History of Pharma Phd

BRITISHPHARMACEUTICALINDUSTRY, SYNTHETICDRUGMANUFACTUREANDTHE CLINICALTESTINGOFNOVELDRUGS 18951939.

AthesissubmittedtotheUniversityofManchesterfor thedegreeofDoctorofPhilosophyintheFacultyof LifeSciences,2005.

KeithJohnWilliams CentrefortheHistoryofScience,Technologyand Medicine.

Listofcontents,abbreviationsanddeclarations

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LISTOFCONTENTS TABLEOFABBREVIATIONS ABSTRACT DECLARATIONANDCOPYRIGHTSTATEMENT ACKNOWLEDGEMENTS CHAPTERONE:GeneralIntroduction,AimsandScopeofthisThesis. 1.1 1.2 1.3 1.4 BackgroundtotheThesis. GeneralIntroductionandHistoriography. ClinicalTestingofNovelDrugs. SourcesandThesisOutline. 12 14 26 34 8 9 10 11

CHAPTERTWO:TheOriginsofthePharmaceuticalIndustry. 2.1 TheGrowthofthePharmaceuticalIndustryintheNineteenth Century. 2.2 2.3 2.4 EvolutionfromSmallPharmacyFirmsinAmerica. GermanyandtheSyntheticModelfromthe1860s. Ehrlich:Collaboration,StructureactivityTests,Biological Standardisation,andClinicalTrials. 2.5 TheScopeofChemicalResearchinGermanPharmaceutical Firms. 2.6 FailureofBritainandOtherCountriestoDevelopSynthetic Drugs. 2.7 2.7.1 2.7.2 FactorsInhibitingtheDevelopmentofBritishFirms. Introduction. TheLackofPracticallyTrainedBritishChemistsandChemical Engineers. 67 69 63 60 43 48 55 40

Listofcontents,abbreviationsanddeclarations 2.7.3 2.7.4 2.8 PatentProtection. AlcoholSuppliesandDuty. TheExtentofRelianceonGermanyforPharmaceuticalsand EspeciallySynthetics. 2.9 ConcludingRemarks. 78 73 74 75

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CHAPTERTHREE:BurroughsWellcome:BritishOriginsof CollaborativeResearch. 3.1 3.2 3.3 Introduction. TheEstablishmentofBurroughsWellcome(1880). ChemicalLaboratoriesforResearchandChemicalWorksfor Manufacturing. 3.4 3.5 TheWellcomePhysiologicalResearchLaboratoriesupto1901. InteractionsBetweentheBurroughsWellcomeLaboratoriesand Worksafter1901. 3.6 Conclusions:TheImpactoftheLaboratories. 130 109 114 79 81 99

CHAPTERFOUR:WarandtheEstablishmentofaBritishSynthetic DrugIndustry. 4.1 4.2 Introduction:TheRelianceonGermanDrugsandChemicals. GovernmentResponsestotheConditionsofWarandDrug Shortages. 4.3 WhichDrugswereRequiredandCouldtheybeManufacturedin Britain? 4.4 4.5 CallsforFurtherGovernmentIntervention. BritishProductionofSalvarsanMedicalResearchCommittee (MRC)TestingofQuality. 4.6 4.7 TheMRCandtheFirstSalvarsanCommittee. TechnologyTransferfromBurroughsWellcometoBootsand May&Baker. 4.8 ProductionofFurtherSyntheticDrugsandAlkaloidsinBritain. 175 163 167 150 157 144 137 141

Listofcontents,abbreviationsanddeclarations 4.9 TheTrainingofChemistsandtheCoordinationofthe PharmaceuticalIndustry. 4.9.1 EstablishmentoftheAssociationofBritishChemical Manufacturers(ABCM). 4.9.2 TheDepartmentofScientificandIndustrialResearchandthe TrainingofChemists. 4.10 4.11 TheMRCProposeClinicalTesting. TheSecondSalvarsanCommittee. 189 194 190 179 179

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4.12

Conclusions.

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CHAPTERFIVE:PostWarProblems,PatriotismandProtectionism: IndustryledCampaignsandtheRiseofFrancisCarr. 5.1 5.2 Introduction. PostWarCampaignsfortheProtectionofthePharmaceutical Industry. 5.3 5.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.6 TheABCMMissiontoGermanManufacturingSites. TheSankeyJudgementanditsConsequences. BritishPharmaceuticalFirmsPostWar. May&Baker. Boots. Howards. Glaxo. Allen&Hanburys. BritishDrugHouses. ProtectingtheBritishPublic:TheMRCandtheNational InstituteofMedicalResearch(NIMR) Biological StandardisationandGovernmentLegislationofDrugs. 5.7 ChemicalWorkersinBritain:FrancisCarrandChemical 245 210 213 219 220 221 223 223 225 227 229 207 208

Listofcontents,abbreviationsanddeclarations Engineering. 5.8 5.9 PostWarGermanyandOtherForeignCompetition. Conclusions. 249 254

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CHAPTERSIX:TheCampaignforClinicalTrials. 6.1 6.2 6.3 Introduction. TheMRCandClinicalResearchCentres. TheABCMApproachtotheMRCforaClinicalTestingScheme in1922. 6.4 6.5 6.6 Insulin:anMRCPreoccupationandaProductionChallenge. FrancisCarrandhisGrowingInfluence. MRCExtendedRoleinClinicalTrials:IndividualMRC Subcommittees. 6.7 LobbyingforClinicalTrials:TheABCMandtheChemotherapy Committee. 6.8 CollaborationwiththeDSIR Establishmentofthe ChemotherapyCommittee. 6.9 FurtherMRCTrials:Synthalin,PneumococcalSerumandLiver Therapy. 6.10 TheThirdCampaignoftheABCMforClinicalTrials,1927 1931. 6.11 6.11 FormationoftheTherapeuticTrialsCommitteein1931. Conclusions. 308 310 304 300 297 295 277 286 291 258 259 271

CHAPTERSEVEN:BurroughsWellcomeStrategyintheInterwar Period. 7.1 7.2 7.3 7.4 Introduction. StaffChangesandFacilities. TheScientificandTechnicalCommittee. BurroughsWellcomeandVitamins:IndecisionandDecisions. 312 312 316 327

Listofcontents,abbreviationsanddeclarations 7.5 7.6 7.7 ClinicalTrialsArrangedbyBurroughsWellcome. TropicalDiseaseaCaseStudyfromLaboratorytoClinic. Conclusions. 332 334 343

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CHAPTEREIGHT:TheTherapeuticTrialsCommitteeoftheMRC. 8.1 8.2 8.3 8.4 Introduction. TheTherapeuticTrialsCommittee19311939. Clinical TrialsEstablishedbytheTherapeuticTrialsCommittee. CollaborationinOrganotherapyandVitaminsLeadsto IncreasedCapacity. 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.5 8.6 Oestrin. SuprarenalCorticalExtract(Cortin). ProgestationalAgents. PerniciousAnaemia. Vitamins. Prontosil:aNewEraofChemotherapy. ClinicalTrialsofOtherAntisyphiliticsIncreasedSynthetic Activity. 8.7 NovelCompoundsPutForwardforTestingbyBritishFirms 19311939. 8.7.1 8.7.2 8.7.3 8.7.4 8.7.5 8.7.6 8.7.7 BootsPureDrugCompany. May&Baker. BurroughsWellcome. Glaxo. BritishDrugHouses. Allen&Hanburys. ImperialChemicalIndustriesandOtherBritishFirms. 379 382 385 394 397 399 400 379 358 362 364 366 367 368 377 345 350 355 356

Listofcontents,abbreviationsanddeclarations 8.7.8 8.8 ForeignFirms. MRCStudiesofAntisera:LargeCooperativeTrialsand Statistics. 8.9 ConclusionsRegardingtheTherapeuticTrialsCommittee. 412 421 403 408

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CHAPTERNINE Conclusions. BIBLIOGRAPHY

440 484.

Listofcontents,abbreviationsanddeclarations ABBREVIATIONS A&H ABCM AGFA BASF BDH BIPM BMA BP CIBA DSIR FRS ICRF ICI IG(Farben) LSHTM M&B MRC Allen&Hanburys AssociationofBritishChemicalManufacturers AktiengesellschaftfrAnilinfabrikation,(Berlin) BadischeAnilinundSodaFabrik BritishDrugHouses BritishInstituteofPreventativeMedicine(laterListerInstitute) BritishMedicalAssociation BritishPharmacopoeia GesellschaftfrChemischeIndustrieBasel DepartmentofScientificandIndustrialResearch FellowoftheRoyalSociety ImperialCancerResearchFund ImperialChemicalIndustries Interessengemeinschaft(orcommunityofinterests) LondonSchoolofHygieneandTropicalMedicine MayandBaker MedicalResearchCommittee19131920 MedicalResearchCouncil 1920onwards NHI NIMR PRO RAMC SCI STC UCH WBSR WCRL WPRL NationalHealthInsurance NationalInstituteforMedicalResearch PublicRecordOffice RoyalArmyMedicalCorps. SocietyoftheChemicalIndustry ScientificandTechnicalCommittee UniversityCollegeHospital WellcomeBureauforScientificResearch WellcomeChemicalResearchLaboratory WellcomePhysiologicalResearchLaboratory

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ABSTRACT BritishPharmaceuticalIndustry,SyntheticDrugManufactureandthe ClinicalTestingofNovelDrugs18951939.ThisthesisaddresseshowandwhenBritishpharmaceuticalfirmsfirst manufacturedsyntheticdrugs,andhowtheypersuadeddoctorstotestnoveltherapiesin clinicaltrials.EdwardianBritainwasreliantonGermanyforsyntheticdrugs,sohowdid BritishfirmsmeetthischallengeintheFirstWorldWar,andhowwasthisnewformof theBritishpharmaceuticalindustrynurturedintheinterwarperiod? Previousstudieshavecoveredtheindustrysoriginsinpharmacyrootsand dyestuffs,andthegrowthoftheAmericanindustry,butwithoutanoverallsynthesis. ThereareseveralgoodcompanyhistoriesforBritain,andRobsonandQuirkecompared pharmaceuticalsinFranceandBritain,whilstTanseyexaminedphysiologicalresearchat BurroughsWellcomebutlittlehasappearedonchemicalresearchandsynthetic manufacture.IwillemphasisetheworkofFrancisCarrwhodevelopedsyntheticdrugsat BurroughsWellcome,BootsandBritishDrugHouses.Asfortesting,theliteraturecovers earlystatisticsandtheclinicaltrialsofmajorbiologicaldrugssuchasinsulinbutthese didnotoriginatewithindustry.Withsyntheticandothernoveldrugs,asIshow,firms founditdifficulttoarrangeclinicaltrialsandtheyturnedtotheMRCforassistance.I examinethesenegotiationsandtrialsinsomedetail. Chapter1reviewsthehistoriographyofthepharmaceuticalindustryandthe clinicaltestingofdrugs.Chapter2examinesthevariedoriginsoftheindustry,contrasting ethicalandpatentmedicines,andcomparingBritainwithGermanyandAmerica.Chapter 3showshowBurroughsWellcomecombinednoveldrugsinsophisticateddosageforms, adoptingnewsalesstrategiesandestablishinglaboratoriestostandardisedrugs.Their experienceinsmallscalesynthesisfrom1896enabledthemtoprepareGermandrugs whenpatentswereabrogatedintheFirstWorldWar(chapter4).TheMRCandother firmspoachedBurroughsWellcomeresearchers,andtheMRCtookstandardisationasa centraltheme,soestablishinganinternationalreputation.Chapter5addressesthepost warcampaignsfortariffprotection,andtheextensionofMRCdrugevaluationsasBritish firmsstrovetoremaincompetitive.Novelvitaminandhormonaldrugsallowedthemto expandtheirmanufacturingcapacitywhilegainingfurtherexperienceofdrugsynthesis. Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom1922 1930andexplainswhyaTherapeuticTrialsCommittee(TTC)wasestablishedin1931. Chapter7examinesthestrategyofBurroughsWellcomepostwar,byanalysingthe strategicdebateswithintheirScientificandTechnicalCommittee.Chapter8examinesthe TTC,howtheyfavouredBritishdrugs,andhowstudiescomplementedtheirownresearch interestsitprovidesinsightintotheresearchstrategiesofBritish(andforeign)firms,plus anassessmentoftheTTCasseenbytheMRCandbycompanies.Chapter9offersgeneral conclusionsandcontraststhepositionofBritishmanufacturersattheoutbreakofthe SecondWorldWarwiththeirpositionattheoutbreakoftheGreatWarinAugust1914. Someopportunitiesforfurtherworkarethenidentified.


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DECLARATIONNoportionoftheworkreferredtointhisthesishasbeensubmittedinsupportofan applicationforanotherdegreeorqualificationofthisoranyotherUniversityorother Instituteoflearning.

