imposemarcoblaze

Chapter3–CenterforDrugEvaluationandResearchContentsBioresearchMonitoring.
3-2CounterfeitDrugs.
3-6CurrentGoodManufacturingPractice/Adulteration.
3-7MakingFalseandMisleadingClaimsontheInternet.
3-14MisleadingClaims.
3-18Over-the-CounterProducts.
3-19MarketingClaims3-20PharmacyCompounding.
3-22MarketingofUnapprovedDrugs.
3-25CombinationEnforcementActivities3-31CGMPforFinishedPharmaceuticals3-32EnforcementStatistics.
3-40CenterforDrugEvaluationandResearchFiscalYear20083-2BioresearchMonitoringClinicalInvestigatorReceivedWarningOnMay28,2008,theFoodandDrugAdministration(FDA),CenterforDrugEvaluationandResearch(CDER),OfficeofCompliance(OC),DivisionofScientificInvestigations(DSI)issuedaWarningLettertoArturoCorces,M.
D.
,Miami,Florida.
BetweenMarch20andApril26,2007,FDAofficialsconductedaninspectionofclinicalinvestigationsconductedbyDr.
ArturoCorces.
TheFDA'sinvestigationwasconductedaspartofitsBioresearchMonitoring(BIMO)ProgramtoensurethatdatasubmittedinsupportofNewDrugApplications(NDAs)arescientificallyvalidandaccurate.
Theinvestigationrevealedseriousnon-adherencetothestatutoryrequirementsandFederalregulationsgoverningtheconductofclinicalinvestigations.
Violationsincluded:Failuretopersonallyconductorsupervisetheclinicalinvestigations;Failuretomeetinformedconsentrequirementsthatinformationgiventothesubjectorthesubject'srepresentativeshallbeinalanguageunderstandabletothesubjectortherepresentative;andFailuretomaintainadequatedrugdispositionrecords.
TheclinicalinvestigatorrespondedinwritingtoFDA'sinspectionalfindingsinaletterdatedJune14,2008,andCDERregardedtheresponseasadequate.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6837c.
pdfTheWarningLetterspresentedinthischapterwerechosentoprovideexamplesofthetypesofWarningLettersissuedforviolationsofFDAlaws.
ThehyperlinksprovidedmaychangeandtolocatethearchivedWarningLettersgotohttp://www.
fda.
gov/foi/warning.
htm.
CenterforDrugEvaluationandResearchFiscalYear20083-3ClinicalInvestigatorReceivedWarningOnOctober26,2007,CDER'sOC'sDSIissuedaWarningLettertoDr.
AlanRapoport,ofStamford,Connecticut.
TheinspectionwasconductedbetweenMay1andJune5,2007,aspartoftheBIMOProgram.
Theinvestigationrevealednon-adherencetothestatutoryrequirementsandFDAregulationsgoverningtheconductofclinicalinvestigations.
Violationsincluded:Failuretoensurethattheinvestigationswereconductedaccordingtothesignedinvestigatorstatement;Failuretomaintainadequateandaccuratecasehistoriesoneachsubjectinvolvedinthetrial;andFailuretoobtaininformedconsent.
ThefulltextofFDA'sWarningLettertoDr.
RapoportisavailableonFDA'sWebsiteat:http://www.
fda.
gov/foi/warning_letters/archive/s6582c.
htmDrugSponsorReceivedWarningOnOctober23,2007,CDER'sOC'sDSIissuedaWarningLettertoSanofi-Aventis,ofBridgewater,NewJersey.
FDAconductedaninspectionofAventisPharmaceuticals'(Aventis)roleasasponsorofastudyofaninvestigationalnewdrug,Ketek.
Theinvestigationrevealednon-adherencetothestatutoryrequirementsandFDAregulationsgoverningtheconductofclinicalinvestigations.
Violationsincluded:FailuretosecureinvestigatorcompliancewiththeinvestigationalplanandapplicableFDAregulations;Failuretoensurepropermonitoringoftheclinicalinvestigation;andFailuretoselectqualifiedinvestigatorsandprovideinvestigatorswiththeinformationneededtoconductthestudyproperly.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/cder/warn/2007/07-HFD-45-1002.
pdfCenterforDrugEvaluationandResearchFiscalYear20083-4ApplicantFailedtoProvideDatatoFDAOnJanuary18,2008,CDER'sOC'sDSIissuedaWarningLettertoMr.
KennethCollins,PresidentandChiefExecutiveOfficer(CEO)ofReplidyne,Inc.
,locatedinLouisville,Colorado.
FDAconductedinspectionsofReplidyne,Inc.
,initiallybetweenJuly19andAugust8,2006,andforafollow-upinspection,betweenSeptember11andOctober17,2006.
TheinvestigationwaspartofFDA'sBIMOProgram.
Afterreviewoftheestablishmentinspectionreports(EIRs),thedocumentssubmittedwiththatreport,thefirm'swrittenresponses(datedSeptember11,2006,andFebruary8,2007)totheinspectionalobservations,andthedocumentsfortheclinicalinvestigatorsthatwereinspectedfortheNDA,FDAconcludedthatReplidyne,Inc.
,didnotadheretotheapplicablestatutoryrequirementsandregulationsgoverninganapplicant'sresponsibilitiesconcerningsubmissionofdataandinformationtotheFDA.
Replidyne,Inc.
,refusedtomakeavailabletheunderlyingrawdatafromtheinvestigationfortheFDA'saudit,andfailedtoprovideadequatedescriptionsandanalysesofanyotherdataorinformationrelevanttotheevaluationofthesafetyandeffectivenessofthedrugproductobtainedbytheapplicantfromanysource.
Inaddition,Replidyne,Inc.
,submitteddatafromseveralclinicalinvestigativeresearchsitesinsupportofanNDA,butdidnotadequatelyverifytheintegrityofthedataatthosesites.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/archives/s6638c.
htmInvestigationalReviewBoardFailedtoComplywithRegulationsOnFebruary25,2008,CDER'sOC'sDSIissuedaWarningLettertoDr.
AlfredE.
Abuanza,ChiefMedicalOfficeratWestJeffersonMedicalCenter(WestJefferson),inMarrero,Louisiana.
FDAinspectedtheInvestigationalReviewBoard(IRB)atWestJeffersonbetweenJuly23andJuly26,2007,todeterminewhethertheIRBproceduresfortheprotectionofhumansubjectscompliedwiththeCodeofFederalRegulations(CFR)Parts50and56.
CDERconcludedthattheIRBdidnotadheretotheapplicablestatutoryrequirementsandFDAregulationsgoverningtheprotectionofhumansubjects.
ViolationsofFDAregulationsincluded:CenterforDrugEvaluationandResearchFiscalYear20083-5Failuretoexcuseamemberfromparticipatingintheinitialreviewofaprojectinwhichthememberhadaconflictinginterest,excepttoprovideinformationrequestedbytheIRB;FailuretoreviewproposedresearchatconvenedmeetingsatwhichamajorityofthemembersoftheIRBwerepresent,includingatleastonememberwhoseprimaryconcernswereinnonscientificareas(forotherthanexpeditedreviews);Failuretoconductcontinuingreviewofresearchatintervalsofnotlessthanonceperyear;andFailuretodetermine,atthetimeofinitialreview,thatstudiesinvolvingchildrenareincompliancewith21CFRPart50SubpartD,"AdditionalSafeguardsforChildreninClinicalInvestigations.
"TheFDAwillconductadditionalfollow-upinspectionstoensurethatadequatecorrectiveactionshavebeenimplemented.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6717c.
htmBIMODrug-DeviceCombinationProductOnJune30,2008,CDER'sOC'sDSIissuedaWarningLettertoRobertCohen,PresidentandCEOofTravantiPharma,Inc.
,inMendotaHeights,Minnesota,afteraninspectiontoreviewthefirm'spracticesasthesponsorofaclinicalinvestigationofaninvestigationaldevice-drugcombinationproduct.
TheinspectiontookplacebetweenFebruary19and28,2008,aspartoftheFDA'sBIMOProgram.
Theinvestigationrevealednon-adherencetothestatutoryrequirementsandFDAregulationsgoverningtheconductofclinicalinvestigations.
Violationsincluded:FailuretosubmitanInvestigationalNewDrug(IND)fortheconductofclinicalinvestigationswithaninvestigationalnewdrug;Failuretoobtainaninvestigatorstatement,FormFDA1572,beforepermittinganinvestigatortoparticipateinaninvestigation;andCenterforDrugEvaluationandResearchFiscalYear20083-6Failuretoselectamonitorqualifiedbytrainingandexperiencetomonitortheprogressoftheinvestigation.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6854c.
htmPostmarketingAdverseDrugExperienceOnMarch25,2008,theFDAsentaWarningLettertoJean-PierreGarnier,Ph.
D.
,CEOofGlaxoSmithKline(GSK),locatedinResearchTrianglePark,NorthCarolina.
TheletterreferredtoaninspectionconductedAugust20throughNovember13,2007.
Theinspectionfocusedonthefirm'scompliancewithpostmarketingadversedrugexperiencereportingrequirementsandotherpostmarketreportingrequirementsrelatingtoAvandia,approvedbyFDAonMay25,1999.
TheinspectionrevealedthatthefirmfailedtoadequatelyreportmultiplepostmarketingstudiesinvolvingAvandiainmandatoryperiodicand/orNDAannualreports.
FDAconsideredthefirm'sinitialresponsetotheinspectionreportinadequatebecausetheresponsedidnotexplainhowthefirmwillensureithadsubmittedtoFDAallmandatorypostmarketingreportsandotherinformationconcerningitsapproveddrugproducts.
FDAexpectedthecorrectiveactionstoincludeacomprehensiveevaluationofthefirm'sreportingofpostmarketingstudiesforalldrugproductsforwhichthefirmholdsanapprovedapplication.
GSKrepresentativesmetwithFDAofficialsonJune26,2008,todiscusstheirremediationplantoaddresstheFDAWarningLetter.
Thefirm'scompleted,promised,andremedialcorrectiveactionsappearedadequatetoFDA.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6714c.
htmCounterfeitDrugsFDAIssuedWarningRegardingCounterfeitDrugsOnAugust8,2008,theFDAissuedawarningtoconsumerswhofilledprescriptionsatTheMedicineShoppepharmacieslocatedat8035ALibertyRoadCenterforDrugEvaluationandResearchFiscalYear20083-7and5900ReisterstownRoadinBaltimore,Maryland.
Thewarningindicatedthatconsumersmayhavereceiveddrugsthatwereeitherexpiredorsuspectedcounterfeit.
TheFDAwasparticularlyconcernedbecauseanumberofthedrugsdispensedwerelabeledforthetreatmentofseriousdiseasesandtheuseoftheseproductscouldresultinadverseeffectsforpatients.
