Globalization Clinical Trials

TheCaseforGlobalization: EthicalandBusinessConsiderationsin ClinicalResearch
July 21, 2009

ToddD.Clark President ValueofInsightConsulting,Inc. www.voiconsulting.com
TheCaseforGlobalization: EthicalandBusinessConsiderationsinClinicalResearch

TableofContents
TableofContents....................................................................................................................................2 ExecutiveSummary.................................................................................................................................3 Introduction ............................................................................................................................................6 . TheContextofGlobalClinicalTrials........................................................................................................7 TheClinicalResearchSystem................................................................................................................11 EthicalConsiderations...........................................................................................................................13 SocialJusticeIssues...........................................................................................................................13 PatientSafeguards............................................................................................................................16 InformedConsent .........................................................................................................................16 . UndueInfluences..........................................................................................................................18 QualitySafeguards................................................................................................................................21 TheRoleofMarketForcesinClinicalResearch................................................................................23 ImprovingEnvironments.......................................................................................................................24 RoleofClinicalResearchOrganizations................................................................................................27 Conclusion.............................................................................................................................................29 AppendixA:EstimatedTimetoEnrollAllOpenPhaseIIICancerStudiesinU.S.onlyversusGlobally31 AppendixA:Overview.......................................................................................................................32 AppendixA:Methodology ................................................................................................................32 . AboutVOIConsulting,Inc.....................................................................................................................34 AbouttheAuthor..................................................................................................................................34 Notes.....................................................................................................................................................35
ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 2

ExecutiveSummary
Asclinicaltrialshavebecomeincreasinglyglobalizedoverthepasttentofifteenyears,thepossibility ofconductingstudiesthatofferadequatesubjectprotectionandyieldreliableresultsinemerging countrieshasunderstandablyattractedconsiderableattention.Inthisanalysis,weexaminethefacts regardingthecurrentstateofclinicalresearchandtherolethatbiopharmaceuticalcompaniesand theirclinicalresearchorganization(CRO)partnersplayinensuringthatthedualgoalsoftrialsafety andqualityaremet. Althoughconcernshavebeenraisedabouttheglobalizationofbiomedicalresearch,therealityisthat emergingcountriesplayavitalroleintheadvancementofmedicalscience.Clinicaltrialsinthese countries,particularlythosewithindustrysponsorship,areconductedatthehighstandards necessarytoobtainregulatoryapprovalinmajormarkets.Inaddition,theinvestmentsmadebytrial sponsors,whicharefrequentlyimplementedbyCROs,areamajorcontributortoimprovingthe healthsystemsandeconomiesofthedevelopingworld. Amongthekeyfindingsofthisreport: Increaseddemandforclinicaltrialsubjectscombinedwithlowerparticipationratesindeveloped countrieshasthepotentialtodramaticallyslowtheprogressofmedicalscience.Indeed,VOI Consultingestimatesthatitwouldrequireapproximately5.8yearstofullyenrollallcurrently openPhaseIIIcancertrialsifonlyU.S.locationswereusedascomparedto1.9yearsusingboth U.S.andglobaltrialsites. Whiletrialsinemergingcountrieshavereceivedanenormousamountofattentioninrecent years,thevastmajorityofclinicalresearchcontinuestobeconductedincountrieswithwell establishedinfrastructures.AfewstatisticspointoutjusthowbigaroletheU.S.,Western Europeandotherdevelopedregionscontinuetoplay: MembercompaniesofthePharmaceuticalResearchandManufacturersofAmerica (PhRMA)spentapproximately96%ofclinicalphasedollarsindevelopedcountriesduring 2007. ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 3
InitsSeptember2008reportonCROs,Frost&SullivanestimatesthatNorthAmericahas a49%shareofglobalR&DspendingwhileWesternEuropehada37%share.Theshare forAsiaPacific,aregionthatincludesestablishedmarketssuchasJapanandAustraliaas wellasemergingcenterssuchlikeIndiaandChina,isapproximately13.5%andtherest oftheworldhasonly0.5%. SeventysixpercentofallPhaseIstudiestakeplaceinjustthreecountries,theU.S., CanadaandtheNetherlands. AnalysisofdatafromClinicalTrials.govshowsthat51.8%ofallnewlyregisteredindustry sponsoredtrialsin2008hadatleastsomeU.S.activity;theexactsameshareasin2006. ThiscompareswithIndias2.7%participationrate,Chinas1.8%,Russias3.3%and Mexicos2.4%. Trialsinemergingcountriesaresubjecttothesamestandardsthatprevailinthedeveloped world.Thisisespeciallytrueofindustrysponsoredtrialsastheseareultimatelyaimedatgaining regulatoryapprovalfornewproducts.Toengageinunethicalorpoorqualityresearchistorun theriskthattheproductwillberejected,leavingthesponsornowaytorecouptheirR&D investments.Thepowerofthemarkettocorrectimproperpracticesisshownbya2009incident inwhichaU.S.basedcommercialInstitutionalReviewBoardwasforcedtocloseduetoclient lossesjustoneweekafterreceivinganFDAwarningletter. Regulatoryandculturalnormsregardingclinicalresearchinemergingcountriesareoftenmore, ratherthanless,strictthanindevelopedregions.Examplesofthisincludethedifficultyof conductingearlyphasestudiesinIndiaandplacebobasedstudiesinLatinAmerica.Patientsin thesecountriesmayalsoseekgreaterinputfromfriendsandfamilybeforedecidingtoenrollina trial. Clinicalresearchplaysanimportantroleinimprovingthehealthsystemsandeconomiesof emergingcountries.InPoland,forexample,30%ofhospitalcancertherapyisfundedbyclinical trialsponsors. Thetermemergingmarketdisguisesawiderangeofexperiencelevels.After15yearsof experiencewithclinicaltrials,capabilitiesofthelargerCentralEuropeancountriesare ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 4
consideredtobeverynearlyonaparwiththoseinWesternEurope.Othercountries,suchas SouthKoreaandTaiwan,haveadvancedmedicalinfrastructuresandshouldbeconsidered emergingonlyinthesensethattheirtrialactivityisgrowingrapidly. WorkingwithCROsoffersanumberofadvantagesforsponsorsinvolvedinemergingcountry trials.Inadditiontothebenefitsofreducedcostsandfastertimetomarket,CROsprovide standardizationofoperatingprocedures(SOPs)and,atthesametime,aremorelikelytohavea deeperunderstandingoflocallanguage,cultureandnorms,qualitieswhichleadtobetter relationswithinvestigatorsandimprovedtrialexecution. ThepresenceofCROsbenefitshostcountriesaswell.Theyprovideadvancedequipmentand trainedpersonnel,offerhighpayingjobsinareaswhereemploymentopportunitiesarescarce andhavebeeninstrumentalinharmonizingresearchnormsinemergingcountrieswith developedworldstandards. Althoughlegitimateconcernshavebeenraisedinthepastaboutclinicaltrialsinemergingcountries, theabilitytoconducthighqualitystudiesintheselocationshasbeenenormouslyimprovedoverthe previoustentofifteenyears.Ratherthanplacingfurtherbarrierstodrugdevelopment,efforts shouldbefocusedonenhancingtheprogressthathasalreadybeenmadewhilecontinuingtotrain andmonitorresearchersthroughouttheworldtoensuretheircompliancewiththehighest standards.Asthisreportdemonstrates,muchofthisisalreadybeingdoneaspartofthenormal businesspracticesofbiopharmaceuticalcompaniesandCROs,allofwhomhaveamajorstakeina strongandimprovingclinicalresearchenvironment.

Introduction
Since1948whenresultsofthefirstrandomizedclinicalstudywerepublished,1clinicaltrialshave becometheestablishedcornerstoneofmedicalresearch.Clinicaltrialsarenowanintegralpartof therigorousapprovalprocessemployedbytheU.S.FoodandDrugAdministrationtoshowthat drugsandmedicaldeviceshavebeendeterminedtobesafeandeffectivefortheirrespective indications.2 Giventhatclinicaltrialsareanecessarypreconditionforgainingregulatoryapprovalforamedical product,itisnotsurprisingthatapproximately75%ofclinicalstudiesarefundedbycompaniesthat seektomarketdrugsanddevices.3Indeed,pharmaceuticalandbiotechcompaniesarethegreatest contributortoresearchonaglobalscale,4spendingapproximately$130billiononR&Din2008.5Of thisamount,60to70%wasspentonclinicalstageactivities.6,7Althoughithasbeensaidthatthe profitmotiveofcommercialresearchcanconflictwithparticipantprotectionandthescientific validityofclinicaltrials,8researchersinnonprofitfieldsareoftensimilarlymotivatedbymonetary researchgrants,opportunitiesforcareeradvancementandprominence,andevenindividual pecuniarygainsthatcomefromfindingmedicaladvances.Whiletheriskofconflictsmustbe managedbybothforprofitandnonprofitinstitutions,monetaryrewardsassociatedwithsuccessful researchoftenservetofueltheachievementoflifesavingmedicalcuresandthisholdstruewhether theresearchtakesplaceinacommercialoracademicenvironment.Toplaceexcessiverestrictionson clinicalresearchwouldclearlyhavedamagingrepercussionsforglobalhealth,inbothaphysicaland economicsense.AstheU.S.DepartmentofHealthandHumanServicesOfficeoftheInspector Generalhasstated,thecriticalchallengeistoensureessentialhumansubjectprotectionswithout unnecessarilyslowingthepaceofresearchanddiscovery.9 Likemanyscientificandbusinessactivities,clinicalresearchhasexperiencedasignificantdegreeof globalizationinrecentyears.Thistrendtowardsinternationalclinicalstudieshasraisedanumberof
issues,ofwhichthemajorconcernsaretheethicaltreatmentofparticipantsandthequalityofthe resultingresearch. Moreprecisely,theseconcernsarenotaboutinternationaltrialsassuch.Fewwouldarguethat Canada,Australia,JapanandthecountriesofWesternEuropearenotonaparwiththeUnitedStates intermsofensuringthatpatientsarerecruitedinanethicalmanner,thattrialsareconductedin safe,wellregulatedenvironmentsandthatstudiesproducereliableresults.Concernsarefocused, instead,onincreasedclinicaltrialactivityinemerginglocationssuchasIndia,China,andthe countriesofLatinAmerica,CentralandEasternEurope(CEE)andAfrica. Thisanalysisexaminestheneedforglobalclinicalresearchandlooksatthefactsregardingthe natureofclinicaltrialsinemergingcountries.Thefocusisontheroleofthepharmaceuticalindustry andtheirclinicalresearchorganization(CRO)partners.Researchonhumanbeingsisoneofthemost ethicallyseriousactivitiesthathumanbeingsengageinand,assuch,rightlydeservestobesubjectto clearrulesandrigorousenforcement.Aswillbeshown,trialsconductedwithindustrysponsorship meetthehighestethicalandqualitystandards,regardlessofwheretheyareperformed;research capabilitiesfoundindevelopingcountriesaremuchstrongerthaniscommonlyperceived;andthe involvementofemergingcountriesinclinicalresearchadvancesmedicalsciencewhilealso contributingtotheimprovementofhealthsystemsandeconomies.