COPYRIGHTDECLARATIONCopyrightinthetextofthethesis/dissertationrestswiththeauthor.Copies(byany process)eitherinfull,orofextracts,maybemadeonlyinaccordancewithinstructions givenbytheAuthorandlodgedintheJohnRylandsUniversityLibraryofManchester. DetailsmaybeobtainedfromtheLibrarian.Thispagemustformpartofanysuchcopies made.Furthercopies(byany process)ofcopiesmadeinaccordancewithsuch instructionsmaynotbemadewithoutthepermission(inwriting)oftheAuthor.

Theownershipofanyintellectualpropertyrightswhichmaybedescribedinthis thesis/dissertationisvestedintheUniversityofManchester,subjecttoanyprior agreementtothecontrary,andmaynotbemadeavailableforusebythirdpartieswithout thepermissionoftheUniversity,whichwillprescribethetermsandconditionsofany sucharrangement.

Furtherinformationontheconditionsunderwhichdisclosuresandexploitationmaytake placeisavailablefromtheHeadoftheCentrefortheHistoryofScience,Technologyand Medicine.


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ACKNOWLEDGMENTSOvertheseveralyearsithastakentowritethisthesisIhavemanyindividualstothank. FirstlyIwouldliketothankmyoriginalandfinalsupervisorJohnPickstoneatthe ManchesterWellcomeUnitfortheHistoryofMedicinewhohassolidlysupportedme. Severalotherslookedaftermeatvarioustimes.InparticularIwishtoextendthanksto SteveSturdy,whomovedtoEdinburghpartwaythroughandbeforehimGeoffrey Tweedalewhogavemeinitialguidance.AtvariouscongressesandmeetingsIhave receivedencouragementfromJudySlinn,andDesireCoxMaximov. Morerecently VivianneQuirkecommentedonsomeofmyearlydraftchapters.Ioweagreatdealto JohnDavies,whowasthearchivistattheWellcomeInstitute,inLondonandtoMrs. MaryNicholas,attheMRC.Archives,beforetheirmovetothePRO. ThanksalsotoJulieSheppard,archivistandherassistantLesleyHallatthe ContemporaryarchivecentreandarchivistsattheRoyalSocietyandtheImperialInstitute andJ.M.LevertonintheresearchlibraryatBootsPharmaceuticalsandtoMrs.Barbara RobertswhokindlyforwardedtwobooksatonetimeownedbyThomasHenryof BurroughsWellcome. IalsoreceivedsupportfromthelibrariansattheRoyalSocietyandatAstraZeneca, thoughwhenIstarteditwasImperialChemicalIndustriesLtd.ThanksalsotoMichael PayneandJanetteMackinatTheBritishLibrary,BostonSpa,Wetherbyforhelpingto trackdownsomerelatedtheses.Finallyspecialthankstomyparentswhohavesupported methroughthisprolongedexperienceandtoLorraine,Jane,ClaireandNeilespecially.

ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis

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CHAPTERONE:GeneralIntroduction,AimsandScopeofthisThesis.1.1BackgroundtotheThesis. Thecentralquestionsofthisthesisare: HowdidBritishpharmaceuticalcompaniesfirstpreparenovelsyntheticdrugs,andhow didtheygetdoctorstotesttheseandtheirothernoveldrugsinclinicaltrials? Thequestionarosebecausethemodernpharmaceuticalindustryisbasedlargelyon novelsyntheticdrugs.DuringtheFirstWorldWartheimportanceofaBritish pharmaceuticalindustrybecamerecognisedandBritishfirmsswitchedfrompreparing drugsattherequestofphysicians,toofferingcompletelynovelagentsthatweretobe testedforthefirsttimeinman.ManyofthesehadpreviouslycomefromGermany.Notall weresynthetic,buttheywereuniqueintheirpotency.Thewiderquestionsthatemerged concernhowBritaincompetedwithGermanyintheinterwarperiod,andhowBritishfirms definedtheirstrategiesofdrugdevelopment,todecidewhethertocommittoproducing syntheticdrugsasopposedtoplantandanimalextracts,inorganicdrugsandantisera,and whatinternalandexternalfactorswereconsideredinmakingthesedecisions?Wasit necessaryforBritishfirmstofollowaGermanmodelorindeedanAmericanmodelofdrug research? Thethesisisthereforebroaderinscopethanoriginallyplannedanddemonstrates howcloseinterrelationshipswereforgedinBritainbetweenindustry,academia, governmentandmedicalresearch,particularlyfortheperiod19141939.Itevaluates significantstructuralchangeswithintheframeworkoftheBritishPharmaceuticalindustry, fromsmallfamilyownedfirmsoperatingindependently,tolargerbusinessesthat recognisedtheirinterdependenceandthevaluesofcollaborationandnegotiationthrough a representativetradebody. WhentheFirstWorldWarwasdeclared,BritainwasdependentonGermanyfor1 syntheticdrugs,aswellasmanyalkaloidsandchemicalintermediates. HowdidBritish

pharmaceuticalfirmssynthesisecomplexessentialdrugswithinweeksoftheoutbreakof

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W.Ormandy,BritainandGermanyinRelationtotheChemicalTradeinW.M. Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline(London: Williams&Norgate,1915):335350.

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war?Whatweretheprecedentsonwhichtheybuilt?Havingpreparedthesedrugsona manufacturingscaleintheabsenceofGermancompetitionundertheemergency conditionsofwar,howdidBritishfirmscompetewithGermanypostwar? IexaminehowtheBritishcompaniesusedtherecognitionoftheirachievementsin theGreatWartonegotiateabetterdealintheinterwarperiod,whentheywereoffered variousformsofprotectioninadditiontotariffs,includingnewmethodsfortestingthe purityandstandardisationofdrugs,andthenasystemofclinicaltrialswhichseemedto favourthetestingofBritishdrugs.ItisimportanttorecognisethatBritishfirmsthemselves requestedtheseoperationalframeworksandtheywerenotimposed. TheultimatemeasureofthesuccessofBritishfirmsshouldnotrelatesimplytothe successofindividualproducts.Thistypeofappraisalhaspreviouslyledtotheconclusion thatBritishfirmsachievedlittleofconsequenceintermsofnovel discoveries.Rather,I prefertocomparehowindependentofGermany,Britainhadbecomebytheoutbreakofthe SecondWorldWar.IntakingthisapproachIidentifyaseriesoffactorsthatcontributedto thissuccess,includingthelargescalemanufactureofnoveltherapiesotherthansynthetics, andinparticularorganotherapies(hormones)andvitamins.Thecommonthemewasthat continuedinvestmentwasimportantandawiderangeofproductscontributedtoan increaseinmanufacturingcapacity.Thisthen bringsrecognitionoftheimportanceof largescalemanufactureandchemicalengineering.Athemethroughoutthewholethesisis theprominentroleofindividualsoriginatingfromBurroughsWellcomeandIgive particularprominencetoFrancisHowardCarr.FollowinghistrainingattheImperial InstituteandPharmaceuticalSociety,Carrwasresponsibleforthedailyrunningofthe ChemicalWorksreportingtoHooperA.D.JowettatBurroughsWellcomefor16years, andthenestablishedsyntheticdrugmanufactureatbothBootsandBritishDrugHouses. HealsoplayedaprominentroleintheestablishmentoftheAssociationofBritishChemical Manufacturersandtheircampaignsforprotectionandclinicaltrials,andfollowinghis successinlargescaleproduction ofinsulin,hetooktheinfluentialroleofPresidentofthe SocietyoftheChemicalIndustryandcampaignedforbettereducationofchemists,further protectionoftheBritishindustry,syntheticdrugmanufactureandagainforthe establishmentofclinicaltrials.Inasensehebecomesthecentralheroofthethesis,and yethiscareerhaspreviouslyreceivedlimitedattention.

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InthelatterchaptersIexamineaseriesoffactorsthatinfluencedhowBritishfirms gottheirnewdrugstested.Firstlythey collaboratedwiththeMRCandthePharmaceutical Societytodemonstratethatbiologicalcompoundswerestandardised,andthenthey negotiatedameansofclinicaltesting.Akeypointaboutthesechaptersisthattheyconsider thedrugsthatBritishindustrywasproducingandnotsuccessfulimporteddrugssuchas insulin.TheMRCbuiltupanetworkofresearchcentresthatbecametheircentresfor clinicaltrials,buttheycontrolledaccesstothephysicians,somuchsothatwhenBritish firmsdiddevelopimportantnovelcompounds,theybegantoemploytheirownphysicians inthe1930stomanagetheprocessofestablishingclinicaltrials.Acombinationoffactors thereforeledtothesuccessoftheBritishfirmsprotectionfromGermany,synthetic chemistswithmanufacturingexpertise,theestablishmentoflaboratories,theintroduction ofnovelorganotherapiesandvitaminsandphysiologysupport,andtheassociatedincreased manufacturingcapacity.Importantly,collaborationswerealsoestablishedwithuniversity chemistsandwiththeMRC,whichthenallowedtherapiddevelopmentofnovelvariantsof sulphonamidesfrom1936.TheBritishpharmaceuticalindustrywasakeypartnerindriving thisforward. 1.2GeneralIntroductionandHistoriography. AlthoughthereareseveralgeneralaccountsofAmericanandBritishpharmaceutical firms,therehasnotyetbeenageneralsynthesisofhowthemodernBritishpharmaceutical2 industrydeveloped,andoftheexternalfactorsinvolved. Therehavebeenaccountsof

individualcompanieswithlongpedigreesinpharmacy,butnonefocusingonchemistryand3 largescaledrugsynthesis. Thehistoriographyofdrugshasfocusedalmostexclusivelyon

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J.T.Mahoney,TheMerchantsofLife:anAccountoftheAmericanPharmaceutical Industry (NewYork:Harper,1959)S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBenn,1931)F.N.L.Poynter,TheEvolutionofPharmacy (London: Pitman,1965)C.J.Thomas,ThePharmaceuticalIndustryinDuncanBurn(ed.),The StructureofBritishIndustry volume2(Cambridge:CambridgeUniversityPress,1958): 33175.3

E.M.Tansey,Pills,ProfitsandPropriety:theEarlyPharmaceuticalIndustryin BritainMedicalHistory 25.3(1994):15157JonathanLiebenau,TheRiseoftheBritish PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428 Goldonthe Green:50YearsofGlaxoatGreenford(London:Glaxo,1985)D.ChapmanHustonand E.C.Cripps,ThroughaCityArchway,theStoryofAllen&Hanburys17151954 (London:JohnMurray,1954)S.Chapman,JesseBootofBootstheChemist (London: Hodder&Stoughton,1974)BootsPureDrugCo.Ltd.(Nottingham:Boots,1938)R.P.

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majornaturaldrugssuchasinsulinandpenicillin,ratherthandrugsinventedbythe pharmaceuticalindustry.ThesehistoriesthereforegivenoinsightintohowBritish4 companiesdevelopedproductsoftheirownresearch,orthestrategiestheyfollowed.

Thisintroductionoutlinesthepreviousworkdoneinthisfieldandidentifiessomeof thegaps.Chapter2developsthedetailsofhowthepharmaceuticalindustryevolved,sothe frameworkisdescribedonlybrieflyhere.Acommonthemeisthathistorianshavetriedto categorisetheBritishindustryassuccessfulornotbymeasuringhowitcomparedwith Germanyintermsofsyntheticdrugs,orwithAmericaintermsofexternalcollaborations, oftensimplifyingacomplexissuebythechoiceofunrepresentativecasestudies.Economic historianshavedescribedhowthegeneralgrowthof thepharmaceuticalindustrywas5 achievedbydiscoveringnewdrugs,withoutgivinganinsightintohowthiswasachieved.

Insomecases,theymeasuredsuccessbysimplycountingthenumberofpatentsfiledor salesfigures,whichmaybeverymisleading,especiallyifthefirmhadinterestsotherthan justpharmaceuticals,asmanydid,oriftherewereaseriesofsimilarproducts,someof6 whichnevermadeittomarket. Companypoliciesonpatentingcertainlyvariedgreatly.

