.Placebo(§312.23(a)(7)(iv)(c)) 16

6.Labeling(§312.23(a)(7)(iv)(d)) 16

7.EnvironmentalAssessmentorClaimofCategoricalExclusion(§312.23(a)(7)(iv)(e)) 17

C.Pharmacology/ToxicologyInformation 17

1.AllMarketedBotanicalProducts 17

2.Foreign-MarketedBotanicalProducts 18

D.Bioavailability 18

E.ClinicalConsiderations 18

VIII.INDSFORPHASE1ANDPHASE2CLINICALSTUDIESFOR

NONMARKETEDBOTANICALPRODUCTSANDPRODUCTSWITHKNOWN

SAFETYCONCERNS 19

A.DescriptionofProductandDocumentationofHumanUse 19

1.DescriptionofBotanicalsUsed(§312.23(a)(3)(i)) 19

2.HistoryofUse(IfAny)(§312.23(a)(3)(ii),(a)(9)) 19

3.CurrentInvestigationalUse(IfAny)(§312.23(a)(3)(ii),(a)(9)) 20

B.Chemistry,Manufacturing,andControls 20

1.BotanicalRawMaterial(§312.23(a)(7)(i)) 20

2.BotanicalDrugSubstance(§312.23(a)(7)(iv)(a)) 21

3.BotanicalDrugProduct(§312.23(a)(7)(iv)(b)) 23

4.Placebo(seesectionVII.B.5) 25

5.Labeling(seesectionVII.B.6) 25

6.EnvironmentalAssessmentorClaimofCategoricalExclusion 25

C.NonclinicalSafetyAssessment 25

1.TraditionalPreparations 25

2.Others 26

3.ProductswithKnownSafetyIssues 26

D.Bioavailability 26

E.ClinicalConsiderations 27

IX.INDSFORPHASE3CLINICALSTUDIESOFALLBOTANICALPRODUCTS 27

A.DescriptionofProductandDocumentationofHumanExperience 27

B.Chemistry,Manufacturing,andControls 28

1.ExpandedClinicalStudies 28

2.End-of-Phase3ClinicalStudiesandPre-NDAConsiderations 32

C.NonclinicalSafetyAssessment 34

1.Repeat-DoseGeneralToxicityStudies 35

2.NonclinicalPharmacokinetic/ToxicokineticStudies 35

3.ReproductiveToxicology 36

4.GenotoxicityStudies 36

5.CarcinogenicityStudies 36

6.SpecialPharmacology/ToxicologyStudies 37

7.RegulatoryConsiderations 37

D.BioavailabilityandClinicalPharmacology 37

E.ClinicalConsiderations 38

GLOSSARY 39

QUESTIONSANDANSWERS 42

ATTACHMENTA:REGULATORYAPPROACHESFORMARKETINGBOTANICAL

DRUGPRODUCTS 47

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GuidanceforIndustry

1

BotanicalDrugProducts

ThisguidancerepresentstheFoodandDrugAdministration's(FDA's)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheappropriatenumberlistedonthetitlepageofthisguidance.

I.INTRODUCTION

Thisguidanceexplainswhenabotanicaldrugmaybemarketedunderanover-the-counter(OTC)drugmonographandwhenFDAregulationsrequireapprovalformarketingofanewdrugapplication(NDA),submittedundersection505(b)oftheFederalFood,Drug,andCosmeticAct(theAct),21U.S.C.355(b).Inaddition,thisdocumentprovidessponsorswithguidanceonsubmittinginvestigationalnewdrugapplications(INDs)forbotanicaldrugproducts,includingthosebotanicalproducts(orbotanicals)currentlylawfullymarketedasfoods(includingconventionalfoodsanddietarysupplements)intheUnitedStates.

Thisguidancealsodiscussesseveralareasinwhich,becauseoftheuniquenatureofbotanicals,FDAfindsitappropriatetoapplyregulatorypoliciesthatdifferfromthoseappliedtosynthetic,semisynthetic,orotherwisehighlypurifiedorchemicallymodifieddrugs(includingantibioticsderivedfrommicroorganisms).Thislattergroupofdrugsubstancesisreferredtointhisguidanceassyntheticorhighlypurifieddrugs.Therefore,whentherecommendationsonaspecifictopicdiscussedinthisguidancedifferfromthoseinotherexistingguidances(e.g.,

SubmittingSupportingDocumentationinDrugApplicationsfortheManufactureofDrugSubstances,1987),

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thisguidancetakesprecedence.Inparticular,thisguidancestatesthatapplicantsmaysubmitreduceddocumentationofnonclinical(preclinical)safetyandofchemistry,manufacturing,andcontrols(CMC)tosupportanINDforinitialclinicalstudiesof

1ThisguidancehasbeenpreparedbyworkinggroupsintheMedicalPolicy,PharmacologyandToxicology,andComplexDrugSubstancesCoordinatingCommitteesintheCenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration(FDA).