TheContextofGlobalClinicalTrials
ApproximatelyhalfofallpivotalstudiessubmittedtotheFDAcontainatleastsomeforeigndata.10 Between2004and2007,thenumberofFDAregulatedinvestigatorsincreasedby15.9%inCentral andEasternEurope(CEE),by12.1%inLatinAmericaandby10.2%intheAsiaPacificregion. Meanwhile,thenumberofNorthAmericanandWesternEuropeaninvestigatorsdeclinedby5.2% and6.1%,respectively.11 Lowercostistheusualreasoncitedforconductingclinicaltrialsinemergingmarketsandthisisan importantfactor.ThecostperpatientinIndiaandChinahasbeenestimatedatonethirdofthatin theUnitedStates.12Althoughperpatientcostsarelower,whenlogisticalandotherfactorsare ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 7
considered,thefullyloadedcostofconductingstudiesindevelopingcountriesoftenapproaches levelsthatwouldbefoundinmoreestablishedareas.13Intruth,thelargestbenefitofglobalized trialscomesfromfastertimetomarketreducingdevelopmenttimebyhalfresultsinnearlytwo thirdsreductioninoveralldevelopmentcostandprovidesalongerpostapprovalpatenttermin whichtorecouptheinvestment.14Fastertrialsalsomeanthatpatientsareabletoaccesssafeand effectivemedicinesmorequickly. Whilebusinessconsiderationsareimportantfortrialsponsors,ofgreaterrelevanceforsocietyisthe factthatiftrialswererestrictedtoestablishedresearchmarketswhereonlysome15%oftheworlds populationlives,15itwouldsimplynotbepossibletosuccessfullyrecruitsufficientnumbersof patientstofillthegrowingdemandsofclinicalresearch.Ithasbeenestimated,forexample,thatthe numberofpatientsrequiredtofillallspotsinindustrysponsoredtrialsincreasedfrom2.8millionin 1999to19.8millionin2005.16 Anumberoffactorsaredrivingthisrapidgrowth.ConsiderthatasofFebruary2009,therewere approximately2,900newdrugcompoundsinclinicaltrialsorundergoingFDAreview,a52.6% increaseover1999levels.17Further,theaveragenumberofdaystocompleteatrialgrewby70% from1999to2005whileenrollmentratesdeclinedby21%andretentionratesfellby30%.18 Asaresultoflowparticipationratesindevelopedcountries,trialsareunabletorecruitsufficient numbersofpatientsonschedule.OnlysevenpercentoftrialsintheU.S.beginontimeand70%are delayedformorethanamonth.19IntheUnitedKingdom,30%ofinvestigativesitesinindustry sponsoredtrialsfailtorecruitasinglepatientand70%ofsitesfailtomeetrecruitmenttargets.20 Alongwithagrowinglevelofresearchactivity,longertrialsandlowerparticipationrates,the numberofpatientspertrialisalsoincreasingacrossallphasesofclinicalresearch.Arecentsurveyby theFrenchindustryassociation,Lesentreprisesdumdicament(LEEM),founda40%jumpinthe numberofenrolledpatientsinstudiesconductedbymajorpharmaceuticalcompaniesbetween2006 and2008alone.21AsshowninTable1,thesamesurveyfoundthattrialsitesinmoreestablished countriesrecruitedanaverageof7.2patientsin2008whilesitesinemergingareaswere63%more ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 8
productivewithanaverageof11.8patients.Notably,siteproductivityintheUnitedStates,which wasalreadylowincomparisontootherlocations,actuallydeclinedinthetwoyearperiod. Table1NumberofPatientsEnrolledperActiveTrialSite:EstablishedversusEmergingMarkets22
Patients peractive site2008 7.6 8.3 8.1 6.5 5.7 7.2 Change(in patients) since2006 +1.3 +1.5 +2.5 +0.3 0.4 +1.0 Patients Change(in peractive patients) site2008 since2006 13.0 +2.6 11.4 +2.3 11.1 +0.1
EstablishedMarkets France Germany UnitedKingdom Canada UnitedStates AverageAboveCountries
EmergingMarkets EasternEurope LatinAmerica Asia
AverageAboveRegions
11.8
+1.7
Theabovefiguresindicatethattheinvolvementofemergingcountriesisabsolutelynecessaryif medicalresearchistocontinueadvancingattherapidpacetowhichwehavebecomeaccustomed. Asasingleillustration,ithasbeenreportedthatonlythreetofivepercentofU.S.cancerpatients participateinclinicaltrials.23,24Usingthehigherfigureoffivepercent,VOIConsultingestimatesthat itwouldrequireapproximately5.8yearstofullyenrollallcurrentlyopenPhaseIIIcancertrialsifonly U.S.locationswereused.Thiscomparesto1.9yearsusingbothU.S.andglobaltrialsites.This3.8 yearreductionindevelopmenttimetranslatestoimprovementsinpharmaceuticalindustry performanceand,ofgreaterimportance,fasteraccesstolifesavingtherapiesforpatients.Further, theseestimatesarebasedonlyoncurrentlyopentrials;ifnewtrialswereaddedwithoutclearingthe backlog,thetimeneededtobringnewdrugstomarketwouldcontinuetogrow.(SeeAppendixAfor methodologyandcalculations.) Althoughemergingmarketshaveexperiencedrapidgrowthinrecentyears,itisimportantto understandtheirroleintheoverallcontextofdrugresearch.Infact,theU.S.,WesternEuropeand otherdevelopedcountriescontinuetohostthevastmajorityofclinicaltrials.Afterall,theconverse oftheabovementionedstatisticthathalfofallpivotalstudiessubmittedtotheFDAcontainsome foreigndataisthatapproximatelyhalfofthesestudiesincludenoforeigndatawhatsoever.Giventhe ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 9
degreeofattentionthatglobaltrialshavereceivedinrecentyears,thisisasomewhatmore surprisingfinding. VOIConsultinganalysisofdatafromClinicalTrials.govshowsthat51.8%ofallnewlyregistered industrysponsoredtrialsin2008hadatleastsomeU.S.activity;theexactsameshareasin2006. ThiscompareswithIndias2.7%participationrate,Chinas1.8%,Russias3.3%andMexicos2.4%.25 ThismethodisnotperfectasClinicalTrials.govmaytendtooverrepresentU.S.basedresearch. Nonetheless,allreliablesourcessupportthefindingthatclinicalresearchisstillverymuch dominatedbycountrieswithestablishedresearchhistories.Forexample: In2007,membercompaniesofthePharmaceuticalResearchandManufacturersofAmerica (PhRMA,)alistthatincludesU.S.aswellasmanymajorforeignfirms,spentonly3%ofallR&D dollarsinemergingcountries.Preclinicalactivityaccountsfor27.3%oftotalspendinganditis likelythatvirtuallyallpreclinicalworkwasdoneinregionswithestablishedresearchcapabilities. Ifweremovepreclinicalexpenditures,thetotalamountofR&Dspentindevelopingcountries risesto4.1%.26 InitsSeptember2008reportonCROs,Frost&SullivanestimatesthatNorthAmericahasa49% shareofglobalR&DspendingwhileWesternEuropehada37%share.TheshareforAsiaPacific, aregionthatincludesestablishedmarketssuchasJapanandAustraliaaswellasemerging centerslikeIndiaandChina,isapproximately13.5%andtherestoftheworldhasonly0.5%.27 EightythreepercentofactiveinvestigativesitesareinthedevelopedcountriesofNorth America,WesternEuropeandOceania.28 TheUnitedStateshad36,281sitesauthorizedtoconductclinicaltrialsin2007.Thisrepresented nearlyhalf(48.9%)ofallgloballyauthorizedsites.Incontrast,twelveleadingemergingresearch countrieshadacombinedtotalofapproximately7,400authorizedsites,or20%oftheU.S. number.29 Indiaisbelievedtohaveaccountedforjust0.1%ofR&DbudgetsfromU.S.pharmaceutical companiesin2006.30 Approximately70%ofFDAregulatedinvestigatorsareintheU.S.orWesternEurope.31 ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 10
SeventysixpercentofallPhaseIstudiestakeplaceinjustthreecountries,theU.S.,Canadaand theNetherlands,allofwhichpossesshighlyadvancedresearchcapabilities.Althoughemerging countriesmayeventuallyplayalargerroleinPhaseIbioequivalencestudiesforestablished drugs,itisexpectedthatthemorenovel,sophisticated,complex[PhaseI]studies[will] predominantlyplayoutinNorthAmericaandWesternEurope.32 Althoughonlyasmallportionofresearchcurrentlytakesplaceinemergingcountries,concernshave beenraisedaboutthenatureofthestudiesthataredoneintheseregions.A1996Nigeriabasedtrial oftheantibiotic,Trovan(trovafloxacin),isfrequentlycitedasanexampleofresearchthatwouldnot havebeenallowedtoproceedinmoredevelopedmarkets.Theexactfactsofthecaseareindispute and,asofmid2009,itappearsthatPfizer,thetrialsponsor,andtheplaintiffsareclosetoreaching anoutofcourtsettlement.33Accordingtosomereports,however,theresearchersfailedtoobtain informedconsentandthetrialresultedinthedeathsof11children.34 Obviously,itisextremelytroublingwhenresearchsubjectsexperienceharmofanykind,andeven moresowhenthesesubjectsarechildren.Itisnonethelessimportanttonotethatthistrialtook placemorethanadecadeagowheninternationalresearchwasinafarlessmaturestatethanat present.Today,emergingcountriesexhibitstrongerethicalandregulatoryoversight,greater institutionalcapacityandhigherlevelsofprofessionalism.Aswewillsee,thedrivingforcebehind theseimprovementshasbeentheexperiencegainedintrialsrunbypharmaceuticalcompaniesand theirCROpartners.