T.DavenportHines,J.Slinn,Glaxo,AHistoryto1962 (Cambridge:Cambridge UniversityPress,1992)GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen &HanburysandtheBritishPharmaceuticalIndustry (London:JohnMurray,1990)Judy Slinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984).4

GladysHobby,Penicillin:MeetingtheChallenge(NewHaven:YaleUniversityPress, 1985)H.F.Dowling,FightingInfection:ConquestsoftheTwentiethCentury (Cambridge, Mass:HarvardUniversityPress,1977)R.Hare,TheBirthofPenicillin,andtheDisarming ofMicrobes (London:GeorgeAllen&Unwin,1978)R.Hare,NewLightontheHistory ofPenicillinMedicalHistory 26(1982)1.5

W.DuncanReekie,M.H.Weber,Profits,PoliticsandDrugs(London:MacMillan, 1975)MichaelH.Cooper,PricesandProfitsinthePharmaceuticalIndustry (Oxford: PergamonPress,1966)W.DuncanReekie,TheEconomicsofthePharmaceuticalIndustry (London:MacMillanPress,1975)BjornLundgren(ed.),PharmaceuticalEconomics (Stockholm:TheSwedishInstituteofHealthEconomics,1984)D.Schwartzman, InnovationinthePharmaceuticalIndustry (Baltimore:JohnsHopkins,1977)Sainsbury Report:CommitteeofEnquiryintotheRelationshipofthePharmaceuticalIndustrywith theN.H.S.19657(London:HMSO,Cmnd.3410,1967).6

J.Kemp,PharmaceuticalPatents:InBritain,India,Italy,JapanandtheUSinG. TeelingSmith(ed.),InnovationandtheBalanceofPayments:theExperienceinthe PharmaceuticalIndustry (London:OfficeofHealthEconomics,1967):23J.Liebenau,

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Thepoliticsandmarketingofdrugshavedominatedmorerecentinvestigations.The7 OfficeofHealthEconomics hassupportedtheindustry,whilemanyauthorshavebeen 8 9 criticalofdrugsafety, pricing ,promotion,animaltesting,ormorerecently,policiesin 10 developingandmarketingdrugsfortheThirdWorld, oftenfrompreconceived

11 positions.

Haber,inhisotherwiseexhaustivediscussionofthechemicalindustriesin1971 concluded:Thereisnotenoughmaterialonthegrowthofproprietarymedicinesand, duringtheearlypartofthepresent(twentieth)century,ofthepharmaceuticalindustry.He wenton:Althoughitwouldencountergreatobstacles,astudyoftheearlyyearsofthe pharmaceuticalindustryintheprincipalcountrieswouldmakearewardingcontributionto12 moderneconomichistory. InhisearliervolumeHaberhadstated:

Economichistorianshavefrequentlydescribedthedevelopmentof technologyinindustriesinwhichchangewassimpleandhaveneglectedthe

PatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ.Liebenau(ed.),The ChallengeofNewTechnology:InnovationinBritishBusiness(Aldershot:Gower,1988).7

G.TeelingSmith,ThePharmaceuticalIndustryandSociety:AStudyoftheChanging EnvironmentandEconomicsoftheInternationalIndustry (London:OfficeofHealth Economics,1972).8 9

A.Chetley,ProblemDrugs(London:AtlanticHighlands,N.J.ZedBooks,1995).

L.Marsa,PrescriptionforProfits:HowthePharmaceuticalIndustryBankrolledthe UnholyMarriagebetweenScienceandBusiness(NewYork:Scribner,1997).10

G.Gereffi,ThePharmaceuticalIndustryandDependencyintheThirdWorld (Princeton:PrincetonUniversityPress,1983)T.Heller,PoorHealth,RichProfits: MultinationalDrugCompaniesandtheThirdWorld(Nottingham:SpokesmanBooks, 1977)M.Silverman,M.Lydecker,P.R.Lee,BadMedicine:thePrescriptionDrug IndustryintheThirdWorld(Stanford:StanfordUniversityPress,1992).11

RichardHarris,TheRealVoice(NewYork:MacMillan,1964)C.Medawar, FailingsofthePharmaceuticalIndustryPharmaceuticalMedicine2(1987):259263 MiltonSilverman,PhilipR.Lee,Pills,ProfitsandPolitics(Berkeley:Universityof CaliforniaPress,1974)JamesS.Turner,TheChemicalFeast(NewYork:Grossman, 1970)BrianS.Inglis,Drugs,DoctorsandDisease(London:AndreDeutsch,1965)M. Silverman,TheDruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976) WyndhamDavies,ThePharmaceuticalIndustry:aMedical,EconomicandPoliticalSurvey oftheWorldwidePharmaceuticalIndustry (Oxford:PergamonPress,1967).12

L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971):7.

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morecomplexbutequallyimportantdevelopmentofchemical 13 manufacture. Thisquotecapturessomeofthereasonswhythepharmaceuticalindustryhasreceivedlittle attention,asthefactorsinvolvedarecomplexandmultifactorial,thesourcesarescattered, andgainingaccesstopharmaceuticalcompanyrecordsisproblematic,eveniftheyexist. Althoughsomeprogresshasbeenmadeinunderstandingthedevelopmentofthe pharmaceuticalindustry,Quirkewrotein2000that:historiesofthemajornational pharmaceuticalindustriesarerelativelyrare,especiallyincomparisonwiththechemical industry.Itisasectorthatisdifficulttoapprehend(sic)asawholebecauseofits14 complexityduepartlytoitsvarietyoforigins.

Forthepurposeofthisintroduction,Ireferprimarilytothedozenmainauthorsthat haveprovidedmostofthebackground:manyothercontributionswillbereferredtointhe mainbodyofthetext.TheseareSwann,ParascandolaandLiebenaufortheAmerican industry,andLiebenau,RobsonandQuirkeforBritain,(andthelattertwoforFrance).For clinicaltrials,althoughLiebenausetoutsomeofthegroundwork,recentthesesbyDesire CoxMaksimovandHelenValierhavedevelopedthistheme,withsomereferencetoHarry MarksforAmerica,whileforcompanyhistoriesthemostexhaustivemodernhistoric accountshavebeenbyTweedale,DavenportHinesandSlinnregardingAllen&Hanburys, GlaxoandMay&Baker.ForBurroughsWellcometherehavebeennumerous contributions,themostimportantformebeingthatofTansey,whoexplainedthe backgroundtothedevelopmentofthePhysiologicalLaboratoriesandthelicensingofthe laboratory,allowingmetofocusprimarilyonthechemicaldevelopmentswithinthe15 laboratoriesinwhichnewdrugswerecreatedtoreplacenaturalextracts. Otherhistories 16 havefocusedonHenryWellcomehimself.

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L.F.Haber,(1958):ix.

VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).15

E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory 33 (1989):141.16

HelenTurner,HenryWellcome,theMan,hisCollectionandhisLegacy (London: Heinemann,1980).

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Nineteenthcenturypharmaceuticalmanufacturingexistedintwomainformsinallof themajorcountries.Ethicaldrugfirmsmanufacturedsciencebaseddrugsforphysicians, withemphasisonactiveprinciples,anddifferentiatedtheirproductsfromotherfirmsbased onthenoveltyoftheirtabletsorpills,theirstrength,thelevelofimpurities,theirbenefits andtolerance,andlaterpharmacologicalexperimentsandclinicalexperience. Patent medicineswereadvertiseddirectlytopatients,withfancifulnamesandextravagantclaims. Formanyyearsthetwosystemscoexistedbutthemedicalprofessionbecameincreasingly criticaloftheunsubstantiatedclaimsofpatentmedicines.TheBritishMedical AssociationsSecretremedycampaignsin190709highlightedtheunreliabilityofpatent medicines,andconcernsaboutadulteratedmedicinesinAmericaledtolegislativecontrols17 onsecretremediesandonadvertisingofdrugs. LegislationinBritaincurbedonlythe

worstexcessesassociatedwithextravagantclaimstheheavyuseofalcohol,narcoticsor tonicsor,attheotherextreme,thefailuretoincorporateanyknownbeneficial substances. Anewformoflargescalepharmaceutical manufactureevolvedinGermanyinthe lasttwodecadesofthenineteenthcentury,basedonchemicalsynthesisfrombyproducts ofthedyestuffsindustry.Syntheticdrugsweredevelopedwithassistancefromexternal pharmacologists.Afurtherdevelopmentaround1891wasdiphtheriaantitoxinandGerman firmswerewellplacedtotakeadvantageofthisthroughtheirclosecollaborationwiththe universities.BytheendofthecenturymostGermanfirmshaddevelopedlaboratoriesfor assayingrawmaterials,forcheckingthepurityofsynthesisedproducts,butalsofor productresearch,andtestingtherelationshipofchemicalstructuretophysiological function. MuchoftheresearchonGermanfirmsfocusesontheevolutionofchemical18 manufacturefromdyesandstatesupport. IntheEnglishliterature,anexcellentinsight

intothecollaborationofindustrywithPaulEhrlichandotheracademicscientistsisgivenin

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J.B.Blake(ed.),SafeguardingthePublic:HistoricalAspectsofMedicinalDrug Control (Baltimore:JohnsHopkinsUniversityPress,1970):112122,144157.18

T.Lenoir,RevolutionfromAbove:TheRoleoftheStateinCreatingtheGerman ResearchSystem,18101910TheAmericanEconomicReview(May1998):2227.

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19 Bumlersaccount,towhichIreferextensivelyinChapter2. Beergivesanexcellent 20 accountof thedevelopmentoflaboratoriesinGermanfirms, whileFox,Haberand 21 Readerprovidebackgroundondyestuffsdevelopments.

ForAmerica,historianshaveconcentratedontheethicalmanufacturersthat characterisedtheirproductsscientifically,andontherelationshipbetweenindustryand academia.Liebenaucoveredtheperiodupto1914,showingthatAmericanfirmsflourished duringandaftertheAmericanCivilWarandwerenotedfortheirdevelopmentofnovel dosageforms,particularlytablets.HeshowedthatAmericanfirmsadoptedtheGerman laboratorymodellater,andalsoprepareddiphtheriaantitoxinin1895.Heshowedthat ParkeDavisemployedachemisttomeasureandstandardiseactiveprincipleswithinergot, andbothLillyandSearleemployedlaboratorystaffinthe1880s.SmithKline&French hadananalyticallaboratoryfrom1893andperformedassaysasearlyas1884.However, Liebenauassumesthattheselaboratoryworkerseventuallygotinvolvedin(unspecified)22 productdevelopment. Howscientifictheselaboratorieswereisopentodebateas

SwannreportedthatEdwardKendallleftthelaboratoryatParkeDavisin1910becauseof23 thelackofascholarlyatmosphereandbecausehewastreatedlikeafactoryworker.

Swannarguedthatthefoundationsfortheriseofindustrialpharmaceuticalresearchinthe interwarperiodwereprogressinnaturalsciences,aninstitutionalframework,which

19 20

E.Bumler,PaulEhrlich,ScientistforLife (NewYork:Holmes&Meier,1984).

J.J.Beer,TheOriginsoftheGermanChemicalIndustry (Urbana:Universityof IllinoisPress,1959)J.J.Beer,CoalTarDyeManufactureandtheOriginsoftheModern IndustrialResearchLaboratoryIsis49(1958)123131.21

M.R.Fox,DyemakersofGreatBritain18561976:aHistoryofChemists, Companies,ProductsandChanges(Manchester:I.C.I.plc,1987)W.J.Reader,Imperial ChemicalIndustriesLtd.AHistory:TheForerunners18701926volume1(London: OxfordUniversityPress,1970)L.F.Haber,(1958)and(1971).22

JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe AmericanPharmaceuticalIndustry (Basingstoke:MacMillan,1987):5,125Jonathan Liebenau,"MarketingHighTechnology:EducatingPhysicianstouseInnovative MedicinesinR.P.T.DavenportHines(ed.),History,BagmenandMarkets:Studiesin theHistoryofMarketingandBritishIndustry (Aldershot:Gower,1986):82101,183236.23

JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.

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20

facilitateditsapplication,andthewillingnessofindustrialiststorecognisetheimportanceof scienceandofscientiststoworkwithindustrialfirms.24 25 LikeLiebenau ,Swann concludedthatinBritainupto1920,researchdeveloped

fromassaysandlaboratorycontrols,assumingagainthatthoseperformingassaysin laboratorieslaterbeganperformingresearchfornewproducts.NeitherSwannnor Liebenaugaveanyevidenceforthis.Oneimmediateconclusionisthatamorecarefully wordeddefinitionisrequiredofwhatconstitutesresearchandtheremustbeaclear recognitionthatlaboratoriescomeindifferentforms.Alaboratoryworker,skilledin performingassaysdoesnotnecessarilyhavetheskillstosynthesiseanddevelopnewdrugs. Nordosmallstudiesinlaboratoriesequatetodevelopingasuccessfulmanufacturing procedureandtransferringthistechnologytothemanufacturingworks.26 ParascandolaexaminedpharmaceuticaldevelopmentsinAmerica, withparticular 27 emphasisonpharmacologyandtheevolvingroleofstructureactivitystudies andshowed

theimportanceofcollaborationswithexternalpharmacologistsandpharmacistsin WisconsinandPhiladelphia.28

24

JonathanLiebenau,ScientificAmbitions:thePharmaceuticalIndustry,19001920 PharmacyinHistory 27.1(1985):311J.Liebenau,TheRiseoftheBritish PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428.25

JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.26

J.Parascandola,ThePharmaceuticalSciencesinAmerica,18521902J.Am.Pharm. Assoc.40.6(2000):73335J.Parascandola,DrugTherapyinColonialandRevolutionary AmericaAm.J.Hosp.Pharm.5.12(1976):6977.27

J.Parascandola,IndustrialResearchComesofAge:theAmericanPharmaceutical Industry19201940PharmacyinHistory 27.1(1985):1221J.Parascandola,Structure ActivityRelationshipstheEarlyMiragePharm.Hist.13(1971):310:J.Parascandola, TheControversyoverStructureActivityRelationshipsintheEarlyTwentiethCentury Pharm.Hist.16(1974):5463.28

J.Parascandola,TheFoundingoftheUniversityofWisconsinSchoolofPharmacy Pharm.Hist.38.2(1996):5161J.Parascandola,J.Swann,DevelopingPharmacologyin AmericanSchoolsofPharmacyPharm.Hist.25.3(1983):95115J.Parascandola,John J.AbelandtheEarlyDevelopmentofPharmacologyattheJohnsHopkinsUniversityBull. Hist.Med.56.4(1982):51227.