Theproductsinquestioninclude:Lisinopril(20mg)Guaifenesin/Dextromethorphan(600mgand1000mg)Gabapentin(100mg,300mg,and400mg)Metoprolol(50mg)Nifedipine(30mg)DiclofenacSodium(30mg)Glucophage(500mgExtendedRelease)Glucovance(125mgand500mg)Glipizide/Metformin(2.
50mg/250mg)Furosemide(20mg)TamoxifenCitrate(10mg)MetforminHClER(500mg)Calcitrol(0.
25g)TheFDAhadnoevidencethatanyotherMedicineShoppepharmaciesoutsideofthe8035ALibertyRoadand5900ReisterstownRoadfacilitieswereinvolved.
Becausethelisteddrugsmayhavebeencounterfeit,thesafetyandefficacywasinquestion.
TheFDAhasstronglyadvisedconsumerswhofilledprescriptionsforthesedrugsatthesetwopharmacylocationstocontacttheprescribingphysicianimmediatelyfornewprescriptions.
ConsumersinpossessionoftheabovelistedprescriptiondrugsfromthesepharmacieswereadvisedtocalltheFDAforfurtherinformationonhowtodisposeofthedrugs.
ToreadthefulltextoftheFDAPressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2008/NEW01873.
html.
CurrentGoodManufacturingPractice/AdulterationChangzhouSPLWarningLetterforCGMPViolationsOnApril18,2008,theFDA'sCenterforDrugEvaluationandResearch,OC,issuedaWarningLettertoDr.
YanWang,GeneralManagerofChangzhouSPLCenterforDrugEvaluationandResearchFiscalYear20083-8Company,inWujinCity,Changzhou,China.
ThefirmwasinspectedFebruary20through26,2008,followingrecallsbyBaxterofheparinsodiumU.
S.
Pharmacopeia(USP)andcrudeheparinsodiumusedinthemanufactureofsteriledosageformsduetocontaminationissues.
SignificantCurrentGoodManufacturingPractice(CGMP)deficiencieswerenotedduringthisinitialinspectionoftheSPLfacility,including:nocriticalprocessingstepsidentifiedforthemanufacturingprocess;stepwiseremovalofimpuritieswasnotevaluated;noimpurityprofileestablishedforheparinsodiumUSPactivepharmaceuticalingredient(API);noevaluationofdegradationoftheAPIduringstability;useofcrudeheparinsodiumlotsfromanunacceptablevendorworkshopusedtoproduceseverallotsofheparinsodiumUSPAPIfortheU.
S.
market;andtestmethodsusedintestingheparinsodiumUSPandcrudeheparinsodiummaterialshavenotbeenevaluatedforsuitabilityofuse.
ThefirmsubmittedtworesponsesdatedMarch17andApril15,2008,whichweredeemedinadequate.
Subsequently,theWarningLetterwasissuedtothefirmcitingthefollowingdeficiencies:Failuretoevaluatetheeffectivenessofcriticalprocessingstepsdesignedtoremoveimpurities;Failuretoidentifycriticalprocessingparameters;useofcrudematerialfromanunacceptableworkshopusedinthemanufactureofheparinsodiumUSPAPIshippedtotheU.
S.
;FailuretoverifyunderactualconditionssomeUSPcompendialtestmethods;andFailuretodocumentthatthetanksusedinthefinalprocessingstepswereobservedwithunidentifiedmaterialadheringtothesurfaceseventhoughtheequipmentwaslabeledclean.
ThefirmiscurrentlyonImportAlert(IA)underIA66-40forallheparinproducts.
CenterforDrugEvaluationandResearchFiscalYear20083-9FDAIssuedWarningLettersandanImportAlerttoRanbaxyLaboratoriesCitingSeriousManufacturingDeficienciesTheFDAonSeptember16,2008,issuedtwoWarningLetterstoRanbaxyLaboratoriesLtd.
,oftheRepublicofIndia,andanIAforgenericdrugsproducedbyRanbaxy'sDewasandPaontaSahibplantsinIndia.
FDAinspectedthepharmaceuticalmanufacturingfacilitiesonJanuary28throughFebruary12andMarch3through7,2008,respectively.
TheWarningLettersidentifiedtheAgency'sconcernsaboutdeviationsfromCGMPregulations.
Becauseoftheextentandnatureoftheviolations,theFDAissuedanImportAlert,underwhichU.
S.
officialsmaydetainattheU.
S.
borderanyAPI(theprimarytherapeuticcomponentsofafinisheddrugproduct),andbothsterileandnon-sterilefinisheddrugproductsmanufacturedattheseRanbaxyfacilitiesofferedforimportintotheUnitedStates(U.
S.
).
TheproblemsFDAinvestigatorsidentifiedatthesetwoRanbaxyplantsrelatetodeficienciesinthecompany'sdrugmanufacturingprocess.
TheactionswereproactivemeasuresthattheFDAundertookinordertoassurethatalldrugsthatreachtheAmericanpublicaremanufacturedaccordingtoCGMPrequirements.
TheactiondidnotinvolveremovingproductsfromthemarketbecausetheFDAhadnoevidencetodatethatRanbaxyhadshippeddefectiveproducts.
TheFDAcontinuestomonitorthesituation.
ThecurrentannouncementdidnotimpactproductsfromRanbaxy'sotherplants.
FDAhadinspectedthosefacilitiesand,todate,thefacilitieshadmetCGMPrequirementsfordrugmanufacturing.
Earlier,theFDAinformedRanbaxythatuntilthefirmresolvedthedeficienciesateachofthesetwofacilitiesandtheplantscameintocompliancewithCGMPrequirements,FDAwouldrecommenddenialofapprovalofanyNDAsandAbbreviatedNewDrugApplications(ANDA)thatlistthePaontaSahiborDewasplantsrespectivelyasthemanufacturerofAPIsorfinisheddrugproducts.
RanbaxyisoneofthelargestforeignsuppliersofgenericdrugstotheU.
S.
TheFDAImportAlertcoversmorethan30differentgenericdrugproducts(http://www.
fda.
gov/cder/drug/infopage/ranbaxy/ranbaxy_list.
htm)producedinmultipledosageformsanddosageamounts(i.
e.
,25mg,50mg,and100mg)atthesetwolocations.
TheFDAevaluatedwhethertheseactionswouldcreateanypotentialdrugshortagesintheU.
S.
,anddeterminedthatwithoneexception,othersupplierscouldmeetmarketdemand.
BecauseRanbaxywasCenterforDrugEvaluationandResearchFiscalYear20083-10thesolesuppliertotheU.
S.
ofonedrugproduct,Gancicloviroralcapsules(anantiviraldrug),toavoidcreatingashortageofthedrug,theFDAdidnotdetainshipmentsofthisproduct,andplannedtoarrangeforadditionaloversightandcontrolsuntilthecompanyresolvedthemanufacturingissues.
CDERsaidwiththisactionFDAwassendingaclearsignalthatdrugproductsintendedforusebyAmericanconsumersmustmeetFDAstandardsofsafetyandquality.
TheFDAnotifiedotheragenciesandhealthcareprofessionalssothatappropriateactioncouldbetakentoadvisepatientsasneeded.
Followingthetwoinspections,theAgencyevaluatedthefindings,Ranbaxy'sresponses,andthefirm'soverallinspectionalhistory.
Theevaluationwascomplexduetothescientificandtechnicalissuesatbothsitesandtheidentifieddeficiencies.
Ultimately,FDAconcludedthatthefirm'sresponseswerenotadequateandthatWarningLettersweretheappropriateregulatoryresponse.
ThisrepresentsthesecondtimeinlessthanthreeyearsFDAissuedaWarningLettertoRanbaxy.
In2006,FDAcitedRanbaxyforviolationsofU.
S.
CGMPregulationsatthePaontaSahibfacility.
ToreadthefulltextoftheFDAWarningLetters:http://www.
fda.
gov/foi/warning_letters/s6922c.
htmhttp://www.
fda.
gov/foi/warning_letters/s6923c.
htmNortheastPharmaceuticalReceivedWarningLetterforPoorCompliancewithCGMPOnOctober31,2007,FDA'sCenterforDrugEvaluationandResearch,OC,issuedaWarningLettertoMr.
LiuZhen,PresidentandGeneralManagerofNortheastPharmaceuticalFactory,inShenyang,Liaoning,China.
AninspectionofthefacilityonAugust27through30,2007,revealedsignificantdeviationsfromCGMPsinthemanufactureofAPI.
OnOctober1,2007,thefirmrespondedtotheobservations.
FDAsaidthefirm'sresponsedidnotadequatelyaddressthefollowing:FailuretomaintainmanufacturingfacilitiesandequipmenttopreventAPIcontamination;Failuretoteststabilitysamplesatthescheduledintervals;andCenterforDrugEvaluationandResearchFiscalYear20083-11FailureoftheQualityControlUnit(QCU)tooverseeandevaluatemanufacturingandlaboratorycontrols.
TheWarningLetterreferredtoaguidancedocumententitled"Q7AGoodManufacturingPracticeGuidanceofActivePharmaceuticalIngredients(API)"(ICHCGMPGuidance),preparedundertheauspicesoftheInternationalConferenceonHarmonisation(ICH)CommitteeonTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse.
TheICHCGMPguidancedescribesCGMPformanufacturingofAPItohelpensurethatallAPImeetthestandardsforqualityandpuritytheypurportorarerepresentedtopossess.
AlthoughtheICHCGMPGuidancedoesnotimposerequirements,FDAconsidersitsrecommendations,aswellasalternativesintendedtoaccomplishthesamegoals,provideanequivalentlevelofassurancethatafirm'sAPIhavebeenmanufactured,processed,packed,andheldaccordancewithCGMP.
ToobtaintheICHCGMPGuidanceforreference,refertothefollowingWebsite:http://www.
fda.
gov/cder/guidance/4286fnl.
htmToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/archive/s6566c.
htmSeizureofDrugsandDietarySupplementsDuetoUnsanitaryConditionsandUnapprovedStatusAttherequestoftheFDA,onOctober31,2007,U.
S.
Marshalsseizedmorethan$300,000worthofproduct,includingNCSolution,anantifungalproduct,andotherdrugsforhumanoranimaluse,dietarysupplements,andingredientstomakethoseproducts.
TheseproductswereseizedbecausesomelackedFDAapprovalandallweremaintainedundergrosslyunsanitaryconditionsbyGeneralTherapeuticsCorp.
,ofSt.
Louis,Missouri.
Allofthefinishedproductsandrawmaterialsweredeemedadulterated.
TheFDAconsideredNCSolutiontobeadrugbecauseitwasintendedfortheuseinthediagnosis,cure,ortreatmentofdiseaseinpeopleoranimals.
NCSolutionwasalsoanewdrugbecauseitwasnotgenerallyrecognizedassafeandeffectiveforitsintendeduses.
ThisactionwastheculminationofconcertedeffortsbytheFDAtogetthefirmtofollowthelawwhenitcomestomanufacturingsafeproductsforconsumers.