TheClinicalResearchSystem
Clinicalresearchonhumansissubjecttocertainethicalandregulatorynorms.Althoughthesemay beinterpretedorimplementedsomewhatdifferentlyfromonecountrytoanother,theystandas generalprinciplesthatapplytostudiesregardlessofwheretheyareperformed.Tounderstandthe implicationsofconductingtrialsindevelopingcountries,itisimportanttofirstunderstandthese globalnorms.
TheNuremburgCode,whicharoseoutofthepostWorldWarTwoDoctorsTrial,servesasthe ethicalfoundationofhumanresearch.TheCodeconsistsoftenprinciples,ofwhichthemost importantstatesthatthevoluntaryconsentofthehumansubjectisabsolutelyessential.TheCode alsostatesthatthesubjectmustbeinapositiontoexercisefreepowerofchoicebasedon accurateinformationandfreefromanyelementofcoercion.Inaddition,theexperimentshould besuchastoyieldfruitfulresultsforthegoodofsociety,unprocurablebyothermethodsormeans; thedegreeofrisktobetakenshouldneverexceedthatdeterminedbythehumanitarian importanceoftheproblemtobesolved;andduringthecourseoftheexperimentthehuman subjectshouldbeatlibertytobringtheexperimenttoanend.35Theprincipleofinformedconsent hasbeencalledthemostimportantcontributionoftheCodeandhasbeenwidelyadoptedbythe researchcommunity.36 TheothermajorguidingdocumentistheDeclarationofHelsinki,firstpublishedbytheWorld MedicalAssociationin1964.Oneofitsbiggestcontributionswastointroducetheethicscommittee (EC).37TheDeclarationstates,the[trial]protocolshouldbesubmittedforconsideration,comment, guidance,andwhereappropriate,approvaltoaspeciallyappointedethicalreviewcommittee,which mustbeindependentoftheinvestigator,thesponsororanyotherkindofundueinfluence.38The roleoftheECistoensurethatthebenefitsofastudyoutweighitsrisks,thatpatientsareproperly informedabouttheirrightsandtherisksinvolvedinparticipationandthattheyarenotsubjectto unduepressuretoenroll(e.g.viaexcessivepayments).Inadditiontoprovidinginitialreview,theEC ischargedwithreviewingthetrialonanongoingbasis39(astepthattakesplaceinparallelwith regularmonitoringbythesponsororCRO). EthicscommitteesgobyvariousnamesaroundtheworldincludingInstitutionalReviewBoards(or IRBsintheU.S.),ResearchEthicsBoards(REBs,Canada),ResearchEthicsCommittees(RECs,many WesternEuropeancountries),HelsinkiCommittees(Israel),BioethicsCommittees(Poland)and CommitteesforEthicalProtection(CEPs,Brazil).Althoughmoreestablishedresearchmarketsoften offercentralizedethicalreviewformultisitetrials,thesecommitteesareusuallyhousedwithinthe
institutionthatisconsideringwhethertohostthestudy.Inadditiontomedicalprofessionals,EC membershipgenerallyincludesconsumersaswellaslegalandethicalexperts. Clinicaltrialsmustalsoreceivesomeformofapprovalfromalegallyauthorizedregulatoryauthority. TheGuidelineforGoodClinicalPractice(GCP)fromtheInternationalConferenceonHarmonisation (ICH)providestheprinciplesforregulatoryoversight.OriginallyadoptedbytheU.S.,Japanandthe EuropeanUnionin1996,ICHGCPhassincebeenwrittenintothelawsofmanyemergingresearch countriesandisfolloweduniformlybyCROsthroughouttheworld.
EthicalConsiderations
Noneofthebenefitsofgreateraccesstoclinicaltrialpopulationsareworthwhileifthepatients involvedaresubjectedtoundueriskorifthestudiesthemselvesfailtoprovidereliableresults.This raisesanumberofquestionsaboutinternationalresearchsuchas: Atagenerallevel,whatsocialjusticeconcernsareraisedbyhumanresearchindeveloping countriesandhowarethesedifferentfromconcernsindevelopedcountries? Areexistingpatientsafeguardsadequatetoprotectresearchparticipantsandensurequality results? Aretherulesprotectingpatientseffectivelyenforced?
SocialJusticeIssues
Onecommoncomplaintaboutglobalizedresearchisthatthepharmaceuticalindustryusespoor countriestotestdrugsthatwillbenefitrichcountries.Specifically,itishasbeenassertedthattrials tendtofocusonchronicconditionsassociatedwithagingratherthanacuteinfectiousdiseasesthat plaguethedevelopingworld.40 Whiletropicaldiseasesarenotgenerallyamainfocusofpharmaceuticalcompanies,neitherarethey completelyignored.A2008studybyCenterWatchfound19drugsinvariousstagesofdevelopment againsttropicaldiseasesrelatedtobacterial,viralandparasiticinfections.Theseincludedvaccines andprophylacticagentsaswellasagentstocombatexistinginfections.41Admittedly,thisrepresents ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 13
asmallpercentageofthepreviouslymentioned2,900totaldrugsindevelopmentbutthereare enormousvariationsinthenumberofpeoplethatanindividualagentcanhelp.Penicillin,for example,haslikelysavedmillionsoflivessinceitwasfirstusedintheearly1940s.42Further,deaths fromtropicaldiseasesareinmanycasesmoreafunctionofinfrastructurethandrugtherapy.Thisis shownbyanApril2009studyfromtheWHOwhichreportedthatdeathsfrommalariadeclined47% inZambiabetween2006and2008followingthedistributionof3.6millioninsecticidetreatedbed nets.43 Inanycase,tocriticizetheforprofitpharmaceuticalindustryforconductingresearchthatwillresult inprofitableproductsignoresthefactthat,bydefinition,patientsenrolledinaclinicaltrialsuffer fromtheconditionbeingstudied.Whilecancermightnotbeamajorcauseofdeathwithinacountry, individualpatientsarefacedwithasinglecauseofdeathand,iftheyhavecancer,thenthatisthe singlecauseofdeaththeyaremostlikelyfacing. Wearguethatconductingtrialsinthedevelopingworldshouldbeconsideredunethicalonlyif patientstherearetreateddifferentlythanthoseindevelopedcountries.Forexample,iftrialsinpoor countrieshaveahigherrateofrandomizationtoplacebo,thenthisdoespresentaseriousethical problem.Itappearsthatsuchdifferentialtreatmenthasindeedhappenedinisolatedcasesinthe past.Asshownlaterinthisanalysis,however,risingexperiencelevelshavestrengthenedthe institutionschargedwithoversightindevelopingcountriesandraisedawarenessamongdeveloped worldregulatorsaboutthepotentialforabuseandtheneedtoscrutinizethequalityofclinical research. Itisalsoworthrepeatingthatfirstinhumantrialsi.e.PhaseIresearchoninvestigationalagents arealmostexclusivelyconductedincountrieswithadvancedcapabilities.(Althoughemerging marketsmayreportPhaseIactivity,thesetendtobebioequivalencestudiesusedtoshowthata genericdrugpossessesthesamequalitiesasawellestablishedbrandedproduct.)Firstinhuman researchisgenerallyconductedonhealthyvolunteersandthereforeoffersthesubjectno therapeuticbenefit.Whilecertainlynotriskfree,thePhaseIIandlatertrialsthataremuchmore
likelytobeconductedindevelopingcountriesrepresentapotentialforpatientstobenefitdirectly fromtheinvestigationaldrug. Althoughproblemswithtrialssponsoredbymultinationalcompaniesarelikelytoreceivemorepress attention,ethicalandqualityviolationsoftenoccurintrialsinitiatedbylocalinvestigators.In2002 and2003,forexample,Indiandoctorsinitiatedseveralunauthorizedtrialsofcancer,contraceptive andfertilityagents,noneofwhichinvolvedparticipationbyWesternsponsors.44Exposureto developedworldresearchproceduresandstrictadherencetoindustrystandardGCPwillmorelikely servetoreduceratherthanexacerbatetheseproblems.Thisisdemonstratedby2008studyonthe qualityofclinicaltrialsinChina.Althoughtheauthorsfoundproblemswiththewayinwhichtrialists reportedtheirfindings(forexample,inadequatediscussionofinformedconsentprocedures),itwas alsoapparentthatresearchersinWesternmedicinetrials,atleastsomeofwhichwerepresumably sponsoredbypharmaceuticalcompaniesorCROs,wereingreatercompliancewithstandard practicesthanwereresearchersinvolvedintrialsofTraditionalChineseMedicines.45 Clinicalresearchalsoprovidesbenefitswellbeyondthedirecteffectsofthetherapeuticintervention. Patientsgetaccesstoastandardofcarethatmightotherwisebeunavailable,investigatorsare exposedtoadvancedmedicaltechniquesandthelargersocietybenefitsfromimprovedhealth infrastructureandeconomicdevelopment.46PhaseIIandPhaseIIItrials,inparticular,tendtoresult innewinvestmentandjobgrowth.47Forexample,Westernpharmaceuticalcompaniesspentonly $30millionontrialsinIndiain2004.48By2006,thishadreached$140million49andby2010total investmentisexpectedtoreach$1.5billion.50Inacountrywheretotal2005spendingonhealthwas approximately$42billion,51thisrepresentsasignificantinfusionofcapital. Incountriesthatareparticularlystrappedforhealthcarefunds,clinicaltrialsalsoprovideamajor sourceofsubsidizedmedicaltreatment.Forexample,a2006studybyPricewaterhouseCoopers reportedthatapproximately30%ofhospitalcancertherapyinPolandisfundedbyclinicaltrial sponsors.52Itisdifficulttounderstandhowwithdrawingthesesubsidieswouldbeanimprovementin eithermedicalorethicalterms.