2FDAhasissuedadraftguidanceentitledDrugSubstance:Chemistry,Manufacturing,andControlsInformation,which,whenfinalized,willreplacethe1987guidance(see69FR929,January7,2004).

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botanicalsthathavebeenlegallymarketedintheUnitedStatesand/oraforeigncountryasdietarysupplementswithoutanyknownsafetyconcerns.

FDA'sguidancedocuments,includingthisguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency'scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.

II.BACKGROUND

Botanicalproductsarefinished,labeledproductsthatcontainvegetablematterasingredients.

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Abotanicalproductmaybeafood(includingadietarysupplement),adrug(includingabiologicaldrug),amedicaldevice(e.g.,gutta-percha),oracosmeticundertheAct.Anarticleisgenerallyafoodifitisusedforfood(21U.S.C.312(f)(1)).Whetheranarticleisadrug,medicaldevice,orcosmeticundertheActturnsonits“intendeduse”(21U.S.C.312(g)(1)(B)and(C),(h)(2)and(3),(i)).“Intendeduse”iscreatedbyclaimsmadebyoronbehalfofamanufacturerordistributorofthearticletoprospectivepurchasers,suchasinadvertising,labeling,ororalstatements.

Forthepurposesofthisdocument,thetermbotanicalsincludesplantmaterials,algae,macroscopicfungi,andcombinationsthereof.Itdoesnotinclude:

•Materialsderivedfromgeneticallymodifiedbotanicalspecies(i.e.,byrecombinantDNAtechnologyorcloning).

•Fermentationproducts(i.e.,productsproducedbyfermentationofyeast,bacteria,andothermicroscopicorganisms,includingwhenplantsareusedasasubstrate,andproductsproducedbyfermentationofplantcells),evenifsuchproductsarepreviouslyapprovedfordruguseoracceptedforfooduseintheUnitedStates(e.g.,antibiotics,aminoacids,andvitamins).

•Highlypurifiedsubstances(e.g.,paclitaxel)orchemicallymodifiedsubstances(e.g.,estrogenssynthesizedfromyamextracts)derivedfrombotanicalsources.

Thisguidanceaddressesallbotanicaldrugproducts(inalldosageforms)thatareregulatedundertheAct,exceptthosealsoregulatedundersection351ofthePublicHealthServiceAct(42

U.S.C.262).Althoughthisguidancedoesnotaddressdrugsthatcontainanimalsoranimalparts(e.g.,insects,annelids,sharkcartilage)and/orminerals,eitheraloneorincombinationwithbotanicals,manyscientificprinciplesdescribedinthisguidancemayalsoapplytothoseproducts.Whenadrugproductcontainsbotanicalingredientsincombinationwitheither(1)asyntheticorhighlypurifieddrugor(2)abiotechnologyderivedorothernaturallyderiveddrug,thisguidanceonlyappliestothebotanicalportionoftheproduct.

BotanicalproductandothertermsusedinthisguidancearedefinedintheGlossaryguidanceonly;thesedefinitionsmaynotbeappropriateinothercontexts.

3foruseinthis

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III.GENERALREGULATORYAPPROACHES

ManybotanicalproductsareusedwidelyintheUnitedStates.Dependingonitslabelingandintendeduse,abotanicalproductcanbeafood,adietarysupplement,and/oradrug.Botanicalsusedforfoodandconsumedprimarilyfortheirtaste,aroma,ornutritivevalue(e.g.,lettuce,herbsusedasseasonings)areregulatedasfoods.Botanicalscanalsobedietarysupplementsiftheyarelabeledasdietarysupplementsandotherwisemeetthedietarysupplementdefinitioninsection201(ff)oftheAct(21U.S.C.321(ff)).