InAugustandSeptember,FDAinspectorsfoundthatthecompanywasstillmanufacturingdrugsanddietarysupplementsunderunsanitaryconditions,includingfindingsofinsectsandrodentfilthonandaroundmanufacturingCenterforDrugEvaluationandResearchFiscalYear20083-12equipmentdespitewarningsbyFDAofsimilarseriousviolationsin1999.
Followingthe1999inspection,acompanyofficialtoldtheFDAinJanuary2000thatthefirmwouldstopmanufacturingdrugs.
TheFDA'sactionagainstthecompanywasconsistentwiththeAgency'sinitiativeonunapproveddrugswhichposepotentiallyharmfulriskstoconsumers.
ToreadFDA'sPressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01736.
htmlFDAWarnsTransdermalDrugManufacturerNovenPharmaceuticalsAboutNotConformingtoCGMPOnJanuary4,2008,FloridaDistrictissuedaWarningLettertoRobertC.
Strauss,President,CEOandChairmanofNovenPharmaceuticals,locatedinMiami,Florida.
TheFDAconductedaninspectiononJune11-14,19-22,25-26,28-29,andJuly2,2007,whichrevealedsignificantCGMPproblemsintransdermaldrugproductsmanufacturedatthesite.
TheWarningLettercitedthefirmforfailuretoestablishscientificallysoundandappropriatespecificationsandthefailuretoassurethatthetransdermalpatchmeetsapplicablestandardsofidentity,strength,quality,andpurity.
Observationsincludedfailuretohaveappropriatespecificationsandtoestablishanexpirationdatethatassuresthedrugproducthasacceptablereleasecharacteristics.
ThefirmprovidedawrittenresponsedatedJuly23,andanupdatedresponsedatedOctober16,2007,totheFDA.
TheresponseswerenotadequateinthattheFDAneededmoreinformationabouttheactionstakenbythefirmtocorrectidentifieddeficiencies.
Also,FDAwasconcernedthattheunderlyingsystemproblemsresultingintheviolationshadnotbeenfullyaddressed.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6632c.
htmWarningLetterIssuedforMarketingofUnapprovedDrugsandforNotConformingtoCGMPforDrugsOnNovember7,2007,theFDA'sNewEnglandDistrictissuedaWarningLettertoAmerifitBrand,Inc.
,ofCromwell,Connecticut.
TheFDAinspectionoftheCenterforDrugEvaluationandResearchFiscalYear20083-13facilityonApril10toMay10,2007,documentedsignificantdeviationsfromtheCGMPfordrugproducts.
TheFDAinvestigatorfoundthetestmethodsusedin,andproceduresandcontrolsusedfor;themanufacture,processing,andholdingofthedrugsdidnotconformtoCGMP.
AmerifitBrand,Inc.
,failedtoassurethattheyhavetheidentityandstrength,andmeetthequalityandpuritycharacteristics,whichthedrugswererepresentedtopossess.
TheWarningLettercitedCGMPdeficiencieswithfinaldrugproductandincomingmaterialtestinganddisposition.
Thefirmfailedtoestablishappropriatespecifications,documentqualityprograms,storedrugproductsunderappropriateconditions,andhaveadequaterecordprocedures.
Additionally,thefirmwasmarketingnewdrugsinviolationoftheAct.
UntilanFDA-approvedapplicationisineffectforthesenewproducts,theFDAconsiderstheseprescriptiondrugsmisbrandedbecausethelabelingfailedtobearadequatedirectionsforuse.
AlthoughtherewerenumerousdrugproductsmarketedbeforetheenactmentoftheActin1938anditsamendmentin1962,theFDAbelievedthatitwasunlikelythatthecurrentlymarketedproductssuchastheonesthefirmmanufacturesweregrandfatheredorotherwisenotanewdrug.
Thegrandfatherclauseshavebeenconstruedverynarrowlybythecourts,anddrugproductsonthemarketwouldnotbeentitledtograndfatherstatusifthedrugsdifferedfromthepreviousversionsinsomerespect,suchasformulation,dosageorstrength,dosageform,routeofadministration,indications,orintendedpatientpopulation.
(SeetheappendixoftheFDA'sMarketedUnapprovedDrugs-CompliancePolicyGuide(CPG),http://www.
fda.
gov/cder/guidance/6911fnl.
htm,lines323-329.
)Further,itwasFDA'sviewthatcompaniesclaimingthattheproductsaregrandfatheredbearresponsibilitytofullydocumenttheproducts'grandfatheredstatus.
Anycompanymarketingproductsonthisbasisshouldhaveavailabledocumentationtodemonstratethemarketpresenceoftheproductpriortotheenactmentofthenewdrugrequirementsthatwereestablishedin1938and1962.
AmerifitBrand,Inc.
shoulddiscontinuemanufacturinganddistributinganyandallnewdrugs,untilanFDA-approvedapplicationisineffect.
AmerifitBrand,Inc.
,shouldtakepromptactiontocorrecttheCGMPdeviationscitedforanyofCenterforDrugEvaluationandResearchFiscalYear20083-14theotherproductsthatmaybelegallymarketedwithoutanapprovedapplication.
Additionally,FDAmaywithholdapprovalofrequestsforexportcertificatesorapprovalofpendingNDAslistingthefacilityasamanufactureruntiltheaboveviolationswerecorrected.
Areinspectionofthefacilitymaybenecessary.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6713c.
htmMakingFalseandMisleadingClaimsontheInternetWarning:FDAWarnedCompaniesImportingandMarketingDrugsOvertheInternetOnMarch6,2008,theFDAissuedWarningLetterstosevenU.
S.
companiesandoneforeignindividualformarketingunapprovedandmisbrandeddrugsovertheInternettoU.
S.
consumersforthepreventionandtreatmentofsexuallytransmitteddiseases(STDs).
CDERstatedthatsomeoftheproductsfalselyclaimedtohave"FDAApproval"andsomeclaimedtobe"moreeffective"thanconventionalmedicine.
TheproductsposedaserioushealththreattounsuspectingconsumerswhodidnotknowthattheseproductswerenotFDA-approvedandhadnotbeenprovensafeoreffective.
STDsareveryseriousdiseases,andtheseproductsgaveconsumersafalsesenseofsecuritythattheywereprotectedfromSTDs.
TheproductsclaimedtopreventortreatavarietyofSTDs,includingherpes,chlamydia,humanpapillomavirusinfections,cervicaldysplasia,andhumanimmunodeficiencyvirus/acquiredimmunodeficiencysyndrome.
TheFDAconsideredtheseU.
S.
andimportedproductstobeunapprovednewdrugsbeingmarketedinviolationoftheAct.
Thedrugswerealsomisbrandedunderthelawbecausethedrugslackedproperdirectionsforusebyconsumers.
Inaddition,someoftheproductsweremisbrandedbecauseoffalseandmisleadingclaims.
Examplesofclaimsthattheseproductsmadeinclude"TreatmentKillsallHerpesVirusesWITHOUThavingtouseconventionaldrugsormedications,""GreatestSTDProtectionWithoutCondoms,"(SlicPlus)and"TheactiveCenterforDrugEvaluationandResearchFiscalYear20083-15ingredientinourproductisFDAcertifiedtodestroy99.
9992percentofallpathogenicorganisms[i.
e.
]Chlamydia"(OXi-MED).
ToviewthefulltextoftheWarningLetters:http://www.
fda.
gov/foi/warning_letters/s6680c.
htm-AviralexInt.
http://www.
fda.
gov/foi/warning_letters/s6681c.
htm-AidanceSkincarehttp://www.
fda.
gov/foi/warning_letters/s6682c.
htm-Health-science-reporthttp://www.
fda.
gov/foi/warning_letters/s6683c.
htm-NeumaLifehttp://www.
fda.
gov/foi/warning_letters/s6684c.
htm-IMULUX,LLChttp://www.
fda.
gov/foi/warning_letters/s6685c.
htm-SaferexLaboratorieshttp://www.
fda.
gov/foi/warning_letters/s6686c.
htm-McKinnon,BlairFDAWarnedIndividualsandFirmsSellingFakeCancer"Cures"onInternetSitesInJune2008,FDAsentWarningLettersto28U.
S.
companiesandtwoforeignindividualsmarketingawiderangeofproductsfraudulentlyclaimingtopreventandcurecancer.
AsofSeptember18,2008,theFDAhasissuedanadditionalfivewarningletterstoothercompaniessellingfakecancer"cures",bringingthetotalnumberoffakecancerproductsaddressedinWarningLettersto187.
Thecompletelistoffakecancer"cure"productsandtheirmanufacturersalongwiththeWarningLettersandaconsumerarticleonhealthscamscanbefoundat:http://www.
fda.
gov/cder/news/fakecancercures.
htm.
Whilepromotionsofboguscancer"cures"havealwaysbeenaproblem,theInternethasprovidedamediumforthemtoflourish.
TheseWarningLettersareanimportantsteptoensurethatconsumersdonotbecomethevictimoffalse"cures"thatmaycausegreaterharmtotheirhealth.
Theproductscontainedingredientssuchasbloodroot,sharkcartilage,coralcalcium,cesium,ellagicacid,Cat'sClaw,anherbalteacalledEssiac,andmushroomvarietiessuchasAgaricusBlazeii,Shitake,Maitake,andReishi.
CenterforDrugEvaluationandResearchFiscalYear20083-16Theproductsclaimedtocure,treat,mitigateorpreventdisease,andhavenotbeenshowntobesafeandeffectiveforthelabeledconditionsofuse.
TheproductsareunapprovednewdrugsmarketedinviolationoftheAct.
Examplesoffraudulentclaimsfortheseproductsincluded:"Treatsallformsofcancer""Causescancercellstocommitsuicide!
""80%moreeffectivethantheworld'snumberonecancerdrug""Skincancersdisappear""Targetcancercellswhileleavinghealthycellsalone""Shrinksmalignanttumors""Avoidpainfulsurgery,radiotherapy,chemotherapy,orotherconventionaltreatments"TolearnabouttheFederalTradeCommission's"OperationFalseHope"anditseffortstoeducateconsumersabouthealthscams,gotowww.
ftc.
gov/curious.
ToreadabouteffortsinCanadatoeducateconsumersabouthealthscams,gotohttp://www.
competitionbureau.
gc.
ca/epic/site/cb-bc.
nsf/en/02614e.
html.
FDASentWarningLetterforMisleadingWebsiteandNewsletterPromotionalMaterialTheFDADivisionofDrugMarketing,Advertising,andCommunications(DDMAC)issuedaWarningLetteronDecember13,2007,toKurtOrlofski,CEOofMortonGrovePharmaceuticals,Inc.
,inMortonGrove,Illinois,forpromotionalpiecesforLindaneShampoo.
TheWebsitespromotingLindaneShampoo(http://www.
alliantpharma.
com/alliant_products.
htmlandhttp://www.
lindane4lice.
com)andapromotionalpieceentitledTheNitPickingNews(LINS06-602)weremisleadinginthattheyomittedand/orminimizedthemostseriousandimportantriskinformationassociatedwiththeuseofLindaneShampoo,particularlyinpediatricpatients,includedamisleadingdosingclaim,andoverstatedtheefficacyofLindaneShampoo.