PatientSafeguards
Thetwomostcommonconcernssurroundingpatientprotectionintrialsconductedindeveloping countriesarewhetherproperinformedconsentcanbeobtainedandwhetherpaymentofferedfor participationexertsunduepressureonpoorpatients.Incidentally,essentiallythesameconcerns havebeenexpressedbytheDepartmentofHealthandHumanServicesOfficeoftheInspector GeneralregardingtrialrecruitmentintheUnitedStates.53 InformedConsent Table2showsliteracyratesforsamplecountriesintheemergingandestablishedcategories.Literacy mightbeconsideredareasonableproxymeasurementfortheabilitytograntinformedconsent basedonanunderstandingoftheimplicationsoftrialenrollment.Unsurprisingly,ratesinemerging countriesarelowerthaninthedevelopedworld.Forthemostpart,however,thedifferencesareless thanmightbeexpected.CountriesinCentralandEasternEuropeexhibitliteracyratescomparable to,orinsomecaseshigherthan,advancedeconomieswhileChina,Thailand,ArgentinaandMexico areallabove90%.Theaverageliteracyforthesecountries(93.5%)iswellabovetheworldaverageof (82%).OnenotableexceptionisIndia,whereonly61%ofthepopulationisliterate.Evenherethe implicationsforinformedconsentarebetterthanthatstatisticwouldindicatewhenoneconsiders thatclinicalresearchisconductedprimarilyinurbanareasand,perthe2001IndianCensus,literacy inurbanareasissubstantiallyhigher(80.3%)thaninruralareas(59.4%).54
Table2LiteracyRatesinSampleEmergingandEstablishedTrialLocations55
EmergingTrialLocations Argentina Brazil China CzechRepublic Hungary India Mexico Poland Romania Russia Slovakia Singapore SouthAfrica SouthKorea Taiwan Thailand Ukraine UnweightedAverageLiteracyRate LiteracyRate 97.2% 88.6% 90.9% 99.0% 99.5% 61.0% 91.0% 99.8% 97.3% 99.4% 99.6% 92.5% 86.4% 97.9% 96.1% 92.6% 99.4% 93.4% WorldAverage EstablishedTrialLocations Australia Canada Denmark France Germany Italy Japan Netherlands Norway Spain Sweden Switzerland UnitedKingdom UnitedStates LiteracyRate 99.0% 99.0% 99.0% 99.0% 99.0% 98.8% 99.0% 99.0% 100.0% 97.9% 99.0% 99.0% 99.0% 99.0%
UnweightedAverageLiteracyRate 82.0%
99.0%
Basicliteracyis,ofcourse,noguaranteethatapatientcanunderstandtheimplicationsoftrial enrollment,butpoorunderstandingofthenatureofclinicalresearchishardlyconfinedtothe developingworld.InGermany,forexample,parentsofchildrenaskedtoparticipateinatrialofan investigationalattentiondeficitandhyperactivitydrughaddifficultiesunderstandingthenatureof theplacebocomparativearmanddidnotproperlyunderstandthattheprimaryobjectiveofthe studywasresearchratherthanthebestindividualizedmedicalcare.56Indeed,thetendencyamong patientstohaveanoptimisticbiasandtherapeuticmisconceptionsabouttrialsiswelldocumented, regardlessofwheretheresearchtakesplace.57 Onefactorthatmayhelpprotectdevelopingworldpatientsfromparticipatinginatrialagainsttheir interestisthegreaterinvolvementoffamilyandfriendsinthedecisionmakingprocess.Arecent studyinIndia,forexample,foundthat92%ofpatientsinvolvedotherpeoplebeforedecidingto enrollinatrialwhileonly62%ofU.S.patientsdidso.58 ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 17
UndueInfluences Anothercommonlyraisedethicalconcernaboutresearchinpoorcountriesisthatthemonetary compensationprovidedforparticipationcanbesufficientinandofitselftoconstituteundue influence.59Itshouldbenotedthatresearchnormsdictatethatanypaymentsassociatedwiththe trialbeexaminedaspartoftheethicalreviewprocessandthatsubjectsinPhaseIIandlatertrials (i.e.thosewhoactuallyhavetheconditionbeingstudied)areusuallypaidverylowamounts. Standardpracticeistoreimburseformeals,transportationandsimilaroutofpocketexpenses relatedtoparticipationinthetrial.HealthyvolunteersinPhaseItrialsmaybepaidsubstantially morebut,asdiscussedelsewhere,thesestudiestakeplacealmostexclusivelyinthedeveloped world. Itistruethatevenasmallamountofmoneymaybeaconsiderableenticementinverypoor countries.Nonetheless,theargumentoverwhetherthisconstitutesundueinfluenceignoresthefact thatpatientsinthedevelopedworldarealsosubjecttopressuresthatareextrinsictothetrialitself. IntheUnitedStates,forexample,45.7millionpeopleor15.3%ofthepopulationdidnothavehealth insurancein2007.60Asaresult,theymaybeespeciallywillingtoparticipateinresearchinsofaras theyconsideritawaytogethealthcareortreatmentsthatareotherwiseunavailabletothem.61 Further,inmanycountrieswithuniversalhealthcaresystems,patientsmustendureextensive waitingperiodspriortoreceivingappropriatecare.Afewexamples: Fromthetimetheyreceiveageneralpractitionersreferralforinpatienttreatment,patientsin theU.K.NationalHealthSystemmustwaitanaverageofapproximatelytwomonths(8.6weeks) beforetheyareadmittedtothehospital.62 Canadianpatientsfaceevenlongerwaitingtimes:in2008,theaverageswere8.5weeksbetween GPreferralandaspecialistvisit,thenanadditional8.7weeksfromthespecialistvisittoreceiving care,acombinedtotalof17.3weeks.Candidatesforneurosurgeryandorthopedicsurgeryhadto waitatotalof31.7and36.7weeks,respectively.63
Swedishguidelinescallfor80%oflungcancerpatientstoreceiveatreatmentplanwithin28days ofdiagnosisbutnoneofthecountryshealthregionsactuallymeetthisgoal.Inthecapital, Stockholm,only34%ofpatientsreceiveatreatmentplanwithinthetargetperiod.64 Itisreasonabletoassumethatthefasteraccesstocarethatmightbeavailabletopatientsviatrial participationservesasamotivatingfactorinthesesituations. Withtheaboveconsiderationsinmind,itisworthnotingthatpharmaceuticalcompaniesearnthe vastmajorityoftheirrevenuesindevelopedcountries.65Evenifweignoreallethicalresearchnorms, itwouldclearlybeextremelypoorbusinessstrategytoinvestinresearchthatwouldultimatelybe rejectedbyregulatoryagenciesinthesemajormarkets.Whatsortofpolicies,then,doregulators andothergovernmentauthoritieshaveregardingethicalconductoftrialsconductedoutsidetheir borders? AccordingtoFDAregulationsthatwentintoeffectonOctober27,2008,allforeignstudies conductedinassociationwithadrugormedicaldeviceapprovalmustfollowGCPguidelines.The newregulationsrequireindependentethicalcommittee(IEC)reviewandoversight, documentationofIEC,investigatorandsitequalifications,theabilityforonsiteFDAinspection andsponsormaintenanceofrecordsforatleasttwoyearsfollowingtheFDAsdecisiononthe application.Sponsorsmustalsoexplainhowtheyobtainedinformedconsentandthismust includeadescriptionofincentivesprovidedtoparticipants.MonitoringandGCPtraining proceduresmustalsobedescribed.Theseregulationsapplytoallforeignclinicalstudies regardlessofwhethertheyarenew,ongoingorcompleted.66 TheEuropeanUnionwillnotrecognizetheresultsoftrialsanywhereintheworldiftheseviolate theprevailingethicalstandardsofthedevelopedworld.67AccordingtotheAdditionalProtocol oftheCouncilofEuropesConventiononHumanRightsandBiomedicine(CHRB),studiescarried outby"sponsorsorresearcherswithinthejurisdictionofaPartytothisProtocol[i.e.inE.U. countries]"thattakesplaceinacountryoutsidethejurisdictionoftheProtocolmustcomply withthetermsoftheProtocoliftheydifferfromthoseintheothercountry.TheAdditional ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 19
