Non-human primates in medical research and drug de

BiogenicAmines,Vol.19,No.4-6,pp.235–255(2005)VSP2005.Alsoavailableonline-∗SchoolofPopulationandHealthSciences,UniversityofNewcastleuponTyne,NE24AA,UKReceived20March2005;accepted20July2005Abstract—Thereismuchcurrentdebatesurroundingtheuseofnon-humanprimates(NHPs)inmedicalresearchanddrugdevelopment.Thisreview,stimulatedbycallsforevidencefromUK-basedinquiriesintoNHPresearch,takesacriticalviewinordertoprovidesomeimportantbalanceagainstpaperssupportingNHPresearchandcallingforittobeexpanded.WeshowthatthereisapaucityofevidencetodemonstratethepositivecontributionorsuccessfultranslationofNHPresearchtohumanmedicine,thatthereisagreatdealofoftenoverlookeddatashowingNHPresearchtobeirrelevant,unnecessary,evenhazardoustohumanhealthandtohavelittleornopredictivevalueorapplicationtohumanmedicine.Webrieflydiscussthereasonswhythismaybeso,reflectupontheconsequencesforfuturemedicalprogressand,onthebasisofourfindings,suggestamorescientificallyrobustandpromisingwayforward.Keywords:Primates;NHP;monkeys;animal.INTRODUCTIONSuchisthecurrentlevelofcontroversysurroundingtheissueofNHPexper-imentation,thatinrecentyearsanumberofinquirieshavetakenplaceintothepractice.Forexample,inDecember2002theAnimalProceduresCom-mittee(APC)intheUKpublishedareportcontainingrecommendationsforitsfuture(AnimalProceduresCommittee,2002);earlierthisyearthecommitteeheldandpublishedtheproceedingsofasubsequentstakeholders’forum,forwhichithasinvitedcomments(HomeOfficePrimatesStakeholderForum,2004).Also,inMarch2005anewcommitteewassetuptoexaminethescientificba-sisofNHPexperimentation,forwhichsubmissionsofevidencewereinvited().Thisistobewarmlyencour-aged;onlybyobjectivelyquestioningandevaluatingscientificmethodologieswith-outbiascanwehopetoensurethatitisofoptimalefficacyandlikelytoachieve∗E-mail:[e-mail],wemustbeconsciousofwhocommissions,overseesandpublishessuchreports:objectivityisoftencompromisedbyvestedinterests.Nevertheless,suchinquiriesatleastprovideanopportunityfortheairingofviewsacrossthewholespectrum,andsomeassessmentisbetterthannoneatall.Itisfairtosaythat,wereitnotfortheseinquiries,itwouldbelefttoNHPresearchreportsinthescientificliteraturetoshapescientists’views.Arguably,thisareaofendeavoursuffersmorethanmostfromthe‘positivebias’thataffectsthepublica-tionpoliciesofmanyjournals,perhapsduetotheattentionthatisfocussedonit.Intakingacritical,yetstillbalancedandcomprehensivestanceinthisreview,whichisdrawnfromsubmissionsofevidencetotheabovetwoinquiries,wehopetoredressthisbalancetosomedegreewhileatalltimesmaintainingascientificandfactualattitudetostimulatedebateonthematter.Manypapersrevealfindingsthat,whileconstitutinginterestingcontributionstothescientificknowledge-base,arenotrelevantorapplicabletohumanmedicine.Tobeofuseandscientificallyjustifiabletheymustbepredictiveofthehumansituation,providinginformationthatiscapableoftranslationtotheclinic.Manystudiesprovideonlyfortuitous‘experimentalconfirmation’ofpreviouslyknownhumanclinicaldata,orarechampionedwhentheycorrelateretrospectivelywithhumanstudies.Inbothofthesecases,orwhenthereportedstudieshavedemonstratedfundamentalinter-speciesdifferences,theauthors’conclusionstendtowardscrucial‘furtherwork’based,naturally,onmoreexperimentsinvolvingNHPs.Wesuggestthatamorecriticalapproachwouldbemorebeneficialtomedicine,andweprovideabriefoutlineofsuchanapproachhere.USEOFNON-HUMANPRIMATESINDRUGDEVELOPMENT/TOXICOLOGYThemajoruseofNHPsremainsasthe‘secondspecies’ofanimalinpre-clinicalsafetyassessmentofnewdrugs.Inspiteofsuchtesting,theattritionrateofdrugsenteringhumanclinicaltrialsis92%(Harding,2004).Manydrugsthatdopasstheclinicaltrialphasetoreachthemarketplacehaveaquestionablesafetyprofile:adversedrugreactions(ADRs)remainthefourthbiggestkillerinthewesternworld,despiteapparentsafetyinanimal(oftenNHP)models(Lazaruetal.,1998).Importantexamplesinclude:•HormoneReplacementTherapy—prescribedtomillionsofwomen,andthoughttoprotectagainstheartdiseaseandstrokeonthebasisofNHPexperiments,HRTisnowknowntoincreasetheriskofthesediseases,aswellasbreastcancerinhumans.TheChairmanoftheGermanCommissionontheSafetyofMedicinesdescribedHRTas‘thenewThalidomide’.Ithascausedupto20000casesofbreastcanceroverthepastdecadeinBritainalone(Gray,2003).•AIDSVAX—aftersuccessfulresultsofthisHIVvaccineinchimpanzees,itfailedtoprotectanyofthe8000humanvolunteersinclinicaltrials.•Teratology(riskofbirthdefects)—inthewakeofThalidomide,animals,oftenNHPs,havebeenusedtoassesstheriskoffoetaldamageduringpregnancyasNon-humanprimatesinmedicalresearchanddrugdevelopment:acriticalreview237aresultofexposuretodrugsandotherchemicals.ResultsfromNHPscorrelatewithknownhumanteratogensonly50%ofthetime,lesseventhanresultsfrommoreevolutionarilydistantspeciessuchasrats,hamstersandferrets(Schardein,1993;Baileyetal.,2005).Aspirin,forexample,isteratogenicinmonkeysthoughnotinhumans.•Asthma—Isoprenalinedoses,derivedfromanimaldata,were