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29 ForEngland,Tansey gavethebackgroundtothedevelopmentoflaboratoriesat

BurroughsWellcomeandtheproblemsofovercomingtheantivivisectionistmovementin Britain.EvenaftertheformationoflaboratoriesinBritain,andespeciallyafterthe DangerousDrugsActof1923,whenpharmacistshadtobeincharge,QuirkesawBritish andFrenchlaboratories,asdemandpulledratherthanresearchpushed,andthis30 conclusioniseasytounderstand.However,asTweedalepointedout ,firmssuchasAllen

&HanburysdidnotseethemselvescompetingdirectlywithGermanfirms,evenafterthey31 developedlaboratoriesandthisisapointthatIwilldevelop.Quirke emphasisedthe

importanceofmajormergerstoformImperialChemicalIndustries(ICI)andRhne Poulencin1926and1938respectively,thoughIfoundithardtofollowherargumentthat ICIdevelopedpharmaceuticalsin1926andthesefirmsbecametrendsetters.InfactICI onlydedicatedastaffofseventoexploratorymedicinalchemistryfrom1936afterthe discoveryofsulphonamides,andalthoughtheyexpandedtheireffortsduringandafterthe32 SecondWorldWar,theydidnotformapharmaceuticaldivisionuntil1954.

SwannrecognisedthatsomeAmericanfirmsbecameimportantpoolsofscientists, collaboratingwithpharmacologistsinuniversitiesandmedicalschoolsintheinterwar33 period. TheexamplesgivenincludedEliLilly,Merck,ParkeDavis,AbbottandE.R.

Squibb,allofwhichevolvedtobemajorU.S.pharmaceuticalmanufacturers.Swann identifiedthreemaintypesofexternalcollaborator:thegeneralist,thespecialistandthe projectspecificconsultant,andtheywereprimarilypharmacologistsandchemists.Froma

29

E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory 33 (1989):141.30

GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry (London:JohnMurray,1990).31

VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).32

FrankL.Rose,OriginandRiseoftheSyntheticDrugsinF.N.L.Poynter(ed.), ChemistryintheServiceofMedicine(London:Pitman,1963):179197.IntheRose accountitsays1954andthemainsiteatAlderleyParkdidnotopenuntil1957.33

JohnP.Swann,(1988):34,3334,45,51,6583Richardsperformedresearchwith HenryDaleattheNationalInstituteofMedicalResearchinLondon:C.F.Schmidt,A.N. RichardsBiographicalMemoirsofFellowsoftheRoyalSociety 13(1967):32742.

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companyperspectivethebestknownarethecollaborationsofEliLillywithToronto UniversityregardinginsulinandthecollaborationofHarvardUniversitywithseveralfirms withlivertherapyforperniciousanaemia.Swannaddressedsomeofthedifficultiesof collaborativeworkincludingproprietaryinterests,sharinginformationwithoutsiders, publicationsandpatenting,butconcludedthatthiswasaparticularsuccessforthe Americanindustry. VivianeQuirkedrewparallelsbetweenthesystemsthatevolvedinFranceand Englandupto1965.ShesuggestedthatHenryDaleattheNationalInstituteofMedical ResearchandErnstFourneauatthePasteurInstituteexhibitedmanyparallelsbothcoming fromacademicbackgrounds,workinginthepharmaceuticalindustry,thenreturningto academia,butinvestingheavilyincollaborativeresearch.Shearguedthatcollaborative workdevelopedwidelyinFranceintheinterwarperioddespitealackofsupport,whereas34 itdevelopedinBritainasaresultofgovernmentsupportandlargelythroughDale.

RobsondescribedtheBritishdrugindustryascomprisingfourdistincttypesoffirm35 attheendofthenineteenthcentury :

1.

Traditionaltradersthatimportedrawmaterials,purifiedandprocessed them suchfirmsincludedMorsons,Whiffens,May&Baker,Allen& HanburysandHowards.

2.

Marketingfirmsconcentratingontheretailtrade,exemplifiedbyBoots, TaylorsandtheLondonDrugCompany.

3.

EdinburghbasedalkaloidmanufacturerssuchasMacFarlans,T.H.Smith andDuncanFlockhardt.

4.

MoreresearchorientedfirmsincludingBurroughsWellcomeandEvans Sons,Lescher&Webb.

Thetraditionalfirmshavereceivedlittleattention,exceptinindividualcompany historiesbyTweedaleandChapmanHuston(Allen&Hanburys),Slinn(May&Baker)34 35

VivianeQuirke,(UniversityofLondon:PhDthesis,1999).

M.Robson,TheBritishPharmaceuticalIndustryandtheFirstWorldWarinJ. Liebenau(ed.),TheChallengeofNewTechnology:InnovationinBritishBusinessSince 1850 (Aldershot:Gower,1988):82105.

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andDavenportHinesandSlinn(Glaxo)andalthoughadefinitivehistoryofBurroughs Wellcomeisawaited,mostattentionhasfocussedonphysiologicalstandardisationby36 TanseyasBurroughsWellcomeproducedvaccinesandantitoxinsfrom 1895.

RegardingBritishfirmsintheperiodto1940,Liebenauconcludedthat:successful astheywereinmaintainingtheirsmallbusinessesandaturnoverofbasicproducts,and givenfewincentivestogrow,BritishfirmssuchasHowards,Evans,Morsons,Bells, evenAllen&Hanburys,didrelativelylittletoextendtheirmarkets.Hedidnotrefer,asI do,tothosefirmsthatdidgrowmostsignificantly,namelyBurroughsWellcome,May&37 Baker,BootsandBritishDrugHouses. Inhisthesis,Michael Robsoncomparedthe

economicsoftheBritishpharmaceuticalindustrywithFranceandSwitzerlandbutagain38 withlittleemphasisonthedevelopmentandtestingofdrugs. Heexpandedpreviouswork

tocomparethenumberofpatentsandpublicationsfromindustry.However,hisindepth analysisshowsthatfirmsmayhavedifferedgreatlyintheirpolicy,evenfromproductto product. Thesurprisingfindingthereforeisthatthereisasignificantpartofthehistoryofthe Britishpharmaceuticalindustrythathasnotbeenexamined.Havingreferredtotherhetoric ofbackwardnessanddeclineininterwarBritainandFrance,Quirkenotesthestronger BritishpharmaceuticalindustrythatemergedfromtheSecondWorldWarandarguesthat thiswasaresultofcollaborationwithintheTherapeuticResearchCommittee,involving severalfirms,andthevictoryofpenicillin.Oncemorethisconclusionarisesfromthe focusonmajordevelopments(inthiscasepenicillin)andanacceptancethatlittlewas achievedintheinterwarperiod.Andyetthereisaremarkablecontrastbetweentheposition oftheBritishindustryin1938,preparingtomakedrugsthatmightberequiredforwar, comparedtothestarkrealisationattheoutbreakoftheFirstWorldWarthatBritainrelied soheavilyonGermany,notonlyfordrugsbutforthechemicalintermediatesrequiredto

36

D.ChapmanHustonandE.C.Cripps,(1954)R.P.T.DavenportHinesandJ. Slinn,(1992)GeoffreyTweedale,(1990)JudySlinn(1984)E.M.Tansey,(1989):141.37 38

M.Robson,(1988):94.

M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939(Dept.of EconomicHistory,LondonSchoolofEconomics:PhD.thesis,June1988)J.Sigvard, DrugIndustryinFrance:SomeHistoricalPointsBull.Acad.Natl.Med. 166(June 1982):82934.

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24

makethem.ExaminingtheFirstWarinisolationisinsufficientasitwasanartificial situationwithdisruptionoftradeandtheabsenceofacompetitivethreatfromGermany. Oneofthemainchallengeswastoproducedrugsonalargescaleandcosteffectivelyto competewithGermany afterthewar. Syntheticdrugsarethemainstayofthemodernpharmaceuticalindustry,butthe molecularmanipulationthatgaverisetonewdrugsbeganinGermanyattheendofthe nineteenthcentury,andGermanyheldamonopolyinsyntheticdrugspriortotheFirst WorldWar,withdrugssuchasSalvarsan,NovocaineandAspirin.Asaresulttherehas beenadearthofinterestinthisaspectofthedevelopmentofthepharmaceuticalindustry outsidetheGermaniccountriesandanassumptionthatAmericaandBritaineventually followedtheGermanmodel.Iwilldiscusshowthiswasnotalwaysthecase,atleastuntil after1939. SwannmadeonlypassingreferencetothefactthatEliLillyestablishedaresearch teamonsyntheticdrugsin1912,involvingupto20researchershedidnotexplainwhere theycamefromorwhethertheydidevolvefromassaywork.HedescribedhowAbbott firstdevelopedsyntheticdrugs,butasaresultofexternalcollaboration,andthenby employingapostdoctoralstudentin1918.BeyerdescribedhowDilantin(phenytoin)was firstsynthesisedatParkeDavisin1911,buthedidnotdescribetheinitialevaluation only pointingoutthatitshypnoticeffectswereonlyfoundaspartofaroutinescreenin1926 anditsbenefitsinepilepsywerenotdescribeduntil10yearslater:hestatedthatParke39 DavisdidnotformallyestablishaChemistrydepartmentuntilthe1920s.

IntheGreatWar,America,likeBritainwasdeniedGermandrugs,initiallyasaresult ofnavalblockade.The1916versionofNewandNonOfficialRemedieslisted228of 592drugsascomingfromGermany.AftertheUSAdeclaredwarinApril1917,some GermanpatentswereabrogatedandAmerica,likeBritain,hadaTradingwiththeEnemy Act,andyetSwannsuggestedthat:U.S.pharmaceuticalfirmssoonfilledthedemandfor these(synthetic)drugs.However,elsewhereinhisbookSwanndemonstratedthatitwas onlyafterthewarinmostAmericanfirmsthatinternalresearchfacilitieswereestablished, initiallyappointingexternalscientists,notablyatAbbott(1918),Lilly(1919),ParkeDavis39

KarlH.Beyer,Discovery,DevelopmentandDeliveryofNewDrugs(NewYork:S.P. MedicalandScientificBooks,1978):43.

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(1920),andMerck(1930),althoughUpjohnandSquibbappointedtheirfirstresearch scientistsin1913and1915respectively.ItremainsunclearhowAmericanpharmaceutical firmsfirstestablishedsyntheticdrugsynthesisandnothinghasbeenwrittenon manufacturingcapacity.Certainlyseveralfirmscontinuedtodependonexternal collaborationsfordiscoveriesandthisseemstobeastrongfeatureoftheAmerican40 industry.

LiebenauaddressedtheproductionofSalvarsanbytheDermatologicalResearch LaboratoriesinChapter8ofhisbookMedicalScienceandMedicalIndustry.Robson brieflyaddressedtheproblemsofwartimedrugshortages:ItwastheFirstWorldWarthat disturbedthestatusquoandmarkedtheturningpointforthestandingofsciencewithinthe pharmaceuticalindustry.However,heconcludedthattherewerenoimmediate shortagesasaresultofthedislocationoftrade,withoutgoingintodetailabouthowthe41 essentialdrugsweredefined,manufacturedortested. Thiscontrastswithmyfindingthat

BritainwasheavilyreliantonGermany forsyntheticdrugsandcertainalkaloids. BothRobsonandQuirketoadegreerefertosomeofthestaffmobilitybetweenthe MRCandindustry,withRobsonmakingabriefreferencetoFrancisCarrandhisdeparture fromBurroughsWellcome.However,Carrsrolewasperhapsnotfullyunderstoodby QuirkewhobrieflydescribedhimasbeingtakenonbyBDHtoproduceinsulin,whereasit washisestablishmentofthemanufacturingcapacityofBDHintheperiod192022that madetheinsulindevelopmentthesuccessthatitwas.SimilarlyIdidnotfollowQuirkes argumentthatafocusonantiserapreventedtheearlierexploitationofpenicillinin Britain.ShearguedthatFlemingwasobsessedwithdemonstratingthatpenicillincouldbe usedasaselectiveinhibitorofbacterialgrowthandspecificallyamethodtoisolate Haemophilusinfluenzae,andthatthistiedinwiththeinfluenceofAlmrothWrightin promotingvaccines,includingoneforinfluenza. AmoreobviousexplanationisthatneitherFleming,northemanyothersthat investigatedpenicillininthenext14yearscouldenvisageamethodoflargescale productionandthisseparatesaninterestinglaboratoryphenomenonfromapracticaldrug.