Protocolwasspecificallydraftedwithglobalizedclinicalresearchinmindandensuresthatclinical researchcomplieswithhighstandards,regardlessofwhereitisconducted.68 AJanuary2009rulingbytheU.S.CourtofAppealsfortheSecondCircuitfoundthatobtaining informedconsentfromresearchsubjectshasbecomeauniversalnormacceptedbythe civilizedworld.Inpracticalterms,thisrepresentsaverymeaningfulrestraintagainstunethical behaviorasitopensupthepossibilityforplaintiffstosueinU.S.courtsundertheAlienTort Statute.69 Inadditiontothesafeguardsputinplacebydevelopedworldagencies,thedomesticregulatoryand legalsystemsofemergingresearchcentersprovideanotherlayerofpatientprotection.Indeed, developingcountriesoftenhaveregulationsornormsthataremorestringentthaninestablished regions.Forexample,untilafewyearsago,trialsinIndiaweresubjecttoaphaselag.Thismeant thattoinitiateaPhaseIItrialinIndia,itwasnecessarythattheagentbeunderstudyinaPhaseIII trialsomewhereelseintheworld.Underregulationsthatwererevisedin2005,thisrequirementwas dropped.However,itisstillnotpossibletoconductaPhaseItrialinIndiafornewdrugsubstances discoveredelsewhereunlessPhaseIdatafromothercountriesisavailable.70ArgentinaandBrazilare examplesoflocationswheresponsorswillhaveaverydifficulttimeobtainingethicalorregulatory approvalfortrialswithplacebobasedcomparativearmsunlessnootherproventherapyexists.71 Interestingly,inmanydevelopedcountries,regulatoryagenciesprovidetacitratherthanexplicit consent.Inotherwords,sponsorsmayproceedwithatrialunlesstheyareinformedotherwise withinacertain(relativelyshort)periodoftime.InGermany,forexample,trialauthorizationfor mostinvestigationalagentsmaybeassumediftheregulatoryagencydoesnotcommunicate objectionstothesponsorwithin30regulatorydaysafterreceiptoftheappropriatedocuments.72 Australiahasanevenmoreexpeditiousapproach:95%ofallstudiesareapprovedviatheClinical TrialNotificationschemewherebytheregulatoryagencydoesnotreviewanyinformationrelatingto theprotocol,insteadplacingtheonusofresponsibilityforapprovalononeofthecountrysHuman ResearchEthicsCommittees.73
Bycontrast,lawsgoverningresearchinthemajoremergingresearchcountriesuniversallyrequire explicitapprovalbytheregulatoryagency;China,India,Poland,Russia,Argentina,BrazilandSouth Africaareamongthelocationsthatusetheexplicitapprovalapproach.Inaddition,regulatory proceduresinemergingcountriesaremorelikelytorequireprotocolstoundergosequentialrather thanparallelreviewsbytheECandregulatoryauthorities.74 Thegoalinpointingoutthesedifferencesisnottodisparagethequality,ethicalorotherwise,oftrial approvalmethodsusedincountrieswithestablishedresearchcapabilities.Bydefinition,regulators andresearchersintheseplaceshavemoreexperiencewithtrialevaluationandmonitoring.As emergingregionsgainexposuretoworldclassstandardsandtechniques,itislikelythattheir regulatorysystemswillmoveinthedirectionofexpeditedapproval.Inthemeantime,however,the requirementforexplicitapproval(andinmostcases,sequentialreview)providesanotherlayerof oversightinlessdevelopedcountries. Researchpracticesindevelopedcountriescanalsobeinconsistentorincomplete.Indeed,ithasbeen saidthatthereisahugediversityinnationalregulationsregardingclinicalresearch.75Forexample, FrancehasmorelenientrulesthantheUnitedStatesconcerningwhichstudiesrequireapprovalfrom anethicalcommittee.76AU.K.studyfoundthat16%ofauthorsofpapersoninterventionaltrialsdid notspecifywhethertheyhadobtainedethicalapprovalfortheirstudies.77Anotherauthorwritingon theethicalreviewprocessintheU.K.citesacontinualprocessofradicalchangeandinherent variabilityinmoraljudgment.78
QualitySafeguards
Inadditiontoethicaltreatmentofstudyparticipants,theothermajorconcernishowthe involvementofemergingcountriesaffectsresearchresults.Theissuesatstakeincludewhetherthe datawasaccuratelyassessed,capturedandreported;whetherthetrialenvironmentwasin compliancewithdevelopedworldstandards;andwhetherthetrialwasconductedandreported withoutbias.
Table3belowshowstheresultsofFDAclinicalinvestigatorinspectionsfortheperiod2000to2008. NotethatNoActionIndicatedmeansthatnoobjectionableconditionsorpracticeswerefound duringtheinspection;VoluntaryActionIndicatedmeansthatproblemswerefoundbuttheywere notsufficienttojustifyregulatoryactionandthechoiceofwhethertocorrecttheproblemswasleft totheinvestigator;OfficialActionIndicatedmeansthatproblemssufficienttowarrantregulatory actionswerefound.Althoughitistruethatonlyarelativelysmallnumberofinspectionshavebeen conductedinemergingtrialcountries(oranyothercountryoutsidetheUnitedStates),the inspectionsthathavebeendoneindicatethatthequalityofresearchisinlinewithdevelopedworld norms.Indeed,inspectionsintheU.S.haveyieldedahigherpercentageofOfficialActionIndicated findingsthaninanyothercountry. Table3ResultsofFDAClinicalInvestigatorInspections20000879
Voluntary Action OfficialAction Indicated Indicated Total 59% 0% 29 38% 0% 16 50% 0% 4 67% 0% 94 57% 1% 183 94% 0% 17 60% 0% 10 0% 0% 1 100% 0% 2 67% 3% 117 73% 9% 11 65% 10% 4,014 74% 1% 314 3,157 407 4,812
Africa Asia/Pacific,other Australia/NewZealand Canada Central,EasternEurope China India Japan Korea LatinAmerica MiddleEast US WesternEurope Total
NoAction Required 41% 63% 50% 33% 42% 6% 40% 100% 0% 31% 18% 25% 25% 1,248
AlthoughFDAinspectionswereslowtoadapttotherisinglevelofglobaltrialactivity,significant strideshavebeenmadeinrecentyears.Forexample,thenumberofinternationalGCPinspections doubledfrom50in2000to100in2007whenforeigninspectionsrepresented10%oftotal bioresearchmonitoringactivity.80TheFDAhasorsoonwillopenofficesinChinaandIndiaaswellas ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 22
inEurope,LatinAmericaandtheMiddleEast.ThisbeganinNovember2008withnewlocationsin Beijing,ShanghaiandGuangzhou,China.Inearly2009,officeswereopenedinNewDelhiand Mumbai,India.81ThefirstLatinAmericanofficewasstartedinCostaRicainJanuary2009;thiswillbe followedwithadirectFDApresenceinMexicoandSouthAmericalaterintheyear.82Initially,the primarytaskofthesenewofficeswillbetomonitormanufacturingquality.However,inspectionsof researchsiteswillalsobeconductedandarelikelytoincreaseinnumberovertime.83 Inanotherefforttoimproveresearchoversight,theFDAhasrecentlychangedfromapolicyof conductinginspectionsaspartoftheapplicationreviewprocessorinresponsetocomplaintstoa moreproactiveapproachofreviewingongoingtrials.Thisallowsforproblemidentificationand correctivemeasureswhilethestudyisstillunderway.TheFDAisalsodoingmorefollowupworkto determinewhethercorrectivemeasuresweretakenintrialsfoundtobeinviolation.84 Aspreviouslymentioned,Europeanregulatoryauthoritiesrequirethattrialsconformtothesame ethicalandqualitystandardsregardlessofwhethertheyareconductedwithintheE.U.orelsewhere. Since2005,allmarketingauthorizationapplicationsmustcontaininformationregardingthelocation ofconductandethicalstandardsappliedinrespectofclinicaltrialsconductedin[nonE.U.] countries.In2006,theEuropeanMedicinesAgency(EMEA)establishedasystemofroutineGCP inspectionswithparticularfocusondevelopingcountriesandstudiesinwhichvulnerable populations,includingchildren,areenrolled.Aspartofits2009actionplan,theEMEAannounced thatitwillconducttheseinspectionsatearlierstagesbeforeandduringtheconductoftheclinical trials.85
TheRoleofMarketForcesinClinicalResearch
Giventhatthedebateoverthequalityofstudiesconductedindevelopingcountriesissomewhat intertwinedwiththedebateovertheroleofforprofitcompaniesinclinicalresearch,itisworth notingthatnoformofresearchiscompletelyimmunefromthepotentialforbias.Pressuresfacedin purelyacademicresearchincludetheneedtoobtaingrantfundingandtoadvancecareersthrough publicationofsuccessfulstudies.Unlikenoncommercialresearch,industrysponsoredtrialsarealso subjecttoadditionalscrutinyaspartoftheproductapprovalprocess.IntheU.S.,theFDAmay ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 23