TheFDAsaysthatLindaneShampoowasplainlylabeledassecondlinetreatment,suitableonlywhenother,safertreatmentsfailedorwerenottolerated.
ThematerialsontheWebsiteconveyedlittlesenseofthislimitationandlittleaboutthemagnitudeandnatureoftherisksassociatedwiththedrug.
CenterforDrugEvaluationandResearchFiscalYear20083-17ThematerialsappearedtodownplaythesignificantrisksassociatedwithLindaneShampoouseandencouragedwideruse,withlesscare,thanisappropriateunderapprovedlabeling.
Thepackageinsertorproductlabeling(PI)includedcontraindicationsandwarningsfortheelderly,nursingmothersandpediatricpatients.
CoincidingwiththeadditionoftheboxedwarningtothePIforLindaneShampooandLindaneLotion,FDAreleasedaPublicHealthAdvisoryinMarch2003,addressingthesignificantpotentialtoxicityassociatedwiththeuseoftopicalformulationsofLindaneLotionforthetreatmentofscabiesandLindaneShampooforthetreatmentoflice.
AnFDATalkPaperwasreleasedatthesametimediscussingthesignificanceoftheriskfromapublichealthperspectivegiventheprevalenceofheadliceandscabies,whichoccurmostlyinschool-agedchildren.
ThesignificantrisksarefurtheremphasizedintheMedicationGuideforLindaneShampoo.
TheMedicationGuideisalabelingfeaturereservedforproductsthattheFDAdeterminesposeaseriousandsignificantpublichealthconcernrequiringdistributionofFDA-approvedpatientinformation.
ToviewthefulltextoftheWarningLetters:http://www.
fda.
gov/foi/warning_letters/s6604c.
htmInternetSellingofIllicitStreetDrugOnJanuary31,2008,theFDAsentaWarningLettertoMs.
JenniferGullaofLagunaNiguel,California,formarketingtheproduct"Blow"onherWebsite.
"Blow"ismarketedasanalternativetoanillicitstreetdrugandisintendedtoaffectthestructureorfunctionofthebody.
"Blow"iswellknownstreetdrugterminologyforillicitcocaine,andthetermmaysuggestthattheproducthaseffectsonthebodysimilartococaine.
TheFDAhadbecomeawareoftheproliferationofvariousproductsthatwerebeingmanufactured,marketed,ordistributedasalternativestoillicitstreetdrugs.
FDAisconcernedthattheseproductsposeapotentialthreattothepublichealth.
Somestreetdrugalternativesarebeingmarketedasdietarysupplements.
FDAdoesnotbelievethatstreetdrugalternativesareintendedtobeusedtoaugmentthediet,topromotehealth,ortoreducetheriskofdisease.
Accordingly,streetdrugalternativesdonotqualifyasdietarysupplements.
InMarchof2000,FDAmadeavailableguidanceforindustryonstreetdrugCenterforDrugEvaluationandResearchFiscalYear20083-18alternatives.
Thisdocumentcontainsadditionalinformationandisavailableat:http://www.
fda.
gov/cder/guidance/3602fnl.
htm.
FDAconsiders"Blow"adrugbecauseitwasintendedtoaffectthestructureorfunctionofthebodyofmanorotheranimals.
Moreover,thisproductisanewdrugbecauseitwasnotgenerallyrecognizedassafeandeffectiveforitslabeleduses.
Thesaleof"Blow"withoutanapprovedapplicationviolatesthelaw.
ToviewthefulltextoftheWarningLetters:http://www.
fda.
gov/foi/warning_letters/s6674c.
htmMisleadingClaimsFDAIssuedWarningLettertoWyethforOverstatingDrugEfficacyTheFDA'sDDMACissuedaWarningLetteronDecember10,2007,toRobertEssner,ChairmanandCEOofWyethPharmaceuticals,Inc.
,inPhiladelphia,Pennsylvania.
TheFDAreviewedaprofessionaljournaladsubmittedbyWyethforEffexorXR(venlafaxineHCL)tablets.
Thejournaladwasmisleadingbecauseit:overstatedtheefficacyofEffexorXR;madeunsubstantiatedsuperiorityandotherclaims;andminimizedtherisksassociatedwiththeuseofEffexorXR.
AccordingtoFDA'sapprovedPI,EffexorXRisindicated,amongotherthings,forthetreatmentofmajordepressivedisorder.
EffexorXRuseisassociatedwithanumberofseriousrisks.
ThePIforEffexorXRincludesablackboxwarningregardingsuicidalityinchildrenandadolescents.
Furthermore,therearenumerouswarningsassociatedwithEffexorXRuse,includingclinicalworseningandsuiciderisk,theneedtoscreenpatientsforbipolardisorder,thepotentialforinteractionswithmonoamineoxidaseinhibitors,serotoninsyndrome,sustainedhypertension,andmydriasis.
ThePIforEffexorXRalsocontainsprecautionsconcerningdiscontinuationofEffexorXR,insomniaandnervousness,changesinweight,changesinheight,changesinappetite,activationofmania/hypomania,hyponatremia,seizures,abnormalbleeding,serumcholesterolelevation,anduseinpatientswithconcomitantillness.
Thejournaladclaimedthat"Inanopen-labelstudyofpatientswhofailedpreviousantidepressanttreatment,nearly60%achievedremissionwhenchangedtoEffexorXR.
"ThisclaimwasmisleadingbecauseitsuggeststhatEffexorXRwasmoreeffectivethanhadbeendemonstratedbysubstantialCenterforDrugEvaluationandResearchFiscalYear20083-19evidenceorsubstantialclinicalexperience.
Inaddition,byimplyingthatEffexorXRcansuccessfullytreatpatientswhohadnotrespondedtootherantidepressanttreatments,theclaimmisleadinglysuggestedthatEffexorXRwassuperiortootherantidepressanttreatmentswhenthishadnotbeendemonstratedbysubstantialevidenceorsubstantialclinicalexperience.
ThestudyprovidednoinformationaboutwhetherEffexorXRwassuperiortopriorfailedtherapybecausestudysubjectswerenotrandomizedforthepriorfailedtherapy.
Becauseimprovementindepressioncanoccurovertime,subjectsintheEffexorXRarmofthestudywhorespondedwelltotreatmentmighthaverespondedjustaswellhadtheycontinuedonthepriorfailedtherapy.
Otherclaimsintheadcitednosupportingreferencesbutaddedtothemisleadingimplicationdiscussedabove,claimingthatEffexorXRwasmoreeffectivethanotherantidepressants.
ThejournaladadditionallyoverstatedEffexorXR'seffectivenesswhenitclaimed,"InthePREVENTstudy,theprobabilityofpreventinganewepisodeofdepressionwas92%withEffexorXRinthesecondmaintenanceyearversus55%withplacebo.
"ThisclaimmisleadinglyoverstatedtheprobabilityofpreventinganewepisodeofdepressionwithEffexorXRinthesecondmaintenanceyearbecauseitisbasedonastudythatisinadequatetosupportthisclaim.
Specifically,byselectingonlypatientswhorespondedtoEffexorXRtocontinuetothenextphaseoftreatment,andbyfailingtoproperlyaccountforpotentialrecurrentdepressiveepisodesinthosepatientswhodiscontinuedEffexorXR,thestudydesignisbiasedinfavorofEffexorXRtreatment.
DDMACrequestedthatWyethimmediatelyceasethedisseminationofviolativepromotionalmaterialsforEffexorXR.
ToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/s6603c.
htmOver-the-CounterProductsFDASeizedDietarySupplementsMarketedasNewDrugsOnOctober9,2007,attherequestoftheFDA,U.
S.
Marshalsseized$71,000ofgoodsfromFulLifeNaturalOptions,Inc.
,ofBocaRaton,Florida,whichmarketedanddistributedCharanteaAmpalayaCapsulesandtea.
CenterforDrugEvaluationandResearchFiscalYear20083-20TheComplaint,filedbytheU.
S.
Attorney'sOfficefortheSouthernDistrictofFlorida,chargedtheproductswereinviolationofthedrugandmisbrandingprovisionsoftheActbecausetheproductswerelabeledasdietarysupplementsandwerebeingpromotedbyFulLifeforuseintreatingseriousconditions,suchasdiabetes,anemia,andhypertension.
Theclaimswereevidentintheproducts'labeling,includingpromotionalliteratureandFulLife'sInternetWebsite.
TheAgencytakesseriouslyitsresponsibilitytoprotectAmericansfromunapproveddrugs.
TheFDAconsideredtheseproductstobeunapprovednewdrugsbecausetheymadeclaimsrelatedtothepreventionortreatmentofdiseasesintheproducts'labeling.
Beforeanewdrugproductmaybelegallymarketed,itmustbeshowntobesafeandeffective,andapprovedbyFDA.
Thisactionprotectsconsumerswhomayrelyonunapprovedproductsandunsubstantiatedclaimsassociatedwiththeseproductswhenmakingimportantdecisionsabouttheirhealth.
ToreadthefulltextoftheCompliancePolicyGuideSec.
440.
100MarketedNewDrugsWithoutApprovedNDAsorANDAs,goto:http://www.
fda.
gov/ora/compliance_ref/cpg/cpgdrg/cpg440-100.
html.
ToreadFDA'sPressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01723.
html.
MarketingClaimsGlaxoSmithKlineReceivedWarningLetterforThreeHealthcarePractitionerLettersOnNovember21,2007,CDER'sDDMACissuedaWarningLettertoGlaxoSmithKlineofTriangleResearchPark,NorthCarolinaafterreviewingthreeHealthcarePractitionerletterswhichwerepartofthelaunchcampaignforTykerb.
TheFDAstatedthelettersweremisleadinginthattheyomittedandminimizedthemostseriousandimportantriskinformationforTykerbandselectivelypresentedefficacyinformationforTykerb,therebyoverstatingtheefficacyofthedrug.
Thematerials,whichweredisseminatedtohealthcareprofessionalsduringtheproduct'slaunchandformedthebasisoftheirfirstimpressionsofthedrug,suggestedtohealthcareprofessionalsthatTykerbwassaferandmoreeffectivethanhadbeendemonstrated.
CenterforDrugEvaluationandResearchFiscalYear20083-21DDMACrequestedthatGlaxoSmithKlineimmediatelyceasethedisseminationofviolativepromotionalmaterialsforTykerb.
FDArequestedawrittenresponsetotheirWarningLetterstatingwhetherGlaxoSmithKlineintendedtocomplywiththerequest,listingallviolativepromotionalmaterialsforTykerb,andexplainingtheplanfordiscontinuinguseofsuchmaterials.
Becausetheviolationsdescribedareserious,FDAalsorequestedthatthesubmissionincludeacomprehensiveplanofactiontodisseminatetruthful,non-misleading,andcompletecorrectivemessagesabouttheissuesdiscussedinthelettertotheaudience(s)thatreceivedtheviolativepromotionalmaterials.
ToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/s6585c.
htmProfessionalMailerIncludesMisleadingInformationOnApril18,2008,CDER'sDDMACsentaWarningLettertoDavidR.
Bethune,CEOofZilaPharmaceuticals,Inc.
,(Zila)inPhoenix,Arizona.
FDAreviewedaprofessionalmailerforPeridex(chlorhexidinegluconate0.
12%)OralRinse(Peridex)submittedbyZila.
Theprofessionalmailerincludesaletter,abrochure,andtheapprovedPIforPeridex.
ThepromotionalpiecesinthemailerarefalseormisleadingbecausetheypresentefficacyclaimsforPeridexbutfailtocommunicateanyinformationabouttherisksassociatedwithitsuse,makeunsubstantiatedsuperiorityclaims,failtousetherequiredestablishedname,overstatetheefficacyandomitmaterialfacts,andbroadentheindication.
Thesepromotionalmaterialsalsomakefalseormisleadingrepresentationsaboutacompetitiveproduct.
TheFDAsaysthatpromotionalmaterialsaremisleadingiftheyfailtorevealmaterialfactsinlightoftherepresentationsmadebythematerialsorwithrespecttoconsequencesthatmayresultfromtheuseofthedrugasrecommendedorsuggestedbythematerials.
BoththeletterandbrochureprovidedintheprofessionalmailermakenumerousefficacyclaimsforPeridex,includingclaimsthatitis"thegoldstandardingingivitistreatment,"an"idealsolutionforyourgrowingdentalpractice,"and"aprovenwaytocombatgingivitis.
"However,thesepromotionalmaterialsentirelyomitriskinformationforPeridex,includingthecontraindication,warnings,precautions,andmostfrequentlyreportedadverseeventsfromthePI.
FDAnotedthatthePIisincludedintheenvelopealongwiththeletterandbrochure,buttheinclusionofthePIisnotsufficienttoprovideappropriatequalificationorpertinentinformationfortheclaimsmadeintheletterandbrochure.
Forpiecestobenon-CenterforDrugEvaluationandResearchFiscalYear20083-22misleading,theymustcontainriskinformationineachpartasnecessarytoqualifyanysafetyoreffectivenessclaimsmade.
DDMACrequestedthatZilaimmediatelyceasethedisseminationofviolativepromotionalmaterialsforPeridex.
ToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/s6751c.
htmWarningLetterforLabelingClaimsonMagnetOnMay1,2008,CDER'sDDMACsentaWarningLettertoLudwigHantson,HeadofPharmaNorthAmericaandCEOofNovartisPharmaceuticalsCorporation,inEastHanover,NewJersey.
TheFDAreviewedlabelingclaimsonaPartialSeizureLenticularMagnet(TPL-OT-0167-A)(magnet)forTrileptal(oxcarbazepine)TabletsandOralSuspension(Trileptal)submittedbyNovartisPharmaceuticalsCorporation(Novartis).
ThemagnetwasviolativebecauseitomittedthefullindicationforTrileptalandomittedinformationabouttherisksassociatedwithitsuse.
TheseviolationswereconcerningfromapublichealthperspectivebecausetheymayencouragetheuseofTrileptalincircumstancesotherthanthoseforwhichthedrughadbeenshowntobesafeandeffectiveandsuggestedthatTrileptalwassaferandmoreeffectivethanhadbeendemonstrated.
DDMACrequestedthatNovartisimmediatelyceasethedisseminationofviolativepromotionalmaterialsforTrileptal.
ToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/s6765c.
htmPharmacyCompoundingFDAIssuedWarningLetterstoPharmacyOperationsRegardingFalseandMisleadingClaimsInJanuary2008,theFDAsentletterswarningninepharmacyoperationsthattheclaimedsafetyandeffectivenessoftheirso-called"bio-identicalhormonereplacementtherapy"or"BHRT"productswasunsupportedbymedicalevidence,andwasconsideredfalseandmisleadingbytheAgency.
FDAisCenterforDrugEvaluationandResearchFiscalYear20083-23concernedthatunfoundedclaimslikethesemisleadwomenandhealthcareprofessionals.
Thepharmacyoperationsimproperlyclaimedthatthedrugs,whichcontainhormonessuchasestrogen,progesterone,andestriol(whichisnotacomponentofanFDA-approveddrugandhasnotbeenprovensafeandeffectiveforanyuse),weresuperiortoFDA-approvedmenopausalhormonetherapydrugsandpreventedortreatedseriousdiseases,includingAlzheimer'sdisease,stroke,andvariousformsofcancer.
TheFDAwasconcernedthattheclaimsforsafety,effectiveness,andsuperioritythatthepharmacyoperationsweremakingcouldmisleadpatients,aswellasdoctorsandotherhealthcareprofessionals.
CompoundeddrugsarenotreviewedbytheFDAforsafetyandeffectiveness,andFDAencouragespatientstouseFDA-approveddrugswheneverpossible.
TheWarningLettersstatedthatthepharmacyoperationsviolatefederallawbymakingfalseandmisleadingclaimsaboutthehormonetherapy.
PharmacyoperationsreceivingWarningLettersusedtheterms"bio-identicalhormonereplacementtherapy"and"BHRT"toimplythattheirdrugswerenaturaloridenticaltothehormonesmadebythebody.
FDAregardstheuseoftheterm"bio-identical"asamarketingtermimplyingabenefitforthedrugforwhichthereisnomedicalorscientificbasis.
PharmacyoperationsalsomadeunsupportedclaimsthatthedrugswerebetterthanFDA-approvedmenopausalhormonetherapydrugsandcouldbeusedtopreventandtreatseriousdiseasessuchasAlzheimer'sdisease,stroke,andvariousformsofcancer.
Inaddition,thepharmacyoperationscompoundedhormonetherapydrugsthatcontainedestriol.
NodrugproductcontainingestriolhasbeenapprovedbyFDAandthesafetyandeffectivenessofestriolisunknown.
FDA'sactiondidnottargetpharmacistswhopracticetraditionalpharmacycompoundingandwhodidnotmakefalseormisleadingclaimsaboutcompoundedproducts.
Traditionalpharmacycompoundingtypicallyinvolvespreparationofadrugforanindividualpatientbyapharmacistinresponsetoavalidprescriptionfromalicensedpractitioner.
Thiscompoundingfollowsapractitioner'sdecisionthathisorherpatienthasaspecialmedicalneedthatcannotbemetbyFDA-approveddrugs.
FDA'scurrentviewonhumandrugcompoundingisaddressedinitscompoundingCompliancePolicyGuide,availableathttp://www.
fda.
gov/cder/pharmcomp/default.
htm.
FDAalsorespondedtoacitizenpetitionfromWyeth,inMadison,NewJersey,askingtheFDAtotakeregulatoryactionagainstcompoundingpharmacyCenterforDrugEvaluationandResearchFiscalYear20083-24operationsthatproducecompounded"BHRT"drugs.
Healthcareproviders,consumergroups,andotherstakeholdershavealsoraisedconcernsabout"BHRT"drugs.
WarningLettersandQandA'sareavailableat:http://www.
fda.
gov/cder/pharmcomp/default.
htm.
WarningLetterIssuedtoNewmanInc.
,dbaMedi-StatOnJune24,2008,FDAsentaWarningLettertoNewmanInc.
,dbaMedi-Stat,ofMobile,Alabama,regardingtheproductionofalargevolumeofstandardizedtransdermal,prescriptionproductsinanticipationofreceivingprescriptions.
Thepharmacyoperationengagedinthecommercial-leveldistributionofstandardizeddrugproducts,employedateamofsalesrepresentativestovisitphysicians'offices,andprovidedpromotionalmaterialanddrugproductsamplestophysicians.
Inaddition,thelabelingofthefirm'stransdermalproductsincludedfalseandmisleadingclaimsregardingtreatmentofdiseasessuchasosteoarthritis,complicatedneuropathicpain,fibromyalgia,andneuroma.
TheFDAisnotawareofsubstantialevidenceconsistingofadequateandwell-controlledclinicalinvestigationssupportingtheseclaims.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6836c.
pdfWarningLetterIssuedtoFarmaciaLaSalud,Inc.
,RegardingCompoundingCopies,orNearCopies,ofCommerciallyAvailable,FDA-ApprovedDrugsOnMarch26,2008,FDAissuedalettertoFarmaciaLaSalud,Inc.
,warningthattheproductionvolumeofthefirmexceededthepracticesassociatedwithtraditionalextemporaneouscompoundingandthatthefirmoperationismoreakintoadrugmanufacturer.
Thefirmcompoundedseveralinhalationsolutiondrugsthatarecopies,oressentiallycopies,ofcommerciallyavailable,FDA-approveddrugs.
ThefirmwasalsonotinconformancewiththePuertoRicoDepartmentofHealthrequirements.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6723c.
pdfCenterforDrugEvaluationandResearchFiscalYear20083-25MarketingofUnapprovedDrugsFDAIssuesWarningLettertoJen-OnHerbalScienceInternationalforMarketingClaimsOnOctober12,2007,theFDAsentaWarningLettertoJen-OnHerbalScienceInternational,Inc.
,CityofIndustry,California,fortheproductHSJoyofLove.
ThestatementsintheinsertsthataccompanyHSJoyofLovedescribedtheintendeduseoftheproducttodiagnose,cure,mitigate,treat,orpreventdisease,ortoaffectthestructureorfunctionofthebody.
TheHSJoyofLoveproductcontainspiperadinovardenafil,ananalogofvardenafil.
VardenafilistheactivepharmaceuticalingredientinLevitra,anFDA-approveddrugthatisusedtotreaterectiledysfunction(ED).
Theproductlabelingdidnotdeclarethatthisproductcontainedpiperadinovardenafil.
Further,aninsertstated"clinicalexperimentsprovethatJoyofLoveistheonlynaturalhealthproductthatcanimprovepotencyandenergyinstantlywithoutcausinganysideeffects.
"Thisstatementfalselyassertedthattheproductdidnothavethepotentialtocausesideeffects,eventhoughpiperadinovardenafillikelyexhibitssimilarpharmacologicalactiontovardenafil.
FDAregardscompliancewithitsNDAapprovalandover-the-counter(OTC)drugmonographrequirementstobeintegraltodrugsafety.
Withoutthisfoundationofcompliance,itisnotpossibletoensurethatconsumersandthehealthcarecommunityareprovidedwithestablishedandemergingdrugsafetyinformationsothattheycanmakethebestpossiblemedicaldecisionsaboutthesafeandeffectiveuseofdrugs.
AdescriptionofthenewdrugapprovalprocesscanbefoundonFDA'sInternetWebsiteathttp://www.
fda.
gov/cder/reulatory/applications/default.
htmToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6731c.
htmFDAIssuedWarningLettertoHealthFreedomNutritionforMarketingClaimsOnOctober18,2007,FDAsentaWarningLettertoHealthFreedomNutrition,inReno,Nevada,citinginspectionaldeficienciesfromaninspectiononJanuaryCenterforDrugEvaluationandResearchFiscalYear20083-2630andFebruary2and6,2007.