Ifabotanicalproductisintendedforuseindiagnosing,mitigating,treating,orcuringdisease,itisadrugundersection201(g)(1)(B)oftheActandissubjecttoregulationassuch.Ifabotanicalproductisintendedtopreventdisease,itisalsoadrugundersection201(g)(1)(B),exceptthataproductthatbearsahealthclaimauthorizedinaccordancewithsection403(r)oftheAct(21U.S.C.343(r))isnotadrugsolelybecauseitslabelingcontainssuchaclaim.Iftheintendeduseofabotanicalproductistoaffectthestructureorfunctionofthehumanbody,itmayberegulatedeitherasadietarysupplementorasadrug,dependingonthecircumstances.

UndertheDietarySupplementHealthandEducationActof1994(DSHEA),anorallyingestedproductthatmeetsthedefinitionofa“dietarysupplement”undersection201(ff)oftheActmaybelawfullymarketedwithastatementthat(1)claimsabenefitrelatedtoaclassicalnutrientdeficiencydisease(anddisclosestheprevalenceofthediseaseintheUnitedStates),(2)describeshowtheproductisintendedtoaffectthestructureorfunctionofthehumanbody,(3)characterizesthedocumentedmechanismbywhichtheproductactstomaintainsuchstructureorfunction,or(4)describesgeneralwell-beingfromconsumptionoftheproduct(section403(r)(6)(A)oftheAct).

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Adietarysupplementstatementofthetypedescribedabovemaynotclaimtodiagnose,mitigate,treat,cure,orpreventaspecificdiseaseorclassofdiseases(section403(r)(6)oftheAct).

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Ifabotanicalproductisintendedtoaffectthestructureorfunctionofthebodybutdoesnotmeetthedefinitionofadietarysupplement,ordoesnotmeettherequirementsformakingastructure/functionclaimundersection403(r)(6)oftheAct,itissubjecttoregulationasadrugundersection201(g)(1)(C)oftheAct.Asnotedabove,abotanicalproductissubjecttoregulationasadrugundersection201(g)(1)(B)oftheActifitisintendedforuseindiagnosing,mitigating,treating,curing,orpreventingdisease(exceptforaproductmarketedwithcertainhealthclaimsauthorizedundersection403(r)oftheAct).Undersection505(b)oftheAct,a

4Themanufacturermusthavesubstantiationthatsuchstatementistruthfulandnotmisleading(section403(r)(6)(B)oftheAct)andmustnotifyFDAthatthestatementisbeingusednolaterthan30daysafterthefirstmarketingofthedietarysupplementwiththestatement(section403(r)(6)oftheAct).Inaddition,thestatementmustbeaccompaniedbythefollowingdisclaimer:“ThisstatementhasnotbeenevaluatedbytheFoodandDrugAdministration.Thisproductisnotintendedtodiagnose,treat,cure,orpreventanydisease”(section403(r)(6)(C)oftheAct).FDAregulationsat21CFR101.93(b)-(e)prescribetherequiredformatandplacementofthedisclaimerindietarysupplementlabeling.

5FDAregulationsat§101.93(g)definediseaseforpurposesofthisprovisionandsetforthwhattypesofstatementsFDAwillconsidertobeclaimstodiagnose,mitigate,treat,cure,orpreventdisease.

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drugmustbemarketedunderanapprovedNDA

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unlesstheproductisexcludedfromthedefinitionofanewdrugundersection201(p)oftheAct.CertainproductsthatFDAdeterminesaregenerallyrecognizedassafeandeffectiveinaccordancewithsection201(p)maybemarketedunderFDA′sOTCdrugmonographsystem.

A.MarketingUnderOTCDrugMonographVersusApprovedNDA

AbotanicaldrugproductmaybemarketedintheUnitedStatesunder(1)anOTCdrugmonographor(2)anapprovedNDAorANDA.AbotanicalproductthathasbeenmarketedintheUnitedStatesforamaterialtimeandtoamaterialextentforaspecificOTCdrugindicationmaybeeligibleforinclusioninanOTCdrugmonographcodifiedin

21CFRparts331-358.Themanufacturerwouldneedtosubmitapetitioninaccordancewith21CFR10.30toamendthemonographtoaddthebotanicalsubstanceasanewactiveingredient.