considerclinicalstudiesinadequateandthedatainadequateif,amongotherthings,appropriate stepshavenotbeentakeninthedesign,conduct,reportingandanalysisofthestudiestominimize bias.86 Further,intheU.S.ahighernumberofdeathsintrialswithhealthyvolunteershaveinvolvedstudies approvedbyacademicratherthancommercialIRBs.87Ina2008article,EzekielJ.Emanuel,chairman ofclinicalbioethicsattheNationalInstitutesofHealth,reportedthattheFDAhasissuedhundreds ofwarningletterstoacademicIRBsbutthishashappenedonlyonceinthecaseofforprofitIRBs.88 InApril2009,theFDAsentanotherwarninglettertoacommercialIRB.Theoutcomeofthiscase, however,confirmstheexistenceofstrongmarketforcesdictatingthatindustrysponsored researchersconformtoveryhighstandards.Itisdifficulttoimagineanacademiccenterclosingits doorsafterreceivinganFDAwarningletterrelatedtoitsethicalreviewprocessbutthisisexactly whathappenedwithCoastIRB.AccordingtotheWallStreetJournal,anApril14warningletterfrom theFoodandDrugAdministrationdescribingthecompany'sviolationsledseveralhighprofile customerstopulltheirbusiness.Asaresult,CoastIRB'sownersdecided,throughcounsel,tocease futurecompanyoperations."Thisannouncementoccurredjustoneweekafterreceiptofthe warningletter.89
ImprovingEnvironments
Theblankettermemergingmarketactuallydisguisesawiderangeofexperiencelevels.Poland,the CzechRepublic,HungaryandRomaniaareamongtheCEEcountrieswithexpandingresearch capabilitiesthataremembersoftheEuropeanUnionand,assuch,aresubjecttotheE.U.Clinical TrialsDirective(CTD).ThishasledtoconsiderableimprovementinGCPcomplianceintheCEE regionsince2004.90AsaresultoftheCTDandtheexperiencegainedbyresearchersduringmore thanadecadeofworkingontrials,manyexpertsnowconsiderthat,whilethesecountriescontinue toofferrelativelyrapidpatientrecruitment,theyareactuallymaturemarketswithclinicalresearch capabilitiesveryclosetothoseofWesternEurope.91
LookingfurthereasttoRussia,thefirsttrialssponsoredbyWesternpharmaceuticalcompaniestook placeasfarbackas1993.Sincethen,thecountryhasadoptedinternationalGCPandhasparticipated inwellover1,000internationalmulticentertrials.Approximately90%oftrialmonitorshavemedical doctoratedegrees.92In2008,therewere946institutionsauthorizedtohostclinicalresearchandthe Russianregulatoryauthority,RZN,approved615newtrialsduringtheyear.Fiftyninepercentof theseweremultinational,multicentertrials.Inthefourthquarterof2008alone,theFDAapproved 12newdrugs,expandedindications,manufacturingorformulationchangesrelyinginpartonstudies thatinvolvedRussianparticipation.TheEMEAmade10approvaldecisionsthatinvolvedRussiandata duringthesameperiod.93 ConsideringtherelativelyadvancedstateofclinicalresearchinCEEcountries,itisworthnotingthat althoughthecombinedpopulationoftheentireregionislessthanhalfthatofeitherChinaorIndia, thenumberoftrialsinitiatedintheCEEduring2007wasmorethandoublethatoftheentireAsia Pacificregion.94 Similarly,whilecountrieslikeSouthKoreaandTaiwanareincludedintheemergingcategory,thisis moreareflectionofrapidgrowththanofalackofscientificormedicalexpertise.Indeed,both countrieshaveinvestedconsiderableamountstoincreasetheirattractivenessaslocationsfor advancedresearch.In2006,forexample,thegovernmentofSouthKoreaannounceda$14.3billion programtobuildthecountrysbiomedicalresearchcapabilities.95Taiwanhasnamedbiomedicine oneofsixpriorityindustriestoimprovethecountrysglobalcompetitiveposition,therebybuilding onaclinicalresearchhistorywhichgoesbacktoatleast1993.96 Inthesamewaythatwidevariationsexistbetweenemergingcountries,therearealsosignificant differencesbetweenthecapabilitiesofvariousinstitutionswithinasinglecountry.AstheRand Institutehasnoted,itispossiblethataworldclass[scientificortechnological]capabilityexistsin whatwouldotherwisebecalledadevelopingcountry.97Asanexampleofthisphenomenon,China hasestablishedclinicalresearchcenterswithexperiencedtrialistsandadvancedequipmentwithin majorhospitals.Tostaffthesecenters,thegovernmenthasbeenengagedinanactiveeffortto attractknowledgeableexpatriateshome.Thus,Westerntrainedphysiciansandresearchersare ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 25
supplementingthealreadylarge(200,000medicalschoolgraduatesannually)homegrowntalent pool.98 Foritspart,Indiaproduces17,000physiciansand1,500newPhDsalongside500,000newcollege graduateswithdegreesinthelifescienceseachyear.AsignificantnumberofIndiannativeseducated inWesterninstitutionsarealsoreturningtothecountryastheireconomicoptionsimprove.99 Startingin2006,theDrugsControllerGeneralofIndiaimplementedatwotrackapprovalsystemfor clinicaltrials:CategoryAstudiesarethosewithprotocolsthathavebeenapprovedbyregulatorsin theU.S.,Canada,U.K.,Germany,Japanandothercountrieswithadvancedreviewcapabilities;these receiveexpedited(threemonth)approval.AllothertrialsfallintoCategoryBandundergothe normal(sixmonth)approvalprocess.100 SouthAfricafirstimplementedGCPguidelinesin2000andupdatedthemmostrecentlyin2006. TheseareinlinewithICHandWHOpoliciesbuthavebeenhavebeenadaptedsomewhatforthe SouthAfricancontext.Onemeasuredesignedtoincreaseaccountabilityisthatthestudymust includeaprincipalinvestigatorwhoisresidentinthecountry.101 EthicscommitteesinNigeriawereweakornonexistentadecadeago,accordingtoTheLancet. Sincethetrovafloxacintrial,however,arenewedinterestbyinternationalresearcherswishingto workinNigeriahasledtobioethicsfellowshipsandplacementsinwesternuniversitiesforNigerian researchers,andmorerecentlyprogrammeshavebeenestablishedwithinthecountry.Capacity buildinginitiativesaimedattrainingbioethicistsandresearchershavebeenlaunched,andtwo nationalresearchethicstrainingprogrammeshavebeenundertakeninthepastfiveyears,inwhich morethan100healthresearchersandethicscommitteememberstookpart.102Further,the AssociationforGoodClinicalPracticeinNigeria(AGCPN),anorganizationaimedatexpandingthe clinicaltrialinfrastructureinNigeriaandcreatingaforumforclinicalresearchpractitionersto exchangeideason/encouragebestpracticeshastrainedmorethan350healthprofessionalssince itsfoundingin2005.103AGCPNisalsoworkingtoimprovetheinformedconsentprocess,using schematicsandtranslatorsforpatientswhomayfaceliteracyorlanguageproblems.104
Clinicaltrialregistriesarealeadingmechanismforincreasingtheleveloftransparencyinthe researchprocess.Indeed,duetoeffortssuchastheWHOInternationalClinicalTrialsRegistry PlatformandadecisionbytheInternationalCommitteeofMedicalJournalEditors(ICMJE)torequire registrationasapreconditionforpublishingstudyresults,registriesarebecomingpartofthe researchparadigminternationally.105Giventheheightenedsafetyandethicalconcernsassociated withtrialsindevelopingcountries,itisworthnotingthatseveraloftheemergingresearchcenters arefollowingand,insomecasesleading,thisnewparadigm.Forexample,theLatinAmericanClinical TrialRegister(Latinrec;www.latinrec.org)wasinitiatedin2003andhasbeenofferingasearchable databaseofstudiesintheregionsincemid2006.106TheClinicalTrialsRegistryIndia(www.ctri.in) waslaunchedinJuly2007andbyJuly2009hadwellover300trialsregistered.107Thesponsorsare alsoworkingwithethicscommitteestomakeregistrationaprerequisiteforapproval.108InSouth Africa,trialsmustbelistedontheSouthAfricanNationalClinicalTrialsRegister(www.sanctr.gov.za) beforeenrollmentbegins. Inshort,emergingresearchlocationshavemadeenormousstridestowardsimprovingtheir infrastructuresandproceduresinthelasttentofifteenyears.Thebillionsofdollarsinvestedby pharmaceuticalcompaniesandCROshaveplayedavitalroleinthisevolutionandarean irreplaceableresourceforensuringthatitcontinues.