Theinspectionwasconductedtodeterminethefirm'scompliancewiththeActandapplicableimplementingregulations.
BasedontheclaimsfoundintheirlabelingandontheirWebsite,theFDAdeterminedthatmanyoftheproductswerepromotedforconditionsthatcausetheproductstobedrugs.
Someoftheproductswereintendedtobeusedinsomemannerotherthaningestion.
Becausetheproductswerenotingested,theproductsfailedtomeetthedefinitionoffoodordietarysupplements.
LinolenicEsterCreamcontainsingredientsthatwerenotevaluatedastopicalanalgesicsundertheOTCDrugReview,norisFDAawareofanyOTCmarketinghistoryintheU.
S.
forthelistedingredientsastopicalanalgesics.
LinolenicEsterCreamfallsoutsideoftheOTCReviewandwasanewdrug.
TransMistNaturalProgesteroneSpraywassubjecttofinalregulationscoveringtopicallyappliedhormone-containingdrugproductsforOTChumanuse.
Theproductcontainedatherapeuticclaimthatcausedtheproducttobeclassifiedasanewdrug.
Inaddition,bothoftheproductsweremisbrandedinthattheyweredrugsmanufacturedinafacilitythatwasnotregistered.
Itisthefirm'sresponsibilitythattheyareincompliancewiththeActanditsimplementingregulations.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/archive/s6557c.
htmFDAsentWarningLettertoHeartlandProductsforLabeling,PromotionalMaterialsandInternetClaimsTheFDAonOctober22,2007,sentaWarningLettertoHeartlandProducts,Inc.
,inValleyCity,NorthDakota,citinginspectionaldeficienciesfoundattheirfacilityduringaninspectionconductedonFebruary1and2,2007.
Areviewoftheproductlabeling,promotionalmaterialsandWebsitesshowedseriousviolations.
ManyoftheproductclaimsontheWebsitecausedtheproductstobedrugs.
Becausetheseproductswerenotgenerallyrecognizedassafeandeffectivewhenusedaslabeled,theywereclassifiedasnewdrugs.
AnewdrugmaynotCenterforDrugEvaluationandResearchFiscalYear20083-27belegallymarketedintheU.
S.
withoutanapprovedNDA.
FDAapprovesanewdrugonthebasisofscientificdatasubmittedbyadrugsponsortodemonstratethatthedrugissafeandeffective.
Further,theproductsweremisbrandedinthatthelabelingforthedrugsfailedtobearadequatedirectionsforuse.
Additionally,theFDAdeterminedthatthefacilitywassubjecttotheregistrationrequirementandimplementingregulations.
FDAadvisedHeartlandProducts,Inc.
,oftheserequirementsduringtheinspection.
FDArecordsindicatedthat,todate,thisfacilityhasnotbeenregisteredwithFDA.
Theresponsibleofficialofafacilitythatmanufactures,processes,packs,orholdsfoodforhumanoranimalconsumptionintheU.
S.
isresponsibleforensuringthattheoveralloperationandtheproductsdistributedareincompliancewiththelaw.
FDAregulationsareavailableofFDA'sWebsiteatwww.
fda.
gov.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6558c.
htmRecallof'TrueManSexualEnergy'and'EnergyMax'DietarySupplementOnNovember1,2007,FDArequestedarecallofTrueManSexualEnergyNutrientCapsulesandEnergyMaxEnergySupplementMen'sFormulaCapsules,illegaldrugproductsthatcontainedpotentiallyharmful,undeclaredingredients.
Theproducts,oftenadvertisedas"allnatural"alternativestoapprovedEDdrugs,couldinteractwithmedicationsandcausedangerouslylowbloodpressure.
Theproductscontainedsubstancesthathavesimilarstructurestoactiveingredientsinapprovedprescriptiondrugs.
ChemicalanalysishadshownthatEnergyMaxcontainedathioneanalogofsildenafil,asubstancesimilartotheactiveingredientintheapprovedEDdrugViagra.
Inaddition,FDAinvestigatorsfoundthatTrueMancontainedthesameanalogorananalogofvardenafil,theactiveingredientinLevitra,anotherapprovedEDtreatment.
NeitheroftheanalogsusedinTrueManorEnergyMaxwerecomponentsofFDA-approveddrugproducts.
TheFDAissuedanalertonMay10,2007,advisingconsumersnottobuyoruseTrueManorEnergyMaxproductsbecauseconsumersmaynotknowthattheingredientscaninteractwithmedicationsanddangerouslylowertheirbloodpressure.
CenterforDrugEvaluationandResearchFiscalYear20083-28ToreadFDA'sPressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01737.
htmlSentenceforWomanWhoClaimedtoCure"LouGehrig'sDisease"OnDecember,19,2007,theFDAOfficeofCriminalInvestigations(OCI)todayannouncedthataNewJerseywomanhadbeensentencedto33monthsinprisonforfalselyclaimingthatshecouldcureamyotrophiclateralsclerosis(ALS),commonlycalled"LouGehrig'sDisease.
"TheFDA'sOCIaggressivelypursuesthosethatprovidefalsehopetopatientsbymakingunprovenmedicalclaimstounsuspectingpatients,manywithseriousorlife-threateningconditionswhoaredesperateforamedicalcure.
ElizabethLerner,a.
k.
a.
"ElizabethCooperman,"ofEggHarborCity,NewJersey,andherco-conspiratorCharleneC.
DeMarco,aformerdoctorofosteopathyinEggHarborCity,wereconvictedinDecember2006ofallchargescontainedinan11-countfederalindictment.
Theindictmentincludedonecountofconspiracytocommitmailandwirefraud,threecountsofmailfraud,sixcountsofwirefraud,andonecountofmoneylaundering.
EvidenceshowedthatfromOctober2002untilNovember2004,DeMarcoandLerneragreedtodefraudALSpatientsandtheirfamiliesbyclaimingtheycouldtreatALSpatientswithstemcelltherapy,eventhoughtheyknewtheycouldnot.
ThedefendantsfalselytoldtheirpatientsandtheirfamiliesthatDeMarcohadpreviouslyreceivedFDAapprovaltotreatALS.
ToreadthefulltextofthePressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01760.
html.
FDAWarnedConsumersNottoUse"BlueSteel"and"Hero"ProductsOnMarch25,2008,theFDAadvisedconsumersnottopurchaseoruse"BlueSteel"or"Hero"productsmarketedasdietarysupplementsthroughouttheU.
S.
becausetheywereconsideredunapproveddrugsandhadnotbeenproventobesafeoreffective.
Theproductscontainedundeclaredingredients.
TheproductswerepromotedandsoldovertheInternetforthetreatmentofEDandforsexualenhancement.
Theproductsweretoutedas"allnatural"andlabeledasdietarysupplements.
However,BlueSteelandHeroproductsdonotCenterforDrugEvaluationandResearchFiscalYear20083-29qualifyasdietarysupplementsbecausetheproductscontainundeclaredandunapprovedsubstancesthataresimilarinchemicalstructuretosildenafil,theactiveingredientinViagra,anFDA-approvedprescriptiondrugforED.
Theundeclaredingredientsintheproductsmayinteractwithnitratesfoundinsomeprescriptiondrugs(suchasnitroglycerin),andcanlowerbloodpressuretodangerouslevels.
Consumerswithdiabetes,highbloodpressure,highcholesterol,orheartdiseaseoftentakenitrates.
EDisacommonprobleminmenwiththesemedicalconditions.
BecausetheymayhavebeenadvisedagainsttakingEDdrugs,thesemenmayseekproductslikeBlueSteelandHerobecausetheproductsweremarketedas"allnatural"orasnotcontainingtheactiveingredientsinapprovedEDdrugs.
Also,theproductlabelsforthesedietarysupplementsdidnotlisttheingredients.
Formoreinformation,visit:http://www.
fda.
gov/consumer/updates/erectiledysfunction010408.
html.
ToreadthefulltextofthePressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01809.
html.
AuthoritiesSeizedUnapprovedDrugsMarketedas"NaturalSupplements"U.
S.
Marshalsseizedmorethan14,000dosageunitsofShangaiRegular,ShangaiUltra,SuperShangai,NaturalSuperPlus,andLadyShangai.
Labeledasnaturalsupplements,theseizedproductswereallmarketedtotreatED,impotency,and/ortoprovidesexualenhancement.
Theseizedproducts,valuedatmorethan$100,000,containundeclaredactiveingredientsfoundinFDA-approvedprescriptiondrugsforEDorinsimilarsubstances.
Useoftheseproductsmayresultinserioussideeffectsandmayinteractindangerouswayswithmedicationsthataconsumermayalreadybetaking.
ShangaiDistributors,Inc.
,ofCoamo,PuertoRico,packagedanddistributedtheseizedproductswhichoriginatedinChina.
Althoughtheproducts'labelsstatedtheproductswerenaturalsupplements,theproductsweredrugsandtheirsalewasillegalwithoutFDAapproval.
Beforeanewdrugproductmaybelegallymarketed,thedrugmustbeshowntobesafeandeffective.
Inresponsetoaconsumercomplaint,theFDAconductedaninspectionofShangaiDistributors,Inc.
,inNovember2007.
TheFDA'sinvestigationandCenterforDrugEvaluationandResearchFiscalYear20083-30testingrevealedthattheseizedproductscontainedactivedrugingredientsfoundinFDA-approvedEDprescriptiondrugsand/orasubstancewithastructuresimilartosuchdrugsthatmaycausesimilarsideeffectsanddruginteractions.
Noneofthedrugingredientswerelistedonthelabelsofanyoftheseizedproducts.
Despitebeingadvisedofthefindingsandthepotentialadversehealthriskposedbytheseizedproducts,andthatregulatoryactionwaspossible,thecompanydidnottakeanyactiontocorrecttheviolations.
TheFDAissuedapressreleaseonDecember28,2007,advisingconsumersnottobuyorusetheproducts.
Priortotheseizure,thePuertoRicoDepartmentofHealthembargoedtheseizedproductstoprotectthecitizensofPuertoRicoandtosupporttheFDA'senforcementactions.
TheFDAreaffirmsitspolicythatwhenadrugandadietaryingredientarecombinedintoasingledosageform,thecombinationisdeemedadrug,whichrequiresanapprovedNDA.
TheAgencynotesthatneitherproductwasthesubjectofanapprovedNDA.
ToreadthefulltextofthePressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01817.
htmlFDASeizedXiadafilVIPTabsAfterCompanyRefusestoRecallProductOnMay27,2008,theFDArequestedthatSEIPharmaceuticals,ofMiami,Florida,recallallXiadafilVIPTabssoldineighttabletbottles(Lot#6K029)orblistercardsoftwotablets(Lot#6K029-SEI)becausetheproductscontainedapotentiallyharmful,undeclaredingredientthatmaydangerouslyaffectaperson'sbloodpressureandcancauseotherlife-threateningsideeffects.