4041

JohnP.Swann,(1988):356. M.Robson,(1988):82105.

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Iteventuallytookamassiveinternationalefforttodeveloppenicillinandthiswasonly stimulatedbythewartimeneedsandfollowingthesuccessofthesulphonamides.Nonew drugisusefulunlessitcanbemanufacturedreliablyandpartofthechallengeforBritainin thisinterwarperiodwastoencouragethetrainingofchemicalengineersandmanufacturing chemiststomakethispossible. However,detailsasideQuirkeprovidesavaluablecomparisonofBritainandFrance, inwhichshecontraststhecentralcoordinatingrolesofthePasteurInstituteandtheMRC forwhichsheidentifiedtheimportantroleofDaleinbreakingdownthebarriersbetween industryandacademia,thoughasIwillshowbarriersstillexistedtogettingclinicaltrials performed. 1.3ClinicalTestingofNovelDrugs. Stilllessattentionhasbeengiventotheoriginsofclinicaltrialsofnewdrugsfrom industry.Someauthorshavechartedancienttrialsorthedevelopmentofmeasurement42 inmedicine. Thehistoriographysuggeststhatnumericalmethodsofassessmentin

medicinespreadfrom ParisatthestartofthenineteenthcenturyandTroehlerexamined43 thisinathesis,whichfocussedonthetechniquesandthescopeofdatacollected. His

thesisisanexcellentinitialsourceforanunderstandingofthedevelopmentofthenumerical accountinmedicine,offeringaseriesofindividualexamplesofwellrecordedproperly recordedobservations,startingwithJamesLindandcollectionsofstatisticsintheNavy onscurvyin1763,ratherthanaclearpathofinfluences.Heshowsthatthereweremany earlyexamplesoflargewellcontrolledstudies,andyetthemethodswereintermittently adopted.JohnFerriar,aManchesterphysician,wrotein1792thatthetendencyso42

J.P.Bull,TheHistoricalDevelopmentofClinicalTherapeuticTrialsJournalof ChronicDiseases10(1959):218248H.J.C.J.L'Etang,HistoricalAspectsofDrug EvaluationinE.L.Harris,J.D.Fitzgerald(eds.),PrinciplesandPracticeofClinical Trials.(Edinburgh:ChurchillLivingstone,1970)JanP.Vandenbroucke,AShortNote ontheHistoryoftheRandomisedControlledTrialJournalofChronicDiseases40(1987): 985987A.M.Lilienfeld,CeterisParibus:theEvolutionoftheClinicalTrialsBulletin oftheHistoryofMedicine56(1982):118U.Troehler,QuantificationinBritish MedicineandSurgery,17501830withSpecialReferencetoitsIntroductioninto Therapeutics(UniversityofLondon:PhDthesis,1978).43

ErwinAckerknecht,MedicineattheParisHospital17941848(Baltimore:Johns th Hopkins,1967)J.P.Vandenbrouke,ClinicalInvestigationinthe20 Century:the AscendancyofNumericalReasoningTheLancet(October1998)Sii:1216.

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fashionableatpresentofpublishingsinglecases,appearsnotwellcalculatedtoenlargeour knowledgeeitherofthenatureorcureofdiseases.Troehlerdemonstratedthatthe numericalmethodwasoftenadoptedtodefendnewapproachestosurgery,orintestinga newmethodoftreatment,withseveralexamplesfromearlydebatesonvaccination,buthis mainthesiscoveredtheperiod17501830,soitdoesnotaddresshowthepharmaceutical industrygotitsdrugstested. RecognisingthatthenineteenthcenturyBritishpharmaceuticalindustry manufactureddrugsrequiredbythemedicalprofession,thatwereacceptedwithout challenge,anewsituationaroseintheinterwarperiodwhentheethicalpharmaceutical industryinBritainproducednoveldrugsandhadtopersuadedoctorstoevaluateandthen utilisethem.Agreyarea existedbetweensomeofthenoveldrugsandpatentmedicines thatwereheavilypromoted.Howwouldcompaniesgettheirnewdrugsevaluatedand whichwerethedrugsthatdoctorsneeded?Swanndescribedhowthelongstandingconflict betweenlaboratoryworkersandclinicianswasgraduallyovercomebyclinicianresearchers, biochemists,andphysiologistsreturningtoAmericafromperiodsoftraininginGermany, andestablishingUniversityChairsofClinicalResearch,basedonthemodeloutlinedin AbrahamFlexners1910reportIwilldescribeparallelstothesystemdevelopedbythe44 MRCinBritain. HarryMarksexaminedtheestablishmentofcooperativeclinicaltrialsin

America,emphasisingthatotherformsoftherapeutictrialspredatedrandomised45 controlledtrials. Heexaminedhowtherapeuticdecisionsweremadeandemphasisedthe

roleoftheAmericanMedicalAssociationsCouncilonPharmacyandTherapeuticsandof academicresearchcentreswithintheNationalResearchCouncilsDivisionofMedical Science.Hecautionedagainsttakingapurelymethodologicalapproach,astherewasmore tochangingviewsontherapeuticsthanthedesignoftheexperiments.Cliniciansdeferredto moreknowledgeableexpertsandpartoftherationaleforcollaborativetrialswastoengage

44

AbrahamFlexner,MedicalEducationintheUnitedStatesandCanada(NewYork: CarnegieFoundation,1910).45

HarryM.Marks,IdeasasSocialReforms:TheLegaciesofRandomizedClinicalTrials (PhDThesis,HarvardMedicalSchool,1983)HarryM.Marks,TheProgressof Experiment:ScienceandTherapeuticReformintheUnitedStates,19001990(Cambridge: UniversityPress,2000).

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manycentressothattherewasnotanundueinfluenceofoneortwophysiciansineach centre.Heexaminedthemajorchemotherapeuticagents,includingSalvarsan, sulphonamidesandpenicillinandconcludedwithsomelaterworkonoralhypoglycaemic drugs,buthedidnotexaminehowindustrygottheirdrugstested.LikeQuirke,Iconclude thatthesysteminBritainwasmorecentrallycoordinatedbytheMRC,thanthe independentsystemofcollaborationsthatexistedinAmerica. InBritain,even afterBurroughsWellcomedemonstratedphysiologicalactivityof theirdrugs,testedthemforpurityandstandardisedthemintheirownlaboratories,theystill haddifficultyinestablishingclinicaltrials.WhereasinGermanytheclosecollaborations betweenfirmsandpharmacologistsledtoearlytestingofnewproductsinclinicaltrials,it wasdifficulttomakethesearrangementsinothercountries.GeraldGeisondescribedthisin46 Dividedwestand andSwannreferredtolongstandingconflictsbetween laboratory

workersandclinicians.Mostofthehistoricresearchonthepharmaceuticalindustryhas focussedondrugdiscovery,tellinguswhatwasdiscoveredandwhen,andwithlittleon drugdevelopment. Thedevelopmentphasethathasevolvedsincenoveldrugswerepreparedwas initiallyasimpleprocess,buthasbecomeincreasinglycomplexitinvolvesturninganewly discovereddrugintoamedicinethatcanbeprescribedsafelytopatients.Itinvolves selectingthedose,formulatingthedrugasaninjection,tabletorsomeotherform,and testingitfirstinanimalsandtheninpatients,producingdatatoencourageotherdoctors totrythedrugandultimatelytomakeitacommercialsuccess.Anotherpartofdrug developmentoperatesatastrategiclevelandconcernsdecisionsregarding,whichdrugsto developandwhatresourcesandfacilitiesarerequiredtosupporteachpotentialdrug.This phaseofdrugdevelopmenthasreceivedlimitedattentionandIexploredthisthroughthe internalrecordsoftheBurroughsWellcomeScientificandTechnicalCommittee,andbased onmyownconclusionsofwhatothercompaniesproducedandhadtestedbythe TherapeuticTrialsCommittee.

46

G.L.Geison,DividedWeStand:PhysiologistsandCliniciansintheAmerican Contextin M.J.VogelandC.E.Rosenberg,TheTherapeuticRevolution:Essaysinthe SocialHistoryofAmericanMedicine(Philadelphia:UniversityofPennsylvaniaPress, 1979).

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LiebenauconcludedthattheMRCstudiesoninsulinformedthemodelforfuture collaborativeresearch,andbothQuirkeandRobsonreferredtohisseminalwork.Thus, onthebasisofalimitedappraisalaviewhasbeenperpetuatedthatthiswasafoundation modeluponwhichtheMRCrefinedstudydesignsandadrugdevelopmentprocess culminatinginthefirsteverrandomisedcontrolledtrialofstreptomycinin1946.Toa degreethishasbeenfuelledbythewritingsofmanyoftheparticipantsinthoselater47 trials.

Theconclusionthatasystemofclinicaltrialswasmodelledonthoseforinsulinand thattheMRCbuiltuponthisinanefforttocontroltheindustryhasnotbeenchallenged sinceLiebenausaccountinwhichhereferredmistakenlytoinsulinasapituitaryhormone.48

BoothexaminedthegrowthofMRCsponsoredclinicalresearchcentres,butonlyby

49 referringtoMRCannualreports. Wastheinsulinmodelrepresentativeofotherstudies

performedbytheMRCintheperiodupto1946oristhismodelonlyapplicabletothe developmentofproductswheretheMRCheldthepatentandcouldcontrolthe collaborators?Intheirrecenttheses,bothDesireCoxMaksimovandthenVivianeQuirke tookinsulinastheacceptedmodel.Theimpressionisgivenintheseaccountsthatdrugs simplycameintogeneraluse,asifitwereobviousthatdrugsthatworkedinthelaboratory wouldbeefficaciousandsafeinman.Thismayhavebeenthecaseforinsulinandpenicillin, regardingtheirspectacularactivity,butthisfocusonmajorsuccessesgivesnoinsightinto theroutineresearchfornovel drugsthatwasthebreadandbutterofthepharmaceutical industry.Whataboutthosedrugsthatdidnotworkorcausedadverseeffects?The forefrontofthisresearchwasintheclinic.Evenattheendofthenineteenthcentury, Ehrlichrecognisedthattheonlytruetestofadrugwasinmanandcompaniesusedtheir earlyexperienceinpatientstomodifytheirproducts,toevaluatenewdosageforms,to

47

J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulinin JoanAustokerandLindaBryder(eds.),HistoricalPerspectivesontheRoleoftheMRC (OxfordUniversityPress,1989):163180.48

J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulin (1989):169.49

C.C.Booth,ClinicalResearchinJ.Austoker,L.Bryder(eds.)Historical PerspectivesontheRoleoftheMRC.(Oxford:OxfordUniversityPress,1989):205241.

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modifythedoseordurationoftreatmentoreventosubstituteonedrugforabetter alternative,asindeedEhrlichdidwithneosalvarsan.50 Quirke defendedtheprogressofBritishindustryindevelopingacollaborative

networkthroughtheworkoninsulin butitwasnotdifficultfortheMRCtofinddoctors readytotestinsulin,afterithadalreadybeenshowninCanadaandtheUSAto dramaticallylowerbloodglucose.ItwasquiteanotherthingforaBritishfirmtotesta novelchemicalinmanforthefirsttime.ThemorethatIlookedatthisproblem,themore surprisedIwasthatithadbeenignored.Itseemedtomethattheresearchtodatehadbeen fittedaroundthebestavailablesourcematerialratherthanconsideringthisfundamental question. DesireCoxMaksimovdescribedtheTherapeuticTrialsCommittee(TTC)asthe modelthatemergedfromtheearlierChemotherapyCommitteeforrandomisedcontrolled51 trials. Herstudywascarriedoutinparallelwithmyownresearchandcoversmyperiod

ofinterest.BecauseshealsoexaminedtheTTC,herthesisbearstheclosestparallelsto mineandthereforedeservescloseattention.Inaseriesofcasestudiesshecontrastedthe effortsofpatentmedicinemanufacturerswiththescientificapproachesofthemedical establishmentandtheState,whichsupportedthemoreacceptablestandardisedmedicines52 evaluatedbytheMRC. Sheexaminedtrialsofinsulinfordiabetes,trialsofpneumococcal 53 serum,andpatulinforthecommoncold.

Thus,herapproachwasverydifferent,ignoringtheproductsarisingfrom pharmaceuticalindustryresearchandconcentratingonthemethodologyofthelargertrials54 ratherthantheprinciplesoftestingnewagents. Patulin,likeinsulinwasanaturalproduct

50 51

VivianeQuirke,(UniversityofLondon:PhDthesis,1999).

D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.52

D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.53 54

D.CoxMaksimov,(1997):183262. Ibid..