RoleofClinicalResearchOrganizations
ThevalueoftheglobalCROindustryhasbeenestimatedatbetween$15and$24billion109with growthratesintheneighborhoodof15%annually.110Asaresultofincreasingrecognitionofthe valuethatCROsoffer,spendingonCROsandotheroutsideresearchsuppliersisexpectedtogrow from20%ofallR&Dspendingin2007to25%by2010.Further,thishigherlevelofparticipationona relativebasistakesplaceinacontextofR&Dexpendituresthatareexpectedtoincreaseby50%on anabsolutebasisbetween2005and2010.111 ReasonsforoutsourcingR&Dincludereducedcosts,accesstoadditionalcapacity,consistencyof researchmethods,expertiseandtechnologies,areductioninfixedcostswithacorresponding ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 27
increaseinoperationalflexibilityandaccelerateddevelopmentschedules.112Ofthese,accelerated developmentisamongthemostimportantconsiderations.AstudybytheTuftsCenterfortheStudy ofDrugDevelopmentsurveyfoundthatprojectswhichrelyheavilyonCROsaresubmittedmore than30daysclosertotheirprojectedsubmissiondatethanthosewithlowCROusage.Projectswere alsodeliveredwithlevelsofqualitycomparabletoinhousework.113Itisdifficulttooverstatethe importanceofdeliveringqualityresultsonschedule.Considerthatforeachdaythatadrug'slaunch isdelayedinclinicaltrialsortheregulatoryreviewprocess,approximately$37,000ofadditional developmentcostsaretackedonandthelostrevenuesintheU.S.alonecanequal$23million.114 CROshavebeenaleadingforceintheincreasingglobalizationofclinicalresearchandinthe implementationofuniformstandardsofquality.115MembersoftheAssociationofClinicalResearch Organizations(ACRO),whichrepresentsthemajorglobalCROs,employnearly70,000people,more thanhalfofwhomareoutsidetheU.S.In2008,ACROmembercompaniesconductedmorethan 9,000clinicaltrialsgloballywithresearchcarriedoutin115countries.116 CROcapabilitiesareespeciallyimportantindevelopingcountriesastheiradvantagesrelativeto companyrunclinicaltrialsmaybeevenmorepronouncedthaninestablishedmarkets.Forexample, bymaintaininglocalofficesandworkingacrossmultipletherapeuticcategories,CROsallowsponsors totakeadvantageofexistingnetworksinsteadofhavingtoduplicatetheseeffortsineachcountry. Giventheirexperiencelevels,CROsaremorelikelytohaveadeeperunderstandingoflocallanguage, cultureandnorms,qualitieswhichleadtobetterrelationswithinvestigatorsandimprovedtrial execution.117 ThepresenceofCROsbenefitshostcountriesaswell.Forexample,theyprovideadvanced equipmentandtrainedpersonnelwhicharerequiredforthestudybutareavailableforuseinother aspectsofaninstitutionspractice.CROshavealsobeeninstrumentalinharmonizingresearchnorms inemergingcountrieswithdevelopedworldstandards.118Thiscreatesavirtuouscycleofknowledge transfertopoorcountriesandexpandedopportunitiestoconductresearchthatoffersworldwide benefits.Inaddition,byconductingstudiesin115countries,119CROsareinmanycasesproviding highpayingjobsinareaswhereemploymentopportunitiesarescarce.ByrelyingonpreexistingCRO ValueofInsightConsulting,Inc. www.voiconsulting.com July21,2009 28
capabilities,trialsponsorsareabletomoveintotheclinicaltestingphasewithouthavingtocreatein houseR&Dinfrastructure.120Thishasbecomeincreasinglyimportantasbiopharmaceuticalfirmsin emergingmarketssuchasSouthKorea,Taiwan,ChinaandIndiahavebeguntomoveintooriginal drugresearchwithinthelastfewyears.
Conclusion
Althoughlegitimateconcernshavebeenraisedinthepastaboutclinicaltrialsinemergingcountries, theabilitytoconducthighqualitystudiesintheselocationshasbeenenormouslyimprovedoverthe previoustentofifteenyears.TheresearchinfrastructuresinCentralandEasternEuropeanaswellas inseveralEastAsiancountries,whichwereamongthefirstemergingareastoparticipateintrials,are nowcomparabletothoseinwellestablishedregions.Countriesthatbeganhostingstudiesmore recentlyarealsomakingrapidprogresstoensurethattheyareabletoattractclinicaltrialsandthe benefitsthattrialsprovide.BiopharmaceuticalfirmsandtheirCROpartnershaveplayedand continuetoplayaleadingroleinadvancingresearchcapabilitiesthroughouttheworld. Aswehaveseen,ethicalresearchnormsareglobalinnatureanddonotvaryfromplacetoplace. Further,commercialsponsorshaveverystrongincentivestoensurethattheirinvestmentsinclinical researchwillbeacceptedbyregulatoryagenciesinthedevelopedcountrieswheretheyearnthevast majorityoftheirrevenues.Indeed,companiesthatworkexclusivelyintheclinicalresearchfieldcan easilybeforcedoutofbusinessbymarketforcesthatdemandstrictcompliancewiththeseethical rules. Inlightofgrowingactivityinemergingcountries,majorregulatoryagencieshaverecognizedthe needforgreateroversightofinternationaltrialsandarerespondingwithasubstantialcommitment ofresourcestoensurethatallresearchmeetsthehighestethicalandqualitystandards.Thereare nowmoreinspectionsthaninthepastandthesearetakingplaceatanearlierstagethanhas traditionallybeenthecase.Thisisawelcomemovethatprovidesyetanotherlevelofconfidence thatstudieswillyieldreliableresultswhileprovidingasafeenvironmentforpatients.
Theadvanceofmedicalscienceisleadingtomoreclinicaltrialsandthesetrialsareincreasingly complex,timeconsumingandexpensive.Restrictingtheabilityofemergingcountriestoparticipate inclinicalresearchwouldaddstillmoreexpensesandfurtherdelaytheabilityofpatientstoaccess newtherapies.Itwouldalsodenyanimportantsourceofinvestment,employment,healthcareand knowledgetransfertoareasthataredesperatelyinneedofallthesethings.Ratherthanplacing furtherbarrierstodrugdevelopment,effortsshouldbefocusedonenhancingtheprogressthathas alreadybeenmadewhilecontinuingtotrainandmonitorresearchersthroughouttheworldto ensuretheircompliancewiththehigheststandards.Fortunately,muchofthisisalreadybeingdone aspartofthenormalbusinesspracticesofbiopharmaceuticalcompaniesandCROs,allofwhomhave amajorstakeinastrongandimprovingclinicalresearchenvironment.
AppendixA:EstimatedTimetoEnrollAllOpenPhaseIIICancerStudiesinU.S.onlyversusGlobally
Geography USOnly Line A B C D E F G H I Statistic TotalCancerIncidenceinUS ParticipationRate TotalAnnualPatientsWillingtoEnroll NumberPhaseIIICancerStudiesinUS PatientsWillingtoEnrollPerStudy PercentExcludedduetoScreeningFactors PatientsWillingandAbletoEnrollPerStudy AveragePatientsinaPhaseIIICancerDrugTrial YearsNecessarytoFullyEnrollallPhaseIIICancerTrialswithUSPatients Figure 1,437,180 5% 71,859 481 149 20% 120 691 5.8 SourceorCalculation AmericanCancerSociety2008 IndustryStatistics AxB Clinicaltrials.gov(openPhaseIIIcancerstudies) C/D IndustryStatistics Ex(1F) VOIConsulting:Labelanalysisofcancerdrugsapproved200609 H/G
Geography Global
Line J K L M N O P Q R S T
Statistic TotalCancerIncidenceWorldwide/Male TotalCancerIncidenceWorldwide/Female TotalWorldwideCancerIncidence ParticipationRate TotalAnnualPatientsWillingtoEnroll NumberPhaseIIICancerStudiesGlobally PatientsWillingtoEnrollPerStudy PercentExcludedduetoScreeningFactors PatientsWillingandAbletoEnrollPerStudy AveragePatientsinaPhaseIIICancerDrugTrial YearsNecessarytoFullyEnrollallPhaseIIICancerTrialswithGlobalPatients DifferencebetweenUSonlyandGlobalTrials(Years)
Figure 5,801,839 5,060,657 10,862,496 5.0% 543,125 1,218 446 20% 357 691 1.9 (3.8)
SourceorCalculation Globocan2002 Globocan2002 J+K AssumessameasUS.Conservativeestimate. LxM Clinicaltrials.gov(openPhaseIIIcancerstudiesworldwide) N/O IndustryStatistics Px(1Q) VOIConsulting:Labelanalysisofcancerdrugsapproved200609 S/R TI
AppendixA:Overview
Thisappendixprovidesthemethodologyusedtocalculatethepreviouslycitedestimatesonthetimetoenrollall currentlyopenPhaseIIIoncologydrugtrialsifstudieswererestrictedtotheU.S.ascomparedtousingbothU.S. andglobalsites.Thedetailedcalculationsareshownonthepreviouspage.