Althoughlabeledasadietarysupplementandtoutedas"all-natural,"XiadafilVIPTabswereanillegallymarketeddrugthatcontainedapotentiallyharmfulundeclaredingredient.
FDAchemicalanalysisrevealedthatXiadafilVIPTabscontainedhydroxyhomosildenafil,whichisananalogofsildenafil,theactiveingredientinViagra,anFDA-approvedprescriptiondrugforED.
Theundeclaredingredientmayinteractwithnitratesfoundinsomeprescriptiondrugs(suchasnitroglycerin)andcanlowerbloodpressuretolife-threateninglevels.
Consumerswithdiabetes,highbloodpressure,highcholesterol,orheartdiseaseoftentakenitrates.
EDisacommonprobleminmenwiththesemedicalconditions.
CenterforDrugEvaluationandResearchFiscalYear20083-31ThesafetyandeffectivenessofXiadafilVIPTabsisunknown.
Theproductwaspromoted,soldovertheInternet,givenawayasfreesamplesattradeshows,andsoldinhealthfoodstoresnationwide.
OnMay13,2008,Floridaofficialsissueda"stopsale"actionatSEI'sdistributionfacility.
Thisactionrequiredthefirmtohold,intact,violativeXiadafilVIPTabsfoundon-handatthefacility.
TheStateofFlorida'sactiontocontrolthesupplyoftheproduct,coupledwiththeformalrequestbyFDAtorecallthisproductfromthemarketplace,furtherreducedthelikelihoodthatunsuspectingconsumerswouldusethispotentiallydangerousproduct.
AlternativeproductslikeXiadafilVIPTabswereoftensoughtoutbecausetheyweremarketedas"allnatural"orasnotcontainingtheactiveingredientsinapproved,prescribedEDdrugs.
Becausethemanufacturingsourceoftheactiveingredientsinmanyofthesealternativeproductsisunknown,consumersshouldalsobeawarethatthesafety,efficacy,andpurityoftheseingredientshavenotbeenverifiedbytheFDA.
OnJuly24,2008,U.
S.
FederalMarshallsseizednearly$74,000worthofXiadafilVIPtablets.
Theseizureactionprotectedthepublicfromdietarysupplementscontainingprescriptiondrugingredientsthatarepotentiallyharmful.
Formoreinformation,visit:www.
fda.
gov/consumer/updates/erectiledysfunction010408.
html.
ToreadthefulltextofthePressReleases,goto:FDARequestsRecallofXiadafilVIPTabsCombinationEnforcementActivitiesTheFDAintends,incircumstancesthatitconsidersappropriate,tocontinueitspolicyofenforcingthepreapprovalrequirementsoftheActagainstadrugorfirmthatalsoviolatesanotherprovisionoftheAct,evenifthereareotherunapprovedversionsofthedrugmadebyotherfirmsonthemarket.
Forinstance,ifafirmthatsellsanunapprovednewdrugalsoviolatesCurrentGoodManufacturingPractice(CGMP)regulations,theAgencyisnotinclinedtolimitanenforcementactioninthatinstancetotheCGMPviolations.
Rather,theAgencymayinitiatearegulatoryactionthattargetsboththeCGMPviolationandtheviolationofsection505oftheAct(21U.
S.
C.
355).
ThispolicyefficientlyCenterforDrugEvaluationandResearchFiscalYear20083-32preservesscarceAgencyresourcesbyallowingtheAgencytopursueallapplicablechargesagainstadrugand/orafirmandavoidingduplicativeaction.
SeeU.
S.
v.
SagePharmaceuticals,Inc.
,210F.
3d475,479-80(5thCir.
2000).
CGMPforFinishedPharmaceuticalsWarningLetterIssuedforCGMPViolations,MarketingUnapprovedPrescriptionDrugs,andMisbrandingOTCDrugsOnMay8,2008,theFDA'sDallasDistrictsentaWarningLettertoLarryGremminger,R.
Ph.
,President,Elge,Inc.
,inRichmond,Texas.
AninspectionconductedJanuary14throughFebruary14,2008,revealedthatthemethodsforthemanufacture,processing,packingorholdingofproductdidnotconformtoCGMPregulations.
ThefirmwasalsomarketingnewdrugsandmisbrandeddrugsinviolationoftheAct.
ViolationsofCGMPregulationsincluded:FailureoftheQualityControlUnit(QCU)tofollowwrittenprocedures;Failuretoconductcompleteinvestigations;FailuretoconductadequateidentitytestingforAPIcontainingtannates;Failuretoprovide100%ofthelabeledamountofactiveingredientfordrugproductscontainingtannates;Failuretoconductacceleratedstabilitystudiesasnecessary;Failuretocorrectdeficienciesindissolutiontestingandestablishingspecifications;Failuretoqualifyreferencestandardsusedinthetestingofproductscontainingtannates;Failuretomaintainstabilityindicatingtestingmethods;andFailuretoestablishthereliabilityofthesupplier'sanalysis.
CenterforDrugEvaluationandResearchFiscalYear20083-33Elge,Inc.
,manufacturesnumerousprescriptiondrugproductsandproductsforOTCuse.
Someofthefirm'sprescriptioncoughandcoldproductswereunapprovednewdrugsbecausetheywerenotgenerallyrecognizedassafeandeffectivefortheirlabeleduses.
Additionally,theseproductsweremisbrandedbecausethedrugswereprescriptiondrugsandthelabelingfailedtobearadequatedirectionsforuse.
Prescriptiondrugsmusthaveadequatewrittendirectionsforusesothatalaymancouldusetheproductssafelyfortheintendeduses.
SeveralproductsthatweremanufacturedinappropriatelybeartheRx(prescription)legendbutwereOTCdrugproductsbasedontheirformulationanddirectionsforuseasdescribedinthemonographcovering"Cold,Cough,Allergy,Bronchodilator,andAntiasthmaticDrugProductsforOTCHumanUse.
"TheFDAconsideredtheresponsedatedMarch26,2008,addressingthedeviationsfromtheinspectionobservationsasinadequatebecausethefirmfailedtoprovidesufficientinformationtofullyassesstheadequacyoftheproposedcorrectiveactions.
Furthermore,theinformationsubmittedtoaddressmanyoftheinspectionalobservationsonlyindicatedthattheobservationswillbecorrected;however,aspecifictimeframeforimplementingtheproposedcorrectiveactionswasnotindicated.
ToviewthefulltextoftheWarningLetter,gotohttp://www.
fda.
gov/foi/warning_letters/s6771c_2.
htmFederalAgentsSeizedMoreThan$24MillioninUnapprovedNewDrugsOnJuly30,2008,theFDAandtheU.
S.
MarshalsServiceseized$24.
2millionworthofunapprovednewdrugsfromKVPharmaceuticalCompany,ofSt.
Louis,Missouri.
Theseizurefollowedaninspectionofseveralofthecompany'splantswhereanFDAinvestigatorfoundthatthecompanywasnotcomplyingwithanFDAenforcementnoticeaswellasmanufacturingunapprovednewdrugssuchasproductsforcough,cold,topicalwoundhealing,skinbleaching,andgastrointestinalconditions,aswellasnarcoticdrugproducts.
Consumersneedtobeconfidentthatthedrugsandmedicalproductstheyusearesafeandeffective,andtheFDAwilltakethenecessarymeasurestoensuresafetyandeffectivenessthroughoutthelifecycleoftheproducts,includingkeepingtheproductfromreachingthemarketplaceshouldconditionswarrantthisaction.
CenterforDrugEvaluationandResearchFiscalYear20083-34InaroutineinspectionofKVPharmaceutical'sfacilitiesinearly2008,theFDAfoundthecompanywasviolatingitsMay29,2007,noticerequiringcompaniestostopmanufacturingalltimed-releasedrugproductscontainingguaifenesin,includingcombinationdrugproductswhichcontainguaifenesinbecausetheywereunapprovednewdrugs.
FDAtooktheactionaspartofitsefforttoensurethatalldrugsmarketedintheU.
S.
havetherequiredFDAapprovalandthattheyaresafe,effective,ofgoodquality,andappropriatelylabeled.
Forproductsintimed-releaseform,theapprovalincludesmakingsurethattheproductreleasesitsactiveingredientsatthecorrectrate.
Improperlymanufacturedtimed-releaseproductsmayreleasetheactiveingredientstooquickly,tooslowly,ornotatall,makingtheproductunsafeorineffective.
Theinspectionalsoexposedthecompany'smanufacturinganddistributionofotherunapproveddrugproducts.
Theactionaddressednumerousunapproveddrugproductsmanufacturedanddistributedbythecompany.
TheseizeddrugshadbeenheldunderembargobytheStateofMissouri.
Sincethetimeoftheembargo,KVPharmaceuticalhadbeencooperatingwithFDAofficials.
InJune2006,theFDAissuedaguidancedocumenttitle,"MarketUnapprovedDrugs–CompliancePolicyGuide"(CPG).
ThisCPGmakesclearthatcompaniesmaynotmarketdrugsthatrequireapprovalwithoutfirstestablishing,throughapplicationsforapproval,thattheproductsaresafeandeffective.
ThelinktotheCPGguidanceisat:http://www.
fda.
gov/cder/Guidance/6911fnl.
htm.
FDAObtainsPermanentInjunctionAgainstScientificLaboratories,Inc.
TheFDAannouncedonMay16,2008,thatScientificLaboratoriesInc.
,anditspresident,RajeshwariPatel,andCEO,AmitRoy,signedaconsentdecreeofpermanentinjunctionandarebarredfrommanufacturinganddistributingdrugproductsuntiltheybringtheirmanufacturingoperationsintocompliancewiththelawandobtainapprovalfortheirproducts.
ScientificLaboratoriesisacontractmanufactureranddistributorofvariousprescriptioncoughandcoldproducts.
Thegovernment'scomplaint,filedbytheU.
S.
DepartmentofJustice,allegedviolationsoftheAct.
ThecompanyfailedtoseekrequiredFDAapprovalforsomeofitsproductsandfailedtocomplywithCGMPrequirements.
CenterforDrugEvaluationandResearchFiscalYear20083-35TheunapprovednewdrugsmanufacturedbythefirmhavenotundergoneFDAreviewforsafetyandefficacyandmayposepotentialhealthrisks.
TheFDAhadwarnedScientificLaboratoriesagainstviolatingtheActandabouttheriskofenforcementactionifitfailedtotakecorrectivemeasures.
TheFDAwilltakeactionagainstcompaniesandtheirexecutiveswhoviolatethelawandendangerpublichealth.
TheFDAwillcarefullymonitortheprovisionsofthisinjunctionaswellasinvestigateandtakeactionagainstothermarketersofunapproveddrugs.
TheconsentdecreebarredthedefendantsfrommanufacturinganddistributinganydruguntiltheyobtainrequiredFDAapprovalandfullycomplywithCGMPrequirements.