Undercurrentregulations,ifthereisnomarketinghistoryintheUnitedStatesoraforeigncountryforabotanicaldrugproduct,

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ifavailableevidenceofsafetyandeffectivenessdoesnotwarrantinclusionoftheproductinanOTCdrugmonograph,oriftheproposedindicationwouldnotbeappropriatefornonprescriptionuse,themanufacturermustsubmitanNDAtoobtainFDAapprovaltomarkettheproductfortheproposeduse(sections201(p)and505oftheAct).AnNDAforabotanicaldrugcouldseekapprovalforeitherprescriptionorOTCuse,dependingontheindicationandcharacteristicsoftheproductandwhetheritissafeforuseoutsideofthesupervisionofapractitionerlicensedbylawtoadministerit.IfexistinginformationonthesafetyandeffectivenessofabotanicaldrugproductisinsufficienttosupportanNDA,werecommendthatnewclinicalstudiesbeconductedtodemonstratesafetyandeffectiveness.

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WhenafinalOTCdrugmonographispublishedforaspecificuseofabotanicaldrug,anypersonmaymarketaproductcontainingthesamesubstanceandforthesameuse,providedthelabelingandotheractiveingredients(ifpresent)areinaccordwithallrelevantmonographsandotherapplicableregulations.Incontrast,whenaproductisapprovedunderanNDA,theapprovalisspecifictothedrugproductthatisthesubjectoftheapplication(theapplicant’sdrugproduct),andtheapplicantmaybeeligiblefor

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Undersection505(j)oftheAct,abotanicaldrugproductmayalsobemarketedasagenericdrugunderanabbreviatednewdrugapplication(ANDA).Thegenericversionofthepreviouslyapproveddrugwouldhavetobebothpharmaceuticallyequivalentandbioequivalenttosuchdrug.ForinformationonthesubmissionofANDAs,seeFDAregulationsin21CFRparts314and320aswellasAgencyguidancedocuments.

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FDAhasissuedafinalrulethatestablishescriteriaandproceduresbywhichconditionsmaybecomeeligibleforinclusionintheOTCdrugmonographsystem(67FR3060,January23,2002).Amongotherthings,thefinalruleaddresseshowFDAconsidersforeignmarketingdataindeterminingwhetheradrughasbeenusedunderparticularconditionstoamaterialextentandforamaterialtime(asrequiredundersection201(p)oftheAct)toqualifyforinclusioninanOTCdrugmonograph.

8See21CFR312.20(concerningrequirementforanIND).

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marketingexclusivityforeither5years(ifitisanewchemicalentity)or3yearsfromthetimeofapproval,evenintheabsenceofpatentprotection.Anewbotanicaldrug(containingmultiplechemicalconstituents)mayqualifyasanewchemicalentityunder§314.108(a).Ifaproductqualifiesasanewchemicalentity,duringtheperiodofexclusivity,FDAwillnotapprove,orinsomecasesevenreview,certaincompetitorproductsunlessthesecondsponsorconductsallstudiesnecessarytodemonstratethesafetyandeffectivenessofitsproductandsubmitsa505(b)(1)application.Therefore,ifapersonwishingtomarketabotanicaldrugproductthatisnotincludedinanexistingOTCdrugmonographdesiresmarketingexclusivityfortheproduct,thepersonshouldseekapprovalofanNDAratherthanpetitiontheAgencytoamendamonograph.AttachmentAcontainsaschematicshowingdifferentregulatoryapproachesthatcanbetakenformarketingbotanicaldrugproductsintheUnitedStates,includingOTCdrugmonographandNDAprocedures.

B.CMCInformationforBotanicalDrugProducts

BotanicaldrugproductshavecertainuniquecharacteristicsthatshouldbetakenintoaccountintheapplicationofFDAregulationsandguidance.Botanicaldrugsarederivedfromvegetablematterandareusuallypreparedascomplexmixtures.Theirchemicalconstituentsarenotalwayswelldefined.Inmanycases,theactiveconstituentinabotanicaldrugisnotidentified,norisitsbiologicalactivitywellcharacterized.Therefore,theCMCdocumentationthatshouldbeprovidedforbotanicaldrugswilloftenbedifferentfromthatforsyntheticorhighlypurifieddrugs,whoseactiveconstituentscanbemorereadilychemicallyidentifiedandquantified.Forexample,FDAwouldexpectanNDAforasyntheticorhighlypurifieddrugtoidentifytheactiveingredient.However,itwouldnotbeessentialforthesponsorofabotanicaldrugtoidentifytheactiveconstituents(althoughFDArecommendsthatthisbedoneiffeasible).EvenifthesponsorweretoeventuallyidentifytheactiveconstituentsintheNDA,theactiveconstituentsmightnotbeidentifiedduringtheINDstage.