AppendixA:Methodology
Toarriveattheresults,VOIConsultingusedtheannualnumberofnewlydiagnosedcancercasesintheU.S. (CancerSociety,2008)dividedbythe5%ofpatientswillingtoenroll.121Thisgivestheannualpotentialenrolled patientbase(approximately72,000).Next,weusedClinicalTrials.govtofindthenumberofongoingPhaseIII cancertrialsintheU.S.(481asofApril14,2009).Dividingthepotentialpatientbasebythenumberoftrialsgives theaveragenumberofpatientswillingtoenrollperstudy(149).Assumingthat20%oftheseareexcludedfor variousreasonsduringthescreeningprocess,theresultis120patientswillingandabletoenrollperstudy. AswiththeU.S.,thetoplineoftheglobalestimatecontainsthenumberoftotalcancercasesdiagnosedinayear. ThesourcefortheworldwidedataistheGlobocan2002estimatesmaintainedbytheInternationalAgencyfor CancerResearch(http://wwwdep.iarc.fr).ThisistheclosestavailablesourcetotheU.S.figuresprovidedbythe AmericanCancerSociety. Fortheglobalparticipationrate,weusedthesame(5%)figureasintheU.S.Althoughthisisalmostcertainlya conservativeestimate,itisconsistentacrossgeographiesinotherwords,weusethesameapproachtoarriveat theU.S.andglobalfigures. LineOintheglobalestimatesreflectsthetotalnumberofPhaseIIIcancertrialslistedonclinicaltrials.govthatare takingplaceanywhereintheworld.ThisisahighernumberthanusedinthesectionforU.S.estimates(1,218 versus481)andreflectsthefactthatexU.S.studieswouldfacecompetitionforpatientsfromtrialsalready underwayinthesecountries. TodeterminetheaveragesizeofaPhaseIIIcancerdrugtrial,welookedattheprescribinglabelsofcancerdrugs approvedintheU.S.betweenJanuary2006andMarch2009.Thisyieldedanaveragefigureof691patientsper PhaseIIItrial. Bydividingthe691averagepatientsperPhaseIIIdrugtrialbythe120U.S.patientswillingandabletoparticipate perstudyperyear,wearriveatthebottomlineresulti.e.thatitwouldtake5.8yearstofullyenrollthecurrently
ongoingstudiesusingU.S.patientsalone(691/120=5.76).ReplacingtheU.S.numberinthedenominatorwith theglobalfigureof357patientswillingandabletoparticipateperstudyperyearindicatesthatitwouldrequire 1.9yearstofullyenrollallPhaseIIItrialscurrentlyunderwayaroundtheworld.Parenthetically,thebottomline resultsarehighlysensitivetotheparticipationratefigure:forexample,if10%ofpatientsparticipatedonaglobal basis,thetimetocompleteallPhaseIIIstudieswoulddroptooneyear. Therearesomelimitationstothismethodology.Forexample,weusedallcancerPhaseIIIstudies(including academic,governmentsponsored,drug,etc)todeterminehowmanypatientswereavailablepertrialbutusedthe averagesizeofaPhaseIIItrialaimedatdrugapprovalasthemeasurementfortheaverageenrollmentobjective. Inreality,nondrugPhaseIIItrialsarelikelytobesignificantlysmallerthandrugapprovaltrials.Wechosetouse thisapproachbecausedrugtrialscompeteforpatientsagainstalltrialsnotjustotherdrugtrials. Also,weusedthenumberofnewlydiagnosedcancerpatients(i.e.incidence)asthestartingpointfortheoverall patientpopulationsize.Somemightarguethatthisshouldbethetotalnumberofpatientslivingandever diagnosedwithcancer(i.e.prevalence).Ourrationalehereisthatcancerisaparticularlyaggressivediseasethatis likelytobetreatedatornearthetimeofdiagnosis.Sincetherehasbeenahighlevelofclinicaltrialactivityinthis areaforyears,mostpatientswhoarewillingandabletoenrollinatrialwouldlikelydosoaroundthetimethey starttreatment.Therefore,wecansaywithreasonableconfidencethatthenumberofnewlydiagnosedcancer patientsistherelevantmeasurementforhowmanynewlyavailableclinicaltrialparticipantscouldbeexpectedto jointrialsinayear.
AboutVOIConsulting,Inc.
Foundedin1998,VOIConsultingisalifesciencesadvisoryandpublishingcompanydedicatedtoproviding pharmaceuticalandbiopharmaceuticalclientswithfactbasedanalysisandbusinessintelligencetomeetmarket challengesintodayshighlycompetitiveglobalenvironment.Byskillfullyemployinginnovativeresearchtechniques andadvancedanalyticaltoolsVOIsserviceshelpclientsminimizerisks,cutcostsandmaximizecommercial opportunities. VOIConsultingsservicesareglobalinreach,arerelevantforanytherapeuticcategoryandspantheentirerangeof thepharmaceuticallifecycle.Whetherclientsareplanningaclinicaltrialorneedtoassessthemarketforageneric drug,whethertheyoperateindevelopedcountriesorarelookingatemergingworldopportunities,VOIhelpsthem executebetter,fasterandcheaper. Inadditiontoitsstrategicadvisoryservices,ValueofInsightConsulting(VOI)haspublishedmanydozenbooks, articles,reportsandreferenceguidesforthelifesciencesfield.Inparticular,ourannualpublications, PharmaHandbook:AGuidetotheInternationalPharmaceuticalIndustryandGenericHandbook:AGuidetotheUS MultisourceDrugIndustry,havebecomethestandardresourcesontheirrespectivetopicswithcustomersinmore than45countriesandhighlyfavorablereviewsinthebusinessandacademicpress.
AbouttheAuthor
ToddClarkisthePresidentofVOIandtheauthorofmanypharmaceuticalindustrypublications,including PharmaHandbookandGenericHandbook.Duringnearly20yearsexperienceinthelifesciencesfield,hehas consultedwith17ofthetop25drugcompanies,aswellasleadingbiotechfirms,investmentbanksandcutting edgehealthtechnologyservicesadvisingthemonmarketentry,clinicaltrialdesign,regulatorycompliance, marketingstrategy,forecasting,competitiveintelligence,pricing,allocationofsalesforceresources,promotional programsandmore.HeisamemberofthepharmaceuticaladvisoryteamfortheGersonLehrmanGroupandhas beencertifiedasanexpertwitnessinpharmaceuticalpatentlitigation. ToddisagraduateofTulaneUniversityandhasanMBAfromtheKelloggSchoolofManagementatNorthwestern Universitywherehemajoredinstrategy,financeandmarketing.InadditiontohisdutieswithVOI,hehastaught coursesinmarketing,businessstrategyandmanagerialdecisionmaking,atLoyolaUniversityandTulane University.Forthelatterinstitution,hedevelopedahealthcaremanagementcurriculumandtaughthealthcare policy,paymentandregulationwithinthatprogram.Inaddition,heservesontheBusinessStudiesAdvisory CommitteeforTulane.

Notes
Sood,Aetal(2009,March).Patients'attitudesandpreferencesaboutparticipationandrecrutimentstrategiesin clinicaltrials.MayoClinicProceedings.243. 2 Meyer,R(2004,April1).TestimonyofFDA'sDrugApprovalProcessbeforetheSubcommitteonCriminalJustice, DrugPolicyandHumanResources,CommitteeonGovernmentReform.RetrievedMay22,2009,Website: http://www.hhs.gov/asl/testify/t040401.html 3 MajorDeficienciesintheDesignandFundingofClinicalTrials:AReporttotheNationImprovingonHowHuman StudiesAreConducted.(2008,April1).EliminatingDisparitiesinClinicalTrialsProject.BaylorCollegeofMedicine. 4 Rogers,W,&Ballantyne,A(2009,Spring).Justiceinhealthresearch:whatistheroleofevidencebased medicine?PerspectivesinBiologyandMedicine. 5 Space,S(2007,November).CompetitionchallengesU.S.siteprofitability.CenterWatchMonthly 6 ClinicalTrials.RetrievedMay22,2009,fromPfizer:ResearchandDevelopmentWebsite: http://www.pfizer.com/research/clinical_trials/clinical_trials.jsp 7 PhRMA.(2009).PharmaceuticalIndustryProfile:2009.Washington,DC. 8 TriCouncilPolicyStatement:EthicalConductforResearchInvolvingHumans.(2008).2ndEdition(Draft),Canada: InteragencyAdvisoryPanelonResearchEthics 9 (2000).RecruitingHumanSubjectsPressuresinIndustrySponsoredClinicalResearch.U.S.DepartmentofHealth andHumanServicesOfficeoftheInspectorGeneral. 10 Weschsler,Jill(2008,September).Globaltrialsdrawregulatoryscrutiny:FDAisconductingmoreinspectionsto ensurethatforeignclinicalresearchmeetsGCPstandards.AppliedClinicalTrials 11 Gambrill,S(2008,August).CentralandEasternEuropetriplesglobaltrialparticipation.CenterWatchMonthly 12 Gross,Aetal(2009May).LookingEastforR&DandClinicalTrials.MedicalProductOutsourcing 13 Tsuei,S(2009).TheroleoftheAsiaPacificregioninglobaldrugdevelopmentstrategy.DrugInformationJournal. 43,3540. 14 DiMasiJA.Thevalueofimprovingtheproductivityofthedrugdevelopmentprocessfastertimesandbetter decisions.PharmacoEconomics2002:20(Suppl3):110 15 UnitedNationsHumanDevelopmentIndex 16 Anthes,E.U.S.CancerResearchersGoAbroadforTrials.(2007,December29).TheBostonGlobe 17 VOIConsultinganalysisofdatafoundin:PhRMA.(2009).PharmaceuticalIndustryProfile:2009.Washington,DC. DevelopingcountriesaretheU.S.,Canada,countriesofWesternEurope,Japan,AustraliaandNewZealand. 18 TuftsCenterfortheStudyofDrugDevelopment,GrowingProtocolDesignComplexityStressesInvestigators, Volunteers,ImpactReport10,no.1(January/February2008). 19 Space,S(2007,November).CompetitionchallengesU.S.siteprofitability.CenterWatchMonthly 20 (2002).ClinicalResearchReport.PharmaceuticalIndustryCompetitiveTaskForce.UKDepartmentofHealth 21 LesEntreprisesduMedicament(LEEM).(2008).TheattractivepositionofFranceinInternationalClinical Research:2008surveyassessedbyLeem.Paris,France 22 LesEntreprisesduMedicament(LEEM).(2008).TheattractivepositionofFranceinInternationalClinical Research:2008surveyassessedbyLeem.Paris,France 23 Stark,N(2007,July1).ASurveyofSurvivors.AppliedClinicalTrials 24 Sateren,WBetal(2002).Howsociodemographics,presenceofoncologyspecialists,andhospitalCancer programsaffectaccrualtoCancertreatmenttrials.JournalofClinicalOncology.20(8),21092117. 25 VOIConsultinganalysisofdatafoundonClinicalTrials.gov;RetrievedMay15,2009,from https://www.cia.gov/library/publications/theworldfactbook/fields/2103.html
1

26
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