Thedefendantsmustdestroyanyillegaldrugs.
TheconsentdecreealsoallowstheFDAtoorderthedefendantstoshutdownintheeventoffutureviolations.
Italsosubjectsthedefendantstoliquidateddamagesintheamountof$5,000perdayiftheyfailtocomplywithanyoftheprovisionsofthedecreeandanadditionalsumof$5,000foreachviolation,upto$1millionperyear.
InJune2006,theFDAissuedaguidancedocumenttitled,"MarketedUnapprovedDrugs–CompliancePolicyGuide"(CPG).
TheCPGclearlystatesthatcompaniesmaynotmarketdrugsthatrequireapprovalwithoutfirstestablishingthattheproductsaresafeandeffective,anditalsoexplainsthatFDAmaytakeactionagainstmanufacturersandmarketersofunapproveddrugsthatviolateotherprovisionsoftheAct,includingCGMPrequirements.
ThedecreewassignedThursday,May8,2008,byJudgeWilliamD.
Quarles,Jr.
,intheU.
S.
DistrictCourtfortheDistrictofMaryland.
ToreadthefulltextofthePressRelease,goto:http://www.
fda.
gov/bbs/topics/NEWS/2007/NEW01837.
htmlForinformationaboutFDA'songoingeffortsonmarketingunapproveddrugsgoto:http://www.
fda.
gov/cder/drug/unapproved%5Fdrugs/ForCDER'sWebsiteonCompliancewithCGMPgoto:http://www.
fda.
gov/cder/dmpq/CenterforDrugEvaluationandResearchFiscalYear20083-36NewDrugsClaimedasGrandfatherDrugsOnNovember16,2007,theCincinnatiDistrictOfficeissuedaWarningLettertoThomasMurphy,President,BenVenueLaboratories,Inc.
,locatedinBedford,Ohio.
ThefirmwasinspectedMay7throughJune15,2007.
TheinspectionrevealedsignificantdeviationfromCGMPregulationsandthatthefirmwasproducingdrugproductsthatdonothaveFDAapproval.
ThefollowingCGMPdeviationswerecited:Failuretoestablishwrittencontrolprocedurestomonitortheoutputandvalidatetheperformanceofthosemanufacturingprocessesthatmayberesponsibleforcausingvariabilityinthecharacteristicsofin-processmaterialandthedrugproduct;andFailuretothoroughlyinvestigateanyunexplaineddiscrepancyorthefailureofabatchoranyofitscomponentstomeetanyofitsspecificationswhetherornotthebatchhasalreadybeendistributed.
ThefirmwasproducingLevothyroxineSodiumforInjection,ColchicineInjectionUSP,EphedrineSulfateInjectionUSP,PapaverineHClInjectionUSP,andCaffeineandSodiumBenzoateInjection.
AccordingtoFDAinvestigators,thefirmbelievedthattheseproductsweregrandfatheredasunapproveddrugs.
ItisFDA'sviewthatcompaniesclaimingthattheirproductsaregrandfatheredbearresponsibilitytofullydocumenttheirproducts'grandfatheredstatus.
Anycompanymarketingproductsonthisbasisshouldhaveavailabledocumentationtodemonstratethemarketpresenceoftheproductpriortotheenactmentofthenewdrugrequirementsthatwereestablishedin1938and1962.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6579c.
htmWarningLetterforCGMPforFinishedPharmaceuticalsandNewDrugOnJuly24,2008,theFDAissuedaWarningLettertoG&WLaboratories,inSouthPlainfield,NewJersey,afteraninspectionconductedDecember3throughDecember20,2007,revealedsignificantdeviationsfromtheCGMPforfinishedpharmaceuticalsregulations.
Thefirmwasalsocitedformanufacturingunapprovednewdrugs.
CenterforDrugEvaluationandResearchFiscalYear20083-37ThefirmrespondedtothecitedviolationsonJanuary15andJanuary31,2008.
Theresponseswereincompleteinthatthefirmstateditwouldcompleteadditionalanalysesforpreservativetesting.
However,theresponselackedtimeframesforcompletion.
TheCGMPdeviationsconcernedfailuretoestablishappropriatestatisticalcriteriawhereappropriateforbatchrelease,failuretovalidatescale-up,specificallyregardingmixingtimes,failuretorejectin-processmaterialnotmeetingspecifications,poormaintenanceofthemanufacturingfacilitydisrepair,incompleteinvestigationintothepresenceofblackparticlesinfinishedproduct,watersamplemicrobialtestfailure,andfailuretotestvalidationlotsforpreservativecontentuniformity.
Duringtheinspection,thefirmsuppliedFDAwithinformationaboutthemanufactureoftwoprescriptiondrugs:ChloralHydrateRectalSuppositoryandAnucort-HC.
Thesearedrugsbecausetheyareintendedforuseinthediagnosis,cure,mitigation,treatment,orpreventionofdiseases.
Thedrugsare"newdrugs"becausethedrugsarenotgenerallyrecognizedassafeandeffectivefortheirlabeleduses.
AnewdrugmaynotbeintroducedintoordeliveredforintroductionintointerstatecommerceunlessanFDA-approvedapplicationisineffectforthedrug.
ThefirmdoesnothaveanyFDA-approvedapplicationsonfileforthesedrugproducts.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6874c.
htmCombinationWarningLettertoPharmaceuticalCompanyAfteraninspectionofMidlandPharmaceuticalLLC,amanufacturingfacilitylocatedinKansasCity,Kansas,betweenJuly24andSeptember5,2007,theFDAissuedaWarningLettercitingnumerousdeviationsfromCGMPforfinishedpharmaceuticals.
OnNovember12,2007,thefirmrespondedtotheviolationsnotedduringtheinspectionbuttheresponsewasunacceptablebecauseitdidnotadequatelyaddressthefollowing:theprocessvalidationdeficiencies;theimpactofanalyticalmethodchanges;rootcauseintooutofspecification(OOS)results;thestatus;andthedispositionofreturneddrugproducts.
ThefirmalsoviolatedtheActbyintroducingintocommerce"newdrugs"thatdidnothaveFDAapproval.
CenterforDrugEvaluationandResearchFiscalYear20083-38ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6769c.
htmWarningLettertoU.
S.
ApothecaryLabsOnDecember18,2007,theFDA'sLosAngelesDistrictOfficeissuedaWarningLettertoJamesMcDaniel,President,U.
S.
ApothecaryLabs,inSanteFeSprings,California.
TheinspectionofthefirmwasreopenedonAugust9,2007,forthepurposeofcollectingasample.
TheinspectionconductedattheendofJuly2007revealedsignificantdeviationsfromtheCGMPregulations.
TheinspectionrevealedthatthefirmwasmanufacturingRadBlock—anunapprovednewdrugthatmaynotbelegallymarketedintheU.
S.
withoutanapprovedNDA.
AlthoughSection802oftheAct[21U.
S.
C.
§382]permitstheexportofcertainunapprovednewdrugsifspecificrequirementsaremet,Section802(f)(1)oftheAct[21U.
S.
C.
382]prohibitsexportationofdrugsthatarenotmanufacturedinsubstantialconformitywithCGMPregulations.
RadBlockisnotinsubstantialcompliancewithCGMPregulationsasCGMPdeficienciesincludedfailuretoconductfinishedproducttestingbeforerelease;lotsreleasedwithoutQCUapproval;undefinedtestmethodsandsamplingplansforfinishedproducttesting;lackofdatatosupportthreeyearexpirationdate;reservesamplesizesnotdefined;failuretovalidatemanufacturingprocess;notestingofincomingrawmaterials;andinadequateCGMPtraining.
ThefirmrespondedtwicetotheFDA'sobservations,buttheresponsesweredeemedinadequateinthattheydidnotadequatelyaddressallofFDAsconcerns.
Thefirm'sresponseslackedanexplanationforhowthetestingjustifiedthedeclarationthatthetablets'"weightvariationmeetsUSPrequirements.
"Weightvariationisthemethodusedtodemonstrateuniformityofdosageunits.
Theassayisusedintheactualweightvariationcalculation.
Also,thefirm'stestresultsonlystated"arangeoftabletweightsisreported.
"Theresponsealsofailedtoaddresswhetherthefirmevaluatedthecontractlaboratory'sfindingsthatthetestmethodwasinadequate.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6707c.
htmCenterforDrugEvaluationandResearchFiscalYear20083-39VintagePharmaceuticalsReceivesWarningLetterOnFebruary1,2008,theFDA'sNewOrleansDistrictOfficesentaWarningLettertoVintagePharmaceuticals,LLC,ofHuntsville,Alabama,afteraninspectiononJuly16-20,23-25,andAugust8,2007,revealedsignificantviolationsoftheCGMPregulationsandthatthefirmismarketingunapprovednewdrugs.
InalettertoFDA,Vintagerespondedtoeachofthedeviationsfoundduringtheinspection.
FDAfoundthatthattheresponsefailedtopromiseadequatecorrectionsandtheWarningLetterwasissued.
TheWarningLettercitedthefirmforvariousCGMPdeviationssuchasinadequateinvestigationsintomicrobiologicaltestfailures;failuretofollowmicrobialtestprocedures;useofunvalidatedmicrobialtestingmethods;failuretofollowtheretestingprocedures;unjustifieduseofalternativetestmethods;andenvironmentalmonitoringdeficiencies.
TheWarningLetteralsolistedunapprovednewdrugsthatwerebeingmarketedbyVintageinviolationoftheAct.
FollowingreceiptoftheWarningLetter,inmeetingsandcorrespondence,Vintagemanagementpromisedextensivecorrections.
FDAhasbeenmonitoringthefirm'sprogressandhasfoundthatsignificantcorrectionshavebeenmade.
ToviewthefulltextoftheWarningLetter,goto:http://www.
fda.
gov/foi/warning_letters/s6667c.
htmCenterforDrugEvaluationandResearchFiscalYear20083-40EnforcementStatisticsCenterforDrugEvaluationandResearchFDAForeignandDomesticInspectionsFiscalYears2004-20082,6002,4112,3052,2212,68201,0002,0003,00020042005200620072008CenterforDrugEvaluationandResearchSurveillance:ImportandDomesticSamplesFiscalYears2004-20082601,4341,1831,5483402,3683541,4793611,74205001,0001,5002,0002,50020042005200620072008ImportSamplesDomesticSamplesCenterforDrugEvaluationandResearchFiscalYear2008CenterforDrugEvaluationandResearchEnforcementActivityFiscalYears2004–200841672250125110024681020042005200620072008SeizuresInjunctionsDisqualifiedClinicalInvestigatorNB:ThesedataarenotcomparabletothosereportedinFY07aspartialseizureshavebeenassignedtooneCenter.
AsingleseizuremayinvolvemorethanoneCenter'sproducts.
CenterforDrugEvaluationandResearchFive-YearTotalProductRecallStatisticsFiscalYears2004–20081616813418314170451891271486710736176167030060090020042005200620072008ClassIClassIIClassIII3-41