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55 arisingfromacademicresearch ratherthanadrugfromindustryandthepatulinstudies

wereusedtodescribethemechanisationoftrialsandthekeyroleofthestatistician,Major56 Greenwood,whohadbeeninvolvedinclinicaltrialdesignformanyyears. TheMRC

werebecomingarbitersofdrugevaluation,determininghowmedicalresearchwas reported,thecharacterisationandstandardisationofmedicines,therecognitionand authorityofexperts,howtheresearchwasreportedeventhecentresinvolved. AccordingtoCoxMaksimov,theTTCwasaboutpromotingacertaintypeof medicalresearch,butwasitreally?My argumentisthatbyselectingonlythewinning drugssuchasinsulinhistoriansmayhaveintroducedabias.Quirkealsoevaluatedthe impactoftheinsulinclinicalstudiesandconcluded,likeLiebenau,thattheseformedthe modelforallfuturetrialsandcollaborationswithindustry.Liebenau,QuirkeandCox Maksikovdonotaddresstheissueofmanufacturinginsulinorwhowasinvolved.Innot doingsotheymissedtheimportantlinkthatFrancisCarr,whohadpreparedSalvarsanat BurroughsWellcome,hadmovedfirsttoBootsthentoBritishDrugHouseswherehe establishedthecapacitytomanufacture95%ofBritishrequirementsforinsulin.Carr, amongothersledtherequestsfromindustryforasystemofclinicaltestingofnewdrugs andthecompaniesatthetimeclearlydidnotseeinsulintrialsasamodeltomeettheir needs. Thetrialofpneumococcalserumwasnotatallrepresentativeofthemainworkof theTTCasitwasalreadyplannedin1929,twoyearsbeforetheestablishmentoftheTTC in 1931.Furthermorethestudyaddressedquestionsabouttheneedtovaccinaterather thanbeingastudyofnewdrugs,andfurthermore,initialvaccinesuppliescamefrom America. CoxMaksimovexaminedinturnhowalloftheproceduralelementsof the randomisedclinicaltrialwereinplaceby1946andarguedthatthepneumococcaltrial definedprocedures.Iamnotconvincedthatthepneumococcalstudywasthemajor influencethatshesuggestsandwithoutintendingtoclaimanincreasedvalidityof afirst55

H.Raistrick(firstofseveralpresentations),PatulinintheCommonCold. CollaborativeResearchonaDerivativeofPenicilliumpatulumBainierLancet (20 November1943):62534.56

L.Hogben,MajorGreenwoodBiographicalMemoirsofFellowsoftheRoyalSociety 7(1950):13954.

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handsource,herinterpretationconflictswiththeaccountrecalledtomebySirAustin BradfordHill,thefounderoftherandomisedcontrolledtrialandbyhissurviving57 colleagues. Therewerequitedifferentobjectivesandalsoethicalconstraintsin

vaccinatingindividualsagainstthepossibilityofacquiringacommondiseasecompared withtreatingthemwithanovelchemicaltotreatadiseasealreadypresentandparticularly regardingwithholdingtherapyintheplacebogroup.CoxMaksimovmadetheimportant pointthatrecentaccountshavebeenwinnershistoriesofClinicalTrials,oneinwhich58 statisticianssuchasPeterArmitage ,RichardDoll,59 RichardPetoandSirAustin

BradfordHilldominateandclaimownershipofclinicaltrials.Theirargumentsconcernthe qualityofthedesignofexperiments,theremovalofsourcesofbias,andacertainwayof reportingdataandinthisrespecttheirauthoritycannotbequestioned,butwasthislater modelofrelevanceinthe1930s?CoxMaksimovarguedforanaturalprogression throughtheTTCpneumococcalstudy,theMRCstreptomycinstudies,andpatulin60 studies, arguingthatArmitagehadreferredtoBradfordHillhavingaroleintheTTC,

thoughsherecognisedtherewasnodocumentaryevidenceandIfoundlittleeitherthefirst61 referencetohimwashisattendanceatthetenthcommitteemeetingin1939. Lilienfeld

tookanalmostgenealogicalapproachandtriedtotracethecontrolledtrialslinkback furthertostudiesofthegoldtherapy,sanocrysinin1925,andothershavealsoarguedthat

57

LettertomyselffromSirAustinBradfordHill(6October1988)P.DArcyHart, EarlyControlledTrialsBritishMedicalJournal 312(10February1996):37879A. BradfordHill,MeasurementinMedicine:TheClinicalTrialBrit.Med.Bull.7.4(1951): 27882A.BradfordHill,TheClinicalTrialNewEnglandJ.Med.247(1952):113P. Armitage,BradfordHillandtheRandomisedControlledTrialPharmaceuticalMedicine6 (1992):2337R.Doll,SirAustinBradfordHillandtheProgressofMedicalScience BritishMedicalJournal 305(1926December1992):152126I.Chalmers,M.Clarke,J. G.Scadding,inI.Chalmers,I.Milne,U.Troehler(eds.),TheJamesLindLibrary( www.jameslindlibrary.org)accessed7January2003.58

P.ArmitageisEmeritusProfessorofAppliedStatisticsattheUniversityofOxford:P. Armitage,(1992):2337.59 60

RichardDoll,(1992):152126.

J.M.Stansfield,A.E.Francis,C.H.StuartHarris,LaboratoryandClinicalTrialsof Patulin:MedicalResearchCouncil,ClinicalTrialofPatulinintheCommonCold(16 September1944)Lancet:37375.61

BradfordHillwasonlyappointedtotheTTCforthetenthandfinalmeetingin1939: TTCMinutes10,(28March1939),MRCFile1523/15(TTC).

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62 therewereevenearlierisolatedcasesofrandomisedcontrolledtrials. InthisthesisI

showthatmanyofthetrialsorganisedbytheTTCwereoflimitedscopeandstatisticians werenotinvolvedandthestudieswerejustlargeenoughtosatisfythecompanyneedfor somedata.AsubgroupofstudiesinareasofspecificinteresttotheMRCwaslarger,not bydesignbutonaccountofthetypesofpatientsselectedandtheexperienceofthecentres involved.AsitwasthepharmaceuticalfirmsthatrequestedtheestablishmentoftheTTC, weshouldseehowBritishfirmsjudgeditssuccess,orotherwiseratherthanacceptingthe accountoftheTTCSecretary,FrankGreen.Hencethereremainsmuchscopeforan evaluationoftheinteractionbetweentheBritishpharmaceuticalindustryandtheMRCin evaluatingnoveldrugs. CoxMaksimovdidnotrecognisethestrongpushfrommanufacturerstohavenovel drugstestedbytheMRC.Shesuggestedtherewasnotmuchdifferencebetween pharmaceuticalfirmsandpatentmedicinemanufacturersattheturnofthe(nineteenth)63 century. TheachievementsoftheBritishinpurifyingandisolatingactiveingredientsand

intablettingtechnologywereignoredandachievementswereminimisedsothatratherthan emphasisingtheremarkabletechnicalachievementofthesynthesisandproductionof Salvarsan,sheemphasisedonlythat: SalvarsanproducedbyBurroughsWellcomeintheWarwastoxicandthere wereproblemswithitsquality duringthewarandhowtheBoardofTrade forcedcompaniestogetofficialcertificatestheembarrassmenttolegitimate companieslikeBurroughsWellcomeandMay&Bakershouldnotbe 64 underestimated. IproposethattheoriginsofclinicaltestinggobacktothoseearlydayswithSalvarsanand thattheTherapeuticTrialsCommitteeestablishedbytheMRCin1931evolvedoutofa morecomplexrelationshipwiththefirmsoveralongertimeperiod.Itwasthe pharmaceuticalcompaniesthatcajoledtheMRCintotheestablishmentoftheTTC,after

62

D.B.E.C.Gill,RandomisedMentalHealthTrialBeganin1935andM.Clarke. QuasirandomAllocationofTreatmentwasReportedin1930,bothin BritishMedical Journal 312(18May1996):1298A.M.Lilienfeld,Ceterisparibis,theEvolutionofthe ClinicalTrial. BulletinoftheHistoryofMedicine56(1982):118.63 64

D.CoxMaksimov,(1997):21. D.CoxMaksimov,(1997):21.

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twopreviousfailedattempts,justasBurroughsWellcomehadledthewayonbiological standardisationandhadrequestedthetestingofSalvarsan. Insummary,therehavebeenlimitedattemptstoreviewtheestablishmentofthe Britishpharmaceuticalindustryandinparticulartounderstandhowitdevelopedfrom preparingextractsatdoctorsrequeststosynthesisingnewdrugsandtherehashardlybeen anyattentiongiventotheproblemsfacedbyBritishmanufacturersingettingtheirownnew drugstestedclinically. 1.4SourcesandThesisOutline. Ihaveexaminedinformationfromdiversesecondarysourcesinchemistry, dyestuffs,chemicalengineering,pharmacy,medicine,clinicalresearch,therapeutics,65 pharmacology,physiology,economics,businesshistories,andbiographies. However,I

alsoconcentratedonarchivematerial,particularlytherecordsoftheWellcomeChemical ResearchLaboratory,themanufacturingworks,andpersonalarchivesofstaffmembers, physiciansandresearchers.SomeFirstWorldWarmaterial,discussingthefirsttestingof BritishproducedsyntheticdrugsisbasedonfilesoftheMRCSalvarsanCommittee,the laboratorybooksfromBurroughsWellcome,theCommitteeandCouncilMinutesofthe MRC,andfilesoftheAssociationofBritishChemicalManufacturers.Theoriginalsource referencesaregiveninthebibliographyandreflectthereferencingsystemsinplaceatthe timeofmyoriginalexamination,andalthoughmuchoftheMRCmaterialhasbeen reclassifiedandisavailableattheNationalArchives,formerlythePublicRecordOffice, somewasdestroyedpriortothemove. Thethesisissetoutalongbroadlychronologicallinesbutitincludesrecurring themes,suchastheinteractionsbetweenthepharmaceuticalindustry,basicscientific research,medicine,andgovernment.Ishowhowclosetheserelationshipswere,whereas previousauthorssuchasMoonmanstated:itisonlysincetheendofthesecondwarthat

65

PietroCorsi,P.Weindling,InformationSourcesintheHistoryofScienceand Medicine(London:Butterworth,1983)P.Weindling,ResearchMethodsandSourcesin E.Clarke(ed.),ModernMethodsintheHistoryofMedicine(London:Athlone,1971): 173.

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66 theideaofGovernmentshapingindustryhastakenroot. Amajoremphasisisplacedon

67 theroleofsignificantindividuals,andparticularlyFrancisCarr.

TheearlypartofthethesisaddressesthedominanceofGermanchemistrywithina researchorientedindustry.Dyestuffsandchemicalintermediateswereprimarilyimported fromGermany.Universitybasedchemists,manyofwhomwereconsultantstoindustrial firms,hadwarnedbeforetheFirstWorldWaraboutthefactorsleadingtothedominance68 ofGermany. AgeneralthemethroughoutistheshortageofsuitablytrainedBritish

chemists,particularlythosewithmanufacturingexperience.Manyofthechemicalprocesses dovetailedintoeachotherandthemanycomplexinterdependenciesbetweenfirmsreliedon chemicalintermediates.LittlepreparationwasmadefortheoutbreakofWaranditis interestingtocontrasthowbetterpreparedBritainwasbetween19371939andhowmuch thecountrydependedontheinterwarefforts. ThethemesthatemergethereforeareofsustainedeffortstoensurethatBritainnever againhadtorelyonaforeignpowerforkeyresources.Thisinvolveddefiningwhatdrugs wereessential,whomadethem,whatchemicalintermediatesandsolventswereneeded, howthedrugscouldbestandardisedandhowtheirpotencycouldbemeasured. Additionallythesyntheticarsenicaldrugs,replacingthosehithertoonlymadeinGermany, werepotentiallytoxicandhadtobeshowntobesafeandeffective. TheMRCtookacentralroleintheevaluationof Salvarsanbutmanyoftheirstaff camefromindustryandparticularlyBurroughsWellcome.Giventhescarcityofchemists, pharmacologists,physicianresearchersandotherkeymembersofstaff,itisinterestingto charttheircareerstoseetheeffectthattheyhadonthedevelopmentofseveralBritish pharmaceuticalfirms.TheMRCandgovernmentcontinuedtosupporttheBritishindustry throughouttheperiodunderstudy,andanotherthemewhichemergesistheeffortmadeto protecttheevolvingresearchbasedBritishpharmaceuticalindustry,firstlyunderthe

66

EricMoonman,ReluctantPartnerships:aCriticalStudyoftheRelationshipBetween GovernmentandIndustry (London:VictorGollanez,1971):17.67

JosephBenDavid,TheScientistsRoleinSociety (EnglewoodCliffs:PrenticeHill, 1979):16068.68

W.M.Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline (London:Williams&Norgate,1915).