Becauseofthecomplexnatureofatypicalbotanicaldrugandthelackofknowledgeofitsactiveconstituent(s),FDAmayrelyonacombinationoftestsandcontrolstoensuretheidentity,purity,quality,strength,potency,andconsistencyofbotanicaldrugs.Thesetestsandcontrolsinclude(1)multipletestsfordrugsubstanceanddrugproduct(e.g.,spectroscopicand/orchromatographicfingerprints,chemicalassayofcharacteristicmarkers,andbiologicalassay),(2)rawmaterialandprocesscontrols(e.g.,strictqualitycontrolsforthebotanicalrawmaterialsandadequatein-processcontrols),and(3)processvalidation(especiallyforthedrugsubstance).

C.CMCandToxicologyInformationtoSupportInitialStudies

ManybotanicalproductsarelegallyavailableintheUnitedStatesasdietarysupplements.Giventhewideavailabilityofsuchproductsoutsideofclinicaltrials,itisimportanttoassesstheeffectivenessofsuchproducts.Tosupportinitialclinicaltrials,thenonclinicalpharmacologyandtoxicologyinformationthatmustbeprovidedunder21CFR312.22(b)forlegallyavailablebotanicalproductswithnoknownsafetyissues(see

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sectionVI.A)maybemarkedlyreducedcomparedtothatexpectedforsyntheticorhighlypurifiednewdrugsthatarenotlegallymarketedandforwhichthereisnopriorhumanexperience.Inmostcases,additionaltoxicologyandCMCdatawillnotberequiredforsuchinitialtrials.

D.ApplicabilityofCombinationDrugRegulations

Botanicaldrugproductsthatarederivedfromasinglepartofaplant(e.g.,leaves,stems,roots,orseeds),orfromasinglespeciesofalgaormacroscopicfungus(e.g.,amushroom),arenotconsideredtobefixed-combinationdrugswithinthemeaningof21CFR300.50and330.10(a)(4)(iv).Consequently,theydonothavetomeettherequirementsforcombinationdrugs,principallytheneedtodemonstratethateachcomponentoractiveingredientmakesacontributiontoclaimedeffects.

Botanicaldrugscomposedofmultiplepartsofasinglespeciesofplant,alga,ormacroscopicfungus,orofpartsfromdifferentspeciesofplantsalgae,ormacroscopicfungi,currentlyaresubjecttothecombinationdrugrequirements.However,FDAisconsideringrevisingitsregulationstoallowfortheexemptionofsuchbotanicaldrugsfromapplicationofthecombinationdrugrequirementsundercertaincircumstances.

IV.MARKETINGABOTANICALDRUGUNDERANOTCDRUGMONOGRAPH

AbotanicalproductthathasbeenmarketedintheUnitedStatesforamaterialtimeandtoamaterialextentforaspecificOTCindicationmaybeeligibleforconsiderationintheOTCdrugmonographsystem.Currently,thereareseveralbotanicaldrugs,includingcascara,psyllium,andsenna,thatareincludedintheOTCdrugreview.ForabotanicaldrugsubstancetobeincludedinanOTCdrugmonograph,theremustbepublisheddataestablishinggeneralrecognitionofsafetyandeffectiveness,usuallyincludingresultsofadequateandwell-controlledclinicalstudies(see§§314.126(b)and330.10).Requirementsrelatedtosafety,effectiveness,andlabelingfordrugstobeincludedinanOTCdrugmonographaresetforthin21CFRpart

330.

ArequesttoamendanOTCdrugmonographtoincludeabotanicalsubstancemustbesubmittedbycitizenpetitioninaccordancewith§§10.30and330.10(a)(12).Thereshouldbepubliclyavailablequalitystandardsforsuchabotanicaldrugsubstanceinthedrugsection(i.e.,notintheNationalFormularyorothernondrugsections)oftheUnitedStatesPharmacopeia(USP).

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IntheabsenceofaUSPdrugmonograph,thepetitionershouldincludesuitablequalitystandardsforthebotanicaldrugsubstanceinitscitizenpetitionandsimultaneouslyproposeadoptionofthosestandardsintheUSP.Additionalcriteriaandproceduresbywhichabotanicaldrug