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artificialsituationofWar,butthenbyaseriesofdirectandindirectmeasures.Adistrustof foreignmedicines,hadbeensparkedbytheincreasingimportsofpatentmedicines,with exaggeratedorevenfraudulentclaims,butcontinuedintothetwentiethcenturythroughthe assayofantitoxinsandorganextractsinwhichmanyforeigndrugswerefoundwanting. EthicalBritishmanufacturerswantedtoshowthemedicalprofessionthattheirnoveldrugs werestandardised,pureandhadareliableandquantifiabledegreeofactivityinfactthat theywereasgoodorbetterthanGermandrugs.Assaysofimpuritiesinstartingmaterials, measurementoftotalalkaloidcontent,amountsofactiveingredients,impuritiesinthefinal drug,biologicalstandardisationandmeasurementofclinicalactivitywereallmeansof showingthebenefitsofdrugspreparedbyBritishfirmsandofhighlightingtheproblems inherentinforeigndrugs.HereitwastheinteractionbetweentheGovernment,theMRC, thePharmaceuticalSociety,individualfirms,theAssociationofBritishChemical ManufacturersandrelatedgroupssuchastheSocietyoftheChemicalIndustrythatbecame important.ThroughoutthisworkIhavetriedtotaketheholisticviewofwhatfirmswere tryingtoachieveintheirdailychallenges.Inadditiontoinsulin,thenewlydiscovered vitaminsandthemanyorganotherapiesarisingfromacademicadvanceswerebeneficialto thegrowthofBritishindustryBritishfirmswereattheforefrontofinvestigatingthese opportunities,involvingcomplexextractionandmanufacturingtechniques,buttheir successwiththesenoveltherapiesledtoincreasesofmanufacturingpotentialand commercialsuccessesandtheircloserelationshipwithphysiologistsanduniversitychemists ledtosyntheticformsofbothvitaminsandhormonesbeingdeveloped.FirmssuchasAllen &HanburysandGlaxoexpandedsignificantlyasaresultoftheseopportunities. Amajorrecurrentandpreviouslyignoredtheme,isthegraduallyacquiredexpertise insyntheticdrugmanufacture,firstseeninsomeofthealkaloidsandfurtherexemplifiedby Salvarsanduringthewarandotherdrugspostwar.Syntheticdrugsbroughttogether manyofthepreviousintertwinedissuessuchasthelackofchemists,theneedtotestnew drugsinanimalmodels,theunderstandinggainedinrelatingchemicalstructureto physiologicalfunction,andtheclinicalstudiesrequiredtoevaluatethesafetyandefficacy oftheseagents.HerewasakeydevelopmentoftheBritishpharmaceuticalindustry, perhapsignoredbecauseitdidnotturnonasingleeventoraparticularstudy.For companiesthiswasnotanissueofdemandingaspecifictypeofclinicaltrial.Thefirms evaluatedheresimplywantedtheirdrugstestedinwhatevermannerpossibleastheyhad

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majordifficultiesinarrangingstudiesdirectly,atleastinBritain.Evenifthestudywasonly inahandfulofcases,thatwasenoughaslongastheMRCultimatelyvouchedforthedrug andgaveitapositiveappraisal.Evenmanyofthesuccessfuldrugsmentionedhereare longforgotten.Theyplayedtheirpartinthetherapyoftheperiodasevidencedbytheir inclusioninthepharmacopoeiaof1948butmanyhavebeenreplacedsincethen.The consequenceofthesestudieswastherecognitionthen,asnow,thatnotalldrugswouldbe marketedeitherbecauseinsufficientactivitywasdemonstrated,orthereweresomesafety issues,ortherewasinsufficientdataordemandtomakethedrugcommerciallyviable. ThefirmsandtheMRChadacommoninterestincollaboratingasthestudiesallowed theMRCtoexpandthenumberofcentresinvolvedinclinicalresearch.HowevertheTTC andtheearlytestsofbiologicalstandardisationprobablyhadasmuchofaneffectby excludingforeigndrugsasbyhelpingBritishdrugstosecureaplaceonthemarket.A constantfrustrationforboththeMRCandthecompanieswastheslowprogressofthe TTCsclinicaltrialsanditisnotsurprisingthatafterthesecondworldwar,whichbrought afurtherstimulustotheBritishpharmaceuticalindustrythroughpenicillinandincreased manufactureofsyntheticdrugs,companiesbegantoemploytheirownpharmacistsand69 physicianstoestablishtheclinicaltestingofdrugs, andthistrendevenbeganinthelate

1930s. Despitethebroadchronologyofthethesis,inevitablytherearesomeslightoverlaps betweensections.ForexampleitseemedsensibletoincludealloftheWaractivities, includingproductionandtestingofSalvarsaninonechapter,soIalsoincludedthework thatcontinuedonSalvarsanafter1918asitinvolvedthesameindividuals. FollowingonfromthisIntroduction,Chapter2describesthevariedoriginsofthe Pharmaceuticalindustryin thenineteenthcenturyandassessesthepositionofthesmall Britishcompaniesinrelationtotheirlargerinternationalrivals,contrastingtheethical manufacturerswithproducersofpatentmedicines.

69

K.J.Williams,B.Gennery,TheHistoryofthePharmaceuticalIndustryinJ.Lloyd, A.Raven(eds.),HandbookofClinicalResearch (London:Churchill,1994):122K. Williams,ATenthAnniversaryfortheAssociationforClinicalResearchinthe PharmaceuticalIndustry(ACRPi)PharmaceuticalMedicine3(1988):219224.

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Chapter3describesthemostresearchorientedBritishfirm,BurroughsWellcome, andhowtheycombinedthebestofGermansyntheticchemistrywithAmericanadvancesin drugformulation,especiallytablets.ItwastheonlyBritishfirminitiallyinapositionto rapidlytakeupthesynthesisofthemorecomplexGermandrugsandtodevelopthestrong linkswiththenewlyfoundedMRC.Iintroduceindividualswhoweretoplayanimportant roleinthedevelopmentandtestingofdrugsthroughouttheinterwarperiodof191970 1931.

Chapter4examineshowtheFirstWorldWarforcedtheBritishGovernmentto interveneinpharmaceuticals,firstbyestablishingcommitteestoestablishwhichdrugswere essentialandthenhowtoresolvetheirproduction.IexaminehowBritishfirmsbeganto collaborateformallyforthefirsttimeastheAssociationofBritishChemicalManufacturers, howBritishfirmsmasteredlargescalechemicalsynthesis,andhowtheMRCfirstgot involvedintestingSalvarsanasanextensionofthestandardisationworkcarriedoutbyits staff whentheywereatBurroughsWellcome. Thenfollow3chaptersthatbroadlycoverthesameperiod: Chapter5coverstwoaspectsofpostwarBritain.ItexamineshowBritish pharmaceuticalfirmssoughtprotectionpostwar,firstbytariffs,thenbystandardisationof biologicalandhormonalextracts.TheMRCassistedandindoingsoestablishedtheir internationalreputationfordrugstandardisation,whileextendingtheirinterestinclinical outcomes. Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom 19221930anddemonstrateshowtheMRCwasanidealintermediarybetweenthefirms andresearcherstoestablishgroundrulesforearlyclinicaltrialsinBritain.Thespecialised MRCsubcommitteesandtheChemotherapyCommitteedidnotmeettheneedsofthe pharmaceuticalcompaniesandIdemonstratethedistinctionbetweenMRCresearchto supportindustryandtheirownmoreacademicallyorientedstudiesandtheutilisationof theiremergingnetworkofclinicalcentres.

70

FrancisJ.Griffin,Obituary,FrancisCarrChemistryandIndustry (15February 1969):196.

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Chapter7examinesthestrategyofBurroughsWellcomepostwarandespeciallythe period1925to1931,uptotheestablishmentoftheTherapeuticTrialsCommitteethrough thestrategicdebateswithintheirScientificandTechnicalCommittee. Chapter8examinestheactualworkingsoftheTherapeuticTrialsCommittee,how theyinitiallyfavouredBritishdrugsandhowthestudiescomplementedtheirownresearch andinterests.Thisexaminationofallofthedrugstestedgivesaninsightintotheresearch strategiesof British(andsomeforeign)firmsandallowsanassessmentofthesuccessor otherwiseoftheTTCgivinginsightsintothetesting,bothfromtheMRCperspectiveand thatofBurroughsWellcome(fromSTCMinutes19311939)andotherfirms. Chapter9offerssomeconclusions,bothbyreviewingthekeytopicsidentifiedandby comparingthepositionofBritishmanufacturersattheoutbreakoftheSecondWorldWar withthepositionthattheyfoundthemselvesinattheoutbreakofWarinAugust1914. Someopportunitiesforfurtherworkarethenidentified. Afullbibliographyofsourcesisgivenattheend.

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TheOriginsofthePharmaceuticalIndustry

40

CHAPTERTWO:TheOriginsofthePharmaceuticalIndustry.

2.1TheGrowthofthePharmaceuticalIndustryintheNineteenthCentury. Earlynineteenthcenturydrugtherapywasaimedatalleviatingsymptomssuchas1 feverandpain. By1900twoparallelbutoverlappingsystemsofdrugmarketinghad

evolvedinallofthemainmanufacturingcountries.Patentmedicineshadbeenavailable2 forovertwocenturies,buttheiruseexpandeddramaticallyduringthenineteenthcentury.

Theywerepreparationswhoseingredientswerekeptsecret,andwhichweresoldunder3 brandnamesforawiderangeofillnesses. Theirsuccessdependeduponheavy

advertisinginthepopularpress,andthefactthattheysparedpatientstheexpenseofa doctor'sconsultationfee.Patentmedicineswereofvariablequality,wereoftenlacedwith opiatesoralcohol,oronlyincorporatedminutequantitiesofwhatdoctorsandpharmacists consideredactivedrugs.Doctorswereconcernedthattheywereineffectiveandeven4 potentiallydangerous.

Ethicalmanufacturerstookadifferentapproach.Theidentification,extraction,and purificationofmorphineinParisin1803stimulatedtheestablishmentofseveralalkaloid manufacturingfirmsinFrance,followedbyBoehringer,Merck,andScheringin1

A.Burman,TheHeroicApproachtoNineteenthCenturyTherapeuticsBulletinof theAmericanSocietyofHospitalPharmacists11(1954):32027DavidL.Dykstra,The MedicalProfessionandPatentandProprietaryMedicinesDuringtheNineteenthCentury BulletinfortheHistoryof Medicine29(1955):40119.2

PatentMedicineTaxReceipts18291914Chemist&Druggist85.1(8August 1914):3536T.Hughes,ThePatentMedicineStampDuty:itsOriginandHistory BritishMedicalJournal (9January1932):3233RevenuefromPatentMedicineTax Stamps18001931Chemist&Druggist114(30May1931):639.3

V.Coleman,TheMedicineMen (London:TempleSmith,1975)B.McNamara,Step RightUp:anIllustratedHistoryoftheAmericanMedicineShow(NewYork:Doubleday &Co.,1976)RoyPorter, Quacks,FakesandCharlatansinEnglishMedicine(Charleston: Tempus,2001)WilliamH.Helfand,TheSellersofNostrumsinPrints,Posters,Ephemera andBooks(Chicago:ChicagoUniversityPress,2002).4

JamesH.Young, TheToadstoolMillionaires:aSocialHistoryofPatentMedicinesin AmericaBeforeFederalRegulationinAmerica16601850(Princeton:Princeton UniversityPress,1961)JamesH.Young,TheMedicalMessiahs:aSocialHistoryof HealthQuackeryinTwentiethCenturyAmerica(Princeton:PrincetonUniversityPress, 1967)M.Silverman,MagicinaBottle(NewYork:McMillan,1941)M.Silverman,The DruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976).

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5 Germany. Suchmanufacturersdifferentiatedthemselvesfurtherbyproducingthenewly 6 discoveredchemicalelementsbromineandiodine,inrichsupplyinGermany. Luke7 HowardinLondonproducedcalcinedmagnesium,bismuthandmercurysaltsfrom1801.

MorsonsandHowardssoldquininesulphateinsteadofcinchonafrom1821,andfirms wereabletocomparethebestsourcesofquinine.From1827firmssuchasMercksold8 purifiedmorphine,insteadofopium,asdidT.H.SmithinEdinburghby1837. Firms

manufacturedplantextractsandinorganicremediesaccordingtothedemandsof9 physicians. Inotherwords,doctorsdecidedwhichdrugswereneededandpharmaceutical

manufacturersprovidedthem. Somedoctorsproducedtheirownmedicines,butasextractionofalkaloidsbecame morecomplex,requiringsolvents,distillationandcrystallisation,manufacturerssaved themtheexpenseofpurchasingmachinery.Ascapacityincreased,standardpackswere preparedanddistributedwidelyfortreatingstandardandspecificdiseases.Manyfirms producedthesamebasicdrugs,butindividualfirmsdistinguishedtheirdrugsfrom competitorsbyassayingchemicalconstituentsandimpuritiesinsimplelaboratorytests.

5

M.Weatherall,InSearchofaCure:aHistoryofPharmaceuticalDiscovery (Oxford: OxfordUniversityPress,1990)WalterSneader, DrugDiscovery:theEvolutionof ModernMedicines(London:JohnWiley,1985):67,914C.D.Leake,AnHistorical AccountofPharmacologytotheTwentiethCentury (Springfield,Illinois:C.C.Thomas, 1975):1201JohnHarleyWarner,TheTherapeuticPerspective:MedicalPractice, KnowledgeandIdentityinAmerica18201885(Cambridge,Massachusetts:Harvard UniversityPress,1986) E.MerckofDarmstadt:aHistoryofChemicalAchievement 18271937(Darmstadt:Merck,1937).67

WalterSneader,(1985):4142. D.L.Howard, Brit.Col.Pharmacist(August1926):241.

8

W.Bernsmann,ArzneimittelforschungundEntwicklunginDeutschlandinder ZweitenHlftedes19JahrhundertsPharmazeutischeIndustrie29(1967):6Mark Honigsbaum,TheFeverTrail:TheHuntfortheCureforMalaria(London:MacMillan, 2001).9

E.Kremers,G.Urdang,TheHistoryofPharmacy (Philadelphia:J.B.Lippincott, 4thedition,1976)R.D.Mann,ModernDrugUse,anEnquiryonHistoricalPrinciples (Boston:MTPPress,1984)F.N.L.Poynter,TheEvolutionofPharmacy (London: PitmanMedical,1965):13149E.H.Ackerknecht, TherapeuticsFromthePrimitivesto theTwentiethCentury (NewYork:Hafner,1973):8889JonathanLiebenau,TheRise oftheBritishPharmaceuticalIndustryBritishMedicalJournal (3October1990):72428, 733.

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Thepurityofdrugsproducedbyreputablefirmsimprovedastheirpharmacistsadopteda10 moreprofessionalrole.

JacobBellofJohnBell&Co.wasoneofthefoundersofThePharmaceutical11 SocietyofBritainin1841andwasPresident18569. WilliamAllenofAllen&

12 Hanburyswasthefirstpresident. TheSocietywasmodelleduponthePhiladelphia 13 CollegeofPharmacy,foundedinAmericain1821. WhereasFrenchfirmsmade

referencetoexperimentsinanimalsbyphysiologistssuchasFrancoisMagendieand ClaudeBernard,andGermansreferredtoEmil Fischer,HermannKolbeandothers,such assayswerecontinuouslyhamperedinBritainbytheantivivisectionlobbyfromthe1860s andthisinhibitedthedevelopmentofpharmacologyandinteractionsbetweenthe14 pharmaceuticalindustryandexternalacademicsinBritain. Bythecloseofthe

nineteenthcentury,theBritishpharmaceuticalindustrywasstrugglingtokeepupwithits15 counterpartsinGermanyandinAmerica. Pharmaceuticalsevolvedonalargescalein

Germany,whereasAmericanfirmsmadesignificantadvancesinnovelmeansof administeringdrugs.AnappreciationofthecompetitionfacedbyBritishfirmswillenable ustounderstandmuchaboutthewaysinwhichasectionoftheBritishpharmaceutical

10

J.K.Crellin,TheGrowthofProfessionalisationinNineteenthCenturyBritish PharmacyMedicalHistory 11(1967):215227F.A.Filby,AHistoryofAdulteration andAnalysis(London:GeorgeAllen&Unwin,1934)E.W.Stieb,G.A.Sonnedecker, DrugAdulteration,DetectionandControlin19thCenturyBritain (Madison:Universityof WisconsinPress,1966)J.A.Blake(ed.),(1970).11

JohnBellaComingCentenaryChemist&Druggist52(11June1898):1605S. W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991:APolitical andSocialHistory (London:ThePharmaceuticalPress,1991):appendix.12

L.G.Matthews,HistoryofPharmacyinBritain (EdinburghandLondon:E.&S. Livingstone,1962):11827L.G.Matthews,AnUnrecordedWilliamAllenCaricature MedicalHistory 15(1971):3056.13

J.W.England(ed.), TheFirstCenturyofthePhiladelphiaCollegeofPharmacy 18211921(Philadelphia:PhiladelphiaCollegeofPharmacy,1922).14

J.M.D.Olmsted,FrancoisMagendie(NewYork:Schumanns,1944)Claude Bernard,AnIntroductiontotheStudyofExperimentalMedicineTrans.H.C.Greene, (NewYork:Dover,1957)R.D.French,AntiVivisectionandMedicalSciencein VictorianSociety (Princeton:PrincetonUniversityPress,1975).15

J.T.Mahoney,Merchantsof Life:AnAccountoftheAmericanPharmaceutical Industry (NewYork:Harper,1959).

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industryadaptedandmadeuseoflaboratoryscienceasameansofdevelopingand16 marketingcompetitivenewproductsinthe1880s.

2.2EvolutionfromSmallPharmacyFirmsinAmerica. IntheearlynineteenthcenturymostmedicinesusedintheUSAwereimported fromBritain.PhiladelphiabecamethecradleofpharmacyfortheAmericannation, famousfortheCollegeofPharmacyfoundedin1821,aroundwhichanAmerican pharmaceuticalindustrywasestablished.EarlygraduatesoftheCollegesuchasErnstR.17 Squibbattackedthefraudulenceandadulterationassociatedwithpatentmedicines.

Philadelphiabasedfirmscreatedandeffectivelycontrolledalucrativenewsector18 ofthepharmaceuticalmarket,ethicaldrugssoldsolelytomedicalprofessionals. The

termethicalmedicinecameintousein theUSAafterthe1847codeofethicsofthe AmericanMedicalAssociationforbadedoctorsfromprocuringapatentforaremedy,and19 fromsellingpatentmedicinesornostrums,orgivingtestimonials. AsinBritain,there20 wasahugemarketfortheseremedies,oftensoldwithfancynames. The1877byelaws

ofthePhiladelphiasectionoftheAmericanMedicalAssociationstated: Anyphysicianwhoshallprocureapatentforaremedyorforany instrumentofsurgery,orwhosellsorisinterestedinthesaleofpatent remediesornostrums,orshallgiveacertificateinfavourofapatentor proprietaryremedyorpatentedinstrument,orwhoshallenterintoagreement16

ThePharmaceuticalIndustry'tovaryingdegreesincluded'theChemicalandAllied Trades'and'theFineChemicalIndustry':WhatisaFineChemicalChemist&Druggist 85.2(29August1914):51.17

L.G.Blochman,DoctorSquibb:TheLifeandTimesofaRuggedIdealist(New York:Simon&Shuster,1958)J.T.Mahoney,Philadelphia,CradleofPharmacy:Smith, Kline&French,WyethandOthers(1959):3041.18

J.F.Marion,TheFineOldHouse:Smith,KlineCorporation'sFirst150Years (Philadelphia:SmithKline,1980).19

R.M.Shryock, TheDevelopmentofModernMedicine.AnInterpretationofthe SocialandScientificFactorsInvolved(NewYork:Hafner,1969)M.Fishbein,AHistory oftheAMA18471947(Philadelphia:W.B.Saunders,1947):3542Peter Temin,Taking YourMedicineDrugRegulationintheUnitedStates(Cambridge,Mass:Harvard UniversityPress,1980):2.20

B.McNamara,(1976)D.Armstrong,E.M.Armstrong, TheGreatAmerican MedicineShow(NewYork:PrenticeHall,1991).

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toreceivepecuniarycompensationorpatronageforsendingprescriptionsto 21 anyapothecaryshallbedisqualifiedfrombecomingamember.

AseriesoffurthergraduatesofthePhiladelphiaSchoolofPharmacygaverisetoanew breedofpharmaceuticalmanufacturersthathadtheskillstodevelopnoveldosageformsof ethicaldrugs.ThefirmofWilliamR.WarnerwasfoundedinPhiladelphiain1856andhis futurepartnerinWarnerLambertwasapharmacygraduateofPhiladelphiain1884,as weremanyotherfoundersofpharmaceuticalfirms,includingHenryWellcomein1874 andSilasBurroughsin1877. FrederickBeldingPower,wholaterjoinedBurroughs22 Wellcomeasachemistalsotrainedthere.

ThefirmofJohnWyeth&Co.originatedfromapharmacyopenedbyFrankand JohnWyethin1860.JohnWyethgraduatedfromthePhiladelphiaCollegeofPharmacy withathesisonthechemicalconstituentsofvariousplantsandFrankWyeth,achemist,23 alsoattendedthecollege. JohnWyeth&Co.prosperedbysellingproprietarymedicines 24 duringtheAmericancivilwarwithaturnoverofover$600,000. Buttheywerealsoan

innovativefirmthatintroducednewmarketingpracticesaswellasnewdrugformulations. Asearlyas1861theyjoinedthetwomostlikemindedfirms,H.K.MulfordandSmith& Kline,tofoundthePhiladelphiaDrugExchange,tocampaignfortheabolitionofstamp dutyonpatentmedicines,becausemanyoftheethicalfirmsstillsoldtheseinparallel.The Exchangealsoestablishedasystemforchemicallytestingimporteddrugs,particularly patentmedicines,whichenteredAmericadespitealawbanningtheimportationofpoor25 qualitymaterials.

WyethandtheircolleaguesintheDrugExchangeactivelydistinguishedthemselves fromthemanufacturerswhomadeonlypatentmedicines,byalsoproducingpurifieddrugs ofknowncompositionsoldonlytodoctorsandpharmacists,oftenusingesotericscientific21

JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe AmericanPharmaceuticalIndustry,(Basingstoke:MacMillan,1987):2627.22

J.W.England(ed.),(1922):1378,200ff.,216,410.

23

J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth andOthers(1959):3041L.G.Blochman,(1958)JonathanLiebenau,(1987):2223.24 25

J.WyethtoBurroughsWellcome,(31October1887),WF:88/47:8. JonathanLiebenau,(1987):23J.W.England(ed.),(1922):132.

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26 terminologysuchas'dialysed'iron. TheymetareadymarketamongAmericandoctors

whowishedtominimisethepracticeofselfprescribingbypatients.OtherUSfirmswith rootsinpharmacyincludedA.P.Sharp,foundedin1827inBaltimore,thefirstinAmerica27 toproducealkaloids. CharlesErhardtandCharlesPfizerestablishedtheirfirmin28 Brooklyn,NewYorkbetween18458afterPfizerhadbeenapprenticedtoanapothecary.

HarveyC.ParkeandGeorgeS.DavisformedParkeDavisasasmallmanufacturing businessinDetroitin1866,andW.E.UpjohnfoundedTheUpjohnPillandGranule29 CompanyinKalamazooin1886toproducefriablepills.

TheprincipaladvancesbyAmericanfirmswereincreatingnoveldosageforms suchassugarcoatedpills,whichwereconvenienttocarry,andsugarmaskedanybitter30 tastes. Large scalemanufactureofpillsdevelopedfrom1857,andelixirs(solubleliquid

31 forms)from1859. Wyethpreparedcompressedhypodermictablets,andtablettriturates

werefirstmadein1861.Thesecouldbereadilydissolvedforinjectionorfortakingas32 solutions. Thefirstmouldedmedicinesandcompressedpillsweremanufacturedin 33 Philadelphiain1863andtabletsweremadecommerciallyfrom1869. Wyethemployees

designedandpatentedthefirstrotarytabletpressinAmericain1872toproduceopiates, digitalis,strophanthusandquininetablets.By1876patentsweresecuredontheprocess

26 2728

J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. J.T.Mahoney,Merck&Co.(1959):2012.

S.Miles,Pfizer,anInformalHistory (NewYork:Pfizer,1978)J.G.Lombardino, ABriefHistoryofPfizerCentralResearchBull.Hist.Chem.25.1(2000):1015.29

LeonardEngel,MedicineMakersofKalamazoo (NewYork:McGraw Hill,1961) CecilRoberts,ACenturyofCaring,Upjohn:Achievement (Kalamazoo:Upjohn,1938).30

C.Gunn,AHistoryofSomePharmaceuticalFormulationsinF.N.L.Poynter (ed.),(1965):13150.31

L.F.Kebler,TheTabletIndustry itsEvolutionandPresentStatus:Compositionof TabletsandMethodsofAnalysisJournaloftheAmericanPharmaceuticalAssociation 3 (1914):82048,937,958,106299.32

J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth andOthers(1959):312.33

NoteaboutBrockedon'sPatentPharmaceuticalJournal 3(1844):554T.H. Bishop,InventoroftheCompressedTablet,WilliamBrockedonChemist&Druggist 162(28August1954):209F.N.L.Poynter,(1965):13149.

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34 andthemethodofcompressionofpills. Incontrast,Britainspillsweremadebyhand

untilAllen&HanburysboughttheirfirstpillmakingmachineatthePharmaceutical exhibitioninPhiladelphiain1876,buteventhennotabletswe

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